Emerging priorities and concerns in the wake of the COVID-19 pandemic: qualitative and quantitative findings from a United States national survey.

Purpose: The present study examines how the coronavirus disease 2019 (COVID-19) experience affected values and priorities. Methods: This cross-sectional study collected data between January and April 2023, from 1,197 individuals who are chronically ill or part of a general population sample. Using open-ended prompts and closed-ended questions, we investigated individuals' perceptions about COVID-19-induced changes in what quality of life means to them, what and who are important, life focus, and changes in norms and stressors. Data analyses included content and psychometric analysis, leading to latent profile analysis (LPA) to characterize distinct groups, and analysis of variance and chi-squared to compare profile groups' demographic characteristics. Results: About 75% of the study sample noted changes in values and/or priorities, particularly in the greater prominence of family and friends. LPA yielded a four-profile model that fit the data well. Profile 1 (Index group; 64% of the sample) had relatively average scores on all indicators. Profile 2 (COVID-Specific Health & Resignation to Isolation Attributable to COVID-19; 5%) represented COVID-19-specific preventive health behaviors along with noting the requisite isolation and disengagement entailed in the social distancing necessary for COVID-19 prevention. Profile 3 (High Stress, Low Trust; 25%) represented high multi-domain stress, with the most elevated scores both on focusing on being true to themselves and perceiving people to be increasingly uncivil. Profile 4 (Active in the World, Low Trust; 6%) was focused on returning to work and finding greater meaning in their activities. These groups differed on race, marital status, difficulty paying bills, employment status, number of times they reported having had COVID-19, number of COVID-19 boosters received, whether they had Long COVID, age, BMI, and number of comorbidities. Conclusion: Three years after the beginning of the worldwide COVID-19 pandemic, its subjective impact is notable on most study participants' conceptualization of quality of life, priorities, perspectives on social norms, and perceived stressors. The four profile groups reflected distinct ways of dealing with the long-term effects of COVID-19.

Joint regional uptake quantification of thorium-227 and radium-223 using a multiple-energy-window projection-domain quantitative SPECT method.

Thorium-227 (227Th)-based α-particle radiopharmaceutical therapies (α-RPTs) are currently being investigated in several clinical and pre-clinical studies. After administration, 227Th decays to 223Ra, another α-particle-emitting isotope, which redistributes within the patient. Reliable dose quantification of both 227Th and 223Ra is clinically important, and SPECT may perform this quantification as these isotopes also emit X- and γ-ray photons. However, reliable quantification is challenging for several reasons: the orders-of-magnitude lower activity compared to conventional SPECT, resulting in a very low number of detected counts, the presence of multiple photopeaks, substantial overlap in the emission spectra of these isotopes, and the image-degrading effects in SPECT. To address these issues, we propose a multiple-energy-window projection-domain quantification (MEW-PDQ) method that jointly estimates the regional activity uptake of both 227Th and 223Ra directly using the SPECT projection data from multiple energy windows. We evaluated the method with realistic simulation studies conducted with anthropomorphic digital phantoms, including a virtual imaging trial, in the context of imaging patients with bone metastases of prostate cancer who were treated with 227Th-based α-RPTs. The proposed method yielded reliable (accurate and precise) regional uptake estimates of both isotopes and outperformed state-of-the-art methods across different lesion sizes and contrasts, as well as in the virtual imaging trial. This reliable performance was also observed with moderate levels of intra-regional heterogeneous uptake as well as when there were moderate inaccuracies in the definitions of the support of various regions. Additionally, we demonstrated the effectiveness of using multiple energy windows and the variance of the estimated uptake using the proposed method approached the Cramér-Rao-lower-bound-defined theoretical limit. These results provide strong evidence in support of this method for reliable uptake quantification in 227Th-based α-RPTs.

Positionally distinct interferon stimulated dermal immune acting fibroblasts promote neutrophil recruitment in Sweet's syndrome.

Sweet's syndrome is a poorly understood inflammatory skin disease characterized by neutrophil infiltration to the dermis. Single-nucleus and bulk transcriptomics of archival clinical samples of Sweet's syndrome revealed a prominent interferon signature in Sweet's syndrome skin that was reduced in tissue from other neutrophilic dermatoses. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured primary human dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, single-molecule resolution spatial transcriptomics of skin in Sweet's syndrome identified positionally distinct immune acting fibroblasts that included a CXCL1+ subset proximal to neutrophils and a CXCL12+ subset distal to the neutrophilic infiltrate. This study defines the cellular landscape of neutrophilic dermatoses and suggests dermal immune acting fibroblasts play a role in the pathogenesis of Sweet's syndrome through recognition of type I interferons.

Subjective cognitive concerns, APOE ε4, PTSD symptoms, and risk for dementia among older veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups. METHODS: Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older. RESULTS: PTSD symptoms (B = 0.50-0.52, p < 1E-250) and probable TBI (B = 0.05-0.19, p = 1.51E-07 - 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13-1.21), APOE ε4 (HR = 1.73-2.05) and SCC (HR = 1.18-1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18). CONCLUSIONS: The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors.

The Effect of Retinoic Acid on Neutrophil Innate Immune Interactions With Cutaneous Bacterial Pathogens.

Vitamin A and its biologically active derivative, retinoic acid (RA), are important for many immune processes. RA, in particular, is essential for the development of immune cells, including neutrophils, which serve as a front-line defense against infection. While vitamin A deficiency has been linked to higher susceptibility to infections, the precise role of vitamin A/RA in host-pathogen interactions remains poorly understood. Here, we provided evidence that RA boosts neutrophil killing of methicillin-resistant Staphylococcus aureus (MRSA). RA treatment stimulated primary human neutrophils to produce reactive oxygen species, neutrophil extracellular traps, and the antimicrobial peptide cathelicidin (LL-37). Because RA treatment was insufficient to reduce MRSA burden in an in vivo murine model of skin infection, we expanded our analysis to other infectious agents. RA did not affect the growth of a number of common bacterial pathogens, including MRSA, Escherichia coli K1 and Pseudomonas aeruginosa; however, RA directly inhibited the growth of group A Streptococcus (GAS). This antimicrobial effect, likely in combination with RA-mediated neutrophil boosting, resulted in substantial GAS killing in neutrophil killing assays conducted in the presence of RA. Furthermore, in a murine model of GAS skin infection, topical RA treatment showed therapeutic potential by reducing both skin lesion size and bacterial burden. These findings suggest that RA may hold promise as a therapeutic agent against GAS and perhaps other clinically significant human pathogens.

A morphoscopic exploration of cranial sexual dimorphism among modern South Africans using computed tomography scans.

Continual re-evaluation of standards for forensic anthropological analyses are necessary, particularly as new methods are explored or as populations change. Indian South Africans are not a new addition to the South African population; however, a paucity of skeletal material is available for analysis from medical school collections, which has resulted in a lack of information on the sexual dimorphism in the crania. For comparable data, computed tomography scans of modern Black, Coloured and White South Africans were included in addition to Indian South Africans. Four cranial morphoscopic traits, were assessed on 408 modern South Africans (equal sex and population distribution). Frequencies, Chi-squared tests, binary logistic regression and random forest modelling were used to assess the data. Males were more robust than females for all populations, while White South African males were the most robust, and Black South African females were the most gracile. Population differences were noted among most groups for at least two variables, necessitating the creation of populations-specific binary logistic regression equations. Only White and Coloured South Africans were not significantly different. Indian South Africans obtained the highest correct classifications for binary logistic regression (94.1%) and random forest modelling (95.7%) and Coloured South Africans had the lowest correct classifications (88.8% and 88.0%, respectively). This study provides a description of the patterns of sexual dimorphism in four cranial morphoscopic traits in the current South African population, as well as binary logistic regression functions for sex estimation of Black, Coloured, Indian and White South Africans.

Phenome-wide association study identifies new clinical phenotypes associated with Staphylococcus aureus infections.

BACKGROUND: Phenome-Wide Association study (PheWAS) is a powerful tool designed to systematically screen clinical observations derived from medical records (phenotypes) for association with a variable of interest. Despite their usefulness, no systematic screening of phenotypes associated with Staphylococcus aureus infections (SAIs) has been done leaving potential novel risk factors or complications undiscovered. METHOD AND COHORTS: We tailored the PheWAS approach into a two-stage screening procedure to identify novel phenotypes correlating with SAIs. The first stage screened for co-occurrence of SAIs with other phenotypes within medical records. In the second stage, significant findings were examined for the correlations between their age of onset with that of SAIs. The PheWAS was implemented using the medical records of 754,401 patients from the Marshfield Clinic Health System. Any novel associations discovered were subsequently validated using datasets from TriNetX and All of Us, encompassing 109,884,571 and 118,538 patients respectively. RESULTS: Forty-one phenotypes met the significance criteria of a p-value < 3.64e-5 and odds ratios of > 5. Out of these, we classified 23 associations either as risk factors or as complications of SAIs. Three novel associations were discovered and classified either as a risk (long-term use of aspirin) or complications (iron deficiency anemia and anemia of chronic disease). All novel associations were replicated in the TriNetX cohort. In the All of Us cohort, anemia of chronic disease was replicated according to our significance criteria. CONCLUSIONS: The PheWAS of SAIs expands our understanding of SAIs interacting phenotypes. Additionally, the novel two-stage PheWAS approach developed in this study can be applied to examine other disease-disease interactions of interest. Due to the possibility of bias inherent in observational data, the findings of this study require further investigation.

Self-Reported Hypersensitivity to Smells: Objective Evidence for Hyposmia, not Hyperosmia.

OBJECTIVE: To compare, using state-of-the-art psychophysical tests, the olfactory function of patients complaining and not complaining of olfactory hypersensitivity. STUDY DESIGN: Retrospective cross-sectional. SETTING: The Smell and Taste Center at the University of Pennsylvania. METHODS: University of Pennsylvania Smell Identification Test (UPSIT) scores were obtained from 148 patients complaining of hyperosmia and 494 patients with no such complaints; detection threshold test scores were obtained from 77 and 483 patients of these respective groups. The effects of subject group, age, and sex on the test scores were assessed using analyses of variance. Categorical variables were evaluated by χ2. Responses to items within a detailed intake questionnaire, for example, the Beck Depression Inventory (BDI-II), were also evaluated. RESULTS: Unexpectedly, those complaining of hyperosmia had lower olfactory test scores than those with no such complaints (respective UPSIT means [95% confidence interval [CIs]] = 27.86 (26.85, 28.87) and 32.19 (31.67, 32.71); P < .001; respective threshold means (log vol/vol) = -4.49 (-4.89, -4.09) and -5.22 (-5.36, -5.06); P < .001). Remarkably, 70.95% of the self-identified hyperosmics exhibited mild to severe microsmia. The hyposmia complainers also exhibited elevated BDI scores (11.02 [9.53, 12.51] vs 7.58 [6.80, 8.34]). CONCLUSION: When objectively tested, many patients who complain of hypersensitivity to odors are actually less sensitive to them. The basis of this phenomenon is unclear. It could reflect the presence of emotionally disturbing altered smell sensations, or one or more comorbidities, such as hypochondria or osmophobia. These findings point to the importance of objective testing of persons with complaints of chemosensory dysfunction and reiterate the inaccuracy of self-reports.

Effect of Different Isolation Methods on Bioaerosol Distribution: An In Vitro Study.

Purpose: The purposes of this in vitro study were to evaluate the effect of three isolation methods to mitigate bioaerosols during stainless steel crown (SSC) preparations and assess the distribution of Streptococcus mutans by aerosolization in closed-room operatories. Methods: Melamine teeth coated in laboratory-grown S. mutans biofilm were prepared for SSCs using three different isolation methods. Agar plates were placed in five locations throughout the operatory and opened during each preparation as well as for 10 minutes immediately following to collect aerosolized S. mutans. Bacterial colonies were counted after incubating plates for 48 hours. Data were analyzed for differences between the isolation method and plate locations. Results: Bacterial colony counts for teeth prepared using high-volume evacuation suction (HVE) with dental dam (DD) isolation were statistically significantly higher than for those prepared using HVE with a DryShield®(DS) and HVE with no isolation at the assistant (A) (P<0.001), operator face shield (FS) (P<0.001), and patient (Pt) (P=0.002) locations. No significant differences were found among isolation methods for parent (Pa) or rear delivery (RD) locations. The location that produced the most bacterial colony counts using HVE with DD isolation was FS (P<0.001), followed by A (P=0.04), Pt (P<0.001), and RD and Pa (P<0.001). Counts produced from teeth prepared with DS isolation were significantly higher at the Pt location than the A (P<0.001), FS (P=0.002), RD (P<0.001), and Pa (P=0.008) locations. Conclusion: The use of dental dam with high-volume evacuation suction during stainless steel crown preparations increased bioaerosols near the procedure, while dental evacuation systems (DryShield®) may effectively limit their spread.

Increasing Adoption of Left Atrial Appendage Occlusion in Isolated Coronary Artery Bypass Grafting.

BACKGROUND: Recent randomized trial data showed fewer strokes with left atrial appendage occlusion (LAAO) following cardiac surgery in patients with atrial fibrillation. We developed a quality initiative to increase LAAO adoption. METHODS: Among 11,099 patients undergoing isolated CABG between January 2019-March 2021 at 33 hospitals in Michigan, those with atrial fibrillation undergoing first-time, on-pump CABG were eligible (n=1,241). A goal LAAO rate of 75% was selected as a quality improvement target through a statewide collaborative. An interrupted time series analysis evaluated the change in LAAO rate before (January-December 2019) versus after (January 2020-March 2021) implementation. RESULTS: Implementation of the quality metric improved LAAO rate from 61% (357/581) before to 79% (520/660) after implementation (p<0.001). Compared to patients not undergoing concomitant LAAO, LAAO patients (71%, 877/1,241) were older, more frequently male, and had a lower STS-PROM (2.9±3.5% vs. 3.7±5.7%, p=0.003), while other baseline characteristics including CHA2DS2-VASc scores were similar. Mean bypass and cross-clamp times were 7 and 6 minutes longer, respectively, in the LAAO group among those who did not undergo concomitant ablation. Operative mortality, major morbidity, blood product administration, and thromboembolic events were similar between groups. Interrupted time series analysis showed a significant increase in LAAO rate after implementation (p=0.009). CONCLUSIONS: LAAO in patients with atrial fibrillation undergoing isolated CABG did not add operative risk versus isolated CABG without LAAO. A statewide quality improvement initiative was successful in increasing the rate of concomitant LAAO and could be further evaluated as a potential quality metric in cardiac surgery.

An innovative approach to aligning healthcare with what matters most to patients: A hybrid type 1 trial protocol of patient priorities care for older adults with multiple chronic conditions.

BACKGROUND: Providing healthcare for older adults with multiple chronic conditions (MCC) is challenging. Polypharmacy and complex treatment plans can lead to high treatment burden and risk for adverse events. For clinicians, managing the complexities of patients with MCC leaves little room to identify what matters and align care options with patients' health priorities. New care approaches are needed to navigate these challenges. In this clinical trial, we evaluate implementation and effectiveness outcomes of an innovative, structured, patient-centered care approach (Patient Priorities Care; PPC) for reducing treatment burden and aligning health care decisions with the health priorities of older adults with MCC. METHODS: This is a multisite, assessor-blind, two-arm, parallel hybrid type 1 randomized controlled trial. We are enrolling 396 older (65+) Veterans with MCC who receive primary care at the Veterans Affairs Medical Center. Veterans are randomly assigned to either PPC or usual care. In the PPC arm, Veterans have a brief telephone call with a study facilitator to identify their personal health priorities. Then, primary care providers use this information to align healthcare with Veteran priorities during their established clinic appointments. Data are collected at baseline and 4-month follow up to assess for changes in treatment burden and use of home and community services. Formative and summative evaluations are also collected to assess for implementation outcomes according to Proctor's implementation framework. CONCLUSIONS: This work has the potential to significantly improve the standard of care by personalizing healthcare and helping patients achieve what is most important to them.

MYC and HSF1 Cooperate to Drive PLK1 inhibitor Sensitivity in High Grade Serous Ovarian Cancer.

Ovarian cancer is a deadly female cancer with high rates of recurrence. The primary treatment strategy for patients is platinum-based therapy regimens that almost universally develop resistance. Consequently, new therapeutic avenues are needed to overcome the plateau that current therapies have on patient outcomes. We describe a gene amplification involving both HSF1 and MYC, wherein these two genes on chromosome 8q are co-amplified in over 7% of human tumors that is enriched to over 30% of patients with ovarian cancer. We further found that HSF1 and MYC transcriptional activity is correlated in human tumors and ovarian cancer cell lines, suggesting they may cooperate in ovarian cancer cells. CUT&RUN for HSF1 and MYC in co-amplified ovarian cancer cells revealed that HSF1 and MYC have overlapping binding at a substantial number of locations throughout the genome where their binding peaks are near identical. Consistent with these data, a protein-protein interaction between HSF1 and MYC was detected in ovarian cancer cells, implying these two transcription factors have a molecular cooperation. Further supporting their cooperation, growth of HSF1-MYC co-amplified ovarian cancer cells were found to be dependent on both HSF1 and MYC. In an attempt to identify a therapeutic target that could take advantage of this dependency on both HSF1 and MYC, PLK1 was identified as being correlated with HSF1 and MYC in primary human tumor specimens, consistent with a previously established effect of PLK1 on HSF1 and MYC protein levels. Targeting PLK1 with the compound volasertib (BI-6727) revealed a greater than 200-fold increased potency of volasertib in HSF1-MYC co-amplified ovarian cancer cells compared to ovarian cancer cells wild-type HSF1 and MYC copy number, which extended to several growth assays, including spheroid growth. Volasertib, and other PLK1 inhibitors, have not shown great success in clinical trials and this study suggests that targeting PLK1 may be viable in a precision medicine approach using HSF1-MYC co-amplification as a biomarker for response.

Comparison of stereotactic brain biopsy techniques in dogs: neuronavigation, 3D-printed guides, and neuronavigation with 3D-printed guides.

The objective of this research was to compare two previously described stereotactic brain biopsy (SBB) techniques, three-dimensional skull contoured guides (3D-SCGs) and neuronavigation with Brainsight, to a novel SBB technique using Brainsight combined with a 3D-printed headframe (BS3D-HF) to improve the workflow of SBB in dogs. This was a prospective methods comparison with five canine cadavers of different breeds and size. Initial helical CT was performed on cadavers with fiducial markers in place. Ten different target points were randomly selected for each method. The headframe for the BS3D-HF was designed and printed. Trajectories were planned for each method. Steinmann pins (SPs) were placed into the target points using the planned trajectories for each method, and CT was repeated (post CT). Accuracy was assessed by overlaying the initial CT onto the post CT and measuring the difference of the planned target point to the SP placement. For 3D-SCG, the median deviation was 2.48 mm (0.64-4.04). With neuronavigation, the median deviation was 3.28 mm (1.04-4.64). For BS3D-HF, the median deviation was 14.8 mm (8.87-22.1). There was no significant difference between 3D-SCG and neuronavigation for the median deviation (p = 0.42). When comparing BS3D-HF to 3D-SCG, there was a significant difference in the median deviation (p < 0.0001). Additionally, when comparing BS3D-HF to neuronavigation, there was a significant difference for the median deviation (p < 0.0001). Our findings concluded that both 3D-SCGs and neuronavigation were accurate for SBB, however BS3D-HF was not. Although feasible, the current BS3D-HF technique requires further refinement before it can be recommended for use for SBB in dogs.

3D vector MR elastography applications in small organs.

BACKGROUND: Magnetic resonance elastography (MRE) is a rapidly developing medical imaging technique that allows for quantitative assessment of the biomechanical properties of the tissue. MRE is now regarded as the most accurate noninvasive test for detecting and staging liver fibrosis. A two-dimensional (2D MRE) acquisition version is currently deployed at >2000 locations worldwide. 2D MRE allows for the evaluation of the magnitude of the complex shear modulus, also referred to as stiffness. The development of 3D vector MRE has enabled researchers to assess the biomechanical properties of small organs where wave propagation cannot be adequately analyzed with the 2D MRE imaging approach used in the liver. In 3D vector MRE, the shear waves are imaged and processed throughout a 3D volume and processed with an algorithm that accounts for wave propagation in any direction. Additionally, the motion is also imaged in x, y, and z directions at each voxel, allowing for more advanced processing to be applied. PURPOSE: This review describes the technical principles of 3D vector MRE, surveys its clinical applications in small organs, and discusses potential clinical significance of 3D vector MRE. CONCLUSION: 3D vector MRE is a promising tool for characterizing the biomechanical properties of small organs such as the uterus, pancreas, thyroid, prostate, and salivary glands. However, its potential has not yet been fully explored.

Improved quantification of tumor adhesion in meningiomas using MR elastography-based slip interface imaging.

Meningiomas, the most prevalent primary benign intracranial tumors, often exhibit complicated levels of adhesion to adjacent normal tissues, significantly influencing resection and causing postoperative complications. Surgery remains the primary therapeutic approach, and when combined with adjuvant radiotherapy, it effectively controls residual tumors and reduces tumor recurrence when complete removal may cause a neurologic deficit. Previous studies have indicated that slip interface imaging (SII) techniques based on MR elastography (MRE) have promise as a method for sensitively determining the presence of tumor-brain adhesion. In this study, we developed and tested an improved algorithm for assessing tumor-brain adhesion, based on recognition of patterns in MRE-derived normalized octahedral shear strain (NOSS) images. The primary goal was to quantify the tumor interfaces at higher risk for adhesion, offering a precise and objective method to assess meningioma adhesions in 52 meningioma patients. We also investigated the predictive value of MRE-assessed tumor adhesion in meningioma recurrence. Our findings highlight the effectiveness of the improved SII technique in distinguishing the adhesion degrees, particularly complete adhesion. Statistical analysis revealed significant differences in adhesion percentages between complete and partial adherent tumors (p = 0.005), and complete and non-adherent tumors (p<0.001). The improved technique demonstrated superior discriminatory ability in identifying tumor adhesion patterns compared to the previously described algorithm, with an AUC of 0.86 vs. 0.72 for distinguishing complete adhesion from others (p = 0.037), and an AUC of 0.72 vs. 0.67 for non-adherent and others. Aggressive tumors exhibiting atypical features showed significantly higher adhesion percentages in recurrence group compared to non-recurrence group (p = 0.042). This study validates the efficacy of the improved SII technique in quantifying meningioma adhesions and demonstrates its potential to affect clinical decision-making. The reliability of the technique, coupled with potential to help predict meningioma recurrence, particularly in aggressive tumor subsets, highlights its promise in guiding treatment strategies.

Empagliflozin's role in reducing ventricular repolarization heterogeneity: insights into cardiovascular mortality decline from the EMPATHY-HEART trial.

BACKGROUND: The incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM) than in the general population. Strategies for the prevention of fatal arrhythmias are often insufficient, highlighting the need for additional non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index measures variations in ventricular repolarization and has emerged as a promising predictor for severe ventricular arrhythmias. Although the EMPA-REG trial reported reduced cardiovascular mortality with empagliflozin, the underlying mechanisms remain unclear. This study investigates the potential of empagliflozin in mitigating cardiac electrical instability in patients with T2DM and coronary heart disease (CHD) by examining changes in TWH. METHODS: Participants were adult outpatients with T2DM and CHD who exhibited TWH > 80 µV at baseline. They received a 25 mg daily dose of empagliflozin and were evaluated clinically including electrocardiogram (ECG) measurements at baseline and after 4 weeks. TWH was computed from leads V4, V5, and V6 using a validated technique. The primary study outcome was a significant (p < 0.05) change in TWH following empagliflozin administration. RESULTS: An initial review of 6,000 medical records pinpointed 800 patients for TWH evaluation. Of these, 412 exhibited TWH above 80 µV, with 97 completing clinical assessments and 90 meeting the criteria for high cardiovascular risk enrollment. Empagliflozin adherence exceeded 80%, resulting in notable reductions in blood pressure without affecting heart rate. Side effects were generally mild, with 13.3% experiencing Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced mean TWH from 116 to 103 µV (p = 0.01). CONCLUSIONS: The EMPATHY-HEART trial preliminarily suggests that empagliflozin decreases heterogeneity in ventricular repolarization among patients with T2DM and CHD. This reduction in TWH may provide insight into the mechanism behind the decreased cardiovascular mortality observed in previous trials, potentially offering a therapeutic pathway to mitigate the risk of severe arrhythmias in this population. TRIAL REGISTRATION: NCT: 04117763.

Efficient carbene transfer reactivity mediated by Fe(II) complexes supported by bulky alkoxides.

Herein we describe the stoichiometric and catalytic carbene-transfer reactivity of iron(II) alkoxide complexes with iodonium ylide precursors. Treatment of PhIC(CO2Me)2 with styrene in the presence of catalytic amounts of several different Fe(OR)2(THF)2 precursors results in efficient cyclopropanation for a variety of styrenes. Computational and reactivity studies suggest a novel remote metallocarbene/vinyl radical intermediate, Fe(OR)2(κ2-(OC(OMe))2C), which could be responsible for the reactive nature of the catalyst.

Converging cytokine and metabolite networks shape asymmetric T cell fate at the term human maternal-fetal interface.

Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI) which affect T cell programming, but the identities (i.e., memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as pro-inflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of co-stimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although pro-inflammatory molecules elicit T cell effector functions, we show that additional cytokine (TGF-ß1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, we demonstrate an additional facet of fetal tolerance, wherein T cells are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments where they are enriched.

Image-domain material decomposition for dual-energy CT using unsupervised learning with data-fidelity loss.

BACKGROUND: Dual-energy computed tomography (DECT) and material decomposition play vital roles in quantitative medical imaging. However, the decomposition process may suffer from significant noise amplification, leading to severely degraded image signal-to-noise ratios (SNRs). While existing iterative algorithms perform noise suppression using different image priors, these heuristic image priors cannot accurately represent the features of the target image manifold. Although deep learning-based decomposition methods have been reported, these methods are in the supervised-learning framework requiring paired data for training, which is not readily available in clinical settings. PURPOSE: This work aims to develop an unsupervised-learning framework with data-measurement consistency for image-domain material decomposition in DECT. METHODS: The proposed framework combines iterative decomposition and deep learning-based image prior in a generative adversarial network (GAN) architecture. In the generator module, a data-fidelity loss is introduced to enforce the measurement consistency in material decomposition. In the discriminator module, the discriminator is trained to differentiate the low-noise material-specific images from the high-noise images. In this scheme, paired images of DECT and ground-truth material-specific images are not required for the model training. Once trained, the generator can perform image-domain material decomposition with noise suppression in a single step. RESULTS: In the simulation studies of head and lung digital phantoms, the proposed method reduced the standard deviation (SD) in decomposed images by 97% and 91% from the values in direct inversion results. It also generated decomposed images with structural similarity index measures (SSIMs) greater than 0.95 against the ground truth. In the clinical head and lung patient studies, the proposed method suppressed the SD by 95% and 93% compared to the decomposed images of matrix inversion. CONCLUSIONS: Since the invention of DECT, noise amplification during material decomposition has been one of the biggest challenges, impeding its quantitative use in clinical practice. The proposed method performs accurate material decomposition with efficient noise suppression. Furthermore, the proposed method is within an unsupervised-learning framework, which does not require paired data for model training and resolves the issue of lack of ground-truth data in clinical scenarios.