Selective Use of CT Fractional Flow at a Large Academic Medical Center: Insights from Clinical Implementation after 1 Year of Practice.

Purpose This special report outlines a retrospective observational study of CT fractional flow reserve (CT-FFR) analysis using dual-source coronary CT angiography (CTA) scans performed without heart rate control and its impact on clinical outcomes. Materials and Methods All patients who underwent clinically indicated coronary CTA between August 2020 and August 2021 were included in this retrospective observational study. Scans were performed in the late systolic to early diastolic period without heart rate control and analyzed at the interpreting physician's discretion. Demographics, coronary CTA features, and rates of invasive coronary angiography (ICA), percutaneous coronary intervention (PCI), myocardial infarction, and all-cause death at 3 months were assessed by chart review. Results During the study period, 3098 patients underwent coronary CTA, of whom 113 with coronary bypass grafting were excluded. Of the remaining 2985 patients, 292 (9.7%) were referred for CT-FFR analysis. Two studies (0.7%) were rejected from CT-FFR analysis, and six (2.1%) analyses did not evaluate the lesion of concern. A total of 160 patients (56.3%) had CT-FFR greater than 0.80. Among patients with significant stenosis at coronary CTA, patients who underwent CT-FFR analysis presented with lower rates of ICA (74.5% vs 25.5%, P = .04) and PCI (78.9% vs 21.1%, P = .05). Conclusion CT-FFR was implemented in patients not requiring heart rate control by using dual-source coronary CTA acquisition and showed the potential to decrease rates of ICA and PCI without compromising safety in patients with significant stenosis and an average heart rate of 65 beats per minute. Keywords: Angiography, CT, CT-Angiography, Fractional Flow Reserve, Cardiac, Heart, Arteriosclerosis Supplemental material is available for this article. © RSNA, 2024.

Sybil: A Validated Deep Learning Model to Predict Future Lung Cancer Risk From a Single Low-Dose Chest Computed Tomography.

PURPOSE: Low-dose computed tomography (LDCT) for lung cancer screening is effective, although most eligible people are not being screened. Tools that provide personalized future cancer risk assessment could focus approaches toward those most likely to benefit. We hypothesized that a deep learning model assessing the entire volumetric LDCT data could be built to predict individual risk without requiring additional demographic or clinical data. METHODS: We developed a model called Sybil using LDCTs from the National Lung Screening Trial (NLST). Sybil requires only one LDCT and does not require clinical data or radiologist annotations; it can run in real time in the background on a radiology reading station. Sybil was validated on three independent data sets: a heldout set of 6,282 LDCTs from NLST participants, 8,821 LDCTs from Massachusetts General Hospital (MGH), and 12,280 LDCTs from Chang Gung Memorial Hospital (CGMH, which included people with a range of smoking history including nonsmokers). RESULTS: Sybil achieved area under the receiver-operator curves for lung cancer prediction at 1 year of 0.92 (95% CI, 0.88 to 0.95) on NLST, 0.86 (95% CI, 0.82 to 0.90) on MGH, and 0.94 (95% CI, 0.91 to 1.00) on CGMH external validation sets. Concordance indices over 6 years were 0.75 (95% CI, 0.72 to 0.78), 0.81 (95% CI, 0.77 to 0.85), and 0.80 (95% CI, 0.75 to 0.86) for NLST, MGH, and CGMH, respectively. CONCLUSION: Sybil can accurately predict an individual's future lung cancer risk from a single LDCT scan to further enable personalized screening. Future study is required to understand Sybil's clinical applications. Our model and annotations are publicly available.[Media: see text].

Cloacaenodin, an Antimicrobial Lasso Peptide with Activity against Enterobacter.

Using genome mining and heterologous expression, we report the discovery and production of a new antimicrobial lasso peptide from species related to the Enterobacter cloacae complex. Using NMR and mass spectrometric analysis, we show that this lasso peptide, named cloacaenodin, employs a threaded lasso fold which imparts proteolytic resistance that its unthreaded counterpart lacks. Cloacaenodin has selective, low micromolar, antimicrobial activity against species related to the E. cloacae complex, including species implicated in nosocomial infections and against clinical isolates of carbapenem-resistant Enterobacterales. We further used site-directed mutagenesis to probe the importance of specific residues to the peptide's biosynthesis, stability, and bioactivity.

Coronary Artery Disease Reporting and Data System (CAD-RADS) Adoption: Analysis of Local Trends in a Large Academic Medical Center.

PURPOSE: To perform a retrospective review of Coronary Artery Disease Reporting and Data System (CAD-RADS) adoption at a high-volume cardiac CT service. MATERIALS AND METHODS: In this retrospective study, the adoption of CAD-RADS in 6562 coronary CT angiography (CTA) reports from January 1, 2017, to February 13, 2020, was evaluated. Reports without CAD-RADS were classified as opt-outs or exceptions to CAD-RADS. CAD-RADS classifications were retrospectively assigned to the opt-outs and the clinical indications for coronary CTA. RESULTS: CAD-RADS scores were reported in 95% (6264 of 6562) of cases. Among the 5% (n = 298) of reports not reported according to CAD-RADS, 58% (n = 172) were considered opt-outs and 42% (n = 126) were exceptions. Cases with higher degree of stenosis, stents, and coronary artery bypass grafts (CABGs) occurred more often in opt-outs versus reports with CAD-RADS (odds ratio [OR], 8.3 [95% CI: 1.6, 42.1]; P < .001). The quarterly opt-out rate decreased over consecutive quarters in the 1st year (OR, 0.77 [95% CI: 0.61, 0.96]; P = .01), then stabilized. Quarterly opt-out rate for patients with stents decreased over time (OR, 0.82 [95% CI: 0.73, 0.92]; P = .008), as did the opt-out rates in patients with CABG (OR, 0.83 [95% CI: 0.76, 0.91]; P < .001). Exceptions (n = 126) included coronary dissections (44%), anomalous coronary arteries (41%), coronary artery aneurysms or pseudoaneurysms (10%), vasculitis (2%), stent complications (2%), and extrinsic compression of grafts (2%). CONCLUSION: CAD-RADS was adopted rapidly and widely. Readers opted out of its use most often in complex cases of CAD, and the most common exceptions were coronary dissections and anomalous coronary artery.Keywords: Coronary Arteries, CT Angiography© RSNA, 2021.

Use of whole genome sequencing to complement characterisation of a typhoid fever outbreak among a Marshallese community: Oklahoma, 2015.

Typhoid fever is an illness caused by Salmonella enterica serotype Typhi. In developing regions, it affects an estimated 20 million people annually, causing 200 000 deaths. Although uncommon, cases occur in the USA each year, predominantly due to international travel. During February 2015, the Oklahoma State Department of Health (OSDH) detected an outbreak of typhoid fever among residents of northwestern Oklahoma. OSDH conducted case-patient interviews to identify the source and symptomatic contacts. Whole genome sequencing (WGS) was performed to characterise the genetic relatedness of isolates among the four outbreak-associated pulsed-field gel electrophoresis (PFGE) patterns. We identified 38 cases, 25 confirmed and 13 probable, in two states. WGS revealed a 0-10 single-nucleotide polymorphism variation between isolates. Although we were unable to determine the source, almost all case-patients were members of the Marshallese community that attended a common event in Oklahoma, or were contacts to a confirmed case. This is the largest outbreak of typhoid fever in the USA since 1989, and first to apply WGS to complement interpretation of PFGE results during a typhoid fever outbreak investigation. This investigation illustrates the potential risk of outbreaks among communities comprised of international populations from regions where typhoid fever remains endemic.

When fragments link: a bibliometric perspective on the development of fragment-based drug discovery.

Fragment-based drug discovery (FBDD) is a highly interdisciplinary field, rich in ideas integrated from pharmaceutical sciences, chemistry, biology, and physics, among others. To enrich our understanding of the development of the field, we used bibliometric techniques to analyze 3642 publications in FBDD, complementing accounts by key practitioners. Mapping its core papers, we found the transfer of knowledge from academia to industry. Co-authorship analysis showed that university-industry collaboration has grown over time. Moreover, we show how ideas from other scientific disciplines have been integrated into the FBDD paradigm. Keyword analysis showed that the field is organized into four interconnected practices: library design, fragment screening, computational methods, and optimization. This study highlights the importance of interactions among various individuals and institutions from diverse disciplines in newly emerging scientific fields.

Multistate outbreak of Listeria monocytogenes infections linked to whole apples used in commercially produced, prepackaged caramel apples: United States, 2014-2015.

Whole apples have not been previously implicated in outbreaks of foodborne bacterial illness. We investigated a nationwide listeriosis outbreak associated with caramel apples. We defined an outbreak-associated case as an infection with one or both of two outbreak strains of Listeria monocytogenes highly related by whole-genome multilocus sequence typing (wgMLST) from 1 October 2014 to 1 February 2015. Single-interviewer open-ended interviews identified the source. Outbreak-associated cases were compared with non-outbreak-associated cases and traceback and environmental investigations were performed. We identified 35 outbreak-associated cases in 12 states; 34 (97%) were hospitalized and seven (20%) died. Outbreak-associated ill persons were more likely to have eaten commercially produced, prepackaged caramel apples (odds ratio 326·7, 95% confidence interval 32·2-3314). Environmental samples from the grower's packing facility and distribution-chain whole apples yielded isolates highly related to outbreak isolates by wgMLST. This outbreak highlights the importance of minimizing produce contamination with L. monocytogenes. Investigators should perform single-interviewer open-ended interviews when a food is not readily identified.

Epidemiology of restaurant-associated foodborne disease outbreaks, United States, 1998-2013.

Although contamination of food can occur at any point from farm to table, restaurant food workers are a common source of foodborne illness. We describe the characteristics of restaurant-associated foodborne disease outbreaks and explore the role of food workers by analysing outbreaks associated with restaurants from 1998 to 2013 reported to the Centers for Disease Control and Prevention's Foodborne Disease Outbreak Surveillance System. We identified 9788 restaurant-associated outbreaks. The median annual number of outbreaks was 620 (interquartile range 618-629). In 3072 outbreaks with a single confirmed aetiology reported, norovirus caused the largest number of outbreaks (1425, 46%). Of outbreaks with a single food reported and a confirmed aetiology, fish (254 outbreaks, 34%) was most commonly implicated, and these outbreaks were commonly caused by scombroid toxin (219 outbreaks, 86% of fish outbreaks). Most outbreaks (79%) occurred at sit-down establishments. The most commonly reported contributing factors were those related to food handling and preparation practices in the restaurant (2955 outbreaks, 61%). Food workers contributed to 2415 (25%) outbreaks. Knowledge of the foods, aetiologies, and contributing factors that result in foodborne disease restaurant outbreaks can help guide efforts to prevent foodborne illness.

Long-Term Training with a Brain-Machine Interface-Based Gait Protocol Induces Partial Neurological Recovery in Paraplegic Patients.

Brain-machine interfaces (BMIs) provide a new assistive strategy aimed at restoring mobility in severely paralyzed patients. Yet, no study in animals or in human subjects has indicated that long-term BMI training could induce any type of clinical recovery. Eight chronic (3-13 years) spinal cord injury (SCI) paraplegics were subjected to long-term training (12 months) with a multi-stage BMI-based gait neurorehabilitation paradigm aimed at restoring locomotion. This paradigm combined intense immersive virtual reality training, enriched visual-tactile feedback, and walking with two EEG-controlled robotic actuators, including a custom-designed lower limb exoskeleton capable of delivering tactile feedback to subjects. Following 12 months of training with this paradigm, all eight patients experienced neurological improvements in somatic sensation (pain localization, fine/crude touch, and proprioceptive sensing) in multiple dermatomes. Patients also regained voluntary motor control in key muscles below the SCI level, as measured by EMGs, resulting in marked improvement in their walking index. As a result, 50% of these patients were upgraded to an incomplete paraplegia classification. Neurological recovery was paralleled by the reemergence of lower limb motor imagery at cortical level. We hypothesize that this unprecedented neurological recovery results from both cortical and spinal cord plasticity triggered by long-term BMI usage.

Dual-function vector for protein expression in both mammalian cells and Xenopus laevis oocytes.

Both Xenopus laevis oocytes and mammalian cells are widely used for heterologous expression of several classes of proteins, and membrane proteins especially, such as ion channels or receptors, have been extensively investigated in both cell types. A full characterization of a specific protein will often engage both oocytes and mammalian cells. Efficient expression of a protein in both systems have thus far only been possible by subcloning the cDNA into two different vectors because several different molecular requirements should be fulfilled to obtain a high protein level in both mammalian cells and oocytes. To address this problem, we have constructed a plasmid vector, pXOOM, that can function as a template for expression in both oocytes and mammalian cells. By including all the necessary RNA stability elements for oocyte expression in a standard mammalian expression vector, we have obtained a dual-function vector capable of supporting protein production in both Xenopus oocytes and CHO-K1 cells at an expression level equivalent to the levels obtained with vectors optimized for either oocyte or mammalian expression. Our functional studies have been performed with hERGI, KCNQ4, and Kv1.3 potassium channels.

Pharmacological modulation of SK3 channels.

Small-conductance, calcium-activated K+ channels (SK channels) are voltage-insensitive channels that have been identified molecularly within the last few years. As SK channels play a fundamental role in most excitable cells and participate in afterhyperpolarization (AHP) and spike-frequency adaptation, pharmacological modulation of SK channels may be of significant clinical importance. Here we report the functional expression of SK3 in HEK293 and demonstrate a broad pharmacological profile for these channels. Brain slice studies commonly employ 4-aminopyridine (4-AP) to block voltage-dependent K+ channels or a methyl derivative of bicuculline, a blocker of gamma-aminobutyric acid (GABA)-gated Cl- channels, in order to investigate the role of various synapses in specialized neural networks. However, in this study both 4-AP and bicuculline are shown to inhibit SK3 channels (IC50 values of 512 microM and 6 microM, respectively) at concentrations lower than those used for brain slice recordings. Riluzole, a potent neuroprotective drug with anti-ischemic, anticonvulsant and sedative effects currently used in the treatment of amyotrophic lateral sclerosis, activates SK3 channels at concentrations of 3 microM and above. Amitriptyline, a tricyclic antidepressive widely used clinically, inhibits SK3 channels with an IC50 of 39.1 +/- 10 microM (n=6).

An ERG channel inhibitor from the scorpion Buthus eupeus.

The isolation of the peptide inhibitor of M-type K(+) current, BeKm-1, from the venom of the Central Asian scorpion Buthus eupeus has been described previously (Fillipov A. K., Kozlov, S. A., Pluzhnikov, K. A., Grishin, E. V., and Brown, D. A. (1996) FEBS Lett. 384, 277-280). Here we report the cloning, expression, and selectivity of BeKm-1. A full-length cDNA of 365 nucleotides encoding the precursor of BeKm-1 was isolated using the rapid amplification of cDNA ends polymerase chain reaction technique from mRNA obtained from scorpion telsons. Sequence analysis of the cDNA revealed that the precursor contains a signal peptide of 21 amino acid residues. The mature toxin consists of 36 amino acid residues. BeKm-1 belongs to the family of scorpion venom potassium channel blockers and represents a new subgroup of these toxins. The recombinant BeKm-1 was produced as a Protein A fusion product in the periplasm of Escherichia coli. After cleavage and high performance liquid chromatography purification, recombinant BeKm-1 displayed the same properties as the native toxin. Three BeKm-1 mutants (R27K, F32K, and R27K/F32K) were generated, purified, and characterized. Recombinant wild-type BeKm-1 and the three mutants partly inhibited the native M-like current in NG108-15 at 100 nm. The effect of the recombinant BeKm-1 on different K(+) channels was also studied. BeKm-1 inhibited hERG1 channels with an IC(50) of 3.3 nm, but had no effect at 100 nm on hEAG, hSK1, rSK2, hIK, hBK, KCNQ1/KCNE1, KCNQ2/KCNQ3, KCNQ4 channels, and minimal effect on rELK1. Thus, BeKm-1 was shown to be a novel specific blocker of hERG1 potassium channels.

Examination of the cognitive effects of cimetidine in normal elderly volunteers.

The authors evaluated the cognitive effects of acute challenges with the H2 receptor-antagonist cimetidine in normal older volunteers. The study was a double-blind, placebo-controlled, crossover study of 12 volunteers, average age 71.25 years. Baseline assessment was followed by randomized administration of a placebo or ascending doses of cimetidine (400 mg, 800 mg, or 1,600 mg) in test sessions separated by 1 week. Cognitive performance was evaluated with a 1-hour battery of tests beginning 90 minutes after administration of a single dose of drug (or placebo). There were no significant cognitive decrements associated with cimetidine. Despite numerous case reports of cognitive toxicity, this study found no observable decrements in cognitive performance in a group of healthy elderly subjects; therefore, case reports in the literature may be reporting effects for patients with specific impairments or sensitivities.

Identification of medications that cause cognitive impairment in older people: the case of oxybutynin chloride.

OBJECTIVES: To evaluate the cognitive effects of acute challenges with the antispasmodic agent oxybutynin hydrochloride in normal older volunteers and to compare these effects with those attributable to diphenhydramine, another commonly used medication with anticholinergic (muscarinic-blocking) activity. DESIGN: A double-blind, placebo-controlled cross-over study. SETTING: Laboratory evaluations of community subjects. PARTICIPANTS: A convenience sample of 12 volunteers, average age 69.17 years. INTERVENTION: Baseline assessment was followed by randomized administration of a placebo, oxybutynin hydrochloride (5 and 10 mg), and diphenhydramine hydrochloride (50 mg) in test sessions separated by 1 week. MEASUREMENTS: Evaluation of cognitive performance with a 1-hour battery of pencil and paper, interviewer-administered, and computer-administered tests beginning 90 minutes after drug (or placebo) administration. RESULTS: Random regression analyses demonstrated that oxybutynin caused significant cognitive decrements on seven of 15 cognitive measures, and diphenhydramine caused decrements on five measures. The most sensitive measures for detecting the effects of oxybutynin hydrochloride were the Buschke Selective Reminding Test and Reaction Time. CONCLUSIONS: These findings demonstrate that oxybutynin can cause cognitive impairment and suggest that physicians prescribing it should monitor their patients to facilitate the early recognition of those who experience drug-related cognitive deficits. More generally, the findings demonstrate that systematic research with normal volunteers can identify cognitive toxicity not recognized during the process of drug development or postmarketing surveillance.

Identification of drug-related cognitive impairment in older individuals. Challenge studies with diphenhydramine.

The authors tested the use of repeated cognitive measures to identify those older individuals who experience cognitive decline after administration of a centrally acting medication. Subjects were 30 medically stable, older volunteers, mean age 71.4. Administration was a double-blind, placebo-controlled, crossover "challenge" from baseline to placebo, 50 mg, or 75 mg of diphenhydramine. More patients exhibited significant cognitive decrements after 75 mg of diphenhydramine than after placebo on the Buschke Selective Reminding Test Total Recall and the Trails B test. Data were consistent with models based on prediction intervals. Quantitative algorithms using prediction equations can characterize the normal limits of within-subject variability and define excessive cognitive change in elderly subjects, showing promise for use in monitoring patients to identify those who experience mild cognitive toxicity from prescribed medications.