Monkeypox Virus Detection in Different Clinical Specimen Types.

A global monkeypox outbreak began in May 2022. Limited data exist on specimen type performance in associated molecular diagnostics. Consequently, a diverse range of specimen sources were collected in the initial weeks of the outbreak in Ontario, Canada. Our clinical evaluation identified skin lesions as the optimal diagnostic specimen source.

Low Rates of Linkage and Retention Into Care Among Patients With Chronic HBV Infection.

Successful linkage and retention of newly diagnosed hepatitis B virus (HBV) patients is critical for disease monitoring. Existing studies have demonstrated significant gaps in the HBV care continuum among U.S. veterans1 and have mostly focused on adherence to laboratory testing or initial linkage. However, retention is especially important, given that decisions to start antiviral therapies are often not made until subsequent evaluation, and studies report high rates of becoming treatment-eligible among patients who were not eligible at initial evaluation.2 Given the existing system and socioeconomic barriers in access to care, understanding contributors to gaps and delays in HBV linkage and retention among safety-net populations is critical. We aim to evaluate prevalence and predictors of linkage and retention among HBV patients at an urban safety-net hospital.

The macula densa prorenin receptor is essential in renin release and blood pressure control.

The prorenin receptor (PRR) was originally proposed to be a member of the renin-angiotensin system (RAS); however, recent work questioned their association. The present paper describes a functional link between the PRR and RAS in the renal juxtaglomerular apparatus (JGA), a classic anatomical site of the RAS. PRR expression was found in the sensory cells of the JGA, the macula densa (MD), and immunohistochemistry-localized PRR to the MD basolateral cell membrane in mouse, rat, and human kidneys. MD cell PRR activation led to MAP kinase ERK1/2 signaling and stimulation of PGE2 release, the classic pathway of MD-mediated renin release. Exogenous renin or prorenin added to the in vitro microperfused JGA-induced acute renin release, which was inhibited by removing the MD or by the administration of a PRR decoy peptide. To test the function of MD PRR in vivo, we established a new mouse model with inducible conditional knockout (cKO) of the PRR in MD cells based on neural nitric oxide synthase-driven Cre-lox recombination. Deletion of the MD PRR significantly reduced blood pressure and plasma renin. Challenging the RAS by low-salt diet + captopril treatment caused further significant reductions in blood pressure, renal renin, cyclooxygenase-2, and microsomal PGE synthase expression in cKO vs. wild-type mice. These results suggest that the MD PRR is essential in a novel JGA short-loop feedback mechanism, which is integrated within the classic MD mechanism to control renin synthesis and release and to maintain blood pressure.

Diagnostic test accuracy of a novel smartphone application for the assessment of attention deficits in delirium in older hospitalised patients: a prospective cohort study protocol.

BACKGROUND: Delirium is a common and serious clinical syndrome which is often missed in routine clinical care. The core cognitive feature is inattention. We developed a novel bedside neuropsychological test for assessing inattention in delirium implemented on a smartphone platform (DelApp). We aim to evaluate the diagnostic performance of the DelApp in a representative cohort of older hospitalised patients. METHODS: This is a prospective study of older non-scheduled hospitalised patients (target n = 500, age ≥ 65), recruited from elderly care and acute orthopaedic wards. Exclusion criteria are: non-English speakers; severe vision or hearing impairment; photosensitive epilepsy. A structured reference standard delirium assessment based on DSM-5 criteria will be used, which includes a cognitive test battery administered by a trained assessor (Orientation-Memory-Concentration Test, Abbreviated Mental Test-10, Delirium Rating Severity Scale-Revised-98, digit span, months and days backwards, Vigilance A' test) and assessment of arousal (Observational Scale of Level of Arousal, Richmond Agitation Sedation Scale). Prior change in cognition will be documented using the Informant Questionnaire on Cognitive Decline in the Elderly. Patients will be categorized as delirium (with/without dementia), possible delirium, dementia, no cognitive impairment, or undetermined. A separate assessor (blinded to diagnosis and assessments) will administer the DelApp index test within 3 h of the reference standard assessment. The DelApp comprises assessment of arousal (score 0-4) and sustained attention (score 0-6), yielding a total score between 0 and 10 (higher score = better performance). Outcomes (length of stay, mortality and discharge location) will be collected at 12 weeks. We will evaluate a priori cutpoints derived from a previous case-control study. Measures of the accuracy of DelApp will include sensitivity, specificity, positive and negative predictive values, and area under the ROC curve. We plan repeat assessments on up to 4 occasions in a purposive subsample of 30 patients (15 delirium, 15 no delirium) to examine changes over time. DISCUSSION: This study evaluates the diagnostic test accuracy of a novel smartphone test for delirium in a representative cohort of older hospitalised patients, including those with dementia. DelApp has the potential to be a convenient, objective method of improving delirium assessment for older people in acute care. TRIAL REGISTRATION: Clinical trials.gov, NCT02590796 . Registered on 29 Oct 2015. Protocol version 5, dated 25 July 2016.

Evaluation of Altona Diagnostics RealStar Zika Virus Reverse Transcription-PCR Test Kit for Zika Virus PCR Testing.

With the emerging Zika virus (ZIKV) epidemic, accessible real-time reverse transcription-PCR (rRT-PCR) assays are needed to streamline testing. The commercial Altona Diagnostics RealStar ZIKV rRT-PCR test kit (Altona PCR) has been approved for emergency use authorization by the U.S. FDA. Our aim was to verify the Altona PCR by comparing it to the CDC-designed dual-target ZIKV rRT-PCR reference assay (reference PCR) and describe the demographics of patients tested for ZIKV by rRT-PCR in Ontario, Canada. A large set of clinical specimens was tested for ZIKV by the Altona PCR and the reference PCR. Positive or equivocal specimens underwent PCR and Sanger sequencing targeting the ZIKV NS5 gene. A total of 671 serum specimens were tested by the reference PCR: 58 (8.6%) were positive, 193 (28.8%) were equivocal, and 420 (62.6%) were negative. Ninety percent of the reference PCR-positive patients were tested in the first 5 days after symptom onset. The Altona PCR was performed on 284/671 specimens tested by the reference PCR. The Altona PCR was positive for 53/58 (91%) reference PCR-positive specimens and 16/193 (8%) reference PCR-equivocal specimens; the ZIKV NS5 PCR was positive for all 68 Altona PCR-positive specimens and negative for all 181 Altona PCR-negative specimens that underwent the NS5 PCR. The Altona PCR has very good sensitivity (91%) and specificity (97%) compared to the reference PCR. The Altona PCR can be used for ZIKV diagnostic testing and has less extensive verification requirements than a laboratory-developed test.

Haemodynamic impact of stent implantation for lateral tunnel Fontan stenosis: a patient-specific computational assessment.

BACKGROUND: The physiological importance of the lateral tunnel stenosis in the Fontan pathway for children with single ventricle physiology can be difficult to determine. The impact of the stenosis and stent implantation on total cavopulmonary connection resistance has not been characterized, and there are no clear guidelines for intervention. Methods and results A computational framework for haemodynamic assessment of stent implantation in patients with lateral tunnel stenosis was developed. Cardiac magnetic resonances images were reconstructed to obtain total cavopulmonary connection anatomies before stent implantation. Stents with 2-mm diameter increments were virtually implanted in each patient to understand the impact of stent diameter. Numerical simulations were performed in all geometries with patient-specific flow rates. Exercise conditions were simulated by doubling and tripling the lateral tunnel flow rate. The resulting total cavopulmonary connection vascular resistances were computed. A total of six patients (age: 14.4 ± 3.1 years) with lateral tunnel stenosis were included for preliminary analysis. The mean baseline resistance was 1.54 ± 1.08 WU · m(2) and dependent on the stenosis diameter. It was further exacerbated during exercise. It was observed that utilising a stent with a larger diameter lowered the resistance, but the resistance reduction diminished at larger diameters. CONCLUSIONS: Using a computational framework to assess the severity of lateral tunnel stenosis and the haemodynamic impact of stent implantation, it was observed that stenosis in the lateral tunnel pathway was associated with higher total cavopulmonary connection resistance than unobstructed pathways, which was exacerbated during exercise. Stent implantation could reduce the resistance, but the improvement was specific to the minimum diameter.

Durability and survival are similar after elective endovascular and open repair of abdominal aortic aneurysms in younger patients.

OBJECTIVE: The role of endovascular repair (EVAR) of aortic aneurysms in young patients is controversial. The purpose of this study was to determine the long-term outcomes and reintervention rates in patients 60 years of age or younger who underwent elective open or endovascular repair of an abdominal aortic aneurysm. METHODS: Retrospective review of a prospectively collected vascular surgery database at a university-affiliated medical center was performed to identify all patients who underwent elective repair of an abdominal aortic aneurysm between 2000 and 2013 and were 60 years of age or younger at the time of the repair. Preoperative anatomic measurements were performed and compared with instructions for use (IFU) criteria for the endografts. RESULTS: The study cohort comprised 169 patients 60 years of age or younger (mean age, 56.7 ± 2.8 years) who underwent elective repair (119 open repair, 50 EVAR). Patients treated with open repair and EVAR had similar comorbidities, except that EVAR patients were more likely to have hypertension (P = .03) and poor left ventricular function (P = .04). The open repair group had significantly larger suprarenal (P = .004) and infrarenal (P = .005) neck angles, shorter neck lengths (P < .001), and larger maximum aneurysm diameter (P = .02) compared with the EVAR group. Only five patients (13%) in the EVAR group did not meet all IFU criteria. The overall in-hospital mortality rate was 1.8% (0% EVAR, 2.5% open repair; P = .56). Overall mean life expectancy was 11.5 years (9.8 years EVAR, 11.9 years open repair; P = .09). The 1-year (98% EVAR, 96% open repair), 5-year (86% EVAR, 88% open repair), and 10-year (54% EVAR, 75% open repair) survival did not differ between EVAR and open repair (P = .16). Long-term survival (78% EVAR, 85% open repair; P = .09) and reintervention rates (12% EVAR, 16% open repair; P = .80) did not differ. No late aneurysm rupture or aneurysm-related deaths were observed. The most common causes of long-term mortality were malignant disease and cardiovascular events. Reinterventions in the open repair group were exclusively laparotomy related (incisional hernia repairs), whereas all reinterventions in the EVAR group were aortic related, including one conversion to open repair. CONCLUSIONS: After elective aneurysm repair, younger patients have a moderate life expectancy related to malignant disease and cardiovascular health. EVAR offers durability and long-term survival similar to those with open repair in these younger patients as long as aneurysm anatomy and IFU are adhered to.

The prostamide-related glaucoma therapy, bimatoprost, offers a novel approach for treating scalp alopecias.

Balding causes widespread psychological distress but is poorly controlled. The commonest treatment, minoxidil, was originally an antihypertensive drug that promoted unwanted hair. We hypothesized that another serendipitous discovery, increased eyelash growth side-effects of prostamide F(2α)-related eyedrops for glaucoma, may be relevant for scalp alopecias. Eyelash hairs and follicles are highly specialized and remain unaffected by androgens that inhibit scalp follicles and stimulate many others. Therefore, we investigated whether non-eyelash follicles could respond to bimatoprost, a prostamide F(2α) analog recently licensed for eyelash hypotrichosis. Bimatoprost, at pharmacologically selective concentrations, increased hair synthesis in scalp follicle organ culture and advanced mouse pelage hair regrowth in vivo compared to vehicle alone. A prostamide receptor antagonist blocked isolated follicle growth, confirming a direct, receptor-mediated mechanism within follicles; RT-PCR analysis identified 3 relevant receptor genes in scalp follicles in vivo. Receptors were located in the key follicle regulator, the dermal papilla, by analyzing individual follicular structures and immunohistochemistry. Thus, bimatoprost stimulates human scalp follicles in culture and rodent pelage follicles in vivo, mirroring eyelash behavior, and scalp follicles contain bimatoprost-sensitive prostamide receptors in vivo. This highlights a new follicular signaling system and confirms that bimatoprost offers a novel, low-risk therapeutic approach for scalp alopecias.

Variability in perioperative management of pheochromocytoma in Canada.

INTRODUCTION: Despite recent consensus guidelines, there is substantial variability in the management of pheochromocytomas. Our study aimed to characterize the current state of perioperative pheochromocytoma management by Canadian surgeons. METHODS: A 23-item online survey was sent to Canadian surgeons who perform adrenalectomies for pheochromocytoma. We assessed personal and institutional practices, including preoperative and postoperative management. RESULTS: National response rate was 51.8%. Surgeons from nine provinces responded; the majority were general surgeons (70.4%). Reviewing pheochromocytoma patients at a multidisciplinary tumor board was not routine practice (12%) and only 42.3% consistently referred patients for genetic testing. Preoperative α- and ß-blockade at half of the respondent institutions were performed by endocrinology alone (53.8%), with the other half employing a multidisciplinary approach. Half of respondents admitted their pheochromocytoma patients to hospital prior to the day of surgery. Postoperatively, 11.5% of respondents routinely admitted their patients to the intensive care unit (ICU) for monitoring based on personal preference or institutional convention. Multivariate analyses found no significant relationships between demographics or preoperative factors and perioperative management. CONCLUSIONS: Perioperative surgical management of patients undergoing adrenalectomy for pheochromocytoma was highly variable across Canada. Less than half of respondents routinely refer patients for genetic testing, despite recent practice guidelines. Surgeon preference and institutional convention are the main drivers behind preoperative admission and routine postoperative ICU admission, despite a lack of evidence to support this practice.

User Experience of a Just-in-Time Smartphone Resonance Breathing Application for Substance Use Disorder: Acceptability, Appropriateness, and Feasibility.

BACKGROUND: Addressing the negative impact of substance use disorders (SUDs) on individuals, families, and communities is a public health priority. Most treatments and interventions require engagement with a healthcare provider or someone who can offer recovery support. The need for interventions that facilitate self-management of relapse triggers at the moment they occur is also critical. Our study aimed to explore the user experience of individuals using a just-in-time smartphone episodic resonance breathing (eRPB) intervention to address stress, anxiety, and drug cravings. METHODS: We conducted an 8-week pilot study of the eRPB with 30 individuals in recovery from SUD. Data on 3 indicators of user experience-acceptability, appropriateness, and feasibility-were collected using survey questions (n = 30) and semi-structured interviews (n = 11). We performed univariate analysis on the survey data and deductive thematic analysis on the qualitative data. RESULTS: A majority of the survey respondents agreed that the application (app) was acceptable (> 77%), appropriate (> 82%), and feasible (> 89%). Several interview participants stated that the app helped them relax and manage stress and cravings and expressed appreciation for the simplicity of its design. Participants also reported barriers to feasibility (such as forgetting to use the app) and recommendations for improvement (such as the addition of motivational messages). CONCLUSIONS: Our findings show that individuals in recovery from SUD had highly positive experiences with the eRPB app. A positive user experience may improve adherence to the intervention and, ultimately, the self-management of stress, anxiety, and craving relapse triggers.

Hemodynamic effects of implanting a unidirectional valve in the inferior vena cava of the Fontan circulation pathway: an in vitro investigation.

The Fontan surgical procedure used for treating patients with single ventricle congenital heart disorders results in a total cavopulmonary connection (TCPC) of the vena cavae to the pulmonary arteries (PAs). Sluggish TCPC flow and elevated hepatic venous pressures are commonly observed in this altered physiology, which in turn can lead to long-term complications including liver congestion and cirrhosis. The hypothesis of this study is that placement of a unidirectional valve within the inferior vena cava (IVC) will improve hemodynamics of the Fontan circulation by preventing retrograde flow and lowering hepatic venous pressure. An in vitro experimental setup consisting of an idealized TCPC model with flexible walls was used for investigation, and a bovine venous valve was inserted in the IVC below the TCPC. Pressure fluctuations were introduced in the flow through the model to simulate venous pulsatility. Hemodynamics of baseline and valve-implanted conditions were compared across total caval flows ranging from 1.0 to 2.5 l/min with varying caval flow distributions. The results indicated that valve closure occurred for 15-20% of the total cycle, with consequent reduction in the upstream hepatic venous pressure by 5 to 10 mmHg. Energy loss (EL) through the TCPC was lowered with valve implantation to 20-50% of baseline, occurring across all flow conditions considered with mean caval and PA pressures greater than 10 mmHg. The results of this in vitro modeling suggest that IVC valve placement has the potential to improve hemodynamics in the Fontan circulation by decreasing hepatic venous hypertension and EL.

The biodisposition and hypertrichotic effects of bimatoprost in mouse skin.

Studies on bimatoprost were performed with two objectives: (i) to determine whether bimatoprost possesses hair growth-stimulating properties beyond eyelash hypertrichosis and (ii) to investigate the biodisposition of bimatoprost in skin for the first time. Bimatoprost, at the dose used clinically for eyelash growth (0.03%) and given once daily for 14 days, increased pelage hair growth in C57/black 6 mice. This occurred as a much earlier onset of new hair growth in shaved mice and the time taken to achieve complete hair regrowth, according to photographic documentation and visual assessment. Bimatoprost biodisposition in the skin was determined at three concentrations: 0.01%, 0.03% and 0.06%. Dose-dependent C(max) values were obtained (3.41, 6.74, 12.3 µg/g tissue), and cutaneous bimatoprost was well maintained for 24 h following a single dose. Bimatoprost was recovered from the skin only as the intact molecule, with no detectable levels of metabolites. Thus, bimatoprost produces hypertrichosis as the intact molecule.

Septic arthritis caused by Mycoplasma hominis in a patient with systemic lupus erythematosus.

Mycoplasma hominis is one of the most common commensal organisms of the genitourinary tract. Immunocompromised patients are susceptible to developing severe infections secondary to M. hominis, and rarely, septic arthritis. This case report describes the occurrence of septic arthritis secondary to M. hominis in a 27-year-old woman with systemic lupus erythematosus (SLE), who presented with a 2-week history of left elbow swelling and tenderness, elevated inflammatory markers and joint aspiration findings consistent with infection. Serial blood cultures were negative. She was treated with flucloxacillin; however, failed to respond and so doxycycline was added to cover for atypical organisms. Subsequently, PCR analysis from the joint aspirate found M. hominis on day 16. Fortunately, doxycycline was an effective treatment for this atypical organism. This case outlines the importance of considering atypical organisms such as M. hominis as a cause of septic arthritis in immunosuppressed patients especially those with SLE.

Fontan Geometry and Hemodynamics Are Associated With Quality of Life in Adolescents and Young Adults.

BACKGROUND: Despite favorable short-term outcomes, Fontan palliation is associated with comorbidities and diminished quality of life (QOL) in the years after completion. We hypothesized that poor Fontan hemodynamics and ventricular function are associated with worse QOL. METHODS: This was a single-center study of Fontan survivors aged more than 12 years. Subjects completed a cardiac magnetic resonance scan and QOL questionnaire. Cardiac magnetic resonance-derived variables included Fontan geometry, and hemodynamics. Computational fluid dynamics simulations quantified power loss, pressure drop, and total cavopulmonary connection resistance across the Fontan. Quality of life was assessed by completion of the Pediatric Quality of Life Inventory. Longitudinal and cross-sectional comparisons were made between cardiac magnetic resonance and computational fluid dynamics parameters with patient-reported QOL. RESULTS: We studied 77 Fontan patients, median age 19.7 years (interquartile range, 17.1 to 23.6), median time from Fontan completion 16 years (interquartile range, 13 to 20). Longitudinal data were available for 48 patients; median time between cardiac magnetic resonance and QOL was 8.1 years (interquartile range, 7 to 9.4). Median patient-reported Pediatric Quality of Life Inventory total score was 80 (interquartile range, 67.4 to 88). Greater power loss and smaller left pulmonary artery diameter at baseline were associated with worse QOL at follow-up. Greater pressure drop was associated with worse QOL at the same time point. CONCLUSIONS: For Fontan survivors, measures of computational fluid dynamics hemodynamics and geometry are associated with worse QOL. Interventional strategies targeted at optimizing the Fontan may improve QOL.

Fluid-Structure Interaction Simulation of an Intra-Atrial Fontan Connection.

Total cavopulmonary connection (TCPC) hemodynamics has been hypothesized to be associated with long-term complications in single ventricle heart defect patients. Rigid wall assumption has been commonly used when evaluating TCPC hemodynamics using computational fluid dynamics (CFD) simulation. Previous study has evaluated impact of wall compliance on extra-cardiac TCPC hemodynamics using fluid-structure interaction (FSI) simulation. However, the impact of ignoring wall compliance on the presumably more compliant intra-atrial TCPC hemodynamics is not fully understood. To narrow this knowledge gap, this study aims to investigate impact of wall compliance on an intra-atrial TCPC hemodynamics. A patient-specific model of an intra-atrial TCPC is simulated with an FSI model. Patient-specific 3D TCPC anatomies were reconstructed from transverse cardiovascular magnetic resonance images. Patient-specific vessel flow rate from phase-contrast magnetic resonance imaging (MRI) at the Fontan pathway and the superior vena cava under resting condition were prescribed at the inlets. From the FSI simulation, the degree of wall deformation was compared with in vivo wall deformation from phase-contrast MRI data as validation of the FSI model. Then, TCPC flow structure, power loss and hepatic flow distribution (HFD) were compared between rigid wall and FSI simulation. There were differences in instantaneous pressure drop, power loss and HFD between rigid wall and FSI simulations, but no difference in the time-averaged quantities. The findings of this study support the use of a rigid wall assumption on evaluation of time-averaged intra-atrial TCPC hemodynamic metric under resting breath-held condition.

Impact of Free-Breathing Phase-Contrast MRI on Decision-Making in Fontan Surgical Planning.

Fontan surgical planning ranks proposed surgical options according to their hemodynamics assessed by computational fluid dynamic (CFD) modeling. CFD commonly utilizes blood flow acquired under breath-holding (BH) conditions. Ignoring the free-breathing (FB) effect on blood flow waveforms may impact the ranking of surgical options. This study investigates such a potential impact by including ten Fontan patients who had blood flow acquisitions under both BH and FB conditions. A virtual surgery platform was used to generate two surgical options for each patient: (1) a traditional Fontan conduit and (2) a Y-graft. These options were ranked based on clinically relevant hemodynamic metrics: power loss (PL) and hepatic flow distribution (HFD). No difference was found in the ranking of options between using FB and BH flow acquisitions. The findings indicated that decision-making is not affected by the types of flow acquisition for Fontan surgical planning.

A smartphone-based test for the assessment of attention deficits in delirium: A case-control diagnostic test accuracy study in older hospitalised patients.

BACKGROUND: Delirium is a common and serious acute neuropsychiatric syndrome which is often missed in routine clinical care. Inattention is the core cognitive feature. Diagnostic test accuracy (including cut-points) of a smartphone Delirium App (DelApp) for assessing attention deficits was assessed in older hospital inpatients. METHODS: This was a case-control study of hospitalised patients aged ≥65 years with delirium (with or without pre-existing cognitive impairment), who were compared to patients with dementia without delirium, and patients without cognitive impairment. Reference standard delirium assessment, which included a neuropsychological test battery, was based on Diagnostic and Statistical Manual of Mental Disorders-5 criteria. A separate blinded assessor administered the DelApp arousal assessment (score 0-4) and attention task (0-6) yielding an overall score of 0 to 10 (lower scores indicate poorer performance). Analyses included receiver operating characteristic curves and sensitivity and specificity. Optimal cut-points for delirium detection were determined using Youden's index. RESULTS: A total of 187 patients were recruited, mean age 83.8 (range 67-98) years, 152 (81%) women; n = 61 with delirium; n = 61 with dementia without delirium; and n = 65 without cognitive impairment. Patients with delirium performed poorly on the DelApp (median score = 4/10; inter-quartile range 3.0, 5.5) compared to patients with dementia (9.0; 5.5, 10.0) and those without cognitive impairment (10.0; 10.0, 10.0). Area under the curve for detecting delirium was 0.89 (95% Confidence Interval 0.84, 0.94). At an optimal cut-point of ≤8, sensitivity was 91.7% (84.7%, 98.7%) and specificity 74.2% (66.5%, 81.9%) for discriminating delirium from the other groups. Specificity was 68.3% (56.6%, 80.1%) for discriminating delirium from dementia (cut-point ≤6). CONCLUSION: Patients with delirium (with or without pre-existing cognitive impairment) perform poorly on the DelApp compared to patients with dementia and those without cognitive impairment. A cut-point of ≤8/10 is suggested as having optimal sensitivity and specificity. The DelApp is a promising tool for assessment of attention deficits associated with delirium in older hospitalised adults, many of whom have prior cognitive impairment, and should be further validated in representative patient cohorts.

Alpha-1-adrenergic receptor agonist activity of clinical alpha-adrenergic receptor agonists interferes with alpha-2-mediated analgesia.

BACKGROUND: The use of alpha-2 adrenergic agonists for analgesia is limited due to a narrow therapeutic window. Definition of the role of alpha receptor subtypes in alpha agonist mediated analgesia may identify strategies to separate the analgesic from sedative and cardiovascular effects. METHODS: Analgesic activity of brimonidine, clonidine, and tizanidine was investigated in wild-type C57B/6, alpha-2A, and alpha-2C knockout mice with allodynia induced by N-methyl-D-aspartate or sulprostone. The alpha receptor selectivity of the alpha agonists was assessed using functional in vitro recombinant assays. RESULTS: Brimonidine, clonidine, and tizanidine reduced N-methyl-D-aspartate- and sulprostone-induced allodynia in wild-type mice, but not alpha-2A knockout mice. In alpha-2C knockout mice, brimonidine and tizanidine reduced allodynia in both models, whereas clonidine only reduced N-methyl-D-aspartate-induced allodynia. In vitro, clonidine and tizanidine activated alpha-1 and alpha-2 receptors with similar potencies, whereas brimonidine was selective for alpha-2 receptors. In alpha-2C knockout mice with sulprostone-induced allodynia, blockade of clonidine's alpha-1 receptor agonist activity restored clonidine's analgesic efficacy. In wild-type mice, the analgesic potency of intrathecal clonidine and tizanidine was increased 3- to 10-fold by coadministration with the alpha-1A-selective antagonist 5-methylurapidil without affecting sedation. Following intraperitoneal administration, the therapeutic window was negligible for clonidine and tizanidine, but greater for brimonidine. 5-Methylurapidil enhanced the therapeutic window of intraperitoneal clonidine and tizanidine approximately 10-fold. CONCLUSIONS: Alpha-1A receptor agonist activity can counterbalance alpha-2 receptor agonist-induced analgesia. Greater alpha-2 selectivity may enhance the therapeutic window of alpha-2 agonists in the treatment of pain.

The effect of respiration-driven flow waveforms on hemodynamic metrics used in Fontan surgical planning.

OBJECTIVE: Poor total cavopulmonary connection (TCPC) hemodynamics have been hypothesized to be associated with long-term complications in Fontan patients. Image-based Fontan surgical planning has shown great potential as a clinical tool because it can pre-operatively evaluate patient-specific hemodynamics. Current surgical planning paradigms commonly utilize cardiac-gated phase contrast magnetic resonance (MR) imaging to acquire vessel flows. These acquisitions are often taken under breath-held (BH) conditions and ignore the effect of respiration on blood flow waveforms. This study investigates the effect of respiration-driven flow waveforms on patient-specific hemodynamics using real-time MR acquisitions. METHODS: Patient-specific TCPCs were reconstructed from cardiovascular MR images. Real-time phase contrast MR images were acquired under both free-breathing (FB) and breath-held conditions for 9 patients. Numerical simulations were employed to assess flow structures and hemodynamics used in Fontan surgical planning including hepatic flow distribution (HFD) and indexed power loss (iPL), which were then compared between FB and BH conditions. RESULTS: Differences in TCPC flow structures between FB and BH conditions were observed throughout the respiratory cycle. However, the average differences (BH - FB values for each patient, which are then averaged) in iPL and HFD between these conditions were 0.002 ±â€¯0.011 (p = 0.40) and 1 ±â€¯3% (p = 0.28), respectively, indicating no significant difference in clinically important hemodynamic metrics. CONCLUSIONS: Respiration affects blood flow waveforms and flow structures, but might not significantly influence the values of iPL or HFD. Therefore, breath-held MR acquisition can be adequate for Fontan surgical planning when focusing on iPL and HFD.

High Prevalence of Cirrhosis at Initial Presentation Among Safety-Net Adults with Chronic Hepatitis B Virus Infection.

BACKGROUND AND AIMS: Delays in diagnosis of chronic hepatitis B virus infection (HBV) may be more common among underserved safety-net populations, contributing to more advanced disease at presentation. We aim to evaluate rates of and predictors of cirrhosis and cirrhosis-related complications among adults with chronic HBV. METHODS: We retrospectively evaluated consecutive chronic HBV adults from gastroenterology clinics from July 2014 to May 2016 at a community-based safety-net hospital. Prevalence of cirrhosis or cirrhosis-related complications (ascites, variceal bleeding, hepatic encephalopathy (HE), hepatocellular carcinoma (HCC)) at initial presentation was stratified by sex and race/ethnicity. Predictors of cirrhosis or cirrhosis-related complications at presentation were evaluated with multivariate logistic regression. RESULTS: Among 329 chronic HBV patients (mean age 49.1 years, 55.3% male, 66.5% Asian, 18.6% HBeAg positive) 27.7% had cirrhosis at presentation, 4.3% ascites, 3.7% variceal bleeding, 4.9% HE, and 4.0% HCC. Compared to women, men were more likely to have cirrhosis (34.6% vs. 19.1%, P < 0.01) and variceal bleeding (5.6% vs. 1.4%, P < 0.05) at presentation. On multivariate regression, older age at presentation (OR, 1.04; 95% CI, 1.01-1.07; P = 0.003) and positive HBeAg (OR, 2.57; 95% CI, 1.20-5.51; P = 0.015) were associated with higher odds of cirrhosis at presentation, whereas men had a non-significant trend toward higher odds of cirrhosis (OR, 1.88; 95% CI, 0.99-3.58; P = 0.055). CONCLUSION: Among adults with chronic HBV at an ethnically diverse safety-net hospital system, nearly 30% of patients had cirrhosis at initial presentation, with the greatest risk seen among patients of male sex, older age, and with positive HBeAg.