Monitoring clonal burden as an alternative to blast count for myelodysplastic neoplasm treatment response.

Accurate assessment of therapy response in myelodysplastic neoplasm (MDS) has been challenging. Directly monitoring mutational disease burden may be useful, but is not currently included in MDS response criteria, and the correlation of mutational burden and traditional response endpoints is not completely understood. Here, we used genome-wide and targeted next-generation sequencing (NGS) to monitor clonal and subclonal molecular disease burden in 452 samples from 32 patients prospectively treated in a clinical trial. Molecular responses were compared with International Working Group (IWG) 2006-defined response assessments. We found that myeloblast percentage consistently underestimates MDS molecular disease burden and that mutational clearance patterns for marrow complete remission (mCR), which depends on myeloblast assessment, was not different than stable disease or bone marrow aplasia, underscoring a major limitation of using mCR. In contrast, achieving a complete remission (CR) was associated with the highest level of mutation clearance and lowest residual mutational burden in higher-risk MDS patients. A targeted gene panel approach was inferior to genome-wide sequencing in defining subclones and their molecular responses but may be adequate for monitoring molecular disease burden when a targeted gene is present in the founding clone. Our work supports incorporating serial NGS-based monitoring into prospective MDS clinical trials.

Large-scale application of ClinGen-InSiGHT APC-specific ACMG/AMP variant classification criteria leads to substantial reduction in VUS.

Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) based on the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). A streamlined algorithm using the APC-specific criteria was developed and applied to assess all APC variants in ClinVar and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) international reference APC Leiden Open Variation Database (LOVD) variant database, which included a total of 10,228 unique APC variants. Among the ClinVar and LOVD variants with an initial classification of (likely) benign or (likely) pathogenic, 94% and 96% remained in their original categories, respectively. In contrast, 41% ClinVar and 61% LOVD VUSs were reclassified into clinically meaningful classes, the vast majority as (likely) benign. The total number of VUSs was reduced by 37%. In 24 out of 37 (65%) promising APC variants that remained VUS despite evidence for pathogenicity, a data-mining-driven work-up allowed their reclassification as (likely) pathogenic. These results demonstrated that the application of APC-specific criteria substantially reduced the number of VUSs in ClinVar and LOVD. The study also demonstrated the feasibility of a systematic approach to variant classification in large datasets, which might serve as a generalizable model for other gene- or disease-specific variant interpretation initiatives. It also allowed for the prioritization of VUSs that will benefit from in-depth evidence collection. This subset of APC variants was approved by the VCEP and made publicly available through ClinVar and LOVD for widespread clinical use.

Urban wastewater contains a functional human antibody repertoire of mucosal origin.

Wastewater-based surveillance of human disease offers timely insights to public health, helping to mitigate infectious disease outbreaks and decrease downstream morbidity and mortality. These systems rely on nucleic acid amplification tests for monitoring disease trends, while antibody-based seroprevalence surveys gauge community immunity. However, serological surveys are resource-intensive and subject to potentially long lead times and sampling bias. We identified and characterized a human antibody repertoire, predominantly secretory IgA, isolated from a central wastewater treatment plant and building-scale wastewater collection points. These antibodies partition to the solids fraction and retain immunoaffinity for SARS-CoV-2 and Influenza A virus antigens. This stable pool could enable real-time tracking for correlates of vaccination, infection, and immunity, aiding in establishing population-level thresholds for immune protection and assessing the efficacy of future vaccine campaigns.

A Review of Meta-Analyses of Prevention Strategies for Problematic Cannabis Use.

Purpose of Review: This narrative review summarizes research-to-date on strategies to prevent problematic cannabis use. Recent Findings: Ten meta-analytic reviews of cannabis use prevention strategies published after 2010 were identified for this review. The meta-analytic reviews were based on studies evaluating the effectiveness of school-based programs, online/digital interventions, mass-media approaches, culturally specific interventions, and brief interventions. Results indicate that school-based programs, online/digital interventions, and culturally specific interventions may help to prevent or reduce cannabis use, though effect sizes were modest. Brief interventions were found to have no effect on cannabis use frequency, but had small beneficial effects on cannabis use disorder, consequences, and abstinence. Mass media approaches were not effective in preventing cannabis use. Summary: School-based programs, online/digital interventions, culturally specific interventions, and brief interventions can have modest effects on problematic cannabis use. Research is needed to evaluate environmental strategies to prevent problematic cannabis use at the population level.

A suboptimal OCT4-SOX2 binding site facilitates the naïve-state specific function of a Klf4 enhancer.

Enhancers have critical functions in the precise, spatiotemporal control of transcription during development. It is thought that enhancer grammar, or the characteristics and arrangements of transcription factor binding sites, underlie the specific functions of developmental enhancers. In this study, we sought to identify grammatical constraints that direct enhancer activity in the naïve state of pluripotency, focusing on the enhancers for the naïve-state specific gene, Klf4. Using a combination of biochemical tests, reporter assays, and endogenous mutations in mouse embryonic stem cells, we have studied the binding sites for the transcription factors OCT4 and SOX2. We have found that the three Klf4 enhancers contain suboptimal OCT4-SOX2 composite binding sites. Substitution with a high-affinity OCT4-SOX2 binding site in Klf4 enhancer E2 rescued enhancer function and Klf4 expression upon loss of the ESRRB and STAT3 binding sites. We also observed that the low-affinity of the OCT4-SOX2 binding site is crucial to drive the naïve-state specific activities of Klf4 enhancer E2. Altogether, our work suggests that the affinity of OCT4-SOX2 binding sites could facilitate enhancer functions in specific states of pluripotency.

Utility of rest magnetocardiography in patients presenting to the emergency department with chest pain: A case series on the CardioFlux MCG.

Background: Magnetocardiography (MCG) may provide a rapid diagnostic option for patients presenting with chest pain in the emergency department (ED). Case summaries: This case series presents two instances from a multicenter study, where MCG could have served as a rapid, non-invasive diagnostic tool for chest pain patients. In both cases, multiple high-sensitivity troponin (hsTn) tests yielded incorrect evidence of ischemia. In the first case, multiple positive hsTn tests led to the patient requiring 23 h of observation care, while MCG rapidly ruled out acute coronary syndrome (ACS). In the second case, MCG revealed findings indicative of cardiac ischemia where serial ECGs did not indicate ischemia and serial hsTns were normal. Subsequent cardiac catheterization confirmed 99 % stenosis in the patient's left main and left anterior descending arteries, necessitating coronary artery bypass grafting (CABG). Conclusion: MCG offers a rapid, painless, non-invasive, radiation free assessment for patients presenting with acute chest pain. Integrating MCG into ED workflows has the potential to improve throughput, reduce the need for subsequent patient observation or inpatient admission, and minimize or eliminate the need for other more expensive non-invasive cardiac testing. MCG avoids some of the problems associated with other methods for diagnosing ischemia. MCG does not involve radiation or the use of pharmacologic agents which have a risk for allergic reactions and anaphylaxis, or the need for an intravenous line. Stress tests are frequently contraindicated or unable to be performed in patients on various medications, may require patient cooperation and in the case of exercise stress tests, the patient's capability to exercise. MCG requires no special patient preparation.

Synchronous Bilateral Ovarian Carcinomas With Right Mesonephric-like Adenocarcinoma and Left High-grade Serous Carcinoma: A Case Report and Review of the Literature.

Mesonephric-like adenocarcinomas (MLAs) are rare neoplasms of the uterus corpus and ovary, while high-grade serous carcinoma (HGSC) is the most common and lethal epithelial ovarian malignancy. We report a case of a 56-yr-old woman who presented with bilateral solid and cystic ovarian masses. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy, lymphadenectomy, omentectomy, and peritoneal biopsies. Histopathologic examination of the bilateral ovarian masses revealed 1 ovary with MLA, and the other ovary showed HGSC in association with serous tubal intraepithelial carcinoma. The morphology, immunophenotypes, and molecular profiling of the HGSC and the MLA were distinct and as expected for the different tumor types: HGSC was diffusely positive for WT-1, estrogen receptor, and p53 (mutant pattern), while negative for GATA-3 and TTF-1; MLA was positive for GATA-3 and TTF-1, while negative for WT1, estrogen receptor, and p53 (wild-type pattern); both tumors were diffusely positive for PAX-8. The HGSC revealed a TP53 c.659A>G (p.Y220C) mutation, and the MLA revealed a KRAS c. 34G>T (p. G12C) mutation and a PIK3CA c. 1034A>T (p. N345I) mutation. To the best of our knowledge, this is the first reported case of synchronous bilateral ovarian carcinomas with MLA and contralateral ovarian HGSC.

Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders.

Genomic instability disorders are characterized by DNA or chromosomal instability resulting in various clinical manifestations including developmental anomalies, immunodeficiency, and increased risk to develop cancers beginning in childhood. Many of these genomic instability disorders also present with exquisite sensitivity to anticancer treatments such as ionizing radiation and chemotherapy, which may further increase the risk of second cancers. In July 2023, the American Association of Cancer Research held the second Childhood Cancer Predisposition Workshop where multidisciplinary international experts discussed, reviewed, and updated recommendations for children with cancer predisposition syndromes. This article will discuss childhood cancer risks and surveillance recommendations for the group of genomic instability disorders with predominantly recessive inheritance, including the DNA repair disorders ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, Xeroderma Pigmentosum, Bloom syndrome, and Rothmund-Thomson syndrome, as well as the telomere biology disorders and mosaic variegated aneuploidy. Recognition of children with genomic instability disorders is important in order to make the proper diagnosis, enable genetic counseling, and inform cancer screening, cancer risk reduction, and choice of anti-cancer therapy.

Implementation of a dyadic nomenclature for monogenic diseases.

A core task when establishing the strength of evidence for a gene's role in a monogenic disorder is determining the appropriate disease entity to curate. Establishing this concept determines which evidence can be applied and quantified toward the final gene-disease validity, variant pathogenicity, or actionability classification. Genes with implications in more than one phenotype can necessitate a process of lumping and splitting, disease reorganization, and updates to disease nomenclature. Reappraisal of the names that are used as labels for disease entities is therefore a necessary and perpetual process. The Clinical Genome Resource (ClinGen), in collaboration with representatives from Monarch Disease Ontology (Mondo) and Online Inheritance in Man (OMIM), formed the Disease Naming Advisory Committee (DNAC) to develop guidance for groups faced with the need to establish the "curated disease entity" for gene-phenotype validity and variant pathogenicity and to update disease names for clinical use when necessary. The objective of this group was to harmonize guidance for disease naming across these nosologic entities and among ClinGen curation groups in collaboration with other disease-related professional groups. Here, we present the initial guidance developed by the DNAC with representative examples provided by the ClinGen expert panels and working groups that warranted nomenclature updates. We also discuss the broader implications of these efforts and their benefits for harmonization of gene-disease validity curation. Overall, this work sheds light on current inconsistencies and/or discrepancies and is designed to engage the broader community on how ClinGen defines monogenic disorders using a consistent approach for disease naming.

Plant "intelligence" and the misuse of historical sources as evidence.

Proponents of the concepts of plant intelligence and plant neurobiology often use historical sources as "evidence" and argue that eminent past scientists have supported ideas of plant intelligence, memory, learning, decision-making, agency, and consciousness. Historical sources include writings by Charles Darwin, Julius von Sachs, F. W. Went, K. V. Thimann, Barbara McClintock, and J. B. Lamarck. Advocates of plant neurobiology also argue that the ideas of J. C. Bose, an Indian scientist who is considered an important forerunner of plant neurobiology, were suppressed chiefly because of racism. Plant neurobiology has been criticized on scientific grounds, but there has not been close scrutiny of the use of historical sources as a form of evidence. We provide the first in-depth analysis of how historical sources have been used and misused, and conclude that there is a consistent pattern of distortion of these sources. Distortions include the use of erroneous quotations, alteration of quotations, selective quotations without context, and misinterpretation and exaggeration of historical statements. In the case of Bose, we show that there were legitimate scientific reasons for questioning his interpretations of botanical experiments and argue that this context cannot be ignored in evaluating contemporary responses to Bose. Overall, the common practice by proponents of plant intelligence and plant consciousness of uncritically citing the words of eminent scientists of the past, taken out of their historical context to bolster their arguments, should not be confused with scientific evidence supporting these concepts, even when the quotations, themselves, are accurate.

Faecal microbiota and cytokine profiles of rural Cambodian infants linked to diet and diarrhoeal episodes.

The gut microbiota of infants in low- to middle-income countries is underrepresented in microbiome research. This study explored the faecal microbiota composition and faecal cytokine profiles in a cohort of infants in a rural province of Cambodia and investigated the impact of sample storage conditions and infant environment on microbiota composition. Faecal samples collected at three time points from 32 infants were analysed for microbiota composition using 16S rRNA amplicon sequencing and concentrations of faecal cytokines. Faecal bacterial isolates were subjected to whole genome sequencing and genomic analysis. We compared the effects of two sample collection methods due to the challenges of faecal sample collection in a rural location. Storage of faecal samples in a DNA preservation solution preserved Bacteroides abundance. Microbiota analysis of preserved samples showed that Bifidobacterium was the most abundant genus with Bifidobacterium longum the most abundant species, with higher abundance in breast-fed infants. Most infants had detectable pathogenic taxa, with Shigella and Klebsiella more abundant in infants with recent diarrhoeal illness. Neither antibiotics nor infant growth were associated with gut microbiota composition. Genomic analysis of isolates showed gene clusters encoding the ability to digest human milk oligosaccharides in B. longum and B. breve isolates. Antibiotic-resistant genes were present in both potentially pathogenic species and in Bifidobacterium. Faecal concentrations of Interlukin-1alpha and vascular endothelial growth factor were higher in breast-fed infants. This study provides insights into an underrepresented population of rural Cambodian infants, showing pathogen exposure and breastfeeding impact gut microbiota composition and faecal immune profiles.

Comparing the Diagnostic Yield of Germline Exome Versus Panel Sequencing in the Diverse Population of the Texas KidsCanSeq Pediatric Cancer Study.

PURPOSE: To evaluate the relative diagnostic yield of clinical germline genomic tests in a diverse pediatric cancer population. PATIENTS AND METHODS: The KidsCanSeq study enrolled pediatric cancer patients across six sites in Texas. Germline analysis included both exome sequencing and a therapy-focused pediatric cancer gene panel. The results were categorized by participants demographics, the presence of pathogenic or likely pathogenic (P/LP) variants, and variants of uncertain significance (VUS) in cancer predisposition genes (CPGs). Pediatric actionable CPGs were defined as those with cancer surveillance recommendations during childhood. RESULTS: Cancer P/LP variants were reported by at least one platform in 103 of 578 (17.8%) participants of which 76 were dominant cancer genes (13.1%) with no significant differences by self-described race or Hispanic ethnicity. However, the proportion of participants with VUS was greater in Asian and African American participants (P = .0029). Diagnostic yield was 16.6% for exome versus 8.5% for panel (P < .0001) with 42 participants with concordant germline results. Exome-only results included P/LP variants in 30 different CPGs in 54 participants, whereas panel-only results included seven participants with a copy number or structural P/LP variants in CPGs. There was no significant difference in diagnostic yield limited to pediatric actionable CPGs (P = .6171). CONCLUSION: Approximately 18% of a diverse pediatric cancer population had germline diagnostic findings with 50% of P/LP variants reported by only one platform because of CPGs not on the targeted panel and copy number variants (CNVs)/rearrangements not reported by exome. Although diagnostic yields were similar in this diverse population, increases in VUS results were observed in Asian and African American populations. Given the clinical significance of CNVs/rearrangements in this cohort, detection is critical to optimize germline analysis of pediatric cancer populations.

Increased Morbidity and One-Year Post-Discharge Mortality in Patients with Bacteremia Undergoing Emergent Cholecystectomy: An Exploratory Retrospective Observational Study.

Background: Gallbladder disease, one of the most common diseases in the United States, ranges from symptomatic gallstones to severe systemic infections from cholangitis. Little research is available on how often patients undergoing emergent cholecystectomy also have bacteremia. We hypothesized that blood cultures would be performed rarely in patients undergoing emergent cholecystectomy, and that positive cultures would be associated with worse outcomes. Methods: Exploratory retrospective observational cohort study of patients admitted to a single institution from January 17, 2011, to December 31, 2018, and undergoing emergent cholecystectomy by acute care surgeons within ∼72 hours, or three days, of admission. Analyses included descriptive and by-variable statistics, binary logistic regression, and negative binomial regression. Results: Of 892 patients undergoing emergent cholecystectomy, 145 (16.2%) had blood cultures obtained three days before or on the day of surgery, of whom 33 (22.8%) had at least one positive blood culture. Male and older patients had significantly higher rates of blood cultures being obtained. One-year post-discharge mortality and complication rates were significantly higher in those with blood cultures. Versus patients with negative blood cultures, those with positive cultures were significantly older and had higher rates of sepsis and septicemia, longer hospital stays, lower rates of being discharged home, and higher one-year post-discharge mortality rates (18.2% vs. 6.3%). Cholangitis, accounting for 29% of positive blood cultures, was diagnosed in 4.5% of emergent cholecystectomies performed. Gram-negative Escherichia coli were the most common bacteria isolates. Conclusions: Positive blood cultures were associated with significantly worse patient outcomes. Surgeons performing emergent cholecystectomies could consider implementing blood culture protocols to better identify patients at risk for greater hospital morbidity and post-discharge mortality.

Neutralizing Antibody Immune Correlates for a Recombinant Protein Vaccine in the COVAIL Trial.

For COVAIL recipients of a COVID-19 Sanofi booster vaccine, neutralizing antibody titers were assessed as a correlate of risk (CoR) of COVID-19. Peak and exposure-proximal titers were inverse CoRs with covariate-adjusted hazard ratios (95% confidence intervals) 0.30 (0.11, 0.78) and 0.25 (0.07, 0.85) per 10-fold increase in weighted average titer.

Meeting Report: 2023 Muscular Dystrophy Association Summit on 'Safety and Challenges in Gene Therapy of Neuromuscular Diseases'.

 This meeting report summarizes the presentations and discussions held at the summit on Challenges in Gene Therapy hosted by the Muscular Dystrophy Association (MDA) in 2023. Topics covered include safety issues, mitigation strategies and practical considerations pertaining to the clinical translation of gene therapies for neuromuscular disease. The listing of actionable recommendations will assist in overall efforts in the field to achieve safe and efficacious translation of gene therapies for neuromuscular disease patients.

Association of changes in HerQLes scores with objective hernia outcomes: an analysis of the ACHQC database.

BACKGROUND: There are both objective and subjective measures of success following ventral hernia repair (VHR). Using the Abdominal Core Health Quality Collaborative (ACHQC) database, we sought to determine if there is an association between 30-day wound events (objective) and changes in the hernia-related quality-of-life (HerQLes) scores, (subjective). We hypothesized that patients who do not experience a 30-day wound event have a greater improvement in their HerQLes score over the short-term. METHODS: All adult patients who underwent VHR with 30-day follow-up data available between 2013 and 2022 were identified within the ACHQC database. The 30-day wound events included surgical site infection (SSI), surgical site occurrence (SSO), and SSO requiring procedural intervention (SSOPI). The association between 30-day wound events and changes in HerQLes scores was measured using propensity matched score analysis. Further, regression analysis was used to determine if an improvement in HerQLes score at 30-days postoperatively was associated with the likelihood of experiencing a 30-day wound event. RESULTS: Following a 3:1 matched analysis, 17,796 patients were available for analysis; 4449 (25%) patients experienced a 30-day wound event. The most common SSI was a superficial SSI and the most common SSO was a seroma. A 10-point improvement in the HerQLes score was statistically associated with a 3% decrease in SSI and a 4% decrease in the odds of experiencing an SSO. While not statistically significant, a 10-point improvement in the HerQLes score was associated with a 2.4% decrease in the odds of experiencing an SSOPI. CONCLUSIONS: Subjective and objective measures of success following VHR seem to be correlated with one another over the short-term. Additional studies are needed to determine if this correlation exists with other subjective and objective measures of success and to determine if these correlations persist over the long-term. If present, these associations may help to guide patient counseling as experiencing a postoperative wound event following ventral hernia repair may not be detrimental to their quality-of-life over the long-term.

Thermal measurement of erythema across skin tones: Implications for clinical identification of early pressure injury.

AIM: To assess the effectiveness of thermography, colorimetry, and oximetry at detecting temperature changes after erythema induction across diverse skin tones in healthy adults. MATERIALS AND METHODS: Erythema was induced at the forearm and ulnar head (UH) using a cupping device. Temperature via thermal image, erythema value via colorimeter, and oxygen saturation via oximeter were collected immediately and 5-10 min (delayed) after cupping at both sites. RESULTS: At the forearm, the delayed timepoint was significantly warmer than baseline. At the UH, the immediate timepoint was significantly colder than baseline. Erythema increased at both timepoints and both locations. The correlation between temperature change and erythema change was weak. Change in temperature did not differ between skin tone groups. The Intermediate Low Eumelanin skin tone group had more change in erythema compared to the Intermediate Mid (i.e., darkest) skin tone group immediately after cupping at the UH and at the delayed timepoint at the forearm. CONCLUSIONS: This study observed differences in the change of erythema across skin tones but did not observe differences in temperature across skin tones. Given high variability in results, it is premature to conclude thermal imaging works equally well across all skin tones. Further research is necessary to validate the effectiveness of thermal imaging in diverse populations. Results suggest visual erythema may be a problematic indicator as less erythema was consistently noted in participants with dark skin tones. The potential of technology to increase our ability to detect erythema warrants further investigation.