A pilot study of longitudinal changes in neurocognition, white matter hyperintensities, and cortical thickness in atrial fibrillation patients following catheter ablation vs medical management.

Background: Cerebral microembolization and atrophy complicate atrial fibrillation (AF). Objectives: We aimed to compare changes in neuroimaging findings between AF patients treated with catheter ablation and those treated with medical therapy. Methods: In this pilot study, we evaluated differences in the change in regional white matter hyperintensity burden (WMHb) and cognitive function from baseline to 6 weeks and 1 year in patients treated with AF ablation (n = 12) and patients treated with medical management alone (n = 11). Change in cortical thickness over time in Alzheimer's disease (AD) risk, aging-associated, and shared AD risk/aging regions was also compared between groups. Results: The mean age was 69.7 ± 5.0 years, 78% of patients were male, 39% had persistent AF, and all received oral anticoagulation. There were no significant differences between groups in the change in cognitive function. At 6 weeks, there were no significant differences in periventricular WMHb changes between groups (0.00 vs 0.04, P = .12), but changes in attention/concentration were inversely correlated with periventricular (P = .01) and total (P = .03) WMHb. Medical management patients demonstrated significantly greater cortical thinning in AD risk regions from baseline to 1 year (P = .003). Conclusions: AF patients who underwent ablation demonstrated less cortical thinning in regions associated with AD risk than patients treated with medical therapy. Larger, prospective studies are needed to better understand the relationship between AF therapies and the development of cognitive decline.

Natural Killer Cell Dysfunction in Premenopausal BRCA1 Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis.

BACKGROUND: Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in BRCA1 mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline BRCA1 mutation in the context of cancer immunosurveillance of CD3- CD56+ natural killer (NK) cells. METHODS: Premenopausal BRCA1 mutation carriers versus age-matched non-carriers were compared. Daily urinary 5ß-pregnanediol levels were used to determine progesterone metabolomics across an ovarian cycle. Using peripherally acquired NK cells the cell-mediated cytotoxicity of tumor targets (OVCAR-3, K-562) was determined using live cellular impedance (xCELLigence®) and multicolor flow cytometry. Hypoxia-inducible factor 1-alpha (HIF-1α) immunohistochemistry of cancer-free fallopian tube specimens allowed a comparison of proximal versus distal portions. Utilizing these findings the role of environmental factors relevant to the fimbrial fallopian tube (progesterone, hypoxia) on NK cell functional activity were studied in an ovarian phase-specific manner. RESULTS: BRCA1 mutation carriers demonstrate a differential progesterone metabolome with a phase-specific reduction of peripheral NK cell functional activity. Progesterone exposure further impairs NK cell-mediated cytotoxicity in a dose-dependent manner, which is reversed with the addition of mifepristone (1.25 µM). The fimbrial fallopian tube demonstrated significantly higher HIF-1α staining, particularly in BRCA1 mutation carriers, reflecting a site-specific 'hypoxic niche'. Exposure to hypoxic conditions (1% O2) can further impair tumor cytotoxicity in high-risk carriers. CONCLUSIONS: Phase-specific differential NK cell activity in BRCA1 mutation carriers, either systemically or locally, may favor site-specific pre-invasive carcinogenesis. These cumulative effects across a reproductive lifecycle in high-risk carriers can have a detrimental effect further supporting epidemiological evidence for ovulation inhibition.

Efficacy and safety of using auditory-motor entrainment to improve walking after stroke: a multi-site randomized controlled trial of InTandemTM.

Walking slowly after stroke reduces health and quality of life. This multi-site, prospective, interventional, 2-arm randomized controlled trial (NCT04121754) evaluated the safety and efficacy of an autonomous neurorehabilitation system (InTandemTM) designed to use auditory-motor entrainment to improve post-stroke walking. 87 individuals were randomized to 5-week walking interventions with InTandem or Active Control (i.e., walking without InTandem). The primary endpoints were change in walking speed, measured by the 10-meter walk test pre-vs-post each 5-week intervention, and safety, measured as the frequency of adverse events (AEs). Clinical responder rates were also compared. The trial met its primary endpoints. InTandem was associated with a 2x larger increase in speed (Δ: 0.14 ± 0.03 m/s versus Δ: 0.06 ± 0.02 m/s, F(1,49) = 6.58, p = 0.013), 3x more responders (40% versus 13%, χ2(1) ≥ 6.47, p = 0.01), and similar safety (both groups experienced the same number of AEs). The auditory-motor intervention autonomously delivered by InTandem is safe and effective in improving walking in the chronic phase of stroke.

A Physical Activity and Diet Just-in-Time Adaptive Intervention to Reduce Blood Pressure: The myBPmyLife Study Rationale and Design.

BACKGROUND: Smartphone applications and wearable devices are promising mobile health interventions for hypertension self-management. However, most mobile health interventions fail to use contextual data, potentially diminishing their impact. The myBPmyLife Study is a just-in-time adaptive intervention designed to promote personalized self-management for patients with hypertension. METHODS AND RESULTS: The study is a 6-month prospective, randomized-controlled, remotely administered trial. Participants were recruited from the University of Michigan Health in Ann Arbor, Michigan or the Hamilton Community Health Network, a federally qualified health center network in Flint, Michigan. Participants were randomized to a mobile application with a just-in-time adaptive intervention promoting physical activity and lower-sodium food choices as well as weekly goal setting or usual care. The mobile study application encourages goal attainment through a central visualization displaying participants' progress toward their goals for physical activity and lower-sodium food choices. Participants in both groups are followed for up for 6 months with a primary end point of change in systolic blood pressure. Exploratory analyses will examine the impact of notifications on step count and self-reported lower-sodium food choices. The study launched on December 9, 2021, with 484 participants enrolled as of March 31, 2023. Enrollment of participants was completed on July 3, 2023. After 6 months of follow-up, it is expected that results will be available in the spring of 2024. CONCLUSIONS: The myBPmyLife study is an innovative mobile health trial designed to evaluate the effects of a just-in-time adaptive intervention focused on improving physical activity and dietary sodium intake on blood pressure in diverse patients with hypertension. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05154929.

Identifying Design Opportunities for Adaptive mHealth Interventions That Target General Well-Being: Interview Study With Informal Care Partners.

BACKGROUND: Mobile health (mHealth) interventions can deliver personalized behavioral support to users in daily contexts. These interventions have been increasingly adopted to support individuals who require low-cost and low-burden support. Prior research has demonstrated the feasibility and acceptability of an mHealth intervention app (CareQOL) designed for use with informal care partners. To further optimize the intervention delivery, we need to investigate how care partners, many of whom lack the time for self-care, react and act in response to different behavioral messages. OBJECTIVE: The goal of this study was to understand the factors that impact care partners' decision-making and actions in response to different behavioral messages. Insights from this study will help optimize future tailored and personalized behavioral interventions. METHODS: We conducted semistructured interviews with participants who had recently completed a 3-month randomized controlled feasibility trial of the CareQOL mHealth intervention app. Of the 36 participants from the treatment group of the randomized controlled trial, 23 (64%) participated in these interviews. To prepare for each interview, the team first selected representative behavioral messages (eg, targeting different health dimensions) and presented them to participants during the interview to probe their influence on participants' thoughts and actions. The time of delivery, self-reported perceptions of the day, and user ratings of a message were presented to the participants during the interviews to assist with recall. RESULTS: The interview data showed that after receiving a message, participants took various actions in response to different messages. Participants performed suggested behaviors or adjusted them either immediately or in a delayed manner (eg, sometimes up to a month later). We identified 4 factors that shape the variations in user actions in response to different behavioral messages: uncertainties about the workload required to perform suggested behaviors, concerns about one's ability to routinize suggested behaviors, in-the-moment willingness and ability to plan for suggested behaviors, and overall capability to engage with the intervention. CONCLUSIONS: Our study showed that care partners use mHealth behavioral messages differently regarding the immediacy of actions and the adaptation to suggested behaviors. Multiple factors influence people's perceptions and decisions regarding when and how to take actions. Future systems should consider these factors to tailor behavioral support for individuals and design system features to support the delay or adaptation of the suggested behaviors. The findings also suggest extending the assessment of user adherence by considering the variations in user actions on behavioral support (ie, performing suggested or adjusted behaviors immediately or in a delayed manner). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/32842.

Comparative estrogen exposure from compounded transdermal estradiol creams and Food and Drug Administration-approved transdermal estradiol gels and patches.

OBJECTIVE: The aim of this study was to evaluate the amount of estrogen exposure associated with the use of compounded transdermal estradiol (E2) creams and compare it with estrogen exposure associated with the use of Food and Drug Administration (FDA)-approved transdermal E2 patches and gels. METHODS: This was a retrospective cohort study that used clinical laboratory data collected from January 1, 2016, to December 31, 2019. Participants were first divided into three groups: postmenopausal women on no menopausal hormone therapy (n = 8,720); postmenopausal women using either a transdermal E2 patch, gel, or cream (n = 1,062); and premenopausal women on no hormonal therapy (n = 16,308). The postmenopausal menopausal hormone therapy group was further subdivided by formulation (patch [n = 777], gel [n = 132], or cream [n = 153]) and dose range (low, mid, or high). The Jonckheere-Terpstra trend test was used to determine if there was a dose-dependent trend in urinary E2 with increasing dose of compounded E2 cream (dose categories for E2 cream subanalysis, <0.5 mg [n = 49], ≥0.5-≤1.0 mg [n = 50], ≥1.0-≤1.5 mg [n = 58], and >1.5-≤3.0 mg [n = 46]). Urinary E2 and other characteristics were compared across formulations (within each dose range) using Kruskal-Wallis one-way analysis of variance. RESULTS: A dose-dependent, ordered trend existed for urinary E2 with increasing doses of compounded E2 cream (urinary E2 medians [ng/mg-Cr], 0.80 for <0.5 mg, 0.73 for ≥0.5-≤1.0 mg, 1.39 for ≥1.0-≤1.5 mg, and 1.74 for >1.5-≤3.0 mg; Jonckheere-Terpstra trend test, P < 0.001). Significant differences in urinary E2 concentrations were observed in all three dose ranges (Kruskal-Wallis one-way analysis of variance, P = 0.013 for low dose, P < 0.001 for mid dose, P = 0.009 for high dose). Comparison of E2 concentrations of compounded creams to E2 concentrations obtained with similar doses of FDA-approved patches and gels showed that the creams had significantly lower values than the patches and gels. CONCLUSIONS: Estrogen exposure from compounded transdermal E2 creams increases in a dose-dependent manner; however, the amount of estrogen exposure associated with compounded creams is significantly lower than estrogen exposure associated with FDA-approved transdermal E2 patches and gels. Clinicians should be aware of the direction and magnitude of these potential differences in estrogen exposure when encountering women who have either previously used or are currently using compounded E2 creams.

Ancient hybridization in Curcuma (Zingiberaceae)-Accelerator or brake in lineage diversifications?

Hybridization is a widespread phenomenon in the evolution of plants and exploring its role is crucial to understanding diversification processes of many taxonomic groups. Recently, more attention is focused on the role of ancient hybridization that has repeatedly been shown as triggers of evolutionary radiation, although in some cases, it can prevent further diversification. The causes, frequency, and consequences of ancient hybridization remain to be explored. Here, we present an account of several events of ancient hybridization in turmeric, the economically important plant genus Curcuma (Zingiberaceae), which harbors about 130 known species. We analyzed 1094 targeted low-copy genes and plastomes obtained by next-generation sequencing of 37 species of Curcuma, representing the known genetic diversity and spanning the geographical distribution of the genus. Using phylogenetic network analysis, we show that the entire genus Curcuma as well as its most speciose lineage arose via introgression from the genus Pyrgophyllum and one of the extinct lineages, respectively. We also document a single event of ancient hybridization, with C. vamana as a product, that represents an evolutionary dead end. We further discuss distinct circumstances of those hybridization events that deal mainly with (in)congruence in chromosome counts of the parental lineages.

Biomechanical Comparison of Cortical Lag Screws and Cortical Position Screws for Their Generation of Interfragmentary Compression and Area of Compression in Simulated Lateral Humeral Condylar Fractures.

OBJECTIVE: The aim of this study was to compare the interfragmentary compressive force and area of compression generated by cortical screws inserted as either a lag screw or position screw in simulated lateral humeral condylar fractures. STUDY DESIGN: Ex vivo biomechanical study. MATERIALS AND METHODS: Thirteen pairs of cadaveric humeri from skeletally mature Merinos with simulated lateral humeral condylar fractures were used. Pressure sensitive film was inserted into the interfragmentary interface prior to fracture reduction with fragment forceps. A cortical screw was inserted as a lag screw or a position screw and tightened to 1.8Nm. Interfragmentary compression and area of compression were quantified and compared between the two treatments groups at three time points. RESULTS: After fracture reduction using fragment forceps (Time point 1: T1), there was no significant difference in interfragmentary compression and area of compression between the two treatments. A combination of fragment forceps and a cortical screw inserted as a lag screw (Time point 2: T2) produced significantly greater interfragmentary compression and area of compression compared with the same screw inserted as a positional screw. After removal of the fragment forceps, leaving only the cortical screw (Time point 3: T3), both the interfragmentary compression and area of compression remain significantly greater in the lag screw group. CONCLUSION: Lag screws generate a greater force of compression and area of compression compared with position screws in this mature ovine humeral condylar fracture model.

Management of ground-glass opacities and sub-solid pulmonary nodules: a surgeon's perspective.

The regular use of high-resolution computed tomogram scans has led to an increase in the detection of asymptomatic ground-glass opacities and sub-solid nodules at an early stage. Different growth patterns of these lesions are making decision-making a real challenge. With growing experience and improving radiology interventions, management of these lesions is changing constantly. However, with variations in growth patterns and outcomes, immediate treatment options as well as follow-up surveillance and subsequent interventions can be confounding for the clinicians. This mini review describes algorithms for managing these ground-glass opacities (GGOs) and sub-solid nodules (SSNs) with a focus on the surgical options.

Surgical Management of Massive Pulmonary Embolism Presenting with Cardiopulmonary Arrest: How Far Is Too Far?

ABSTRACT The incidence of diagnosed massive pulmonary embolism presenting to the Emergency Department is between 3% and 4.5% and it is associated with high mortality if not intervened timely. Cardiopulmonary arrest in this subset of patients carries a very poor prognosis, and various treating pathways have been applied with modest rate of success. Systemic thrombolysis is an established first line of treatment, but surgeons are often involved in the decision-making because of the improving surgical pulmonary embolectomy outcomes.

A Community Participatory Approach to Creating Contextually Tailored mHealth Notifications: myBPmyLife Project.

Just-in-time adaptive interventions (JITAIs) are a novel approach to mobile health (mHealth) interventions, sending contextually tailored behavior change notifications to participants when they are more likely to engage, determined by data from wearable devices. We describe a community participatory approach to JITAI notification development for the myBPmyLife Project, a JITAI focused on decreasing sodium consumption and increasing physical activity to reduce blood pressure. Eighty-six participants were interviewed, 50 at a federally qualified health center (FQHC) and 36 at a university clinic. Participants were asked to provide encouraging physical activity and low-sodium diet notifications and provided feedback on researcher-generated notifications to inform revisions. Participant notifications were thematically analyzed using an inductive approach. Participants noted challenging vocabulary, phrasing, and culturally incongruent suggestions in some of the researcher-generated notifications. Community-generated notifications were more direct, used colloquial language, and contained themes of grace. The FQHC participants' notifications expressed more compassion, religiosity, and addressed health-related social needs. University clinic participants' notifications frequently focused on office environments. In summary, our participatory approach to notification development embedded a distinctive community voice within our notifications. Our approach may be generalizable to other communities and serve as a model to create tailored mHealth notifications to their focus population.

Phylogenomics and genome size evolution in Amomum s. s. (Zingiberaceae): Comparison of traditional and modern sequencing methods.

BACKGROUND AND AIMS: A targeted enrichment NGS approach was used to construct the phylogeny of Amomum Roxb. (Zingiberaceae). Phylogenies based on hundreds of nuclear genes, the whole plastome and the rDNA cistron were compared with an ITS-based phylogeny. Trends in genome size (GS) evolution were examined, chromosomes were counted and the geographical distribution of phylogenetic lineages was evaluated. METHODS: In total, 92 accessions of 54 species were analysed. ITS was obtained for 79 accessions, 37 accessions were processed with Hyb-Seq and sequences from 449 nuclear genes, the whole cpDNA, and the rDNA cistron were analysed using concatenation, coalescence and supertree approaches. The evolution of absolute GS was analysed in a phylogenetic and geographical context. The chromosome numbers of 12 accessions were counted. KEY RESULTS: Four groups were recognised in all datasets though their mutual relationships differ among datasets. While group A (A. subulatum and A. petaloideum) is basal to the remaining groups in the nuclear gene phylogeny, in the cpDNA topology it is sister to group B (A. repoeense and related species) and, in the ITS topology, it is sister to group D (the Elettariopsis lineage). The former Elettariopsis makes a monophyletic group. There is an increasing trend in GS during evolution. The largest GS values were found in group D in two tetraploid taxa, A. cinnamomeum and A. aff. biphyllum (both 2n = 96 chromosomes). The rest varied in GS (2C = 3.54-8.78 pg) with a constant chromosome number 2n = 48. There is a weak connection between phylogeny, GS and geography in Amomum. CONCLUSIONS: Amomum consists of four groups, and the former Elettariopsis is monophyletic. Species in this group have the largest GS. Two polyploids were found and GS greatly varied in the rest of Amomum.

Assessing estrogen exposure from transdermal estradiol patch therapy using a dried urine collection and a GC-MS/MS assay.

BACKGROUND: Transdermal estradiol patch therapy is often dosed based on patient reported symptoms. Although dosing based on serum estradiol concentrations has been considered, serum sampling is too invasive and inconvenient to use in real-world settings. The primary aim of this study was to determine if a dried urine assay could be used to assess estrogen exposure resulting from transdermal estradiol patch therapy at increasing doses. METHODS: This was a retrospective analysis of clinical laboratory data. Urinary estrogen profiles of postmenopausal women being treated with transdermal estradiol patches at differing doses (age = 56.8 ± 7.5) were selected from the database along with the profiles of women on no therapy for comparison (age = 55.1 ± 9.5). Metabolite concentrations were obtained using a multi-spot dried urine collection and a gas chromatography-tandem mass spectrometry assay. The Jonckheere-Terpstra test was used to assess for ordered differences across dose groups to determine if dose-dependent increases in urinary estrogens occurred with increasing doses. RESULTS: Median concentrations of estradiol and other estrogen metabolites increased with increasing doses of transdermal estradiol patch therapy (p < 0.001; Jonckheere-Terpstra test). For women who collected samples before and after initiating therapy, there were significant differences between before and after concentrations of estradiol and other estrogen metabolites. CONCLUSION: This large study conducted using real-world data demonstrated that a dried urine assay offers a viable method of assessing estrogen exposure differences that occur with the use of differing doses of transdermal estradiol patches. Further studies with prospective designs that include outcome measures are needed to confirm the findings of this study.

Next-generation sequencing data show rapid radiation and several long-distance dispersal events in early Costaceae.

The monocot family Costaceae Nakai consists of seven genera but their mutual relationships have not been satisfactorily resolved in previous studies employing classical molecular markers. Phylogenomic analyses of 365 nuclear genes and nearly-complete plastome data provide almost fully resolved insights into their diversification. Paracostus is identified as sister to all other taxa, followed by several very short branches leading to discrete lineages, suggesting an ancient rapid radiation of these early lineages and leaving the exact relationships among them unresolved. Relationships among Chamaecostus, Dimerocostus and Monocostus confirmed earlier findings that these genera form a monophyletic group. The Afro-American Costus is also monophyletic. By contrast, Tapeinochilos appeared as a well-supported crown lineage of Cheilocostus rendering it paraphyletic. As these two genera differ morphologically from one another owing to a shift from insect- to bird-pollination, we propose to keep both names. The divergence time within Costaceae was estimated using penalized likelihood utilizing two fossils within Zingiberales, †Spirematospermum chandlerae and †Ensete oregonense, indicated a relatively recent diversification of Costaceae, between 18 and 9 Mya. Based on these data, the current pantropical distribution of the family is hypothesized to be the result of several long-distance intercontinental dispersal events, which do not correlate with global geoclimatic changes.

Surgical Management of Massive Pulmonary Embolism Presenting with Cardiopulmonary Arrest: How Far Is Too Far?

The incidence of diagnosed massive pulmonary embolism presenting to the Emergency Department is between 3% and 4.5% and it is associated with high mortality if not intervened timely. Cardiopulmonary arrest in this subset of patients carries a very poor prognosis, and various treating pathways have been applied with modest rate of success. Systemic thrombolysis is an established first line of treatment, but surgeons are often involved in the decision-making because of the improving surgical pulmonary embolectomy outcomes.

A randomized, double-blind, placebo-controlled, cross-over trial to evaluate the effect of EstroSense® on 2-hydroxyestrone:16α-hydroxyestrone ratio in premenopausal women.

OBJECTIVES: Some estrogen metabolites are associated with increased breast cancer risk, while others are protective. Research efforts have focused on modifiable factors, including bioactive compounds found in food or supplements, promoting estrogen profiles with anti-cancer properties. EstroSense® is a nutraceutical product with bioactive compounds, including Indole-3-carbinol and green-tea catechins, which may favourably affect estrogen profiles. This study was conducted to determine if EstroSense use, compared to placebo, promotes a higher urinary 2-hydroxyestrone:16α-hydroxyestrone ratio (2-OHE1:16α-OHE1), a biomarker associated with a lowered risk of breast cancer. METHODS: A total of 148 premenopausal women were recruited from British Columbia, Canada to participate in a randomized, double-blind, cross-over, multicentre, placebo-controlled study in which women were randomized to a treatment sequence that consisted of either EstroSense®, followed by placebo or vice-versa. The women were instructed to consume three capsules per day of EstroSense® or the placebo for three menstrual cycles (∼12 weeks). The primary outcome was the measurement of 2-OHE1:16α-OHE1 in casual samples at baseline and after each treatment phase. RESULTS: After 12 weeks of intervention, the mean (95% CI) urinary 2-OHE1:16α-OHE1 was 4.55 (2.69, 6.42) (p<0.001) higher following EstroSense than placebo adjusted for baseline values. CONCLUSIONS: EstroSense use led to markedly higher urinary 2-OHE1:16α-OHE1 than the placebo, a biomarker associated with a lower risk of breast cancer. REGISTRATION: http://clinicaltrials.gov (NCT02385916).

Aortic Root and Distal Arch Management During Type A Aortic Dissection Repair: Expanding Horizons

ABSTRACT The management of Type A aortic dissection has evolved over a period of a decade or so, and contemporary reports are suggesting a paradigm shift from a conservative approach to complete excision of the diseased aorta including root and distal arch. Improved cardiopulmonary bypass perfusion techniques, better understanding of the cerebral perfusion, and wide-ranging obtainability of prosthetic conduits gave surgical teams numerous choices. With improving outcomes and maturing surgical techniques, surgeons are performing extensive resections of the diseased aorta, but there is no standard protocol as far as the extent of the proximal and distal diseased aortic tissue resection is concerned. Aortic root replacement is associated with good early- and long-term outcomes and proffered solution in young and stable patients, for that reason many busy centres are endorsing total arch replacement in complex distal aortic dissections. This systemic review is discussing contemporary literature and associated pros and cons during surgical decision-making for these high-risk cases.