Viral SARS-CoV-2 Rebound Rates in Linked Commercial Pharmacy-Based Testing and Health Care Claims.

Background: Viral SARS-CoV-2 rebound (viral RNA rebound) is challenging to characterize in large cohorts due to the logistics of collecting frequent and regular diagnostic test results. Pharmacy-based testing data provide an opportunity to study the phenomenon in a large population, also enabling subgroup analyses. The current real-world evidence approach complements approaches focused on smaller, prospective study designs. Methods: We linked real-time reverse transcription quantitative polymerase chain reaction test data from national pharmacy-based testing to health care claims data via tokenization to calculate the cumulative incidence of viral RNA rebound within 28 days following positive test results in nirmatrelvir/ritonavir (NMV-r)-treated and untreated individuals during the Omicron era (December 2021-November 2022) and prior to the Omicron era (October 2020-November 2021). Results: Among 30 646 patients, the rate of viral RNA rebound was 3.5% (95% CI, 2.0%-5.7%) in NMV-r-treated infections as compared with 1.5% (95% CI, 1.3%-1.7%) in untreated infections during the Omicron era and 1.9% (95% CI, 1.7%-2.1%) prior to the Omicron era. Viral RNA rebound in patients who were vaccinated (n = 8151), high risk (n = 4411), or older (≥65 years, n = 4411) occurred at comparable rates to the overall cohort (range, 1.1%-4.8%). Viral rebounds to high RNA levels in NMV-r-treated infections occurred in 8% of viral rebounds as compared with 5% to 11% in untreated infections. Rates of hospitalization were comparable between patients with NMV-r-treated infections with viral RNA rebound (0%) and untreated patients with viral RNA rebound (0%-1.2%). Conclusions: Our findings suggest viral RNA rebound is rare (< 5%), with rates that were consistent with those from the EPIC-HR trial (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients). Most occurrences of viral RNA rebound were associated with low viral RNA levels, and viral RNA rebound progression to severe disease was not observed.

Locomotor play behavior evolves by random genetic drift but not as a correlated response to selective breeding for high voluntary wheel-running behavior.

Locomotor play is vigorous and seemingly purposeless behavior, commonly observed in young mammals. It can be costly in terms of energy expenditure, increased injury risk, and predator exposure. The main hypothesized benefit of locomotor play is enhancement of neuromuscular development, with effects persisting into adulthood. We hypothesized that levels of locomotor play would have evolved as a correlated response to artificial selection for increased voluntary exercise behavior. We studied mice from 4 replicate lines bred for voluntary wheel running (High Runner or HR) at 6-8 weeks of age and four non-selected Control (C) lines. Mice were weaned at 21 days of age and play behavior was observed for generations 20 (22-24 days old), 68 (22-23 days old), and 93 (15 days old). We quantified locomotor play as (1) rapid, horizontally directed jerk-run sequences and (2) vertical "bouncing." We used focal sampling to continuously record behavior in cages containing 4-6 individuals during the first 2-3 h of the dark cycle. Observations were significantly repeatable between observers and days. A two-way, mixed-model simultaneously tested effects of linetype (HR vs. C), sex, and their interaction. Contrary to our hypothesis, HR and C lines did not differ in any generation, nor did we find sex differences. However, differences among the replicate HR lines and among the replicate C lines were detected, and may be attributed to the effects of random genetic drift (and possibly founder effects). Thus, play behavior did evolve in this selection experiment, but not as a correlated response to selection for voluntary exercise.

Comparison of platelet quality and function across apheresis collection platforms.

BACKGROUND: Platelet concentrates (PLT) can be manufactured using a combination of apheresis collection devices and suspension media (plasma or platelet additive solution (PAS)). It is unclear how platelet quality and hemostatic function differ across the current in-use manufacturing methods in the United States. The objective of this study was therefore to compare baseline function of PLT collected using different apheresis collection platforms and storage media. STUDY DESIGN AND METHODS: PLT were collected at two sites with identical protocols (N = 5 per site, N = 10 total per group) on the MCS® + 9000 (Haemonetics; "MCS"), the Trima Accel® 7 (Terumo; "Trima"), and the Amicus Cell Separator (Fresenius Kabi, "Amicus"). MCS PLT were collected into plasma while Trima and Amicus PLT were collected into plasma or PAS (Trima into Isoplate and Amicus into InterSol; yielding groups "TP", "TI" and "AP", "AI", respectively). PLT units were sampled 1 h after collection and assayed to compare cellular counts, biochemistry, and hemostatic function. RESULTS: Differences in biochemistry were most evident between plasma and PAS groups, as anticipated. MCS and TP had the highest clot strength as assessed by viscoelastometry. AI had the lowest thrombin generation capacity. Both TP and TI had the highest responses on platelet aggregometry. AI had the greatest number of microparticles. DISCUSSION: Platelet quality and function differ among collection platforms at baseline. MCS and Trima platelets overall appear to trend toward higher hemostatic function. Future investigations will assess how these differences change throughout storage, and if these in vitro measures are clinically relevant.

Relationship Between High Blood Pressure, Atrial Cardiopathy, and Mortality in the General Population.

BACKGROUND: Atrial cardiopathy is associated with an increased risk of mortality. However, it is unclear whether this association is modified by hypertension, a risk factor for both atrial cardiopathy and mortality. METHODS: This analysis included 8,023 participants from the Third National Health and Nutrition Examination Survey. Electrocardiographic deep terminal negativity of P-wave in V1 ≥100 µV defined atrial cardiopathy. National Death Index was used to identify the date and cause of death. Cox proportional hazard analysis was used to examine the association of atrial cardiopathy with mortality among participants stratified by hypertension status. RESULTS: In total 2.7% of the participants had atrial cardiopathy. Over a median follow-up of 14 years, 2,922 all-cause deaths occurred, of which 1,058 were CVD. All-cause death rates were almost double among participants with concomitant atrial cardiopathy and elevated blood pressure (BP) (120-129/<80), stage 1 (130-139/80-89), or stage 2 hypertension (≥140/≥90) compared to their counterparts in the same hypertension stages without atrial cardiopathy (47.8, 61.3, and 80.2 vs. 23, 24.7, and 44.8 per 1,000 person-years (PY), respectively). In multivariable-adjusted models, a stronger association between atrial cardiopathy and all-cause mortality was observed in the presence compared to the absence of hypertension (HR (95% CI): 1.59 (1.25-2.01) vs. 0.67 (0.41-1.10), respectively, interaction P-value = 0.009). Similarly, an association between atrial cardiopathy and cardiovascular disease (CVD) mortality was observed in the presence compared to the absence of hypertension (HR (95% CI): 1.64 (1.08-2.47) vs. 0.63 (0.20-2.00), respectively, interaction P-value = 0.20). CONCLUSIONS: Concomitant presence of high BP and atrial cardiopathy carries a higher risk of mortality, and the risk increases with higher BP levels.

Clinician vs. imaging-based subthalamic nucleus deep brain stimulation programming.

INTRODUCTION: We sought to explore whether electrode visualization tools (EVT) can accurately predict the selection of optimal Deep Brain Stimulation (DBS) electrode contacts. METHODS: Twelve patients with Parkinson's disease (PD) undergoing STN-DBS at The Ohio State University were enrolled in a prospective analysis to evaluate the accuracy of EVT-based vs. standard DBS programming. EVTs were generated by the Surgical Information Sciences (SIS) system to develop a 3D model showing the implanted lead location relative to the STN. Then, imaging-based data were compared to the results of a standard monopolar review to evaluate concordance with clinical data and time spent selecting useable, non-useable, and borderline electrode contacts. RESULTS: A total of 18 DBS leads (n = 68 electrode contacts) were analyzed. The concordance between EVT and standard clinical programming expressed as the kappa coefficient was 0.65 (82.35% raw agreement) for non-useable, 0.52 for useable (64.71% raw agreement), and 0.52 for borderline (58.82% raw agreement). The average time spent determining whether an electrode contact was useable, non-useable, or borderline was 1.46 ± 0.76 min with EVT vs. 61.25 ± 17.47 with standard monopolar review. Eight different categories of side effects were identified, with facial pulling and speech difficulties being observed with the most frequency. The type of side effect observed was accurately predicted using EVT 90% of the time. CONCLUSIONS: This study demonstrates that next-generation EVT-based programming can be implemented into STN-DBS programming workflows with a considerable saving of time and effort spent in testing combinations of stimulation settings, particularly for the identification of non-useable electrode contacts.

17ß-estradiol ameliorates delirium-like phenotypes in a murine model of urinary tract infection.

Urinary tract infections (UTIs) are common and frequently precipitate delirium-like states. Advanced age coincident with the postmenopausal period is a risk factor for delirium following UTIs. We previously demonstrated a pathological role for interleukin-6 (IL-6) in mediating delirium-like phenotypes in a murine model of UTI. Estrogen has been implicated in reducing peripheral IL-6 expression, but it is unknown whether the increased susceptibility of postmenopausal females to developing delirium concomitant with UTIs reflects diminished effects of circulating estrogen. Here, we tested this hypothesis in a mouse model of UTI. Female C57BL/6J mice were oophorectomized, UTIs induced by transurethral inoculation of E. coli, and treated with 17ß-estradiol. Delirium-like behaviors were evaluated prior to and following UTI and 17ß-estradiol treatment. Compared to controls, mice treated with 17ß-estradiol had less neuronal injury, improved delirium-like behaviors, and less plasma and frontal cortex IL-6. In vitro studies further showed that 17ß-estradiol may also directly mediate neuronal protection, suggesting pleiotropic mechanisms of 17ß-estradiol-mediated neuroprotection. In summary, we demonstrate a beneficial role for 17ß-estradiol in ameliorating acute UTI-induced structural and functional delirium-like phenotypes. These findings provide pre-clinical justification for 17ß-estradiol as a therapeutic target to ameliorate delirium following UTI.

Prone positioning reduces frontal and hippocampal neuronal dysfunction in a murine model of ventilator-induced lung injury.

Prone positioning is an established treatment for severe acute lung injury conditions. Neuronal dysfunction frequently occurs with mechanical ventilation-induced acute lung injury (VILI) and clinically manifests as delirium. We previously reported a pathological role for systemic interleukin 6 (IL-6) in mediating neuronal injury. However, currently no studies have investigated the relationship between prone or supine positioning and IL-6 mediated neuronal dysfunction. Here, we hypothesize that prone positioning mitigates neuronal injury, via decreased IL-6, in a model of VILI. VILI was induced by subjecting C57BL/6J mice to high tidal volume (35 cc/kg) mechanical ventilation. Neuronal injury markers [cleaved caspase-3 (CC3), c-fos, heat shock protein 90 (Hsp90)] and inflammatory cytokines (IL-6, IL-1ß, TNF-α) were measured in the frontal cortex and hippocampus. We found statistically significantly less neuronal injury (CC3, c-Fos, Hsp90) and inflammatory cytokines (IL-6, IL-1ß, TNF-α) in the frontal cortex and hippocampus with prone compared to supine positioning (p < 0.001) despite no significant group differences in oxygen saturation or inflammatory infiltrates in the bronchoalveolar fluid (p > 0.05). Although there were no group differences in plasma IL-6 concentrations, there was significantly less cortical and hippocampal IL-6 in the prone position (p < 0.0001), indicating supine positioning may enhance brain susceptibility to systemic IL-6 during VILI via the IL-6 trans-signaling pathway. These findings call for future clinical studies to assess the relationship between prone positioning and delirium and for investigations into novel diagnostic or therapeutic paradigms to mitigate delirium by reducing expression of systemic and cerebral IL-6.

Evaluation of the Victorian Healthy Homes Program: protocol for a randomised controlled trial.

INTRODUCTION: The evaluation of the Victorian Healthy Homes Program (VHHP) will generate evidence about the efficacy and cost-effectiveness of home upgrades to improve thermal comfort, reduce energy use and produce health and economic benefits to vulnerable households in Victoria, Australia. METHODS AND ANALYSIS: The VHHP evaluation will use a staggered, parallel group clustered randomised controlled trial to test the home energy intervention in 1000 households. All households will receive the intervention either before (intervention group) or after (control group) winter (defined as 22 June to 21 September). The trial spans three winters with differing numbers of households in each cohort. The primary outcome is the mean difference in indoor average daily temperature between intervention and control households during the winter period. Secondary outcomes include household energy consumption and residential energy efficiency, self-reported respiratory symptoms, health-related quality of life, healthcare utilisation, absences from school/work and self-reported conditions within the home. Linear and logistic regression will be used to analyse the primary and secondary outcomes, controlling for clustering of households by area and the possible confounders of year and timing of intervention, to compare the treatment and control groups over the winter period. Economic evaluation will include a cost-effectiveness and cost-benefit analysis. ETHICS AND DISSEMINATION: Ethical approval was received from Victorian Department of Human Services Human Research Ethics Committee (reference number: 04/17), University of Technology Sydney Human Research Ethics Committee (reference number: ETH18-2273) and Australian Government Department of Veterans Affairs. Study results will be disseminated in a final report and peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12618000160235.

Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome.

In an exploratory trial treating "long COVID" with the CCR5-binding antibody leronlimab, we observed significantly increased blood cell surface CCR5 in treated symptomatic responders but not in nonresponders or placebo-treated participants. These findings suggest an unexpected mechanism of abnormal immune downmodulation in some persons that is normalized by leronlimab. Clinical Trials Registration. NCT04678830.

Suppression of human and simian immunodeficiency virus replication with the CCR5-specific antibody Leronlimab in two species.

The CCR5-specific antibody Leronlimab is being investigated as a novel immunotherapy that can suppress HIV replication with minimal side effects. Here we studied the virological and immunological consequences of Leronlimab in chronically CCR5-tropic HIV-1 infected humans (n = 5) on suppressive antiretroviral therapy (ART) and in ART-naïve acutely CCR5-tropic SHIV infected rhesus macaques (n = 4). All five human participants transitioned from daily combination ART to self-administered weekly subcutaneous (SC) injections of 350 mg or 700 mg Leronlimab and to date all participants have sustained virologic suppression for over seven years. In all participants, Leronlimab fully occupied CCR5 receptors on peripheral blood CD4+ T cells and monocytes. In ART-naïve rhesus macaques acutely infected with CCR5-tropic SHIV, weekly SC injections of 50 mg/kg Leronlimab fully suppressed plasma viremia in half of the macaques. CCR5 receptor occupancy by Leronlimab occurred concomitant with rebound of CD4+ CCR5+ T-cells in peripheral blood, and full CCR5 receptor occupancy was found in multiple anatomical compartments. Our results demonstrate that weekly, self-administered Leronlimab was safe, well-tolerated, and efficacious for long-term virologic suppression and should be included in the arsenal of safe, easily administered, longer-acting antiretroviral treatments for people living with HIV-1. Trial Registration: ClinicalTrials.gov Identifiers: NCT02175680 and NCT02355184.

Strategies for Imputation of High-Resolution Environmental Data in Clinical Randomized Controlled Trials.

Time series data collected in clinical trials can have varying degrees of missingness, adding challenges during statistical analyses. An additional layer of complexity is introduced for missing data in randomized controlled trials (RCT), where researchers must remain blinded between intervention and control groups. Such restriction severely limits the applicability of conventional imputation methods that would utilize other participants' data for improved performance. This paper explores and compares various methods to impute high-resolution temperature logger data in RCT settings. In addition to the conventional non-parametric approaches, we propose a spline regression (SR) approach that captures the dynamics of indoor temperature by time of day that is unique to each participant. We investigate how the inclusion of external temperature and energy use can improve the model performance. Results show that SR imputation results in 16% smaller root mean squared error (RMSE) compared to conventional imputation methods, with the gap widening to 22% when more than half of data is missing. The SR method is particularly useful in cases where missingness occurs simultaneously for multiple participants, such as concurrent battery failures. We demonstrate how proper modelling of periodic dynamics can lead to significantly improved imputation performance, even with limited data.

CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab.

CCR5 plays a central role in infectious disease, host defense, and cancer progression, thereby making it an ideal target for therapeutic development. Notably, CCR5 is the major HIV entry co-receptor, where its surface density correlates with HIV plasma viremia. The level of CCR5 receptor occupancy (RO) achieved by a CCR5-targeting therapeutic is therefore a critical predictor of its efficacy. However, current methods to measure CCR5 RO lack sensitivity, resulting in high background and overcalculation. Here, we report on two independent, flow cytometric methods of calculating CCR5 RO using the anti-CCR5 antibody, Leronlimab. We show that both methods led to comparable CCR5 RO values, with low background on untreated CCR5+CD4+ T cells and sensitive measurements of occupancy on both blood and tissue-resident CD4+ T cells that correlated longitudinally with plasma concentrations in Leronlimab-treated macaques. Using these assays, we found that Leronlimab stabilized cell surface CCR5, leading to an increase in the levels of circulating and tissue-resident CCR5+CD4+ T cells in vivo in Leronlimab-treated macaques. Weekly Leronlimab treatment in a chronically SIV-infected macaque led to increased CCR5+CD4+ T cells levels and fully suppressed plasma viremia, both concomitant with full CCR5 RO on peripheral blood CD4+ T cells, demonstrating that CCR5+CD4+ T cells were protected from viral replication by Leronlimab binding. Finally, we extended these results to Leronlimab-treated humans and found that weekly 700 mg Leronlimab led to complete CCR5 RO on peripheral blood CD4+ T cells and a statistically significant increase in CCR5+CD4+ T cells in peripheral blood. Collectively, these results establish two RO calculation methods for longitudinal monitoring of anti-CCR5 therapeutic antibody blockade efficacy in both macaques and humans, demonstrate that CCR5+CD4+ T cell levels temporarily increase with Leronlimab treatment, and facilitate future detailed investigations into the immunological impacts of CCR5 inhibition in multiple pathophysiological processes.

Factors Associated With Laser Trabeculoplasty Response Duration: Analysis of a Large Clinical Database (IRIS Registry).

PRCIS: In eyes with trabeculoplasty response, those with lower baseline pressure, angle recession or uveitis had shorter survival. Eyes without medications before treatment remained medication-free for a median of 197 days. PURPOSE: We examined patients in a large clinical registry to assess factors associated with laser trabeculoplasty (LTP) response durations. METHODS: This is a retrospective cohort study with LTP patients in the Intelligent Research in Sight Registry. Data were extracted if the eye had a LTP procedure code and a glaucoma diagnosis. In responders [≥20% intraocular pressure (IOP) reduction], any post-LTP IOP that was above 80% of baseline was considered a failure event. Eyes were censored if IOP-lowering medication/procedure was added/performed, or if the eye reached the end of follow-up. First eye of bilaterally treated patients were included. RESULTS: A total of 79,332 patients/eyes were included; 53.2% female; mean age 71.5 years; 64.5%White; 71.2% primary open angle glaucoma. Mean baseline IOP was 21.6±5.3 mm Hg (2.1±1.5 medications). Eyes with higher baseline IOP had longer survival (>24 mm Hg median 349 d; 18 to 24 mm Hg median 309 d; <18 mm Hg median 256 d, P<0.001 for all comparisons). Overall failure at 0, 6, 12, 18 and 24 months were 0.2%, 6.1%, 16.8%, 29.1%, and 40.8%. Angle recession and uveitis increased the risk of failure (hazard ratios 1.69 and 1.80, respectively). Eyes without medications at baseline remained medication-free for a median of 197 days (interquartile range 106, 395 d). CONCLUSIONS: Angle recession and uveitis increase the risk of LTP failure. LPT may be effective in prolonging medication-free IOP-control in some patients.

Mummichog gill and operculum exhibit functionally consistent claudin-10 paralog profiles and Claudin-10c hypersaline response.

Claudin (Cldn)-10 tight junction (TJ) proteins are hypothesized to form the paracellular Na+ secretion pathway of hyposmoregulating mummichog (Fundulus heteroclitus) branchial epithelia. Organ-specific expression profiles showed that only branchial organs [the gill and opercular epithelium (OE)] exhibited abundant cldn-10 paralog transcripts, which typically increased following seawater (SW) to hypersaline (2SW) challenge. Post-translational properties, protein abundance, and ionocyte localization of Cldn-10c, were then examined in gill and OE. Western blot analysis revealed two Cldn-10c immunoreactive bands in the mummichog gill and OE at ∼29 kDa and ∼40 kDa. The heavier protein could be eliminated by glycosidase treatment, demonstrating the novel presence of a glycosylated Cldn-10c. Protein abundance of Cldn-10c increased in gill and OE of 2SW-exposed fish. Cldn-10c localized to the sides of gill and OE ionocyte apical crypts and partially colocalized with cystic fibrosis transmembrane conductance regulator and F-actin, consistent with TJ complex localization. Cldn-10c immunofluorescent intensity increased but localization was unaltered by 2SW conditions. In support of our hypothesis, cldn-10/Cldn-10 TJ protein dynamics in gill and OE of mummichogs and TJ localization are functionally consistent with the creation and maintenance of salinity-responsive, cation-selective pores that facilitate Na+ secretion in hyperosmotic environments.

Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission.

In the absence of a prophylactic vaccine, the use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition by uninfected individuals is a promising approach to slowing the epidemic, but its efficacy is hampered by incomplete patient adherence and ART-resistant variants. Here, we report that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of CCR5-tropic SHIVSF162P3. Injection of Leronlimab weekly at 10 mg/kg provides significant but partial protection, while biweekly 50 mg/kg provides complete protection from SHIV acquisition. Tissue biopsies from protected macaques post challenge show complete CCR5 receptor occupancy and an absence of viral nucleic acids. After Leronlimab washout, protected macaques remain aviremic, and adoptive transfer of hematologic cells into naïve macaques does not transmit viral infection. These data identify CCR5 blockade with Leronlimab as a promising approach to HIV prophylaxis and support initiation of clinical trials.

Clinical Outcomes of Rhegmatogenous Retinal Detachment Treated With Pneumatic Retinopexy.

IMPORTANCE: Pneumatic retinopexy (PR) is the only clinic-based method of rhegmatogenous retinal detachment (RRD) repair. Registry-acquired clinical practice setting outcomes data with this procedure have not yet been reported. OBJECTIVE: To describe the clinical outcomes associated with RRD treated primarily with PR. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, data from patients 19 years and older with noncomplex RRD treated at academic and private ophthalmology practices participating in the American Academy of Ophthalmology IRIS Registry (Intelligent Research in Sight) were analyzed. Data were collected from January 1, 2013, to December 31, 2019, and data were analyzed from January to December 2020. EXPOSURES: Data from the IRIS Registry were queried for eyes that underwent PR for noncomplex RRD and had at least 3 months of follow-up. Cases were identified by a combination of diagnosis code for RRD and a Current Procedural Terminology code for PR. MAIN OUTCOMES AND MEASURES: The number of eyes that achieved single-operation success (SOS), defined as retinal reattachment without a subsequent retinal detachment surgery or repeated PR. RESULTS: Of 9553 included patients, 5827 (61.0%) were male, and the mean (SD) age was 62 (10) years. A total of 9659 eyes were identified. SOS was achieved in 6613 eyes (68.5%). Best-corrected visual acuity significantly differed 9 to 12 months after treatment between the SOS group, with a mean of 0.24 logMAR (95% CI, 0.23-0.25; approximate Snellen equivalent, 20/35), and the single-operation failure group, with a mean of 0.43 logMAR (95% CI, 0.40-0.46; approximate Snellen equivalent, 20/54). Among all patients, the mean time to maximal visual recovery was 268 days (95% CI, 260-276). Endophthalmitis was observed in 3 eyes (0.03%). SOS was associated with female sex (odds ratio, 1.51; 95% CI, 1.38-1.65), while current smoking status was associated single-operation failure (odds ratio, 0.78; 95% CI, 0.68-0.91). CONCLUSIONS AND RELEVANCE: In this registry-based study, which encompasses a large number of eyes drawn from multiple, heterogenous electronic health record systems, SOS was achieved in 68.5% of eyes with noncomplex RRD treated by primary PR. It is unknown how these outcomes would have compared with other methods of RRD repair in this cohort.

Ion-poor water and dietary salt deprivation upregulate the ghrelinergic system in the goldfish (Carassius auratus).

Because the ghrelinergic system in teleost fishes is broadly expressed in organs that regulate appetite as well as those that contribute to the regulation of salt and water balance, we hypothesized that manipulating salt and water balance in goldfish (Carassius auratus) would modulate the ghrelinergic system. Goldfish were acclimated to either freshwater (FW) or ion-poor FW (IPW) and were fed either a control diet containing 1% NaCl or low-salt diet containing 0.1% NaCl. Endpoints of salt and water balance, i.e., serum Na+ and Cl- levels, muscle moisture content and organ-specific Na+ -K+ -ATPase (NKA) activity, were examined in conjunction with brain, gill and gut mRNA abundance of preproghrelin and its receptor, growth hormone secretagogue receptor (ghs-r). Acclimation of fish to IPW reduced serum osmolality and Cl- levels and elevated kidney NKA activity, while FW fish fed a low NaCl diet exhibited a modest reduction in muscle moisture content but otherwise no apparent osmoregulatory disturbance. In contrast, a combined treatment of IPW acclimation and low dietary NaCl content reduced serum osmolality and Cl- levels, elevated muscle moisture content and increased gill, kidney and intestinal NKA activity. This intensified response to the combined effects of water and dietary ion deprivation is consistent with an increased effort to enhance ion acquisition. In association with these latter observations, a significant upregulation of preproghrelin mRNA expression in brain and gut was observed. A significant increase in ghs-r mRNAs was also observed in the gill of goldfish acclimated to IPW alone but a reduction in dietary NaCl content did not impact the ghrelinergic system of goldfish in FW. The results support the hypothesis that the ghrelinergic system is modulated in response to manipulated salt and water balance. Whether the central and peripheral ghrelinergic system contributes to ionic homeostasis in goldfish currently remains unclear and warrants further research.

Tube Versus Trabeculectomy IRISⓇ Registry 1-Year Composite Outcome Analysis with Comparisons to the Randomized Controlled Trial.

PURPOSE: This study compared 1-year results for the composite treatment outcome from the Tube Versus Trabeculectomy (TVT) randomized controlled trial (RCT) to those from an IRISⓇ (Intelligent Research In Sight) Registry cohort of analogous eyes. DESIGN: Retrospective clinical study with comparison to an RCT. METHODS: Subjects' eyes in the IRIS Registry received either a glaucoma drainage implant (tube) or underwent trabeculectomy after a previous trabeculectomy and/or cataract extraction and had data for 1-year follow-up analyses. OUTCOME: Eyes were classified as failing if they had hypotony (intraocular pressure (IOP) ≤5 mm Hg) or inadequate IOP control (IOP >21 mm Hg or not reduced at least 20% below baseline) on 2 consecutive follow-up visits after 3 months, a reoperation for glaucoma, or no light perception vision and as successful otherwise. Failure risk was compared by treatment, demographic, and clinical variables and was compared to analogous failure risks from the TVT RCT. RESULTS: The TVT IRIS Registry cohort included 419 eyes, 236 tube eyes (56.3%) and 183 trabeculectomy eyes (43.7%). In this cohort, there was no significant failure risk difference (12.3% for tube eyes and 16.4% for trabeculectomy eyes, P = 0.231). Comparing the studies, there was a significantly greater risk of failure in the TVT IRIS Registry tube eyes than in the TVT RCT tube eyes (3.8%; P <.001). Reasons for treatment failure included reoperations for glaucoma (none in the TVT RCT at 1 year). CONCLUSIONS: Our results were different from those in the TVT RCT. Possible reasons include non-Baerveldt tubes, greater severity among tube eyes, and practice patterns that reflect real-world data, which are different than those in RCTs.