International expert opinion on the considerations for combining vosoritide and limb surgery: a modified delphi study.

BACKGROUND: Achondroplasia is the most common form of skeletal disorder with disproportionate short stature. Vosoritide is the first disease-specific, precision pharmacotherapy to increase growth velocity in children with achondroplasia. Limb surgery is a standard approach to increase height and arm span, improve proportionality and functionality, as well as correcting deformities. The aim of this study was to gain expert opinion on the combined use of vosoritide and limb surgery in children and adolescents with achondroplasia. METHODS: An international expert panel of 17 clinicians and orthopaedic surgeons was convened, and a modified Delphi process undertaken. The panel reviewed 120 statements for wording, removed any unnecessary statements, and added any that they felt were missing. There were 26 statements identified as facts that were not included in subsequent rounds of voting. A total of 97 statements were rated on a ten-point scale where 1 was 'Completely disagree' and 10 'Completely agree'. A score of ≥ 7 was identified as agreement, and ≤ 4 as disagreement. All experts who scored a statement ≤ 4 were invited to provide comments. RESULTS: There was 100% agreement with several statements including, "Achieve a target height, arm span or upper limb length to improve daily activities" (mean level of agreement [LoA] 9.47, range 8-10), the "Involvement of a multidisciplinary team in a specialist centre to follow up the patient" (mean LoA 9.67, range 7-10), "Planning a treatment strategy based on age and pubertal stage" (mean LoA 9.60, range 8-10), and "Identification of short- and long-term goals, based on individualised treatment planning" (mean LoA 9.27, range 7-10), among others. The sequence of a combined approach and potential impact on the physes caused disagreement, largely due to a lack of available data. CONCLUSIONS: It is clear from the range of responses that this modified Delphi process is only the beginning of new considerations, now that a medical therapy for achondroplasia is available. Until data on a combined treatment approach are available, sharing expert opinion is a vital way of providing support and guidance to the clinical community.

Early Outcomes in Heart Transplantation using Donation after Circulatory Death Donors in Patients Bridged with Durable Left Ventricular Assist Devices.

OBJECTIVE: Donation after circulatory death (DCD) heart transplantation potentially increases donor allografts, especially for patients with lower listing status. We assessed outcomes of DCD heart transplantation in patients bridged with durable left ventricular assist devices (LVAD). METHODS: The United Network for Organ Sharing (UNOS) database was queried for adult heart transplants utilizing DCD donors from 2019-2022. Patients were stratified between those with durable LVAD versus those with intra-aortic balloon pump, inotropic, or no bridging support (control group). Primary outcome was 1-year mortality. Secondary endpoints were hospital length of stay, stroke, pacemaker implantation, dialysis, and acute rejection before discharge. RESULTS: 160 LVAD recipients and 311 control recipients met study inclusion criteria. Recipients bridged with LVAD were younger (55 vs. 58 years, p<0.001) with lower BMI (28.3 vs. 30.3, p<0.001), longer waitlist times (112 vs. 34 days, p<0.001), longer out of body times (5.7 vs 4.6 hours, p<0.001), and less frequent normothermic regional perfusion (31% vs 40%, p=0.049). LVAD patients were commonly transplanted at UNOS status 3-4 (92%), while control patients were transplanted at status 2 (27%), status 3 (10%), status 4 (30%), or status 6 (30%). Kaplan-Meier analysis showed no difference in 1-year mortality between groups (p=0.34). However, acute rejection was higher in the unadjusted LVAD cohort (26% vs. 13%, p<0.001). On multivariable logistic regression, LVAD was an independent predictor of acute rejection (OR: 2.21, 95% CI:1.32-3.69, p=0.002). CONCLUSIONS: Durable LVAD may be associated with higher risk of developing an early inflammatory response in DCD heart transplantation; however, 1-year survival was similar between groups.

Intention-to-treat outcomes of patients with hepatocellular carcinoma receiving immunotherapy before liver transplant: the multicenter VITALITY study.

BACKGROUND AND AIMS: The use of immune checkpoint inhibitors (ICI) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention to treat (ITT) outcomes in the peri transplant setting are currently based on small and heterogenous single center reports. METHODS: This first multiregional US study (2016-2023) included 117 consecutive HCC patients assessed for LT and treated preoperatively with ICIs. Intention to treat ITT and survival analyses were conducted with evaluation of post LT rejection rates. RESULTS: In total, 86 (73.5%) patients exceeded MC and 65 (75.6%) were successfully downstaged (DS) within a median of 5.6 months. 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) initially beyond and DS. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4-5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included: being beyond MC (p<0.001), AFP doubling from baseline (p=0.014) and radiographic responses (p<0.001). The 3-year ITT survival was 71.1% (73.5% within MC vs 69.7% beyond MC, p=0.329), with 3-year post LT survival rate of 85%. Post-LT rejection occurred in 7 patients, six received their last dose of ICI less than 3 months prior to LT, resulting in one graft loss. CONCLUSIONS: The first multicenter evaluation of HCC patients receiving ICI pre-LT demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of AFP levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes. IMPACT AND IMPLICATIONS: The first multicenter evaluation of pre-transplant immune-checkpoint-inhibitors in hepatocellular carcinoma to show promising intention-to-treat survival, safety and rejection rates. Immune-checkpoint-inhibitors, either alone or combined with LRT, demonstrate reliable efficacy. This preoperative strategy could be particularly beneficial for high-risk patients, including those requiring downstaging or with elevated AFP levels despite locoregional treatment. These findings fill current knowledge gaps and offer reassuring evidence for the feasibility of pre-transplant use of immune-checkpoint-inhibitors, pending results from ongoing trials.

Clinical, Radiographic, and Biomechanical Evaluation of the Upper Extremity in Patients with Osteogenesis Imperfecta.

Introduction: Osteogenesis imperfecta (OI) is a hereditary disorder primarily caused by mutations in type I collagen genes, resulting in bone fragility, deformities, and functional limitations. Studies on upper extremity deformities and associated functional impairments in OI are limited. This cross-sectional study aimed to evaluate upper extremity deformities and functional outcomes in OI. Methods: We included patients regardless of their OI subtypes with a minimum age of 7 years. Radiographic analysis of radial head dislocation, ossification of the interosseous membrane, and/or radioulnar synostosis of the forearm were performed, and deformity was categorized as mild, moderate, or severe. Clinical evaluation was performed using the Quick Disabilities of Arm, Shoulder, and Hand (qDASH) questionnaire and shoulder-elbow-wrist range of motion (ROM). Three-dimensional motion analysis of the upper limb was conducted using the Southampton Hand Assessment Procedure (SHAP). The SHAP quantifies execution time through the Linear Index of Function (LIF) and assesses the underlying joint kinematics using the Arm Profile Score (APS). Additionally, the maximum active Range of Motion (aRoM) was measured. Results: Fourteen patients aged 8 to 73 were included. Radiographic findings revealed diverse deformities, including radial head dislocation, interosseous membrane ossification, and radioulnar synostosis. Six patients had mild, six moderate, and two severe deformities of the upper extremity. Severe deformities and radial head dislocation correlated with compromised ROM and worse qDASH scores. The qDASH score ranged from 0 to 37.5 (mean 11.7). APS was increased, and LIF was reduced in OI-affected persons compared with non-affected peers. APS and LIF also varied depending on the severity of bony deformities. aRoM was remarkably reduced for pro-supination. Conclusion: Patients with OI showed variable functional impairment from almost none to severe during daily life activities, mainly depending on the magnitude of deformity in the upper extremity. Larger multicenter studies are needed to confirm the results of this heterogeneous cohort. Level of evidence: Retrospective clinical study; Level IV.

Durable left ventricular assist devices as a bridge to transplantation: what to expect along the way?

INTRODUCTION: The scarcity of donors coupled with the improvements in left ventricular assist devices (LVAD) technology has led to the use of LVAD as a bridge to transplantation (BTT). AREAS COVERED: The authors provide an overview of the current status of LVAD BTT implantation with special focus ranging from patient selection and pre-implantation optimization to post-transplant outcomes. EXPERT OPINION: The United Network for Organ Sharing 2018 policy amendment resulted in a significant reduction in the number of LVADs used for BTT in the US. To overcome this issue, modifications in the US allocation policy to consider factors such as days on device support, age, and type of complications may be necessary to potentially increase implantation rates.

Quantifying variant contributions in cystic kidney disease using national-scale whole-genome sequencing.

BACKGROUNDCystic kidney disease (CyKD) is a predominantly familial disease in which gene discovery has been led by family-based and candidate gene studies, an approach that is susceptible to ascertainment and other biases.METHODSUsing whole-genome sequencing data from 1,209 cases and 26,096 ancestry-matched controls participating in the 100,000 Genomes Project, we adopted hypothesis-free approaches to generate quantitative estimates of disease risk for each genetic contributor to CyKD, across genes, variant types and allelic frequencies.RESULTSIn 82.3% of cases, a qualifying potentially disease-causing rare variant in an established gene was found. There was an enrichment of rare coding, splicing, and structural variants in known CyKD genes, with statistically significant gene-based signals in COL4A3 and (monoallelic) PKHD1. Quantification of disease risk for each gene (with replication in the separate UK Biobank study) revealed substantially lower risk associated with genes more recently associated with autosomal dominant polycystic kidney disease, with odds ratios for some below what might usually be regarded as necessary for classical Mendelian inheritance. Meta-analysis of common variants did not reveal significant associations, but suggested this category of variation contributes 3%-9% to the heritability of CyKD across European ancestries.CONCLUSIONBy providing unbiased quantification of risk effects per gene, this research suggests that not all rare variant genetic contributors to CyKD are equally likely to manifest as a Mendelian trait in families. This information may inform genetic testing and counseling in the clinic.

PSMA-PET/CT response after metastasis-directed radiotherapy of bone oligometastases in prostate cancer.

OBJECTIVE: Bone metastases are very common in advanced prostate cancer and can sensitively be detected utilizing PSMA-PET/CT. Therefore, our goal was to evaluate the suitability of PSMA-PET/CT-guided metastasis-directed external beam radiotherapy (MDT) as treatment option for patients with biochemical recurrence and oligometastatic bone lesions. MATERIALS & METHODS: We retrospectively examined 32 prostate cancer patients with biochemical recurrence and PSMA-positive oligometastatic disease limited to the bone (n = 1-3). A total of 49 bone lesions were treated with MDT. All patients received a post-radiotherapy PSMA-PET/CT-Scan. Changes in SUVmax, PSMA-positive tumor volume per lesion and PSA, as well as the correlation between the PET/CT-interval and SUVmax response were calculated. RESULTS: MDT lead to a SUVmax decrease in 46/49 (94%) of the lesions. The median relative decline of SUVmax was 60.4%, respectively. Based on PSMA-positive lesion volume with a SUV cut-off of 4, 46/49 (94%) of lesions showed complete response, two (4%) partial response and one lesion (2%) was stable on PSMA-PET/CT after MDT. Most of the treated patients (56.3%) showed an initial PSA decline at three months and a PSA nadir of median 0.14 ng/ml after a median time of 3.6 months after MDT. The median relative PSA change at three months after MDT was 3.9%. CONCLUSION: MDT is a very effective treatment modality for prostate cancer bone oligometastases and lesion response to MDT can be assessed using the (semi-)quantitative parameters SUVmax and PSMA-positive lesion volume with established SUV cut-offs.

Pre-operative pectoralis muscle area index is associated with biomarkers of inflammation and endotoxemia and predicts clinical outcomes after left ventricular assist device implantation: A cohort study.

BACKGROUND: Pre-left ventricular assist device (LVAD) pectoralis muscle assessment, an estimate of sarcopenia, has been associated with postoperative mortality and gastrointestinal bleeding, though its association with inflammation, endotoxemia, length-of-stay (LOS), and readmissions remains underexplored. METHODS: This was a single-center cohort study of LVAD patients implanted 1/2015-10/2018. Preoperative pectoralis muscle area was measured on chest computed tomography (CT), adjusted for height squared to derive pectoralis muscle area index (PMI). Those with PMI in the lowest quintile were defined as low-PMI cohort; all others constituted the reference cohort. Biomarkers of inflammation (interleukin-6, adiponectin, tumor necrosis factor-α [TNFα]) and endotoxemia (soluble (s)CD14) were measured in a subset of patients. RESULTS: Of the 254 LVAD patients, 95 had a preoperative chest CT (median days pre-LVAD: 7 [IQR 3-13]), of whom 19 (20.0%) were in the low-PMI cohort and the remainder were in the reference cohort. Compared with the reference cohort, the low-PMI cohort had higher levels of sCD14 (2594 vs. 1850 ng/mL; p = 0.04) and TNFα (2.9 vs. 1.9 pg/mL; p = 0.03). In adjusted analyses, the low-PMI cohort had longer LOS (incidence rate ratio 1.56 [95% confidence interval 1.16-2.10], p = 0.004) and higher risk of 90-day and 1-year readmissions (subhazard ratio 5.48 [1.88-16.0], p = 0.002; hazard ratio 1.73 [1.02-2.94]; p = 0.04, respectively). CONCLUSIONS: Pre-LVAD PMI is associated with inflammation, endotoxemia, and increased LOS and readmissions.

Plaque Characteristics Derived from Intravascular Optical Coherence Tomography That Predict Cardiovascular Death.

This study aimed to investigate whether plaque characteristics derived from intravascular optical coherence tomography (IVOCT) could predict a long-term cardiovascular (CV) death. This study was a single-center, retrospective study on 104 patients who had undergone IVOCT-guided percutaneous coronary intervention. Plaque characterization was performed using Optical Coherence TOmography PlaqUe and Stent (OCTOPUS) software developed by our group. A total of 31 plaque features, including lesion length, lumen, calcium, fibrous cap (FC), and vulnerable plaque features (e.g., microchannel), were computed from the baseline IVOCT images. The discriminatory power for predicting CV death was determined using univariate/multivariate logistic regressions. Of 104 patients, CV death was identified in 24 patients (23.1%). Univariate logistic regression revealed that lesion length, calcium angle, calcium thickness, FC angle, FC area, and FC surface area were significantly associated with CV death (p < 0.05). In the multivariate logistic analysis, only the FC surface area (OR 2.38, CI 0.98-5.83, p < 0.05) was identified as a significant determinant for CV death, highlighting the importance of the 3D lesion analysis. The AUC of FC surface area for predicting CV death was 0.851 (95% CI 0.800-0.927, p < 0.05). Patients with CV death had distinct plaque characteristics (i.e., large FC surface area) in IVOCT. Studies such as this one might someday lead to recommendations for pharmaceutical and interventional approaches.

Long-term effects on cardiorespiratory and behavioral responses in male and female rats prenatally exposed to cannabinoid.

Development of the respiratory system can be affected by the use of drugs during pregnancy, as the prenatal phase is highly sensitive to pharmacological interventions, resulting in long-term consequences. The deleterious effects of external cannabinoids during gestation may be related to negative interference in central nervous system formation, cardiorespiratory system function, and behavioral disorders. Nevertheless, the impact of external cannabinoids on cardiorespiratory network development, chemosensitivity, and its future consequences in adulthood is still unclear. We evaluated the effects of prenatal exposure to a synthetic cannabinoid (WIN 55,212-2, 0.5 mg·kg-1·day-1) on the cardiorespiratory control and panic-like behavior of male and female rats in adulthood. Exogenous cannabinoid exposure during pregnancy resulted in a sex-dependent difference in breathing control. Specifically, males showed increased chemosensitivity to CO2 and O2, whereas females exhibited decreased sensitivity. Altered cardiovascular control was evident, with prenatally treated males and females being more susceptible to hypertension and tachycardia under adverse environmental conditions. Moreover, WIN-treated males exhibited higher fragmentation of sleep episodes, whereas females displayed anxiolytic and panicolytic behavioral responses to CO2. However, no changes were observed in the mechanical component of the respiratory system, and there were no neuroanatomical alterations, such as changes in the expression of CB1 receptors in the brainstem or in the quantification of catecholaminergic and serotonergic neurons. These findings highlight that external interference in cannabinoid signaling during fetal development causes sex-specific, long-lasting effects for the cardiorespiratory system and behavioral responses in adulthood.NEW & NOTEWORTHY The surge in recreational cannabis use and cannabinoid-based medication prescription among pregnant women has been notable in recent years, fueled by the misconception that natural products are inherently safe. Significant gaps persist regarding the potential risks of maternal consumption of cannabinoids and the long-term effects on the cardiorespiratory system of their offspring, which may be determined by sex. Accordingly, this research aims to diminish this lack of information and raise a note of caution.

VITREORETINAL OUTCOMES FOLLOWING SECONDARY INTRAOCULAR LENS IMPLANTATION WITH PARS PLANA VITRECTOMY.

BACKGROUND: Retrospective cohort study of 561 adult patients undergoing secondary intraocular lens (IOL) implantation by vitreoretinal surgeons at a single institution from April 2015 to December 2020. METHODS: Patient historical factors, intraoperative/postoperative complications, and outcomes of IOL type (anterior chamber IOL versus scleral sutured IOL versus scleral fixated IOL versus. sulcus) were assessed. Primary outcomes were rates of postoperative retinal tears and rhegmatogenous retinal detachment. Secondary outcomes were rates of intraoperative endolaser, intraoperative retinal tear, and further IOL surgery. RESULTS: The incidence of intraoperative retinal tears was 7.3% and not significantly different between techniques. Rates of intraoperative endolaser use were 17.5% among all techniques and not significantly different between techniques. Rates of postoperative retinal tear were low (0%-2.7%). Rates of postoperative rhegmatogenous retinal detachment were not significantly different between techniques (anterior chamber IOL 9/198 [4.5%], SFIOL 1/54 [1.9%], scleral sutured IOL 14/274 [5.1%], sulcus 2/35 [5.7%], total 26/561 [4.6%], P = 0.79). Rates of repeat IOL surgery trended higher in sulcus lenses (anterior chamber IOL 5/198 [2.5%], SFIOL 4/54 [7.4%], scleral sutured IOL 16/274 [5.8%], sulcus 5/35 [14.3%], total 30/561 [5.3%], P = 0.12). CONCLUSION: Intraoperative endolaser use and intraoperative retinal tear are not uncommon in secondary IOL surgery and underscore the importance of careful vitreoretinal management among these patients.

Clinical Utility of the Molecular Microscope Diagnostic System in a Real-World Transplant Cohort: Moving Towards a New Paradigm.

Objectives: To evaluate the clinical implications of adjunctive molecular gene expression analysis (MMDx ) of biopsy specimens in heart transplant (HT ) recipients with suspected rejection. Introduction: Histopathological evaluation remains the standard method for rejection diagnosis in HT. However, the wide interobserver variability combined with a relatively common incidence of "biopsy-negative" rejection has raised concerns about the likelihood of false-negative results. MMDx, which uses gene expression to detect early signs of rejection, is a promising test to further refine the assessment of HT rejection. Methods: Single-center prospective study of 418 consecutive for-cause endomyocardial biopsies performed between November 2022 and May 2024. Each biopsy was graded based on histology and assessed for rejection patterns using MMDx. MMDx results were deemed positive if borderline or definitive rejection was present. The impact of MMDx results on clinical management was evaluated. Primary outcomes were 1-year survival and graft dysfunction following MMDx-guided clinical management. Secondary outcomes included changes in donor-specific antibodies, MMDx gene transcripts, and donor-derived cell-free DNA (dd-cfDNA) levels. Results: We analyzed 418 molecular samples from 237 unique patients. Histology identified rejection in 32 cases (7.7%), while MMDx identified rejection in 95 cases (22.7%). Notably, in 79 of the 95 cases where MMDx identified rejection, histology results were negative, with the majority of these cases being antibody-mediated rejection (62.1%). Samples with rejection on MMDx were more likely to show a combined elevation of dd-cfDNA and peripheral blood gene expression profiling than those with borderline or negative MMDx results (36.7% vs 28.0% vs 10.3%; p<0.001). MMDx results led to the implementation of specific antirejection protocols or changes in immunosuppression in 20.4% of cases, and in 73.4% of cases where histology was negative and MMDx showed rejection. 1-year survival was better in the positive MMDx group where clinical management was guided by MMDx results (87.0% vs 78.6%; log rank p=0.0017). Conclusions: In our cohort, MMDx results more frequently indicated rejection than histology, often leading to the initiation of antirejection treatment. Intervention guided by positive MMDx results was associated with improved outcomes.

Validation of the HeartMate 3 survival risk score in a large left ventricular assist device center.

OBJECTIVE: The HeartMate 3 survival risk score was recently validated in the Multicenter study Of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 to predict patient-specific survival in HeartMate 3 left ventricular assist device candidates. The HeartMate 3 survival risk score stratifies individuals into tertiles according to survival probability. METHODS: We performed a single-center retrospective review of all HeartMate 3 left ventricular assist device recipients between September 2017 and August 2022. Baseline characteristics were collected from the electronic medical records. HeartMate 3 survival risk scores were calculated for all eligible patients. One- and 2-year Kaplan-Meier survival analyses were conducted. A univariate and multivariable Cox regression model was used to identify predictors. RESULTS: A total of 181 patients were included in this final analysis. The median age was 62 years, 83% were male, and 26% were Interagency Registry for Mechanically Assisted Circulatory Support Profile 1. The mean HeartMate 3 survival risk score for the entire cohort was 2.66 ± 0.66. Two-year survivals in the high, average, and low survival groups were 93.5% ± 3.2%, 81.6% ± 7.4%, and 82.0% ± 6.6%, respectively. As a continuous variable, the unadjusted HeartMate 3 survival risk score was a significant predictor of mortality (hazard ratio, 2.20; 95% CI, 1.08-4.45; P = .029). The areas under the curve were 0.70 and 0.66 at 1 and 2 years, respectively. We were unable to demonstrate the discriminatory ability of the HeartMate 3 survival risk score using the original stratification, but we found significantly increased survival in the high survival group using a binary cutoff (hazard ratio, 4.8; 95% CI, 1.01-20.9; P = .038). CONCLUSIONS: The unadjusted HeartMate 3 survival risk score was associated with postimplant survival in patients outside of the Multicenter study Of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 but did not remain an independent predictor after adjusting for ischemic etiology and severe diabetes. The HeartMate 3 survival risk score was able to identify patients at high survival using a binary cutoff, but we were unable to demonstrate its discriminatory ability among the previously published risk tertiles.

Retrospective Cohort Study of Sickle Cell Disease and Large Vessel Retinal Vascular Occlusion Risk in a National United States Database.

OBJECTIVE: To determine if differences exist in the risk of developing large vessel retinal vascular occlusions in patients with sickle cell states. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with sickle cell disease (SCD) or trait evaluated by an ophthalmologist were compared with matched controls without SCD or sickle cell trait (SCT) also evaluated by an ophthalmologist. METHODS: This study used deidentified data from a national database (2006-2024), using International Classification of Diseases 10 codes to select for retinal vascular occlusions. Propensity score matching was performed with respect to age, sex, race, ethnicity, smoking, hypertension, diabetes, dyslipidemias, and obesity, resulting in hemoglobin SS (HbSS), hemoglobin SC (HbSC), and SCT cohorts and matched control cohorts. MAIN OUTCOME MEASURES: Risk ratios (RRs) and 95% confidence intervals (CIs) of retinal vascular occlusion diagnosis, including central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO), central retinal vein occlusion, branch retinal vein occlusion, and corneal dystrophy as a negative control, given SCD or SCT. RESULTS: After propensity score matching, HbSS (n = 10 802; mean age ± standard deviation, 38.6 ± 20.6 years), HbSC (n = 4296, 34.3 ± 17.8 years), and SCT (n = 15 249, 39.8 ± 23.7 years) cohorts were compared with control cohorts (n = 10 802, 38.7 ± 20.7 years; n = 4296, 34.6 ± 18.0 years; n = 15 249, 39.9 ± 23.8 years, respectively). Patients with SCD (HbSS) had higher risk of developing any retinal vascular occlusion (RR, 2.33; 95% CI, 1.82-3.00), CRAO (RR, 2.71; 95% CI, 1.65-4.47), and BRAO (RR, 4.90; 95% CI, 2.48-9.67) than matched controls. Patients with HbSC disease had higher risk (RR, 3.14; 95% CI, 1.95-5.06) of developing any retinal vascular occlusion than matched controls without SCD. Patients with SCT did not have higher risk of developing retinal vascular occlusions (RR, 1.01; 95% CI, 0.81-1.26) than matched controls. CONCLUSIONS: In a retrospective cohort study, patients with HbSS SCD have an increased risk of developing retinal vascular occlusions, and more specifically CRAO and BRAO, compared with patients without SCD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Kidney function assessment using cystatin C and serum creatinine in heart transplantation recipients: Implications for valganciclovir dosing.

BACKGROUND: Among heart transplantation (HT) recipients, the accuracy of serum creatinine (sCr)-based estimated glomerular filtration rate (eGFR) may be limited by fluctuations in muscle mass. Cystatin C (cysC) is less influenced by muscle mass, but its levels may increase with obesity and steroid use. Herein, we (1) longitudinally compared eGFRcysC and eGFRsCr among HT recipients; (2) investigated the association of body mass index (BMI), steroid use, and muscle mass with discrepancies between eGFRs; and (3) explored the implications of eGFRcysC use on valganciclovir (VGC) dosing. METHODS: cysC and sCr were measured in 294 blood samples obtained from 80 subjects. Intraindividual differences between eGFRs (eGFRdiffcysC-sCr) were calculated with negative values corresponding to eGFRsCr > eGFRcysC and positive values to eGFRcysC > eGFRsCr. In a patient subset (n = 21), pectoralis muscle measures were obtained. RESULTS: Marked differences between eGFRcysC and eGFRsCr were observed, particularly early post-HT (1-week post-HT, median eGFRdiffcysC-sCr -28 ml/min/1.73 m2). eGFRcysC demonstrated stability following a transient postoperative decline, while eGFRsCr decreased in the first year post-HT. Lower BMI and higher prednisone dose displayed a modest association with more negative eGFRdiffcysC-sCr values. Pectoralis muscle measures indicative of greater muscle mass and better tissue quality exhibited a stronger association with more positive eGFRdiffcysC-sCr values. The use of eGFRcysC would have led to VGC dose adjustment in 46% of samples, predominantly resulting in dose reduction. CONCLUSIONS: Among HT recipients, eGFRcysC and eGFRsCr markedly differ with implications for VGC dosing. The observed discrepancies may reflect changes in body composition and steroid use.

Waterborne atenolol disrupts neurobehavioral and neurochemical responses in adult zebrafish.

Environmental contamination by pharmaceuticals from industrial waste and anthropogenic activities poses adverse health effects on non-target organisms. We evaluated the neurobehavioral and biochemical responses accompanying exposure to ecological relevant concentrations of atenolol (0, 0.1, 1.0, and 10 µg/L) for seven uninterrupted days in adult zebrafish (Danio rerio). Atenolol-exposed fish exhibited anxiety-like behavior, characterized by significant bottom-dwelling with marked reduction in vertical exploration. Atenolol-exposed fish exhibited marked increase in the duration and frequency of aggressive events without altering their preference for conspecifics. Biochemical data using brain samples indicated that atenolol disrupted antioxidant enzyme activities and induced oxidative stress. Exposure to atenolol markedly decreased ATP and AMP hydrolysis without affecting ADP hydrolysis and acetylcholinesterase (AChE) activity. Atenolol significantly upregulated tryptophan hydroxylase 1 (tph1) mRNA expression but downregulated brain-derived neurotrophic factor (bdnf) mRNA. Collectively, waterborne atenolol elicits aggressive and anxiety-like responses in adult zebrafish, accompanied by oxidative stress, reduced nucleotide hydrolysis, altered tph1 and bdnf mRNA expression, which may impact the survival and health of fish in aquatic environment.

Voxel-based tumor dose correlates to complete pathologic necrosis after transarterial radioembolization for hepatocellular carcinoma.

PURPOSE: The transarterial radioembolization (TARE) dose is traditionally calculated using the single-compartment Medical Internal Radiation Dose (MIRD) formula. This study utilized voxel-based dosimetry to correlate tumor dose with explant pathology in order to identify dose thresholds that predicted response. METHODS: All patients with HCC treated with TARE using yttrium-90 [90Y] glass microspheres at a single institution between January 2015 - June 2023 who underwent liver transplantation were eligible. The [90Y] distribution and dose-volume histograms were determined using Simplicity90 (Mirada Medical, Oxford UK) with a Bremsstrahlung SPECT/CT. A complete response was assigned if explant pathology showed complete necrosis and the patient had not undergone additional treatments to the same tumor after TARE. Logistic regression and receiver operator characteristic (ROC) curves were constructed to evaluate dose thresholds correlated with response. RESULTS: Forty-one patients were included. Twenty-six (63%) met criteria for complete response. Dose to 95% (D95), 70% (D70), and 50% (D50) of the tumor volume were associated with likelihood of complete response by logistic regression (all p < 0.05). For lesions with complete response versus without, the median D95 was 813 versus 232 Gy, D70 was 1052 versus 315 Gy, and D50 was 1181 versus 369 Gy (all p < 0.01). A D95 > 719 Gy had the highest accuracy at 68% (58% sensitivity, 87% specificity) for predicting complete response. Median percent of tumor volume receiving at least 100 Gy (V100), 200 Gy (V200), 300 Gy (V300), and 400 Gy (V400) also differed by pathologic response: the median V100, V200, V300, and V400 was 100% versus 99%, 100% versus 97%, 100% versus 74%, and 100% versus 43% in the complete response versus non-complete response groups, respectively (all p < 0.05). CONCLUSION: Voxel-based dosimetry was well-correlated with explant pathology. The D95 threshold had the highest accuracy, suggesting the D95 may be a relevant target for multi-compartment dosimetry.

Granulomatous Tubulointerstitial Nephritis in a Kidney Allograft: Treatment with Interleukin-6 Receptor Antagonist Stabilises Kidney Function.

Granulomatous tubulointerstitial nephritis (GTIN) attributed to early onset sarcoidosis is an ultrarare finding in an allograft kidney biopsy. We present the case of a young man with allograft dysfunction who had GTIN upon biopsy. We performed a thorough case review based on recovered records from early childhood and reassessed genetic testing results. We revised his underlying diagnosis from cryopyrin-associated periodic syndrome to early-onset sarcoidosis with wild-type NOD2 and established a rationale to use the interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ). This suppressed his inflammatory disease and stabilised kidney function. We performed a literature review related to the emerging role of IL-6 pathway blockade in kidney transplantation. We identified 18 reports with 417 unique patients treated with TCZ for indications including HLA-desensitisation, transplant immunosuppression induction, treatment of chronic antibody-mediated rejection, and treatment of subclinical rejection. Both TCZ and the direct IL-6 inhibitor clazakizumab are being studied in ongoing randomised control trials.