Effects of Cholecystokinin on Esophageal Motor Response to Distension in Asymptomatic Volunteers.

Background/Aims: Cholecystokinin (CCK) administration has been shown to reduce lower esophageal sphincter (LES) pressure in normal subjects in manometric studies. Functional luminal imaging probe (FLIP) panometry offers a method to assess esophageal motility in response to sustained distension though mechanisms related to this response remain unexplored. The aim of this study is to evaluate the effect of CCK-8 on the esophageal response to distension in asymptomatic volunteers using FLIP. Methods: Esophageal response to distension was studied in 7 asymptomatic volunteers (mean age ± SD [27 ± 2]; 86% female) before and after CCK-8 administration in a crossover study design. During sedated endoscopy, FLIP was performed twice with CCK-8 administered via intravenous push in one of 2 protocols: during filling (n = 4) or during emptying (n = 3). Esophagogastric junction distensibility index (EGJ-DI) at 60 mL fill volume and esophageal body contractile response patterns were analyzed. Results: During the baseline FLIP study, all subjects had a contractile response with repetitive antegrade contractions both before and after CCK-8 administration. However, a sustained LES contraction or a sustained occluding contraction with esophageal shortening was observed in all subjects in the filling protocol, but in none during the emptying protocol. EGJ-DI was similar before and after CCK-8 during both filling (4.7 ± 1.9 mm2/mmHg vs 4.3 ± 1.8 mm2/mmHg) and emptying protocol (7.5 ± 1.4 mm2/mmHg vs 6.9 ± 0.6 mm2/mmHg). Conclusion: While EGJ-DI appeared unaffected by CCK-8 administration in asymptomatic volunteers, CCK induced spastic-reactive contractions of the LES during distention suggesting that exogenous CCK interferes with normal LES relaxation during secondary peristalsis.

Nurses' attitudes, behaviours, and enablers of intravenous to oral switching (IVOS) of antibiotics: a mixed-methods survey of nursing staff in secondary care hospitals across the Midlands region of England.

BACKGROUND: Intravenous (IV) antibiotic use in secondary care in England is widespread. Timely appropriate intravenous to oral switch (IVOS) has the potential to deliver significant clinical and operational benefits. To date, antimicrobial stewardship (AMS) efforts around IVOS have not focused on the nursing staff who administer antibiotics, which represents a significant gap in AMS programmes. AIM: To determine the involvement of bedside nurses in acute trusts in the Midlands region of England in IVOS in their organizations and describe their views regarding how to improve IVOS. METHODS: An anonymous self-administered mixed-methods online survey was developed and distributed to nursing staff in acute trusts via antimicrobial stewardship networks between March and May 2023. Quantitative data was analysed to describe participant demographics and behaviours, whereas barriers and enablers to IVOS were explored through thematic content analysis of responses to open-ended questions. FINDINGS: A total of 545 nursing staff responded to the survey. The majority (65.3%) routinely suggested IVOS to clinicians, despite only 50.6% being aware of local IVOS policies. One-third (34.7%) did not suggest IVOS, relying on doctors, believing their patients needed IV treatment, or lacked knowledge and skills to request IVOS. Content analysis of suggestions for improving the rate of IVOS proposed three major themes (People, Process, System) and identified that education and training, improved confidence and interprofessional relationships, and prompts were important drivers. CONCLUSION: Nursing staff suggest IVOS to other clinicians, but more education and resources are needed to enable and empower them in this role.

The Evaluation and Management of Coronary Artery Disease in the Lung Transplant Patient.

Lung transplantation can greatly improve quality of life and extend survival in those with end-stage lung disease. In order to derive the maximal benefit from such a procedure, patients must be carefully selected and be otherwise healthy enough to survive a high-risk surgery and sometimes prolonged immunosuppressive therapy following surgery. Patients therefore must be critically assessed prior to being listed for transplantation with close attention paid towards assessment of cardiovascular health and operative risk. One of the biggest dictators of this is coronary artery disease. In this review article, we discuss the assessment and management of coronary artery disease in the potential lung transplant candidate.

Obesity is Associated With Greater Improvement in Patient-Reported Outcomes Following Primary Total Knee Arthroplasty.

BACKGROUND: Body mass index (BMI) cutoffs have been established for total knee arthroplasty (TKA) patients due to increased risk of medical complications in obese patients. However, evidence-based medical optimization may mitigate risk in these patients. This study examined the influence of BMI on patient-reported outcome measures (PROMs) following primary TKA with specialized perioperative optimization. METHODS: Between 2016 and 2020, 1,329 consecutive primary TKAs using standardized perioperative optimization were retrospectively reviewed. Patients were categorized into ordinal groups based on BMI in 5 kg/m2 increments (range, 17 to 61). Primary outcomes related to activity level, pain, function, and satisfaction were evaluated. BMI groups ≥35 had significantly lower age, more women, and higher prevalence of comorbidities (P ≤ .004). Mean follow-up was 1.7 years (range, 1 to 5 years). RESULTS: Each successive BMI group from 35 to ≥50 demonstrated continually greater improvement in pain with level walking and stair climbing (P ≤ .001), Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (P = .001), and greater satisfaction (P = .007). No patients who had a BMI ≥35 were revised for aseptic loosening, and rates of periprosthetic joint infection were not different between BMI groups (P = 1.000). CONCLUSION: Despite being more debilitated preoperatively, patients who had a BMI ≥35 experienced greater improvements in PROMs compared to patients who had lower BMI. Given the significant improvements in PROMs and quality of life in obese patients, with appropriate perioperative optimization, these patients should not be prohibited from having a TKA when appropriately indicated. LEVEL OF EVIDENCE: III.

Cancer aneuploidies are shaped primarily by effects on tumour fitness.

Aneuploidies-whole-chromosome or whole-arm imbalances-are the most prevalent alteration in cancer genomes1,2. However, it is still debated whether their prevalence is due to selection or ease of generation as passenger events1,2. Here we developed a method, BISCUT, that identifies loci subject to fitness advantages or disadvantages by interrogating length distributions of telomere- or centromere-bounded copy-number events. These loci were significantly enriched for known cancer driver genes, including genes not detected through analysis of focal copy-number events, and were often lineage specific. BISCUT identified the helicase-encoding gene WRN as a haploinsufficient tumour-suppressor gene on chromosome 8p, which is supported by several lines of evidence. We also formally quantified the role of selection and mechanical biases in driving aneuploidy, finding that rates of arm-level copy-number alterations are most highly correlated with their effects on cellular fitness1,2. These results provide insight into the driving forces behind aneuploidy and its contribution to tumorigenesis.

Recent Thymic Emigrants Require RBPJ-Dependent Notch Signaling to Transition into Functionally Mature Naive T Cells.

Recent thymic emigrant (RTE) cells are nascent T cells that continue their post-thymic maturation in the periphery and dominate T cell immune responses in early life and in adults having undergone lymphodepletion regimens. However, the events that govern their maturation and their functionality as they transition to mature naive T cells have not been clearly defined. Using RBPJind mice, we were able to identify different stages of RTE maturation and interrogate their immune function using a T cell transfer model of colitis. As CD45RBlo RTE cells mature, they transition through a CD45RBint immature naive T (INT) cell population that is more immunocompetent but shows a bias toward IL-17 production at the expense of IFN-γ. Additionally, the levels of IFN-γ and IL-17 produced in INT cells are highly dependent on whether Notch signals are received during INT cell maturation or during their effector function. IL-17 production by INT cells showed a total requirement for Notch signaling. Loss of Notch signaling at any stage of INT cells resulted in an impaired colitogenic effect of INT cells. RNA sequencing of INT cells that had matured in the absence of Notch signals showed a reduced inflammatory profile compared with Notch-responsive INT cells. Overall, we have elucidated a previously unknown INT cell stage, revealed its intrinsic bias toward IL-17 production, and demonstrated a role for Notch signaling in INT cell peripheral maturation and effector function in the context of a T cell transfer model of colitis.

Tumor-restrictive type III collagen in the breast cancer microenvironment: prognostic and therapeutic implications.

Collagen plays a critical role in regulating breast cancer progression and therapeutic resistance. An improved understanding of both the features and drivers of tumor-permissive and -restrictive collagen matrices are critical to improve prognostication and develop more effective therapeutic strategies. In this study, using a combination of in vitro, in vivo and in silico experiments, we show that type III collagen (Col3) plays a tumor-restrictive role in human breast cancer. We demonstrate that Col3-deficient, human fibroblasts produce tumor-permissive collagen matrices that drive cell proliferation and suppress apoptosis in noninvasive and invasive breast cancer cell lines. In human TNBC biopsy samples, we demonstrate elevated deposition of Col3 relative to type I collagen (Col1) in noninvasive compared to invasive regions. Similarly, in silico analyses of over 1000 breast cancer patient biopsies from The Cancer Genome Atlas BRCA cohort revealed that patients with higher Col3:Col1 bulk tumor expression had improved overall, disease-free and progression-free survival relative to those with higher Col1:Col3 expression. Using an established 3D culture model, we show that Col3 increases spheroid formation and induces formation of lumen-like structures that resemble non-neoplastic mammary acini. Finally, our in vivo study shows co-injection of murine breast cancer cells (4T1) with rhCol3-supplemented hydrogels limits tumor growth and decreases pulmonary metastatic burden compared to controls. Taken together, these data collectively support a tumor-suppressive role for Col3 in human breast cancer and suggest that strategies that increase Col3 may provide a safe and effective modality to limit recurrence in breast cancer patients.

A case report of acute heart failure and cardiogenic shock caused by catastrophic antiphospholipid syndrome and lupus myocarditis.

Background: Catastrophic antiphospholipid syndrome and lupus myocarditis are two rare life-threatening conditions. Case summary: We present a case of a 47-year-old woman admitted in profound cardiogenic shock due to catastrophic antiphospholipid syndrome and lupus myocarditis requiring advanced heart failure therapies, including early mechanical circulatory support. She improved with steroids, immunoglobulins, mycophenolate, and eculizumab. Discussion: This case highlights the importance of early identification of cardiogenic shock secondary to catastrophic antiphospholipid syndrome and lupus myocarditis, the arrhythmogenic complications of myocarditis, and the subsequent management of the disease progression with mechanical and medical support.

Tangent normalization for somatic copy-number inference in cancer genome analysis.

MOTIVATION: Somatic copy-number alterations (SCNAs) play an important role in cancer development. Systematic noise in sequencing and array data present a significant challenge to the inference of SCNAs for cancer genome analyses. As part of The Cancer Genome Atlas, the Broad Institute Genome Characterization Center developed the Tangent normalization method to generate copy-number profiles using data from single-nucleotide polymorphism (SNP) arrays and whole-exome sequencing (WES) technologies for over 10 000 pairs of tumors and matched normal samples. Here, we describe the Tangent method, which uses a unique linear combination of normal samples as a reference for each tumor sample, to subtract systematic errors that vary across samples. We also describe a modification of Tangent, called Pseudo-Tangent, which enables denoising through comparisons between tumor profiles when few normal samples are available. RESULTS: Tangent normalization substantially increases signal-to-noise ratios (SNRs) compared to conventional normalization methods in both SNP array and WES analyses. Tangent and Pseudo-Tangent normalizations improve the SNR by reducing noise with minimal effect on signal and exceed the contribution of other steps in the analysis such as choice of segmentation algorithm. Tangent and Pseudo-Tangent are broadly applicable and enable more accurate inference of SCNAs from DNA sequencing and array data. AVAILABILITY AND IMPLEMENTATION: Tangent is available at https://github.com/broadinstitute/tangent and as a Docker image (https://hub.docker.com/r/broadinstitute/tangent). Tangent is also the normalization method for the copy-number pipeline in Genome Analysis Toolkit 4 (GATK4). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Using behavioural science in public health settings during the COVID-19 pandemic: The experience of public health practitioners and behavioural scientists.

INTRODUCTION: The emergence of COVID-19 and the importance of behaviour change to limit its spread created an urgent need to apply behavioural science to public health. Knowledge mobilisation, the processes whereby research leads to useful findings that are implemented to affect positive outcomes, is a goal for researchers, policy makers and practitioners alike. This study aimed to explores the experience of using behavioural science in public health during COVID-19, to discover barriers and facilitators and whether the rapidly changing context of COVID-19 influenced knowledge mobilisation. METHODS: We conducted a semi-structured interview study, with ten behavioural scientists and seven public health professionals in England, Scotland, Wales, The Netherlands and Canada. We conducted an inductive thematic analysis. RESULTS: We report three key themes and 10 sub-themes: 1.Challenges and facilitators of translation of behavioural science into public health (Methods and frameworks supported translation, Lack of supportive infrastructure, Conviction and sourcing of evidence and Embracing behavioural science) 2. The unique context of translation (Rapid change in context, the multi-disciplinary team and the emotional toll). 3. Recommendations to support future behavioural science translation (Embedding experts into teams, Importance of a collaborative network and showcasing the role of behavioural science). DISCUSSION: Barriers and facilitators included factors related to relationships between people, such as networks and teams; the expertise of individual people; and those related to materials, such as the use of frameworks and an overwhelming amount of evidence and literature. CONCLUSION: People and frameworks were seen as important in facilitating behavioural science in practice. Future research could explore how different frameworks are used. We recommend a stepped competency framework for behavioural science in public health and more focus on nurturing networks to facilitate knowledge mobilisation in future emergencies.

Assessment and validation of a novel fast fully automated artificial intelligence left ventricular ejection fraction quantification software.

BACKGROUND: Quantification of left ventricular ejection fraction (LVEF) by transthoracic echocardiography (TTE) is operator-dependent, time-consuming, and error-prone. LVivoEF by DIA is a new artificial intelligence (AI) software, which displays the tracking of endocardial borders and rapidly quantifies LVEF. We sought to assess the accuracy of LVivoEF compared to cardiac magnetic resonance imaging (cMRI) as the reference standard and to compare LVivoEF to the standard-of-care physician-measured LVEF (MD-EF) including studies with ultrasound enhancing agents (UEAs). METHODS: In 273 consecutive patients, we compared MD-EF and AI-derived LVEF to cMRI. AI-derived LVEF was obtained from a non-UEA four-chamber view without manual correction. Thirty-one patients were excluded: 25 had interval interventions or incomplete TTE or cMRI studies and six had uninterpretable non-UEA apical views. RESULTS: In the 242 subjects, the correlation between AI and cMRI was r = .890, similar to MD-EF and cMRI with r = .891 (p = 0.48). Of the 126 studies performed with UEAs, the correlation of AI using the unenhanced four-chamber view was r = .89, similar to MD-EF with r = .90. In the 116 unenhanced studies, AI correlation was r = .87, similar to MD-EF with r = .84. From Bland-Altman analysis, LVivoEF underreported the LVEF with a bias of 3.63 ± 7.40% EF points compared to cMRI while MD-EF to cMRI had a bias of .33 ± 7.52% (p = 0.80). CONCLUSIONS: Compared to cMRI, LVivoEF can accurately quantify LVEF from a standard apical four-chamber view without manual correction. Thus, LVivoEF has the ability to improve and expedite LVEF quantification.

Echocardiography in the time of Covid-19: Ultrasound enhancing agents save time and augment diagnostic information.

BACKGROUND: There are currently no clear guidelines regarding the use of ultrasound enhancing agents (UEAs) with transthoracic echocardiography (TTE) for patients hospitalized with Covid-19. We investigated whether the performance of TTE with UEAs provides more diagnostic information and allows for shorter acquisition time compared to unenhanced TTE imaging in this patient population. METHODS: We analyzed the TTEs of 107 hospitalized Covid-19 patients between April and June 2020 who were administered UEAs (Definity®, Lantheus). The time to acquire images with and without UEAs was calculated. A level III echocardiographer determined if new, clinically significant findings were visualized with the addition of UEAs. RESULTS: There was a mean of 11.84±3.59 UEA cineloops/study vs 20.74±8.10 non-UEA cineloops/study (p < 0.0001). Mean time to acquire UEA cineloop images was 72.28±28.18 s/study compared to 188.07±86.04 s/study for non-UEA cineloop images (p < 0.0001). Forty-eight patients (45%) had at least one new finding on UEA imaging, with a total of 62 new findings seen. New information gained with UEAs was more likely to be found in patients with acute respiratory distress syndrome (21 vs 9, p < 0.001) and in those on mechanical ventilation (21 vs 15, p = 0.046). CONCLUSIONS: TTE with UEAs required less time and fewer cineloop images compared to non-UEA imaging in patients hospitalized with Covid-19. Additionally, Covid-19 patients with severe respiratory disease benefited most with regard to new diagnostic information. Health care personnel should consider early use of UEAs in select hospitalized Covid-19 patients in order to reduce exposure and optimize diagnostic yield.

Racial and ethnic differences in severity of coronary calcification among patients undergoing PCI: Results from a single-center multiethnic PCI registry.

BACKGROUND: Although population-based studies have demonstrated racial heterogeneity in coronary artery calcium (CAC) burden, the degree to which such associations extend to percutaneous coronary intervention (PCI) cohorts remains poorly characterized. We sought to evaluate the associations between race/ethnicity and CAC in a PCI population. METHODS: This single center retrospective study analyzed 1025 patients with prior CAC who underwent PCI between January 1, 2012 and May 15, 2020. Patients were grouped as non-Hispanic White (NHW, N = 779), non-Hispanic Black (NHB, N = 81) and Hispanic (H, N = 165). Associations between race and CAC (Agatston units) were examined using negative binomial regression while adjusting for baseline parameters. RESULTS: Among the 1025 patients (mean age 65.8, 70% male) who underwent PCI, NHW, NHB, and H populations had median CAC scores of 760, 500, and 462 Agatston units, respectively (p < 0.0001). Hispanic patients displayed a higher burden of diabetes mellitus, hypertension and hyperlipidemia compared with other groups. After adjusting for baseline differences and compared with NHW, the inverse association between Hispanic and CAC persisted (ß = -324.1, p < 0.0001) whereas differences were not significant for NHB (ß = -51.5, p = 0.67). CONCLUSIONS: Despite a higher risk clinical phenotype, Hispanic patients who underwent PCI had significantly lower CAC compared with non-Hispanic patients. Thus, current risk stratification models using universalized CAC scores may underestimate the risk for the Hispanic population. Race/ethnicity-informed CAC thresholds may better guide clinical decisions.

DL4-µbeads induce T cell lineage differentiation from stem cells in a stromal cell-free system.

T cells are pivotal effectors of the immune system and can be harnessed as therapeutics for regenerative medicine and cancer immunotherapy. An unmet challenge in the field is the development of a clinically relevant system that is readily scalable to generate large numbers of T-lineage cells from hematopoietic stem/progenitor cells (HSPCs). Here, we report a stromal cell-free, microbead-based approach that supports the efficient in vitro development of both human progenitor T (proT) cells and T-lineage cells from CD34+cells sourced from cord blood, GCSF-mobilized peripheral blood, and pluripotent stem cells (PSCs). DL4-µbeads, along with lymphopoietic cytokines, induce an ordered sequence of differentiation from CD34+ cells to CD34+CD7+CD5+ proT cells to CD3+αß T cells. Single-cell RNA sequencing of human PSC-derived proT cells reveals a transcriptional profile similar to the earliest thymocytes found in the embryonic and fetal thymus. Furthermore, the adoptive transfer of CD34+CD7+ proT cells into immunodeficient mice demonstrates efficient thymic engraftment and functional maturation of peripheral T cells. DL4-µbeads provide a simple and robust platform to both study human T cell development and facilitate the development of engineered T cell therapies from renewable sources.

A Personalized Approach to Chronic Kidney Disease and Cardiovascular Disease: JACC Review Topic of the Week.

Cardiovascular disease is the most common cause of death in patients with end-stage renal disease (ESRD). The initiation of dialysis for treatment of ESRD exacerbates chronic electrolyte and hemodynamic perturbations. Rapid large shifts in effective intravascular volume and electrolyte concentrations ultimately lead to subendocardial ischemia, increased left ventricular wall mass, and diastolic dysfunction, and can precipitate serious arrhythmias through a complex pathophysiological process. These factors, unique to advanced kidney disease and its treatment, increase the overall incidence of acute coronary syndrome and sudden cardiac death. To date, risk prediction models largely fail to incorporate the observed cardiovascular mortality in the CKD population; however, multimodality imaging may provide an additional prognostication and risk stratification. This comprehensive review discusses the cardiovascular risks associated with hemodialysis, and explores the pathophysiology and the novel utilization of multimodality imaging in CKD to promote a personalized approach for these patients with implications for future research.

B.2.16 is a non-lethal modifier of the Dark82 mosaic eye phenotype in Drosophila melanogaster.

Genetic screens have been used to identify genes involved in the regulation of different biological processes. We identified growth mutants in a Flp/FRT screen using the Drosophila melanogaster eye to identify conditional regulators of cell growth and cell division. One mutant identified from this screen, B.2.16, was mapped and characterized by researchers in undergraduate genetics labs as part of the Fly-CURE. We find that B.2.16 is a non-lethal genetic modifier of the Dark82 mosaic eye phenotype.

Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma.

PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.

Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer.

We evaluated ancestry effects on mutation rates, DNA methylation, and mRNA and miRNA expression among 10,678 patients across 33 cancer types from The Cancer Genome Atlas. We demonstrated that cancer subtypes and ancestry-related technical artifacts are important confounders that have been insufficiently accounted for. Once accounted for, ancestry-associated differences spanned all molecular features and hundreds of genes. Biologically significant differences were usually tissue specific but not specific to cancer. However, admixture and pathway analyses suggested some of these differences are causally related to cancer. Specific findings included increased FBXW7 mutations in patients of African origin, decreased VHL and PBRM1 mutations in renal cancer patients of African origin, and decreased immune activity in bladder cancer patients of East Asian origin.

Loss of heterozygosity of essential genes represents a widespread class of potential cancer vulnerabilities.

Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer. Hundreds to thousands of non-driver genes undergo loss of heterozygosity (LOH) events per tumor, generating discrete differences between tumor and normal cells. Here we interrogate LOH of polymorphisms in essential genes as a novel class of therapeutic targets. We hypothesized that monoallelic inactivation of the allele retained in tumors can selectively kill cancer cells but not somatic cells, which retain both alleles. We identified 5664 variants in 1278 essential genes that undergo LOH in cancer and evaluated the potential for each to be targeted using allele-specific gene-editing, RNAi, or small-molecule approaches. We further show that allele-specific inactivation of either of two essential genes (PRIM1 and EXOSC8) reduces growth of cells harboring that allele, while cells harboring the non-targeted allele remain intact. We conclude that LOH of essential genes represents a rich class of non-driver cancer vulnerabilities.