Computed tomographic angiography measures of coronary plaque in clinical trials: opportunities and considerations to accelerate drug translation.

Atherosclerotic coronary artery disease (CAD) is the causal pathological process driving most major adverse cardiovascular events (MACE) worldwide. The complex development of atherosclerosis manifests as intimal plaque which occurs in the presence or absence of traditional risk factors. There are numerous effective medications for modifying CAD but new pharmacologic therapies require increasingly large and expensive cardiovascular outcome trials to assess their potential impact on MACE and to obtain regulatory approval. For many disease areas, nearly a half of drugs are approved by the U.S. Food & Drug Administration based on beneficial effects on surrogate endpoints. For cardiovascular disease, only low-density lipoprotein cholesterol and blood pressure are approved as surrogates for cardiovascular disease. Valid surrogates of CAD are urgently needed to facilitate robust evaluation of novel, beneficial treatments and inspire investment. Fortunately, advances in non-invasive imaging offer new opportunity for accelerating CAD drug development. Coronary computed tomography angiography (CCTA) is the most advanced candidate, with the ability to measure accurately and reproducibly characterize the underlying causal disease itself. Indeed, favourable changes in plaque burden have been shown to be associated with improved outcomes, and CCTA may have a unique role as an effective surrogate endpoint for therapies that are designed to improve CAD outcomes. CCTA also has the potential to de-risk clinical endpoint-based trials both financially and by enrichment of participants at higher likelihood of MACE. Furthermore, total non-calcified, and high-risk plaque volume, and their change over time, provide a causally linked measure of coronary artery disease which is inextricably linked to MACE, and represents a robust surrogate imaging biomarker with potential to be endorsed by regulatory authorities. Global consensus on specific imaging endpoints and protocols for optimal clinical trial design is essential as we work towards a rigorous, sustainable and staged pathway for new CAD therapies.

Investigating the Poverty-Reducing Effects of SNAP on Non-nutritional Family Outcomes: A Scoping Review.

INTRODUCTION/PURPOSE: Poverty-reduction efforts that seek to support households with children and enable healthy family functioning are vital to produce positive economic, health, developmental, and upward mobility outcomes. The Supplemental Nutrition Assistance Program (SNAP) is an effective poverty-reduction policy for individuals and families. This study investigated the non-nutritional effects that families experience when receiving SNAP benefits. METHODS: We conducted a scoping review using the PRISMA Guidelines and strategic search terms across seven databases from 01 January 2008 to 01 February 2023 (n=2456). Data extraction involved two researchers performing title-abstract reviews. Full-text articles were assessed for eligibility (n=103). Forty articles were included for data retrieval. RESULTS: SNAP positively impacts family health across the five categories of the Family Stress Model (Healthcare utilization for children and parents, Familial allocation of resources, Impact on child development and behavior, Mental health, and Abuse or neglect). DISCUSSION/CONCLUSION: SNAP is a highly effective program with growing evidence that it positively impacts family health and alleviates poverty. Four priority policy actions are discussed to overcome the unintentional barriers for SNAP: distributing benefits more than once a month; increasing SNAP benefits for recipients; softening the abrupt end of benefits when wages increase; and coordinating SNAP eligibility and enrollment with other programs.

Primary prevention of cardiovascular disease in women.

Ischemic heart disease is the primary cause of cardiovascular disease (CVD) mortality in both men and women. Strategies targeting traditional modifiable risk factors are essential - including hypertension, smoking, dyslipidemia and diabetes mellitus - particularly for atherosclerosis, but additionally for stroke, heart failure and some arrhythmias. However, challenges related to education, screening and equitable access to effective preventative therapies persist, and are particularly problematic for women around the globe and those from lower socioeconomic groups. The association of female-specific risk factors (e.g. premature menopause, gestational hypertension, small for gestational age births) with CVD provides a potential window for targeted prevention strategies. However, further evidence for specific effective screening and interventions is urgently required. In addition to population-level factors involved in increasing the risk of suffering a CVD event, efforts are leveraging the enormous potential of blood-based 'omics', improved imaging biomarkers and increasingly complex bioinformatic analytic approaches to strive toward more personalized early disease detection and personalized preventative therapies. These novel tactics may be particularly relevant for women in whom traditional risk factors perform poorly. Here we discuss established and emerging approaches for improving risk assessment, early disease detection and effective preventative strategies to reduce the mammoth burden of CVD in women.

Qualitative analysis of healthcare provider perspectives to evaluating beta-lactam allergies.

BACKGROUND: There is a lack of understanding of the barriers reported by healthcare providers when evaluating beta-lactam allergies, but knowledge of these barriers is required for practical and effective implementation interventions. METHODS: Twenty-five healthcare providers, consisting of physicians, nurses and pharmacists practicing in the areas of intensive care, emergency medicine, infectious disease and general hospital practice, were interviewed between September 2021 and July 2023. Twenty-three of these providers were practising in the USA. A semi-structured interview guide grounded in the Theoretical Domain Framework was used for the interviews. Deductive and inductive analysis was performed on the interview transcripts, and translated into intervention recommendations using the Behaviour Change Wheel. RESULTS: Widely held beliefs included a lack of clear policy for the evaluation of allergies, confusing or missing documentation of allergy information, confidence in their own and their colleagues' ability to evaluate allergies when information is available, and pharmacists as the provider most equipped to evaluate beta-lactam allergies. CONCLUSIONS: Health systems should adopt and disseminate policies for the evaluation of beta-lactam allergies, and promote the use of pharmacists in the evaluation of drug allergies when possible. Allergy sections of electronic health records should be reworked to encourage unambiguous documentation of allergy reactions and support using previously tolerated beta-lactam antibiotics.

Spatial population genetics in heavily managed species: Separating patterns of historical translocation from contemporary gene flow in white-tailed deer.

Approximately 100 years ago, unregulated harvest nearly eliminated white-tailed deer (Odocoileus virginianus) from eastern North America, which subsequently served to catalyze wildlife management as a national priority. An extensive stock-replenishment effort soon followed, with deer broadly translocated among states as a means of re-establishment. However, an unintended consequence was that natural patterns of gene flow became obscured and pretranslocation signatures of population structure were replaced. We applied cutting-edge molecular and biogeographic tools to disentangle genetic signatures of historical management from those reflecting spatially heterogeneous dispersal by evaluating 35,099 single nucleotide polymorphisms (SNPs) derived via reduced-representation genomic sequencing from 1143 deer sampled statewide in Arkansas. We then employed Simpson's diversity index to summarize ancestry assignments and visualize spatial genetic transitions. Using sub-sampled transects across these transitions, we tested clinal patterns across loci against theoretical expectations of their response under scenarios of re-colonization and restricted dispersal. Two salient results emerged: (A) Genetic signatures from historic translocations are demonstrably apparent; and (B) Geographic filters (major rivers; urban centers; highways) now act as inflection points for the distribution of this contemporary ancestry. These results yielded a statewide assessment of contemporary population structure in deer as driven by historic translocations as well as ongoing processes. In addition, the analytical framework employed herein to effectively decipher extant/historic drivers of deer distribution in Arkansas is also applicable for other biodiversity elements with similarly complex demographic histories.

Age structuring and spatial heterogeneity in prion protein gene (PRNP) polymorphism in white-tailed deer.

Chronic-wasting disease (CWD) is a prion-derived fatal neurodegenerative disease that has affected wild cervid populations on a global scale. Susceptibility has been linked unambiguously to several amino acid variants within the prion protein gene (PRNP). Quantifying their distribution across landscapes can provide critical information for agencies attempting to adaptively manage CWD. Here we attempt to further define management implications of PRNP polymorphism by quantifying the contemporary geographic distribution (i.e., phylogeography) of PRNP variants in hunter-harvested white-tailed deer (WTD; Odocoileus virginianus, N = 1433) distributed across Arkansas (USA), including a focal spot for CWD since detection of the disease in February 2016. Of these, PRNP variants associated with the well-characterized 96S non-synonymous substitution showed a significant increase in relative frequency among older CWD-positive cohorts. We interpreted this pattern as reflective of a longer life expectancy for 96S genotypes in a CWD-endemic region, suggesting either decreased probabilities of infection or reduced disease progression. Other variants showing statistical signatures of potential increased susceptibility, however, seemingly reflect an artefact of population structure. We also showed marked heterogeneity across the landscape in the prevalence of 'reduced susceptibility' genotypes. This may indicate, in turn, that differences in disease susceptibility among WTD in Arkansas are an innate, population-level characteristic that is detectable through phylogeographic analysis.

(Sub)stellar companions shape the winds of evolved stars.

Binary interactions dominate the evolution of massive stars, but their role is less clear for low- and intermediate-mass stars. The evolution of a spherical wind from an asymptotic giant branch (AGB) star into a nonspherical planetary nebula (PN) could be due to binary interactions. We observed a sample of AGB stars with the Atacama Large Millimeter/submillimeter Array (ALMA) and found that their winds exhibit distinct nonspherical geometries with morphological similarities to planetary nebulae (PNe). We infer that the same physics shapes both AGB winds and PNe; additionally, the morphology and AGB mass-loss rate are correlated. These characteristics can be explained by binary interaction. We propose an evolutionary scenario for AGB morphologies that is consistent with observed phenomena in AGB stars and PNe.

Respiratory and desiccation constraints during encapsulated intertidal development of the marine gastropod Acanthina monodon.

Acanthina monodon commonly deposits its egg capsules in the intertidal zone. Capsule aerial exposure during low-tide can impact oxygen consumption rates (OCR) of embryos and intracapsular oxygen availability, and expose embryos to desiccation. OCR increased as embryonic development progressed, and was greater when capsules were submerged in seawater than when exposed to air. Oxygen available within the capsule was always less than that available in the immediate external environment, whether capsules were immersed or exposed. The highest internal oxygen concentrations were recorded during periods of air exposure for embryos in more advanced development stages. When exposed to air, capsules lost water the fastest when they contained early embryos, and suffered the highest mortalities following exposure. Collectively, these data suggest that, although encapsulation helps the embryos to develop across wildly fluctuating environmental conditions, the amount of stress the embryos experience will vary depending on their exact positioning within the intertidal zone.

Primary superficial Ewing sarcoma: A unique entity? A case report including novel findings of ELF3 and TNFRSF14 copy number loss.

Primary superficial Ewing sarcoma (psES) cases are exceedingly rare, with fewer than 150 cases reported in the literature. Small case series have suggested differences between psES and Ewing sarcoma (ES) of bone or deep soft tissues: psES appears to have a more indolent course and a higher 5-year overall survival rate. PsES is more common in older adolescent females as opposed to younger males in their peak growth velocity years in bone or deep soft tissue ES. We present a case report of a 17-year-old female with a relatively static nodule on her left thigh for 4 years. Morphologic, immunohistochemical, and molecular evaluations confirmed ES. Patient underwent a gross-total resection and a shortened course of adjuvant chemotherapy without radiation. Cancer gene panel testing found three gene abnormalities (in addition to EWSR1-FLI1 fusion): CCND1 copy number gain, ELF3 copy number loss, and TNFRSF14 copy number loss. To our knowledge, this is the first published case report of psES to include genomic sequencing and the first to report ELF3 and TNFRSF14 abnormalities in ES. Larger series of psES cases with genomic profiling are needed to elucidate a possible genetic etiology for its more indolent clinical course and favorable outcomes.

Standardization in Quantitative Imaging: A Multicenter Comparison of Radiomic Features from Different Software Packages on Digital Reference Objects and Patient Data Sets.

Radiomic features are being increasingly studied for clinical applications. We aimed to assess the agreement among radiomic features when computed by several groups by using different software packages under very tightly controlled conditions, which included standardized feature definitions and common image data sets. Ten sites (9 from the NCI's Quantitative Imaging Network] positron emission tomography-computed tomography working group plus one site from outside that group) participated in this project. Nine common quantitative imaging features were selected for comparison including features that describe morphology, intensity, shape, and texture. The common image data sets were: three 3D digital reference objects (DROs) and 10 patient image scans from the Lung Image Database Consortium data set using a specific lesion in each scan. Each object (DRO or lesion) was accompanied by an already-defined volume of interest, from which the features were calculated. Feature values for each object (DRO or lesion) were reported. The coefficient of variation (CV), expressed as a percentage, was calculated across software packages for each feature on each object. Thirteen sets of results were obtained for the DROs and patient data sets. Five of the 9 features showed excellent agreement with CV < 1%; 1 feature had moderate agreement (CV < 10%), and 3 features had larger variations (CV ≥ 10%) even after attempts at harmonization of feature calculations. This work highlights the value of feature definition standardization as well as the need to further clarify definitions for some features.

Correction: Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A multicentre, prospective, observational cohort study of variation in practice in perioperative analgesia strategies in elective laparoscopic colorectal surgery (the LapCoGesic study).

INTRODUCTION: Enhanced recovery programmes are established as an essential part of laparoscopic colorectal surgery. Optimal pain management is central to the success of an enhanced recovery programme and is acknowledged to be an important patient reported outcome measure. A variety of analgesia strategies are employed in elective laparoscopic colorectal surgery ranging from patient-controlled analgesia to local anaesthetic wound infiltration catheters. However, there is little evidence regarding the optimal analgesia strategy in this cohort of patients. The LapCoGesic study aimed to explore differences in analgesia strategies employed for patients undergoing elective laparoscopic colorectal surgery and to assess whether this variation in practice has an impact on patient-reported and clinical outcomes. MATERIALS AND METHODS: A prospective, multicentre, observational cohort study of consecutive patients undergoing elective laparoscopic colorectal resection was undertaken over a two-month period. The primary outcome measure was postoperative pain scores at 24 hours. Data analysis was conducted using SPSS version 22. RESULTS: A total of 103 patients undergoing elective laparoscopic colorectal surgery were included in the study. Thoracic epidural was used in 4 (3.9%) patients, spinal diamorphine in 56 (54.4%) patients and patient-controlled analgesia in 77 (74.8%) patients. The use of thoracic epidural and spinal diamorphine were associated with lower pain scores on day 1 postoperatively (P < 0.05). The use of patient-controlled analgesia was associated with significantly higher postoperative pain scores and pain severity. DISCUSSION: Postoperative pain is managed in a variable manner in patients undergoing elective colorectal surgery, which has an impact on patient reported outcomes of pain scores and pain severity.

Phenotypic alterations in liver cancer cells induced by mechanochemical disruption.

Hepatocellular carcinoma (HCC) is a highly fatal disease recognized as a growing global health crisis worldwide. Currently, no curative treatment is available for early-to-intermediate stage HCC, characterized by large and/or multifocal tumors. If left untreated, HCC rapidly progresses to a lethal stage due to favorable conditions for metastatic spread. Mechanochemical disruption of cellular structures can potentially induce phenotypic alterations in surviving tumor cells that prevent HCC progression. In this paper, HCC response to mechanical vibration via high-intensity focused ultrasound and a chemical disruptive agent (ethanol) was examined in vitro and in vivo. Our analysis revealed that mechanochemical disruption caused a significant overproduction of reactive oxygen species (ROS) in multiple HCC cell lines (HepG2, PLC/PRF/5, and Hep3B). This led to a decrease in cell viability and long-term proliferation due to increased expression and activity of death receptors TNFR1 and Fas. The cells that survived mechanochemical disruption had a reduced expression of cancer stem cell markers (CD133, CD90, CD49f) and a diminished colony-forming ability. Mechanochemical disruption also impeded HCC migration and their adhesion to vascular endothelium, two critical processes in hematogenous metastasis. The HCC transformation to a non-tumorigenic phenotype post mechanochemical disruption was confirmed by a lack of tumor spheroid formation in vitro and complete tumor regression in vivo. These results show that mechanochemical disruption inhibits uncontrolled proliferation and reduces tumorigenicity and aggressiveness of HCC cells through ROS overproduction and associated activation of TNF- and Fas-mediated cell death signaling. Our study identifies a novel curative therapeutic approach that can prevent the development of aggressive HCC phenotypes.

Randomized, Placebo Controlled Trial of NPT088, A Phage-Derived, Amyloid-Targeted Treatment for Alzheimer's Disease.

The engineered fusion protein NPT088 targets amyloid in vitro and in animal models of Alzheimer's disease. Previous studies showed that NPT088 treatment reduced ß-amyloid plaque and tau aggregate loads in mouse disease models. Here, we present the results from an initial clinical study of NPT088 in patients with mild to moderate Alzheimer's disease. Patients were treated with 4 dose levels of NPT088 for 6 months to evaluate its safety and tolerability. Exploratory measurements included measurement of change in ß-amyloid plaque and tau burden utilizing Positron Emission Tomography imaging as well as measures of Alzheimer's disease symptoms. At endpoint NPT088 was generally safe and well-tolerated with the most prominent finding being infusion reactions in a minority of patients. No effect of NPT088 on brain plaques, tau aggregates or Alzheimer's disease symptoms was observed.

Are we choosing wisely in elderly females with breast cancer?

BACKGROUND: The Choosing Wisely Organization and the American College of Surgeons have issued recommendations for patients >70 with breast cancer involving screening and use of radiation therapy (RT) and sentinel lymph node biopsies (SNLB) in early stage tumors. This study evaluated compliance and implementation of these recommendations. METHODS: A database of patients undergoing breast cancer surgery was retrospectively queried from 2002 to 2017. Patients were divided into cohorts before and after the year of each guideline publication. RESULTS: The rate of presentation on mammography was not different before 2009 (65%) vs. after 2009 (66%). RT was given to 57% of patients with T1 ER + Her2-prior to 2013 vs. 27% after (p=<0.001). SLNB was performed in 91% of patients with T1, grade1/2, ER + Her2-tumors prior to 2016 vs. 56% after (p=<0.001). CONCLUSION: Rates of mammography detected breast cancer have not decreased but adjuvant RT and SLNB are less frequently performed in low risk breast cancer in the elderly.

Boot camps in neonatal-perinatal medicine fellowship programs: A national survey.

BACKGROUND: Simulation is widely used in graduate medical education. A prior survey showed that 80% of Neonatal-Perinatal Medicine (NPM) fellowship programs in the U.S. use simulation. There are multiple ways to provide simulation-based education. One such method is through intensive simulation-based education sessions held at the beginning of a training program, common called 'boot camps'. The aim of this study was to describe the use of simulation-based boot camps in NPM fellowship programs. METHODS: Survey study of Accreditation Council for Graduate Medical Education (ACGME) accredited NPM fellowships in the U.S. RESULTS: Fifty-nine of 98 programs (60%) responded. Thirty six (61%) participated in 1st year fellow boot camps, which focused on procedural skills and newborn resuscitation. Nearly half of programs participated in regional boot camps. Most boot camps were one or two days long. Eleven programs (19%) held 2nd or 3rd year fellow boot camps, which focused on advanced resuscitation and communication. Barriers included lack of faculty protected time (57%), funding (39%), and lack of faculty experience (31%). CONCLUSIONS: A majority of ACGME accredited NPM fellowships participate in 1st year fellows' boot camps. Many participate in regional boot camps. A few programs have 2nd or 3rd year fellow boot camps. Lack of time, funding, and faculty experience were common barriers.

Mechanochemical Disruption Suppresses Metastatic Phenotype and Pushes Prostate Cancer Cells toward Apoptosis.

Chemical-based medicine that targets specific oncogenes or proteins often leads to cancer recurrence due to tumor heterogeneity and development of chemoresistance. This challenge can be overcome by mechanochemical disruption of cancer cells via focused ultrasound (FUS) and sensitizing chemical agents such as ethanol. We demonstrate that this disruptive therapy decreases the viability, proliferation rate, tumorigenicity, endothelial adhesion, and migratory ability of prostate cancer cells in vitro. It sensitized the cells to TNFR1-- and Fas--mediated apoptosis and reduced the expression of metastatic markers CD44 and CD29. Using a prostate cancer xenograft model, we observed that the mechanochemical disruption led to complete tumor regression in vivo. This switch to a nonaggressive cell phenotype was caused by ROS and Hsp70 overproduction and subsequent impairment of NFκB signaling. FUS induces mechanical perturbations of diverse cancer cell populations, and its combination with agents that amplify and guide remedial cellular responses can stop lethal cancer progression. IMPLICATIONS: Mechanochemical disruption therapy in which FUS is combined with ethanol can be curative for locally aggressive and castration-resistant prostate cancer.

Author Correction: Computer keyboard interaction as an indicator of early Parkinson's disease.

A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper.