Opioids and Chronic Pain: Impact of the NIH Pathways to Prevention Evidence-Based Workshop Program.

The National Institutes of Health (NIH) Office of Disease Prevention (ODP) sponsors Pathways to Prevention (P2P), an evidence-based scientific workshop program that helps advance prevention research. Each P2P workshop is presided over by an independent expert panel and informed by a systematic evidence review, scientific presentations, and public input. Post-workshop activities include collaborating with federal agency partners to develop an action plan for addressing key research gaps. Primary outcomes of P2P workshops include developing a research agenda and creating or enhancing initiatives to implement the agenda. In 2014, ODP partnered with the NIH Pain Consortium and two NIH institutes to convene "The Role of Opioids in the Treatment of Chronic Pain." This workshop assessed the state-of-the-science on the long-term effectiveness, safety, and harms of opioid use for managing chronic pain. In 2021, ODP initiated an assessment of the outcomes and impact of the Opioids P2P workshop. We applied an evaluation framework and a mixed methods approach encompassing web analytics, bibliometric assessment, grant portfolio analysis, policy assessment, and key informant interviews. Our data showed that the workshop attracted a broad audience, and its published reports had high impact. The workshop also helped inform over 100 new research projects through grants funded by three federal agencies, as well as national legislation and practice guidelines from influential organizations. In sum, the Opioids P2P workshop and follow-up activities have identified gaps in scientific knowledge, informed clinical practice, and catalyzed change on a national level for addressing the prescription opioid crisis.

Characteristics of Scientific Evidence Informing Changed U.S. Preventive Services Task Force Insufficient Evidence Statements.

INTRODUCTION: The U.S. Preventive Services Task Force (USPSTF) issues "Insufficient Evidence" (I) statements when scientific evidence is inadequate for making recommendations about clinical preventive services. Insufficient Evidence statements may be changed to definitive recommendations if new research closes evidence gaps. This study examines the characteristics of evidence that informed changes from I statements to definitive recommendations, including NIH's role as a funder. METHODS: A total of 11 USPSTF Insufficient Evidence statements that were changed between 2010 and 2019 were assessed. Study designs, bibliometric influence, and funding sources for scientific articles cited in USPSTF evidence reviews were characterized for each I statement. Data were analyzed in 2019-2020. RESULTS: Most I statements (82%) changed to a B grade; an average of 8.4 years elapsed between issuing the I statement and releasing the definitive recommendation. An average of 63 (range=19-253) articles were included in each USPSTF evidence review. NIH support was cited in 28.8% of articles, on average. The proportion of NIH-funded articles reporting RCT designs was similar to that of non-NIH-funded articles (64.5% vs 59.5%). A higher proportion of NIH-funded articles were rated good quality for study design (39.0%) than the proportion of non-NIH-funded articles (24.4%). Bibliometric influence measured by relative citation ratios was higher for NIH-funded (mean=14.78) than for non-NIH-funded (mean=5.07) articles. CONCLUSIONS: Study designs and funding supports varied widely across topics, but overall, NIH was the largest single funder of evidence informing 11 changed USPSTF I statements. Enhanced efforts by NIH and other stakeholders to address I statement evidence gaps are needed.

Neuroserpin Differentiates Between Forms of Tissue Type Plasminogen Activator via pH Dependent Deacylation.

Tissue-type plasminogen activator (t-PA), initially characterized for its critical role in fibrinolysis, also has key functions in both physiologic and pathologic processes in the CNS. Neuroserpin (NSP) is a t-PA specific serine protease inhibitor (serpin) found almost exclusively in the CNS that regulates t-PA's proteolytic activity and protects against t-PA mediated seizure propagation and blood-brain barrier disruption. This report demonstrates that NSP inhibition of t-PA varies profoundly as a function of pH within the biologically relevant pH range for the CNS, and reflects the stability, rather than the formation of NSP: t-PA acyl-enzyme complexes. Moreover, NSP differentiates between the zymogen-like single chain form (single chain t-PA, sct-PA) and the mature protease form (two chain t-PA, tct-PA) of t-PA, demonstrating different pH profiles for protease inhibition, different pH ranges over which catalytic deacylation occurs, and different pH dependent profiles of deacylation rates for each form of t-PA. NSP's pH dependent inhibition of t-PA is not accounted for by differential acylation, and is specific for the NSP-t-PA serpin-protease pair. These results demonstrate a novel mechanism for the differential regulation of the two forms of t-PA in the CNS, and suggest a potential specific regulatory role for CNS pH in controlling t-PA proteolytic activity.