Real-world treatment patterns and outcomes in relapsed/refractory multiple myeloma (1-3 prior lines): Flatiron database.

In multiple myeloma (MM), early use of the immunomodulatory drug lenalidomide has led to an increased population of patients with lenalidomide-refractory MM in early-line settings, but their outcomes are not well characterized. Here, we report treatment patterns, survival outcomes, prognostic variables, and attrition rates for patients with proteasome inhibitor-exposed, lenalidomide-refractory MM, treated with 1-3 prior lines of therapy (LOT). From 12 767 patients with MM in the Flatiron Health database between January 2016 and April 2022, 1455 met the inclusion criteria. The most common subsequent treatments were triplet combinations (41.6% of patients); daratumumab/pomalidomide/dexamethasone was the most common treatment regimen (13.2%). Median real-world progression-free survival (RW-PFS) and overall survival (OS) were 6.5 months and 44.4 months, respectively. RW-PFS was similar in patients with 1, 2, or 3 prior LOT. International Staging System stage III, Eastern Cooperative Oncology Group performance status of 1, hemoglobin <12 g/dL, high-risk cytogenetics, and refractoriness to anti-CD38 antibody at baseline were associated with worse RW-PFS and OS. Outcomes remained similar for patients who received National Comprehensive Cancer Network-preferred treatments and those who received treatments after 2020. In 561 patients with 1 prior LOT at inclusion, cumulative attrition rate from LOT 2-5 was 85%, which included 25% patients who died and 60% with no further treatment. Patients with lenalidomide-refractory MM who have received 1-3 prior LOT have poor outcomes and progress rapidly through available therapies, highlighting the need for more effective treatments early in the disease course, before patients are lost to attrition.

Comparative efficacy of ciltacabtagene autoleucel versus idecabtagene vicleucel in the treatment of patients with relapsed or refractory multiple myeloma previously treated with 2-4 prior lines of therapy: a matching-adjusted indirect comparison.

OBJECTIVE: To estimate the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus idecabtagene vicleucel (ide-cel) in patients with relapsed/refractory multiple myeloma (RRMM) treated with 2-4 prior lines of therapy. METHODS: Matching adjusted indirect comparison (MAICs) were performed using individual patient-level data (IPD) for cilta-cel from CARTITUDE-1 and CARTITUDE-4 and published aggregated data for ide-cel from KarMMa-3. Cilta-cel patients who met inclusion criteria from KarMMa-3 were selected, and outcomes were compared against data for ide-cel using simulated IPD derived from aggregate-level data from KarMMa-3. Patient characteristics were adjusted by reweighting cilta-cel IPD to match the distribution of prognostic factors in KarMMa-3. Comparative efficacy was estimated for response outcomes using a weighted logistic regression analysis and for progression-free survival using a weighted Cox proportional hazards model. RESULTS: Patients treated with cilta-cel were 1.2 times more likely to achieve overall response (relative response ratio [RR]: 1.18 [95% confidence interval: 1.03-1.34]; p = 0.04), 1.3 times more likely to achieve very good partial response or better (RR: 1.34 [1.15-1.57]; p = 0.003), and 1.9 times more likely to achieve complete response or better (RR: 1.91 [1.54-2.37]; p < 0.0001) versus ide-cel patients from KarMMa-3. Cilta-cel was associated with a significant 49% reduction in risk of disease progression or death versus ide-cel (hazard ratio: 0.51 [95% confidence interval: 0.31, 0.84]; p = 0.0078). CONCLUSION: For patients with triple-class exposed RRMM treated with 2-4 prior lines of treatment, cilta-cel was found to provide superior clinical benefit over ide-cel in terms of response and progression-free survival.

Plain language summary of the CARTITUDE-4 study of ciltacabtagene autoleucel for the treatment of people with relapsed or refractory multiple myeloma.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a phase 3 clinical trial called CARTITUDE-4. This trial compared the anti-cancer therapy ciltacabtagene autoleucel (or cilta-cel) with standard therapies in people who have multiple myeloma, a cancer that affects specific kinds of blood cells called plasma cells. The people in the study had been treated with 1 to 3 previous treatments for multiple myeloma, including a common anti-myeloma treatment called lenalidomide, but their multiple myeloma did not get better. HOW WAS THE STUDY IN THIS SUMMARY CONDUCTED?: About half of the 419 participants in this study received cilta-cel, while the other half received standard therapies, or therapies that are commonly used to treat multiple myeloma. Participants who received cilta-cel had a type of immune cell called T cells collected from their blood and genetically modified to recognize a specific protein found on myeloma cells. These modified T cells, which comprise cilta-cel, were then infused back into the bloodstream. WHAT WERE THE RESULTS OF THE STUDY?: After approximately 1 year in the study, more participants were alive without their cancer getting worse in the cilta-cel group (76%) than in the standard therapies group (49%). The most common side effects in both groups were infections and low blood cell counts. Cytokine release syndrome (a potentially serious side effect caused by overactivation of the immune system) was common but mostly mild. Neurotoxicities (including immune effector cell-associated neurotoxicity syndrome, which can cause symptoms such as headaches, changes in consciousness, and difficulty with memory, attention, speaking, or understanding others) were less common and were reported in 20.5% of participants treated with cilta-cel. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: In CARTITUDE-4, more participants treated with cilta-cel showed improvements and were alive with control of their disease 12 months after receiving cilta-cel compared with participants who received standard therapies.Clinical Trial Registration: NCT04181827 (CARTITUDE-4) (ClinicalTrials.gov).

What do we know about autism and policing globally? Preliminary findings from an international effort to examine autism and the criminal justice system.

Research has demonstrated that autistic individuals have higher rates of police contact, however, research has seldom explored the fundamental reasons for these interactions and how this might vary across international contexts. To remedy this, the Global Autism and Criminal Justice Consortium created and disseminated the Global Criminal Justice Survey. Descriptive statistics of survey respondents with and without police contact were compared to glean differential characteristics. Frequency and type of recent police interactions (within the last 5 years) among autistic individuals were also examined to better contextualize the reasons that autistic individuals encounter police. Study findings indicated that across a global sample (i.e., North America, Scandinavia, Europe, and Oceania) nearly half of all autistic individuals had an interaction with police and that those with a history of police contact were usually older, had higher educational qualifications, and were more likely to have a co-occurring mental health or developmental disorder. Among types of interactions, noncriminal encounters, such as welfare checks, traffic incidents, wandering, and behaviors associated with autism, were most common, followed by autistic individuals alleging a crime was committed against them. These findings offer important directions for future research and for targeted policy responses that can address the unique needs of autistic individuals within the justice system.

Six Years of Quality Improvement in Pectus Excavatum Repair: Implementation of Intercostal Nerve Cryoablation and ERAS Protocols for Patients Undergoing Nuss Procedure.

BACKGROUND: The Nuss procedure for pectus excavatum is associated with prolonged hospitalizations due to pain. We evaluated implementation of intercostal nerve cryoablation and enhanced recovery after surgery (ERAS) protocols on outcomes of Nuss procedures performed over six years at a single institution. METHODS: This retrospective cohort study included patients who underwent Nuss procedure from 10/2017 to 09/2023. Patients received epidurals prior to 06/2019, cryoablation from 06/2019 to 07/2021, and ERAS with cryoablation and intraoperative methadone administration after 07/2021. We used multivariable linear regression to evaluate length of stay (LOS), inpatient morphine milligram equivalents (MMEs), and discharge opioids. We assessed the balancing measures of operative time, postoperative pain scores, and complications. RESULTS: We identified 62 patients; 15 who received epidurals, 18 cryoablation, and 29 cryoablation with ERAS. Cryoablation was associated with a 62.3% (p < 0.001) decrease in length of stay, an 86.6% (p < 0.001) decrease in inpatient MMEs, and a 72.9% (p < 0.001) decrease in discharge opioids. Cryoablation was additionally associated with 24.5% (p = 0.02) longer operative times and 46.4% (p = 0.04) higher postoperative day one pain scores. Subsequent implementation of an ERAS protocol was associated with a further 82.8% (p = 0.04) decrease in discharge opioids and a 25.0% (p = 0.04) decrease in postoperative day one pain scores. CONCLUSIONS: Over six years of quality improvement efforts, we found the implementation of cryoablation and ERAS protocols to be associated with a significant decrease in length of stay and opioid exposures. Protocolized pain management and cryoablation may work synergistically to improve outcomes without compromising patient experience. LEVEL OF EVIDENCE: Level III - Retrospective comparative study.

Attitudes toward and preparedness for lung transplantation among individuals with cystic fibrosis in the era of highly effective modulators.

BACKGROUND: Outcomes for individuals with cystic fibrosis (CF) have improved due to highly effective modulator therapy (HEMT). However, lung transplant (LTx) remains an important treatment for people with advanced lung disease. This study assessed attitudes and knowledge about LTx in the HEMT era. METHODS: All patients from the University of Washington CF clinic were surveyed March 25-May 30, 2020. Questions addressed self-rated LTx preparedness and knowledge, as well as barriers and facilitators to discussing LTx. Demographic and clinical data were extracted from the electronic health record. RESULTS: There were 159/224 (71%) responses. Respondents had a median forced expiratory volume in one second (FEV1) of 70%, and 142 (89%) were on modulatory therapy. One hundred thirteen (71%) respondents felt that it was moderately or very important to be prepared to make decisions about LTx, though only 56 (35%) felt moderately or very prepared. Only 83 (30%) and 47 (52%) participants correctly answered questions about life expectancy and improved quality of life after LTx, respectively. Respondents with Medicaid insurance less frequently answered questions correctly. The most common barriers to discussing LTx were fear of being a burden on loved ones for 58 respondents (36%) and cost of LTx for 46 (29%). Most participants (94%) trusted their CF doctor, and 75% of participants selected trust as a facilitator for LTx discussions. CONCLUSIONS: Many individuals with CF, especially those with lower socioeconomic status, lacked knowledge and did not feel very prepared for decisions about LTx. Earlier education and discussions about LTx represent an area for improvement in CF care.

Minority Stress, Psychological Distress, Sexual Compulsivity, and Avoidance-Based Motivations Associated with Methamphetamine Use Among Sexual Minority Men Living with HIV: Examining Direct and Indirect Associations Using Cross-Sectional Structural Equation Modeling.

OBJECTIVE: Sexual minority men (SMM) living with HIV report significantly greater methamphetamine use compared with heterosexual and HIV-negative peers. Greater use may be related to stressors (e.g., HIV-related stigma) faced by SMM living with HIV and subsequent psychological and behavioral sequelae. We tested an integrated theoretical model comprised of pathways between stigma, discrimination, childhood sexual abuse, psychological distress, sexual compulsivity, and cognitive escape in predicting methamphetamine use among SMM living with HIV. METHODS: Among 423 SMM living with HIV, we tested a structural equation model examining factors hypothesized to be directly and indirectly associated with methamphetamine use. Analyses were adjusted for demographic covariates and sampling bias. RESULTS: The model showed good fit (CFI = 0.96, RMSEA = 0.01). Heterosexist discrimination was associated with psychological distress (ß = 0.39, p < 0.001) and psychological distress was associated with sexual compulsivity (ß = 0.33, p < 0.001). Sexual compulsivity was associated with cognitive escape (ß = 0.31, p < 0.001), which was associated with methamphetamine use (ß = 0.51, p < 0.001). Psychological distress was associated with methamphetamine use via serial indirect effects of sexual compulsivity and cognitive escape (ß = 0.05, p < 0.05). CONCLUSIONS: Heterosexist discrimination contributed to psychological distress among SMM living with HIV. Psychological distress is linked to methamphetamine use via sexual compulsivity and cognitive avoidance. Interventions seeking to reduce the likelihood that SMM living with HIV use methamphetamine should include coping strategies specific to heterosexism and related psychological distress.

Association of Tumor-informed Circulating Tumor DNA Detectability Before and After Radical Cystectomy with Disease-free Survival in Patients with Bladder Cancer.

BACKGROUND AND OBJECTIVE: Despite curative-intent radical cystectomy (RC), patients with muscle-invasive bladder cancer (MIBC) are at high risk of recurrence. Biomarkers are urgently needed to refine prognostication and selection of appropriate perioperative systemic therapies. Our aim was to evaluate the prognostic and predictive value of tumor-informed circulating tumor DNA (ctDNA) results in a multicenter cohort of patients with bladder cancer who underwent RC. METHODS: We performed a retrospective analysis of real-world data for a commercial ctDNA test (Signatera; Natera, Austin, TX, USA) performed in 167 patients (852 plasma samples) before RC and during molecular residual disease (MRD; adjuvant decision) and surveillance windows. We assessed the correlation between recurrence and ctDNA status before and after RC using Cox regression analysis. RESULTS AND LIMITATIONS: During study-defined postoperative MRD and surveillance windows, detectable ctDNA was associated with shorter disease-free survival (DFS) when compared to undetectable ctDNA (MRD: hazard ratio 6.93; p < 0.001; surveillance: hazard ratio 23.02; p < 0.001). Of note, patients with undetectable ctDNA did not appear to benefit from adjuvant therapy (p = 0.34). Detectable ctDNA in the pre-RC (p = 0.045), MRD (p = 0.002), and surveillance (p < 0.001) windows was the only risk factor independently associated with shorter DFS. Limitations include the retrospective and nonrandomized nature of the study. CONCLUSIONS: ctDNA testing in patients with bladder cancer undergoing RC was prognostic and potentially predictive. Identification of patients at high risk of recurrence may aid in patient counseling and decision-making. PATIENT SUMMARY: We found that outcomes for patients with muscle-invasive bladder cancer are strongly linked to detection of tumor DNA in blood samples. The results show the value of tumor-informed testing for tumor DNA in blood for decisions on the best treatment for each individual patient.

Therapeutic implications of the metabolic changes associated with BRAF inhibition in melanoma.

Melanoma metabolism can be reprogrammed by activating BRAF mutations. These mutations are present in up to 50% of cutaneous melanomas, with the most common being V600E. BRAF mutations augment glycolysis to promote macromolecular synthesis and proliferation. Prior to the development of targeted anti-BRAF therapies, these mutations were associated with accelerated clinical disease in the metastatic setting. Combination BRAF and MEK inhibition is a first line treatment option for locally advanced or metastatic melanoma harboring targetable BRAF mutations. This therapy shows excellent response rates but these responses are not durable, with almost all patients developing resistance. When BRAF mutated melanoma cells are inhibited with targeted therapies the metabolism of those cells also changes. These cells rely less on glycolysis for energy production, and instead shift to a mitochondrial phenotype with upregulated TCA cycle activity and oxidative phosphorylation. An increased dependence on glutamine utilization is exhibited to support TCA cycle substrates in this metabolic rewiring of BRAF mutated melanoma. Herein we describe the relevant core metabolic pathways modulated by BRAF inhibition. These adaptive pathways represent vulnerabilities that could be targeted to overcome resistance to BRAF inhibitors. This review evaluates current and future therapeutic strategies that target metabolic reprogramming in melanoma cells, particularly in response to BRAF inhibition.

Driving macro-scale transformations in three-dimensional-printed biopolymers through controlled induction of molecular anisotropy at the nanoscale.

Motivated by the need to harness the properties of renewable and biodegradable polymers for the design and manufacturing of multi-scale structures with complex geometries, we have employed our additive manufacturing platform that leverages molecular self-assembly for the production of metre-scale structures characterized by complex geometries and heterogeneous material composition. As a precursor material, we used chitosan, a chemically modified form of chitin, an abundant and sustainable structural polysaccharide. We demonstrate the ability to control concentration-dependent crystallization as well as the induction of the preferred orientation of the polymer chains through the combination of extrusion-based robotic fabrication and directional toolpathing. Anisotropy is demonstrated and assessed through high-resolution micro-X-ray diffraction in conjunction with finite element simulations. Using this approach, we can leverage controlled and user-defined small-scale propagation of residual stresses to induce large-scale folding of the resulting structures.

HumanIslets: An integrated platform for human islet data access and analysis.

Comprehensive molecular and cellular phenotyping of human islets can enable deep mechanistic insights for diabetes research. We established the Human Islet Data Analysis and Sharing (HI-DAS) consortium to advance goals in accessibility, usability, and integration of data from human islets isolated from donors with and without diabetes at the Alberta Diabetes Institute (ADI) IsletCore. Here we introduce HumanIslets.com, an open resource for the research community. This platform, which presently includes data on 547 human islet donors, allows users to access linked datasets describing molecular profiles, islet function and donor phenotypes, and to perform various statistical and functional analyses at the donor, islet and single-cell levels. As an example of the analytic capacity of this resource we show a dissociation between cell culture effects on transcript and protein expression, and an approach to correct for exocrine contamination found in hand-picked islets. Finally, we provide an example workflow and visualization that highlights links between type 2 diabetes status, SERCA3b Ca2+-ATPase levels at the transcript and protein level, insulin secretion and islet cell phenotypes. HumanIslets.com provides a growing and adaptable set of resources and tools to support the metabolism and diabetes research community.

Initial Perspectives From Rural-Residing Adults on a Digital Cognitive Health Coaching Intervention: Exploratory Qualitative Analysis.

BACKGROUND: A growing body of research has examined lifestyle-based interventions for dementia prevention. Specifically, health coaching interventions have been linked to decreased risk of Alzheimer disease (AD) comorbidities, such as diabetes. Despite the association, there is a lack of research examining the efficacy and perception of digital health coaching on reducing AD risk. Understanding the perceived benefits of participating in a digital health coach program is critical to ensure long-term use, including participant adherence and engagement. OBJECTIVE: The purpose of this study is to examine the initial attitudes toward a digital health coaching intervention aimed at preventing cognitive decline among at-risk, rural participants. METHODS: This exploratory qualitative study is part of the ongoing Digital Cognitive Multidomain Alzheimer Risk Velocity Study (DC-MARVel; ClinicalTrials.gov NCT04559789), a 2-year randomized control trial examining the effects of a digital health coaching intervention on dementia risk, cognitive decline, and general health outcomes. Participants were recruited from the northwest region of Arkansas via word of mouth, email, local radio, and social media. At the time of the analysis, 103 participants randomly assigned to the health coaching group completed an average of 4 coaching sessions over a 4-month period. The intervention included asynchronous messages 1-2 times per week from their health coach that contained health education articles based on the participant's goals (eg, increase physical activity), unlimited access to their coach for questions and recommendations, and monthly meetings with their coach via videoconference or phone to discuss their goals. Participants were asked 2 open-ended questions, "What were your top 1 or 2 takeaways from your recent Health Coaching session?" and "Is there anything you would change about our Health Coaching sessions?" A thematic analysis was conducted using feedback responses from 80 participants (mean age, SD 7.6 years). RESULTS: The following four themes emerged from participants' feedback: (1) healthy lifestyle and behavioral changes, (2) a sense of self-awareness through introspection, (3) value in coach support, and (4) a desire for a change in program format (eg, frequency). In total, 93% (n=74) of participants expressed that the intervention needed no changes. CONCLUSIONS: Initial participation in the digital cognitive health coaching intervention was well received, as evidenced by participants reporting value in goal setting and strategies for healthy lifestyle and behavioral changes as well as self-reflection on their personal lifestyle choices. Feedback about their assigned coach also offers insight into the importance of the coach-participant relationship and may serve as a significant factor in overall participant success. Given the exploratory nature of this study, more robust research is needed to elicit more information from participants about their experiences to fully understand the acceptability of the digital health coaching intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT04559789; https://clinicaltrials.gov/show/NCT04559789. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/31841.

Perceptions of incarcerated people: prison conditions, public health, and justice in the United States.

Carceral conditions in the United States may serve as a proxy for crises within justice and health systems. This study seeks to consider and measure prison climate from the perspective of incarcerated people. By examining within-facility differences in carceral experiences, results shed light on the complex nexus between the carceral context, health, and justice. We administered the Prison Climate Questionnaire (PCQ) to the complete population of incarcerated men in a correctional facility located in the Eastern United States. In this facility, housing units hold distinct populations, fulfill different functions, and can offer unique programming. We regress select items from the PCQ on a set of dummies corresponding to different residential units within the facility. Responses indicate low but relatively uniform perceptions of overall personal health, as well as access to, and satisfaction with, medical care. Between-unit differences emerge regarding staff relationships, experiences of discrimination, and levels of isolation. The perspectives of incarcerated people can, and should, play a role in understanding and conceptualizing the nature of the prison environment. Policy responses, especially those that impact the health and well-being of currently and formerly incarcerated people, can be informed by these perspectives.

A comparative immunological assessment of multiple clinical-stage adjuvants for the R21 malaria vaccine in nonhuman primates.

Authorization of the Matrix-M (MM)-adjuvanted R21 vaccine by three countries and its subsequent endorsement by the World Health Organization for malaria prevention in children are a milestone in the fight against malaria. Yet, our understanding of the innate and adaptive immune responses elicited by this vaccine remains limited. Here, we compared three clinically relevant adjuvants [3M-052 + aluminum hydroxide (Alum) (3M), a TLR7/8 agonist formulated in Alum; GLA-LSQ, a TLR4 agonist formulated in liposomes with QS-21; and MM, the now-approved adjuvant for R21] for their capacity to induce durable immune responses to R21 in macaques. R21 adjuvanted with 3M on a 0, 8, and 23-week schedule elicited anti-circumsporozoite antibody responses comparable in magnitude to the R21/MM vaccine administered using a 0-4-8-week regimen and persisted up to 72 weeks with a half-life of 337 days. A booster dose at 72 weeks induced a recall response similar to the R21/MM vaccination. In contrast, R21/GLA-LSQ immunization induced a lower, short-lived response at the dose used. Consistent with the durable serum antibody responses, MM and 3M induced long-lived plasma cells in the bone marrow and other tissues, including the spleen. Furthermore, whereas 3M stimulated potent and persistent antiviral transcriptional and cytokine signatures after primary and booster immunizations, MM induced enhanced expression of interferon- and TH2-related signatures more highly after the booster vaccination. Collectively, these findings provide a resource on the immune responses of three clinically relevant adjuvants with R21 and highlight the promise of 3M as another adjuvant for malarial vaccines.

Pipkin IV fracture dislocation of the hip in a football athlete - A case report.

Pipkin type IV fracture dislocation of the hip is a rare, high-energy injury, that is associated with poor functional outcomes and complications. We report a case of a 20-year old male quarterback who sustained a Pipkin type IV fracture dislocation during a football game. He underwent immediate closed reduction, transfer to a Level I trauma centre, surgical management, and progressive rehabilitation. Clinical and radiographic assessments were carried out periodically for 1 year. At 10 months post-injury, the athlete returned to full-time play as the starting quarterback of his University football team. He completed a pain-free season at 1-year post-injury. Clinical and radiographic evaluations demonstrated appropriate healing with no complications. Despite the high-energy and often devastating nature of Pipkin Type IV injuries, this case report demonstrates that prompt, appropriate management and rehabilitation of this injury in a University quarterback led to positive functional outcomes. Further studies on the treatment and outcomes of this rare sport injury are needed to optimize management.

Offering nurse care management for opioid use disorder in primary care: Impact on emergency and hospital utilization in a cluster-randomized implementation trial.

BACKGROUND: Patients with opioid use disorder (OUD) have increased emergency and hospital utilization. The PROUD trial showed that implementation of office-based addiction treatment (OBAT) increased OUD medication treatment compared to usual care, but did not decrease acute care utilization in patients with OUD documented pre-randomization (clinicaltrials.gov/study/NCT03407638). This paper reports secondary emergency and hospital utilization outcomes in patients with documented OUD in the PROUD trial. METHODS: This cluster-randomized implementation trial was conducted in 12 clinics from 6 diverse health systems (March 2015-February 2020). Patients who visited trial clinics and had an OUD diagnosis within 3 years pre-randomization were included in primary analyses; secondary analyses added patients with OUD who were new to the clinic or with newly-documented OUD post-randomization. Outcomes included days of emergency care and hospital utilization over 2 years post-randomization. Explanatory outcomes included measures of OUD treatment. Patient-level analyses used mixed-effect regression with clinic-specific random intercepts. RESULTS: Among 1988 patients with documented OUD seen pre-randomization (mean age 49, 53 % female), days of emergency care or hospitalization did not differ between intervention and usual care; OUD treatment also did not differ. In secondary analyses among 1347 patients with OUD post-randomization, there remained no difference in emergency or hospital utilization despite intervention patients receiving 32.2 (95 % CI 4.7, 59.7) more days of OUD treatment relative to usual care. CONCLUSIONS: Implementation of OBAT did not reduce emergency or hospital utilization among patients with OUD, even in the sample with OUD first documented post-randomization in whom the intervention increased treatment.

Hospital Quality Indicators for Opioid-Exposed Infants: Results From an Expert Consensus Panel.

OBJECTIVE: To elicit expert consensus on quality indicators for the hospital-based care of opioid-exposed infants. METHODS: We used the ExpertLens online platform to conduct a 3-round modified Delphi panel. Expert panelists included health care providers, parents in recovery, quality experts, and public health experts. We identified 49 candidate quality indicators from a literature review and environmental scan. A total of 32 experts rated the importance and feasibility of the indicators using a 9-point Likert scale (Round 1), reviewed and discussed the initial ratings (round 2), and revised their original ratings (Round 3). Numeric scores corresponded with descriptive ratings of "low" (1-3), "uncertain" (4-6), or "high" (7-9). We measured consensus using the RAND/UCLA Appropriateness Method. RESULTS: Candidate quality indicators assessed structures, processes, and outcomes in multiple domains of clinical care. After the final round, 36 indicators were rated "high" on importance and feasibility. Experts had strong consensus on the importance of quality indicators to assess universal screening of pregnant people for substance use disorder, hospital staff training, standardized assessment for neonatal opioid withdrawal syndrome, nonpharmacologic interventions, and transitions of care. For indicators focused on processes and outcomes, experts saw feasibility as dependent on the information routinely documented in electronic medical records or billing records. To present a more complete picture of hospital quality, experts suggested development of composite measures that summarize quality across multiple indicators. CONCLUSIONS: A panel of experts reached consensus on a range of quality indicators for hospital-based care of opioid-exposed infants, with potential for use in national benchmarking, intervention studies, or hospital performance measurement.

Diastereoselective Synthesis of the HIV Protease Inhibitor Darunavir and Related Derivatives via a Titanium Tetrachloride-Mediated Asymmetric Glycolate Aldol Addition Reaction.

Darunavir is a potent HIV protease inhibitor that has been established as an effective tool in the fight against the progression of HIV/AIDS in the global community. The successful application of this drug has spurred the development of derivatives wherein strategic regions (e.g., P1, P1', P2, and P2') of the darunavir framework have been structurally modified. An alternate route for the synthesis of darunavir and three related P1 and P1' derivatives has been developed. This synthetic pathway involves the use of a Crimmins titanium tetrachloride-mediated oxazolidine-2-thione-guided asymmetric glycolate aldol addition reaction. The resultant aldol adduct introduces the P1 fragment of darunavir via an aldehyde. Transamidation with a selected amine (isobutylamine or 2-ethyl-1-butylamine) to cleave the auxiliary yields an amide wherein the P1' component is introduced. From this stage, the amide is reduced to the corresponding ß-amino alcohol and the substrate is then bis-nosylated to introduce the requisite p-nitrobenzenesulfonamide component and activate the secondary alcohol for nucleophilic substitution. Treatment with sodium azide yielded the desired azides, and the deprotection of the p-methoxyphenoxy group is achieved with the use of ceric ammonium nitrate. Finally, hydrogenation to reduce both the aniline and azide functionalities with concurrent acylation yields darunavir and its derivatives.