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ABSTRACT Little is known about the urinary virome and how it interacts with the host, particularly in renal transplant diseases. Using metagenomic sequencing, we characterized the urinary virome of 23 kidney transplant recipients longitudinally (11 BKV+ patients and 12 BKV− patients). We applied linear mixed effects models, PERMANOVA, k-means clustering, and MaAsLin2 algorithms to determine virome signatures associated with post-transplant time, BK viremia status, and patient sex. We found that the richness and alpha diversity of urinary virome were significantly different in renal transplant recipients with BKV+ over time in comparison to BKV− (richness P = 0.012, alpha P < 0.0001). Female BKV− patients had significantly higher virome richness than males (P = 0.0063). Virome beta diversity was significantly different between patients by BKV status (P < 0.001). Additionally, we identified underlying interactions between patient sex and BKV status, in terms of virome beta diversity (P = 0.008). BK polyomavirus infections were primarily of subtypes IA, IB1, and IB2. The non-BK dominant samples clustered into six urinary virome community states. BKV− samples had more anelloviruses than BKV+ samples though this difference was not statistically significant. Lastly, we identified specific viruses, associated with BKV+ and time in our samples. Our results indicate that dynamic alterations in the urinary virome over the post-transplant period in kidney transplant recipients can be shaped by BK viremia and patient sex. These findings advance our fundamental understanding of the urinary virome and support a new line of investigation in renal disease and transplantation.IMPORTANCEThe urinary microbiome is increasingly implicated in renal health and disease. While most research focuses on bacteria communities of the microbiome, factors that influence the urinary virome are not understood. Here, we investigated the urinary virome of 23 adult kidney transplant recipients longitudinally over 14 weeks post-transplant. We show that alterations in the urinary virome are associated with kidney transplant recipients with BK polyomavirus viremia that can lead to BK nephropathy and allograft rejection. By modeling the temporal dynamics post-transplant, we delineated specific profiles of the urinary virome associated with patient sex and urinary community states. These findings reveal fundamental aspects of the urinary virome that can be leveraged to better manage kidney diseases.

Background: As life expectancy improves for patients with dementia, the demand for mobility-improving surgeries such as total joint arthroplasty (TJA) will increase. There is little research on patients with dementia undergoing TJA, although dementia has been shown to be a risk factor for complications. The purpose of this study is to compare postoperative outcomes of patients with dementia undergoing TJA at 90 days, 2 years, and 5 years. Methods: The TriNetX database was retrospectively queried for all patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA). Patients were divided into cohorts by preoperative diagnosis of dementia and propensity score matched. The following outcomes were evaluated between groups at 90 days, 2 years, and 5 years postoperatively: revision, resection arthroplasty, closed reduction (THA only), femur fracture plating, and prosthetic joint infection. Readmission and manipulation under anesthesia (TKA only) were evaluated at 90 days postoperatively. Univariate and multivariate analyses were performed. Results: After matching, there were no differences in demographics or comorbidities between groups. TKA (odds ratio [OR] = 1.75, 95% confidence interval [CI] 1.42-2.15, P < .001) and THA (OR = 2.17, 95% CI 1.92-2.45, P < .001) patients with dementia were more likely to be readmitted than patients without dementia. At 2 years (OR = 2.07, 95% CI 1.14-3.77, P = .015) and 5 years (OR = 2.14, 95% CI 1.32-3.48, P = .002) postoperatively, THA patients with dementia were more likely to have proximal femur fracture plating than patients without dementia. Conclusions: Patients undergoing THA with dementia had worse outcomes than patients undergoing THA without dementia and TKA with dementia. The overall rate of complications was low, and a diagnosis of dementia should not be an absolute contraindication to proceeding with TJA.

Abstract Background Various episode-of-care bundled payment models for patients undergoing total joint arthroplasty have been implemented. However, participation in bundled payment programs has dropped given the challenges of meeting continually lower target prices. The purpose of our study is to investigate the cost of outpatient physical therapy (PT) and the potential for stand-alone outpatient PT bundled payments for patients undergoing total hip arthroplasty (THA). Methods A retrospective review of 501 patients who underwent primary unilateral THA from November 2017 to February 2020 was performed. All patients included in this study received postoperative PT care at a single hospital-affiliated PT practice. Patients above the 75th percentile of therapy visits were then classified as high-PT utilizers and compared with the rest of the population using univariate statistics. Stepwise multivariate logistic regression was used to assess the predictors of high therapy utilization. Results Patients averaged 65 ± 10 years of age and a BMI of 29 ± 5 kg/m2. Overall, 80% of patients were white and 53% were female. The average patient had 11 ± 8 total therapy sessions in 42 days: one initial evaluation, one re-evaluation and 9 standard sessions. High-PT utilizers incurred estimated average costs of $1934 ± 431 per patient, compared to $783 ± 432 (P 0.08). In the multivariate analysis, women (OR = 1.68, P = 0.017) and those with sleep apnea (OR = 2.02, P = 0.012) were nearly twice as likely to be high utilizers, while white patients were 42% less likely to be high utilizers than patients of other races (OR = 0.58, P = 0.028). Conclusions Outpatient PT utilization is highly variable in patients undergoing THA. However, despite using more services and incurring increased cost, patients in the top quartile of utilization experienced similar outcomes to the rest of the population. If outpatient therapy bundles are to be developed, 16 visits appear to be a reasonable target for pricing, given this provides adequate coverage for 75% of THA patients.

Abstract Recovery from depression often demonstrates a nonlinear pattern of treatment response, where the largest reduction in symptoms is observed early followed by smaller improvements. This study investigated whether this exponential pattern could model the antidepressant response to repetitive transcranial magnetic stimulation (TMS). Symptom ratings from 97 patients treated with TMS for depression were collected at baseline and after every five sessions. A nonlinear mixed-effects model was constructed using an exponential decay function. This model was also applied to group-level data from several published clinical trials of TMS for treatment-resistant depression. These nonlinear models were compared to corresponding linear models. In our clinical sample, response to TMS was well modeled with the exponential decay function, yielding significant estimates for all parameters and demonstrating superior fit compared to a linear model. Similarly, when applied to multiple studies comparing TMS modalities as well as to previously identified treatment response trajectories, the exponential decay models yielded consistently better fits compared to linear models. These results demonstrate that the antidepressant response to TMS follows a nonlinear pattern of improvement that is well modeled with an exponential decay function. This modeling offers a simple and useful framework to inform clinical decisions and future studies.

Abstract Background Immunosuppression in transplantation continues to be associated with a multitude of adverse effects. Induction of immune tolerance may be a viable strategy to reduce dependence on immunosuppression. Various trials are currently underway to assess the efficacy of this strategy. However, long-term safety data for these immune tolerance regimes has yet to be established. Methods/design At the completion of primary follow-up of various Medeor kidney transplant studies, subjects receiving cellular immunotherapy products will be followed annually as per protocolized schedule for up to an additional 84 months (7 years) to evaluate long-term safety. Long-term safety will be assessed by summarizing incidence of serious adverse events, adverse events leading to study withdrawal and hospitalization rates. Discussion This extension study will be an important step in evaluating safety issues pertaining to immune tolerance regimens, long-term effects of which are largely unknown. These data are essential for furthering an unrealized goal of kidney transplantation- graft longevity without the adverse effects from long-term immunosuppression. The study design utilizes the methodology of a master protocol, wherein multiple therapies can be assessed simultaneously with accompanied gathering of long-term safety data.

Introduction: Hip arthroscopy (HA) for femoroacetabular impingement syndrome (FAIS) has been demonstrated to improve outcomes but carries inherent risks of complications and the need for revision arthroscopy or conversion to total hip arthroplasty (THA). The objective of this study is to evaluate preoperative radiographs, patient outcomes, and risk factors for reoperation in patients undergoing HA for FAIS. Methods: A retrospective review of 351 consecutive patients undergoing HA for FAIS from July 2015 to June 2018 was conducted. The primary endpoints were revision hip arthroscopy (RHA) and THA. Univariate and multivariate analysis was performed to evaluate the risk factors for these endpoints. Results: By the end of the study period, 21 (6.0%) patients had undergone an RHA and 27 (7.7%) patients had undergone a THA. When comparing patients who had an RHA to those that did not, there were significant differences in preoperative radiographic characteristics, including smaller sourcil angle (P = 0.012) and lower Tönnis grade (P = 0.038) between groups. These patients were also more likely to have had a postoperative injection in the 1st year (P < 0.001). No factor was independently predictive of revision HA in multivariate analysis. Patients who underwent a subsequent THA were significantly older (P < 0.001) and required more suture anchors for repair (P < 0.001) than those that did not. On preoperative radiographs, Tönnis grade (P = 0.43) skewed higher. The multivariate regression models generated area under the curve of 0.740 and 0.864 for RHA and THA, respectively, indicating acceptable to strong predictive performance. Conclusion: Individual preoperative patient characteristics and radiographic findings are of limited value in assessing risk for RHA or THA after HA for FAIS. However, predictive models incorporating demographic and radiographic findings hold promise for identifying patients at risk for these outcomes. Further study is needed to refine models and assess their value in preoperative patient selection and counseling.

Abstract Background Despite the pervasiveness of migraine, the underlying pathophysiological mechanisms initiating migraine attacks are far from well understood and are matter of scientific debate. Objective In this narrative review, we discuss key evidence for that suggest a peripheral origin or central origin and provide directions for future studies that may provide further clarification. Discussion Migraine pathogenesis is considered to involve the trigeminovascular system, a term that encompasses the trigeminal nerve and its axonal projections to the intracranial blood vessels. Beyond any doubt both peripheral and central mechanisms are involved in migraine pathogenesis, but an unresolved question is the how the initial activation occurs in a migraine attack. Evidence favoring a peripheral origin of migraine attacks, i.e., initial events occur outside of the blood–brain barrier, include the importance of sensitization of perivascular sensory afferents early on in a migraine attack. Evidence favoring a central origin include the occurrence of prodromal symptoms, migraine aura, and activation of structures within the central nervous system early in and during a migraine attack. Conclusions Both peripheral and central mechanisms are likely involved in a migraine attack, e.g., peripheral nociceptive input is necessary for pain transmission and cortical activity is necessary for pain perception. Yet, the debate of whether migraine attacks are initiated a peripheral or central site remains unresolved. The increased focus on prodromal symptoms and on the development of a human model of migraine aura will possibly provide key arguments needed to answer this question in the near future. Until then, we cannot draw firm conclusions and the debate goes on. Video link Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at: https://www.youtube.com/watch?v=NC0nlcKohz0 . Graphical Abstract

Background. The optimal strategy for cytomegalovirus (CMV) disease prevention in CMV donor/recipient kidney transplant recipients remains uncertain. Conclusions of prior meta-analyses that CMV disease rates with preemptive therapy (PET) and universal prophylaxis (UP) were comparable may have been affected by inclusion of studies lacking key determinants of efficacy of the respective strategies. Methods. We conducted a systematic review and meta-analysis of PET with weekly CMV polymerase chain reaction monitoring for ≥3 mo and UP with 6 mo of valganciclovir. PubMed and Embase databases were reviewed from January 1, 2010, to April 1, 2022. Risk of bias was assessed with 3 instruments (Cochrane RoB, Cochrane RoBINS-I, and an instrument for assessing risk in observational studies). The primary outcome was CMV disease incidence by 1-y posttransplant. Secondary outcomes by 1-y were graft loss, acute allograft rejection, and mortality. Results were synthesized using generalized linear mixed model meta-analysis. PET studies were stratified into low-threshold (LT) and high-threshold (HT) PET based on the viral load threshold for initiation of antiviral therapy. Results. Twenty-five studies met inclusion criteria (6 PET, 19 UP). CMV disease incidence was significantly higher in HT (0.30 [95% confidence interval (CI), 0.22-0.39]) versus LT PET (0.06 [95% CI, 0.03-0.12]). LT PET was associated with a significantly lower CMV disease incidence (0.06 [95% CI, 0.03-0.12]) versus UP (0.21 [95% CI, 0.17-0.27]). Incidence of graft loss, acute allograft rejection, or mortality was not significantly different between LT PET and UP (P > 0.05 for all comparisons). Receipt of lymphocyte-depleting antibodies was not associated with a significant difference in CMV disease incidence (odds ratio = 1.34 [95% CI, 0.80-2.25]). Conclusions. LT PET is associated with a significantly lower incidence of CMV disease compared to UP with similar rates of other clinical outcomes. These findings provide rationale and preliminary data for a randomized superiority trial of optimized LT-PET versus UP in donor seropositive recipient seronegative kidney transplant recipients.

Solid organ transplants are associated with a modestly increased risk of colorectal cancers (CRC). However, the molecular profile of these cancers has not been described. We hypothesized that transplant-related immunosuppression may promote development of more immunogenic tumors as suggested by a high tumor mutation burden or mismatch repair deficiency. We performed an electronic medical record search for patients seen in the Johns Hopkins University Health System (JHHS) between 2017 and 2022 who developed CRC following solid organ transplantation. A comparator cohort of patients treated for CRC at JHHS with molecular profiling data was also identified. In this case, 29 patients were identified that developed post-transplant CRC (renal transplant, n = 18; liver transplant, n = 8; kidney-liver transplantation, n = 3). Compared to the JHHS general population CRC cohort, patients who developed post-transplant CRC had a higher rate of mismatch repair deficiency (41% versus 12%, p-value = 0.0038), and elevated tumor mutation burden (median of 22 mut/Mb versus 3.5 mut/Mb, p-value = 0.033) (range 3.52–53.65). Post-transplant tumors were enriched for PIK3CA mutations (43% versus 24%, p-value = 0.042). Post-Transplant CRCs are associated with clinical and molecular features of immune sensitivity, supporting a potential role for impaired immune surveillance in shaping the landscape of CRCs. These results may help inform the management of patients with post-transplant CRC.

Abstract A contiguous carbonate‐rich hydroxyapatite microcoating in a microfluidic device represents a substrate that has chemical and structural similarity to bone mineral. The present work describes a low‐temperature method to deposit a carbonate‐rich hydroxyapatite microcoating on a glass slide and its incorporation within the microchannels of a microfluidic device. A glass slide is covered/masked with polypropylene‐based tape and CaCO3 nanoparticles are deposited on exposed areas by convective self assembly. The precursor CaCO3 is converted to carbonate‐rich hydroxyapatite by dissolution‐recrystallization in phosphate‐buffered saline. The microcoating is aligned/incorporated within a microchannel when the underlying glass is bonded to a polydimethylsiloxane structure with the device layout. X‐ray diffraction, laser Raman microspectroscopy, and X‐ray photoelectron spectroscopy indicate that the microcoating was comprised of carbonate‐rich hydroxyapatite. Scanning electron microscopy and 3D laser confocal microscopy showed that was comprised of nanocrystalline rod‐like clusters that collectively exhibit a thickness of ∼20 µm. Monocultures/cocultures of osteoblast‐lineage (MC3T3‐E1, MG63) and preosteoclast‐lineage (RAW 264.7) cells were performed. Osteoblast‐lineage cells adhered to the microcoating and deposited an extracellular matrix of collagen fibrils and mineral accretions. Mineralization was detected in/near the inlet wells. The microcoating is analogous to bone mineral and could be applied to various layouts and mineral systems.

Background. Enteric hyperoxalosis (EH) is an emerging cause of kidney transplantation (KT) dysfunction. We sought to determine the prevalence of EH and factors that affect plasma oxalate (POx) among at-risk KT candidates. Methods. We prospectively measured POx among KT candidates evaluated at our center from 2017 to 2020 with risk factors for EH namely bariatric surgery, inflammatory bowel disease, or cystic fibrosis. EH was defined by a POx ≥10 μmol/L. Period-prevalence of EH was calculated. We compared mean POx across 5 factors: underlying condition, chronic kidney disease (CKD) stage, dialysis modality, phosphate binder type, and body mass index. Results. Of 40 KT candidates screened, 23 had EH for a 4-y period prevalence of 58%. Mean POx was 21.6 ± 23.5 μmol/L ranging from 0 to 109.6 μmol/L. 40% of screened had POx >20 μmol/L. Sleeve gastrectomy was the most common underlying condition associated with EH. Mean POx did not differ by underlying condition (P = 0.27), CKD stage (P = 0.17), dialysis modality (P = 0.68), phosphate binder (P = 0.58), and body mass index (P = 0.56). Conclusions. Bariatric surgery and inflammatory bowel disease were associated with a high prevalence of EH among KT candidates. Contrary to prior studies, sleeve gastrectomy was also associated with hyperoxalosis in advanced CKD. POx concentrations observed in EH reached levels associated with tissue and potentially allograft deposition. Concentrations can be as high as that seen in primary hyperoxaluria. More studies are needed to assess if POx is indeed a modifiable factor affecting allograft function in patients with EH.

Purpose of review: To review the data on the immunogenicity of COVID-19 vaccines, administered by different strategies, in solid organ transplant recipients (SOTRs). Recent findings: COVID-19 booster vaccines were given to SOTRs as a widespread practice in many transplant centers, mostly as the third and/or fourth dose in an extended vaccine series, with a significantly improved humoral response compared with the initial two-dose scheme. However, one-third of SOTRs remained unresponsive, despite these boosters. Next steps: Vaccination with standard dosing remains the most feasible strategy for attaining protection against COVID-19. Additional booster doses and temporarily holding or reducing mycophenolate mofetil/mycophenolic acid may provide immunogenicity to vaccines, according to recent studies demonstrating some efficacy with these measures. Preexposure prophylaxis with monoclonal antibodies showed benefit in immunocompromised patients but is no longer recommended by the National Institutes of Health (NIH) due to diminished efficacy against Omicron and recent variants. Screening for the presence and titers of SARS-CoV-2-specific antibodies in SOTRs is not recommended in most clinical settings. T cell-based techniques are needed to evaluate vaccine efficacy and risk of infection. As SARS-CoV-2 continues to evolve, new vaccines based on conservative protein component/complexes of the COVID virus, in addition to its spike protein, are warranted to offer prolonged protection.

Total joint arthroplasty (TJA) implants are composed of metal components. Although they are regarded safe, the long-term immunological effects of chronic exposure to the specific implant materials are unknown. We recruited 115 hip and/or knee TJA patients (mean age 68 years) who provided a blood draw for measurement of chromium, cobalt, titanium concentrations, inflammatory markers and systemic distribution of immune cells. We examined differences between the immune markers and the systemic concentrations of chromium, cobalt and titanium. CD66-b neutrophils, early natural killer cells (NK), and eosinophils were present in higher percentages in patients with chromium and cobalt concentrations greater than the median. The opposite pattern was observed with titanium where the percentages of CD66-b neutrophils, early NK, and eosinophils were higher in patients with undetectable titanium. Cobalt concentrations were positively correlated with a higher percentage of gamma delta T cells. Both chromium and cobalt concentrations were positively correlated with higher percentages of plasmablasts. Titanium concentrations were positively correlated with higher CD4 effector memory T cells, regulatory T cell count and Th1 CD4 helper cells. In this exploratory study, we observed altered distribution of immune cells in TJA patients with elevated systemic metal concentrations. Although these correlations were not strong, these exploratory findings warrant further investigation into the role of increased metals circulating in blood and its role in immune modulation.

Whether GPCRs support the sensing of temperature as well as other chemical and physical modalities is not well understood.Introduction: Extracellular Ca2+ concentration (Ca2+o) modulates core body temperature and the firing rates of temperature-sensitive CNS neurons, and hypocalcemia provokes childhood seizures. However, it is not known whether these phenomena are mediated by Ca2+o-sensing GPCRs, including the calcium-sensing receptor (CaSR). In favor of the hypothesis, CaSRs are expressed in hypothalamic regions that support core temperature regulation, and autosomal dominant hypocalcemia, due to CaSR activating mutations, is associated with childhood seizures.Methods: Herein, we tested whether CaSR-dependent signaling is temperature sensitive using an established model system, CaSR-expressing HEK-293 cells.Results: We found that the frequency of Ca2+o-induced Ca2+i oscillations but not the integrated response was linearly dependent on temperature in a pathophysiologically relevant range. Chimeric receptor analysis showed that the receptor’s C-terminus is required for temperature-dependent modulation and experiments with the PKC inhibitor GF109203X and CaSR mutants T888A and T888M, which eliminate a key phosphorylation site, demonstrated the importance of repetitive phosphorylation and dephosphorylation.Discussion and Conclusion: CaSRs mediate temperature-sensing and the mechanism, dependent upon repetitive phosphorylation and dephosphorylation, suggests that GPCRs more generally contribute to temperature-sensing.

Background: Health disparities disproportionately affect minority groups across the United States with respect to care access, quality, and outcomes. The aim of this study is to examine existing disparities between white and African American (AA) patients regarding postoperative outcomes following total joint arthroplasty and provide insight into disparity trends over a 9-year period. Methods: A retrospective review of 16,779 total joint arthroplasty patients at a single institution between January 2013 and December 2021 was performed. Patients were grouped by race as AA or white. Outcomes of interest included length of stay (LOS), home discharge, 30-day emergency department return, and 30-day readmission. Univariate statistics and multivariate regressions were utilized to analyze results. Results: Significant improvements in LOS and rates of home discharge occurred for both white and AA patients at our institution over a 9-year period, while rates of 30-day emergency department returns and readmissions demonstrated a downward but non–statistically significant trend. Despite these trends, AA patients continued to experience longer lengths of stay, less likelihood of 0- or 1-day LOS, and higher risk of nonhome discharge for most years examined. However, after controlling for demographic and comorbidity differences, the differences between groups narrowed over time resulting in no significant differences in the aforementioned 3 measures by 2021. Conclusions: Although racial disparities in outcomes are still apparent, over time, the differences in resource utilization between AA and white patients have narrowed. Initiatives aimed at creating healthier communities with increased access to care and the ultimate goal of equitable care must continue to be pursued.

Rationale and objectives: to investigate the relationship between radiologists' experience in reporting mammograms, their caseloads, and the classification of category ‘3′ or ‘Probably Benign’ on normal mammograms. Materials and Methods: A total of 92 board-certified radiologists participated. Self-reported parameters related to experience, including age, years since qualifying as a radiologist, years of experience reading mammograms, number of mammograms read per year, and hours spent reading mammograms per week, were documented. To assess the radiologists' accuracy, ''Probably Benign fractions” was calculated by dividing the number of ''Probably Benign findings'' given by each radiologist in the normal cases by the total number of normal cases Probably Benign fractions were correlated with various factors, such as the radiologists' experience. Results: The results of the statistical analysis revealed a significant negative correlation between radiologist experience and 'Probably Benign' fractions for normal images. Specifically, for normal cases, the number of mammograms read per year (r = −0.29, P = 0.006) and the number of mammograms read over the radiologist's lifetime (r = −0.21, P = 0.049) were both negatively correlated with 'Probably Benign' fractions Conclusion: The results indicate that a relationship exists between increased reading volumes and reduced assessments of 'Probably Benign' in normal mammograms. The implications of these findings extend to the effectiveness of screening programs and the recall rates.

Previous studies showed that radiologists can detect the gist of an abnormality in a mammogram based on a half-second image presentation through global processing of screening mammograms. This study investigated the intra- and inter-observer reliability of the radiologists' initial impressions about the abnormality (or "gist signal"). It also examined if a subset of radiologists produced more reliable and accurate gist signals. Thirty-nine radiologists provided their initial impressions on two separate occasions, viewing each mammogram for half a second each time. The intra-class correlation (ICC) values showed poor to moderate intra-reader reliability. Only 13 radiologists had an ICC of 0.6 or above, which is considered the minimum standard for reliability, and only three radiologists had an ICC exceeding 0.7. The median value for the weighted Cohen's Kappa was 0.478 (interquartile range = 0.419-0.555). The Mann-Whitney U-test showed that the "Gist Experts", defined as those who outperformed others, had significantly higher ICC values (p = 0.002) and weighted Cohen's Kappa scores (p = 0.026). However, even for these experts, the intra-radiologist agreements were not strong, as an ICC of at least 0.75 indicates good reliability and the signal from none of the readers reached this level of reliability as determined by ICC values. The inter-reader reliability of the gist signal was poor, with an ICC score of 0.31 (CI = 0.26-0.37). The Fleiss Kappa score of 0.106 (CI = 0.105-0.106), indicating only slight inter-reader agreement, confirms the findings from the ICC analysis. The intra- and inter-reader reliability analysis showed that the radiologists' initial impressions are not reliable signals. In particular, the absence of an abnormal gist does not reliably signal a normal case, so radiologists should keep searching. This highlights the importance of "discovery scanning," or coarse screening to detect potential targets before ending the visual search.

For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNI-based therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break established immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability.

Mammography interpretation is challenging with high error rates. This study aims to reduce the errors in mammography reading by mapping diagnostic errors against global mammographic characteristics using a radiomics-based machine learning approach. A total of 36 radiologists from cohort A (n = 20) and cohort B (n = 16) read 60 high-density mammographic cases. Radiomic features were extracted from three regions of interest (ROIs), and random forest models were trained to predict diagnostic errors for each cohort. Performance was evaluated using sensitivity, specificity, accuracy, and AUC. The impact of ROI placement and normalization on prediction was investigated. Our approach successfully predicted both the false positive and false negative errors of both cohorts but did not consistently predict location errors. The errors produced by radiologists from cohort B were less predictable compared to those in cohort A. The performance of the models did not show significant improvement after feature normalization, despite the mammograms being produced by different vendors. Our novel radiomics-based machine learning pipeline focusing on global radiomic features could predict false positive and false negative errors. The proposed method can be used to develop group-tailored mammographic educational strategies to help improve future mammography reader performance.

Background: The purpose of this study is to evaluate and redefine patients at high risk for increased resource utilization and complications after total joint arthroplasty (TJA), so interventions may focus on patients standing to receive the most benefit. Material and methods: This is a retrospective study of 787 patients undergoing primary unilateral TJA from September 1, 2020, to September 31, 2021. Patients were deemed to be at “high risk” based on criteria derived from published literature and triaged to an enhanced preoperative education program. Patients that were discharged to a skilled nursing facility, had a length of stay ≥ 2 days, returned to the emergency department, or readmitted within 30 days were classified as having a composite outcome. A univariate analysis compared patients who did and did not experience the composite outcome, and multivariate regression was performed to evaluate predictors of this endpoint. Results: Differences in rates of 5 of the 28 risk factors were present between patients who did and did not experience composite outcomes. After controlling for other factors, African American race, planned discharge to skilled nursing facility, mental health conditions or drug use, cardiac, and neurologic conditions were predictive of the composite outcome. Patients who were reclassified as “high risk” with 1 or more of these characteristics, experienced longer length of stay and lower rates of home discharge than the rest of the population. Conclusion: This study presents a profile of high-risk TJA patients that can be incorporated into clinical practice for risk stratification and targeted intervention.

Background: This study aims to investigate the diagnostic efficacy of radiologists when reading screening mammograms in the absence of previous images, and with the presence of prior images from the same and different vendors. Methods: 612 radiologists’ readings across 9 test sets, consisting of 540 screening mammograms (361-normal and 179-cancer) with 245 cases having prior images obtained from same vendor as current images, 129 from a different vendor and 166 cases having no prior images, were retrospectively analysed. True positive (sensitivity), true negative (specificity) and area under ROC curve (AUC) values of radiologists were calculated for three groups of cases (without prior images (NP), with prior images from same vendor (SP), and with prior images from different vendor (DP)). Logistic regression was used to estimate the odds ratio (OR) of true positive, true negative and true cancer localization among case groups with different levels of breast density and lesion characteristics. Results: Radiologists obtained 12.8% and 10.3% higher sensitivity in NP and DP than SP (0.803-and-0.785 vs. 0.712; p < 0.0001). Specificity in NP and DP cases were 4.8% and 2.0% lower than SP cases (0.749 and 0.771 vs. 0.787). The AUC values for NP and DP were significantly higher than SP cases across different levels of breast density (0.814-and-0.820 vs. 0.782; p < 0.0001). The odds ratio (OR) of true positive for NP relative to SP was 1.6 (p < 0.0001) and DP relative to SP was 1.5 (p < 0.0001). Radiologists were more like to detect architectural distortion in DP than SP cases (OR = 3.2; p < 0.0001), whilst the OR for abnormal calcifications was 2.85 (p < 0.0001). Conclusions: Cases without previous mammograms or with prior mammograms obtained from different vendors were more likely to benefit radiologists in cancer detection, whilst prior mammograms undertaken from the same vendor were more useful for radiologists in evaluating normal cases.

Atomic layer deposition (ALD) has been identified as a promising growth method for high-uniformity superconducting thin films for superconducting quantum photonic applications, offering superior uniformity, thickness control and conformality to techniques such as reactive sputtering. The potential scalability of ALD makes this method especially appealing for fabrication of superconducting nanowires and resonators across large areas. We report on the growth of highly uniform superconducting NbN thin films via plasma-enhanced atomic layer deposition (PEALD) with radio frequency substrate biasing, on a 200 mm (8 inch) Si wafer, specifically for superconducting nanowire single-photon detector applications. Niobium nitride films were grown using (tert-butylimido)-tris(diethylamido)-niobium(V) precursor and an H _2 /Ar plasma. The superconducting properties of a variable thickness series of films (5.9–29.8 nm) show critical temperature ( T _c ) of 13.5 K approaching bulk thickness (28.8 nm) with low suppression down to the ultrathin regime (5.9 nm), with T _c = 10.2 K. T _c across the 200 mm wafer with 8 nm thick NbN, measured in 15 mm intervals, exhibits minimal variation ( 10 MA cm ^−2 at 2.6 K. PEALD could therefore be a pivotal technique in enabling large-scale fabrication of integrated quantum photonic devices across a variety of applications.

Chickpea (Cicer arietinum) is a globally important food legume but its yield is negatively impacted by the fungal pathogen Ascochyta blight (Ascochyta rabiei) causing necrotic lesions leading to plant death. Past studies have found that Ascochyta resistance is polygenic. It is important to find new resistance genes from the wider genepool of chickpeas. This study reports the inheritance of Ascochyta blight resistance of two wide crosses between the cultivar Gokce and wild chickpea accessions of C. reticulatum and C. echinospermum under field conditions in Southern Turkey. Following inoculation, infection damage was scored weekly for six weeks. The families were genotyped for 60 SNPs mapped to the reference genome for quantitative locus (QTL) mapping of resistance. Family lines showed broad resistance score distributions. A late responding QTL on chromosome 7 was identified in the C. reticulatum family and three early responding QTLs on chromosomes 2, 3, and 6 in the C. echinospermum family. Wild alleles mostly showed reduced disease severity, while heterozygous genotypes were most diseased. Interrogation of 200k bp genomic regions of the reference CDC Frontier genome surrounding QTLs identified nine gene candidates involved in disease resistance and cell wall remodeling. This study identifies new candidate chickpea Ascochyta blight resistance QTLs of breeding potential.

PURPOSEWe aimed to evaluate the capacity to treat retinoblastoma in the Middle East, North Africa, and West Asia region.METHODSA Web-based assessment that investigated retinoblastoma-related pediatric oncology and ophthalmology infrastructure and associated capacity at member institutions of the Pediatric Oncology East and Mediterranean group was distributed. Data were analyzed in terms of availability, location, and confidence of use for each resource needed for the management of retinoblastoma. Resources were categorized by diagnostics, focal therapy, chemotherapy, advanced treatment, and supportive care. Responding institutions were further divided into an asset-based tiered system.RESULTSIn total, responses from 23 institutions were obtained. Fifteen institutions reported the availability of an ophthalmologist, 12 of which held primary off-site appointments. All institutions reported the availability of a pediatric oncologist and systemic chemotherapy A significant portion of available resources was located off site. Green laser was available on site at seven institutions, diode laser at six institutions, cryotherapy at 12 institutions, and brachytherapy at nine institutions. There existed marked disparity between the availability of some specific ophthalmic resources and oncologic resources.CONCLUSIONThe assessment revealed common themes related to the treatment of retinoblastoma in low- and- middle-income countries, including decentralization of care, limited resources, and lack of multidisciplinary care. Resource disparities warrant targeted intervention in the Middle East, North Africa, and West Asia region to advance the management of retinoblastoma in the region.

Abstract Background Live kidney donors (LKDs) account for nearly a third of kidney transplants in the United States. While donor nephrectomy poses minimal post-surgical risk, LKDs face an elevated adjusted risk of developing chronic diseases such as hypertension, diabetes, and end-stage renal disease. Routine screening presents an opportunity for the early detection and management of chronic conditions. Transplant hospital reporting requirements mandate the submission of laboratory and clinical data at 6-months, 1-year, and 2-years after kidney donation, but less than 50% of hospitals are able to comply. Strategies to increase patient engagement in follow-up efforts while minimizing administrative burden are needed. We seek to evaluate the effectiveness of using small financial incentives to promote patient compliance with LKD follow-up. Methods/design We are conducting a two-arm randomized controlled trial (RCT) of patients who undergo live donor nephrectomy at The Johns Hopkins Hospital Comprehensive Transplant Center (MDJH) and the University of Maryland Medical Center Transplant Center (MDUM). Eligible donors will be recruited in-person at their first post-surgical clinic visit or over the phone. We will use block randomization to assign LKDs to the intervention ($25 gift card at each follow-up visit) or control arm (current standard of care). Follow-up compliance will be tracked over time. The primary outcome will be complete (all components addressed) and timely (60 days before or after expected visit date), submission of LKD follow-up data at required 6-month, 1-year, and 2-year time points. The secondary outcome will be transplant hospital-level compliance with federal reporting requirements at each visit. Rates will be compared between the two arms following the intention-to-treat principle. Discussion Small financial incentivization might increase patient compliance in the context of LKD follow-up, without placing undue administrative burden on transplant providers. The findings of this RCT will inform potential center- and national-level initiatives to provide all LKDs with small financial incentives to promote engagement with post-donation monitoring efforts. Trial registration ClinicalTrials.gov number: NCT03090646 Date of registration: March 2, 2017 Sponsors: Johns Hopkins University, University of Maryland Medical Center Funding: The Living Legacy Foundation of Maryland

The opportunities for wrought magnesium products in a wide range of structural and functional materials for transportation, energy generation, energy storage and propulsion are increasing due to their light-weighting benefits, high specific strength and ease of recyclability. However, the current uses of wrought magnesium alloys for structural applications are limited due to comparatively low strength, high yield strength asymmetry and poor formability & superplasticity. In the present work, we developed an ultrafine-grained magnesium alloy with an extraordinary strength and ductility combination, exceptional high specific strength, zero yield strength asymmetry and excellent high strain rate superplasticity.

Introduction: Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)–sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes. Methods: APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. Results: The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. Conclusion: This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation. Keywords: African Americans, APOL1, chronic kidney disease, graft failure, kidney transplantation, outcomes