Chest wall pain after single-fraction thoracic stereotactic ablative Radiotherapy: Dosimetric analysis from the iSABR trial.

BACKGROUND AND PURPOSE: Concerns over chest wall toxicity has led to debates on treating tumors adjacent to the chest wall with single-fraction stereotactic ablative radiotherapy (SABR). We performed a secondary analysis of patients treated on the prospective iSABR trial to determine the incidence and grade of chest wall pain and modeled dose-response to guide radiation planning and estimate risk. MATERIALS AND METHODS: This analysis included 99 tumors in 92 patients that were treated with 25 Gy in one fraction on the iSABR trial which individualized dose by tumor size and location. Toxicity events were prospectively collected and graded based on the CTCAE version 4. Dose-response modeling was performed using a logistic model with maximum likelihood method utilized for parameter fitting. RESULTS: There were 22 grade 1 or higher chest wall pain events, including five grade 2 events and zero grade 3 or higher events. The volume receiving at least 11 Gy (V11Gy) and the minimum dose to the hottest 2 cc (D2cc) were most highly correlated with toxicity. When dichotomized by an estimated incidence of ≥ 20 % toxicity, the D2cc > 17 Gy (36.6 % vs. 3.7 %, p < 0.01) and V11Gy > 28 cc (40.0 % vs. 8.1 %, p < 0.01) constraints were predictive of chest wall pain, including among a subset of patients with tumors abutting or adjacent to the chest wall. CONCLUSION: For small, peripheral tumors, single-fraction SABR is associated with modest rates of low-grade chest wall pain. Proximity to the chest wall may not contraindicate single fractionation when using highly conformal, image-guided techniques with sharp dose gradients.

Variability and bias in microbiome metagenomic sequencing: an interlaboratory study comparing experimental protocols.

Several studies have documented the significant impact of methodological choices in microbiome analyses. The myriad of methodological options available complicate the replication of results and generally limit the comparability of findings between independent studies that use differing techniques and measurement pipelines. Here we describe the Mosaic Standards Challenge (MSC), an international interlaboratory study designed to assess the impact of methodological variables on the results. The MSC did not prescribe methods but rather asked participating labs to analyze 7 shared reference samples (5 × human stool samples and 2 × mock communities) using their standard laboratory methods. To capture the array of methodological variables, each participating lab completed a metadata reporting sheet that included 100 different questions regarding the details of their protocol. The goal of this study was to survey the methodological landscape for microbiome metagenomic sequencing (MGS) analyses and the impact of methodological decisions on metagenomic sequencing results. A total of 44 labs participated in the MSC by submitting results (16S or WGS) along with accompanying metadata; thirty 16S rRNA gene amplicon datasets and 14 WGS datasets were collected. The inclusion of two types of reference materials (human stool and mock communities) enabled analysis of both MGS measurement variability between different protocols using the biologically-relevant stool samples, and MGS bias with respect to ground truth values using the DNA mixtures. Owing to the compositional nature of MGS measurements, analyses were conducted on the ratio of Firmicutes: Bacteroidetes allowing us to directly apply common statistical methods. The resulting analysis demonstrated that protocol choices have significant effects, including both bias of the MGS measurement associated with a particular methodological choices, as well as effects on measurement robustness as observed through the spread of results between labs making similar methodological choices. In the analysis of the DNA mock communities, MGS measurement bias was observed even when there was general consensus among the participating laboratories. This study was the result of a collaborative effort that included academic, commercial, and government labs. In addition to highlighting the impact of different methodological decisions on MGS result comparability, this work also provides insights for consideration in future microbiome measurement study design.

Less than whole uterus irradiation for patients with locally advanced cervical cancer.

INTRODUCTION: Current consensus guidelines for definitive cervical cancer intensity modulated radiation therapy (IMRT) recommend inclusion of the entire uterus within the clinical target volume, however this is debated. We aimed to evaluate outcomes of patients with cervical cancer who were treated with less than whole uterus irradiation. METHODS: We identified 109 patients with FIGO Stage IB-IVA cervical cancer treated definitively with concurrent chemoradiation, including IMRT and brachytherapy, from 2010 to 2022 at a single institution where the practice was to include the gross cervix tumor with an internal target volume with differences in bladder filing accounted for, plus additional 5 mm planning target volume (PTV) margin. Local, regional, and distant recurrences were analyzed using competing risk methods, and a Wilcoxon rank sum test was performed to assess differences in dose to organs at risk based on the proportion of the uterus included in the PTV, with the median proportion of the uterus included (75 %) used as the cut-point. RESULTS: The median follow-up time was 65 months (range 3-352 months). The 2-year cumulative incidence of LR for the entire cohort was 4.2 % (95 % confidence interval [CI] 1.3-9.7). Compared with patients who had ≥ 75 % of the uterus included in the PTV, patients who had < 75 % of the uterus included in the PTV had significantly lower bowel D200cc (p = 0.02). The cumulative incidence of local failure (LR) was not significantly different between the two groups. CONCLUSIONS: Including less than the whole uterus for definitive cervix cancer IMRT does not seem to compromise local control. Less than whole uterus irradiation could be considered for carefully selected cervix cancer patients to decrease bowel dose and possible treatment-related toxicity.

Standards for fecal microbiota transplant: Tools and therapeutic advances.

Fecal microbiota transplantation (FMT) has been demonstrated to be efficacious in preventing recurrent Clostridioides difficile (C. difficile) infections, and is being investigated for treatment of several other diseases including inflammatory bowel disease, cancer, obesity, liver disease, and diabetes. To speed up the translation of FMT into clinical practice as a safe and standardized therapeutic intervention, additional evidence-based technical and regulatory guidance is needed. To this end in May of 2022, the International Alliance for Biological Standardization (IABS) and the BIOASTER Microbiology Technology Institute hosted a second webinar to discuss key issues still impeding the advancement and standardization of FMT. The goal of this two-day webinar was to provide a forum for scientific experts to share and discuss data and key challenges with one another. Discussion included a focus on the evaluation of safety, efficacy, clinical trial design, reproducibility and accuracy in obtained microbiome measurements and data reporting, and the potential for standardization across these areas. It also focused on increasing the application potential and visibility of FMT beyond treating C. difficile infections.

Impact of lung transplantation on diastolic dysfunction in recipients with pretransplant pulmonary hypertension.

OBJECTIVE: Pulmonary hypertension can cause left ventricular diastolic dysfunction through ventricular interdependence. Moreover, diastolic dysfunction has been linked to adverse outcomes after lung transplant. The impact of lung transplant on diastolic dysfunction in recipients with pretransplant pulmonary hypertension is not defined. In this cohort, we aimed to assess the prevalence of diastolic dysfunction, the change in diastolic dysfunction after lung transplant, and the impact of diastolic dysfunction on lung transplant outcomes. METHODS: In a large, single-center database from January 2011 to September 2021, single or bilateral lung transplant recipients with pulmonary hypertension (mean pulmonary artery pressure > 20 mm Hg) were retrospectively identified. Those without a pre- or post-transplant echocardiogram within 1 year were excluded. Diastolic dysfunction was diagnosed and graded according to the American Society of Echocardiography 2016 guideline on assessment of diastolic dysfunction (present, absent, indeterminate). McNemar's test was used to examine association between diastolic dysfunction pre- and post-transplant. Kaplan-Meier and Cox regression analysis were used to assess associations between pre-lung transplant diastolic dysfunction and post-lung transplant 1-year outcomes, including mortality, major adverse cardiac events, and bronchiolitis obliterans syndrome grade 1 or higher-free survival. RESULTS: Of 476 primary lung transplant recipients, 205 with pulmonary hypertension formed the study cohort (mean age, 56.6 ± 11.9 years, men 61.5%, mean pulmonary artery pressure 30.5 ± 9.8 mm Hg, left ventricular ejection fraction < 55% 9 [4.3%]). Pretransplant, diastolic dysfunction was present in 93 patients (45.4%) (grade I = 8, II = 84, III = 1), absent in 16 patients (7.8%), and indeterminate in 89 patients (43.4%), and 7 patients (3.4%) had missing data. Post-transplant, diastolic dysfunction was present in 7 patients (3.4%) (grade I = 2, II = 5, III = 0), absent in 164 patients (80.0%), and indeterminate in 15 patients (7.3%), and 19 patients (9.3%) had missing data. For those with diastolic dysfunction grades in both time periods (n = 180), there was a significant decrease in diastolic dysfunction post-transplant (148/169 patients with resolved diastolic dysfunction; McNemar's test P < .001). Pretransplant diastolic dysfunction was not associated with major adverse cardiac events (hazard ratio [HR], 1.08, 95% CI, 0.72-1.62; P = .71), bronchiolitis obliterans syndrome-free survival (HR, 0.67, 95% CI, 0.39-1.56; P = .15), or mortality (HR, 0.70, 95% CI, 0.33-1.46; P = .34) at 1 year. CONCLUSIONS: Diastolic dysfunction is highly prevalent in lung transplant candidates with normal left ventricular systolic function and pulmonary hypertension, and resolves in most patients after lung transplant regardless of patient characteristics. Pre-lung transplant diastolic dysfunction was not associated with adverse lung or cardiac outcomes after lung transplant. Collectively, these findings suggest that the presence of diastolic dysfunction in lung transplant recipients with pulmonary hypertension has no prognostic significance, and as such diastolic dysfunction and the associated clinical syndrome of heart failure with preserved ejection fraction should not be considered a relative contraindication to lung transplant in such patients.

Survival After Simultaneous Heart-kidney Transplant in Recipients With a Durable LVAD and Chronic Kidney Disease: Effect of the 2018 Heart Allocation Policy Change.

BACKGROUND: Heart transplantation remains the most definitive therapy for qualified candidates with end-stage heart failure. Concomitant kidney disease is common in this population prompting an increase in simultaneous heart-kidney (SHK) transplantation in recent years. The goal of our study was to explore the effects of the 2018 heart allocation policy (HAP) change on candidate listing characteristics and compare survival rates at 1 y in patients that were supported with a left ventricular assist device (LVAD) pretransplant and underwent SHK or heart alone transplant (HAT). METHODS: We used data from the Scientific Registry of Transplant Recipients and identified all adults who underwent primary SHK or HAT between January 2010 and March 2022. Recipients supported with a durable LVAD and estimated glomerular filtration rate <60 mL/min/1.73 m 2 were selected (n = 309 SHK; 217 pre- and 92 post-HAP and n = 3,324 HAT; 2738 pre- and 586 post-HAP). RESULTS: Difference in survival at 1 y did not reach statistical significance. Comparing the 1-y survival of SHK and HAT recipients who were bridged with LVAD pre-HAP, we found no significant difference ( P = 0.694). Adjusting for the same covariates in a multivariable model did not affect the results (SHK versus HAT hazard ratio 0.84 [0.51, 1.37]; P = 0.48). In contrast, SHK recipients supported with an LVAD who were listed and transplanted post-HAP change had significantly lower 1-y survival, when compared with HAT ( P = 0.037). CONCLUSIONS: Our findings suggest that the HAP change had a potentially negative impact on the survival of select patients undergoing SHK transplant. Further research is warranted in this area.

Characteristics and Outcomes of De Novo Genitourinary Malignancy in Solid Organ Transplant Recipients at the University of Minnesota.

BACKGROUND: Studies examining outcomes of genitourinary malignancy (GU) in the solid organ transplant (SOT) population predominantly focus on renal transplant recipients and consist of relatively small cohorts. We aimed to expand knowledge of the characteristics and outcomes of de novo GU malignancies in all patients with SOT at a large tertiary center. METHODS: The SOT database was queried for recipients with de novo bladder, renal cell, and prostate malignancy, and a retrospective chart review was performed. Descriptive statistics and Kaplan-Meier survival estimates were calculated. Cox proportional hazards regression was used for multivariate modeling of predictive factors in the development of GU malignancy. RESULTS: Solid organ transplant recipients with de novo bladder malignancy comprised 64.3% with high grade and 38.1% with advanced stage (≥T2) disease at initial diagnosis. Only 3.7% of patients with de novo renal cell carcinoma presented with metastatic disease, and 13.6% with localized disease developed recurrences. The most common stage in de novo prostate cancer patients was pT3 (52.2%). Kaplan-Meier estimates (95% CI) for 5-year overall (OS) and cancer-specific survival (CSS) were 44.12% (31.13-62.52) and 80.80% (68.85-94.81) for bladder, 78.90% (68.93-90.30) and 96.61% (92.10-100.00) for renal cell, and 81.18% (72.01-91.51) and 96.16% (90.95-100.00) for prostate cancer, respectively. Age at transplant and time from transplant to cancer diagnosis were predictive of de novo bladder cancer OS (P = .042 and .021, respectively). CONCLUSION: To our knowledge, this is the largest single-center cohort examined for GU malignancy after SOT. Bladder and renal cell cancer had worse OS but similar CSS as historical rates for nontransplant patients. De novo prostate cancer had similar CSS.

Structural Basis of the Allosteric Inhibition of Human ABCG2 by Nanobodies.

ABCG2 is an ATP-binding cassette transporter that exports a wide range of xenobiotic compounds and has been recognized as a contributing factor for multidrug resistance in cancer cells. Substrate and inhibitor interactions with ABCG2 have been extensively studied and small molecule inhibitors have been developed that prevent the export of anticancer drugs from tumor cells. Here, we explore the potential for inhibitors that target sites other than the substrate binding pocket of ABCG2. We developed novel nanobodies against ABCG2 and used functional analyses to select three inhibitory nanobodies (Nb8, Nb17 and Nb96) for structural studies by single particle cryo-electron microscopy. Our results showed that these nanobodies allosterically bind to different regions of the nucleotide binding domains. Two copies of Nb8 bind to the apex of the NBDs preventing them from fully closing. Nb17 binds near the two-fold axis of the transporter and interacts with both NBDs. Nb96 binds to the side of the NBD and immobilizes a region connected to key motifs involved in ATP binding and hydrolysis. All three nanobodies prevent the transporter from undergoing conformational changes required for substrate transport. These findings advance our understanding of the molecular basis of modulation of ABCG2 by external binders, which may contribute to the development of a new generation of inhibitors. Furthermore, this is the first example of modulation of human multidrug resistance transporters by nanobodies.

Recipient and kidney graft outcomes of deceased donors with human immunodeficiency virus in the United States.

BACKGROUND: The HIV Organ Policy Equity (HOPE) act afforded transplantation of organs from donors who have HIV. Herein we compared the long-term outcomes of recipients with HIV by donor HIV testing status. METHODS: Using the Scientific Registry of Transplant Recipients, we identified all primary adult kidney transplant recipients who were HIV-positive between 1/1/16-12/31/21. Recipients were grouped into three cohorts according to the donor HIV status based on antibody (Ab) and nucleic acid testing (NAT): Donor Ab-/NAT- (n = 810), Donor Ab+ /NAT- (n = 98), and Donor Ab+/NAT+ (n = 90). We compared recipient and death-censored graft survival (DCGS) by donor HIV testing status using Kaplan-Meier curves and Cox proportional hazards regression, censored at 3 years posttransplant. Secondary outcomes were delayed graft function (DGF) and the following 1-year outcomes: acute rejection, re-hospitalization, and serum creatinine. RESULTS: In Kaplan-Meier analyses, patient survival and DCGS were similar by donor HIV status (log rank p = .667; log rank p = .388). DGF occurred more frequently in donors with HIV Ab-/NAT- testing compared with Ab+/NAT- or Ab+/NAT+ testing (38.0% vs. 28.6% vs. 26.7%, p = .028). Average dialysis time before transplant was twice as long for recipients who received organs from donors with Ab-/NAT- testing (p < .001). Acute rejection, re-hospitalization and serum creatinine at 12 months did not differ between the groups. CONCLUSIONS: Patient and allograft survival for recipients living with HIV remains comparable irrespective of donor HIV testing status. Utilizing kidneys from deceased donors with HIV Ab+/NAT- or Ab+/NAT+ testing shortens dialysis time prior to transplant.

Second Kidney Transplant Outcomes in Dialysis Dependent Recipients by Induction Type in the United States.

BACKGROUND: We examined the association between induction type for a second kidney transplant in dialysis-dependent recipients and the long-term outcomes. METHODS: Using the Scientific Registry of Transplant Recipients, we identified all second kidney transplant recipients who returned to dialysis before re-transplantation. Exclusion criteria included: missing, unusual, or no-induction regimens, maintenance regimens other than tacrolimus and mycophenolate, and positive crossmatch status. We grouped recipients by induction type into 3 groups: the anti-thymocyte group (N = 9899), the alemtuzumab group (N = 1982), and the interleukin 2 receptor antagonist group (N = 1904). We analyzed recipient and death-censored graft survival (DCGS) using the Kaplan-Meier survival function with follow-up censored at 10 years post-transplant. We used Cox proportional hazard models to examine the association between induction and the outcomes of interest. To account for the center-specific effect, we included the center as a random effect. We adjusted the models for the pertinent recipient and organ variables. RESULTS: In the Kaplan-Meier analyses, induction type did not alter recipient survival (log-rank P = .419) or DCGS (log-rank P = .146). Similarly, in the adjusted models, induction type was not a predictor of recipient or graft survival. Live-donor kidneys were associated with better recipient survival (HR 0.73, 95% CI [0.65, 0.83], P < .001) and graft survival (HR 0.72, 95% CI [0.64, 0.82], P < .001). Publicly insured recipients had worse recipient and allograft outcomes. CONCLUSION: In this large cohort of average immunologic-risk dialysis-dependent second kidney transplant recipients, who were discharged on tacrolimus and mycophenolate maintenance, induction type did not influence the long-term outcomes of recipient or graft survival. Live-donor kidneys improved recipient and graft survival.

Methods in Nutrition & Gut Microbiome Research: An American Society for Nutrition Satellite Session [13 October 2022].

The microbial cells colonizing the human body form an ecosystem that is integral to the regulation and maintenance of human health. Elucidation of specific associations between the human microbiome and health outcomes is facilitating the development of microbiome-targeted recommendations and treatments (e.g., fecal microbiota transplant; pre-, pro-, and post-biotics) to help prevent and treat disease. However, the potential of such recommendations and treatments to improve human health has yet to be fully realized. Technological advances have led to the development and proliferation of a wide range of tools and methods to collect, store, sequence, and analyze microbiome samples. However, differences in methodology at each step in these analytic processes can lead to variability in results due to the unique biases and limitations of each component. This technical variability hampers the detection and validation of associations with small to medium effect sizes. Therefore, the American Society for Nutrition (ASN) Nutritional Microbiology Group Engaging Members (GEM), sponsored by the Institute for the Advancement of Food and Nutrition Sciences (IAFNS), hosted a satellite session on methods in nutrition and gut microbiome research to review currently available methods for microbiome research, best practices, as well as tools and standards to aid in comparability of methods and results. This manuscript summarizes the topics and research discussed at the session. Consideration of the guidelines and principles reviewed in this session will increase the accuracy, precision, and comparability of microbiome research and ultimately the understanding of the associations between the human microbiome and health.

Substance Use-Associated Mortality among Heart Donors after the COVID-19 National Emergency Increased but Did Not Affect Peri-Transplant Outcomes.

INTRODUCTION: The COVID-19 pandemic and consequent social isolation prompted a surge in mental health disorders and substance use in the general population and, therefore, in potential organ donors. We aimed to evaluate if this led to a change in donor characteristics, including the mechanism and circumstance of death, and how this may have affected clinical outcomes following heart transplantation. METHODS: We identified all heart donors from the SRTR database between 18 October 2018 and 31 December 2021, excluding those who donated immediately after the US national emergency declaration. Donors were stratified into pre-COVID-19 (Pre-Cov; through 12 March 2020) and post-COVID-19 national emergency declaration cohorts (Post-Cov; 1 August 2020 through 31 December 2021) based on the heart procurement date. Relevant demographics, cause of death, and substance use history were collected in addition to graft cold ischemic time, the incidence of primary graft dysfunction (PGD), and recipient survival at 30 days post-transplant. RESULTS: A total of 10,314 heart donors were identified; 4941 were stratified into the Pre-Cov and 5373 into the Post-Cov cohorts. There was no difference in demographics, but illicit drug use was significantly higher in the Post-Cov group, leading to an increased incidence of death from drug intoxication. Fatal gunshot wounds were also more common. Despite these changes, the incidence of PGD remained similar (p = 0.371), and there was no difference in 30 days recipient survival (p = 0.545). CONCLUSION: Our findings confirm that COVID-19 had a major impact on mental health and psychosocial life with an associated increase in illicit substance use and fatal intoxication rates in heart transplant donors. These changes did not alter peri-operative mortality following heart transplantation. Future studies are needed to ensure that long-term outcomes remain unaffected.

Living Donor Kidney Transplant in Recipients With Glomerulonephritis: Donor Recipient Biologic Relationship and Allograft Outcomes.

Using the Scientific Registry of Transplant Recipients, we examined the association between donor-recipient biologic relationship and long-term recipient and allograft survival among glomerulonephritis (GN) patients. Four GN types were studied: membranous nephropathy, IgA, lupus-associated nephritis, and focal segmental glomerulosclerosis (FSGS). We identified all adult primary living-donor recipients between 2000 and 2018 (n = 19,668): related (n = 10,437); unrelated (n = 9,231). Kaplan-Meier curves were generated for the recipient, death-censored graft survival and death with functioning graft through ten years post-transplant. Multivariable Cox proportional hazard models were used to examine the association between the donor-recipient relationship and outcomes of interest. There was an increased risk for acute rejection by 12 months post-transplant among the unrelated compared to the related group in IgA (10.1% vs. 6.5%, p<0.001), FSGS (12.1% vs. 10%, p-0.016), and lupus nephritis (11.8% vs. 9.2%; p-0.049). The biological donor-recipient relationship was not associated with a worse recipient or graft survival or death with functioning graft in the multivariable models. These findings are consistent with the known benefits of living-related-donor kidney transplants and counter the reports of the potential adverse impact of the donor-recipient biologic relationship on allograft outcomes.

Metagenomic Methods for Addressing NASA's Planetary Protection Policy Requirements on Future Missions: A Workshop Report.

Molecular biology methods and technologies have advanced substantially over the past decade. These new molecular methods should be incorporated among the standard tools of planetary protection (PP) and could be validated for incorporation by 2026. To address the feasibility of applying modern molecular techniques to such an application, NASA conducted a technology workshop with private industry partners, academics, and government agency stakeholders, along with NASA staff and contractors. The technical discussions and presentations of the Multi-Mission Metagenomics Technology Development Workshop focused on modernizing and supplementing the current PP assays. The goals of the workshop were to assess the state of metagenomics and other advanced molecular techniques in the context of providing a validated framework to supplement the bacterial endospore-based NASA Standard Assay and to identify knowledge and technology gaps. In particular, workshop participants were tasked with discussing metagenomics as a stand-alone technology to provide rapid and comprehensive analysis of total nucleic acids and viable microorganisms on spacecraft surfaces, thereby allowing for the development of tailored and cost-effective microbial reduction plans for each hardware item on a spacecraft. Workshop participants recommended metagenomics approaches as the only data source that can adequately feed into quantitative microbial risk assessment models for evaluating the risk of forward (exploring extraterrestrial planet) and back (Earth harmful biological) contamination. Participants were unanimous that a metagenomics workflow, in tandem with rapid targeted quantitative (digital) PCR, represents a revolutionary advance over existing methods for the assessment of microbial bioburden on spacecraft surfaces. The workshop highlighted low biomass sampling, reagent contamination, and inconsistent bioinformatics data analysis as key areas for technology development. Finally, it was concluded that implementing metagenomics as an additional workflow for addressing concerns of NASA's robotic mission will represent a dramatic improvement in technology advancement for PP and will benefit future missions where mission success is affected by backward and forward contamination.

Selection and adaptive introgression guided the complex evolutionary history of the European common bean.

Domesticated crops have been disseminated by humans over vast geographic areas. Common bean (Phaseolus vulgaris L.) was introduced in Europe after 1492. Here, by combining whole-genome profiling, metabolic fingerprinting and phenotypic characterisation, we show that the first common bean cultigens successfully introduced into Europe were of Andean origin, after Francisco Pizarro's expedition to northern Peru in 1529. We reveal that hybridisation, selection and recombination have shaped the genomic diversity of the European common bean in parallel with political constraints. There is clear evidence of adaptive introgression into the Mesoamerican-derived European genotypes, with 44 Andean introgressed genomic segments shared by more than 90% of European accessions and distributed across all chromosomes except PvChr11. Genomic scans for signatures of selection highlight the role of genes relevant to flowering and environmental adaptation, suggesting that introgression has been crucial for the dissemination of this tropical crop to the temperate regions of Europe.

Temporary Mechanical Circulatory Support Use and Clinical Outcomes of Simultaneous Heart/Kidney Transplant Recipients in the Pre- and Post-heart Allocation Policy Change Eras.

BACKGROUND: The use of temporary mechanical circulatory support (tMCS) devices (intra-aortic balloon pump; Impella 2.5, CP, 5.0; venoarterial extracorporeal membrane oxygenation) increased significantly across the United States for heart transplant candidates after the allocation policy change. Whether this practice change also affected simultaneous heart-kidney (SHK) candidates and recipient survival is understudied. METHODS: We used the Scientific Registry of Transplant Recipients database to identify adult SHK recipients between January 2010 and March 2022. The population was stratified into pre- and post-heart allocation change cohorts. Kaplan-Meier curves were generated to compare 1-y survival rates. A Cox proportional hazards model was used to investigate the effect of allocation period on patient survival. Recipient outcomes bridged with eligible tMCS devices were compared in the post-heart allocation era. In a separate analysis, SHK waitlist mortality was evaluated between the allocation eras. RESULTS: A total of 1548 SHK recipients were identified, and 1102 were included in the final cohort (534 pre-allocation and 568 post-allocation change). tMCS utilization increased from 17.9% to 51.6% after the allocation change, with venoarterial extracorporeal membrane oxygenation use rising most significantly. However, 1-y post-SHK survival remained unchanged in the full cohort (log-rank P = 0.154) and those supported with any of the eligible tMCS devices. In a separate analysis (using a larger cohort of all SHK listings), SHK waitlist mortality at 1 y was significantly lower in the current allocation era ( P = 0.002). CONCLUSIONS: Despite the remarkable increase in tMCS use in SHK candidates after the heart allocation change, 1 y posttransplant survival remained unchanged. Further studies with larger cohorts and longer follow-ups are needed to confirm these findings.

Genome-wide signatures of the geographic expansion and breeding of soybean.

Soybean is a leguminous crop that provides oil and protein. Exploring the genomic signatures of soybean evolution is crucial for breeding varieties with improved adaptability to environmental extremes. We analyzed the genome sequences of 2,214 soybeans and proposed a soybean evolutionary route, i.e., the expansion of annual wild soybean (Glycine soja Sieb. & Zucc.) from southern China and its domestication in central China, followed by the expansion and local breeding selection of its landraces (G. max (L.) Merr.). We observed that the genetic introgression in soybean landraces was mostly derived from sympatric rather than allopatric wild populations during the geographic expansion. Soybean expansion and breeding were accompanied by the positive selection of flowering time genes, including GmSPA3c. Our study sheds light on the evolutionary history of soybean and provides valuable genetic resources for its future breeding.

BK DNAemia in pediatric kidney transplant recipients: Predictors and outcomes.

BACKGROUND: Pediatric data on risk factors and the clinical course of BK DNAemia are limited. We aimed to determine the effects of BK DNAemia on transplant outcomes and delineate the safety and efficacy of various treatment approaches. METHODS: This retrospective-cohort study included 161 transplants (age ≤ 21 years) performed at a single center between 1/1/2012 and 1/1/2020. We used Cox proportional models to evaluate the effects of BK DNAemia on patient survival (PS), graft survival (GS), and acute rejection (AR), using BK as a time-dependent covariate. We also assessed the effects of pharmacological intervention on BK DNAemia duration using intervention as a time-dependent covariate. RESULTS: BK-free survival was 69.1% at 1-year and 54.6% at 3-year posttransplant. After multivariate adjustment, BK DNAemia was associated with young age at transplant (aHR, age 5-<12 vs. ≥12 (years): 2.5 (1.4-4.5); p = .001) and steroid-based immunosuppression (IS) (aHR: 2.2 [1.1-4.5]; p = .03). We found no effect of DNAemia on AR (aHR: 1.25; p = .5), PS (aHR: 2.85; p = .22), and GS (aHR: 0.56; p = .41). Of 70 patients with DNAemia, 22 (31.4%) received no treatment, 20 (28.6%) received IS reduction alone, and 28 patients (40%) received treatment with at least one pharmacological agent (leflunomide, IVIG, ciprofloxacin, cidofovir). Sixty-three patients (90%) cleared DNAemia with median time to resolution of 2.4 months (IQR:1.4-5.6). We found no significant effect of BK-directed pharmacological treatment on time to resolution (aHR: 0.64;p = .13). BK-directed agents were well tolerated. CONCLUSIONS: BK DNAemia is associated with a young age at transplant and steroid-based maintenance IS. We found no effect of BK DNAemia on AR, GS, and PS.

Recipient and Graft Outcomes in Simultaneous Kidney and Pancreas Transplantation With Steroid Avoidance in the United States.

BACKGROUND: Steroid avoidance in kidney transplantation has been proven noninferior. Long-term outcome data on steroid avoidance in simultaneous pancreas-kidney (SPK) remains scant. METHODS: Utilizing the Scientific Registry of Transplant Recipients between 2000 and 2020, we studied all primary crossmatch negative SPK recipients (N = 5683) who received antithymocyte globulin induction and were discharged alive with functioning grafts on tacrolimus and mycophenolate ± steroid maintenance. Recipients were grouped according to steroid use into 2 groups: steroid maintenance (n = 4191) and steroid avoidance (n = 1492). Kaplan-Meier curves censored at 10 y were generated for recipient and allograft survival by steroid maintenance. Predictors for recipient and graft survival were examined using Cox Proportional Hazards. Models were adjusted for age, body mass index, ethnicity, diabetes type, human leukocyte-antigen mismatches, cold ischemia time, transplant era, preemptive transplantation, and pancreas donor risk index with the transplant center included as a random effect. RESULTS: Steroid avoidance gained popularity over time, accounting for over one-fourth of the studied cohort. One-year acute rejection rates by steroid avoidance were comparable for kidney (8.6% versus 9%, P = 0.783); however, the pancreas rejection rate was lower in the steroid avoidance group (7.9% versus 10%; P = 0.035). After adjustment, steroid avoidance did not influence recipient survival (lower level of confidence interval, adjusted hazard ratio, upper level of confidence interval: 0.94, 1.15, 1.39), pancreas (0.75, 0.93, 1.16), or kidney (0.95, 1.18, 1.45) death-censored survival, compared with steroid maintenance. CONCLUSIONS: Accounting for the recipient and graft characteristics, steroid avoidance is associated with similar recipient, pancreas, and kidney graft outcomes compared with steroid maintenance in SPK recipients after antithymocyte globulin induction with tacrolimus and mycophenolate maintenance.

Chromosome-length genome assemblies of six legume species provide insights into genome organization, evolution, and agronomic traits for crop improvement.

INTRODUCTION: Legume crops are an important source of protein and oil for human health and in fixing atmospheric N2 for soil enrichment. With an objective to accelerate much-needed genetic analyses and breeding applications, draft genome assemblies were generated in several legume crops; many of them are not high quality because they are mainly based on short reads. However, the superior quality of genome assembly is crucial for a detailed understanding of genomic architecture, genome evolution, and crop improvement. OBJECTIVES: Present study was undertaken with an objective of developing improved chromosome-length genome assemblies in six different legumes followed by their systematic investigation to unravel different aspects of genome organization and legume evolution. METHODS: We employed in situ Hi-C data to improve the existing draft genomes and performed different evolutionary and comparative analyses using improved genome assemblies. RESULTS: We have developed chromosome-length genome assemblies in chickpea, pigeonpea, soybean, subterranean clover, and two wild progenitor species of cultivated groundnut (A. duranensis and A. ipaensis). A comprehensive comparative analysis of these genome assemblies offered improved insights into various evolutionary events that shaped the present-day legume species. We highlighted the expansion of gene families contributing to unique traits such as nodulation in legumes, gravitropism in groundnut, and oil biosynthesis in oilseed legume crops such as groundnut and soybean. As examples, we have demonstrated the utility of improved genome assemblies for enhancing the resolution of "QTL-hotspot" identification for drought tolerance in chickpea and marker-trait associations for agronomic traits in pigeonpea through genome-wide association study. Genomic resources developed in this study are publicly available through an online repository, 'Legumepedia'. CONCLUSION: This study reports chromosome-length genome assemblies of six legume species and demonstrates the utility of these assemblies in crop improvement. The genomic resources developed here will have significant role in accelerating genetic improvement applications of legume crops.