United States Physicians' Knowledge, Attitudes, and Practices Regarding Meningococcal Vaccination for Healthy Adolescents and Young Adults.

PURPOSE: The United States Advisory Committee on Immunization Practices (ACIP) recommends vaccination against meningococcal serogroups A, C, W, and Y (MenACWY) for all 11-12-year-olds, with a booster dose for 16-year-olds, and against meningococcal serogroup B (MenB) for 16-23-year-olds under shared clinical decision-making (SCDM). However, uptake of the MenB vaccine and the MenACWY booster dose is low. This study investigated United States physicians' knowledge, attitudes, and practices regarding recommending MenB and MenACWY vaccines to non-high-risk older adolescents and young adults. METHODS: An online survey was conducted in April-May 2022 among pediatricians, family physicians (FPs), general practitioners (GPs), and internists who had recommended the MenB and/or the MenACWY vaccine(s) to at least one 16-23-year-old in the past year. RESULTS: Among 407 participants, 50% correctly identified MenB as the leading cause of meningococcal disease among adolescents and young adults. Furthermore, 46% of physicians (47% of pediatricians, 40% of FPs and GPs, 53% of internists) answered correctly that MenB vaccination is recommended under SCDM, and 82% of physicians (96% of pediatricians, 70% of FPs and GPs, 65% of internists) answered correctly that MenACWY vaccination is routinely recommended. Among MenB-vaccinators, 78% reported having received some training or other information on implementing SCDM, and 65% rated recommending MenB vaccination as very important. DISCUSSION: Knowledge gaps, which varied by specialty, were identified regarding meningococcal disease and vaccine recommendations, particularly regarding MenB. Targeted education of physicians may facilitate discussions about MenB vaccination.

Evaluation of Physician Knowledge of Safety and Safe Use Information for Intravitreal Aflibercept Injection in Europe: A Second Survey of Physicians Following Dissemination of Updated Risk-Minimization Materials.

BACKGROUND: Materials have been distributed in the European Union to inform physicians on the safe use of intravitreal aflibercept (IVT-AFL) as part of the risk-minimization plan for IVT-AFL. OBJECTIVE: We aimed to measure physician knowledge and understanding of key safety information for IVT-AFL. METHODS: The current study was a follow-up cross-sectional survey ('wave 2') to an earlier survey ('wave 1') examining the effectiveness of the IVT-AFL educational materials by assessing physician knowledge of the key safety information. Based on wave 1 results, the educational materials were revised to focus more on items of key concern (e.g., use in women of childbearing potential, procedural information); physicians in France, Germany, Italy, Spain, and the UK completed a questionnaire to evaluate their knowledge of key safety information in the revised educational materials. RESULTS: Among 454 physician respondents (of 4715 invited; response rate 9.6%), most reported having received the IVT-AFL Summary of Product Characteristics (SmPC; 89%) and Prescriber Guide (82%). More than half reported receiving the Injection Procedure Video (54%) and Patient Booklet (65%). The highest percentage of correct answers was observed for questions concerning procedural steps, the most important risks, and safe use as emphasized by the educational materials and the SmPC. CONCLUSION: Physician knowledge and understanding of safe use of IVT-AFL, including for questions that prompted revisions to the educational materials, suggests the need to reconsider methods for developing educational materials to follow best practices (e.g., focusing on only key messages and pretesting with end users).

A post hoc analysis of Projected Retained Ability Scores (PRAS) for the longitudinal assessment of cognitive functioning in patients with neuronopathic mucopolysaccharidosis II receiving intrathecal idursulfase-IT.

BACKGROUND: Norm-based scores used to assess cognitive ability have clinical value when describing functioning of patients with neuronopathic disorders compared with unaffected, same-age peers. However, they have limitations when used to assess change in cognitive ability between two timepoints, especially in children with severe cognitive decline. Calculation of Projected Retained Ability Scores (PRAS) is a novel method developed to characterize absolute change in norm-based ability test scores. In this analysis, PRAS were calculated post hoc for children with mucopolysaccharidosis II (MPS II; Hunter syndrome) and early cognitive impairment in a 52-week phase 2/3 randomized controlled trial (RCT) and its extension study of intrathecal idursulfase (idursulfase-IT). Patients completing the first year of the extension after receiving idursulfase-IT in the RCT and extension (n = 32 of 34 enrolled) or the extension only (n = 15 of 15 enrolled) were categorized according to changes in Differential Ability Scales, Second Edition, General Conceptual Ability (DAS-II GCA) scores and PRAS at 1 and 2 years. Analyses were conducted in the overall population and a subpopulation aged < 6 years at baseline (idursulfase-IT in the RCT and extension [n = 27] and extension only [n = 12]). RESULTS: PRAS methodology differentiated patients with decreases in DAS-II GCA scores into three separate categories reflecting below-average cognitive growth rates, plateauing cognitive development, and deteriorating cognitive functioning. After 1 year in the RCT, 72.4% of patients who initiated idursulfase-IT had above-average or average cognitive growth rates in DAS-II GCA scores compared with 53.3% of those who did not receive idursulfase-IT; 6.9% versus 20.0% experienced deteriorating cognitive functioning. Similar results were seen in children aged < 6 years: 76% (idursulfase-IT group) versus 50% (no idursulfase-IT) had above-average or average cognitive growth rates in DAS-II GCA scores; 4% versus 17% had deteriorating cognitive functioning. The difference in the distributions of cognitive categories at 1 year in children aged < 6 years was significant (p = 0.048). At 2 years, the proportions of patients in different cognitive categories were more similar between treatment groups. CONCLUSIONS: PRAS methodology may help to differentiate changes in cognitive development in MPS II, and therefore may represent a valuable addition to existing approaches for interpreting changes in cognitive scores over time. TRIAL REGISTRATION: ClinicalTrials.gov NCT02055118 (registration date: 4 February 2014) and NCT02412787 (registration date: 9 April 2015).

Knowledge, Attitudes, and Practices of European Healthcare Professionals towards Hepatitis A and Hepatitis B Vaccination in at-Risk Adults.

Despite the occurrence of several hepatitis A (hepA) and hepatitis B (hepB) outbreaks in Europe in the last few decades, not all European countries have implemented hepA and hepB vaccinations in their national immunization programs, especially for adults at risk for hepA and/or hepB infection, such as men who have sex with men or patients with chronic liver disease. Currently, little is known on the attitudes of European healthcare professionals (HCPs) towards hepA and hepB vaccinations for at-risk adults. We conducted an online survey among HCPs in Germany, Spain, and the United Kingdom to assess their awareness of and adherence to their national hepA and hepB vaccination guidelines for at-risk adults. Among the 698 HCPs who took the survey, most (91.1%) were familiar with their national vaccination recommendations and always followed them or followed them most of the time when advising or prescribing hepA or hepB vaccines. Major and moderate barriers for recommending or administering such vaccines were the non-disclosure of risk factors by the patient (53.0-57.6%) and the patient's lack of motivation or knowledge about the risk of the disease (50.3-52.9%). These results may help inform strategies to improve and accelerate hepA and hepB vaccination in European at-risk adults.

Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649.

PURPOSE: In CheckMate 649, first-line nivolumab plus chemotherapy prolonged overall survival versus chemotherapy in patients with advanced/metastatic non-human epidermal growth factor receptor 2 (HER2)-positive gastric/gastroesophageal junction cancer (GC/GEJC) or esophageal adenocarcinoma (EAC). We present exploratory patient-reported outcomes (PROs). METHODS: In patients (N = 1,581) concurrently randomly assigned 1:1 to nivolumab plus chemotherapy or chemotherapy and in those with tumor PD-L1 expression at a combined positive score (CPS) of ≥5, health-related quality of life (HRQoL) was assessed using the EQ-5D and Functional Assessment of Cancer Therapy-Gastric (FACT-Ga), which included the FACT-General (FACT-G) and Gastric Cancer subscale (GaCS). The FACT-G GP5 item assessed treatment-related symptom burden. Longitudinal changes in HRQoL were assessed using mixed models for repeated measures in the PRO analysis population (randomly assigned patients with baseline and ≥1 postbaseline assessments). Time to symptom or definitive deterioration analyses were also conducted. RESULTS: In the PRO analysis population (n = 1,360), PRO questionnaire completion rates were mostly >80% during treatment. Patient-reported symptom burden was not increased with nivolumab plus chemotherapy versus chemotherapy. Mean improved changes from baseline were greater with nivolumab plus chemotherapy versus chemotherapy for FACT-Ga total, GaCS, and EQ-5D visual analog scale in patients with a CPS of ≥5; results were similar for the overall PRO analysis population. In CPS ≥5 and all randomly assigned populations, nivolumab plus chemotherapy reduced the risk of symptom deterioration versus chemotherapy, on the basis of FACT-Ga total score and GaCS; time to definitive deterioration was longer, and the risk of definitive deterioration in HRQoL was reduced with nivolumab plus chemotherapy across EQ-5D and most FACT-Ga measures (hazard ratio [95% CI] <1). CONCLUSION: Compared with chemotherapy alone, first-line nivolumab plus chemotherapy showed stable or better on-treatment HRQoL in patients with advanced/metastatic non-HER2-positive GC/GEJC/EAC and also showed decreased risk of definitive HRQoL deterioration.

Effects of tolvaptan discontinuation in patients with autosomal dominant polycystic kidney disease: a post hoc pooled analysis.

BACKGROUND: Tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) who are at risk of rapid progression. Given that treatment requires commitment to long-term use, we evaluated the effects of tolvaptan discontinuation on the trajectory of ADPKD progression. METHODS: This was a post hoc analysis of pooled data from two clinical trials of tolvaptan (TEMPO 2:4 [NCT00413777] and TEMPO 3:4 [NCT00428948]), an extension trial (TEMPO 4:4 [NCT01214421]), and an observational study (OVERTURE [NCT01430494]) that enrolled patients from the other trials. Individual subject data were linked longitudinally across trials to construct analysis cohorts of subjects with a tolvaptan treatment duration > 180 days followed by an off-treatment observation period of > 180 days. For inclusion in Cohort 1, subjects were required have ≥ 2 outcome assessments during the tolvaptan treatment period and ≥ 2 assessments during the follow-up period. For Cohort 2, subjects were required to have ≥ 1 assessment during the tolvaptan treatment period and ≥ 1 assessment during the follow-up period. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). Piecewise-mixed models compared changes in eGFR or TKV in the on-treatment and post-treatment periods. RESULTS: In the Cohort 1 eGFR population (n = 20), the annual rate of eGFR change (in mL/min/1.73 m2) was -3.18 on treatment and -4.33 post-treatment, a difference that was not significant (P = 0.16), whereas in Cohort 2 (n = 82), the difference between on treatment (-1.89) and post-treatment (-4.94) was significant (P < 0.001). In the Cohort 1 TKV population (n = 11), TKV increased annually by 5.18% on treatment and 11.69% post-treatment (P = 0.06). In Cohort 2 (n = 88), the annual TKV growth rates were 5.15% on treatment and 8.16% post-treatment (P = 0.001). CONCLUSIONS: Although limited by small sample sizes, these analyses showed directionally consistent acceleration in measures of ADPKD progression following the discontinuation of tolvaptan.

Tolvaptan and Kidney Function Decline in Older Individuals With Autosomal Dominant Polycystic Kidney Disease: A Pooled Analysis of Randomized Clinical Trials and Observational Studies.

Rationale & Objective: Tolvaptan is indicated for treatment of patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Participants aged 56-65 years constituted a small proportion of the Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trial population. We assessed effects of tolvaptan on estimated glomerular filtration rate (eGFR) decline in participants aged >55 years. Study Design: This was a pooled data analysis from 8 studies of tolvaptan or non-tolvaptan standard of care (SOC). Setting & Participants: Participants aged >55 years with ADPKD were included. Data on participants in >1 study were linked longitudinally for maximum follow-up duration, with matching for age, sex, eGFR, and chronic kidney disease (CKD) stage to minimize confounding. Interventions: Tolvaptan or non-tolvaptan SOC. Outcomes: Treatment effects on annualized eGFR decline were compared using mixed models with fixed effects for treatment, time, treatment-by-time interaction, and baseline eGFR. Results: In the pooled studies, 230 tolvaptan-treated and 907 SOC participants were aged >55 years at baseline. Ninety-five participant pairs from each treatment group were matched, all in CKD G3 or G4, ranging from 56.0 to 65.0 years (tolvaptan) or from 55.1 to 67.0 years (SOC). The eGFR annual decline rate was significantly reduced by 1.66 mL/min/1.73 m2 (95% CI, 0.43-2.90; P = 0.009) in the tolvaptan group compared with SOC (-2.33 versus -3.99 mL/min/1.73 m2) over 3 years. Limitations: Limitations include potential bias because of study population differences (bias risk was reduced through matching and multiple regression adjustment); vascular disease history data was not uniformly collected, and therefore not adjusted; and natural history of ADPKD precludes evaluating certain clinical endpoints within the study time frame. Conclusions: In individuals aged 56-65 years with CKD G3 or G4, compared to a SOC group with mean GFR rate of decline ≥3 mL/min/1.73 m2/year, tolvaptan was associated with efficacy similar to that observed in the overall indication. Funding: Otsuka Pharmaceutical Development & Commercialization, Inc (Rockville, MD). Trial Registration: TEMPO 2:4 (NCT00413777); phase 1 tolvaptan trial (no NCT number; trial number 156-06-260); phase 2 tolvaptan trial (NCT01336972); TEMPO 4:4 (NCT01214421); REPRISE (NCT02160145); long-term tolvaptan safety extension trial (NCT02251275); OVERTURE (NCT01430494); HALT Progression of Polycystic Kidney Disease (HALT-PKD) study B (NCT01885559).

Hepatitis A and B vaccination in adults at risk: A survey of US healthcare providers' attitudes and practices.

This study aimed to evaluate the attitudes and practices of US healthcare professionals (HCPs) regarding the Advisory Committee on Immunization Practices (ACIP) vaccination recommendations on HepA and HepB for adult patients at risk of contracting these infections or experiencing complications of hepatitis disease. This cross-sectional, web-based survey of 400 US HCPs, which included nurse practitioners and family medicine, internal medicine, infectious disease, emergency department, and gastroenterology physicians, assessed HCPs' attitudes and practices regarding the ACIP recommendations for adult patients at risk for hepatitis disease. HCP participants were identified via a survey research panel. A recruitment quota of 400 HCPs was set, including 50 NPs, 100 FMs, 100 IMs, 50 GIs, 50 EDs, and 50 IDs. The most frequently reported reasons for not recommending either HepA or HepB vaccines were "I think the risk of HepA infection is low in this patient population" and "I am uncertain about what the guidelines say about vaccinating this population." The most reported factors considered when determining eligibility for either vaccine were medical history and the patient's willingness/motivation to be vaccinated. Most reported it was extremely or moderately important to prevent hepatitis disease by vaccinating adult patients at risk, and most also reported recommending a HepA vaccine or HepB vaccine to patients at risk. Although most HCPs reported recommending HepA and HepB vaccines to patients at risk, these findings contrast with the low reported vaccination rates among these populations, and improved awareness of the ACIP recommendations among HCPs is needed.

Although hepatitis A and hepatitis B are vaccine-preventable diseases, not enough adults at risk are vaccinated in the United States (US). The Advisory Committee on Immunization Practices (ACIP) makes recommendations on the use of vaccines in the US. The ACIP recommendations identify groups of people at risk of contracting hepatitis A infection or experiencing complications of hepatitis A disease (e.g., people with chronic liver disease) and hepatitis B infection or its related complications (e.g., people with diabetes).To identify potential barriers to vaccination, we surveyed 400 US healthcare professionals to evaluate their views about the ACIP recommendations on hepatitis A and hepatitis B vaccination for patients at risk of infection or complications. Most reported it was extremely or moderately important to prevent hepatitis A or hepatitis B infection by vaccinating these adult patients. The most commonly reported reasons for not recommending either vaccine were "I am uncertain about what the guidelines say about vaccinating this population" and "I think the risk of hepatitis A or hepatitis B infection is low in this patient population".Our findings show that improved awareness of the guidelines among healthcare professionals is needed, particularly of the importance of hepatitis A vaccination, and hepatitis B vaccination in adults with diabetes. In addition to helping the ongoing multi-state hepatitis A outbreaks, this could aid in the successful implementation of the recent ACIP recommendation for hepatitis B vaccination in all adults that is expected to reduce barriers to vaccination.

Pooled Data Analysis of the Long-Term Treatment Effects of Tolvaptan in ADPKD.

Introduction: In 1- and 3-year randomized trials, tolvaptan slowed kidney function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. The 3-year trial also evaluated effects on total kidney volume (TKV); slowing of TKV growth was demonstrated. Subjects were followed in open-label extension trials. To characterize longer-term effects of treatment, an analysis was conducted comparing tolvaptan-treated subjects with subjects from standard of care (SOC) ADPKD studies without tolvaptan. Methods: This was a pooled, longitudinal analysis of data from 8 tolvaptan clinical trials and 5 studies without tolvaptan (natural history or SOC) in ADPKD. Data from subjects who participated in multiple studies were linked for longer follow-up. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and TKV over 5.5 years. To control for heterogeneity in disease characteristics between tolvaptan and SOC treatment groups, analysis populations matched for baseline demographic and disease characteristics were constructed. Results: Matched analysis (n = 1186 in each treatment group) indicated that tolvaptan slowed annualized eGFR decline by 1.01 ml/min per 1.73 m2 (P < 0.001) versus SOC over 5.5 years. An analysis conducted on the full, unmatched data set (tolvaptan: n = 2928; SOC: n = 4189) confirmed significant reduction in annual eGFR decline. Among subjects with TKV data, TKV was significantly reduced at years 1, 3, and 5 for tolvaptan versus SOC in both matched and full data sets. Conclusion: Comparison of a pooled tolvaptan cohort to a pooled control cohort with ADPKD supports longer-term treatment effects of tolvaptan.

Understanding Barriers in the Pathway to Diagnosis of Ankylosing Spondylitis: Results From a US Survey of 1690 Physicians From 10 Specialties.

OBJECTIVE: Early diagnosis of ankylosing spondylitis (AS) remains challenging because of the high prevalence of chronic back pain in patients initially treated by nonrheumatology health care providers (HCPs). We assessed the patient pathway to rheumatology referral, including HCP recognition of inflammatory back pain (IBP) and other features suggestive of AS, diagnostic workup, treatment, and referral to a specialist with the goal of identifying barriers to patient referral to a rheumatologist. METHODS: US HCPs from 10 specialties were invited to participate in a cross-sectional web-based survey on clinical characteristics and diagnostic measures leading to IBP suspicion and the subsequent referral process. Eligible HCPs were actively practicing and had referred a patient with suspected IBP or ocular findings (ophthalmology only) within 12 months. Data were analyzed descriptively. RESULTS: Of 1690 HCPs, 61% identified morning stiffness lasting more than 30 minutes, 29% sleep disturbance due to back pain, and 28% pain that improves with activity as features suggestive of IBP. Nearly two-thirds of primary care HCPs reported that they were the first HCPs consulted by patients with suspected IBP. Among HCPs ordering diagnostic blood work, approximately 90% selected antinuclear antibody and rheumatoid factor, whereas 76% selected human leukocyte antigen B27. Almost 40% would treat patients with suspected IBP themselves. HCPs cited lack of adequate specialists nearby (35.1%), insurance restrictions (47.1%), and long wait time (77.0%) as barriers to early referral. CONCLUSION: Most HCPs had difficulty identifying features suggestive of IBP and indicated insurance restrictions and long wait times as barriers to early referral of patients with potential AS.

Evaluation of the Feasibility of a Web-Based Survey to Assess Patient-Reported Symptom Improvement and Treatment Satisfaction Among Patients with Psoriatic Arthritis Receiving Secukinumab.

BACKGROUND AND OBJECTIVE: Patient perspectives regarding treatment experience and satisfaction may be useful for clinicians when making treatment strategies. This US-based study assessed the feasibility of evaluating real-world, patient-reported narratives regarding symptom improvement and treatment satisfaction among patients with psoriatic arthritis treated with secukinumab. METHODS: A cross-sectional, web-based survey collected data on demographics, disease characteristics, symptoms before and after secukinumab use, and treatment satisfaction with secukinumab. RESULTS: Of 2755 patients screened, 200 patients with psoriatic arthritis were eligible and included in the analysis. Their mean age was 36.0 (standard deviation, 10.0) years; 55.5% were male and 75.0% were white. Most (87.5%) were biologic experienced; the primary reason for discontinuation of their previous treatment was lack of effectiveness (28.6%). Most patients (79.9%) reported overall psoriatic arthritis symptom improvement after secukinumab initiation compared with before secukinumab initiation; a similar trend was observed for all individual symptoms evaluated. Approximately half of patients reported improvement within 4 weeks after starting secukinumab treatment, and > 90% reported improvement within 6 months. Most patients (≥ 96%) expressed overall satisfaction with secukinumab regarding symptom improvement, speed of symptom improvement, frequency of administration, method of administration, ease of use, patient support services, and side effects, if any. CONCLUSIONS: Patient-reported perspectives may be feasibly collected to provide insights into treatment experience and satisfaction of secukinumab. Most patients with psoriatic arthritis in our real-world study experienced symptom improvement after initiating secukinumab; > 50% of patients reported symptom improvement within 4 weeks. Additionally, almost all patients reported satisfaction with secukinumab treatment.

In-Vivo Retention of 5-Fluorouracil Using 19F Magnetic Resonance Chemical Shift Imaging in Colorectal Cancer in a Murine Model.

Colorectal cancer is the third leading cause of cancer death worldwide. 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapies for treatment of solid tumours, including colorectal cancer. The efficacy of treatment is dependent on tumour type and can only be determined six weeks after beginning chemotherapy, with only 40-50% of patients responding positively to the 5-FU therapy. In this paper, we demonstrate the potential of using Magnetic Resonance (MR) Chemical Shift Imaging (CSI) for in-vivo monitoring of 5-FU tumor-retention in two different colorectal tumour types (HT-29 & H-508). Time curves for 5-FU signals from the liver and bladder were also acquired. We observed significant differences (p < 0.01) in 5-FU signal time dependencies for the HT-29 and H-508 tumours. Retention of 5-FU occurred in the H-508 tumour, whereas the HT-29 tumour is not expected to retain 5FU due to the observation of the negative b time constant indicating a decline in 5FU within the tumour. This study successfully demonstrates that CSI may be a useful tool for early identification of 5-FU responsive tumours based on observed tumour retention of the 5-FU.

A Pilot Study to Assess the Feasibility of a Web-Based Survey to Examine Patient-Reported Symptoms and Satisfaction in Patients with Ankylosing Spondylitis Receiving Secukinumab.

PURPOSE: This real-world study evaluated the feasibility of assessing patient-reported symptom improvement and treatment satisfaction using a web-based survey among patients with ankylosing spondylitis (AS) treated with secukinumab. METHODS: This cross-sectional, web-based survey collected data on demographics, symptoms, treatment history, and treatment satisfaction from US patients with AS who were receiving secukinumab at survey participation. Patients reported AS symptoms experienced before and after secukinumab initiation, time to symptom improvement, and satisfaction with secukinumab treatment. RESULTS: Of 2755 patients screened, 200 with AS were included in the analysis. The mean (SD) age of patients was 34.4 (10.6) years; 86.5% were biologic experienced. Most (74.0%) reported overall improvement ("a little," "moderately," or "much better") in AS symptoms since secukinumab initiation compared with before secukinumab initiation; a similar trend was observed for all the individual symptoms analyzed (pain disrupting sleep, fatigue, morning stiffness, pain and stiffness in lower back or neck, sore areas other than joints, and ankle or heel pain [indicating enthesitis]). Approximately 41.9% of patients reported overall symptom improvement within 4 weeks of secukinumab treatment. Most expressed overall satisfaction ("very," "mostly," or "somewhat satisfied") with secukinumab regarding symptom improvement (99.0%), speed of symptom improvement (97.0%), frequency and method of administration (96.0% and 91.5%, respectively), ease of use (93.5%), patient support services (97.0%), and side effects, if any (93.0%). CONCLUSION: Most patients reported overall symptom improvement and satisfaction with treatment. Our study indicates that patient-reported perspectives may be feasibly collected using a web-based survey to provide insights into treatment experience and satisfaction.

Physician and Patient Knowledge of Safety and Safe Use Information for Aflibercept in Europe: Evaluation of Risk-Minimization Measures.

BACKGROUND: As part of the risk-management plan for aflibercept in the European Union, materials have been developed to educate physicians and patients in Europe on the safe use of aflibercept. OBJECTIVES: The objectives of this study were to measure receipt of the educational materials and to evaluate understanding of key safety information for aflibercept. METHODS: An observational cross-sectional study among physicians and patients with recent aflibercept experience in France, Germany, Italy, Spain, and the UK was conducted. Eligible physicians and patients completed a brief questionnaire regarding their knowledge of key safety information. RESULTS: Among the 8424 physicians invited to participate in the survey, 428 physicians were eligible, completed the questionnaire, and were included in this analysis. Most physicians reported having received the aflibercept summary of product characteristics (87%) and prescriber guide (77%); approximately half reported receiving the injection procedure video (50%) and patient booklet (54%). Physician knowledge of the most important topics (i.e., side effects; preparing patients for aflibercept injection) was high. Physician knowledge of dosing was high for neovascular (wet) age-related macular degeneration and lower for less commonly prescribed indications. Most physicians knew the contraindications for aflibercept and recognized possible side effects. Among the 874 patients approached about participation in the study, 773 patients were eligible, completed the questionnaire, and were included in the analysis. Patients' reported receipt was relatively low for the aflibercept patient booklet (38%) and the audio CD (23%). Patient knowledge of the health conditions to discuss with a doctor prior to injection was generally high; knowledge about possible side effects varied. Most patients knew that they should speak to a physician immediately if they experienced a possible side effect of aflibercept. CONCLUSION: Most physicians reported receiving the summary of product characteristics, prescriber guide, and patient booklet; half reported receiving the intravitreal injection procedure video. Patient receipt of the educational material was variable. Observed patterns of knowledge indicated the greatest knowledge of the most important risks emphasized in the educational material and lower knowledge of more complex or less salient aspects of safe use.

Evaluation of Physician Knowledge of the Key Safety Information for Aflibercept in Canada: Evaluation of Risk-Minimization Measures.

BACKGROUND: As part of the risk-management plan (RMP) for aflibercept, materials have been developed to educate physicians in Canada on the key safety information and safe use for aflibercept. OBJECTIVE: The objectives of this study were to assess whether physicians in Canada received and reviewed the aflibercept educational materials (i.e. vial preparation instruction card, intravitreal injection procedure video, and product monograph) and to evaluate their knowledge of key safety information. METHODS: Retinal specialists and ophthalmologists who prescribe and/or administer aflibercept were recruited to complete a survey. Physicians could complete and return a paper questionnaire by mail or complete the questionnaire online via a study website. RESULTS: Of the 308 physicians invited to participate in the survey, 95 (31%) completed the questionnaire. Nearly all physicians (98%) reported receiving at least one of the educational materials. The proportion of correct responses to individual questions on storage and preparation of aflibercept ranged from 54 to 98%. Physician knowledge was high on the recommended dose of aflibercept (91%), dose preparation (91-96% on individual items), and dosing guidelines (75-95% on individual items). Most physicians knew the contraindications for aflibercept (89%) and that aflibercept should not be used in pregnancy unless clearly indicated by medical need in which benefits outweigh risks (60%); 21% responded more conservatively that aflibercept should never be used in pregnancy. Knowledge was high for most questions about injection procedures (91-99% on individual items); however, fewer physicians (24%) correctly reported that the eye should be covered with a sterile drape. Knowledge was high for possible side effects (89-100% on individual items) and actions to take in relation to the potential for increased intraocular pressure (86-93% on individual items). CONCLUSION: Nearly all physicians (98%) reported having received the product monograph, and most (82%) reported having received the vial preparation instruction card; nearly half (46%) reported having received the intravitreal injection procedure video. Physicians' knowledge of the most important topics was high. Knowledge varied for topics that are less frequently encountered (e.g. use in women of childbearing potential) and for recommendations that are not standard medical practice in Canada (e.g. use of sterile drape).

Monitoring Replication Protein A (RPA) dynamics in homologous recombination through site-specific incorporation of non-canonical amino acids.

An essential coordinator of all DNA metabolic processes is Replication Protein A (RPA). RPA orchestrates these processes by binding to single-stranded DNA (ssDNA) and interacting with several other DNA binding proteins. Determining the real-time kinetics of single players such as RPA in the presence of multiple DNA processors to better understand the associated mechanistic events is technically challenging. To overcome this hurdle, we utilized non-canonical amino acids and bio-orthogonal chemistry to site-specifically incorporate a chemical fluorophore onto a single subunit of heterotrimeric RPA. Upon binding to ssDNA, this fluorescent RPA (RPAf) generates a quantifiable change in fluorescence, thus serving as a reporter of its dynamics on DNA in the presence of multiple other DNA binding proteins. Using RPAf, we describe the kinetics of facilitated self-exchange and exchange by Rad51 and mediator proteins during various stages in homologous recombination. RPAf is widely applicable to investigate its mechanism of action in processes such as DNA replication, repair and telomere maintenance.

Rad51 Nucleoprotein Filament Disassembly Captured Using Fluorescent Plasmodium falciparum SSB as a Reporter for Single-Stranded DNA.

Single-stranded DNA binding (SSB) proteins coordinate DNA replication, repair, and recombination and are critical for maintaining genomic integrity. SSB binds to single-stranded DNA (ssDNA) rapidly and with very high affinity making it a useful molecular tool to detect free ssDNA in solution. We have labeled SSB from Plasmodium falciparum (Pf-SSB) with the MDCC (7-diethylamino-3-((((2-maleimidyl)ethyl)amino)-carbonyl)coumarin) fluorophore which yields a four-fold increase in fluorescence upon binding to ssDNA. Pf-SSBMDCC binding to DNA is unaffected by NaCl or Mg2+ concentration and does not display salt-dependent changes in DNA binding modes or cooperative binding on long DNA substrates. These features are unique to Pf-SSB, making it an ideal tool to probe the presence of free ssDNA in any biochemical reaction. Using this Pf-SSBMDCC probe as a sensor for free ssDNA, we have investigated the clearing of preformed yeast Rad51 nucleoprotein filaments by the Srs2 helicase during HR. Our studies provide a rate for the disassembly of the Rad51 filament by full length Srs2 on long ssDNA substrates. Mutations in the conserved 2B domain in the homologous bacterial UvrD, Rep and PcrA helicases show an enhancement of DNA unwinding activity, but similar mutations in Srs2 do not affect its DNA unwinding or Rad51 clearing properties. These studies showcase the utility of the Pf-SSB probe in mechanistic investigation of enzymes that function in DNA metabolism.

Treatment satisfaction in type 2 diabetes patients taking empagliflozin compared with patients taking glimepiride.

PURPOSE: This exploratory analysis assessed and compared patients' treatment satisfaction with empagliflozin plus metformin versus glimepiride plus metformin, using data obtained from the Diabetes Treatment Satisfaction Questionnaire, status version (DTSQs) collected in a randomized, double-blind, double-dummy clinical trial. METHODS: Observed values for DTSQs scale score and each of its eight items were summarized by visit and treatment arm. Changes from baseline in these scores were analyzed using linear mixed models for repeated measures. RESULTS: The baseline scale score and item scores were comparable between empagliflozin plus metformin (n = 765) and glimepiride plus metformin (n = 780). Compared with baseline, patients reported significant treatment satisfaction increases and significant decreases in perceived hyperglycemia with both treatments at all visits. Also, compared with baseline, a significant increase in perceived frequency of hypoglycemia was observed in the glimepiride treatment group at all visits. No statistically significant treatment difference was observed in DTSQs scale score and its items at week 104. The difference between the treatment groups was significant and in favor of empagliflozin from week 28 onward for perceived frequency of hyperglycemia (P ≤ 0.006) and perceived frequency of hypoglycemia (P ≤ 0.011). CONCLUSIONS: Despite positive trends in favor of empagliflozin, there was no significant difference in DTSQs scale score between empagliflozin and glimepiride at 104 weeks. However, when compared with glimepiride, empagliflozin demonstrated significantly lower perceived frequency of hyperglycemia and hypoglycemia at all visits from week 28 onward. This finding is consistent with the clinical results reported for the EMPA-REG H2H-SU trial.

The role of surgery in the management of thymoma: a systematic review.

The literature describing multimodal treatment of thymomas consists almost exclusively of retrospective case series. We have used a systematic review to investigate the role of surgery in the management of thymomas. The use of surgery as the sole therapeutic maneuver in thymoma depends on the stage considered. Subtotal resection followed by adjuvant treatment may prolong survival, but studies are equivocal. Some data supports re-resection of recurrent thymoma in the belief that survival will be prolonged. Approaches to thymectomy other than sternotomy in early stage thymoma are technically sound, but long-term outcome data are lacking.