Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators.

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.

Development of a Multifaceted Program for Pharmacogenetics Adoption at an Academic Medical Center: Practical Considerations and Lessons Learned.

In 2019, Indiana University launched the Precision Health Initiative to enhance the institutional adoption of precision medicine, including pharmacogenetics (PGx) implementation, at university-affiliated practice sites across Indiana. The overarching goal of this PGx implementation program was to facilitate the sustainable adoption of genotype-guided prescribing into routine clinical care. To accomplish this goal, we pursued the following specific objectives: (i) to integrate PGx testing into existing healthcare system processes; (ii) to implement drug-gene pairs with high-level evidence and educate providers and pharmacists on established clinical management recommendations; (iii) to engage key stakeholders, including patients to optimize the return of results for PGx testing; (iv) to reduce health disparities through the targeted inclusion of underrepresented populations; (v) and to track third-party reimbursement. This tutorial details our multifaceted PGx implementation program, including descriptions of our interventions, the critical challenges faced, and the major program successes. By describing our experience, we aim to assist other clinical teams in achieving sustainable PGx implementation in their health systems.

Prophylactic Peri-Nephric Drain Placement in Renal Transplant Surgery: A Systematic Review and Meta-Analysis.

Renal transplantation is common worldwide, with >25,000 procedures performed in 2022. Usage of prophylactic perinephric drains is variable in renal transplantation; drains are associated with risks, and there is a lack of consensus regarding benefit of routine drain placement in these patients. This meta-analysis assessed whether prophylactic drainage reduced need for reintervention postoperatively. This systematic review and meta-analysis was carried out using the Preferred Reporting Items in Systematic Reviews and Meta-Analysis, and prospectively registered on PROSPERO. Summary statistics for outcomes of interest underwent meta-analyses to a confidence interval (CI) of 95% and are presented as Forest Plots for Odds Ratio (OR). A systematic literature search in June 2023 revealed 1,540 unique articles across four databases. Of these, four retrospective cohort studies were selected. Meta-analysis of three studies showed no significant reduction in reintervention rate with pre-emptive drain placement, OR = 0.59 (95% CI: 0.16-2.23), p = 0.44. Meta-analysis did not show a significant reduction in perinephric collections with prophylactic drain insertion OR = 0.55 (95% CI: 0.13-2.37), p = 0.42. Finally, there is not good evidence that drain placement reduces superficial wound complications or improves 12-month graft survival. Further work is needed, including well-designed, prospective studies to assess the risks and benefits of drain placement in these patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023422685, Identifier PROSPERO CRD42021255795.

Is the Rise of Medicare Advantage Impacting the Fidelity of Traditional Medicare Claims Data? Implications for Reporting of Long-Term Total Hip Arthroplasty Survivorship.

BACKGROUND: Arthroplasty registries often use traditional Medicare (TM) claims data to report long-term total hip arthroplasty (THA) survivorship. The purpose of this study was to determine whether the large number of patients leaving TM for Medicare Advantage (MA) has compromised the fidelity of TM data. METHODS: We identified 10,962 THAs in 9,333 Medicare-eligible patients who underwent primary THA from 2000 to 2020 at a single institution. Insurance type was analyzed, and 83% of patients had TM at the time of THA. Survivorship free from any revision or reoperation was calculated for patients who have TM. The same survivorship end points were recalculated with censoring performed when a patient transitioned to an MA plan after their primary THA to model the impact of losing patients from the TM dataset. Differences in survivorship were compared. The mean follow-up was 7 years. RESULTS: From 2000 to 2020, there was a decrease in TM insurance (93 to 73%) and a corresponding increase in MA insurance (0 to 19%) among THA patients. Following THA, 23% of TM patients switched to MA. For patients who had TM at the time of surgery, 15-year survivorship free from any reoperation or revision was 90% and 93%, respectively. When censoring patients upon transition from TM to MA, survivorship free from any reoperation became significantly higher (92 versus 90% at 15 years; hazard ratio = 1.16, P = .033), and there was a trend toward higher survivorship free from any revision (95 versus 93% at 15 years; hazard ratio = 1.16, P = .074). CONCLUSIONS: Approximately 1 in 4 patients left TM for MA after primary THA, effectively making them lost to follow-up within TM datasets. The mass exodus of patients out of TM appears to have led to a slight overestimation of survivorship free from any reoperation and trended toward overestimating survivorship free from any revision. If MA continues to grow, efforts to obtain MA data will become even more important.

The INGENIOUS trial: Impact of pharmacogenetic testing on adverse events in a pragmatic clinical trial.

Adverse drug events (ADEs) account for a significant mortality, morbidity, and cost burden. Pharmacogenetic testing has the potential to reduce ADEs and inefficacy. The objective of this INGENIOUS trial (NCT02297126) analysis was to determine whether conducting and reporting pharmacogenetic panel testing impacts ADE frequency. The trial was a pragmatic, randomized controlled clinical trial, adapted as a propensity matched analysis in individuals (N = 2612) receiving a new prescription for one or more of 26 pharmacogenetic-actionable drugs across a community safety-net and academic health system. The intervention was a pharmacogenetic testing panel for 26 drugs with dosage and selection recommendations returned to the health record. The primary outcome was occurrence of ADEs within 1 year, according to modified Common Terminology Criteria for Adverse Events (CTCAE). In the propensity-matched analysis, 16.1% of individuals experienced any ADE within 1-year. Serious ADEs (CTCAE level ≥ 3) occurred in 3.2% of individuals. When combining all 26 drugs, no significant difference was observed between the pharmacogenetic testing and control arms for any ADE (Odds ratio 0.96, 95% CI: 0.78-1.18), serious ADEs (OR: 0.91, 95% CI: 0.58-1.40), or mortality (OR: 0.60, 95% CI: 0.28-1.21). However, sub-group analyses revealed a reduction in serious ADEs and death in individuals who underwent pharmacogenotyping for aripiprazole and serotonin or serotonin-norepinephrine reuptake inhibitors (OR 0.34, 95% CI: 0.12-0.85). In conclusion, no change in overall ADEs was observed after pharmacogenetic testing. However, limitations incurred during INGENIOUS likely affected the results. Future studies may consider preemptive, rather than reactive, pharmacogenetic panel testing.

Bariatric surgery improves access to renal transplantation and is safe in renal failure as well as after transplantation: A systematic review and meta-analysis.

INTRODUCTION: Effective workup and listing of end-stage renal disease (ESRD) patients for renal transplantation, often with multiple co-morbidities, poses a challenge for transplant teams. Obesity is a common co-morbidity associated with adverse outcomes in ESRD and kidney transplant (KT) recipients. Bariatric and metabolic surgery (BMS) has long been established as a safe and effective treatment for morbid obesity. In this study, the authors aimed to evaluate the strength of evidence for both the efficacy and safety of bariatric surgery in patients with ESRD or kidney transplantation. METHODS: A literature search was performed using key terms including "transplantation", "kidney", "renal", "obesity", and "bariatric". Databases searched include MEDLINE, EMBASE and Web of Science from inception to date (April 2021). Methodological quality was assessed using the Newcastle-Ottawa tool. Selected articles were then categorised into patients awaiting waiting list acceptance, patients awaiting transplantation, patients undergoing simultaneous BMS + KT and patients undergoing BMS following a previous renal transplant. Summary effects are presented with a level of statistical significance and 95% Confidence Intervals. RESULTS: A total of 28 articles were selected following the literature search. Fourteen studies on patients awaiting listing (n = 1903), nine on patients on the KT waiting list (n = 196), a single study on simultaneous BMS and KT and ten studies on patients undergoing BMS following KT (n = 198). Mean change in BMI for patients awaiting listing was -11.3 kg/m2 (95%CI: -15.3 to -7.3, p < 0.001), mean change in BMI for patients listed for KT was -11.2 kg/m 2(95%CI: -12.9 to -9.5, p 0.001) and mean change for patients with prior KT was -11.0 kg/m2 (95%CI: -7.09 to -14.9, p < 0.001). The combined mortality rate for patients who had undergone both BMS and KT was 4% (n = 15). DISCUSSION: This review demonstrates BMS is both safe and efficacious in patients with ESRD prior to KT and in those post KT. It would enable difficult-to-list obese recipients the possibility to undergo transplantation and should be considered as part of the work up process.

Outcomes Vary Significantly Using a Tiered Approach To Define Success After Total Hip Arthroplasty.

Background: Clinical outcomes following primary total hip arthroplasty (THA) are commonly assessed through patient-reported outcome measures (PROM). The purpose of this study was to use progressively more stringent definitions of success to evaluate clinical outcomes of primary THA at 1-year postoperatively and to determine if demographic variables were associated with achievement of clinical success. Methods: The American Joint Replacement Registry (AJRR) was queried from 2012-2020 for primary THA. Patients that completed the following PROMs preoperatively and 1-year postoperatively were included: Western Ontario and McMaster Universities Arthritis Index (WOMAC), Hip Injury and Osteoarthritis Outcome Score (HOOS) and HOOS for Joint Replacement (HOOS, JR). Mean PROM scores were determined for each visit and between-visit changes were evaluated using paired t-tests. Rates of achievement of minimal clinically important difference (MCID) by distribution-based and anchor-based criteria, patient acceptable symptom state (PASS), and substantial clinical benefit (SCB) were calculated. Logistic regression was used to evaluate associations between demographic variables and odds of success. Results: 7,001 THAs were included. Mean improvement in PROM scores were: HOOS, JR, 37; WOMAC-Pain, 39; WOMAC-Function, 41 (p<0.0001 for all). Rates of achievement of each metric were: distribution-based MCID, 88-93%; anchor-based MCID, 68-90%; PASS, 47-84%; SCB, 68-84%. Age and sex were the most influential demographic factors on achievement of clinical success. Conclusion: There is significant variability in clinical outcomes at 1 year after primary THA when using a tiered approach to define success from the patient's perspective. Tiered approaches to interpretation of PROMs should be considered for future research and clinical assessment. Level of Evidence: III.

Large-scale high-density brain-wide neural recording in nonhuman primates.

High-density, integrated silicon electrodes have begun to transform systems neuroscience, by enabling large-scale neural population recordings with single cell resolution. Existing technologies, however, have provided limited functionality in nonhuman primate species such as macaques, which offer close models of human cognition and behavior. Here, we report the design, fabrication, and performance of Neuropixels 1.0-NHP, a high channel count linear electrode array designed to enable large-scale simultaneous recording in superficial and deep structures within the macaque or other large animal brain. These devices were fabricated in two versions: 4416 electrodes along a 45 mm shank, and 2496 along a 25 mm shank. For both versions, users can programmatically select 384 channels, enabling simultaneous multi-area recording with a single probe. We demonstrate recording from over 3000 single neurons within a session, and simultaneous recordings from over 1000 neurons using multiple probes. This technology represents a significant increase in recording access and scalability relative to existing technologies, and enables new classes of experiments involving fine-grained electrophysiological characterization of brain areas, functional connectivity between cells, and simultaneous brain-wide recording at scale.

Trends in systematic reviews of kidney transplantation: A 10-year analysis of the evidence base.

BACKGROUND: Systematic reviews (SRs) are the highest form of evidence for all types of clinical questions in evidence-based practice. For the first time in 2018, the number of SRs in transplantation outstripped those from randomised controlled trials (RCTs). This raises concerns of duplication or increased use of non-RCT evidence. We aimed to analyse the trends, strength and quality of SRs in kidney transplantation over a 10-year period. METHODS: SRs in kidney transplantation were identified from the Transplant Library, without language restriction. All full-text citations were exported to a custom Research Electronic Data Capture (REDCap) database prior to evaluation. Quality of evidence in all included SRs was assessed using AMSTAR-2. RESULTS: We included 454 SRs, of which, only three were scored as 'high quality'. We found that 96.70% of SRs were identified as 'critically low quality', which increased in number over time. We also found that inclusion of non-RCT data increased in the most recent 5 years. Only 14.12% of SRs had made a clear recommendation for practice. CONCLUSIONS: This review highlights several concerning statistics that need to be addressed. In the last 10 years, only three SRs in kidney transplantation were 'high-quality'. The weaknesses identified in critical domains, alongside the increased use of non-RCT data and lack of conclusive recommendations undermines the confidence in the results of the SRs and purpose of publication. As these SRs are instrumental to clinical decision-making and patient care in kidney transplantation, we advocate for improved reporting quality among SRs in kidney transplantation.