To explore the influence of psychological characteristics in Chronic Obstructive Pulmonary Disease (COPD) self-management.
Patients admitted with an exacerbation of COPD were interviewed for ...psychiatric symptoms, illness beliefs and self-management behaviour using a new COPD Self-Management Interview (COPD-SMI). This comprised three scenarios to mimic
a future evolving exacerbation. Responses were scored for knowledge and actions (adherence) for each scenario.
Of 47 people approached, 39 participated; 41% had panic attacks, 33% general anxiety, 35% a depression history, 31% an anxiety history and 21% an alcohol dependence history. Twenty-six (67%) had a self-management plan. When hypothetically “well” lower (poorer) COPD-SMI Knowledge Scores were associated with an alcohol dependence history (
P=.025), no panic (
P=.021) and males (
P=.028). Those perceiving less influence over COPD had lower Action Scores during this scenario (
P=.01) and the “early exacerbation” scenario (
P=.05). Lower Knowledge Scores for the “early exacerbation” were associated with no panic (
P=.01) and no self-management plans (
P=.03). For the “severe exacerbation”, lower Action Scores were associated with depression history (
P=.004), panic (
P=.002), higher FEV
1% and no self-management plans (
P=.005). Higher PaCO
2 was associated with lower confidence in symptom recognition, self-management ability and medical care influencing COPD.
Anxiety, depression, alcohol use and illness beliefs may differentially influence self-management. Depression, previous alcohol dependence and perceived less influence over COPD inhibited self-management. Those with panic demonstrated more self-management knowledge when “well” but performed poorly on actions during the “severe exacerbation”. Those with self-management plans had better knowledge and actions.
Objective and background: The role of COPD self‐management plans in improving health outcomes remains unclear. The objective of this study was to assess whether self‐management plans administered in ...primary care have beneficial effects on quality of life, self‐care behaviour and health outcomes in the long term for patients with COPD.
Material, patients and methods: The study was a prospective, unblinded, randomized controlled trial of usual care vs. usual care plus structured education on the use of a written self‐management plan and patient‐initiated short courses of antibiotics and oral corticosteroids. The study was conducted in general practice, in Christchurch, New Zealand. Participants were 159 patients with COPD randomized by general practice site into control or intervention groups. The primary outcome measure was change in St. George’s Respiratory Questionnaire. Secondary variables were frequency of hospital and primary‐care attendance, frequency of use of courses of antibiotics and oral corticosteroids over 12 months, and change in Hospital Anxiety and Depression Scale. Self‐management knowledge was assessed using a structured interview, the COPD Self‐Management Interview.
Results: Self‐management plans and structured education were associated with higher levels of self‐management knowledge at 12 months, but had no effect on change in St. George’s Respiratory Questionnaire, health utilization, mental health or self‐reported outcomes of patients with COPD managed in general practice.
Conclusions: Self‐management knowledge was higher in the intervention group but there was no difference in quality of life or health outcomes due to self‐management plans.
The rationale for introducing self-management plans for the whole chronic obstructive pulmonary disease (COPD) population is uncertain. This study’s aim was to investigate whether people with panic ...disorder (PD), compared to non-panic-disordered (NPD), derived additional educational or psychological benefits from having a self-management plan. The 24-week prospective study followed 76 participants hospitalized with an exacerbation of COPD. Participants completed mental health questionnaires including psychological measures of self-management plan impact. Subsequently, a nurse provided education for using a self-management plan. All participants were Plan naïve irrespective of their PD status. Self-management knowledge was assessed before introducing the Plan (baseline), 1 week post discharge and at 24 weeks. At baseline 28 (37%) of participants met the criteria for PD and this group had higher scores (better knowledge) for an impending (p < 0.05) and severe exacerbation (p < 0.05) and capacity to act during a severe exacerbation (p < 0.01). No interaction effect was found between PD and NPD scores over time, indicating that the PD’s knowledge did not improve or deteriorate over time relative to the NPD. Evidence was mixed regarding the Plan’s psychological impact. Self-management confidence improved in both groups. Amongst the PD group, perceived control of self-management tasks increased but so did body vigilance and distress about having COPD. There is mixed evidence regarding educational and psychological benefits of COPD self-management plans for people with PD. No additional educational advantages were found for the PD group. Plans may increase confidence and control over self-management but may also increase body vigilance and distress about having COPD.
Objective: To explore the influence of psychological characteristics in Chronic Obstructive Pulmonary Disease (COPD) self-management. Methods: Patients admitted with an exacerbation of COPD were ...interviewed for psychiatric symptoms, illness beliefs and self-management behaviour using a new COPD Self-Management Interview (COPD-SMI). This comprised three scenarios to mimic a future evolving exacerbation. Responses were scored for knowledge and actions (adherence) for each scenario. Results: Of 47 people approached, 39 participated; 41% had panic attacks, 33% general anxiety, 35% a depression history, 31% an anxiety history and 21% an alcohol dependence history. Twenty-six (67%) had a self-management plan. When hypothetically "well" lower (poorer) COPD-SMI Knowledge Scores were associated with an alcohol dependence history (P=.025), no panic (P=.021) and males (P=.028). Those perceiving less influence over COPD had lower Action Scores during this scenario (P=.01) and the "early exacerbation" scenario (P= .05). Lower Knowledge Scores for the "early exacerbation" were associated with no panic (P=.01) and no self-management plans (P=.03). For the "severe exacerbation", lower Action Scores were associated with depression history (P=.004), panic (P=.002), higher FEVi% and no self-management plans (P= .005). Higher PaCO(sub 2) was associated with lower confidence in symptom recognition, self-management ability and medical care influencing COPD. Conclusion: Anxiety, depression, alcohol use and illness beliefs may differentially influence self-management. Depression, previous alcohol dependence and perceived less influence over COPD inhibited self-management. Those with panic demonstrated more self-management knowledge when "well" but performed poorly on actions during the "severe exacerbation". Those with self-management plans had better knowledge and actions. (Original abstract)
Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. ...Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy.
We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64).
520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 95% CI 0·96–1·47); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of −0·040 (95% central range −0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years.
Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate.
National Institute for Health Research Health Technology Assessment Programme.
Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of ...insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy.
This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64).
990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95–1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83–1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 97·5% CI 1·05 to 1·66) and zonisamide (HR 1·37 1·08–1·73). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319–1·458) compared with 1·222 (1·110–1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs.
These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials.
National Institute for Health Research Health Technology Assessment programme.
Final results of the TRITON2 study of rucaparib in metastatic castration-resistant prostate cancer (mCRPC) with DNA damage repair gene alterations confirm the benefit of rucaparib in BRCA-mutated ...mCRPC with an acceptable safety profile. Responses were also observed with mutations in other homologous recombination genes including PALB2.
Initial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration.
To present the final data from TRITON2.
TRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy.
The primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review IRR); prostate-specific antigen (PSA) response rate (≥50% decrease from baseline PSA50) was a key secondary endpoint.
As of July 27, 2021 (study closure), TRITON2 had enrolled 277 patients, grouped by mutated gene: BRCA (n = 172), ATM (n = 59), CDK12 (n = 15), CHEK2 (n = 7), PALB2 (n = 11), or other DDR gene (Other; n = 13). ORR by IRR was 46% (37/81) in the BRCA subgroup (95% confidence interval CI, 35–57%), 100% (4/4) in the PALB2 subgroup (95% CI, 40–100%), and 25% (3/12) in the Other subgroup (95% CI, 5.5–57%). No patients within the ATM, CDK12, or CHEK2 subgroups had an objective response by IRR. PSA50 response rates (95% CI) in the BRCA, PALB2, ATM, CDK12, CHEK2, and Other subgroups were 53% (46–61%), 55% (23–83%), 3.4% (0.4–12), 6.7% (0.2–32%), 14% (0.4–58%), and 23% (5.0–54%), respectively.
The final TRITON2 results confirm the clinical benefit and manageable safety profile of rucaparib in patients with mCRPC, including those with an alteration in BRCA or select non-BRCA DDR gene.
Almost half of TRITON2 patients with BRCA-mutated metastatic castration-resistant prostate cancer had a complete or partial tumor size reduction with rucaparib; clinical benefits were also observed with other DNA damage repair gene alterations.
Homologous recombination (HR) function is critically important in high-grade serous ovarian cancer (HGSOC). HGSOC with intact HR has a worse prognosis and is less likely to respond to platinum ...chemotherapy and PARP inhibitors. Oncolytic adenovirus, a novel therapy for human malignancies, stimulates a potent DNA damage response that influences overall antitumor activity. Here, the importance of HR was investigated by determining the efficacy of adenovirus type 5 (Ad5) vectors in ovarian cancer. Using matched BRCA2-mutant and wild-type HGSOC cells, it was demonstrated that intact HR function promotes viral DNA replication and augments overall efficacy, without influencing viral DNA processing. These data were confirmed in a wider panel of HR competent and defective ovarian cancer lines. Mechanistically, both BRCA2 and RAD51 localize to viral replication centers within the infected cell nucleus and that RAD51 localization occurs independently of BRCA2. In addition, a direct interaction was identified between RAD51 and adenovirus E2 DNA binding protein. Finally, using functional assays of HR competence, despite inducing degradation of MRE11, Ad5 infection does not alter cellular ability to repair DNA double-strand break damage via HR. These data reveal that Ad5 redistributes critical HR components to viral replication centers and enhances cytotoxicity.
Oncolytic adenoviral therapy may be most clinically relevant in tumors with intact HR function.
Abstract Background Interventions introduced to reduce the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a widespread reduction in childhood infections. However, from ...spring 2021 onwards the United Kingdom and Ireland experienced an unusual out-of-season epidemic of respiratory disease. Methods We conducted a prospective observational study (BronchStart), enrolling children 0–23 months of age presenting with bronchiolitis, lower respiratory tract infection, or first episode of wheeze to 59 emergency departments across England, Scotland, and Ireland from May 2021 to April 2022. We combined testing data with national admissions datasets to infer the impact of respiratory syncytial virus (RSV) disease. Results The BronchStart study collected data on 17 899 presentations for 17 164 children. Risk factors for admission and escalation of care included prematurity and congenital heart disease, but most admissions were for previously healthy term-born children. Of those aged 0–11 months who were admitted and tested for RSV, 1907 of 3912 (48.7%) tested positive. We estimate that every year in England and Scotland 28 561 (95% confidence interval, 27 637–29 486) infants are admitted with RSV infection. Conclusions RSV infection was the main cause of hospitalizations in this cohort, but 51.3% of admissions in infants were not associated with the virus. The majority of admissions were in previously healthy term-born infants.
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