Perioperative opioid management for minimally invasive hysterectomy.

Given the high volume of hysterectomies performed, the contribution of gynecologists to the opioid crisis is potentially significant. Following a hysterectomy, most patients are over-prescribed opioids, are vulnerable to developing new persistent opioid use, and can be the source of misuse, diversion, or accidental exposure. People who misuse opioids are at risk of an overdose related death, which is now one of the leading causes of death in the United States and is rising in other countries. It is the physician's responsibility to reduce opioid use by making impactful practice changes, such as 1) using pre-emptive opioid sparing strategies, 2) optimizing multimodal nonopioid pain management, 3) restricting postoperative opioid prescribing, and 4) educating patients on proper disposal of unused opioids. These changes can be implemented with an enhanced recovery after surgery protocol, shared decision-making, and patient education strategies related to opioids.

Design and rationale for a randomized controlled trial to reduce readmissions among patients with depressive symptoms.

BACKGROUND: The Re-Engineered Discharge (Project RED) reduces 30-day readmission rates by 30%. However, our data indicates that for patients displaying depressive symptoms during hospitalization, Project RED is less effective in preventing unplanned readmission. We aim to examine the effectiveness of RED-D, a modified brief Cognitive behavioral therapy (CBT) protocol delivered as a post-discharge extension of the Re-Engineered Discharge, in reducing 30-day readmissions rates and emergency department (ED) use as well as depressive symptoms for medical patients with comorbid depressive symptoms. METHODS: This paper details the study design and implementation of an ongoing, federally funded randomized controlled trial of our post-discharge mental health intervention, RED-D, compared to the RED plus usual care. This research has two primary objectives: (1) to determine whether RED-D delivered telephonically by a mental health professional immediately following discharge is effective in reducing hospital readmission and emergency department use for patients displaying depressive symptoms during their inpatient stay, and (2) to examine whether this approach yields a clinically significant reduction in depressive symptoms. We intend to recruit 1200 participants randomized to our intervention, RED-D (n=600), and to RED plus usual care (n=600). CONCLUSIONS: Hospitalized patients with depressive symptoms are at increased risk for 30-day readmission. We aim to conduct a randomized clinical trial to evaluate the comparative effectiveness of RED-D, our post-discharge modified brief CBT intervention compared to RED alone in reducing readmissions and depressive symptoms for this at-risk population.

Modeling human retinal development with patient-specific induced pluripotent stem cells reveals multiple roles for visual system homeobox 2.

Human induced pluripotent stem cells (hiPSCs) have been shown to differentiate along the retinal lineage in a manner that mimics normal mammalian development. Under certain culture conditions, hiPSCs form optic vesicle-like structures (OVs), which contain proliferating progenitors capable of yielding all neural retina (NR) cell types over time. Such observations imply conserved roles for regulators of retinogenesis in hiPSC-derived cultures and the developing embryo. However, whether and to what extent this assumption holds true has remained largely uninvestigated. We examined the role of a key NR transcription factor, visual system homeobox 2 (VSX2), using hiPSCs derived from a patient with microphthalmia caused by an R200Q mutation in the VSX2 homeodomain region. No differences were noted between (R200Q)VSX2 and sibling control hiPSCs prior to OV generation. Thereafter, (R200Q)VSX2 hiPSC-OVs displayed a significant growth deficit compared to control hiPSC-OVs, as well as increased production of retinal pigmented epithelium at the expense of NR cell derivatives. Furthermore, (R200Q)VSX2 hiPSC-OVs failed to produce bipolar cells, a distinctive feature previously observed in Vsx2 mutant mice. (R200Q)VSX2 hiPSC-OVs also demonstrated delayed photoreceptor maturation, which could be overcome via exogenous expression of wild-type VSX2 at early stages of retinal differentiation. Finally, RNAseq analysis on isolated hiPSC-OVs implicated key transcription factors and extracellular signaling pathways as potential downstream effectors of VSX2-mediated gene regulation. Our results establish hiPSC-OVs as versatile model systems to study retinal development at stages not previously accessible in humans and support the bona fide nature of hiPSC-OV-derived retinal progeny.

Patient activation and 30-day post-discharge hospital utilization.

BACKGROUND: Patient activation is linked to better health outcomes and lower rates of health service utilization. The role of patient activation in the rate of hospital readmission within 30 days of hospital discharge has not been examined. METHODS: A secondary analysis using data from the Project RED-LIT randomized controlled trial conducted at an urban safety net hospital. Data from 695 English-speaking general medical inpatient subjects were analyzed. We used an adapted, eight-item version of the validated Patient Activation Measure (PAM). Total scores were categorized, according to standardized methods, as one of four PAM levels of activation: Level 1 (lowest activation) through Level 4 (highest activation). The primary outcome measure was total 30-day post-discharge hospital utilization, defined as total emergency department (ED) visits plus hospital readmissions including observation stays. Poisson regression was used to control for confounding. RESULTS: Of the 695 subjects, 67 (9.6 %) were PAM Level 1, 123 (17.7 %) were Level 2, 193 (27.8 %) were Level 3, and 312 (44.9 %) were Level 4. Compared with highly activated patients (PAM Level 4), a higher rate of 30-day post-discharge hospital utilization was observed for patients at lower levels of activation (PAM Level 1, incident rate ratio [IRR] 1.75, 95 % CI,1.18 to 2.60) and (PAM Level 2, IRR 1.50, 95 % CI 1.06 to 2.13). The rate of returning to the hospital among patients at PAM Level 3 was not statistically different than patients with PAM Level 4 (IRR 1.30, 95 % CI, 0.94 to 1.80). The rate ratio for PAM Level 1 was also higher compared with Level 4 for ED use alone (1.68(1.07 to 2.63)) and for hospital readmissions alone (1.93 [1.22 to 3.06]). CONCLUSION: Hospitalized adult medical patients in an urban academic safety net hospital with lower levels of Patient Activation had a higher rate of post-discharge 30-day hospital utilization.

Functional analysis of serially expanded human iPS cell-derived RPE cultures.

PURPOSE: To determine the effects of serial expansion on the cellular, molecular, and functional properties of human iPS cell (hiPSC)-derived RPE cultures. METHODS: Fibroblasts obtained from four individuals were reprogrammed into hiPSCs and differentiated to RPE cells using previously described methods. Patches of deeply pigmented hiPSC-RPE were dissected, dissociated, and grown in culture until they re-formed pigmented monolayers. Subsequent passages were obtained by repeated dissociation, expansion, and maturation of RPE into pigmented monolayers. Gene and protein expression profiles and morphological and functional characteristics of hiPSC-RPE at different passages were compared with each other and to human fetal RPE (hfRPE). RESULTS: RPE from all four hiPSC lines could be expanded more than 1000-fold when serially passaged as pigmented monolayer cultures. Importantly, expansion of hiPSC-RPE monolayers over the first three passages (P1-P3) resulted in decreased expression of pluripotency and neuroretinal markers and maintenance of characteristic morphological features and gene and protein expression profiles. Furthermore, P1 to P3 hiPSC-RPE monolayers reliably demonstrated functional tight junctions, G-protein-coupled receptor-mediated calcium transients, phagocytosis and degradation of photoreceptor outer segments, and polarized secretion of biomolecules. In contrast, P4 hiPSC-RPE cells failed to form monolayers and possessed altered morphological and functional characteristics and gene expression levels. CONCLUSIONS: Highly differentiated, pigmented hiPSC-RPE monolayers can undergo limited serial expansion while retaining key cytological and functional attributes. However, passaging hiPSC-RPE cultures beyond senescence leads to loss of such features. Our findings support limited, controlled passaging of patient-specific hiPSC-RPE to procure cells needed for in vitro disease modeling, drug screening, and cellular transplantation.

iPS cell modeling of Best disease: insights into the pathophysiology of an inherited macular degeneration.

Best disease (BD) is an inherited degenerative disease of the human macula that results in progressive and irreversible central vision loss. It is caused by mutations in the retinal pigment epithelium (RPE) gene BESTROPHIN1 (BEST1), which, through mechanism(s) that remain unclear, lead to the accumulation of subretinal fluid and autofluorescent waste products from shed photoreceptor outer segments (POSs). We employed human iPS cell (hiPSC) technology to generate RPE from BD patients and unaffected siblings in order to examine the cellular and molecular processes underlying this disease. Consistent with the clinical phenotype of BD, RPE from mutant hiPSCs displayed disrupted fluid flux and increased accrual of autofluorescent material after long-term POS feeding when compared with hiPSC-RPE from unaffected siblings. On a molecular level, RHODOPSIN degradation after POS feeding was delayed in BD hiPSC-RPE relative to unaffected sibling hiPSC-RPE, directly implicating impaired POS handling in the pathophysiology of the disease. In addition, stimulated calcium responses differed between BD and normal sibling hiPSC-RPE, as did oxidative stress levels after chronic POS feeding. Subcellular localization, fractionation and co-immunoprecipitation experiments in hiPSC-RPE and human prenatal RPE further linked BEST1 to the regulation and release of endoplasmic reticulum calcium stores. Since calcium signaling and oxidative stress are critical regulators of fluid flow and protein degradation, these findings likely contribute to the clinical picture of BD. In a larger context, this report demonstrates the potential to use patient-specific hiPSCs to model and study maculopathies, an important class of blinding disorders in humans.

Blood-derived human iPS cells generate optic vesicle-like structures with the capacity to form retinal laminae and develop synapses.

PURPOSE: We sought to determine if human induced pluripotent stem cells (iPSCs) derived from blood could produce optic vesicle-like structures (OVs) with the capacity to stratify and express markers of intercellular communication. METHODS: Activated T-lymphocytes from a routine peripheral blood sample were reprogrammed by retroviral transduction to iPSCs. The T-lymphocyte-derived iPSCs (TiPSCs) were characterized for pluripotency and differentiated to OVs using our previously published protocol. TiPSC-OVs were then manually isolated, pooled, and cultured en masse to more mature stages of retinogenesis. Throughout this stepwise differentiation process, changes in anterior neural, retinal, and synaptic marker expression were monitored by PCR, immunocytochemistry, and/or flow cytometry. RESULTS: TiPSCs generated abundant OVs, which contained a near homogeneous population of proliferating neuroretinal progenitor cells (NRPCs). These NRPCs differentiated into multiple neuroretinal cell types, similar to OV cultures from human embryonic stem cells and fibroblast-derived iPSCs. In addition, portions of some TiPSC-OVs maintained their distinctive neuroepithelial appearance and spontaneously formed primitive laminae, reminiscent of the developing retina. Retinal progeny from TiPSC-OV cultures expressed numerous genes and proteins critical for synaptogenesis and gap junction formation, concomitant with the emergence of glia and the upregulation of thrombospondins in culture. CONCLUSIONS: We demonstrate for the first time that human blood-derived iPSCs can generate retinal cell types, providing a highly convenient donor cell source for iPSC-based retinal studies. We also show that cultured TiPSC-OVs have the capacity to self-assemble into rudimentary neuroretinal structures and express markers indicative of chemical and electrical synapses.

Importance of pharmacokinetic profile and timing of coadministration of short- and long-acting formulations of methylphenidate on patterns of subjective responses and abuse potential.

OBJECTIVE: Subjective responses (ie, liking, disliking) to stimulants are thought to be proxies for abuse potential. Greater subjective responses have been documented in formulations that are more rapidly absorbed. However, repeat dosing has not been examined. METHODS: Subjective responses on the Drug Rating Questionnaire were compared in 26 healthy adults after administration of short- (immediate-release [IR] methylphenidate [MPH]) and long- (osmotically controlled-release oral delivery system [OROS] MPH) acting stimulant formulations. The second dose was administered 4 hours after initial dosing. All subjects received all 5 conditions (ie, placebo to placebo; IR-MPH to IR-MPH; IR-MPH to OROS-MPH; OROS-MPH to IR-MPH; or OROS-MPH to OROS-MPH) in a double-blind, counter-balanced design on 5 separate days. RESULTS: Plasma levels and subjective patterns of detection were higher when an IR formulation was administered during the ascending phase of a first-administered long-acting dose (OROS). CONCLUSION: These results emphasize the critical role that formulation type (IR vs OROS) and timing of administration (ascending vs descending phase) play when short- and long-acting formulations are coadministered. Such knowledge provides important information for clinicians about the safety and tolerability of the timing of repeat dosing of various permutations of coadministration of MPH formulations.

Optic vesicle-like structures derived from human pluripotent stem cells facilitate a customized approach to retinal disease treatment.

Differentiation methods for human induced pluripotent stem cells (hiPSCs) typically yield progeny from multiple tissue lineages, limiting their use for drug testing and autologous cell transplantation. In particular, early retina and forebrain derivatives often intermingle in pluripotent stem cell cultures, owing to their shared ancestry and tightly coupled development. Here, we demonstrate that three-dimensional populations of retinal progenitor cells (RPCs) can be isolated from early forebrain populations in both human embryonic stem cell and hiPSC cultures, providing a valuable tool for developmental, functional, and translational studies. Using our established protocol, we identified a transient population of optic vesicle (OV)-like structures that arose during a time period appropriate for normal human retinogenesis. These structures were independently cultured and analyzed to confirm their multipotent RPC status and capacity to produce physiologically responsive retinal cell types, including photoreceptors and retinal pigment epithelium (RPE). We then applied this method to hiPSCs derived from a patient with gyrate atrophy, a retinal degenerative disease affecting the RPE. RPE generated from these hiPSCs exhibited a disease-specific functional defect that could be corrected either by pharmacological means or following targeted gene repair. The production of OV-like populations from human pluripotent stem cells should facilitate the study of human retinal development and disease and advance the use of hiPSCs in personalized medicine.

Bilateral saccades increase intrahemispheric processing but not interhemispheric interaction: Implications for saccade-induced retrieval enhancement.

Retrieval of memories is enhanced when bilateral saccades are made immediately before attempting retrieval. One hypothesis is that saccades enhance retrieval by increasing interaction of the brain hemispheres. To test this, subjects viewed arrays of lateralized letters and indicated whether target letters matched either of two probe letters. Matching targets and probes were presented to either the same hemisphere (within-hemisphere trials) or separate hemispheres (across-hemisphere trials). Match detection requires interhemispheric interaction on across-hemisphere trials but primarily intrahemispheric processing on within-hemisphere trials. Subjects performed letter matching following saccades and a fixation control condition. Saccades increased match-detection accuracy on within-hemisphere trials only, suggesting that, counter to the hypothesis, saccades enhance intrahemispheric processing but not interhemispheric interaction. Across-hemisphere accuracy was higher, however, for subjects who were not strongly right-handed, versus those who were, and the absence of strong right-handedness may reflect greater interhemispheric interaction. We discuss implications for accounts of saccade-induced retrieval enhancement.

Characterizing impaired driving in adults with attention-deficit/hyperactivity disorder: A controlled study.

OBJECTIVE: We sought to confirm previously documented findings that individuals with attention-deficit/hyperactivity disorder (ADHD) demonstrate impaired driving behavior when compared with controls. METHOD: Subjects were adults with (N = 26) and without (N = 23) DSM-IV ADHD ascertained through clinical referrals to an adult ADHD program and through advertisements in the local media. Driving behavior was assessed using the Manchester Driving Behavior Questionnaire (DBQ) and 10 questions from a driving history questionnaire. Neuropsychological testing and structured interviews were also administered to all subjects. RESULTS: Substantially more ADHD subjects had been in an accident on the highway (35% vs. 9%, p = .03) or had been rear-ended (50% vs. 17%, p = .02) compared with controls. Analysis of the DBQ findings showed that ADHD subjects had significantly higher mean +/- SD scores than control subjects on the total DBQ (34.1 +/- 15.2 vs. 18.0 +/- 8.6, p < .001) and in all 3 subscales of the DBQ: errors (9.3 +/- 5.4 vs. 4.6 +/- 3.5, p < .001), lapses (12.4 +/- 6.2 vs. 6.1 +/- 3.5, p < .001), and violations (12.4 +/- 5.2 vs. 7.4 +/- 4.1, p < .001). Using the score that separated ADHD from control drivers on the DBQ as a cutoff, ADHD drivers at high risk for poor driving outcomes had more severe rates of comorbidity and exhibited more impaired scores on neuropsychological testing. CONCLUSIONS: Our results confirm and extend previous work documenting impaired driving behavior in subjects with ADHD. Results also suggest that ADHD individuals at high risk for poor driving behavior might be distinguishable from other ADHD individuals on DBQ scores, neuropsychological deficits, and patterns of comorbidities.