Quantitative Trait Loci Mapping for Bacterial Wilt Resistance and Plant Height in Tomatoes.

Bacterial wilt (BW) of tomatoes, caused by Ralstonia solanacearum, is a devastating disease that results in large annual yield losses worldwide. Management of BW of tomatoes is difficult due to the soil-borne nature of the pathogen. One of the best ways to mitigate the losses is through breeding for disease resistance. Moreover, plant height (PH) is a crucial element related to plant architecture, which determines nutrient management and mechanical harvesting in tomatoes. An intraspecific F2 segregating population (NC 11212) of tomatoes was developed by crossing NC 84173 (tall, BW susceptible) × CLN1466EA (short, BW resistant). We performed quantitative trait loci (QTL) mapping using single nucleotide polymorphic (SNP) markers and the NC 11212 F2 segregating population. The QTL analysis for BW resistance revealed a total of three QTLs on chromosomes 1, 2, and 3, explaining phenotypic variation (R2) ranging from 3.6% to 14.9%, whereas the QTL analysis for PH also detected three QTLs on chromosomes 1, 8, and 11, explaining R2 ranging from 7.1% to 11%. This work thus provides information to improve BW resistance and plant architecture-related traits in tomatoes.

Bridging Radiation Rapidly and Effectively Cytoreduces High-Risk Relapsed/Refractory Aggressive B Cell Lymphomas Prior to Chimeric Antigen Receptor T Cell Therapy.

Greater tumor burden before CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy predicts lower complete response rate and shorter overall survival (OS) in patients with aggressive non-Hodgkin lymphoma (NHL). Recent patterns of failure studies have identified lesion characteristics, including size, standard uptake value (SUV), and extranodal location, as associated with post-CAR-T therapy failure. Here we analyzed the effect of bridging radiation-containing treatment (BRT) on pre-CAR-T therapy lesion- and patient-level characteristics and post-CAR-T therapy outcomes, including patterns of failure. Consecutive NHL patients who received radiation therapy from 30 days before leukapheresis until CAR T cell infusion were reviewed. Metabolic tumor volume (MTV) was contoured with a threshold SUV of 4. The first post-CAR-T therapy failures were categorized as preexisting/new/mixed with respect to pre-CAR-T therapy disease and in-field/marginal/distant with respect to BRT. Forty-one patients with diffuse large B cell lymphoma (DLBCL; n = 33), mantle cell lymphoma (n = 7), or Burkitt lymphoma (n = 1) were identified. BRT significantly improved established high-risk parameters of post-CAR-T therapy progression, including in-field median MTV (45.5 cc to .2 cc; P < .001), maximum SUV (18.1 to 4.4; P < .001), diameter (5.5 cm to 3.2 cm; P < .001), and lactate dehydrogenase (LDH; 312 to 232; P = .025). DLBCL patients with lower LDH levels post-BRT had improved progression-free survival (PFS; P = .001). In DLBCL, first failures were new in 7 of 19 patients, preexisting in 5 of 19, and mixed in 7 of 19; with respect to BRT, 4 of 19 were in-field and 4 of 19 were marginal. Post-CAR-T therapy survival was similar in patients with initially low MTV and those with newly low MTV post-BRT using a statistically determined threshold of 16 cc (PFS, 26 months versus 31 months; OS unreached for both). BRT produced significant cytoreductions in diameter, SUV, MTV, and LDH, all predictors of poor post-CAR-T therapy outcomes. Similar PFS and OS in patients with initially low MTV and those who achieved newly low MTV after BRT suggest that BRT may "convert" poor-risk patients to better risk. In the future, the response to BRT may allow for risk stratification and individualization of bridging strategies.

Recurrent Cushing Syndrome From Metastatic Adrenocortical Carcinoma With Fumarate Hydratase Allelic Variant.

Background: Adrenal Cushing syndrome (CS) is usually benign in etiology; however, although rarely, it can be due to adrenocortical carcinoma (ACC); in which case, diagnosis and management are quite complicated. Case Report: A 34-year-old woman presented with worsening confusion, weight gain, new-onset diabetes, and hypertension. Her history was significant for a 7.4-cm left adrenal mass and CS, which were treated with left adrenalectomy 2 years ago. She received hydrocortisone replacement therapy after the surgery, which was discontinued on admission when evaluation showed hypokalemia, hypercortisolemia, and undetectable adrenocorticotropic hormone. Subsequent testing included 1-mg and 8-mg dexamethasone suppression tests, which did not suppress cortisol; late-night salivary cortisol measurement, which yielded a very high salivary cortisol level; and 24-hour urinary cortisol measurement. The level of 11-deoxycortisol was elevated. A computed tomography scan revealed multiple hepatic lesions, which were fluorodeoxyglucose avid, and a biopsy confirmed metastatic ACC. She received treatment with mitotane, metyrapone (later changed to mifepristone), doxorubicin, cisplatin, and etoposide. Over 8 weeks, mitotane levels became therapeutic at 20 mcg/mL, the hepatic masses decreased in size, and she transitioned to adrenal insufficiency and improved glycemic control. Next-generation sequencing of liver biopsy and germline testing revealed a frameshift loss-of-function allelic variant in the FH gene that encodes the protein fumarate hydratase. Discussion: We report a case of recurrent CS due to metastatic ACC in a patient with a previously resected adrenal adenoma and FH allelic variant. Conclusion: Metastatic ACC presenting with severe CS presents a diagnostic and management challenge where combination therapy guided by a multidisciplinary team is essential. FH allelic variant may contribute to ACC progression.

Errors in aerial survey count data: Identifying pitfalls and solutions.

Accurate estimates of animal abundance are essential for guiding effective management, and poor survey data can produce misleading inferences. Aerial surveys are an efficient survey platform, capable of collecting wildlife data across large spatial extents in short timeframes. However, these surveys can yield unreliable data if not carefully executed. Despite a long history of aerial survey use in ecological research, problems common to aerial surveys have not yet been adequately resolved. Through an extensive review of the aerial survey literature over the last 50 years, we evaluated how common problems encountered in the data (including nondetection, counting error, and species misidentification) can manifest, the potential difficulties conferred, and the history of how these challenges have been addressed. Additionally, we used a double-observer case study focused on waterbird data collected via aerial surveys and an online group (flock) counting quiz to explore the potential extent of each challenge and possible resolutions. We found that nearly three quarters of the aerial survey methodology literature focused on accounting for nondetection errors, while issues of counting error and misidentification were less commonly addressed. Through our case study, we demonstrated how these challenges can prove problematic by detailing the extent and magnitude of potential errors. Using our online quiz, we showed that aerial observers typically undercount group size and that the magnitude of counting errors increases with group size. Our results illustrate how each issue can act to bias inferences, highlighting the importance of considering individual methods for mitigating potential problems separately during survey design and analysis. We synthesized the information gained from our analyses to evaluate strategies for overcoming the challenges of using aerial survey data to estimate wildlife abundance, such as digital data collection methods, pooling species records by family, and ordinal modeling using binned data. Recognizing conditions that can lead to data collection errors and having reasonable solutions for addressing errors can allow researchers to allocate resources effectively to mitigate the most significant challenges for obtaining reliable aerial survey data.

Cell-free DNA profiling informs all major complications of hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) provides effective treatment for hematologic malignancies and immune disorders. Monitoring of posttransplant complications is critical, yet current diagnostic options are limited. Here, we show that cell-free DNA (cfDNA) in blood is a versatile analyte for monitoring of the most important complications that occur after HCT: graft-versus-host disease (GVHD), a frequent immune complication of HCT, infection, relapse of underlying disease, and graft failure. We demonstrate that these therapeutic complications are informed from a single assay, low-coverage bisulfite sequencing of cfDNA, followed by disease-specific bioinformatic analyses. To inform GVHD, we profile cfDNA methylation marks to trace the cfDNA tissues-of-origin and to quantify tissue-specific injury. To inform infection, we implement metagenomic cfDNA profiling. To inform cancer relapse, we implement analyses of tumor-specific genomic aberrations. Finally, to detect graft failure, we quantify the proportion of donor- and recipient-specific cfDNA. We applied this assay to 170 plasma samples collected from 27 HCT recipients at predetermined timepoints before and after allogeneic HCT. We found that the abundance of solid-organ-derived cfDNA in the blood at 1 mo after HCT is predictive of acute GVHD (area under the curve, 0.88). Metagenomic profiling of cfDNA revealed the frequent occurrence of viral reactivation in this patient population. The fraction of donor-specific cfDNA was indicative of relapse and remission, and the fraction of tumor-specific cfDNA was informative of cancer relapse. This proof-of-principle study shows that cfDNA has the potential to improve the care of allogeneic HCT recipients by enabling earlier detection and better prediction of the complex array of complications that occur after HCT.

Black Scoter habitat use along the southeastern coast of the United States.

While the Atlantic Coast of the United States and Canada is a major wintering area for sea ducks, knowledge about their wintering habitat use is relatively limited. Black Scoters have a broad wintering distribution and are the only open water species of sea duck that is abundant along the southeastern coast of the United States. Our study identified variables that affected Black Scoter (Melanitta americana) distribution and abundance in the Atlantic Ocean along the southeastern coast of the United States. We used aerial survey data from 2009 to 2012 provided by the United States Fish and Wildlife Service to identify variables that influenced Black Scoter distribution. We used indicator variable selection to evaluate relationships between Black Scoter habitat use and a variety of broad- and fine-scale oceanographic and weather variables. Average time between waves, ocean floor slope, and the interaction of bathymetry and distance to shore had the strongest association with southeastern Black Scoter distribution.

Future studies using histomorphometry in type 1 diabetes mellitus.

PURPOSE OF REVIEW: This article reviews the current state of research in type 1 diabetes and bone, focusing on human bone turnover markers and histomorphometry. RECENT FINDINGS: Bone turnover markers have been used for decades to document static bone turnover status in a variety of diseases but especially in diabetes. Two new studies focus on dynamic testing conditions to examine the acute effects of insulin and exercise on bone turnover. Publications of human bone histomorphometry in type 1 diabetes are few but there are several new studies currently underway. SUMMARY: Here, we review the most recent literature on human bone turnover markers and histomorphometry. Low bone turnover is thought to be a major underlying factor in bone fragility in T1DM. Further studies in human transilial bone biopsies will be helpful in determining the mechanisms.

Cytomegalovirus events in high-risk allogeneic hematopoietic-cell transplantation patients who received letermovir prophylaxis.

Letermovir is approved for the prevention of cytomegalovirus (CMV) reactivation and clinical disease in patients undergoing allogeneic hematopoietic-cell transplantation (HCT). However, there is uncertainty about letermovir's ability to prevent clinical events during the period of prophylaxis as well as after the discontinuation of prophylaxis in the post-transplant setting. We performed a retrospective cohort study in CMV-seropositive allogeneic HCT recipients at high risk of CMV events, who received letermovir for primary prophylaxis from November 2017 through December 2019. We analyzed CMV outcomes for these patients during and after prophylaxis was discontinued. Patient outcomes were followed through June 2020. Sixty patients received letermovir for a median of 13 weeks (range, 1-72 weeks). Thirteen (22%) patients had quantifiable CMV DNAemia (reactivation) during letermovir prophylaxis a median of 9 days (range, 1-59 days) after starting letermovir. Five (8%) of these patients discontinued prophylaxis and received preemptive therapy (PET) with valganciclovir; eight (13%) continued letermovir as prophylaxis and CMV DNAemia resolved without PET. Thirteen patients (22%) had post-prophylaxis CMV reactivation a median of 33 days (range, 14-109 days) after letermovir discontinuation. In four (7%) of these patients, CMV DNAemia resolved without PET, and nine (15%) received PET. No patient developed CMV disease. Patients who developed CMV reactivation during prophylaxis did so shortly after initiation of letermovir, and most patients who developed CMV reactivation post-prophylaxis did so within 60 days after discontinuation of letermovir. Letermovir prophylaxis has changed the presentation of CMV infection in high-risk HCT patients.

New Perspectives on Antimicrobial Agents: Remdesivir Treatment for COVID-19.

Remdesivir was recently approved by the Food and Drug Administration for the treatment of hospitalized patients with coronavirus disease 2019 (COVID-19). Remdesivir is the prodrug of an adenosine analogue that inhibits viral replication of several RNA virus families, including Coronaviridae Preclinical data in animal models of coronavirus diseases, including COVID-19, have demonstrated that early treatment with remdesivir leads to improved survival, decreased lung injury, and decreased levels of viral RNA. Recent clinical data have demonstrated the clinical activity of remdesivir in terms of faster time to recovery in patients with severe COVID-19 and higher odds of improved clinical status in patients with moderate COVID-19. Here, clinical trials published to date are presented and appraised. Remdesivir's potential benefits and its favorable adverse-event profile make it an option for the treatment of COVID-19. This article examines the available literature describing remdesivir's pharmacology, pharmacokinetics, and preclinical and clinical data.

Trabecular bone score and transilial bone trabecular histomorphometry in type 1 diabetes and healthy controls.

Patients with type 1 Diabetes Mellitus (T1DM) have an increased risk of fracture. Little is known about the microarchitecture of trabecular bone in T1DM, which may account for some of the increased risk. We report here a secondary analysis comparing Trabecular Bone Score (TBS) derived from DXA to 2-D histomorphometric and 3-D micro-computerized tomography (CT) variables obtained from iliac biopsies in 83 subjects (29 T1DM and 54 controls). The transilial bone biopsy specimens were fixed, embedded and scanned using a desktop micro-CT at 16 µm resolution. They were then sectioned and quantitative histomorphometry was performed. TBS of the anterior/posterior (AP) spine was obtained by re-analysis of AP lumbar spine DXA images. Overall, there were no differences in TBS, histomorphometry or micro-CT measurements between T1DM and controls. There was a significant association between TBS and 2-D BV/TV using multivariable linear regression after adjusting for group, age and gender. For every 1 unit increase in 2-D BV/TV, TBS increases by 0.0036 units after adjusting for group, gender and age. In conclusion, T1DM does not result in abnormal TBS, histomorphometric or micro-CT variables in young T1DM patients in the absence of diabetic complications. TBS is a good surrogate measure for trabecular microarchitecture.

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease.

A road map for designing and implementing a biological monitoring program.

Designing and implementing natural resource monitoring is a challenging endeavor undertaken by many agencies, NGOs, and citizen groups worldwide. Yet many monitoring programs fail to deliver useful information for a variety of administrative (staffing, documentation, and funding) or technical (sampling design and data analysis) reasons. Programs risk failure if they lack a clear motivating problem or question, explicit objectives linked to this problem or question, and a comprehensive conceptual model of the system under study. Designers must consider what "success" looks like from a resource management perspective, how desired outcomes translate to appropriate attributes to monitor, and how they will be measured. All such efforts should be filtered through the question "Why is this important?" Failing to address these considerations will produce a program that fails to deliver the desired information. We addressed these issues through creation of a "road map" for designing and implementing a monitoring program, synthesizing multiple aspects of a monitoring program into a single, overarching framework. The road map emphasizes linkages among core decisions to ensure alignment of all components, from problem framing through technical details of data collection and analysis, to program administration. Following this framework will help avoid common pitfalls, keep projects on track and budgets realistic, and aid in program evaluations. The road map has proved useful for monitoring by individuals and teams, those planning new monitoring, and those reviewing existing monitoring and for staff with a wide range of technical and scientific skills.

Barriers to attending an eye examination after vision screening referral within a vulnerable population.

Half of high-risk, uninsured/underinsured individuals identified through vision screening as needing eye exams do not attend. Patients who attended vision screening and were referred for an exam but did not attend that exam were contacted and asked whether they were interested in receiving a free complete eye exam at an offsite center within three blocks of the clinic. Those who agreed were asked why they did not attend their original appointment and what would make it easier to attend. Primary reasons for missing appointments included forgetting (34%), lacking transportation (36%), and scheduling conflicts (26%). Nearly one quarter (24%) stated they could not afford transportation. Findings demonstrate transportation is a key barrier to eye care services. Current eye care delivery can be improved by addressing barriers to attendance in this context. Alternative delivery models should be examined to identify methods for better reaching underserved target populations.