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.

A paradigm shift in trauma resuscitation: evaluation of evolving massive transfusion practices.

IMPORTANCE: The evolution of damage control strategies has led to significant changes in the use of resuscitation after traumatic injury. OBJECTIVE: To evaluate changes in the administration of fluids and blood products, hypothesizing that a reduction in crystalloid volume and a reduced red blood cell (RBC) to fresh frozen plasma (FFP) ratio over the last 7 years would correlate with better resuscitation outcomes. DESIGN: Observational prospective cohort study. SETTING: Urban level I trauma center. PARTICIPANTS: A total of 174 trauma patients receiving a massive transfusion (>10 units of RBCs in 24 hours) or requiring the activation of the institutional massive transfusion protocol from February 2005 to June 2011. EXPOSURE: Patients had to either receive a massive transfusion or require the activation of the institutional massive transfusion protocol. MAIN OUTCOMES AND MEASURES: In-hospital mortality. RESULTS: The mean (SD) Injury Severity Score was 28.4 (16.2), the mean (SD) base deficit was -9.8 (6.3), and median international normalized ratio was 1.3 (interquartile range, 1.2-1.6); the mortality rate was 40.8%. Patients received a median of 6.1 L of crystalloid, 13 units of RBCs, 10 units of FFP, and 1 unit of platelets over 24 hours, with a mean RBC:FFP ratio of 1.58:1. The mean 24-hour crystalloid infusion volume and number of the total blood product units given in the first 24 hours decreased significantly over the study period (P < .05). The RBC:FFP ratio decreased from a peak of 1.84:1 in 2007 to 1.55:1 in 2011 (P = .20). Injury severity and mortality remained stable over the study period. When adjusted for age and injury characteristics using Cox regression, each decrease of 0.1 achieved in the massive transfusion protocol's RBC:FFP ratio was associated with a 5.6% reduction in mortality (P = .005). CONCLUSIONS AND RELEVANCE: There has been a shift toward a reduced crystalloid volume and the recreation of whole blood from component products in resuscitation. These changes are associated with markedly improved outcomes and a new paradigm in the resuscitation of severely injured patients.

Cause and timing of death in massively transfused trauma patients.

BACKGROUND: The purpose of this study was to characterize the cause of death in severely injured trauma patients to define potential responses to resuscitation. METHODS: Prospective analysis of 190 critically injured patients who underwent massive transfusion protocol (MTP) activation or received massive transfusion (>10 U of packed red blood cells [RBC] per 24 hours). Cause of death was adjudicated into one of four categories as follows: (1) exsanguination, (2) early physiologic collapse, (3) late physiologic collapse, and (4) nonsurvivable injury. RESULTS: A total 190 patients underwent massive transfusion or MTP with 76 deaths (40% mortality), of whom 72 deaths were adjudicated to one of four categories: 33.3% died of exsanguination, 16.6% died of early physiologic collapse, 11.1% died of late physiologic collapse, while 38.8% died of nonsurvivable injuries. Patients who died of exsanguination were younger and had the highest RBC/fresh frozen plasma ratio (2.97 [2.24]), although the early physiologic collapse group survived long enough to use the most blood products (p < 0.001). The late physiologic collapse group had significantly fewer penetrating injuries, was older, and had significantly more crystalloid use but received a lower RBC/fresh frozen plasma ratio (1.50 [0.42]). Those who were determined to have a nonsurvivable injury had a lower presenting Glasgow Coma Scale (GCS) score, fewer penetrating injuries, and higher initial blood pressure reflecting a preponderance of nonsurvivable traumatic brain injury. The average survival time for patients with potentially survivable injuries was 2.4 hours versus 18.4 hours for nonsurvivable injuries (p < 0.001). CONCLUSION: Severely injured patients requiring MTP have a high mortality rate. However, no studies to date have addressed the cause of death after MTP. Characterization of cause of death will allow targeting of surgical and resuscitative conduct to allow extension of the physiologic reserve time, therefore rendering previously nonsurvivable injury potentially survivable.

Passing the baton: a grounded practical theory of handoff communication between multidisciplinary providers in two Department of Veterans Affairs outpatient settings.

BACKGROUND: Handoffs are communication processes that enact the transfer of responsibility between providers across clinical settings. Prior research on handoff communication has focused on inpatient settings between provider teams and has emphasized patient safety. This study examines handoff communication within multidisciplinary provider teams in two outpatient settings. OBJECTIVE: To conduct an exploratory study that describes handoff communication among multidisciplinary providers, to develop a theory-driven descriptive framework for outpatient handoffs, and to evaluate the strengths and weaknesses of different handoff types. DESIGN & SETTING: Qualitative, in-depth, semi-structured interviews with 31 primary care, mental health, and social work providers in two Department of Veterans Affairs (VA) Medical Center outpatient clinics. APPROACH: Audio-recorded interviews were transcribed and analyzed using Grounded Practical Theory to develop a theoretical model of and a descriptive framework for handoff communication among multidisciplinary providers. RESULTS: Multidisciplinary providers reported that handoff decisions across settings were made spontaneously and without clear guidelines. Two situated values, clinic efficiency and patient-centeredness, shaped multidisciplinary providers' handoff decisions. Providers reported three handoff techniques along a continuum: the electronic handoff, which was the most clinically efficient; the provider-to-provider handoff, which balanced clinic efficiency and patient-centeredness; and the collaborative handoff, which was the most patient-centered. Providers described handoff choice as a practical response to manage constituent features of clinic efficiency (time, space, medium of communication) and patient-centeredness (information continuity, management continuity, relational continuity, and social interaction). We present a theoretical and descriptive framework to help providers evaluate differential handoff use, reflect on situated values guiding clinic communication, and guide future research. CONCLUSIONS: Handoff communication reflected multidisciplinary providers' efforts to balance clinic efficiency with patient-centeredness within the constraints of day-to-day clinical practice. Evaluating the strengths and weaknesses among alternative handoff options may enhance multidisciplinary provider handoff decision-making and may contribute to increased coordination and continuity of care across outpatient settings.

Prohemostatic interventions in trauma: resuscitation-associated coagulopathy, acute traumatic coagulopathy, hemostatic resuscitation, and other hemostatic interventions.

Trauma is the most common cause of death in the young and hemorrhage is the most important cause of death in patients with trauma. Recently redefined pathways of inflammation and coagulation, together with hypothermia and acidosis contribute to trauma-associated coagulopathy and aggravation of bleeding. Pharmacological prohemostatic agents may be useful to (partly) correct the coagulopathy in trauma patients and may serve as useful adjunctive treatment options in patients with severe blood loss after trauma. Recombinant factor VIIa, fibrinogen and prothrombin complex concentrates, and antifibrinolytic agents have been evaluated in clinical trials. These interventions show promising effects but their efficacy in reducing clinically important outcome parameters need to be confirmed in clinical studies.

Reducing barriers to mental health and social services for Iraq and Afghanistan veterans: outcomes of an integrated primary care clinic.

BACKGROUND: Despite high rates of post-deployment psychosocial problems in Iraq and Afghanistan veterans, mental health and social services are under-utilized. OBJECTIVE: To evaluate whether a Department of Veterans Affairs (VA) integrated care (IC) clinic (established in April 2007), offering an initial three-part primary care, mental health and social services visit, improved psychosocial services utilization in Iraq and Afghanistan veterans compared to usual care (UC), a standard primary care visit with referral for psychosocial services as needed. DESIGN: Retrospective cohort study using VA administrative data. POPULATION: Five hundred and twenty-six Iraq and Afghanistan veterans initiating primary care at a VA medical center between April 1, 2005 and April 31, 2009. MAIN MEASURES: Multivariable models compared the independent effects of primary care clinic type (IC versus UC) on mental health and social services utilization outcomes. KEY RESULTS: After 2007, compared to UC, veterans presenting to the IC primary care clinic were significantly more likely to have had a within-30-day mental health evaluation (92% versus 59%, p < 0.001) and social services evaluation [77% (IC) versus 56% (UC), p < 0.001]. This exceeded background system-wide increases in mental health services utilization that occurred in the UC Clinic after 2007 compared to before 2007. In particular, female veterans, younger veterans, and those with positive mental health screens were independently more likely to have had mental health and social service evaluations if seen in the IC versus UC clinic. Among veterans who screened positive for ≥ 1 mental health disorder(s), there was a median of 1 follow-up specialty mental health visit within the first year in both clinics. CONCLUSIONS: Among Iraq and Afghanistan veterans new to primary care, an integrated primary care visit further improved the likelihood of an initial mental health and social services evaluation over background increases, but did not improve retention in specialty mental health services.