Optimal-Transport Analysis of Single-Cell Gene Expression Identifies Developmental Trajectories in Reprogramming.

Understanding the molecular programs that guide differentiation during development is a major challenge. Here, we introduce Waddington-OT, an approach for studying developmental time courses to infer ancestor-descendant fates and model the regulatory programs that underlie them. We apply the method to reconstruct the landscape of reprogramming from 315,000 single-cell RNA sequencing (scRNA-seq) profiles, collected at half-day intervals across 18 days. The results reveal a wider range of developmental programs than previously characterized. Cells gradually adopt either a terminal stromal state or a mesenchymal-to-epithelial transition state. The latter gives rise to populations related to pluripotent, extra-embryonic, and neural cells, with each harboring multiple finer subpopulations. The analysis predicts transcription factors and paracrine signals that affect fates and experiments validate that the TF Obox6 and the cytokine GDF9 enhance reprogramming efficiency. Our approach sheds light on the process and outcome of reprogramming and provides a framework applicable to diverse temporal processes in biology.

Perturb-Seq: Dissecting Molecular Circuits with Scalable Single-Cell RNA Profiling of Pooled Genetic Screens.

Genetic screens help infer gene function in mammalian cells, but it has remained difficult to assay complex phenotypes-such as transcriptional profiles-at scale. Here, we develop Perturb-seq, combining single-cell RNA sequencing (RNA-seq) and clustered regularly interspaced short palindromic repeats (CRISPR)-based perturbations to perform many such assays in a pool. We demonstrate Perturb-seq by analyzing 200,000 cells in immune cells and cell lines, focusing on transcription factors regulating the response of dendritic cells to lipopolysaccharide (LPS). Perturb-seq accurately identifies individual gene targets, gene signatures, and cell states affected by individual perturbations and their genetic interactions. We posit new functions for regulators of differentiation, the anti-viral response, and mitochondrial function during immune activation. By decomposing many high content measurements into the effects of perturbations, their interactions, and diverse cell metadata, Perturb-seq dramatically increases the scope of pooled genomic assays.

Evolution of gene expression across brain regions in behaviourally divergent deer mice.

The evolution of innate behaviours is ultimately due to genetic variation likely acting in the nervous system. Gene regulation may be particularly important because it can evolve in a modular brain-region specific fashion through the concerted action of cis- and trans-regulatory changes. Here, to investigate transcriptional variation and its regulatory basis across the brain, we perform RNA sequencing (RNA-Seq) on ten brain subregions in two sister species of deer mice (Peromyscus maniculatus and P. polionotus)-which differ in a range of innate behaviours, including their social system-and their F1 hybrids. We find that most of the variation in gene expression distinguishes subregions, followed by species. Interspecific differential expression (DE) is pervasive (52-59% of expressed genes), whereas the number of DE genes between sexes is modest overall (~3%). Interestingly, the identity of DE genes varies considerably across brain regions. Much of this modularity is due to cis-regulatory divergence, and while 43% of genes were consistently assigned to the same gene regulatory class across subregions (e.g. conserved, cis- or trans-regulatory divergence), a similar number were assigned to two or more different gene regulatory classes. Together, these results highlight the modularity of gene expression differences and divergence in the brain, which may be key to explain how the evolution of brain gene expression can contribute to the astonishing diversity of animal behaviours.

Associations of neutral pH, low-GDP peritoneal dialysis solutions with patient survival, transfer to haemodialysis and peritonitis.

BACKGROUND: Peritoneal dialysis (PD) solutions containing low levels of glucose degradation products (GDPs) are associated with attenuation of peritoneal membrane injury and vascular complications. However, clinical benefits associated with neutral-pH, low-GDP (N-pH/L-GDP) solutions remain unclear. METHODS: Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the associations between N-pH/L-GDP solutions and all-cause mortality, cause-specific mortality, transfer to haemodialysis (HD) for ≥30 days and PD peritonitis in adult incident PD patients in Australia and New Zealand between 1 January 2005 and 31 December 2020 using adjusted Cox regression analyses. RESULTS: Of 12 814 incident PD patients, 2282 (18%) were on N-pH/L-GDP solutions. The proportion of patients on N-pH/L-GDP solutions each year increased from 11% in 2005 to 33% in 2017. During the study period, 5330 (42%) patients died, 4977 (39%) experienced transfer to HD and 5502 (43%) experienced PD peritonitis. Compared with the use of conventional solutions only, the use of any form of N-pH/L-GDP solution was associated with reduced risks of all-cause mortality {adjusted hazard ratio [aHR] 0.67 [95% confidence interval (CI) 0.61-0.74]}, cardiovascular mortality [aHR 0.65 (95% CI 0.56-0.77)], infection-related mortality [aHR 0.62 (95% CI 0.47-0.83)] and transfer to HD [aHR 0.79 (95% CI 0.72-0.86)] but an increased risk of PD peritonitis [aHR 1.16 (95% CI 1.07-1.26)]. CONCLUSIONS: Patients who received N-pH/L-GDP solutions had decreased risks of all-cause and cause-specific mortality despite an increased risk of PD peritonitis. Studies assessing the causal relationships are warranted to determine the clinical benefits of N-pH/L-GDP solutions.

Hereditary chronic neutrophilic leukemia in a four-generation family without transformation to acute leukemia.

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) characterized by peripheral blood neutrophilia, marrow granulocyte hyperplasia, hepatosplenomegaly, and driver mutations in the colony-stimulating factor 3 receptor (CSF3R). Designation of activating CSF3R mutations as a defining genomic abnormality for CNL has led to increased recognition of the disease. However, the natural history of CNL remains poorly understood with most patients reported being of older age, lacking germline data, and having poor survival, in part due to transformation to acute leukemia. CSF3R driver mutations in most patients with CNL have been reported to be acquired, although rare cases of germline mutations have been described. Here, we report the largest pedigree to date with familial CNL, spanning four generations with affected family members ranging in age from 4 to 53 years, none of whom have transformed to acute leukemia. A heterozygous T618I CSF3R mutation was identified in peripheral blood and mesenchymal stromal cells from the proband and in all affected living family members, while the unaffected family members tested were homozygous wild type. We show that the T618I mutation also confers a survival advantage to neutrophils in an MCL1-dependent manner. Collectively, these data provide additional insights into the natural history of familial CNL arising from T618I CSF3R mutations and suggest that enhanced neutrophil survival also contributes to the high neutrophil count observed in patients with CNL.

Publisher Correction: The NORAD lncRNA assembles a topoisomerase complex critical for genome stability.

A typo in the 'Reviewer information' section of this Letter was corrected online.

The NORAD lncRNA assembles a topoisomerase complex critical for genome stability.

The human genome contains thousands of long non-coding RNAs1, but specific biological functions and biochemical mechanisms have been discovered for only about a dozen2-7. A specific long non-coding RNA-non-coding RNA activated by DNA damage (NORAD)-has recently been shown to be required for maintaining genomic stability8, but its molecular mechanism is unknown. Here we combine RNA antisense purification and quantitative mass spectrometry to identify proteins that directly interact with NORAD in living cells. We show that NORAD interacts with proteins involved in DNA replication and repair in steady-state cells and localizes to the nucleus upon stimulation with replication stress or DNA damage. In particular, NORAD interacts with RBMX, a component of the DNA-damage response, and contains the strongest RBMX-binding site in the transcriptome. We demonstrate that NORAD controls the ability of RBMX to assemble a ribonucleoprotein complex-which we term NORAD-activated ribonucleoprotein complex 1 (NARC1)-that contains the known suppressors of genomic instability topoisomerase I (TOP1), ALYREF and the PRPF19-CDC5L complex. Cells depleted for NORAD or RBMX display an increased frequency of chromosome segregation defects, reduced replication-fork velocity and altered cell-cycle progression-which represent phenotypes that are mechanistically linked to TOP1 and PRPF19-CDC5L function. Expression of NORAD in trans can rescue defects caused by NORAD depletion, but rescue is significantly impaired when the RBMX-binding site in NORAD is deleted. Our results demonstrate that the interaction between NORAD and RBMX is important for NORAD function, and that NORAD is required for the assembly of the previously unknown topoisomerase complex NARC1, which contributes to maintaining genomic stability. In addition, we uncover a previously unknown function for long non-coding RNAs in modulating the ability of an RNA-binding protein to assemble a higher-order ribonucleoprotein complex.

Diabetes, Hypertension, and Smoking Do Not Affect Outcomes of Iliofemoral Vein Stenting for Chronic Proximal Venous Outflow Obstruction.

BACKGROUND: Diabetes, hypertension, and smoking are well-recognized risk factors for peripheral artery disease (PAD), but little is known of their impact on chronic venous insufficiency (CVI). This study evaluates these factors in patients undergoing iliac vein stenting (IVS) for CVI. METHODS: A registry of 708 patients who underwent IVS from August 2011 to June 2021 was retrospectively analyzed. Symptoms were quantified using venous clinical severity score (VCSS) and CEAP classification. Both major and minor reinterventions were recorded. Logistic regression models were used to determine the unadjusted and adjusted odds ratio of any reintervention. Log-rank test was used to assess differences in reintervention-free survival. RESULTS: The prevalence of hypertension was 51.1% (N = 362), diabetes was 23.0% (N = 163), and smoking was 22.2% (N = 157). Patients with diabetes (3.6 vs. 3.4; P = 0.062), hypertension (3.6 vs. 3.3; P < 0.001), and smoking (3.7 vs. 3.4; P = 0.003) had higher CEAP scores than those without these comorbidities. Improvement in VCSS composite scores showed no differences postoperatively (diabetes: P = 0.513; hypertension: P = 0.053; smoking: P = 0.608), at 1-year follow-up (diabetes: P = 0.666; hypertension: P = 0.681; smoking: P = 0.745), or at 5-year follow-up (diabetes: P = 0.525; hypertension: P = 0.953; smoking: P = 0.146). Diabetes (P = 0.454), smoking (P = 0.355), and hypertension (P = 0.727) were not associated with increased odds of major reintervention. Log-rank test similarly showed no differences in reintervention-free survival for major or minor reoperations between those with and without diabetes (P = 0.79), hypertension (P = 0.14), and smoking (P = 0.80). CONCLUSIONS: Diabetes, hypertension, and smoking were prevalent among CVI patients, but unlike in PAD patients, they had little to no impact on long-term outcomes or reinterventions after IVS.

Stakeholder perspectives on electronic prescribing in primary care: A scoping review.

BACKGROUND: Electronic prescribing (e-prescribing) provides a convenient, efficient, paperless mechanism for the legal transfer of prescriptions between service users, prescribers, and dispensers. There have been advances in e-prescribing processes and increased uptake of e-prescribing globally, in recent years. OBJECTIVE: To explore stakeholder perspectives on e-prescribing in primary care settings. METHODS: A scoping review was conducted by systematically searching Medline, EMBASE, Scopus, and International Pharmaceutical Abstracts databases, using the key concepts "primary care", "e-prescribing", and "perspectives". Publications were selected by screening for eligibility against inclusion and exclusion criteria, whereby any publication written in English exploring e-prescribing in primary care settings from the perspective(s) of at least one type of stakeholder was eligible for inclusion. Following a systematic screening process, relevant data were extracted, collated, and synthesized. RESULTS: Two thousand publications were identified and systematically screened, rendering 44 publications (e.g., primary research articles, abstracts) eligible for inclusion in this review. Most publications reported on studies conducted in the USA, the UK, and Europe and explored the views of pharmacists, pharmacy technicians, and pharmacy staff. Barriers to e-prescribing included system design and technical issues, lack of adequate training and communication issues between stakeholders. Enablers for e-prescribing included time savings, convenience, and increased legibility of prescriptions. CONCLUSIONS: This review highlights many benefits of e-prescribing such as time efficiency, convenience, increased legibility, and less mishandling. Despite this, key barriers to e-prescribing within primary care settings were also recognized, including system design, technical issues, and lack of adequate training. As such, forcing functions, prescription tracking technologies, and better training have been identified as potential ways to address these barriers. While some negative experiences were reported, stakeholders were generally satisfied and had positive experiences with e-prescribing.

Real-world experience among patients with relapsed/refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor failure in Europe: The SCHOLAR-2 retrospective chart review study.

Mantle cell lymphoma (MCL) after relapse is associated with poor prognosis. No standard of care exists and available evidence for treatments is limited, particularly in patients who fail Bruton tyrosine kinase inhibitor (BTKi) therapy. This multicentre retrospective chart review study, SCHOLAR-2, addresses this knowledge gap and reports on data collected from 240 patients with relapsed/refractory MCL in Europe who were treated with BTKi-based therapy between July 2012 and July 2018, and had experienced disease progression while on BTKi therapy or discontinued BTKi therapy due to intolerance. The median overall survival (OS) from initiation of first BTKi therapy was 14.6 months (95% confidence interval [CI] 11.6-20.0) in the overall cohort, 5.5 months (95% CI 3.9-8.2) in 91 patients without post-BTKi therapy, and 23.8 months (95% CI 18.9-30.1) in 149 patients who received post-BTKi therapy (excluding chimeric antigen receptor T-cell treatment). In the latter group, patients received a median of one (range, one to seven) line of post-BTKi therapy, with lenalidomide-containing regimens and bendamustine plus rituximab being the most frequently administered; the median OS from initiation of first post-BTKi therapy was 9.7 months (95% CI 6.3-12.7). These results provide a benchmark for survival in patients with R/R MCL receiving salvage therapy after BTKi failure.

Sex Disparity in Cause-Specific and All-Cause Mortality Among Incident Dialysis Patients.

RATIONALE & OBJECTIVE: Early mortality rates of female patients receiving dialysis have been, at times, observed to be higher than rates among male patients. The differences in cause-specific mortality between male and female incident dialysis patients with kidney failure are not well understood and were the focus of this study. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Incident patients who had initiated dialysis in Australia and New Zealand in 1998-2018. EXPOSURE: Sex. OUTCOMES: Cause-specific and all-cause mortality while receiving dialysis, censored for kidney transplant. ANALYTICAL APPROACH: Adjusted cause-specific proportional hazards models, focusing on the first 5 years following initiation of dialysis. RESULTS: Among 53,414 patients (20,876 [39%] female) followed for a median period of 2.8 (IQR, 1.3-5.2) years, 27,137 (51%) died, with the predominant cause of death attributed to cardiovascular disease (18%), followed by dialysis withdrawal (16%). Compared with male patients, female patients were more likely to die in the first 5 years after dialysis initiation (adjusted hazard ratio [AHR], 1.08 [95% CI, 1.05-1.11]). Even though female patients experienced a lower risk of cardiovascular disease-related mortality (AHR, 0.93 [95% CI, 0.89-0.98]) than male patients, they experienced a greater risk of infection-related (AHR, 1.20 [95% CI, 1.10-1.32]) and dialysis withdrawal-related (AHR, 1.19 [95% CI, 1.13-1.26]) mortality. LIMITATIONS: Possibility of residual and unmeasured confounders. CONCLUSIONS: Compared with male patients, female patients had a higher risk of all-cause mortality in the first 5 years after dialysis initiation, a difference driven by higher rates of mortality from infections and dialysis withdrawals. These findings may inform the study of sex differences in mortality in other geographic settings.

Surgery Improves Patient-Reported Outcomes in Patients with Intestinal and Pancreatic NETs: A Prospective Analysis.

BACKGROUND: Incorporation of patient-reported outcomes such as health-related quality of life has become increasingly important in the management of chronic diseases such as cancer. In this prospective study, we examined the effect of surgical resection on quality of life in patients with intestinal and pancreatic neuroendocrine tumors (NETs). METHODS: Thirty-two patients underwent NET resection at our institution from January 2020 to January 2022. All patients completed the 12-item short-form quality-of-life survey prior to surgery, as well as at the 3-, 6-, and 12-month postoperative time points. The presence and severity of specific carcinoid syndrome symptoms (diarrhea, flushing, and abdominal pain) were also recorded during pre- and postoperative appointments. RESULTS: Patients experienced significant increases in both mental and physical health after surgery. Mental health scores significantly increased at all three time points (baseline: 51.33; 3-month: 53.17, p = 0.02; 6-month: 57.20, p < 0.001; 12-month: 57.34, p = 0.002), and physical health scores increased at 6 and 12 months (baseline: 50.39; 6-month: 53.16, p = 0.04; 12-month: 55.02, p = 0.003). Younger patients benefited more in terms of physical health, while older patients had more significant increases in mental health. Patients with metastatic disease, larger primary tumors, and those receiving medical therapy had lower baseline quality-of-life scores and greater improvements after surgery. The vast majority of patients in this study also experienced alleviation of carcinoid syndrome symptoms. CONCLUSIONS: In addition to prolonging survival, resection of intestinal and pancreatic NETs leads to significantly improved patient-reported quality of life.

A Comparison of Alternative Network Meta-Analysis Methods in the Presence of Nonproportional Hazards: A Case Study in First-Line Advanced or Metastatic Renal Cell Carcinoma.

OBJECTIVES: Network meta-analysis (NMA) of time-to-event outcomes based on constant hazard ratios can result in biased findings when the proportional hazards (PHs) assumption does not hold in a subset of trials. We aimed to summarize the published non-PH NMA methods for time-to-event outcomes, demonstrate their application, and compare their results. METHODS: The following non-PH NMA methods were compared through an illustrative case study in oncology of 4 randomized controlled trials in terms of progression-free survival and overall survival: (1) 1-step or (2) 2-step multivariate NMAs based on traditional survival distributions or fractional polynomials, (3) NMAs with restricted cubic splines for baseline hazard, and (4) restricted mean survival NMA. RESULTS: For progression-free survival, the PH assumption did not hold across trials and non-PH NMA methods better reflected the relative treatment effects over time. The most flexible models (fractional polynomials and restricted cubic splines) fit better to the data than the other approaches. Estimated hazard ratios obtained with different non-PH NMA methods were similar at 5 years of follow-up but differed thereafter in the extrapolations. Although there was no strong evidence of PH violation for overall survival, non-PH NMA methods captured this uncertainty in the relative treatment effects over time. CONCLUSIONS: When the PH assumption is questionable in a subset of the randomized controlled trials, we recommend assessing alternative non-PH NMA methods to estimate relative treatment effects for time-to-event outcomes. We propose a transparent and explicit stepwise model selection process considering model fit, external constraints, and clinical validity. Given inherent uncertainty, sensitivity analyses are suggested.

A Pilot Randomized Trial of a Purposeful and Stimulating Volunteer Opportunity: Program Satisfaction and Potential Impacts on Perceived Cognitive Change in a Neurologically Mixed Sample of Older Adults.

BACKGROUND: Purposeful social interactions are important for healthy aging. We conducted a pilot trial of SPEAK! (Seniors Promoting English Acquisition and Knowledge), an intervention providing older volunteers with a safe, accessible opportunity to converse via webcam with English-language learners. METHODS: A neurologically mixed sample of older adults was randomized to 8 weekly, webcam conversations with English-language learners or a waitlist control. Outcomes included the Cognitive Change Index (CCI) and surveys of program satisfaction. Here, we report on session completion, intervention satisfaction, and follow-up CCI scores. Exploratory analyses of CCI intervention effects controlled for baseline CCI scores and the interaction between group and baseline CCI. RESULTS: Participants (N=38) were on average 70.8 years of age, 28/38 were White, and 16/38 demonstrated possible cognitive impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Pairs completed 115/136 sessions (85%) and all volunteers said they would recommend the program. Controlling for the interaction between baseline CCI and randomization group, SPEAK! volunteers had better follow-up CCI scores than controls (P=0.018). Improvements in CCI were greater among participants with fewer baseline memory problems. CONCLUSIONS: SPEAK! was feasible and appreciated by older adults with and without cognitive impairment. Larger studies should confirm benefits for memory and other determinants of quality of life.

Providing a Purposeful and Stimulating Volunteer Opportunity for Older Adults With Mild Cognitive Impairment: A Pilot Study.

Social interactions have cognitive and emotional benefits for older adults with mild cognitive impairment (MCI). The prevalence of loneliness and isolation in this population has been repeatedly noted, but interventions remain limited. We designed a program to connect older adults with MCI with an engaging volunteering opportunity, through videoconferencing conversations with another adult practicing English (English language learner). Ten MCI-English language learner pairs had conversation sessions over 6 weeks. We tracked session engagement, monitored conversations, and interviewed participants at follow-up. Pairs completed 78% of scheduled sessions; only 7% were missed because the MCI participant canceled or failed to appear. Qualitative interviews suggested that participants felt comfortable and engaged. No negative experiences were observed or reported. This program is feasible and potentially desirable for older adults with MCI. This model is interesting given the concern about in-person volunteering risks, and the millions of people motivated to improve English fluency.

Screening Mammography Utilization Among Women With Visual or Hearing Impairment: Results From the 2019 NHIS.

To evaluate for differences in breast cancer screening among women with visual or hearing impairment, the 2019 National Health Interview Survey was analyzed for mammography use in the past 2 years among women age 50-74, adjusting for demographic characteristics, health care access, and comorbidities. Visual impairment was independently associated with decreased likelihood of recent mammography (odds ratio [OR], 0.71; 95% CI, 0.59-0.85; p < .001). Hearing impairment was not independently associated with mammography use (OR, 0.91; 95% CI, 0.75-1.11; p = .37).

Women are Not at Higher Risk for Reintervention or Major Amputation after Lower Extremity Atherectomy for Peripheral Artery Disease.

BACKGROUND: Our objective was to compare short-term and long-term differences in reintervention-free and major amputation-free survival between female and male patients undergoing lower extremity atherectomy for peripheral artery disease. METHODS: We analyzed lower extremity atherectomy procedures performed on 294 patients between January 2014 and September 2019. Reintervention was defined as either open bypass or endovascular procedure to the same region following the index operation. Kaplan-Meier (KM) survival analysis was performed to compare reintervention-free and major amputation-free survival between sexes. Multivariate logistic regression analyses were performed to determine the adjusted odds of reintervention and major amputation based on sex. We conducted subgroup analyses by anatomic region (femoropopliteal vs. tibial), indication (claudication vs. chronic limb-threatening ischemia (CLTI)), and balloon type (drug-coated balloon (DCB) versus plain balloon angioplasty (POBA)) across sexes. RESULTS: Of the 294 patients, 125 (42.5%) were female. Compared to men, women receiving atherectomy were more likely to be Black (28.0% vs. 16.6%; P = 0.018), a nonsmoker (44.8% vs. 21.3%; P < 0.001), and present with CLTI (55.2% vs. 43.2%; P = 0.042). There were no differences in atherectomy region, lesion type, or balloon type between sexes. KM analysis showed similar 4-year reintervention-free survival (68.8% vs. 75.1%; P = 0.88) and major amputation-free survival (97.6% vs. 97.6%; P = 0.41) between sexes. Women and men had similar reintervention-free survival when grouped by femoropopliteal (67.9% vs. 70.8%; P = 0.69) or tibial (76.2% vs. 83.9%; P = 0.68) atherectomy region. Indication (claudication versus CLTI) did not affect reintervention-free survival in either women (64.5% vs. 69.6%; P = 0.28) or men (68.5% vs. 76.7%; P = 0.84). KM curves for DCB versus POBA were also similar between sexes and showed an early benefit in reintervention rate favoring DCB, which dissipated in both women (65.4% vs. 72.7%; P = 0.61) and men (75.5% vs. 78.4%; P = 0.18) by 3 years. CONCLUSIONS: Compared to men, women demonstrate commensurate benefit from atherectomy for lower extremity revascularization. There were no differences seen in long-term reintervention or major amputation between sexes.

Identifying venous clinical severity score thresholds for Clinical-Etiology-Anatomy-Pathophysiology classifications of venous edema and higher.

OBJECTIVE: Venous Clinical Severity Score (VCSS) is a widely used standard for assessing and grading the severity of chronic venous disease (CVD). Prior research highlighted its high validity in detecting and quantifying venous disease. However, there is little, if any, known about the precise thresholds at which VCSS discriminates important stages of deep venous disease. This study sought to elucidate the diagnostic accuracy, thresholds, and correlation at which VCSS detects salient CEAP (Clinical-Etiology-Anatomy-Pathophysiology) classes in deep venous disease progression. METHODS: A registry of 840 patients who presented with chronic proximal venous outflow obstruction (PVOO) secondary to non-thrombotic iliac vein lesions from August 2011 to June 2021 was retrospectively analyzed. VCSS and CEAP classifications were used to evaluate preoperative symptoms. VCSS was compared to CEAP classes to determine the precise VCSS composite values at which the instrument was able to detect CEAP C3 and higher, C4 and higher, and C5 and higher. Receiver operative characteristic (ROC) curve and area under the curve (AUC) were used to evaluate VCSS for its ability to discriminate disease at these stages of CEAP classification. Spearman's rank coefficient was used to determine the correlation between CEAP VCSS composite as well as individual VCSS components (pain, varicose vein, edema, pigmentation, inflammation, induration, ulcer number, ulcer size, ulcer duration, compression). RESULTS: VCSS composite was able to detect venous edema (C3) and higher at a sensitivity of 68.9% and a specificity of 54.8% at an optimized threshold of 8.5 (AUC = 0.648; 95% C.I. = 0.575-0.721). To detect changes in skin and subcutaneous tissue from CVD (C4) and higher, an optimal threshold of 11.5 was found with a sensitivity of 51.7% and specificity of 76.5% (AUC = 0.694; 95% C.I. = 0.656-0.731). Healed venous ulcer (C4) and higher was detectable at an optimized threshold of 13.5 at a sensitivity of 67.7% and a specificity of 88.9% (AUC = 0.819; 95% C.I. = 0.766-0.873). The correlation between VCSS composites and CEAP was weak (ρ = 0.372; p < .001). Attributes of VCSS that reflect more severe venous disease correlated more closely with CEAP classes, namely pigmentation (ρ = 0.444; p < .001), inflammation (ρ = 0.348; p < .001), induration (ρ = 0.352; p < .001), number of active ulcers (ρ = 0.497; p < .001), active ulcer size (ρ = 0.485; p < .001), and ulcer duration (ρ = 0.497; p < .001). The correlation between CEAP class and the other four components of VCSS were not statistically significant. CONCLUSION: VCSS composite thresholds of 8.5, 11.5, and 13.5 are threshold values for detecting CEAP classification C3 and higher, C4 and higher, and C5 and higher, respectively. Consistent with prior work, VCSS appears to have a better ability to discriminate CVD at more severe CEAP classifications. In this registry, the correlation between VCSS and CEAP was found to be weak while components of VCSS that suggest more advanced disease exhibited the strongest correlation with CEAP.

An Automatically Adaptive Digital Health Intervention to Decrease Opioid-Related Risk While Conserving Counselor Time: Quantitative Analysis of Treatment Decisions Based on Artificial Intelligence and Patient-Reported Risk Measures.

BACKGROUND: Some patients prescribed opioid analgesic (OA) medications for pain experience serious side effects, including dependence, sedation, and overdose. As most patients are at low risk for OA-related harms, risk reduction interventions requiring multiple counseling sessions are impractical on a large scale. OBJECTIVE: This study evaluates whether an intervention based on reinforcement learning (RL), a field of artificial intelligence, learned through experience to personalize interactions with patients with pain discharged from the emergency department (ED) and decreased self-reported OA misuse behaviors while conserving counselors' time. METHODS: We used data representing 2439 weekly interactions between a digital health intervention ("Prescription Opioid Wellness and Engagement Research in the ED" [PowerED]) and 228 patients with pain discharged from 2 EDs who reported recent opioid misuse. During each patient's 12 weeks of intervention, PowerED used RL to select from 3 treatment options: a brief motivational message delivered via an interactive voice response (IVR) call, a longer motivational IVR call, or a live call from a counselor. The algorithm selected session types for each patient each week, with the goal of minimizing OA risk, defined in terms of a dynamic score reflecting patient reports during IVR monitoring calls. When a live counseling call was predicted to have a similar impact on future risk as an IVR message, the algorithm favored IVR to conserve counselor time. We used logit models to estimate changes in the relative frequency of each session type as PowerED gained experience. Poisson regression was used to examine the changes in self-reported OA risk scores over calendar time, controlling for the ordinal session number (1st to 12th). RESULTS: Participants on average were 40 (SD 12.7) years of age; 66.7% (152/228) were women and 51.3% (117/228) were unemployed. Most participants (175/228, 76.8%) reported chronic pain, and 46.2% (104/225) had moderate to severe depressive symptoms. As PowerED gained experience through interactions over a period of 142 weeks, it delivered fewer live counseling sessions than brief IVR sessions (P=.006) and extended IVR sessions (P<.001). Live counseling sessions were selected 33.5% of the time in the first 5 weeks of interactions (95% CI 27.4%-39.7%) but only for 16.4% of sessions (95% CI 12.7%-20%) after 125 weeks. Controlling for each patient's changes during the course of treatment, this adaptation of treatment-type allocation led to progressively greater improvements in self-reported OA risk scores (P<.001) over calendar time, as measured by the number of weeks since enrollment began. Improvement in risk behaviors over time was especially pronounced among patients with the highest risk at baseline (P=.02). CONCLUSIONS: The RL-supported program learned which treatment modalities worked best to improve self-reported OA risk behaviors while conserving counselors' time. RL-supported interventions represent a scalable solution for patients with pain receiving OA prescriptions. TRIAL REGISTRATION: Clinicaltrials.gov NCT02990377; https://classic.clinicaltrials.gov/ct2/show/NCT02990377.