Fusobacterium nucleatum infection modulates the transcriptome and epigenome of HCT116 colorectal cancer cells in an oxygen-dependent manner.

Fusobacterium nucleatum, a gram-negative oral bacterium, has been consistently validated as a strong contributor to the progression of several types of cancer, including colorectal (CRC) and pancreatic cancer. While previous in vitro studies have shown that intracellular F. nucleatum enhances malignant phenotypes such as cell migration, the dependence of this regulation on features of the tumor microenvironment (TME) such as oxygen levels are wholly uncharacterized. Here we examine the influence of hypoxia in facilitating F. nucleatum invasion and its effects on host responses focusing on changes in the global epigenome and transcriptome. Using a multiomic approach, we analyze epigenomic alterations of H3K27ac and global transcriptomic alterations sustained within a hypoxia and normoxia conditioned CRC cell line HCT116 at 24 h following initial infection with F. nucleatum. Our findings reveal that intracellular F. nucleatum activates signaling pathways and biological processes in host cells similar to those induced upon hypoxia conditioning in the absence of infection. Furthermore, we show that a hypoxic TME favors F. nucleatum invasion and persistence and therefore infection under hypoxia may amplify malignant transformation by exacerbating the effects induced by hypoxia alone. These results motivate future studies to investigate host-microbe interactions in tumor tissue relevant conditions that more accurately define parameters for targeted cancer therapies.

Open-Source Ultrasound Trainer for Healthcare Professionals: A Pilot Randomized Control Trial.

INTRODUCTION: This technical report describes the development of a high-fidelity, open-source ultrasound trainer and showcases its abilities through a proof-of-concept, pilot randomized control trial. The open-source ultrasound trainer (OSUT) aims to enhance anatomical visualization during ultrasound education. The OSUT can attach to any ultrasound transducer, uses minimal hardware, and is able to be used during live patient ultrasound examinations. METHODS: After viewing a standardized training video lecture, 24 incoming first-year medical students with no prior ultrasound experience were randomized into a control group given an ultrasound system or an intervention group given the OSUT in addition to an ultrasound system. Both groups were tasked with localizing the thyroid, abdominal aorta, and right kidney on a patient. Performance outcomes were structure localization time, ultrasound image accuracy, and preactivity and postactivity participant confidence. RESULTS: The OSUT decreased right kidney localization time (Kruskal-Wallis, P < 0.001), increased sonographer right kidney accuracy ratings (Mann-Whitney U , U = 10.5, P < 0.05), and increased confidence in structure identification (Mann-Whitney U , U = 37, P = 0.045) and overall ultrasound ability (Wilcoxon signed-rank test, P = 0.007). There was no significant change in localization time, accuracy ratings, or participant confidence for locating the thyroid and abdominal aorta. CONCLUSIONS: A high-fidelity, open-source ultrasound trainer was developed to aid healthcare professionals in learning diagnostic ultrasound. The study demonstrated the potential beneficial effects of the OSUT in localizing the right kidney, showcasing its adaptability and accessibility for ultrasound education for certain anatomical structures.

The Rising Tide of Point-of-Care Ultrasound (POCUS) in Medical Education: An Essential Skillset for Undergraduate and Graduate Medical Education.

As point-of-care ultrasound (POCUS) becomes an integral component of healthcare, both undergraduate and graduate medical POCUS education is urgently necessary in curricula. Despite the apparent need of POCUS curricula, there remains a lingering question: Are there evidence-based benefits to POCUS training in undergraduate and/or graduate medical education settings? Qualitative review of research was conducted to identify common themes for benefits of POCUS and the requirements and/or characteristics for effective POCUS educational curricula. Results for undergraduate medical education were separated into preclinical and clinical education. In preclinical POCUS education, POCUS education improves anatomy education and physical examination skills for sonographic assessment of abdominal, reproductive, cardiovascular, and renal structures. Further enhancement can be achieved via simulation devices that are generalized ultrasound simulation mannequins, one defined body region such as the abdomen, or local regions of interest such as the femoral triangle. In clinical undergraduate POCUS education, benefits involved greater performance on knowledge tests and general ultrasound competency in emergency medicine, surgical, family medicine, and physical medicine and rehabilitation clerkships. These studies also found improved comprehension of specific POCUS examinations such as those for ultrasound-guided injections, FAST, eFAST, and RUSH. Further integration of POCUS education into graduate medical education was found to successfully improve ultrasound knowledge and competency in both academic and military internal medicine residencies. One limitation of this study is that this article is a review resulting in no specific intervention being introduced. The resultant hypothesis of this systematic review cannot be tested; rather evidence-based recommendations are restricted to the currently available literature within the searched databases. From this review, it was found that the inclusion of a properly integrated POCUS curriculum can result in greater confidence in ultrasound use, increased knowledge of anatomy and basic sciences for various organ systems, improved ultrasound knowledge and performance in clinical clerkships, and offers improved confidence and knowledge in ultrasound during residency.

Anatomical Considerations for Gallbladder Sonography: A Cross-Sectional Study of CT Imaging by BMI Group.

Objective The purpose of this study was to establish an association between the body mass index (BMI) group and anatomical gallbladder position to aid novices in gallbladder sonography. Methods This was a cross-sectional, Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)-compliant study that examined the association between gender and the BMI group with quantitative gallbladder position measurements from computed tomography (CT) scans. Results A quantitative analysis determined that the gallbladder was positioned relatively higher and oriented more horizontally within the abdomen of individuals with obese BMI than those with normal BMI (p < 0.001), irrespective of gender. Additionally, the gallbladder was more obstructed by the rib cage in individuals with obese BMI than those with normal BMI (p = 0.007 for females and p < 0.001 for males). The gallbladder was significantly more horizontal in overweight males than females (p < 0.001) and more obstructed by the rib cage in obese males than females (p = 0.013). Conclusion This association provides ultrasound novices knowledge for a more targeted approach in localizing the gallbladder and evidence to recommend an intercostal approach for gallbladder sonography in obese patients.

Targeted Quantitative Mass Spectrometry Analysis of Protein Biomarkers From Previously Stained Single Formalin-Fixed Paraffin-Embedded Tissue Sections.

Formalin-fixed, paraffin-embedded tissues represent a majority of all biopsy specimens commonly analyzed by histologic or immunohistochemical staining with adhesive coverslips attached. Mass spectrometry (MS) has recently been used to precisely quantify proteins in samples consisting of multiple unstained formalin-fixed, paraffin-embedded sections. Here, we report an MS method to analyze proteins from a single coverslipped 4-µm section previously stained with hematoxylin and eosin, Masson trichrome, or 3,3'-diaminobenzidine-based immunohistochemical staining. We analyzed serial unstained and stained sections from non-small cell lung cancer specimens for proteins of varying abundance (PD-L1, RB1, CD73, and HLA-DRA). Coverslips were removed by soaking in xylene, and after tryptic digestion, peptides were analyzed by targeted high-resolution liquid chromatography with tandem MS with stable isotope-labeled peptide standards. The low-abundance proteins RB1 and PD-L1 were quantified in 31 and 35 of 50 total sections analyzed, respectively, whereas higher abundance CD73 and HLA-DRA were quantified in 49 and 50 sections, respectively. The inclusion of targeted ß-actin measurement enabled normalization in samples where residual stain interfered with bulk protein quantitation by colorimetric assay. Measurement coefficient of variations for 5 replicate slides (hematoxylin and eosin stained vs unstained) from each block ranged from 3% to 18% for PD-L1, from 1% to 36% for RB1, 3% to 21% for CD73, and 4% to 29% for HLA-DRA. Collectively, these results demonstrate that targeted MS protein quantification can add a valuable data layer to clinical tissue specimens after assessment for standard pathology end points.

Contrast-Enhanced Ultrasound Tumor Therapy With Abdominal Imaging Transducer.

A diagnostic ultrasound machine add-on module (AOM) was created to enable an off-the-shelf abdominal imaging transducer to perform contrast-enhanced therapeutic ultrasound. The AOM creates plane-wave ultrasound through an abdominal imaging transducer targeting intravascular microbubbles within tumors. This therapeutic antivascular ultrasound (AVUS) causes heating and cavitation effects that destroy tumor vasculature and starves it of nutrients. The AOM can switch between therapeutic and imaging modes for monitoring AVUS treatment. The therapeutic capability of the AOM was validated in murine hepatocellular carcinomas (HCC) grown in adult mice. Contrast-enhanced ultrasound imaging performed before and after the therapeutic treatment evaluated the AVUS response to the treatment. The peak enhancement (PE), perfusion index (PI), and area under the curve (AUC) were measured for the control and AOM treatment groups. The AOM group showed a substantial decrease in these parameters compared to the control group. The difference between the pre- and post-therapy was significant, (p < 0.001) for the AOM group and not significant (p > 0.5) for the control group. Tumor temperatures increased markedly for the AOM group with a thermal dose (CEM43) of 124.8 (±2.5). Histochemical analysis of the excised HCC samples revealed several hemorrhagic pools in tumors from the AOM group, absent in the tumors of the control group. These results demonstrate the theranostic potential of the AOM to induce and monitor vascular disruption within murine tumors.

Diastereo- and enantioselective synthesis of compounds with a trifluoromethyl- and fluoro-substituted carbon centre.

Molecules that contain one or more fluorine atoms are crucial to drug discovery. There are protocols available for the selective synthesis of different organofluorine compounds, including those with a fluoro-substituted or a trifluoromethyl-substituted stereogenic carbon centre. However, approaches for synthesizing compounds with a trifluoromethyl- and fluoro-substituent stereogenic carbon centre are far less common. This potentially impactful set of molecules thus remains severely underdeveloped. Here we introduce a catalytic regio-, diastereo- and enantioselective strategy for the preparation of homoallylic alcohols bearing a stereogenic carbon centre bound to a trifluoromethyl group and a fluorine atom. The process, which involves a polyfluoroallyl boronate and is catalysed by an in situ-formed organozinc complex, can be used for diastereodivergent preparation of tetrafluoro-monosaccharides, including ribose core analogues of the antiviral drug sofosbuvir (Sovaldi). Unexpected reactivity/selectivity profiles, probably originating from the trifluoromethyl- and fluoro-substituted carbon site, are discovered, foreshadowing other unique chemistries that remain unknown.

Mapping hydrologic alteration and ecological consequences in stream reaches of the conterminous United States.

Environmental flows are critical for balancing societal water needs with that of riverine ecosystems; however, data limitations often hinder the development of predictive relationships between anthropogenic modifications to streamflow regimes and ecological responses - these relationships are the basis for setting regional water policy standards for rivers. Herein, we present and describe a comprehensive dataset of modeled hydrologic alteration and consequences for native fish biodiversity, both mapped at the stream-reach resolution for the conterminous U.S. Using empirical observations of reference conditions and anthropogenically altered streamflow at over 7000 stream gauges, we developed a predictive model of hydrologic alteration, which was extended to >2.6 million stream reaches. We then used a previous nationwide assessment of ecological responses to hydrologic alteration to predict fish biodiversity loss in stream reaches resulting from streamflow modification. Validation efforts suggested hydrologic alteration models had satisfactory performance, whereas modeled ecological responses were susceptible to compounded errors. The dataset could ameliorate regional data deficits for setting environmental flow standards while providing tools for prioritizing streamflow protection or restoration.

A river ran through it: Floodplains as America's newest relict landform.

Artificial levees are a major human modification of river corridors, but we still do not have a clear understanding of how artificial levees affect floodplain extent at regional and larger scales. We estimated changes in river-floodplain connectivity due to artificial levees in the contiguous United States (CONUS) using a combination of artificial levee databases, delineations of floodplain areas, and deletion of artificial levees from topography. Our results indicate that artificial levees do not only decrease floodplain extent but also alter locations of floodplain connectivity. Anthropogenically connected and disconnected locations are similar in land cover and are predominantly, in decreasing order of extent, cultivated, wetland, forested, and developed land cover types, with more than 30% of the entire floodplain area in the CONUS cultivated or developed. This study indicates that artificial levees cause complex changes in river-floodplain connectivity and can increase flooded areas in some rivers.

Levees don't protect, they disconnect: A critical review of how artificial levees impact floodplain functions.

Despite the recognition of floodplain importance in the scientific community, floodplains are not afforded the same legal protection as river channels. In the United States alone, flood-related economic losses were much higher in the second half of the 20th century than the first half despite the expenditure of billions of dollars on flood defenses. Partially to blame are the low appraisal and understanding of human impacts to floodplain functions. Here, we explore the impacts of levees on floodplain functions and analyze case studies of floodplain restoration through levee removal. Floodplain functions include (1) fluxes of water, solutes, and particulate materials; (2) enhanced spatial heterogeneity of hydrology and biogeochemistry; (3) enhanced habitat abundance and diversity; (4) enhanced biomass and biodiversity; and (5) hazard mitigation. Case studies of floodplain restoration involving artificial levee adjustment are heavily concentrated in North America, Europe, and Japan, and those case studies assess floodplain functions within 30 years of restoration. In the United States, restoration through levee removal comprises less than 1% of artificial levee length and 1-2% of disconnected floodplains. In Europe, restoration effectiveness was severely limited by upstream flow regulation. Most case studies were impacted by stressors outside the study site and took place in lowland alluvial rivers. Reconfiguration was successful at achieving limited aims while reconnection set floodplains on a trajectory to more fully restore floodplain functions. Case studies illustrated the tension between restoration scale and study resolution in time and space as well as the role of site-specific characteristics in determining restoration outcomes. Numerous knowledge gaps surrounding the integrative relationships between floodplain functions must be addressed in future studies. The ubiquity of flow regulation demands that future floodplain restoration occur in a whole-of-basin manner. Monitoring of restoration must take place for longer periods of time and include multiple functions.

Biogeomorphic influences on river corridor resilience to wildfire disturbances in a mountain stream of the Southern Rockies, USA.

We examine a 9.4-km-long portion of a montane river corridor in the Southern Rockies, the upper 8 km of which burned in 2020. We focus on sediment storage in logjam backwaters and how spatial heterogeneity in the river corridor attenuates downstream fluxes of material following the wildfire. Wider portions of river corridor exhibit greater spatial heterogeneity, as reflected in multithread channel planform and more closely spaced abandoned beaver dams and channel-spanning logjams. Logjams in multithread reaches have greater volumes of backwater storage and store finer sediment than logjams in single-thread reaches. Despite substantial turnover of sediment in backwater storage during the first runoff season after the wildfire, the cumulative volume of sediment stored at 11 monitored logjams following the 2021 runoff season was 71% of the cumulative sediment volume at the logjams immediately after the fire. Floodplain vegetation regrowth was also faster and more complete at multithread reaches. Vegetation recovery contributed to overbank deposition in these reaches, in contrast to the bank erosion observed in single-thread reaches. More spatially heterogeneous portions of the river corridor appear to be disproportionately important in attenuating enhanced inputs of sediment following wildfire, and the cumulative effect of this attenuation across a river network likely enhances watershed-scale resilience to wildfire disturbance.

Proteomic characterisations of ulcerative colitis endoscopic biopsies associate with clinically relevant histological measurements of disease severity.

AIMS AND METHODS: Accurate protein measurements using formalin-fixed biopsies are needed to improve disease characterisation. This feasibility study used targeted and global mass spectrometry (MS) to interrogate a spectrum of disease severities using 19 ulcerative colitis (UC) biopsies. RESULTS: Targeted assays for CD8, CD19, CD132 (interleukin-2 receptor subunit gamma/common cytokine receptor gamma chain), FOXP3 (forkhead box P3) and IL17RA (interleukin 17 receptor A) were successful; however, assays for IL17A (interleukin 17A), IL23 (p19) (interleukin 23, alpha subunit p19) and IL23R (interleukin 23 receptor) did not permit target detection. Global proteome analysis (4200 total proteins) was performed to identify pathways associated with UC progression. Positive correlation was observed between histological scores indicating active colitis and neutrophil-related measurements (R2=0.42-0.72); inverse relationships were detected with cell junction targets (R2=0.49-0.71) and ß-catenin (R2=0.51-0.55) attributed to crypt disruption. An exploratory accuracy assessment with Geboes Score and Robarts Histopathology Index cut-offs produced sensitivities/specificities of 72.7%/75.0% and 100.0%/81.8%, respectively. CONCLUSIONS: Pathologist-guided MS assessments provide a complementary approach to histological scoring systems. Additional studies are indicated to verify the utility of this novel approach.

3-D modeling applications in ultrasound education: a systematic review.

Ultrasound offers a real-time 2-D view of structures within the human body. While many medical education programs have already dedicated a portion of their curriculum to ultrasound, others are concerned about cost, accessibility and limits to student practice. Student benefit may be affected by cognitive errors, which are in part owing to the mental heuristics required to visualize a 3-D structure by interpreting a 2-D image. A possible solution to eliminating subjectivity in ultrasound interpretation is the use of 3-D models to augment the traditional 2-D ultrasound experience. PubMed, Embase and Web of Science were searched for primary literature exploring relationships between 3-D modeling applications and their use in ultrasound education. The search and review process was guided by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. Overall, 14 of the included 16 studies indicated a significant improvement in medical education of ultrasound with the intervention of 3-D modeling applications. This systematic review confirms that 3-D modeling applications benefit student learning in ultrasound education while illuminating the need for more research in this field.

The changing face of floodplains in the Mississippi River Basin detected by a 60-year land use change dataset.

Floodplains provide essential ecosystem functions, yet >80% of European and North American floodplains are substantially modified. Despite floodplain changes over the past century, comprehensive, long-term land use change data within large river basin floodplains are limited. Long-term land use data can be used to quantify floodplain functions and provide spatially explicit information for management, restoration, and flood-risk mitigation. We present a comprehensive dataset quantifying floodplain land use change along the 3.3 million km2 Mississippi River Basin (MRB) covering 60 years (1941-2000) at 250-m resolution. We developed four unique products as part of this work, a(n): (i) Google Earth Engine interactive map visualization interface, (ii) Python code that runs in any internet browser, (iii) online tutorial with visualizations facilitating classroom code application, and (iv) instructional video demonstrating code application and database reproduction. Our data show that MRB's natural floodplain ecosystems have been substantially altered to agricultural and developed land uses. These products will support MRB resilience and sustainability goals by advancing data-driven decision making on floodplain restoration, buyout, and conservation scenarios.

Analysis of Immune Checkpoint Drug Targets and Tumor Proteotypes in Non-Small Cell Lung Cancer.

New therapeutics targeting immune checkpoint proteins have significantly advanced treatment of non-small cell lung cancer (NSCLC), but protein level quantitation of drug targets presents a critical problem. We used multiplexed, targeted mass spectrometry (MS) to quantify immunotherapy target proteins PD-1, PD-L1, PD-L2, IDO1, LAG3, TIM3, ICOSLG, VISTA, GITR, and CD40 in formalin-fixed, paraffin-embedded (FFPE) NSCLC specimens. Immunohistochemistry (IHC) and MS measurements for PD-L1 were weakly correlated, but IHC did not distinguish protein abundance differences detected by MS. PD-L2 abundance exceeded PD-L1 in over half the specimens and the drug target proteins all displayed different abundance patterns. mRNA correlated with protein abundance only for PD-1, PD-L1, and IDO1 and tumor mutation burden did not predict abundance of any protein targets. Global proteome analyses identified distinct proteotypes associated with high PD-L1-expressing and high IDO1-expressing NSCLC. MS quantification of multiple drug targets and tissue proteotypes can improve clinical evaluation of immunotherapies for NSCLC.

Regio- and Enantioselective Synthesis of Trifluoromethyl-Substituted Homoallylic α-Tertiary NH2 -Amines by Reactions Facilitated by a Threonine-Based Boron-Containing Catalyst.

A method for catalytic regio- and enantioselective synthesis of trifluoromethyl-substituted and aryl-, heteroaryl-, alkenyl-, and alkynyl-substituted homoallylic α-tertiary NH2 -amines is introduced. Easy-to-synthesize and robust N-silyl ketimines are converted to NH-ketimines in situ, which then react with a Z-allyl boronate. Transformations are promoted by a readily accessible l-threonine-derived aminophenol-based boryl catalyst, affording the desired products in up to 91 % yield, >98:2 α:γ selectivity, >98:2 Z:E selectivity, and >99:1 enantiomeric ratio. A commercially available aminophenol may be used, and allyl boronates, which may contain an alkyl-, a chloro-, or a bromo-substituted Z-alkene, can either be purchased or prepared by catalytic stereoretentive cross-metathesis. What is more, Z-trisubstituted allyl boronates may be used. Various chemo-, regio-, and diastereoselective transformations of the α-tertiary homoallylic NH2 -amine products highlight the utility of the approach; this includes diastereo- and regioselective epoxide formation/trichloroacetic acid cleavage to generate differentiated diol derivatives.

Accelerated instability testing reveals quantitative mass spectrometry overcomes specimen storage limitations associated with PD-L1 immunohistochemistry.

Immunohistochemistry (IHC) using formalin-fixed, paraffin embedded (FFPE) tissue is limited by epitope masking, posttranslational modification and immunoreactivity loss that occurs in stored tissue by poorly characterized mechanisms. Conformational epitopes recognized by many programmed-death-ligand-1 (PD-L1) IHC assays are particularly susceptible to degradation and provide an ideal model for understanding signal loss in stored FFPE tissue. Here we assessed 1206 tissue sections to evaluate environmental factors impacting immunoreactivity loss. PD-L1 IHC using four antibodies (22C3, 28-8, E1L3N, and SP142), raised against intracellular and extracellular epitopes, was assessed in stored FFPE tissue alongside quantitative mass spectrometry (MS). Global proteome analyses were used to assess proteome-wide oxidation across an inventory of 3041 protein groups (24,737 distinct peptides). PD-L1 quantitation correlated well with IHC expression on unaged sections (R2 = 0.744; P < 0.001), with MS demonstrating no loss of PD-L1 protein, even in sections with significant signal loss by IHC impacting diagnostic category. Clones 22C3 and 28-8 were most susceptible to signal loss, with E1L3N demonstrating the most robust signal (56%, 58%, and 33% reduction respectively; p < 0.05). Increased humidity and temperature resulted in significant acceleration of immunoreactivity loss, which was mitigated by storage with desiccant. MS demonstrated only modest oxidation of 274 methionine-containing peptides and aligned with IHC results suggesting peptide oxidation is not a major factor. These data imply immunoreactivity loss driven by humidity and temperature results in structural distortion of epitopes rendering them unsuitable for antibody binding following epitope retrieval. Limitations of IHC biomarker analysis from stored tissue sections may be mitigated by cost-effective use of desiccant when appropriate. In some scenarios, complementary MS is a preferred approach for retrospective analyses of archival FFPE tissue collections.

Preseason to Postseason Changes on the BTrackS Force Plate in a Sample of College Athletes.

CONTEXT: Balance testing is a vital component in the evaluation and management of sport-related concussion. Few studies have examined the use of objective, low-cost, force-plate balance systems and changes in balance after a competitive season. OBJECTIVE: To examine the extent of preseason versus postseason static balance changes using the Balance Tracking System (BTrackS) force plate in college athletes. DESIGN: Pretest, posttest design. SETTING: Athletic training facility. PARTICIPANTS: A total of 47 healthy, Division-I student-athletes (33 males and 14 females; age 18.4 [0.5] y, height 71.8 [10.8] cm, weight 85.6 [21.7] kg) participated in this study. MAIN OUTCOME MEASURES: Total center of pressure path length was measured preseason and postseason using the BTrackS force plate. A Wilcoxon signed-rank test was conducted to examine preseason and postseason changes. SEM and minimal detectable change were also calculated. RESULTS: There was a significant difference in center of pressure path length differed between preseason (24.6 [6.8] cm) and postseason (22.7 [5.4] cm) intervals (P = .03), with an SEM of 3.8 cm and minimal detectable change of 10.5 cm. CONCLUSIONS: Significant improvements occurred for center of pressure path length after a competitive season, when assessed using the BTrackS in a sample of college athletes. Further research is warranted to determine the effectiveness of the BTrackS as a reliable, low-cost alternative to force-plate balance systems. In addition, clinicians may need to update baseline balance assessments more frequently to account for improvements.

Bioanalytical Assessment of Plasma Concentrations of Angiotensin-Converting Enzyme II Inhibitors and Angiotensin Receptor Blockers: A Pilot Study Among Patients Hospitalized With Acute Heart Failure.

BACKGROUND: Although angiotensin-converting enzyme II inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) improve chronic heart failure (HF) outcomes, their potential harms and benefits in acute HF (AHF) is less clear. STUDY QUESTION: We explored the relationship between ACEI or ARB plasma concentrations among patients with AHF with in-hospital change in estimated glomerular filtration rate (eGFR). DATA SOURCES AND STUDY DESIGN: From August 2016-June 2017, patients with AHF prescribed an outpatient ACEI or ARB were enrolled before AHF treatment. All patients were given twice their home dose of diuretic intravenously and received clinical care at the discretion of the medical team. Of 61 patients in the parent study, saved plasma from 34 who were prescribed an outpatient ACEI or ARB was included in this substudy. MEASURES AND OUTCOMES: Liquid chromatography-tandem mass spectrometry was performed to assess ACEI or ARB plasma concentrations before AHF treatment. Change in eGFR was computed using the Chronic Kidney Disease Epidemiology Collaboration equation, which adjusts for age, sex, and race; diuretic dose and enrollment eGFR were used to adjust for HF severity. Multiple linear regression adjusting for enrollment eGFR and diuretic dose was performed to examine the relationship between drug concentration (undetectable/low vs. in/above-range) and in-hospital change in eGFR. RESULTS: Of 34 patients with AHF, median age was 63 years (interquartile range, 58-78 years), 19 (55.9%) were women, median eGFR at enrollment was 55.6 mL/min (interquartile range, 35.2-75.3 mL/min), and for 11 (32.4%), no ACEI or ARB was detectable in plasma. Medication concentrations in- or above-reference range were associated with in-hospital decrease in eGFR of 8.3 mL/min (95% confidence interval, 15.3-1.3 mL/min decrease), after adjusting for enrollment eGFR and diuretic treatment. CONCLUSIONS: Bioanalytical assessment of medication levels may be useful to guide in-hospital ACEI and ARB therapy for patients with AHF.

A Catalytic Approach for Enantioselective Synthesis of Homoallylic Alcohols Bearing a Z-Alkenyl Chloride or Trifluoromethyl Group. A Concise and Protecting Group-Free Synthesis of Mycothiazole.

A protecting group-free strategy is presented for diastereo- and enantioselective routes that can be used to prepare a wide variety of Z-homoallylic alcohols with significantly higher efficiency than is otherwise feasible. The approach entails the merger of several catalytic processes and is expected to facilitate the preparation of bioactive organic molecules. More specifically, Z-chloro-substituted allylic pinacolatoboronate is first obtained through stereoretentive cross-metathesis between Z-crotyl-B(pin) (pin = pinacolato) and Z-dichloroethene, both of which are commercially available. The organoboron compound may be used in the central transformation of the entire approach, an α- and enantioselective addition to an aldehyde, catalyzed by a proton-activated, chiral aminophenol-boryl catalyst. Catalytic cross-coupling can then furnish the desired Z-homoallylic alcohol in high enantiomeric purity. The olefin metathesis step can be carried out with substrates and a Mo-based complex that can be purchased. The aminophenol compound that is needed for the second catalytic step can be prepared in multigram quantities from inexpensive starting materials. A significant assortment of homoallylic alcohols bearing a Z-F3C-substituted alkene can also be prepared with similar high efficiency and regio-, diastereo-, and enantioselectivity. What is more, trisubstituted Z-alkenyl chloride moiety can be accessed with similar efficiency albeit with somewhat lower α-selectivity and enantioselectivity. The general utility of the approach is underscored by a succinct, protecting group-free, and enantioselective total synthesis of mycothiazole, a naturally occurring anticancer agent through a sequence that contains a longest linear sequence of nine steps (12 steps total), seven of which are catalytic, generating mycothiazole in 14.5% overall yield.