Advancing preclinical models of psychiatric disorders with human brain organoid cultures.

Psychiatric disorders are often distinguished from neurological disorders in that the former do not have characteristic lesions or findings from cerebrospinal fluid, electroencephalograms (EEGs), or brain imaging, and furthermore do not have commonly recognized convergent mechanisms. Psychiatric disorders commonly involve clinical diagnosis of phenotypic behavioral disturbances of mood and psychosis, often with a poorly understood contribution of environmental factors. As such, psychiatric disease has been challenging to model preclinically for mechanistic understanding and pharmaceutical development. This review compares commonly used animal paradigms of preclinical testing with evolving techniques of induced pluripotent cell culture with a focus on emerging three-dimensional models. Advances in complexity of 3D cultures, recapitulating electrical activity in utero, and disease modeling of psychosis, mood, and environmentally induced disorders are reviewed. Insights from these rapidly expanding technologies are discussed as they pertain to the utility of human organoid and other models in finding novel research directions, validating pharmaceutical action, and recapitulating human disease.

Resonant Acoustic Rheometry to Measure Coagulation Kinetics in Hemophilia A and Healthy Plasma: A Novel Viscoelastic Method.

Compared with conventional coagulation tests and factor-specific assays, viscoelastic hemostatic assays (VHAs) can provide a more thorough evaluation of clot formation and lysis but have several limitations including clot deformation. In this proof-of-concept study, we test a noncontact technique, termed resonant acoustic rheometry (RAR), for measuring the kinetics of human plasma coagulation. Specifically, RAR utilizes a dual-mode ultrasound technique to induce and detect surface oscillation of blood samples without direct physical contact and measures the resonant frequency of the surface oscillation over time, which is reflective of the viscoelasticity of the sample. Analysis of RAR results of normal plasma allowed defining a set of parameters for quantifying coagulation. RAR detected a flat-line tracing of resonant frequency in hemophilia A plasma that was corrected with the addition of tissue factor. Our RAR results captured the kinetics of plasma coagulation and the newly defined RAR parameters correlated with increasing tissue factor concentration in both healthy and hemophilia A plasma. These findings demonstrate the feasibility of RAR as a novel approach for VHA, providing the foundation for future studies to compare RAR parameters to conventional coagulation tests, factor-specific assays, and VHA parameters.

Building consensus in defining and conceptualizing acceptability of healthcare: A Delphi study.

BACKGROUND: The concept of healthcare acceptability is important for nursing staff spending most of their time with patients. Nevertheless, acceptability remains confusing without a collective definition in existing literature. OBJECTIVE: This study aimed to create a consensus among experts on definition and conceptual framework of healthcare acceptability. METHODS: We conducted two rounds of Delphi surveys to collect opinions from experts on definition and conceptual framework of healthcare acceptability proposed following thematic content analysis. We calculated the consensus among experts using the modified Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument and followed the guidance on conducting and reporting Delphi studies (CREDES) best practices. RESULTS: A total of 34 experts completed two rounds of Delphi survey. The definition was validated through consensus as: "a multi-construct concept describing the nonlinear cumulative combination in parts or in whole of experienced or anticipated specific healthcare from the relevant patients/participants, communities, providers/researchers or healthcare systems' managers and policy makers' perspectives in a given context." The overall quality rating was 92.6% and 95.1% for the proposed definition and conceptual framework respectively. CONCLUSION: Opinions collected from experts provided significant insights to build a consensus on healthcare acceptability advancing public health nursing.

Outcomes and Complications Associated With Caudal Thoracic and Abdominal Air Sac Cannulation in 68 Birds.

Air sac cannulation is used both as an emergency procedure in avian patients with severe upper respiratory compromise, as well as a means of routine ventilation for surgery of the head and neck. The objective of this retrospective study was to describe and quantify the complications associated with air sac cannulation in birds. Medical records were retrieved for all patients that underwent caudal thoracic or abdominal air sac cannulation at a single center between August 2004 and October 2020. Patient signalment, indication for air sac cannulation, location of air sac cannula (ASC) placement, occurrence and category of complications encountered, and survival data were recorded. Eighty-four ASCs were placed in 68 birds across 6 orders; 95.2% (80/84) of cases survived general anesthesia for initial ASC placement. The side and position of ASC placement were known in 33.3% (28/84) and 21.4% (18/84) of cases, respectively. Survival to ASC removal was known in 91.3% (73/80) of cases; 43 (58.9%) of these 73 cases survived to ASC removal. Complications were observed in 32.5% (26/80) of cases, and 11.5% (3/26) of cases died as a direct result of the complication. The most common reported ASC complication was loss of patency in 23.8% (19/80) of cases. Increased likelihoods for complications were seen in cases where exercise intolerance (P = 0.04) or abnormal respiratory sounds (P = 0.04) were reported at presentation. Increased likelihoods for survival to ASC removal were seen with intercostal placements (P = 0.049) and peri-interventional antibiotic therapy (P = 0.005). Decreased likelihood for survival to ASC removal was seen in cases where voice change was reported at presentation (P = 0.02). This study demonstrates a moderate risk of ASC complication, with a guarded overall prognosis for survival to ASC removal.

Vincristine Sulfate Liposome Injection with Bendamustine and Rituximab as First-Line Therapy for B-Cell Lymphomas: A Phase I Study.

BACKGROUND: We conducted an investigator-initiated, phase I trial of vincristine sulfate liposomal injection (VSLI) in combination with bendamustine and rituximab (BR) for indolent B-cell (BCL) or mantle cell lymphoma. METHODS: Participants received 6 cycles of standard BR with VSLI at patient-specific dose determined by the Escalation with Overdose Control (EWOC) model targeting 33% probability of dose-limiting toxicity (DLT). Maximum tolerated dose (MTD) was the primary endpoint; secondary endpoints included rates of adverse events (AEs), overall response rate (ORR), and complete response (CR). Vincristine sulfate liposomal injection is FDA approved for the treatment of patients with recurrent Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL). RESULTS: Among 10 enrolled patients, VSLI was escalated from 1.80 to 2.24 mg/m2, with one DLT (ileus) at 2.04 mg/m2. Two patients discontinued VSLI early. The most common AE included lymphopenia (100%), constipation, nausea, infusion reaction (each 60%), neutropenia, and peripheral neuropathy (50%). Grade 3/4 AE included lymphopenia (90%), neutropenia (20%), and ileus (10%), with prolonged grade ≥2 lymphopenia observed in most patients. Calculated MTD for VSLI was 2.25 mg/m2 (95% Bayesian credible interval: 2.00-2.40). Overall response was 100% with 50% CR. With median follow-up 26 months, 4/10 patients experienced recurrence and 1 died. CONCLUSION: Vincristine sulfate liposomal injection at 2.25 mg/m2 can be safely combined with BR for indolent B-cell lymphoma, but given observed toxicities and recurrences, we did not pursue an expanded cohort.Clinical Trials Registration Number: ClinicalTrials.gov identifier NCT02257242.

The Choice between Plasma-Based Common Coagulation Tests and Cell-Based Viscoelastic Tests in Monitoring Hemostatic Competence: Not an either-or Proposition.

There has been a significant interest in the last decade in the use of viscoelastic tests (VETs) to determine the hemostatic competence of bleeding patients. Previously, common coagulation tests (CCTs) such as the prothrombin time (PT) and partial thromboplastin time (PTT) were used to assist in the guidance of blood component and hemostatic adjunctive therapy for these patients. However, the experience of decades of VET use in liver failure with transplantation, cardiac surgery, and trauma has now spread to obstetrical hemorrhage and congenital and acquired coagulopathies. Since CCTs measure only 5 to 10% of the lifespan of a clot, these assays have been found to be of limited use for acute surgical and medical conditions, whereby rapid results are required. However, there are medical indications for the PT/PTT that cannot be supplanted by VETs. Therefore, the choice of whether to use a CCT or a VET to guide blood component therapy or hemostatic adjunctive therapy may often require consideration of both methodologies. In this review, we provide examples of the relative indications for CCTs and VETs in monitoring hemostatic competence of bleeding patients.

Erratum: Nucleon Structure and Strong Interactions in Dark Matter Capture in Neutron Stars [Phys. Rev. Lett. 127, 111803 (2021)].

This corrects the article DOI: 10.1103/PhysRevLett.127.111803.

A one-dimensional high-order commensurate phase of tilted molecules.

We report on the formation of a high-order commensurate (HOC) structure of 5,14-dihydro-5,7,12,14-tetraazapentacene (DHTAP) molecules on the highly corrugated Cu(110)-(2 × 1)O surface. Scanning tunnelling microscopy shows that the DHTAP molecules form a periodic uniaxial arrangement in which groups of seven molecules are distributed over exactly nine substrate lattice spacings along the [1̄10] direction. DFT-calculations reveal that this peculiar arrangement is associated with different tilting of the seven DHTAP molecules within the quasi one-dimensional HOC unit cell. The orientational degree of freedom thus adds a new parameter, which can efficiently stabilize complex molecular structures on corrugated surfaces.

Nucleon Structure and Strong Interactions in Dark Matter Capture in Neutron Stars.

We outline two important effects that are missing from most evaluations of the dark matter capture rate in neutron stars. As dark matter scattering with nucleons in the star involves large momentum transfer, nucleon structure must be taken into account via a momentum dependence of the hadronic form factors. In addition, due to the high density of neutron star matter, we should account for nucleon interactions rather than modeling the nucleons as an ideal Fermi gas. Properly incorporating these effects is found to suppress the dark matter capture rate by up to 3 orders of magnitude for the heaviest stars.

Weight Loss, but Not Dairy Composition of Diet, Moderately Affects Satiety and Postprandial Gut Hormone Patterns in Adults.

BACKGROUND: Inclusion of dairy in diet patterns has been shown to have mixed effects on weight loss. A prevailing hypothesis is that dairy improves weight loss by influencing endocrine systems associated with satiety and food intake regulation. OBJECTIVES: The objective of the current study was to evaluate the effect of weight loss with or without adequate dietary dairy on subjective and objective appetitive measures. METHODS: Men and women who were habitual low dairy consumers (n = 65, 20-50 y) participated in a 12-wk randomized controlled feeding weight loss trial. During the 12-wk intervention, a low-dairy (<1 serving dairy/d) was compared with an adequate-dairy (3-4 servings dairy/d) diet, both with a 500-kcal deficit/d. Test days, before and at the end of the intervention, began with 2 fasting blood draws and visual analog scale (VAS) measures, followed by a standard breakfast (25% of prescribed restricted calories), 5 postbreakfast blood draws and VASs, a standard lunch (40% of restricted energy amount), and 12 postlunch blood draws and VASs. Blood samples were used for satiety hormone measurements. On a separate day when matching standard meals were consumed, an ad libitum buffet meal was provided as dinner, at a self-selected time. Meal duration and intermeal interval were recorded. RESULTS: Weight loss (-6.1 kg), irrespective of dairy, resulted in reduced fasting insulin (-20%) and leptin (-25%), and increased fasting acylated ghrelin (+25%) and VAS desire to eat (+18%) (P < 0.05). There were no effects of dairy on objective or subjective satiety measures. Weight loss marginally reduced the intermeal interval (289 min compared with 276 min, P = 0.059) between lunch and the ad libitum buffet. CONCLUSIONS: These results do not support the hypothesis that inclusion of dairy in long-term dietary patterns influences appetite during weight loss. Weight loss per se has a modest impact on select systems that regulate hunger and satiety.This trial was registered at clinicaltrials.gov as NCT00858312.

Publication misrepresentation among pediatric anesthesiology fellowship applicants: A retrospective single-center cohort study.

BACKGROUND: Many medical specialties have found publication misrepresentation in residency and fellowship applications, but pediatric anesthesia fellowship application data is lacking. AIMS: We sought to determine the prevalence of publication misrepresentation among pediatric anesthesia fellowship applications. METHODS: In this retrospective cohort study, fellowship applications to Stanford University's pediatric anesthesiology fellowship program from 2009 to 2019 were reviewed. Only peer-reviewed journal articles listed as accepted or published were included. Nine additional variables were collected: applicant age, gender, citizenship status, American vs. international medical school, public vs. private medical school, allopathic doctor versus osteopathic doctor, number of years between college and medical school, additional degrees, and application year. The primary outcome was the rate of publication misrepresentation, defined as peer-reviewed journal citations listed on the application that could not be verified or on which the applicant was not listed as an author. Secondary outcomes were the associations between publication misrepresentation and the additional collected variables. RESULTS: 1280 peer-reviewed journal publications from 877 applicants were reviewed. 3.4% of all citations listed as peer-reviewed journal articles were misrepresented and 9.0% of all applicants with at least 1 publication had ≥1 misrepresented publications. 30.2% of publications labelled "misrepresented" were located in our search of databases but did not have the applicant as an author, and 69.8% could not be located using the search databases. Only one of the 9 collected variables (public vs private medical school) was significantly associated with publication misrepresentation. CONCLUSIONS: In this single-center retrospective study, publication misrepresentation was found to occur in one out of 11 pediatric anesthesia fellowship applications with at least one publication. Since residency and fellowship applicant publications may be heavily weighted during the application process, programs may want to include additional inquiries into the accuracy of applicant publications.

Intracranial malignant myopericytoma: case report and literature review.

Malignant myopericytoma is an exceedingly rare soft tissue tumour with only 14 documented cases in the scientific literature. Myopericytomas can occur in association with HIV-AIDS and have a predilection for internal organs such as the bronchus, larynx, liver and brain. Ebstein-Barr virus encoded small RNA(EBER) was positive in three out of 14 cases. In this case report we present the second documented case of a malignant myopericytoma, with a positive EBER found intracranially - specifically in the supratentorial compartment - invading the superior sagittal sinus. Gross total excision of the tumour was achieved, and the patient responded well with no recurrence with only highly active antiretroviral therapy (HAART). No chemotherapy or radiotherapy has been necessary.

Diagnosis and Treatment of Trauma-Induced Coagulopathy by Viscoelastography.

This article explores the application of viscoelastic tests (VETs) in trauma-induced coagulopathy and trauma resuscitation. We describe the advantages of VETs over conventional coagulation tests in the trauma setting and refer to previous disciplines in which VET use has reduced blood product utilization, guided prohemostatic agents, and improved clinical outcomes such as the mortality of critically bleeding patients. We describe different VETs and provide guidance for blood component therapy and prohemostatic therapy based on specific VET parameters. Because the two most commonly used VET systems, rotational thromboelastometry and thromboelastography, use different activators and have different terminologies, this practical narrative review will directly compare and contrast these two VETs to help the clinician easily interpret either and use the interpretation to determine hemostatic integrity in the bleeding trauma patient. Finally, we anticipate the future of new viscoelastic technologies that can be used in this setting.

Outcomes Following LSVT BIG in a Person With Idiopathic Normal Pressure Hydrocephalus: A Case Report.

BACKGROUND AND PURPOSE: There is no literature exploring physical therapy interventions for individuals with idiopathic normal pressure hydrocephalus (iNPH). There are parallels between symptoms of iNPH and Parkinson disease (PD), suggesting that similar interventions may be beneficial. An approach that promotes recalibration of movements to produce bigger motions (Lee Silverman Voice Treatment BIG [LSVT BIG]) is an evidence-based intervention for individuals with PD, which could potentially improve function in individuals with iNPH. This case report documents functional outcomes of LSVT BIG in an individual with iNPH. CASE DESCRIPTION: The participant was a 62-year-old man with a 16-year history of iNPH. He demonstrated hypokinesia, impaired balance, and cognitive deficits. These resulted in frequent falls and limited community ambulation. INTERVENTION: The participant completed the standardized 4-week LSVT BIG program in addition to 5 tune-up sessions 7 months later. Outcome measures included the Berg Balance Scale (BBS), Timed Up and Go (TUG), TUG cognitive and manual, Activities-Specific Balance and Confidence (ABC) scale, Five Times Sit to Stand (5TSTS) test, and a timed floor transfer. OUTCOMES: Improvements, exceeding minimal detectable change values, were noted on the BBS and the ABC scale immediately following intervention. Scores declined at 4-month follow-up, but BBS scores increased again after the tune-up sessions. Quicker floor transfer times were also noted. There were no changes in TUG, TUG cognitive and manual, or 5TSTS times. DISCUSSION: Therapists may wish to consider the use of the LSVT BIG program in persons with iNPH; however, a longer program and/or regular tune-up sessions may be necessary for best outcomes.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A315).

Regression of chronic kidney disease in a patient with AL amyloidosis: A case report
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BACKGROUND: AL amyloidosis is a disease that causes significant end-organ damage via deposition of insoluble amyloid fibrils, which cause disruption of normal tissue architecture and function. The mainstay of current treatment employs various chemotherapy regimens, all of which aim to suppress the underlying plasma cell dyscrasia and reduce the production of amyloidogenic precursor proteins. Renal disease is found in between 50 and 80% of sufferers and is often both progressive and irreversible, ultimately leading to end-stage renal failure and death. Recovery from advanced chronic kidney disease is uncommon, however, this case demonstrates that it is possible with ongoing therapy. CASE PRESENTATION: We report the case of a 53-year-old lady with amyloid-induced nephrotic syndrome who underwent intensive chemotherapy. Initially, this lady experienced the gradual decline in renal function typical of the natural history of this disease; her renal function indicated an impending need for dialysis. However, soon after, evidence of recovery became apparent on serum amyloid protein component scintigraphy, measurement of serum free light chains, and measurement of renal parameters. Ultimately, her renal disease was completely resolved. CONCLUSION: This case shows that renal recovery in AL amyloidosis may be possible and also highlights the importance of continued therapy in order to achieve clonal response and recovery of organ function.
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Percloacal Ovocentesis in the Treatment of Avian Egg Binding: Review of 20 Cases.

Egg binding is one of the most commonly diagnosed reproductive disorders in avian medicine. Often, egg binding is caused by multiple factors, including inappropriate diet and husbandry, reproductive tract pathology, and/or systemic disease. Treatment of egg binding can include medical management or egg removal either percloacal or through surgical means. Percloacal ovocentesis is a commonly described technique in avian practice. The aim of this study was to consider the signalment, success of facilitating egg removal, associated complications, and outcome when percloacal ovocentesis was performed. Data were obtained from an avian first-opinion and referral center in the United Kingdom over a 10-year period. Of the 20 cases that met the inclusion criteria, the following orders were represented (Psittaciformes (n = 15; 75%), Anseriformes (n = 1; 5%), Accipitriformes (n = 2; 10%), and Strigiformes (n = 2; 10%) were represented. Patient age ranged from 2 to 26 years, with an average age of 9.4 years. Percloacal ovocentesis successfully facilitated egg removal in 16 of 20 cases (80%) with no complications observed in 14 of 20 cases (70%). Percloacal ovocentesis is not without potential complications; eggs fragmented in 2 of 20 (10%) cases, with coelomic penetration and coelomitis suspected in a single case (5%). Careful risk assessment and case selection should be performed before the use of this technique. In cases that are refractory to medical management, and in which surgical intervention is high risk or not a feasible option, percloacal ovocentesis can facilitate successful resolution of egg binding in an avian patient and should be considered as a viable treatment option.

LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1-Rac1 pathway.

Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a bona fide marker of adult stem cells in several epithelial tissues, most notably in the intestinal crypts, and is highly up-regulated in many colorectal, hepatocellular, and ovarian cancers. LGR5 activation by R-spondin (RSPO) ligands potentiates Wnt/ß-catenin signaling in vitro; however, deletion of LGR5 in stem cells has little or no effect on Wnt/ß-catenin signaling or cell proliferation in vivo Remarkably, modulation of LGR5 expression has a major impact on the actin cytoskeletal structure and cell adhesion in the absence of RSPO stimulation, but the molecular mechanism is unclear. Here, we show that LGR5 interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1), an effector of Rac1/CDC42 GTPases, in the regulation of actin cytoskeleton dynamics and cell-cell adhesion. Specifically, LGR5 decreased levels of IQGAP1 phosphorylation at Ser-1441/1443, leading to increased binding of Rac1 to IQGAP1 and thus higher levels of cortical F-actin and enhanced cell-cell adhesion. LGR5 ablation in colon cancer cells and crypt stem cells resulted in loss of cortical F-actin, reduced cell-cell adhesion, and disrupted localization of adhesion-associated proteins. No evidence of LGR5 coupling to any of the four major subtypes of heterotrimeric G proteins was found. These findings suggest that LGR5 primarily functions via the IQGAP1-Rac1 pathway to strengthen cell-cell adhesion in normal adult crypt stem cells and colon cancer cells.

Accessing Quark Helicity through Dihadron Studies.

We present a new proposal to study the helicity-dependent dihadron fragmentation functions (DiFF), which describe the correlations of the longitudinal polarization of a fragmenting quark with the transverse momenta of the produced hadron pair. Recent experimental searches for this DiFF via azimuthal asymmetries in back-to-back hadron pair production in e^{+}e^{-} annihilation by the BELLE Collaboration did not yield a signal. Here we propose a new way to access this DiFF in e^{+}e^{-} annihilation, motivated by the recently recalculated cross section of this reaction, which explains why there was in fact no signal for the BELLE Collaboration to see. In this new approach the azimuthal asymmetry is weighted by the virtual photon's transverse momentum square multiplying sine and cosine functions of difference of azimuthal angles of relative and total momentum for each pair. The integration over the virtual photon's transverse momentum has the effect of separating the convolution between the helicity-dependent DiFFs in the quark and antiquark jets and results in a nonzero collinear expression containing Fourier moments of helicity-dependent DiFFs. A second new measurement is also proposed for two-hadron production in semi-inclusive deep inelastic scattering, where the asymmetry is weighted in a similar way for a single pair. This results in a collinear factorized form of the asymmetry, which includes the quark helicity parton distribution function and the same helicity-dependent DiFF, as in e^{+}e^{-} production and will allow us to check the universality of this DiFF.

Cardiac Output Measurements Based on the Pulse Wave Transit Time and Thoracic Impedance Exhibit Limited Agreement With Thermodilution Method During Orthotopic Liver Transplantation.

BACKGROUND: Orthotopic liver transplantation (OLT) is characterized by significant intraoperative hemodynamic variability. Accurate and real-time cardiac output (CO) monitoring aids clinical decision making during OLT. The purpose of this study is to compare accuracy, precision, and trending ability of CO estimation obtained noninvasively using pulse wave transit time (estimated continuous cardiac output [esCCO; Nihon Kohden, Tokyo, Japan]) or thoracic bioimpedance (ICON; Osypka Medical GmbH, Berlin, Germany) to thermodilution cardiac output (TDCO) measured with a pulmonary artery catheter. METHODS: Nineteen patients undergoing OLT were enrolled. CO measurements were collected with esCCO, ICON, and thermodilution at 5 time points: (T1) pulmonary artery catheter insertion; (T2) surgical incision; (T3) portal reperfusion; (T4) hepatic arterial reperfusion; and (T5) abdominal closure. The results were analyzed with Bland-Altman plot, percentage error (the percentage of the difference between the CO estimated with the noninvasive monitoring device and CO measured with the thermodilution technique), 4-quadrant plot with concordance rate (the percentage of the total number of points in the I and III quadrant of the 4-quadrant plot), and concordance correlation coefficient (a measure of how well the pairs of observations deviate from the 45-degree line of perfect agreement). RESULTS: Although TDCO increased at T3-T5, both esCCO and ICON failed to track the changes of CO with sufficient accuracy and precision. The mean bias of esCCO and ICON compared to TDCO were -2.0 L/min (SD, ±2.7 L/min) and -3.3 L/min (SD, ±2.8 L/min), respectively. The percentage error was 69% for esCCO and 77% for ICON. The concordance correlation coefficient was 0.653 (95% confidence interval [CI], 0.283-0.853) for esCCO and 0.310 (95% CI, -0.167 to 0.669) for ICON. Nonetheless, esCCO and ICON exhibited reasonable trending ability of TDCO (concordance rate: 95% [95% CI, 88-100] and 100% [95% CI, 93-100]), respectively. The mean bias was correlated with systemic vascular resistance (SVR) and arterial elastance (Ea) for esCCO (SVR, r = 0.610, 95% CI, 0.216-0.833, P < .0001; Ea, r = 0.692, 95% CI, 0.347-0.872; P < .0001) and ICON (SVR, r = 0.573, 95% CI, 0.161-0.815, P < .0001; Ea, r = 0.612, 95% CI, 0.219-0.834, P < .0001). CONCLUSIONS: The noninvasive CO estimation with esCCO and ICON exhibited limited accuracy and precision, despite with reasonable trending ability, when compared to TDCO, during OLT. The inaccuracy of esCCO and ICON is especially large when SVR and Ea were decreased during the neohepatic phase. Further refinement of the technology is desirable before noninvasive techniques can replace TDCO during OLT.

Development of diabetes does not alter behavioral and molecular circadian rhythms in a transgenic rat model of type 2 diabetes mellitus.

Metabolic state and circadian clock function exhibit a complex bidirectional relationship. Circadian disruption increases propensity for metabolic dysfunction, whereas common metabolic disorders such as obesity and type 2 diabetes (T2DM) are associated with impaired circadian rhythms. Specifically, alterations in glucose availability and glucose metabolism have been shown to modulate clock gene expression and function in vitro; however, to date, it is unknown whether development of diabetes imparts deleterious effects on the suprachiasmatic nucleus (SCN) circadian clock and SCN-driven outputs in vivo. To address this question, we undertook studies in aged diabetic rats transgenic for human islet amyloid polypeptide, an established nonobese model of T2DM (HIP rat), which develops metabolic defects closely recapitulating those present in patients with T2DM. HIP rats were also cross-bred with a clock gene reporter rat model (Per1:luciferase transgenic rat) to permit assessment of the SCN and the peripheral molecular clock function ex vivo. Utilizing these animal models, we examined effects of diabetes on 1) behavioral circadian rhythms, 2) photic entrainment of circadian activity, 3) SCN and peripheral tissue molecular clock function, and 4) melatonin secretion. We report that circadian activity, light-induced entrainment, molecular clockwork, as well as melatonin secretion are preserved in the HIP rat model of T2DM. These results suggest that despite the well-characterized ability of glucose to modulate circadian clock gene expression acutely in vitro, SCN clock function and key behavioral and physiological outputs appear to be preserved under chronic diabetic conditions characteristic of nonobese T2DM.