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In this work, we investigate the potential of employing a direct conversion integration mode X-ray detector with micron-scale pixels in two different X-ray phase-contrast imaging (XPCi) configurations, propagation-based (PB) and edge illumination (EI). Both PB-XPCi and EI-XPCi implementations are evaluated through a wave optics model—numerically simulated in MATLAB—and are compared based on their contrast, edge-enhancement, visibility, and dose efficiency characteristics. The EI-XPCi configuration, in general, demonstrates higher performance compared to PB-XPCi, considering a setup with the same X-ray source and detector. However, absorption masks quality (thickness of X-ray absorption material) and environmental vibration effect are two potential challenges for EI-XPCi employing a detector with micron-scale pixels. Simulation results confirm that the behavior of an EI-XPCi system employing a high-resolution detector is susceptible to its absorption masks thickness and misalignment. This work demonstrates the potential and feasibility of employing a high-resolution direct conversion detector for phase-contrast imaging applications where higher dose efficiency, higher contrast images, and a more compact imaging system are of interest.

Amorphous selenium (a-Se) is a glass-former capable of deposition at high rates by thermal evaporation over a large area. It was chosen as a direct conversion material due to its appealing properties for imaging in both low and high X-ray energy ranges (

Background: Cardiorenal dysfunction with impaired cyclic GMP (cGMP) response is common in patients presenting with acute heart failure (HF). Type V phosphodiesterase (PDEV) is known to be upregulated in HF and may explain the dysfunction of renal response. The aim of this study was to determine whether B-type natriuretic peptide (BNP) alone or in combination with PDEV inhibition improves renal function and increases urinary sodium and cGMP excretion in acute HF., Methods: This open-label study included 67 patients hospitalized with acute HF and renal dysfunction. Patients were randomized to standard care, low-dose intravenous BNP (0.005 µg/kg per minute), or combination BNP/PDEV inhibition with sildenafil (25 mg q12 hours) for 48 hours. The coprimary end points were the percent change in estimated glomerular filtration rate and blood urea nitrogen from baseline to 48 hours., Results: Treatment with BNP and BNP/PDEV inhibitor significantly increased plasma cGMP at 24 hours (+25.6% [+9.8%, +84.7%] and +60.8% [+32.3%, +103.8%] for BNP and BNP/PDEV versus -13.5% [-29.1%, +14.2%] with standard care; P =0.001). However, there was no significant change in estimated glomerular filtration rate 0 (-10.8%, +12.7%) for standard care versus 0 (-15.3%, +11.8%) for the BNP group versus -8.8% (-14.3%, +8.3%) for the BNP/PDEV group ( P =0.60) or blood urea nitrogen -1.4% (-10.7%, +12.0%) for standard care versus -5.9% (-14.6%, +9.4%) for the BNP group versus +6.9% (-5.3%, +18.8%) for the BNP/PDEV group ( P =0.38) between groups. Hypotension was more common in the BNP/PDEV inhibitor group., Conclusions: BNP and combination BNP/PDEV inhibition increased plasma cGMP in patients with acute HF but did not improve renal function or urinary sodium/cGMP excretion. Our study does not support the use of intravenous low-dose BNP with or without PDEV inhibition to enhance renal function in patients admitted with acute HF., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00972569.

Background: Elevated mammographic density (MD) for a woman's age and body mass index (BMI) is an established breast cancer risk factor. The relationship of parity, age at first birth, and breastfeeding with MD is less clear. We examined the associations of these factors with MD within the International Consortium of Mammographic Density (ICMD)., Methods: ICMD is a consortium of 27 studies with pooled individual-level epidemiological and MD data from 11,755 women without breast cancer aged 35-85 years from 22 countries, capturing 40 country-& ethnicity-specific population groups. MD was measured using the area-based tool Cumulus. Meta-analyses across population groups and pooled analyses were used to examine linear regression associations of square-root (√) transformed MD measures (percent MD (PMD), dense area (DA), and non-dense area (NDA)) with parity, age at first birth, ever/never breastfed and lifetime breastfeeding duration. Models were adjusted for age at mammogram, age at menarche, BMI, menopausal status, use of hormone replacement therapy, calibration method, mammogram view and reader, and parity and age at first birth when not the association of interest., Results: Among 10,988 women included in these analyses, 90.1% (n = 9,895) were parous, of whom 13% (n = 1,286) had ≥ five births. The mean age at first birth was 24.3 years (Standard deviation = 5.1). Increasing parity (per birth) was inversely associated with √PMD (β: - 0.05, 95% confidence interval (CI): - 0.07, - 0.03) and √DA (β: - 0.08, 95% CI: - 0.12, - 0.05) with this trend evident until at least nine births. Women who were older at first birth (per five-year increase) had higher √PMD (β:0.06, 95% CI:0.03, 0.10) and √DA (β:0.06, 95% CI:0.02, 0.10), and lower √NDA (β: - 0.06, 95% CI: - 0.11, - 0.01). In stratified analyses, this association was only evident in women who were post-menopausal at MD assessment. Among parous women, no associations were found between ever/never breastfed or lifetime breastfeeding duration (per six-month increase) and √MD., Conclusions: Associations with higher parity and older age at first birth with √MD were consistent with the direction of their respective associations with breast cancer risk. Further research is needed to understand reproductive factor-related differences in the composition of breast tissue and their associations with breast cancer risk., (© 2024. The Author(s).)

Background: Nutrition guidance for athletes must consider a range of variables to effectively support individuals in meeting energy and nutrient needs. Resistance exercise is a widely adopted training method in athlete preparation and rehabilitation and therefore is one such variable that will influence nutrition guidance. Given its prominence, the capacity to meaningfully quantify resistance exercise energy expenditure will assist practitioners and researchers in providing nutrition guidance. However, the significant contribution of anaerobic metabolism makes quantifying energy expenditure of resistance exercise challenging., Objective: The aim of this scoping review was to investigate the methods used to assess resistance exercise energy expenditure., Methods: A literature search of Medline, SPORTDiscus, CINAHL and Web of Science identified studies that included an assessment of resistance exercise energy expenditure. Quality appraisal of included studies was performed using the Rosendal Scale., Results: A total of 19,867 studies were identified, with 166 included after screening. Methods to assess energy expenditure included indirect calorimetry (n = 136), blood lactate analysis (n = 25), wearable monitors (n = 31) and metabolic equivalents (n = 4). Post-exercise energy expenditure was measured in 76 studies. The reported energy expenditure values varied widely between studies., Conclusions: Indirect calorimetry is widely used to estimate energy expenditure. However, given its limitations in quantifying glycolytic contribution, indirect calorimetry during and immediately following exercise combined with measures of blood lactate are likely required to better quantify total energy expenditure. Due to the cumbersome equipment and technical expertise required, though, along with the physical restrictions the equipment places on participants performing particular resistance exercises, indirect calorimetry is likely impractical for use outside of the laboratory setting, where metabolic equivalents may be a more appropriate method., (© 2024. The Author(s).)

There has been a long debate about the possibility of multiple contemporaneous species of Australopithecus in both eastern and southern Africa, potentially exhibiting different forms of bipedal locomotion. Here, we describe the previously unreported morphology of the os coxae in the 3.67 Ma Australopithecus prometheus StW 573 from Sterkfontein Member 2, comparing it with variation in ossa coxae in living humans and apes as well as other Plio-Pleistocene hominins. Statistical comparisons indicate that StW 573 and 431 resemble humans in their anteroposteriorly great iliac crest breadth compared with many other early australopiths, whereas Homo ergaster KNM WT 15000 surprisingly also has a relatively anterioposteriorly short iliac crest. StW 573 and StW 431 appear to resemble humans in having a long ischium compared with Sts 14 and KNM WT 15000. A Quadratic Discriminant Function Analysis of morphology compared with other Plio-Pleistocene hominins and a dataset of modern humans and hominoids shows that, while Lovejoy's heuristic model of the Ardipithecus ramidus os coxae falls with Pongo or in an indeterminate group, StW 573 and StW 431 from Sterkfontein Member 4 are consistently classified together with modern humans. Although clearly exhibiting the classic "basin shaped" bipedal pelvis, Sts 14 (also from Sterkfontein), AL 288-1 Australopithecus afarensis, MH2 Australopithecus sediba and KNM-WT 15000 occupy a position more peripheral to modern humans, and in some analyses are assigned to an indeterminate outlying group. Our findings strongly support the existence of two species of Australopithecus at Sterkfontein and the variation we observe in os coxae morphology in early hominins is also likely to reflect multiple forms of bipedality., (© 2024 The Author(s). Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

While precision medicine applications of radiomics analysis are promising, differences in image acquisition can cause "batch effects" that reduce reproducibility and affect downstream predictive analyses. Harmonization methods such as ComBat have been developed to correct these effects, but evaluation methods for quantifying batch effects are inconsistent. In this study, we propose the use of the multivariate statistical test PERMANOVA and the Robust Effect Size Index (RESI) to better quantify and characterize batch effects in radiomics data. We evaluate these methods in both simulated and real radiomics features extracted from full-field digital mammography (FFDM) data. PERMANOVA demonstrated higher power than standard univariate statistical testing, and RESI was able to interpretably quantify the effect size of site at extremely large sample sizes. These methods show promise as more powerful and interpretable methods for the detection and quantification of batch effects in radiomics studies., (© 2024. The Author(s).)

Introduction: Cerebral small vessel disease (SVD) and amyloid beta (Aβ) pathology frequently co-exist. The impact of concurrent pathology on the pattern of hippocampal atrophy, a key substrate of memory impacted early and extensively in dementia, remains poorly understood., Methods: In a unique cohort of mixed Alzheimer's disease and moderate-severe SVD, we examined whether total and regional neuroimaging measures of SVD, white matter hyperintensities (WMH), and Aβ, as assessed by 18 F-AV45 positron emission tomography, exert additive or synergistic effects on hippocampal volume and shape., Results: Frontal WMH, occipital WMH, and Aβ were independently associated with smaller hippocampal volume. Frontal WMH had a spatially distinct impact on hippocampal shape relative to Aβ. In contrast, hippocampal shape alterations associated with occipital WMH spatially overlapped with Aβ-vulnerable subregions., Discussion: Hippocampal degeneration is differentially sensitive to SVD and Aβ pathology. The pattern of hippocampal atrophy could serve as a disease-specific biomarker, and thus guide clinical diagnosis and individualized treatment strategies for mixed dementia., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The natural history of moderate/severe atrial functional mitral regurgitation (AFMR) is unknown., Objectives: The authors sought to study the incidence of left ventricular (LV) systolic dysfunction (LVSD), progression or regression of ≥mild-moderate AFMR, and impact on mortality., Methods: Adults with left atrial (LA) volume index ≥40 mL/m 2 , ≥mild-moderate AFMR, and follow-up echocardiogram were followed for incident LVSD (ejection fraction <50% and ≥10% lower than baseline), progression of mild-moderate/moderate AFMR to severe, and persistent regression of AFMR to no/trivial. Relation of AFMR progression or regression as time-dependent covariates with all-cause mortality was studied. Incidence of LVSD was compared with patients with no/mild AFMR matched on age, sex, comorbidities and ejection fraction. Patients were followed until mitral intervention, myocardial infarction, or last follow-up., Results: A total of 635 patients (median age 75 years, 51% female, 96% mild-moderate/moderate AFMR, 4% severe AFMR) were included. Over a median 2.2 years (Q1-Q3: 1.0-4.3 years), incidence rates per 100 person-years were 3.2 for LVSD (P = 0.52 vs patients with no/mild AFMR), 1.9 for progression of AFMR, and 3.9 for regression. Female sex and larger LA volume index were independently associated with progression, whereas younger age, male sex, absent atrial fibrillation, and higher LA emptying fraction were independently associated with regression. Neither AFMR progression nor regression was independently associated with mortality. Instead, independent risk factors for mortality included older age, concentric LV geometry, and higher estimated LV filling and pulmonary pressures., Conclusions: In patients with predominantly mild-moderate/moderate AFMR, regression of MR was more common than progression, but neither was associated with mortality. Instead, diastolic function abnormalities were more important. Over a median 2-year follow-up, LVSD risk was not increased., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Our thoracic enhanced recovery program (ERP) decreased the use of postoperative morphine equivalents and hospital costs 1 year after implementation at our tertiary center. The sustainability and potential increasing benefit of this program were evaluated., Methods: From 2015 to 2021, we prospectively analyzed the outcomes of patients who underwent elective pleural, pulmonary, or mediastinal operations at our institution. Patients were separated on the basis of the incision (video-assisted thoracoscopic surgery [VATS] or thoracotomy). The ERP protocol was initiated on May 1, 2016, and includes preoperative education, carbohydrate loading, opioid-sparing analgesia, conservative fluid management, protective ventilation, and early ambulation. Outcomes of patients before (2015, pre-VATS and pre-thoracotomy) and after (May 1, 2016, to December 31, 2021, ERP-VATS and ERP-thoracotomy) ERP implementation were compared., Results: The cohort included 1079 patients (pre-ERP era, n = 224 [21%]; ERP era, n = 855 [79%]). There was a median reduction of 1.5 hospital days per patient for ERP-thoracotomy and 1 hospital day per patient for ERP-VATS. Median postoperative morphine equivalents decreased in both groups (125 vs 45 mg, in ERP-thoracotomy; 84 vs 23 mg, ERP-VATS; P < .001), as did total admission cost ($32,118 vs $23,775, ERP-thoracotomy; $17,367 vs $11,560, ERP-VATS; P < .001). Median total fluid balance during the hospital stay decreased significantly. Rates of postoperative atrial fibrillation and urinary retention decreased across both subgroups., Conclusions: ERP for thoracic surgery is sustainable and has been demonstrated to improve patient outcomes, to decrease opioid use, and to lower hospital costs. Therefore, it has the potential to become the standard of care., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Recent spikes in interactions between humans and sharks in the New York Bight have sparked widespread reporting of possible causalities, many of which lack empirical support. Here we comment on the current state of knowledge regarding shark biology and management in New York waters emphasizing that the possible drivers of increased human-shark interactions are confounded by a lack of historical monitoring data. We outline several key research avenues that should be considered to ensure the safe and sustainable coexistence of humans, sharks, and their prey, in an era of accelerated environmental change., (© 2023 Fisheries Society of the British Isles.)

Objective: Tricuspid regurgitation (TR) is a prevalent valve disease associated with significant morbidity and mortality. We aimed to apply machine learning (ML) to assess risk stratification in patients with ≥moderate TR., Methods: Patients with ≥moderate TR on echocardiogram between January 2005 and December 2016 were retrospectively included. We used 70% of data to train ML-based survival models including 27 clinical and echocardiographic features to predict mortality over a 3-year period on an independent test set (30%). To account for differences in baseline comorbidities, prediction was performed in groups stratified by increasing Charlson Comorbidity Index (CCI). Permutation feature importance was calculated using the best-performing model separately in these groups., Results: Of 13 312 patients, mean age 72 ± 13 years and 7406 (55%) women, 7409 (56%) had moderate, 2646 (20%) had moderate-severe and 3257 (24%) had severe TR. The overall performance for 1-year mortality by 3 ML models was good, c-statistic 0.74-0.75. Interestingly, performance varied between CCI groups, (c-statistic = 0.774 in lowest CCI group and 0.661 in highest CCI group). The performance decreased over 3-year follow-up (average c-index 0.78). Furthermore, the top 10 features contributing to these predictions varied slightly with the CCI group, the top features included heart rate, right ventricular systolic pressure, blood pressure, diuretic use and age., Conclusions: Machine learning of common clinical and echocardiographic features can evaluate mortality risk in patients with TR. Further refinement of models and validation in prospective studies are needed before incorporation into the clinical practice., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hypertension and metabolic syndrome frequently coexist to increase the risk for adverse cardiometabolic outcomes. To date, no drug has been proven to be effective in treating hypertension with metabolic syndrome. M-atrial natriuretic peptide is a novel atrial natriuretic peptide analog that activates the particulate guanylyl cyclase A receptor. This study conducted a double-blind, placebo-controlled trial in 22 patients and demonstrated that a single subcutaneous injection of M-atrial natriuretic peptide was safe, well-tolerated, and exerted pleiotropic properties including blood pressure-lowering, lipolytic, and insulin resistance-improving effects. (MANP in Hypertension and Metabolic Syndrome [MANP-HTN-MS]; NCT03781739)., Competing Interests: This work was supported by the Marie Ingalls Cardiovascular Research Career Development Award in honor of Dr Alexander Schirger, Mayo Clinic CV Circulatory Program Award, and Scientist Development Award of the American Heart Association 16SDG29930003 (to Dr Cannone); Postdoctoral Fellowship 903661 (to Dr Ma) from the American Heart Association; and grants R01HL134668 and R01HL136340 (to Dr Burnett) from the National Heart, Lung and Blood Institute. Dr Burnett is the inventor of MANP, which the Mayo Clinic has licensed to E-STAR BIO TECH. All other authors have reported that they have no relationships relevant to the contents in this paper to disclose., (© 2024 The Authors.)

A set of core concepts ("big ideas") integral to the discipline of physiology are important for students to understand and demonstrate their capacity to apply. We found poor alignment of learning outcomes in programs with physiology majors (or equivalent) from 17 Australian universities and the 15 core concepts developed by a team in the United States. The objective of this project was to reach Australia-wide consensus on a set of core concepts for physiology, which can be embedded in curricula across Australian universities. A four-phase Delphi method was employed, starting with the assembling of a Task Force of physiology educators with extensive teaching and curriculum development expertise from 25 Australian universities. After two online meetings and a survey, the Task Force reached agreement on seven core concepts of physiology and their descriptors, which were then sent out to the physiology educator community across Australia for agreement. The seven core concepts and their associated descriptions were endorsed through this process ( n = 138). In addition, embedding the core concepts across the curriculum was supported by both Task Force members (85.7%) and educators (82.1%). The seven adopted core concepts of human physiology were Cell Membrane, Cell-Cell Communication, Movement of Substances, Structure and Function, Homeostasis, Integration, and Physiological Adaptation. The core concepts were subsequently unpacked into themes and subthemes. If adopted, these core concepts will result in consistency across curricula in undergraduate physiology programs and allow for future benchmarking. NEW & NOTEWORTHY This is the first time Australia-wide agreement has been reached on the core concepts of physiology with the Delphi method. Embedding of the core concepts will result in consistency in physiology curricula, improvements to teaching and learning, and benchmarking across Australian universities.

Aims: Tricuspid valve regurgitation (TR) is a common valvular disease associated with increased mortality. There is a need for tools to assess the interaction between the pulmonary artery (PA) circulation and the right ventricle in patients with TR and to investigate their association with outcomes. The pulmonary artery pulsatility index (PAPi) has emerged as a haemodynamic risk predictor in left heart disease and pulmonary hypertension (PH). Whether PAPi discriminates risk in unselected patients with greater than or equal to moderate TR is unknown., Methods and Results: In 5079 patients with greater than or equal to moderate TR (regardless of aetiology) and PA systolic and diastolic pressures measured on their first echocardiogram, we compared all-cause mortality at 5 years based on the presence or absence of PH and PAPi levels. A total of 2741 (54%) patients had PH. The median PAPi was 3.0 (IQR 1.9, 4.4). Both the presence of PH and decreasing levels of PAPi were associated with larger right ventricles, worse right ventricular systolic function, higher NT-pro BNP levels, greater degrees of right heart failure, and worse survival. In a subset of patients who had an echo and right heart catheterization within 24 h, the correlation of non-invasive to invasive PA pressures and PAPi levels was very good (r = 0.76)., Conclusion: In patients with greater than or equal to moderate TR with and without PH, lower PAPi is associated with right ventricular dysfunction, right heart failure, and worse survival. Incorporating PA pressure and PAPi may help stratify disease severity in patients with greater than or equal to moderate TR regardless of aetiology., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers., Aim: To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS., Methods: Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death., Results: There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)]., Conclusion: Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Acute change in gait speed while performing a mental task [dual-task gait cost (DTC)], and hyperintensity magnetic resonance imaging signals in white matter are both important disability predictors in older individuals with history of stroke (poststroke). It is still unclear, however, whether DTC is associated with overall hyperintensity volume from specific major brain regions in poststroke., Methods: This is a cohort study with a total of 123 older (69 ± 7 years of age) participants with history of stroke were included from the Ontario Neurodegenerative Disease Research Initiative. Participants were clinically assessed and had gait performance assessed under single- and dual-task conditions. Structural neuroimaging data were analyzed to measure both, white matter hyperintensity (WMH) and normal appearing volumes. Percentage of WMH volume in frontal, parietal, occipital, and temporal lobes as well as subcortical hyperintensities in basal ganglia + thalamus were the main outcomes. Multivariate models investigated associations between DTC and hyperintensity volumes, adjusted for age, sex, years of education, global cognition, vascular risk factors, APOE4 genotype, residual sensorimotor symptoms from previous stroke and brain volume., Results: There was a significant positive global linear association between DTC and hyperintensity burden (adjusted Wilks' λ = .87, P  = .01). Amongst all WMH volumes, hyperintensity burden from basal ganglia + thalamus provided the most significant contribution to the global association (adjusted β = .008, η 2  = .03; P  = .04), independently of brain atrophy., Conclusions: In poststroke, increased DTC may be an indicator of larger white matter damages, specifically in subcortical regions, which can potentially affect the overall cognitive processing and decrease gait automaticity by increasing the cortical control over patients' locomotion.

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aβ-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aβ-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aβ-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aβ-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aβ-PET related more closely to higher cortical Aβ (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aβ-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.

Background and Purpose: The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years., Methods: Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale., Results: Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline., Conclusion: White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid-stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology., (© 2023 European Academy of Neurology.)

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aβ) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aβ deposition ( 18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aβ and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aβ status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes., Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry., Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10 -6 ) and AC058822.1 (P = 1.47 × 10 -4 ), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C., Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10 -5 ), demonstrating the importance of diversifying study cohorts., (© 2023. The Author(s).)

Purpose: Innovative methods for delivering cardiac rehabilitation (CR) that provide strategies to circumvent the mounting barriers to traditional CR have the potential to widen access to a well-established secondary prevention strategy. Our study assesses the feasibility and acceptability of a novel virtual world-based CR (VWCR) program, Destination Rehab , as an extension of a conventional center-based CR program., Methods: Adult cardiac patients hospitalized at Mayo Clinic hospitals with a diagnosis for CR and ≥1 modifiable, lifestyle risk factor target-sedentary lifestyle (<3 hr physical activity/wk), unhealthy diet (<5 servings fruits and vegetables/d), or current smoking (>1 yr)-were recruited. Patients participated in an 8-wk health education program using a virtual world (VW) platform from a prior proof-of-concept study and a post-intervention focus group. Primary outcome measures included feasibility and acceptability. Secondary outcome measures included changes from baseline to post-intervention in cardiovascular (CV) health behaviors and biometrics, CV health knowledge, and psychosocial factors., Results: Of the 30 enrolled patients (age 59.1 ± 9.7 yr; 50% women), 93% attended ≥1 session and 71% attended ≥75% of sessions. The overall VWCR experience received an 8 rating (scale 0-10) and had high acceptability. Clinically relevant trends were noted in CV health behaviors and biometrics, although not statistically significant., Conclusions: The VWCR program is a feasible, highly acceptable, and innovative platform to potentially influence health behaviors and CV risk and may increase accessibility to disadvantaged populations with higher CV disease burdens., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: COVID-19 vaccine hesitancy in the United States is high, with at least 63 million unvaccinated individuals to date. Socioeconomically disadvantaged populations experience lower COVID-19 vaccination rates despite facing a disproportionate COVID-19 burden., Objective: To assess the factors associated with COVID-19 vaccine acceptance among under-resourced, adult patients., Methods: Participants were patients receiving care at a Federally Qualified Health Center (FQHC) in St. Paul, Minnesota. Data were collected via multiple modes over 2 phases in 2020 (self-administered electronic survey) and 2021 (study team-administered survey by telephone, self-administered written survey) to promote diversity and inclusion for study participation. The primary outcome was COVID-19 vaccine acceptance. Using logistic regression analysis, associations between vaccine acceptance and factors including risk perception, concerns about the COVID-19 vaccine, social determinants of health (SDOH), co-morbidities, pandemic-induced hardships, and stress were assessed by adjusted odds ratios (AORs) and 95% confidence intervals (CI)., Results: One hundred sixty-eight patients (62.5% female; mean age [SD]: 49.9 [17.4] years; 32% <$20 000 annual household income; 69%

Objectives: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics., Methods: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (n snps =5) or sedentary time (n snps =6), or accelerometer-measured (n snps =1) or self-reported (n snps =5) vigorous physical activity., Results: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger)., Conclusion: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women., Competing Interests: Competing interests: MWB conducts research funded by Amgen, Novartis and Pfizer. PAF conducts research funded by Amgen, Novartis and Pfizer. He received honoraria from Roche, Novartis and Pfizer. AWK declares research funding to her institution from Myriad Genetics for an unrelated project (funding dates 2017-2019). SL declares grants and honoraria paid to her institution from Amgen, Novartis, Pfizer, Roche, and, outside the submitted work, grants and/or honoraria paid to her institution from AbbVie, Celgene, Seattle Genetics, PrIME/Medscape, Daiichi-Sankyo, Lilly, Samsung, BMS, Puma, Immunomedics, AstraZeneca, Pierre Fabre, Merck, GlaxoSmithKlein, EirGenix, and Bayer, and personal fees from Chugai; SL also has a patent EP14153692.0 pending. UM declares stock ownership in Abcodia Ltd. RAM has been a consultant for Pharmavite. No other authors have conflicts to declare., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Historically, human monkeypox virus cases in the UK have been limited to imported infections from west Africa. Currently, the UK and several other countries are reporting a rapid increase in monkeypox cases among individuals attending sexual health clinics, with no apparent epidemiological links to endemic areas. We describe demographic and clinical characteristics of patients diagnosed with human monkeypox virus attending a sexual health centre., Methods: In this observational analysis, we considered patients with confirmed monkeypox virus infection via PCR detection attending open-access sexual health clinics in London, UK, between May 14 and May 25, 2022. We report hospital admissions and concurrent sexually transmitted infection (STI) proportions, and describe our local response within the first 2 weeks of the outbreak., Findings: Monkeypox virus infection was confirmed in 54 individuals, all identifying as men who have sex with men (MSM), with a median age of 41 years (IQR 34-45). 38 (70%) of 54 individuals were White, 26 (48%) were born in the UK, and 13 (24%) were living with HIV. 36 (67%) of 54 individuals reported fatigue or lethargy, 31 (57%) reported fever, and ten (18%) had no prodromal symptoms. All patients presented with skin lesions, of which 51 (94%) were anogenital. 37 (89%) of 54 individuals had skin lesions affecting more than one anatomical site and four (7%) had oropharyngeal lesions. 30 (55%) of 54 individuals had lymphadenopathy. One in four patients had a concurrent STI. Five (9%) of 54 individuals required admission to hospital, mainly due to pain or localised bacterial cellulitis requiring antibiotic intervention or analgesia. We recorded no fatal outcomes., Interpretation: Autochthonous community monkeypox virus transmission is currently observed among MSM in the UK. We found a high proportion of concomitant STIs and frequent anogenital symptoms, suggesting transmissibility through local inoculation during close skin-to-skin or mucosal contact, during sexual activity. Additional resources are required to support sexual health and other specialist services in managing this condition. A review of the case definition and better understanding of viral transmission routes are needed to shape infection control policies, education and prevention strategies, and contact tracing., Funding: None., Competing Interests: Declaration of interests LSPM has consulted for or received speaker fees from bioMerieux, DNAelectronics, Eumedica, Dairy Crest, Pfizer, Profile Pharma, Umovis Lab, Kent Pharma, Pulmocide, Sumiovant, and Shionogi, and received research grants from the National Institute for Health Research, CW+ charity, and LifeArc. NG has consulted for or received speaker fees from Viiv Healthcare. JH has received a research grant from the CW+ charity. DA has consulted for or received speaker fees from Viiv Healthcare and Theratechnologies. BM-P has consulted for or received speaker fees from MSD. NM has consulted for or received speaker fees from Pfizer and Shionogi. MBo has consulted for or received speaker fees from Viiv Healthcare, Gilead, GlaxoSmithKline, Pfizer, Cypla, Mylan, and Janssen. MBo has also received research grants from Gilead, Viiv Healthcare, Mylan, Novavax, Janssen, Valneva, Moderna, and Roche. RJ has consulted for or received speaker fees from Viiv Healthcare and Gilead. GW has consulted for or received speaker fees from Viiv Healthcare and Gilead. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk., Methods: Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche., Results: In pooled analyses, later age at menarche was associated with higher per cent density (β √PD  = 0.023 SE = 0.008, P = 0.003) and larger dense area (β √DA  = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (β √DA  = 0.069 SE = 0.028, P = 0.012) and higher per cent density (β √PD  = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups., Conclusions: In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density., (© 2022. The Author(s).)

Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 × 10 -8 as genome-wide significant, and p-values < 1 × 10 -5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 × 10 5 . The strongest evidence was found for rs4674019 (p-value = 2.27 × 10 -7 ), which showed genome-wide significant interaction (p-value = 3.8 × 10 -8 ) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association., (© 2022. The Author(s).)