Characterization and staging of outer plexiform layer development in human retina and retinal organoids.

The development of the first synapse of the visual system between photoreceptors and bipolar cells in the outer plexiform layer (OPL) of the human retina is crucial for visual processing but poorly understood. By studying the maturation state and spatial organization of photoreceptors, depolarizing bipolar cells and horizontal cells in the human fetal retina, we establish a pseudo-temporal staging system for OPL development that we term OPL-Stages 0 to 4. This was validated through quantification of increasingly precise subcellular localization of bassoon to the OPL with each stage (P<0.0001). By applying these OPL staging criteria to human retinal organoids (HROs) derived from human embryonic and induced pluripotent stem cells, we observed comparable maturation from OPL-Stage 0 at day 100 in culture up to OPL-Stage 3 by day 160. Quantification of presynaptic protein localization confirmed progression from OPL-Stage 0 to 3 (P<0.0001). Overall, this study defines stages of human OPL development through mid-gestation and establishes HROs as a model system that recapitulates key aspects of human photoreceptor-bipolar cell synaptogenesis in vitro.

Non-canonical Wnt pathway expression in the developing mouse and human retina.

The non-canonical Wnt pathway is an evolutionarily conserved pathway essential for tissue patterning and development across species and tissues. In mammals, this pathway plays a role in neuronal migration, dendritogenesis, axon growth, and synapse formation. However, its role in development and synaptogenesis of the human retina remains less established. In order to address this knowledge gap, we analyzed publicly available single-cell RNA sequencing (scRNAseq) datasets for mouse retina, human retina, and human retinal organoids over multiple developmental time points during outer retinal maturation. We identified ligands, receptors, and mediator genes with a putative role in retinal development, including those with novel or species-specific expression, and validated this expression using fluorescence in situ hybridization (FISH). By quantifying outer nuclear layer (ONL) versus inner nuclear layer (INL) expression, we provide evidence for the differential expression of certain non-canonical Wnt signaling components in the developing mouse and human retina during outer plexiform layer (OPL) development. Importantly, we identified distinct expression patterns of mouse and human FZD3 and WNT10A, as well as previously undescribed expression, such as for mouse Wnt2b in Chat+ starburst amacrine cells. Human retinal organoids largely recapitulated the human non-canonical Wnt pathway expression. Together, this work provides the basis for further study of non-canonical Wnt signaling in mouse and human retinal development and synaptogenesis.

Full-field Scotopic Threshold Improvement after Voretigene Neparvovec-rzyl Treatment Correlates with Chorioretinal Atrophy.

PURPOSE: To analyze demographic and ophthalmic data in patients with and without chorioretinal atrophy after voretigene neparvovec-rzyl (VN) to identify possible causes for this phenomenon. DESIGN: Retrospective cohort study with longitudinal follow-up. PARTICIPANTS: A total of 71 eyes of 38 patients aged 2 to 44 years with RPE65-mediated retinal dystrophy treated with VN across 2 large gene therapy centers in the United States and Germany. METHODS: Patients treated with VN who developed atrophy were compared with those who did not. MAIN OUTCOME MEASURES: Gender, age, surgical center, spherical equivalent refraction, best-corrected visual acuity (BCVA), baseline full-field scotopic threshold testing (FST), and posttreatment change in FST. RESULTS: A total of 20 eyes of 12 patients developed atrophy after treatment with VN (28% of all eyes). There was no significant difference in gender, age, surgical center, or spherical equivalent refraction between the atrophy group and the no atrophy group. However, patients between school age and young adulthood were predominantly affected, whereas the youngest and the oldest patients did not develop atrophy. Baseline BCVA was better in patients who developed atrophy than those who did not (P = 0.006). The postoperative improvement in FST at 1 month was significantly higher in the atrophy group than in the no atrophy group (P = 0.0005), and this difference remained statistically significant at 1 year (P = 0.0001). There was no correlation to baseline FST, to inflammation, or to which eye was treated first. CONCLUSIONS: The degree of FST improvement after VN appears to be strongly correlated with the development of VN-related chorioretinal atrophy. This finding raises the possibility that atrophy may develop as a toxic or metabolic sequela of vector-mediated RPE65 expression. In light of the expanding number of retinal gene therapy clinical trials, this complication warrants further study because it may not be limited to VN. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Perspectives of patients, family members, health professionals and the public on the impact of COVID-19 on mental health.

BACKGROUND: The coronavirus (COVID-19) pandemic has seen a global surge in anxiety, depression, post-traumatic stress disorder (PTSD), and stress. AIMS: This study aimed to describe the perspectives of patients with COVID-19, their family, health professionals, and the general public on the impact of COVID-19 on mental health. METHODS: A secondary thematic analysis was conducted using data from the COVID-19 COS project. We extracted data on the perceived causes and impact of COVID-19 on mental health from an international survey and seven online consensus workshops. RESULTS: We identified four themes (with subthemes in parenthesis): anxiety amidst uncertainty (always on high alert, ebb and flow of recovery); anguish of a threatened future (intense frustration of a changed normality, facing loss of livelihood, trauma of ventilation, a troubling prognosis, confronting death); bearing responsibility for transmission (fear of spreading COVID-19 in public; overwhelming guilt of infecting a loved one); and suffering in isolation (severe solitude of quarantine, sick and alone, separation exacerbating grief). CONCLUSION: We found that the unpredictability of COVID-19, the fear of long-term health consequences, burden of guilt, and suffering in isolation profoundly impacted mental health. Clinical and public health interventions are needed to manage the psychological consequences arising from this pandemic.

Core Outcome Measures for Trials in People With Coronavirus Disease 2019: Respiratory Failure, Multiorgan Failure, Shortness of Breath, and Recovery.

OBJECTIVES: Respiratory failure, multiple organ failure, shortness of breath, recovery, and mortality have been identified as critically important core outcomes by more than 9300 patients, health professionals, and the public from 111 countries in the global coronavirus disease 2019 core outcome set initiative. The aim of this project was to establish the core outcome measures for these domains for trials in coronavirus disease 2019. DESIGN: Three online consensus workshops were convened to establish outcome measures for the four core domains of respiratory failure, multiple organ failure, shortness of breath, and recovery. SETTING: International. PATIENTS: About 130 participants (patients, public, and health professionals) from 17 countries attended the three workshops. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Respiratory failure, assessed by the need for respiratory support based on the World Health Organization Clinical Progression Scale, was considered pragmatic, objective, and with broad applicability to various clinical scenarios. The Sequential Organ Failure Assessment was recommended for multiple organ failure, because it was routinely used in trials and clinical care, well validated, and feasible. The Modified Medical Research Council measure for shortness of breath, with minor adaptations (recall period of 24 hr to capture daily fluctuations and inclusion of activities to ensure relevance and to capture the extreme severity of shortness of breath in people with coronavirus disease 2019), was regarded as fit for purpose for this indication. The recovery measure was developed de novo and defined as the absence of symptoms, resumption of usual daily activities, and return to the previous state of health prior to the illness, using a 5-point Likert scale, and was endorsed. CONCLUSIONS: The coronavirus disease 2019 core outcome set recommended core outcome measures have content validity and are considered the most feasible and acceptable among existing measures. Implementation of the core outcome measures in trials in coronavirus disease 2019 will ensure consistency and relevance of the evidence to inform decision-making and care of patients with coronavirus disease 2019.

Psychosocial outcomes in young adolescents with type 1 diabetes participating in shared medical appointments.

For youth with type 1 diabetes (T1D), the early adolescent period is associated with worsening diabetes management and high rates of negative psychosocial issues, including depressive symptoms and family conflict. Alternative clinical models may help improve both diabetes and psychosocial outcomes. Our study aims to investigate whether Team Clinic, a shared medical appointment model developed specifically for adolescents with T1D, will improve psychosocial outcomes for middle school-aged youth. Youth with T1D, 11-13 years of age, and their caregivers, participated in a randomized controlled trial comparing Team Clinic to traditional clinic visits (control group). Diabetes characteristics were obtained at every visit. Participants and caregivers completed depression screening and family conflict questionnaires at baseline and end of study. Changes in mean scores on clinical and psychosocial outcomes from baseline to end of study were compared between groups using linear mixed-effects models. Eighty-six youth (51% female; 74% White; 10% Hispanic) completed at least one visit during the 12-month study period. At the end of the study, control group participants reported increases in Emotional Problems compared to Team Clinic participants, including higher levels of Negative Mood/Physical Symptoms (p = 0.02). Team Clinic participants reported reduced family conflict surrounding diabetes at study end, compared to control group participants (p = 0.03). Caregivers did not report change in depressive symptoms or family conflict during the study. Hemoglobin A1C levels did not change over time in either group. Participation in Team Clinic was associated with improved psychosocial outcomes in middle school-aged participants with T1D.

Developmental stage-specific proliferation and retinoblastoma genesis in RB-deficient human but not mouse cone precursors.

Most retinoblastomas initiate in response to the inactivation of the RB1 gene and loss of functional RB protein. The tumors may form with few additional genomic changes and develop after a premalignant retinoma phase. Despite this seemingly straightforward etiology, mouse models have not recapitulated the genetic, cellular, and stage-specific features of human retinoblastoma genesis. For example, whereas human retinoblastomas appear to derive from cone photoreceptor precursors, current mouse models develop tumors that derive from other retinal cell types. To investigate the basis of the human cone-specific oncogenesis, we compared developmental stage-specific cone precursor responses to RB loss in human and murine retina cultures and in cone-specific Rb1-knockout mice. We report that RB-depleted maturing (ARR3+) but not immature (ARR3-) human cone precursors enter the cell cycle, proliferate, and form retinoblastoma-like lesions with Flexner-Wintersteiner rosettes, then form low or nonproliferative premalignant retinoma-like lesions with fleurettes and p16INK4A and p130 expression, and finally form highly proliferative retinoblastoma-like masses. In contrast, in murine retina, only RB-depleted immature (Arr3-) cone precursors entered the cell cycle, and they failed to progress from S to M phase. Moreover, whereas intrinsically highly expressed MDM2 and MYCN contribute to RB-depleted maturing (ARR3+) human cone precursor proliferation, ectopic MDM2 and Mycn promoted only immature (Arr3-) murine cone precursor cell-cycle entry. These findings demonstrate that developmental stage-specific as well as species- and cell type-specific features sensitize to RB1 inactivation and reveal the human cone precursors' capacity to model retinoblastoma initiation, proliferation, premalignant arrest, and tumor growth.

Telehealth for Young Adults With Diabetes: Addressing Social Determinants of Health.

Type 1 diabetes is a challenging chronic condition and can lead to diabetes-related distress and disengagement. Historically disadvantaged, racially and ethnically diverse young adults (YAs) with type 1 diabetes experience higher blood glucose levels and encounter more barriers to care than their White counterparts. Current research shows that telehealth may provide a route for improving psychosocial issues and diabetes care among YAs.

International Survey to Establish Prioritized Outcomes for Trials in People With Coronavirus Disease 2019.

OBJECTIVES: There are over 4,000 trials conducted in people with coronavirus disease 2019. However, the variability of outcomes and the omission of patient-centered outcomes may diminish the impact of these trials on decision-making. The aim of this study was to generate a consensus-based, prioritized list of outcomes for coronavirus disease 2019 trials. DESIGN: In an online survey conducted in English, Chinese, Italian, Portuguese, and Spanish languages, adults with coronavirus disease 2019, their family members, health professionals, and the general public rated the importance of outcomes using a 9-point Likert scale (7-9, critical importance) and completed a Best-Worst Scale to estimate relative importance. Participant comments were analyzed thematically. SETTING: International. SUBJECTS: Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public, and health professionals (including clinicians, policy makers, regulators, funders, and researchers). INTERVENTIONS: None. MEASUREMENTS: None. MAIN RESULTS: In total, 9,289 participants from 111 countries (776 people with coronavirus disease 2019 or family members, 4,882 health professionals, and 3,631 members of the public) completed the survey. The four outcomes of highest priority for all three groups were: mortality, respiratory failure, pneumonia, and organ failure. Lung function, lung scarring, sepsis, shortness of breath, and oxygen level in the blood were common to the top 10 outcomes across all three groups (mean > 7.5, median ≥ 8, and > 70% of respondents rated the outcome as critically important). Patients/family members rated fatigue, anxiety, chest pain, muscle pain, gastrointestinal problems, and cardiovascular disease higher than health professionals. Four themes underpinned prioritization: fear of life-threatening, debilitating, and permanent consequences; addressing knowledge gaps; enabling preparedness and planning; and tolerable or infrequent outcomes. CONCLUSIONS: Life-threatening respiratory and other organ outcomes were consistently highly prioritized by all stakeholder groups. Patients/family members gave higher priority to many patient-reported outcomes compared with health professionals.

Core Outcomes Set for Trials in People With Coronavirus Disease 2019.

OBJECTIVES: The outcomes reported in trials in coronavirus disease 2019 are extremely heterogeneous and of uncertain patient relevance, limiting their applicability for clinical decision-making. The aim of this workshop was to establish a core outcomes set for trials in people with suspected or confirmed coronavirus disease 2019. DESIGN: Four international online multistakeholder consensus workshops were convened to discuss proposed core outcomes for trials in people with suspected or confirmed coronavirus disease 2019, informed by a survey involving 9,289 respondents from 111 countries. The transcripts were analyzed thematically. The workshop recommendations were used to finalize the core outcomes set. SETTING: International. SUBJECTS: Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public and health professionals (including clinicians, policy makers, regulators, funders, researchers). INTERVENTIONS: None. MEASUREMENTS: None. MAIN RESULTS: Six themes were identified. "Responding to the critical and acute health crisis" reflected the immediate focus on saving lives and preventing life-threatening complications that underpinned the high prioritization of mortality, respiratory failure, and multiple organ failure. "Capturing different settings of care" highlighted the need to minimize the burden on hospitals and to acknowledge outcomes in community settings. "Encompassing the full trajectory and severity of disease" was addressing longer term impacts and the full spectrum of illness (e.g. shortness of breath and recovery). "Distinguishing overlap, correlation and collinearity" meant recognizing that symptoms such as shortness of breath had distinct value and minimizing overlap (e.g. lung function and pneumonia were on the continuum toward respiratory failure). "Recognizing adverse events" refers to the potential harms of new and evolving interventions. "Being cognizant of family and psychosocial wellbeing" reflected the pervasive impacts of coronavirus disease 2019. CONCLUSIONS: Mortality, respiratory failure, multiple organ failure, shortness of breath, and recovery are critically important outcomes to be consistently reported in coronavirus disease 2019 trials.

Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia.

Targeted therapies including the engineered afucosylated anti-CD20 monoclonal antibody obinutuzumab, Bruton's tyrosine kinase inhibitor ibrutinib, and B-cell lymphoma protein 2 inhibitor venetoclax have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) and, based on their complementary mechanisms, are ideal for combination. However, combining venetoclax with other active agents raises safety concerns, as it may increase the risk for tumor lysis syndrome. To minimize this risk, we designed and implemented a fixed-duration regimen using sequentially administered obinutuzumab followed by ibrutinib (cycle 2) and venetoclax (cycle 3), for a total of fourteen 28-day cycles. This phase 1b study included 12 patients with relapsed or refractory CLL. We tested 3 dose levels of venetoclax and identified the doses of all 3 agents approved by the US Food and Drug Administration for use in the combination. Adverse events were consistent with known toxicities of the individual agents, with hematologic adverse events being most frequent. No clinically significant tumor lysis syndrome occurred. The overall response rate was 92% (95% confidence interval, 62%-100%), with 42% (5/12) achieving a complete remission or complete remission with incomplete marrow recovery. There were 6 patients with no detectable CLL in both the blood and bone marrow at the end of treatment. We found this regimen to be safe and tolerable in CLL, and capable of inducing deep responses, justifying future study in our ongoing phase 2 cohorts of relapsed or refractory and treatment-naive patients, as well as larger phase 3 trials currently in planning. This trial was registered at www.clinicaltrials.gov as #NCT02427451.

VISUAL AND ANATOMIC OUTCOMES OF PEDIATRIC ENDOSCOPIC VITRECTOMY IN 326 CASES.

PURPOSE: To report on the indications, outcomes, and complications of endoscopic vitrectomy in a large cohort of pediatric vitreoretinal patients. METHODS: This is a retrospective interventional case series consisting of 244 eyes of 211 patients aged 18 years or younger undergoing a total of 326 endoscopic vitrectomies from 2008 to 2017. A 23-gauge vitrectomy was performed with use of a 19-gauge endoscope. RESULTS: Two hundred and eleven patients with a mean age of 7.5 years (range: 0-18 years) and median follow-up since last surgery of 28 months (range: 3 months-8.7 years) were included. The most common indication for endoscopic vitrectomy was retinal detachment (234/326; 72%) with proliferative vitreoretinopathy (162/234; 69%). Other diagnoses included trauma (25%), retinopathy of prematurity (15%), and glaucoma (9%). Twenty-five percent of surgeries (80/326) were performed on eyes with significant corneal opacities. Retinal reattachment was achieved in 67% of eyes with retinal detachment (119/178). Visual acuity improved in 26% of retinal detachment eyes versus 53% of nonretinal detachment eyes (P = 0.005). Surgical complications included band keratopathy (15%), hypotony (8%), cataract (7%), and elevated intraocular pressure (3%). CONCLUSION: In this large series of pediatric endoscopic vitreoretinal surgeries, anatomic outcomes and complication rates were comparable with previous studies.

Blood Schizonticidal Activity and Safety of Tafenoquine When Administered as Chemoprophylaxis to Healthy, Nonimmune Participants Followed by Blood Stage Plasmodium falciparum Challenge: A Randomized, Double-blind, Placebo-controlled Phase 1b Study.

BACKGROUND: Tafenoquine was recently approved for chemoprophylaxis of malaria. Its specific activity against liver and blood stages of Plasmodium species has been separately characterized in animals but not in humans. METHODS: In this randomized, double-blind, placebo-controlled study, 16 malaria-naive, glucose-6-phosphate dehydrogenase-normal participants aged 20-42 years received tafenoquine chemoprophylaxis prior to challenge with blood stage Plasmodium falciparum. Participants were randomly assigned to either tafenoquine (n = 12) or placebo (n = 4) and took blinded study medication (single 200-mg dose) on days 1, 2, 3, and 10, followed by intravenous inoculation with approximately 2800 P. falciparum parasitized erythrocytes on day 13. The primary endpoint was the number of participants requiring rescue treatment with artemether/lumefantrine due to the onset of parasitemia as determined by quantitative polymerase chain reaction. RESULTS: None of the 12 participants who received tafenoquine developed parasitemia, whereas all placebo participants developed parasitemia (P = .0005). Two cases of mild hemoglobin decrease and a single case of mild hyperbilirubinemia occurred in the tafenoquine group. CONCLUSIONS: Tafenoquine chemoprophylaxis is safe and effective in preventing malaria in healthy nonimmune participants challenged with blood stage P. falciparum. CLINICAL TRIALS REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12617000102370.

Porous orbital implant after enucleation in retinoblastoma patients: indications and complications.

This study aims to identify risk factors associated with complications in retinoblastoma patients following primary and secondary enucleations with porous implant placement. A retrospective case-control study was performed between 2010 and 2015. Data pertaining to subjects' demographics, medical history, clinical, and pathological findings, implant characteristics and complications were collected. The analysis included 103 eyes of 101 patients age 27.8 ± 21.9 months undergoing enucleation for retinoblastoma. Postoperatively, 19/103 (18%) eyes developed exposure, extrusion, or hematoma requiring subsequent surgery. Exposure was the most common postoperative complication (12/19, 63%). Age at enucleation 24 months or younger, Hispanic ethnicity, female gender, and intravenous chemotherapy prior to enucleation were associated with increased odds of implant complications. In contrast, patients who were given intravitreal melphalan (IM), subtenons carboplatin (SC), or external beam radiation therapy (EBRT) did not demonstrate an increased risk of complications. In this cohort of retinoblastoma patients undergoing primary or secondary enucleation with porous implants, implant exposure was the most common postoperative complication. Our findings suggest that female gender, Hispanic ethnicity, age at enucleation 24 months or younger, and intravenous chemotherapy prior to enucleation may increase the risk of complications.

Not All Seeds Are Created Equal: Seed Classification Is Predictive of Outcomes in Retinoblastoma.

OBJECTIVE: Intravitreal chemotherapy has emerged as an important modality for treating vitreous seeding in retinoblastoma. A classification system has been described as predictive of response to intravitreal melphalan (IVM) in patients treated predominantly with primary intra-arterial chemotherapy. The objective of this study is to evaluate the outcomes of retinoblastoma treated with intravenous chemotherapy and IVM as salvage for vitreous seeding, and further to determine whether vitreous seed classification (dust, spheres, cloud) is predictive of the total number and dose of IVM injections required for treatment in this cohort. DESIGN: A nonrandomized retrospective review. PARTICIPANTS: Retinoblastoma patients treated at a single center with intravenous chemotherapy and IVM. METHODS: Retrospective review of patients with vitreous seeding from retinoblastoma treated with intravenous chemotherapy and IVM from 2012 to 2016. MAIN OUTCOME MEASURES: Primary outcome measure was eradication of seeds and globe salvage. Secondary measures included IVM-associated toxicity and complications. RESULTS: Overall, 28 eyes of 25 patients were included, with a total of 110 IVM injections. By seed classification, eyes with dust (n = 15) required a median of 3 injections, spheres (n = 8) required 4 injections, and clouds (n = 5) required 6 injections. Spherical seeds were only seen in recurrent vitreous seeding. Of the 28 treated eyes, 9 were enucleated, 6 for recurrent retinal disease, resulting in an overall globe salvage rate of 68%. The salvage rate secondary to active retinoblastoma was 79%. Dust classification was the most prevalent seeding type of the 9 enucleated eyes. There was 100% regression of vitreous seeds after intravitreal injection and no eye was treated with radiation or enucleated for seeding. Twelve eyes demonstrated grade 3 or greater IVM-associated retinal or anterior segment toxicity post injection. Mean follow-up was 33 months (range, 9-51 months). CONCLUSIONS: IVM is an effective treatment for vitreous seeding after intravenous chemotherapy for retinoblastoma. As with eyes treated with intra-arterial chemotherapy, seed classification is predictive of the total number and dose of IVM injections in eyes treated with intravenous chemotherapy. Eyes with clouds required significantly more injections than eyes with dust or spheres.

Predictive overbooking and active recruitment increases uptake of endoscopy appointments among African American patients.

BACKGROUND AND AIMS: Use of GI endoscopy is historically lower in nonwhite ethnic and racial groups compared with whites. These disparities are multifactorial but likely contribute to differences in GI clinical outcomes. We sought to improve endoscopy uptake overall and in minorities by predictive overbooking and active recruitment in a hospital-based GI clinic. METHODS: From January to October 2014, we alternated between traditional booking for Veterans Affairs Healthcare Network patients with a physician recommendation for endoscopy and active recruitment of patients to fill projected open endoscopy appointment slots. On intervention weeks, patients attending a GI clinic were given the opportunity to "fast track" to an endoscopy appointment on short notice. During control weeks, patients were not actively recruited. We compared uptake of endoscopy appointments in both groups and performed logistic regression to determine predictors of participation in fast-track active recruitment. RESULTS: During fast-track active recruitment for endoscopy, the clinic recruited an additional 111 patients for endoscopy over passive recruitment, including 46 African Americans (41.4%). In a logistic regression model controlling for demographic and clinical characteristics, African Americans were twice as likely (adjusted OR, 1.99; 95% CI, 1.26-3.17) than whites to participate in the fast-track option for recommended endoscopy. CONCLUSIONS: Interventions to actively recruit patients for endoscopy increased the overall percentage of GI clinic patients undergoing endoscopy and disproportionately improved endoscopy appointment uptake in African Americans.

Preventing Endoscopy Clinic No-Shows: Prospective Validation of a Predictive Overbooking Model.

OBJECTIVES: Patient absenteeism for scheduled visits and procedures ("no-show") occurs frequently in healthcare systems worldwide, resulting in treatment delays and financial loss. To address this problem, we validated a predictive overbooking system that identifies patients at high risk for missing scheduled gastrointestinal endoscopy procedures ("no-shows" and cancellations), and offers their appointments to other patients on short notice. METHODS: We prospectively tested a predictive overbooking system at a Veterans Administration outpatient endoscopy clinic over a 34-week period, alternating between traditional booking and predictive overbooking methods. For the latter, we assigned a no-show risk score to each scheduled patient, utilizing a previously developed logistic regression model built with electronic health record data. To compare booking methods, we measured service utilization-defined as the percentage of daily total clinic capacity occupied by patients-and length of clinic workday. RESULTS: Compared to typical booking, predictive overbooking resulted in nearly all appointment slots being filled-2.5 slots available during control weeks vs. 0.35 slots during intervention weeks, t(161)=4.10, P=0.0001. Service utilization increased from 86% during control weeks to 100% during intervention weeks, allowing 111 additional patients to undergo procedures. Physician and staff overages were more common during intervention weeks, but less than anticipated (workday length of 7.84 h (control) vs. 8.31 h (intervention), t(161)=2.28, P=0.02). CONCLUSIONS: Predictive overbooking may be used to maximize endoscopy scheduling. Future research should focus on adapting the model for use in primary care and specialty clinics.

Impact of National Institutes of Health Gastrointestinal PROMIS Measures in Clinical Practice: Results of a Multicenter Controlled Trial.

OBJECTIVES: The National Institutes of Health (NIH) created the Patient Reported Outcomes Measurement Information System (PROMIS) to allow efficient, online measurement of patient-reported outcomes (PROs), but it remains untested whether PROMIS improves outcomes. Here, we aimed to compare the impact of gastrointestinal (GI) PROMIS measures vs. usual care on patient outcomes. METHODS: We performed a pragmatic clinical trial with an off-on study design alternating weekly between intervention (GI PROMIS) and control arms at one Veterans Affairs and three university-affiliated specialty clinics. Adults with GI symptoms were eligible. Intervention patients completed GI PROMIS symptom questionnaires on an e-portal 1 week before their visit; PROs were available for review by patients and their providers before and during the clinic visit. Usual care patients were managed according to customary practices. Our primary outcome was patient satisfaction as determined by the Consumer Assessment of Healthcare Providers and Systems questionnaire. Secondary outcomes included provider interpersonal skills (Doctors' Interpersonal Skills Questionnaire (DISQ)) and shared decision-making (9-item Shared Decision Making Questionnaire (SDM-Q-9)). RESULTS: There were 217 and 154 patients in the GI PROMIS and control arms, respectively. Patient satisfaction was similar between groups (P>0.05). Intervention patients had similar assessments of their providers' interpersonal skills (DISQ 89.4±11.7 vs. 89.8±16.0, P=0.79) and shared decision-making (SDM-Q-9 79.3±12.4 vs. 79.0±22.0, P=0.85) vs. CONCLUSIONS: This is the first controlled trial examining the impact of NIH PROMIS in clinical practice. One-time use of GI PROMIS did not improve patient satisfaction or assessment of provider interpersonal skills and shared decision-making. Future studies examining how to optimize PROs in clinical practice are encouraged before widespread adoption.

Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts.

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤ 10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95% C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.

Computer-generated vs. physician-documented history of present illness (HPI): results of a blinded comparison.

OBJECTIVES: Healthcare delivery now mandates shorter visits with higher documentation requirements, undermining the patient-provider interaction. To improve clinic visit efficiency, we developed a patient-provider portal that systematically collects patient symptoms using a computer algorithm called Automated Evaluation of Gastrointestinal Symptoms (AEGIS). AEGIS also automatically "translates" the patient report into a full narrative history of present illness (HPI). We aimed to compare the quality of computer-generated vs. physician-documented HPIs. METHODS: We performed a cross-sectional study with a paired sample design among individuals visiting outpatient adult gastrointestinal (GI) clinics for evaluation of active GI symptoms. Participants first underwent usual care and then subsequently completed AEGIS. Each individual thereby had both a physician-documented and a computer-generated HPI. Forty-eight blinded physicians assessed HPI quality across six domains using 5-point scales: (i) overall impression, (ii) thoroughness, (iii) usefulness, (iv) organization, (v) succinctness, and (vi) comprehensibility. We compared HPI scores within patient using a repeated measures model. RESULTS: Seventy-five patients had both computer-generated and physician-documented HPIs. The mean overall impression score for computer-generated HPIs was higher than physician HPIs (3.68 vs. 2.80; P<0.001), even after adjusting for physician and visit type, location, mode of transcription, and demographics. Computer-generated HPIs were also judged more complete (3.70 vs. 2.73; P<0.001), more useful (3.82 vs. 3.04; P<0.001), better organized (3.66 vs. 2.80; P<0.001), more succinct (3.55 vs. 3.17; P<0.001), and more comprehensible (3.66 vs. 2.97; P<0.001). CONCLUSIONS: Computer-generated HPIs were of higher overall quality, better organized, and more succinct, comprehensible, complete, and useful compared with HPIs written by physicians during usual care in GI clinics.