Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Objective cognitive impairment and subjective cognitive problems in veterans initiating psychotherapy for posttraumatic stress disorder: An exploratory study.

The prevalence of cognitive impairment in Veterans initiating an evidence-based psychotherapy (EBP) for posttraumatic stress disorder (PTSD) is not yet established and has implications for service delivery. Our objectives were to (1) describe the type, severity, and prevalence of objective cognitive impairment and subjective cognitive problems experienced by Veterans at the time they began an EBP for PTSD and (2) determine whether assessments of objective cognitive impairment and subjective cognitive problems agree. We conducted objective and subjective (self-report) cognitive assessments in a sample of 38 Veterans initiating EBP for PTSD at one Veterans Affairs Medical Center. Thirty Veterans produced valid assessments. Almost half (14/30) of the participants demonstrated objective impairment in one or more cognitive domains, primarily in the areas of learning, memory, and processing speed. Almost all (29/30) participants endorsed moderate or greater cognitive problems on at least one self-report measure. After adjustment for multiple comparisons, there were no significant correlations between objective and subjective assessments. Objective cognitive impairment and subjective cognitive problems are common in Veterans beginning an EBP for PTSD. Longitudinal research on a larger sample is warranted to better understand relationships among subjective cognitive problems, objective cognitive impairment, and PTSD treatment participation and outcomes.

Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson's disease trial.

A potential therapeutic role for immune transformation in Parkinson's disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony-stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non-treated controls and 20 Parkinson's disease patients. Both Parkinson's disease patients and controls were monitored for 2 months for baseline profiling. Parkinson's disease patients were then randomized into two equal groups to self-administer placebo (saline) or sargramostim subcutaneously at 6 µg/kg/day for 56 days. Adverse events for the sargramostim and placebo groups were 100% (10/10) and 80% (8/10), respectively. These included injection site reactions, increased total white cell counts, and upper extremity bone pain. One urticarial and one vasculitis reaction were found to be drug and benzyl alcohol related, respectively. An additional patient with a history of cerebrovascular disease suffered a stroke on study. Unified Parkinson's disease rating scale, Part III scores in the sargramostim group showed modest improvement after 6 and 8 weeks of treatment when compared with placebo. This paralleled improved magnetoencephalography-recorded cortical motor activities and Treg numbers and function compared with pretreated Parkinson's disease patients and non-Parkinsonian controls. Peripheral Treg transformation was linked to serum tryptophan metabolites, including L-kynurenine, quinolinic acid, and serotonin. These data offer a potential paradigm shift in modulating immune responses for potential therapeutic gain for Parkinson's disease. Confirmation of these early study results requires larger numbers of enrolled patients and further clinical investigation.

Reasons for not prescribing guideline-recommended medications to adults with heart failure.

BACKGROUND: Little is known about how often contextual factors such as patient preferences and competing priorities impact prescribing of guideline-recommended medications, or about the extent to which these factors are documented in medical records and available to performance measurement systems. METHODS: Mixed-methods study of 295 veterans aged 50 years and older in 4 VA health care systems who had systolic heart failure and were not prescribed a ß-blocker and/or an angiotensin converting enzyme inhibitor or angiotensin-receptor blocker. Reasons for nontreatment were identified from clinic notes and from interviews with 62 primary care clinicians caring for these patients. These reasons were classified using a published taxonomy. RESULTS: Among 295 patients not receiving guideline-recommended drugs for heart failure, chart review identified biomedical reasons for nonprescribing in 42%-58% of patients and contextual reasons in 11%-17%. Clinician interviews identified twice as many reasons for nonprescribing as chart review (mean 1.6 vs. 0.8 reasons per patient, P<0.001). In these interviews, biomedical reasons for nonprescribing were cited in 50%-70% of patients, and contextual reasons in 64%-70%. The most common contextual reasons were comanagement with other clinicians (32%-35% of patients), patient preferences and nonadherence (15%-24%), and clinician belief that the medication is not indicated in the patient (12%-20%). CONCLUSIONS: Contextual reasons for not prescribing angiotensin converting enzyme inhibitor / angiotensin-receptor blockers and ß-blockers are present in two thirds of patients with heart failure who did not receive these medications, yet are poorly documented in medical records. The structure of medical records should be improved to facilitate documentation of contextual reasons for not providing guideline-recommended care.

Influence of patient age and comorbid burden on clinician attitudes toward heart failure guidelines.

BACKGROUND: Clinical practice guidelines have been criticized for insufficient attention to the unique needs of patients of advanced age and with multiple comorbid conditions. However, little empiric research is available to inform this topic. METHODS: We conducted telephone interviews with staff physicians and nurse practitioners in 4 VA health care systems. Respondents were asked to rate the usefulness of national heart failure guidelines for patients of different ages and levels of comorbid burden on a 5-point scale and to comment on the reasons for their ratings. RESULTS: Of 139 clinicians contacted, 65 (47%) completed the interview. Almost half (49%) were women, and 48 (74%) were general internists or family practitioners. On a 5-point scale assessing the usefulness of clinical practice guidelines for heart failure, the mean (SD) response ranged from 4.4 (0.7) for patients younger than 65 years with few comorbid conditions to 3.5 (1.2) for patients older than 80 years with multiple comorbid conditions (P<0.001). The difference in perceived usefulness varied more by patient age than by degree of comorbidity (P = 0.02). Four major concepts underlay the perceived usefulness of guidelines across different patient types: (1) harm of treatment and complexity of the patient's clinical condition and pharmacologic needs, (2) expected benefits of treatment, (3) patient preferences and abilities, and (4) confidence in the validity of guideline recommendations. CONCLUSION: Clinicians perceive heart failure guidelines to be substantially less useful in patients of older age and with greater comorbid burden. Concerns about the clinical and pharmacologic complexity of these patients and the expected benefits of drug therapy were commonly invoked as reasons for this skepticism.

A clinically guided approach for improving performance measurement for hypertension.

BACKGROUND: Performance measures often fail to account for legitimate reasons why patients do not achieve recommended treatment targets. METHODS: We tested a novel performance measurement system for blood pressure (BP) control that was designed to mimic clinical reasoning. This clinically guided approach focuses on (1) exempting patients for whom tight BP control may not be appropriate or feasible and (2) assessing BP over time. Trained abstractors conducted structured chart reviews of 201 adults with hypertension in 2 VA health care systems. Results were compared with traditional methods of performance measurement. RESULTS: Among 201 veterans, 183 (91%) were male, and the mean age was 71±11 years. Using the clinically guided approach, 61 patients (30%) were exempted from performance measurement. The most common reasons for exemption were inadequate opportunity to manage BP (35 patients, 17%) and the use of 4 or more antihypertensive medications (19 patients, 9%). Among patients eligible for performance measurement, there was little agreement on the presence of controlled versus uncontrolled BP when comparing the most recent BP (the traditional approach) with an integrated assessment of BP control (κ 0.14). After accounting for clinically guided exemptions and methods of BP assessment, only 15 of 72 patients (21%) whose last BP was ≥140/90 mm Hg were classified as problematic by the clinically guided approach. CONCLUSIONS: Many patients have legitimate reasons for not achieving tight BP control, and the methods used for BP assessment have marked effects on whether a patient is classified as having adequate or inadequate BP control.

Persistence and adherence to nucleos(t)ide analogue treatment for chronic hepatitis B.

BACKGROUND & AIMS: Long-term treatment with nucleos(t)ide analogues (NUCs) is associated with increasing rates of antiviral drug resistance. Medication adherence is important in preventing drug resistance. This study aimed to determine, first, the persistence rates and the adherence rates to NUCs in patients with chronic hepatitis B (CHB), and second, the factors associated with adherence. METHODS: Pharmacy claims of three cohorts of patients with CHB who were receiving lamivudine, adefovir, or entecavir in January 2007, January 2008, and January 2009, and data of patients receiving tenofovir in January 2009, were analyzed. Persistence was defined as continuing acquisition of pharmacy claims during a 12-month period and adherence as the percent of days in which patients had medication during the period in which the medication was prescribed. RESULTS: A total of 11,100 patients were included, 4.7% were patients newly started on a NUC and 95.3% were existing patients already on a NUC at the start of each year. The mean ± SD persistence rate was 81 ± 3.8%, and was higher among existing patients than among new patients, 81.4% vs. 73.4% (p < 0.001). The mean ± SD adherence rate was 87.8 ± 19.1% and was higher among existing patients than among new patients, 88% vs. 84.6% (p = 0.001). Multivariate analysis showed that new patients (OR = 0.68, 95% CI 0.53-0.86), those receiving lamivudine (OR = 0.66, 95% CI 0.58-0.76), and young adult patients (OR=0.82, 95% CI 0.74-0.91) were less likely to have adherence rate > 90%. CONCLUSIONS: Persistence and adherence to NUCs were high among CHB patients. Counseling of young and/or new patients on medication adherence may decrease the rate of antiviral drug resistance.

A taxonomy of reasons for not prescribing guideline-recommended medications for patients with heart failure.

BACKGROUND: Performance-measurement systems may work best when they account for the reasons why physicians do not provide guideline-recommended interventions. OBJECTIVE: This article develops a conceptual framework for understanding the proximate, patient-centered reasons why physicians do not prescribe angiotensin-converting enzyme (ACE) inhibitors or ß-blockers to patients with heart failure and reduced systolic function. METHODS: This was a focus group study using a 2-stage design. Academically affiliated clinicians of different specialties and levels of training were recruited by e-mailed invitations sent to clinicians within each target group. To be included, candidates needed to be currently practicing in an ambulatory care setting in which they encountered patients with heart failure. In the first part of each group, participants were asked to describe reasons for not prescribing ACE inhibitors or â-blockers for patients with heart failure. Next, participants were asked to develop concept maps that organized these reasons into categories and described the relationships between these categories. The concept maps from each group were synthesized to develop a consensus scheme for categorizing reasons for nonprescribing. RESULTS: There were 31 participants in 7 focus groups; median age was 31 years and 55% (17/31) were women. Two broad themes emerged. First, clinicians hinted at their own attitude-related barriers to prescribing. However, they framed their comments largely in terms of patient-centered reasons for nonprescribing that arose in individual patient encounters. Second, decision making about heart failure drug therapy often involved a complex and overlapping series of considerations. Five categories of reasons for not prescribing ACE inhibitors or â-blockers emerged: (1) adverse effects of drug therapy; (2) nonadherence to therapeutic and monitoring plan; (3) patients' preferences and beliefs; (4) comanagement and transitions of care; and (5) prioritization and patient benefit. CONCLUSIONS: Physicians' reasons for not prescribing guideline-recommended drugs for heart failure are complex but can be organized into a useful taxonomy. This taxonomy may be helpful for performance-measurement and quality-improvement programs that seek to understand reasons for physicians' nonadherence to guidelines.

hSnm1 colocalizes and physically associates with 53BP1 before and after DNA damage.

snm1 mutants of Saccharomyces cerevisiae have been shown to be specifically sensitive to DNA interstrand crosslinking agents but not sensitive to monofunctional alkylating agents, UV, or ionizing radiation. Five homologs of SNM1 have been identified in the mammalian genome and are termed SNM1, SNM1B, Artemis, ELAC2, and CPSF73. To explore the functional role of human Snm1 in response to DNA damage, we characterized the cellular distribution and dynamics of human Snm1 before and after exposure to DNA-damaging agents. Human Snm1 was found to localize to the cell nucleus in three distinct patterns. A particular cell showed diffuse nuclear staining, multiple nuclear foci, or one or two larger bodies confined to the nucleus. Upon exposure to ionizing radiation or an interstrand crosslinking agent, the number of cells exhibiting Snm1 bodies was reduced, while the population of cells with foci increased dramatically. Indirect immunofluorescence studies also indicated that the human Snm1 protein colocalized with 53BP1 before and after exposure to ionizing radiation, and a physical interaction was confirmed by coimmunoprecipitation assays. Furthermore, human Snm1 foci formed after ionizing radiation were largely coincident with foci formed by human Mre11 and to a lesser extent with those formed by BRCA1, but not with those formed by human Rad51. Finally, we mapped a region of human Snm1 of approximately 220 amino acids that was sufficient for focus formation when attached to a nuclear localization signal. Our results indicate a novel function for human Snm1 in the cellular response to double-strand breaks formed by ionizing radiation.

hMutSbeta is required for the recognition and uncoupling of psoralen interstrand cross-links in vitro.

The removal of interstrand cross-links (ICLs) from DNA in higher eucaryotes is not well understood. Here, we show that processing of psoralen ICLs in mammalian cell extracts is dependent upon the mismatch repair complex hMutSbeta but is not dependent upon the hMutSalpha complex or hMlh1. The processing of psoralen ICLs is also dependent upon the nucleotide excision repair proteins Ercc1 and Xpf but not upon other components of the excision stage of this pathway or upon Fanconi anemia proteins. Products formed during the in vitro reaction indicated that the ICL has been removed or uncoupled from the cross-linked substrate in the mammalian cell extracts. Finally, the hMutSbeta complex is shown to specifically bind to psoralen ICLs, and this binding is stimulated by the addition of PCNA. Thus, a novel pathway for processing ICLs has been identified in mammalian cells which involves components of the mismatch repair and nucleotide excision repair pathways.