Loop Catalog: a comprehensive HiChIP database of human and mouse samples.

HiChIP enables cost-effective and high-resolution profiling of regulatory and structural loops. To leverage the increasing number of publicly available HiChIP datasets from diverse cell lines and primary cells, we developed the Loop Catalog (https://loopcatalog.lji.org), a web-based database featuring HiChIP loop calls for 1319 samples across 133 studies and 44 high-resolution Hi-C loop calls. We demonstrate its utility in interpreting fine-mapped GWAS variants (SNP-to-gene linking), in identifying enriched sequence motifs and motif pairs at loop anchors, and in network-level analysis of loops connecting regulatory elements (community detection). Our comprehensive catalog, spanning over 4M unique 5kb loops, along with the accompanying analysis modalities constitutes an important resource for studies in gene regulation and genome organization.

Inhibiting Inducible Nitric Oxide Synthase with 1400W Reduces Soman (GD)-Induced Ferroptosis in Long-Term Epilepsy-Associated Neuropathology: Structural and Functional Magnetic Resonance Imaging Correlations with Neurobehavior and Brain Pathology.

Organophosphate (OP) nerve agent (OPNA) intoxication leads to long-term brain dysfunctions. The ineffectiveness of current treatments for OPNA intoxication prompts a quest for the investigation of the mechanism and an alternative effective therapeutic approach. Our previous studies on 1400W, a highly selective inducible nitric oxide synthase (iNOS) inhibitor, showed improvement in epilepsy and seizure-induced brain pathology in rat models of kainate and OP intoxication. In this study, magnetic resonance imaging (MRI) modalities, behavioral outcomes, and biomarkers were comprehensively investigated for brain abnormalities following soman (GD) intoxication in a rat model. T1 and T2 MRI robustly identified pathologic microchanges in brain structures associated with GD toxicity, and 1400W suppressed those aberrant alterations. Moreover, functional network reduction was evident in the cortex, hippocampus, and thalamus after GD exposure, and 1400W rescued the losses except in the thalamus. Behavioral tests showed protection by 1400W against GD-induced memory dysfunction, which also correlated with the extent of brain pathology observed in structural and functional MRIs. GD exposure upregulated iron-laden glial cells and ferritin levels in the brain and serum, 1400W decreased ferritin levels in the epileptic foci in the brain but not in the serum. The levels of brain ferritin also correlated with MRI parameters. Further, 1400W mitigated the overproduction of nitroxidative markers after GD exposure. Overall, this study provides direct evidence for the relationships of structural and functional MRI modalities with behavioral and molecular abnormalities following GD exposure and the neuroprotective effect of an iNOS inhibitor, 1400W. SIGNIFICANT STATEMENT: Our studies demonstrate the MRI microchanges in the brain following GD toxicity, which strongly correlate with neurobehavioral performances and iron homeostasis. The inhibition of iNOS with 1400W mitigates GD-induced cognitive decline, iron dysregulation, and aberrant brain MRI findings.

The NADPH Oxidase Inhibitor, Mitoapocynin, Mitigates DFP-Induced Reactive Astrogliosis in a Rat Model of Organophosphate Neurotoxicity.

NADPH oxidase (NOX) is a primary mediator of superoxides, which promote oxidative stress, neurodegeneration, and neuroinflammation after diisopropylfluorophosphate (DFP) intoxication. Although orally administered mitoapocynin (MPO, 10 mg/kg), a mitochondrial-targeted NOX inhibitor, reduced oxidative stress and proinflammatory cytokines in the periphery, its efficacy in the brain regions of DFP-exposed rats was limited. In this study, we encapsulated MPO in polyanhydride nanoparticles (NPs) based on 1,6-bis(p-carboxyphenoxy) hexane (CPH) and sebacic anhydride (SA) for enhanced drug delivery to the brain and compared with a high oral dose of MPO (30 mg/kg). NOX2 (GP91phox) regulation and microglial (IBA1) morphology were analyzed to determine the efficacy of MPO-NP vs. MPO-oral in an 8-day study in the rat DFP model. Compared to the control, DFP-exposed animals exhibited significant upregulation of NOX2 and a reduced length and number of microglial processes, indicative of reactive microglia. Neither MPO treatment attenuated the DFP effect. Neurodegeneration (FJB+NeuN) was significantly greater in DFP-exposed groups regardless of treatment. Interestingly, neuronal loss in DFP+MPO-treated animals was not significantly different from the control. MPO-oral rescued inhibitory neuronal loss in the CA1 region of the hippocampus. Notably, MPO-NP and MPO-oral significantly reduced astrogliosis (absolute GFAP counts) and reactive gliosis (C3+GFAP). An analysis of inwardly rectifying potassium channels (Kir4.1) in astroglia revealed a significant reduction in the brain regions of the DFP+VEH group, but MPO had no effect. Overall, both NP-encapsulated and orally administered MPO had similar effects. Our findings demonstrate that MPO effectively mitigates DFP-induced reactive astrogliosis in several key brain regions and protects neurons in CA1, which may have long-term beneficial effects on spontaneous seizures and behavioral comorbidities. Long-term telemetry and behavioral studies and a different dosing regimen of MPO are required to understand its therapeutic potential.

The effects of Src tyrosine kinase inhibitor, saracatinib, on the markers of epileptogenesis in a mixed-sex cohort of adult rats in the kainic acid model of epilepsy.

Neurodegeneration and neuroinflammation are key processes of epileptogenesis in temporal lobe epilepsy (TLE). A considerable number (∼30%) of patients with epilepsy are resistant to currently available antiseizure drugs and thus there is a need to develop adjunct therapies to modify disease progression. A vast majority of interventional strategies to treat TLE have utilized males which limits the translational nature of the studies. In this study, we investigated the effects of repeated low-dose kainic acid (KA) injection on the initial status epilepticus (SE) and the effects of Src kinase inhibitor, saracatinib (SAR/AZD0530; 20 mg/kg, oral, daily for 7 days), in a mixed-sex cohort of adult Sprague Dawley rats during early epileptogenesis. There were no sex differences in response to KA-induced SE, and neither did the stage of estrus influence SE severity. KA-induced SE caused significant astrogliosis and microgliosis across the hippocampus, piriform cortex, and amygdala. SAR treatment resulted in a significant reduction of microgliosis across brain regions. Microglial morphometrics such as branch length and the endpoints strongly correlated with CD68 expression in the vehicle-treated group but not in the SAR-treated group, indicating mitigation by SAR. KA-induced SE caused significant neuronal loss, including parvalbumin-positive inhibitory neurons, in both vehicle (VEH) and SAR-treated groups. SAR treatment significantly mitigated FJB-positive neuronal counts as compared to the VEH group. There was an increase in C3-positive reactive astrocytes in the VEH-treated group, and SAR treatment significantly reduced the increase in the piriform cortex. C3-positive astrogliosis significantly correlated with CD68 expression in the amygdala (AMY) of VEH-treated rats, and SAR treatment mitigated this relationship. There was a significant increase of pSrc(Y419)-positive microglia in both KA-treated groups with a statistically insignificant reduction by SAR. KA-induced SE caused the development of classical glial scars in the piriform cortex (PIR) in both KA-treated groups, while SAR treatment led to a 42.17% reduction in the size of glial scars. We did not observe sex differences in any of the parameters in this study. SAR, at the dose tested in the rat kainate model for a week in this study mitigated some of the markers of epileptogenesis in both sexes.

Impact of obesity on the conversion of immediate-release tacrolimus to extended-release tacrolimus in kidney transplant recipients.

Outcomes analyzing conversion from IR-tacrolimus (IR) to LCP-tacrolimus (LCP) in obesity are limited. This was a retrospective longitudinal cohort study of patients converted from IR to LCP from June 2019 to October 2020. Primary outcomes were conversion ratios for weight-based dose at a steady-state therapeutic level and identification of appropriate dosing weight. Other outcomes included tacrolimus coefficient of variation (CV), time in therapeutic range (TITR), adverse events, infections, donor specific antibodies (DSAs), and acute rejection. A total of 292 patients were included; 156 and 136 patients with a BMI < 30 and BMI ≥ 30 kg/m2 , respectively. Baseline characteristics were similar, except for pancreas transplant, diabetes, and HLA mismatch. IR to LCP conversion ratio ranged from .73 to .79. Mean LCP dose was similar (.08 vs. .07 mg/kg/day for BMI < 30 and BMI ≥ 30 kg/m2 , respectively); there was a significant difference in IR and LCP mg/kg dosing at steady state with TBW (.11 mg/kg vs.09 mg/kg and .08 mg/kg vs. .06 mg/kg, respectively). The most appropriate dosing weight was adjusted body weight (AdjBW), consistent across IR and LCP steady-state doses, and might yield more accurate steady-state dosing requirements. In multivariable modeling, BMI was a significant predictor of steady state mg/kg dosing at therapeutic goal for total body weight (TBW), but not ideal body weight (IBW) or AdjBW.

Clinical Profile and Outcome of Patients presenting with Guillain - Barré Syndrome in a Medical Intensive Care Unit of a Tertiary Care Hospital.

BACKGROUND: Guillain-Barré syndrome (GBS) is an inflammatory, autoimmune disorder of the peripheral nervous system that is acute in onset, self-limited, and can result in significant morbidity, placing a burden on the healthcare system. This study aims to study the clinical profile and outcome of patients with GBS who require intensive care unit (ICU) and mechanical ventilation (MV). MATERIALS AND METHODS: After Institutional Ethics Committee approval, a single-center, prospective, observational study was conducted, recruiting 51 patients from the medical ICU with GBS over 18 months. Patients were categorized into three groups as per the timing of the commencement of immunomodulator therapy. The association between dependent variables like the need for MV, patient outcome, and independent factors like time of initiation of immunomodulator therapy from the time of onset of symptoms and age-groups; were analyzed using the Chi-squared test and the overall disability sum score (ODSS) with Spearman's rank correlation test. RESULTS: Out of 51 patients in the study, (52.94%) were male, with a male:female ratio of 1.12:1. Most of them had quadriparesis (98.04%) or bulbar symptoms (56.86%). A total of 24 (47.05%) patients required MV. The presence of bulbar weakness at admission had a statistically significant positive correlation with the need for MV (Spearman's ρ = 0.663, p = 0.001), the need for prolonged MV (Spearman's ρ = 0.457, p = 0.001), duration of MV (Spearman's ρ = 0.512, p = 0.001) and duration of ICU stay (Spearman's ρ = 0.516, p = 0.001); and a negative correlation with improvement in ODSS (Spearman's ρ = -0.409, p = 0.001). Early commencement of immunomodulator therapy was associated with a significantly decreased probability of requiring ventilatory support (p = 0.001), decreased probability of requiring prolonged MV (p = 0.04), and a decreased duration of ICU stay (p = 0.004). CONCLUSION: Early commencement of immunomodulator therapy decreased the probability of requiring ventilatory support and improved the outcome. Breathlessness and bulbar symptoms at admission were poor prognostic indicators in terms of the need for MV and the duration of both the ICU stay and MV.

Imaging of Gastrointestinal Bleeding: An Update.

Imaging of gastrointestinal bleeding crucial in the diagnosis of occult gastrointestinal bleeding. Gastrointestinal bleeding scintigraphy is a well-established study to aid localisation of gastrointestinal bleeding site. This article discusses about the use of gastrointestinal bleeding scintigraphy in its current practice with emphasis on radiopharmaceutical, imaging techniques, interpretation and pitfalls. There is also discussion on the use of Single Photon Emission Computed Tomography-Computed Tomography (SPECT-CT) within this method of scintigraphy. Meckel's diverticulum is known to be a frequent source of bleeding, mainly in children. It is also know that nuclear medicine imaging can help with Meckel's diverticulum identification. This article also discusses about the technique, imaging, interpretation and SPECT-CT usage for Meckel's diverticulum imaging.

Peripheral and central effects of NADPH oxidase inhibitor, mitoapocynin, in a rat model of diisopropylfluorophosphate (DFP) toxicity.

Organophosphates (OP) are highly toxic chemical nerve agents that have been used in chemical warfare. Currently, there are no effective medical countermeasures (MCMs) that mitigate the chronic effects of OP exposure. Oxidative stress is a key mechanism underlying OP-induced cell death and inflammation in the peripheral and central nervous systems and is not mitigated by the available MCMs. NADPH oxidase (NOX) is one of the leading producers of reactive oxygen species (ROS) following status epilepticus (SE). In this study, we tested the efficacy of the mitochondrial-targeted NOX inhibitor, mitoapocynin (MPO) (10 mg/kg, oral), in a rat diisopropylfluorophosphate (DFP) model of OP toxicity. In DFP-exposed animals, MPO decreased oxidative stress markers nitrite, ROS, and GSSG in the serum. Additionally, MPO significantly reduced proinflammatory cytokines IL-1ß, IL-6, and TNF-α post-DFP exposure. There was a significant increase in GP91phox, a NOX2 subunit, in the brains of DFP-exposed animals 1-week post-challenge. However, MPO treatment did not affect NOX2 expression in the brain. Neurodegeneration (NeuN and FJB) and gliosis [microglia (IBA1 and CD68), and astroglia (GFAP and C3)] quantification revealed a significant increase in neurodegeneration and gliosis after DFP-exposure. A marginal reduction in microglial cells and C3 colocalization with GFAP in DFP + MPO was observed. The MPO dosing regimen used in this study at 10 mg/kg did not affect microglial CD68 expression, astroglial count, or neurodegeneration. MPO reduced DFP-induced oxidative stress and inflammation markers in the serum but only marginally mitigated the effects in the brain. Dose optimization studies are required to determine the effective dose of MPO to mitigate DFP-induced changes in the brain.

Disease-modifying effects of a glial-targeted inducible nitric oxide synthase inhibitor (1400W) in mixed-sex cohorts of a rat soman (GD) model of epilepsy.

BACKGROUND: Acute exposure to seizurogenic organophosphate (OP) nerve agents (OPNA) such as diisopropylfluorophosphate (DFP) or soman (GD), at high concentrations, induce immediate status epilepticus (SE), reactive gliosis, neurodegeneration, and epileptogenesis as a consequence. Medical countermeasures (MCMs-atropine, oximes, benzodiazepines), if administered in < 20 min of OPNA exposure, can control acute symptoms and mortality. However, MCMs alone are inadequate to prevent OPNA-induced brain injury and behavioral dysfunction in survivors. We have previously shown that OPNA exposure-induced SE increases the production of inducible nitric oxide synthase (iNOS) in glial cells in both short- and long- terms. Treating with a water soluble and highly selective iNOS inhibitor, 1400W, for 3 days significantly reduced OPNA-induced brain changes in those animals that had mild-moderate SE in the rat DFP model. However, such mitigating effects and the mechanisms of 1400W are unknown in a highly volatile nerve agent GD exposure. METHODS: Mixed-sex cohort of adult Sprague Dawley rats were exposed to GD (132 µg/kg, s.c.) and immediately treated with atropine (2 mg/kg, i.m) and HI-6 (125 mg/kg, i.m.). Severity of seizures were quantified for an hour and treated with midazolam (3 mg/kg, i.m.). An hour post-midazolam, 1400W (20 mg/kg, i.m.) or vehicle was administered daily for 2 weeks. After behavioral testing and EEG acquisition, animals were euthanized at 3.5 months post-GD. Brains were processed for neuroinflammatory and neurodegeneration markers. Serum and CSF were used for nitrooxidative and proinflammatory cytokines assays. RESULTS: We demonstrate a significant long-term (3.5 months post-soman) disease-modifying effect of 1400W in animals that had severe SE for > 20 min of continuous convulsive seizures. 1400W significantly reduced GD-induced motor and cognitive dysfunction; nitrooxidative stress (nitrite, ROS; increased GSH: GSSG); proinflammatory cytokines in the serum and some in the cerebrospinal fluid (CSF); epileptiform spikes and spontaneously recurring seizures (SRS) in males; reactive gliosis (GFAP + C3 and IBA1 + CD68-positive glia) as a measure of neuroinflammation, and neurodegeneration (especially parvalbumin-positive neurons) in some brain regions. CONCLUSION: These findings demonstrate the long-term disease-modifying effects of a glial-targeted iNOS inhibitor, 1400W, in a rat GD model by modulating reactive gliosis, neurodegeneration (parvalbumin-positive neurons), and neuronal hyperexcitability.

Non-inhibitory levels of oxygen during cultivation increase freeze-drying stress tolerance in Limosilactobacillus reuteri DSM 17938.

The physiological effects of oxygen on Limosilactobacillus reuteri DSM 17938 during cultivation and the ensuing properties of the freeze-dried probiotic product was investigated. On-line flow cytometry and k-means clustering gating was used to follow growth and viability in real time during cultivation. The bacterium tolerated aeration at 500 mL/min, with a growth rate of 0.74 ± 0.13 h-1 which demonstrated that low levels of oxygen did not influence the growth kinetics of the bacterium. Modulation of the redox metabolism was, however, seen already at non-inhibitory oxygen levels by 1.5-fold higher production of acetate and 1.5-fold lower ethanol production. A significantly higher survival rate in the freeze-dried product was observed for cells cultivated in presence of oxygen compared to absence of oxygen (61.8% ± 2.4% vs. 11.5% ± 4.3%), coinciding with a higher degree of unsaturated fatty acids (UFA:SFA ratio of 10 for air sparged vs. 3.59 for N2 sparged conditions.). Oxygen also resulted in improved bile tolerance and boosted 5'nucleotidase activity (370 U/L vs. 240 U/L in N2 sparged conditions) but lower tolerance to acidic conditions compared bacteria grown under complete anaerobic conditions which survived up to 90 min of exposure at pH 2. Overall, our results indicate the controlled supply of oxygen during production may be used as means for probiotic activity optimization of L. reuteri DSM 17938.

Disease-Modifying Effects of a Glial-targeted Inducible Nitric Oxide Synthase Inhibitor (1400W) in Mixed-sex Cohorts of a Rat Soman (GD) Model of Epilepsy.

Background Acute exposure to seizurogenic organophosphate (OP) nerve agents (OPNA) such as diisopropylfluorophosphate (DFP) or soman (GD), at high concentrations, induce immediate status epilepticus (SE), reactive gliosis, neurodegeneration, and epileptogenesis as a consequence. Medical countermeasures (MCMs- atropine, oximes, benzodiazepines), if administered in < 20 minutes of OPNA exposure, can control acute symptoms and mortality. However, MCMs alone are inadequate to prevent OPNA-induced brain injury and behavioral dysfunction in survivors. We have previously shown that OPNA exposure-induced SE increases the production of inducible nitric oxide synthase (iNOS) in glial cells in both short- and long- terms. Treating with a water soluble and highly selective iNOS inhibitor, 1400W, for three days significantly reduced OPNA-induced brain changes in those animals that had mild-moderate SE in the rat DFP model. However, such mitigating effects and the mechanisms of 1400W are unknown in a highly volatile nerve agent GD exposure. Methods Mixed-sex cohort of adult Sprague Dawley rats were exposed to GD (132µg/kg, s.c.) and immediately treated with atropine (2mg/kg, i.m) and HI-6 (125mg/kg, i.m.). Severity of seizures were quantified for an hour and treated with midazolam (3mg/kg, i.m.). An hour post-midazolam, 1400W (20mg/kg, i.m.) or vehicle was administered daily for two weeks. After behavioral testing and EEG acquisition, animals were euthanized at 3.5 months post-GD. Brains were processed for neuroinflammatory and neurodegeneration markers. Serum and CSF were used for nitrooxidative and proinflammatory cytokines assays. Results We demonstrate a significant long-term (3.5 months post-soman) disease-modifying effect of 1400W in animals that had severe SE for > 20min of continuous convulsive seizures. 1400W significantly reduced GD-induced motor and cognitive dysfunction; nitrooxidative stress (nitrite, ROS; increased GSH: GSSG); proinflammatory cytokines in the serum and some in the cerebrospinal fluid (CSF); epileptiform spikes and spontaneously recurring seizures (SRS) in males; reactive gliosis (GFAP + C3 and IBA1 + CD68 positive glia) as a measure of neuroinflammation, and neurodegeneration (including parvalbumin positive neurons) in some brain regions. Conclusion These findings demonstrate the long-term disease-modifying effects of a glial-targeted iNOS inhibitor, 1400W, in a rat GD model by modulating reactive gliosis, neurodegeneration, and neuronal hyperexcitability.

1400 W, a selective inducible nitric oxide synthase inhibitor, mitigates early neuroinflammation and nitrooxidative stress in diisopropylfluorophosphate-induced short-term neurotoxicity rat model.

Organophosphate nerve agent (OPNA) exposure induces acute and long-term neurological deficits. OPNA exposure at sub-lethal concentrations induces irreversible inhibition of acetylcholinesterase and cholinergic toxidrome and develops status epilepticus (SE). Persistent seizures have been associated with increased production of ROS/RNS, neuroinflammation, and neurodegeneration. A total of 1400W is a novel small molecule, which irreversibly inhibits inducible nitric oxide synthase (iNOS) and has been shown to effectively reduce ROS/RNS generation. In this study, we investigated the effects of 1400W treatment for a week or two weeks at 10 mg/kg or 15 mg/kg per day in the rat diisopropylfluorophosphate (DFP) model. 1400W significantly reduced the number of microglia, astroglia, and NeuN+FJB positive cells compared to the vehicle in different regions of the brain. 1400W also significantly reduced nitrooxidative stress markers and proinflammatory cytokines in the serum. However, neither of the two concentrations of 1400W for two weeks of treatment had any significant effect on epileptiform spike rate and spontaneous seizures during the treatment period in mixed sex cohorts, males, or females. No significant sex differences were found in response to DFP exposure or 1400W treatment. In conclusion, 1400W treatment at 15 mg/kg per day for two weeks was more effective in significantly reducing DFP-induced nitrooxidative stress, neuroinflammatory and neurodegenerative changes.

Assessing the difference in racial and ethnic disparities in access to and use of care between Traditional Medicare and Medicare Advantage.

OBJECTIVE: Test whether racial-ethnic disparities in the access and use of care differ between Traditional Medicare (TM) and Medicare Advantage (MA). DATA SOURCE: Secondary data from the 2015-2018 Medicare Current Beneficiary Survey (MCBS). STUDY DESIGN: Measure Black-White and Hispanic-White disparities in access to care and use of preventive services within TM, within MA, and assess the difference-in-disparities between the two programs with and without controls for factors that could influence enrollment, access, and use. DATA COLLECTION/EXTRACTION: Pool 2015-2018 MCBS data and restrict to non-Hispanic Black, non-Hispanic White, or Hispanic respondents. PRINCIPAL FINDINGS: Black enrollees have worse access to care relative to White enrollees in TM and MA, particularly for cost-related measures such as not having problems paying medical bills (11-13 pp. lower for Black enrollees; p < 0.05) and satisfaction with out-of-pocket costs (5-6 pp. lower; p < 0.05). We find no difference in Black-White disparities between TM and MA. Hispanic enrollees have worse access to care relative to White enrollees in TM but similar access relative to White enrollees in MA. Hispanic-White disparities in not delaying care due to cost and not reporting problems paying medical bills are narrower in MA relative to TM by about 4 pp (significant at the p < 0.05 level) each. We find no consistent evidence that Black-White or Hispanic-White differences in the use of preventive services differ between TM and MA. CONCLUSIONS: Across the measures of access and use studied here, racial and ethnic disparities in MA are not substantially narrower than in TM for Black and Hispanic enrollees relative to White enrollees. For Black enrollees, this study suggests that system-wide reforms are required to reduce existing disparities. For Hispanic enrollees, MA does narrow some disparities in access to care relative to White enrollees but, in part, because White enrollees do not do as well in MA as they do in TM.

Impact of CYP3A5 genotype on de-novo LCP tacrolimus dosing and monitoring in kidney transplantation.

OBJECTIVES: LCP tac has a recommended starting dose of 0.14 mg/kg/day in kidney transplant. The goal of this study was to assess the influence of CYP3A5 on perioperative LCP tac dosing and monitoring. METHODS: This was a prospective observational cohort study of adult kidney recipients receiving de-novo LCP tac. CYP3A5 genotype was measured and 90-day pharmacokinetic and clinical were assessed. Patients were classified as CYP3A5 expressors (*1 homozygous or heterozygous) or nonexpressors (LOF *3/*6/*7 allele). RESULTS: In this study, 120 were screened, 90 were contacted and 52 provided consent; 50 had genotype results, and 22 patients expressed CYP3A5*1. African Americans (AA) comprised 37.5% of nonexpressors versus 81.8% of expressors (P = 0.001). Initial LCP tac dose was similar between CYP3A5 groups (0.145 vs. 0.137 mg/kg/day; P = 0.161), whereas steady state dose was higher in expressors (0.150 vs. 0.117 mg/kg/day; P = 0.026). CYP3A5*1 expressors had significantly more tac trough concentrations of less than 6 ng/ml and significantly fewer tac trough concentrations of more than 14 ng/ml. Providers were significantly more likely to under-adjust LCP tac by 10 and 20% in CYP3A5 expressors versus nonexpressors (P < 0.03). In sequential modeling, CYP3A5 genotype status explained the LCP tac dosing requirements significantly more than AA race. CONCLUSION: CYP3A5*1 expressors require higher doses of LCP tac to achieve therapeutic concentrations and are at higher risk of subtherapeutic trough concentrations, persisting for 30-day posttransplant. LCP tac dose changes in CYP3A5 expressors are more likely to be under-adjusted by providers.

Diabetes is a significant and independent predictor for tacrolimus immediate release and LCP-tacrolimus conversion ratios.

Diabetes (DM) is a common comorbidity in transplant patients with known effects on gastrointestinal (GI) motility and absorption; however, DM's impact on immediate release (IR) tacrolimus to LCP-tacrolimus (LCP) conversion ratios has not been studied. This multivariable analysis of a retrospective longitudinal cohort study included kidney transplant recipients converted from IR to LCP between 2019 and 2020. The primary outcome was IR to LCP conversion ratio based on DM status. Other outcomes included tacrolimus variability, rejection, graft loss, and death. Of the 292 patients included, 172 patients had DM and 120 did not. The IR:LCP conversion ratio was significantly higher with DM (67.5% ± 21.1% no DM vs. 79.8% ± 28.7% in DM; P < .001). In multivariable modeling, DM was the only variable significantly and independently associated with IR:LCP conversion ratios. No difference was observed in rejection rates. Graft (97.5% no DM vs. 92.4% in DM; P = .062) and patient survival (100% no DM vs. 94.8% in DM; P = .011) were lower with DM. The presence of DM significantly increased the IR:LCP conversion ratio by 13%-14%, compared to patients without DM. On multivariable analysis, DM was the only significant predictor of conversion ratios, potentially related to GI motility or absorption differences.

Impact of converting adult kidney transplant recipients with high tacrolimus variability from twice daily immediate release tacrolimus to once daily LCP-Tacrolimus.

BACKGROUND: The influence of converting to once daily, extended-release LCP-Tacrolimus (Tac) for those with high tacrolimus variability in kidney transplant recipients (KTRs) is not well-studied. METHODS: Single-center, retrospective cohort study of adult KTRs converted from Tac immediate release to LCP-Tac 1-2 years post-transplant. Primary measures were Tac variability, using the coefficient of variation (CV) and time in therapeutic range (TTR), as well as clinical outcomes (rejection, infections, graft loss, death). RESULTS: A total of 193 KTRs included with a follow-up of 3.2 ± .7 years and 1.3 ± .3 years since LCP-Tac conversion. Mean age was 52 ± 13 years; 70% were African American, 39% were female, 16% living donor and 12% donor after cardiac death (DCD). In the overall cohort, tac CV was 29.5% before conversion, which increased to 33.4% after LCP-Tac (p = .008). In those with Tac CV >30% (n = 86), conversion to LCP-Tac reduced variability (40.6% vs. 35.5%; p = .019) and for those with Tac CV >30% and nonadherence or med errors (n = 16), LCP-Tac conversion substantially reduced Tac CV (43.4% vs. 29.9%; p = .026). TTR significantly improved for those with Tac CV >30% with (52.4% vs. 82.8%; p = .027) or without nonadherence or med errors (64.8% vs. 73.2%; p = .005). CMV, BK, and overall infections were significantly higher prior to LCP-Tac conversion. In the overall cohort, 3% had rejection before conversion and 2% after (p = NS). At end of follow-up, graft and patient survival were 94% and 96%, respectively. CONCLUSIONS: In those with high Tac CV, conversion to LCP-Tac is associated with a significant reduction in variability and improvement in TTR, particularly in those with nonadherence or medication errors.

Sex-based structural and functional MRI outcomes in the rat brain after soman (GD) exposure-induced status epilepticus.

OBJECTIVE: Exposure to the nerve agent, soman (GD), induces status epilepticus (SE), epileptogenesis, and even death. Although rodent models studying the pathophysiological mechanisms show females to be more reactive to soman, no tangible sex differences in brains postexposure have been reported. In this study, we used multimodal imaging using MRI in adult rats to determine potential sex-based biomarkers of soman effects. METHODS: Male and female Sprague Dawley rats were challenged with 1.2 × LD50 soman followed by medical countermeasures. Ten weeks later, the brains were analyzed via structural and functional MRI. RESULTS: Despite no significant sex differences in the initial SE severity after soman exposure, long-term MRI-based structural and functional differences were evident in the brains of both sexes. While T2 MRI showed lesser soman-induced neurodegeneration, large areas of T1 enhancements occurred in females than in males, indicating a distinct pathophysiology unrelated to neurodegeneration. fMRI-based resting-state functional connectivity (RSFC), indicated greater reductions in soman-exposed females than in males, associating with the T1 enhancements (unrelated to neurodegeneration) rather than T2-hyperintensity or T1-hypointensity (representing neurodegeneration). The wider T1 enhancements associating with the decreased spontaneous neuronal activity in multiple resting-state networks in soman-exposed females than males suggest that neural changes unrelated to cellular atrophy impinge on brain function postexposure. Taken together with lower spontaneous neural activity in soman-exposed females, the results indicate some form of neuroprotective state that was not present in males. SIGNIFICANCE: The results indicate that endpoints other than neurodegeneration may need to be considered to translate sex-based nerve agent effects in humans.

Subcutaneous Phaeohyphomycosis in a Renal Transplant Patient by a Rare Fungus Medicopsis romeroi.

Medicopsis romeroi is a dematiaceous fungus that rarely causes subcutaneous phaeohyphomycosis. Here, we report a subcutaneous phaeohyphomycosis caused by a rare dematiaceous fungus, M. romeroi, in a 56-year-old male renal transplant patient. The patient was admitted for graft dysfunction and was found to have painless swelling over the anterior aspect of the right knee, which was aspirated twice within 40 days. Broad septate hyphae (determined by microscopy) and growth of phaeoid in a culture were observed in both the specimens. No sporulation was observed in the slide culture. Swelling recurred even after treatment with voriconazole, so the lesion was surgically excised. Genotypically, the isolate was identified as M. romeroi in both specimens. He was discharged on voriconazole. During a 6-month follow-up, no relapse was noticed. Phaeohyphomycosis caused by M. romeroi is rare, with only a few cases reported in India. Laboratory diagnosis of Medicopsis by conventional methods is challenging. Medicopsis species should be considered one of the etiological agents for subcutaneous phaeohyphomycosis. Molecular methods should be used for the identification of unusual pathogens.

Cardiovascular Complications in Kidney Transplant Recipients with COVID-19: A Case Series.

Kidney transplant recipients (KTRs) are at a higher risk for developing severe COVID-19 which can be associated with cardiovascular complications. We studied five KTRs recipients infected with COVID-19 who developed severe cardiovascular complications. Two patients presented with ST segment myocardial infarction and two with clinically suspected myocarditis. One patient presented with atrial fibrillation. Two of these patients developed cardiogenic shock. Inflammatory markers were at peak during the event in four of these who had presented with severe COVID-19. Coronary angiography done in two patients with STEMI did not reveal any evidence of atherosclerotic coronary artery disease. Also, based on the cardiovascular (CV) risk estimation by Framingham score, four patients had low CV risk and one patient had intermediate CV risk. All five patients survived. Even with low CV risk, KTRs can develop myocardial injury and arrhythmias solely because of severe COVID-19.