Statistical investigation of interdependence of trabecular microarchitectural parameters from micro-computed tomography.

Standard microarchitectural analysis of bone using micro-computed tomography produces a large number of parameters that quantify the structure of the trabecular network. Analyses that perform statistical tests on many parameters are at elevated risk of making Type I errors. However, when multiple testing correction procedures are applied, the risk of Type II errors is elevated if the parameters being tested are strongly correlated. In this article, we argue that four commonly used trabecular microarchitectural parameters (thickness, separation, number, and bone volume fraction) are interdependent and describe only two independent properties of the trabecular network. We first derive theoretical relationships between the parameters based on their geometric definitions. Then, we analyze these relationships with an aggregated in vivo dataset with 2987 images from 1434 participants and a synthetically generated dataset with 144 images using principal component analysis (PCA) and linear regression analysis. With PCA, when trabecular thickness, separation, number, and bone volume fraction are combined, we find that 92 % to 97 % of the total variance in the data is explained by the first two principal components. With linear regressions, we find high coefficients of determination (0.827-0.994) and fitted coefficients within expected ranges. These findings suggest that to maximize statistical power in future studies, only two of trabecular thickness, separation, number and bone volume fraction should be used for statistical testing.

Hypertension is associated with reduced resting-state medial temporal lobe dynamic network flexibility in older African Americans.

Hypertension disproportionately affects African Americans and is a risk factor for Alzheimer's disease (AD). We investigated the relationship of blood pressure (BP) with medial temporal lobe (MTL) dynamic network flexibility (a novel AD biomarker) and cognitive generalization in older African Americans. In a cross-sectional study, 37 normotensive (systolic BP <130 mmHg, 82.5% F, 64.4 ± 4.9 years; 14.3 ± 2.1 years of education) versus 79 hypertensive (systolic BP ≥130 mmHg, 79.5% F, 66.8 ± 4.1 years; 14.0 ± 0.2 years of education) participants were enrolled. All participants completed a 10-min resting-state functional magnetic resonance imaging scan to assess MTL dynamic network flexibility and two generalization tasks to assess cognition. Anthropometrics and aerobic fitness (via 6-min walk test) were also determined. There was no difference in BMI (29.7 ± 6.4 vs. 31.9 ± 6.3 kg/m2, p = 0.083) or aerobic fitness (15.5 ± 2.6 vs. 15.1 ± 2.6 mL/kg/min; p = 0.445) between normotensive and hypertensive groups. However, normotensive participants had higher MTL dynamic network flexibility compared to hypertensive participants (0.42 ± 0.23 vs. 0.32 ± 0.25 mL, p = 0.040), and this was associated with higher mean arterial blood pressure (r = -0.21, p = 0.036). Therefore, hypertensive older African Americans demonstrated lower MTL dynamic network flexibility compared to their normotensive counterparts independent of BMI and aerobic fitness. Further studies are required to determine how blood pressure mediates AD risk in African Americans.

Short-term revision rate of Rigicon Testi10TM testicular prosthesis in adolescents and adults: a retrospective chart review.

Testicular prosthesis implantation is a valuable solution for the physical, cosmetic, and psychological challenges associated with testicular loss which may affect males of any age. We evaluated the safety and reliability of the new Rigicon Testi10TM testicular prosthesis in adults and adolescents by performing an IRB-approved retrospective study of data drawn from Patient Information Forms (PIFs). A total of 427 patients (382 adults and 45 adolescents) had at least one testicular prosthesis implanted. Only one adult patient required revision surgery due to rupture of the Rigicon Testi10 TM saline-filled prosthesis. A 40-year-old patient was found to have a leaking prosthesis approximately one week postoperatively, which was suspected to be due to inadvertently punctured by the surgeon during the sterile saline filling process. There were no post-implantation revisions required for adolescent patients. According to our results, Kaplan-Meier calculation of survival from removal or revision was 99.8% for all patients at 54 months (99.7% for adults and 100% for adolescents). The complication rates among patients in this study are lower than those reported in previous published studies. Our study underscores the generally safe nature of testicular prosthesis implantation, as well as the very rare incidence of revision surgery for this new device.

Streamlining the automated discovery of porous organic cages.

Self-assembly through dynamic covalent chemistry (DCC) can yield a range of multi-component organic assemblies. The reversibility and dynamic nature of DCC has made prediction of reaction outcome particularly difficult and thus slows the discovery rate of new organic materials. In addition, traditional experimental processes are time-consuming and often rely on serendipity. Here, we present a streamlined hybrid workflow that combines automated high-throughput experimentation, automated data analysis, and computational modelling, to accelerate the discovery process of one particular subclass of molecular organic materials, porous organic cages. We demonstrate how the design and implementation of this workflow aids in the identification of organic cages with desirable properties. The curation of a precursor library of 55 tri- and di-topic aldehyde and amine precursors enabled the experimental screening of 366 imine condensation reactions experimentally, and 1464 hypothetical organic cage outcomes to be computationally modelled. From the screen, 225 cages were identified experimentally using mass spectrometry, 54 of which were cleanly formed as a single topology as determined by both turbidity measurements and 1H NMR spectroscopy. Integration of these characterisation methods into a fully automated Python pipeline, named cagey, led to over a 350-fold decrease in the time required for data analysis. This work highlights the advantages of combining automated synthesis, characterisation, and analysis, for large-scale data curation towards an accessible data-driven materials discovery approach.

Cardiovascular Risk Estimation Is Suboptimal in People With HIV.

BACKGROUND: Established cardiovascular disease (CVD) risk prediction functions may not accurately predict CVD risk in people with HIV. We assessed the performance of 3 CVD risk prediction functions in 2 HIV cohorts. METHODS AND RESULTS: CVD risk scores were calculated in the Mass General Brigham and Kaiser Permanente Northern California HIV cohorts, using the American College of Cardiology/American Heart Association atherosclerotic CVD function, the FHS (Framingham Heart Study) hard coronary heart disease function and the Framingham Heart Study hard CVD function. Outcomes were myocardial infarction or coronary death for FHS hard coronary heart disease function; and myocardial infarction, stroke, or coronary death for American College of Cardiology/American Heart Association and FHS hard CVD function. We calculated regression coefficients and assessed discrimination and calibration by sex; predicted to observed risk of outcome was also compared. In the combined cohort of 9412, 158 (1.7%) had a coronary heart disease event, and 309 (3.3%) had a CVD event. Among women, CVD risk was generally underestimated by all 3 risk functions. Among men, CVD risk was underestimated by the American College of Cardiology/American Heart Association and FHS hard CVD function, but overestimated by the FHS hard coronary heart disease function. Calibration was poor for women using the FHS hard CVD function and for men using all functions. Discrimination in all functions was good for women (c-statistics ranging from 0.78 to 0.90) and moderate for men (c-statistics ranging from 0.71 to 0.72). CONCLUSIONS: Established CVD risk prediction functions generally underestimate risk in people with HIV. Differences in model performance by sex underscore the need for both HIV-specific and sex-specific functions. Development of CVD risk prediction models tailored to HIV will enhance care for aging people with HIV.

Benchmarking of X-Ray Fluorescence Microscopy with Ion Beam Implanted Samples Showing Detection Sensitivity of Hundreds of Atoms.

Single impurities in insulators are now often used for quantum sensors and single photon sources, while nanoscale semiconductor doping features are being constructed for electrical contacts in quantum technology devices, implying that new methods for sensitive, non-destructive imaging of single- or few-atom structures are needed. X-ray fluorescence (XRF) can provide nanoscale imaging with chemical specificity, and features comprising as few as 100 000 atoms have been detected without any need for specialized or destructive sample preparation. Presently, the ultimate limits of sensitivity of XRF are unknown - here, gallium dopants in silicon are investigated using a high brilliance, synchrotron source collimated to a small spot. It is demonstrated that with a single-pixel integration time of 1 s, the sensitivity is sufficient to identify a single isolated feature of only 3000 Ga impurities (a mass of just 350 zg). With increased integration (25 s), 650 impurities can be detected. The results are quantified using a calibration sample consisting of precisely controlled numbers of implanted atoms in nanometer-sized structures. The results show that such features can now be mapped quantitatively when calibration samples are used, and suggest that, in the near future, planned upgrades to XRF facilities might achieve single-atom sensitivity.

Improved mouse models of the small intestine microbiota using region-specific sampling from humans.

Our understanding of region-specific microbial function within the gut is limited due to reliance on stool. Using a recently developed capsule device, we exploit regional sampling from the human intestines to develop models for interrogating small intestine (SI) microbiota composition and function. In vitro culturing of human intestinal contents produced stable, representative communities that robustly colonize the SI of germ-free mice. During mouse colonization, the combination of SI and stool microbes altered gut microbiota composition, functional capacity, and response to diet, resulting in increased diversity and reproducibility of SI colonization relative to stool microbes alone. Using a diverse strain library representative of the human SI microbiota, we constructed defined communities with taxa that largely exhibited the expected regional preferences. Response to a fiber-deficient diet was region-specific and reflected strain-specific fiber-processing and host mucus-degrading capabilities, suggesting that dietary fiber is critical for maintaining SI microbiota homeostasis. These tools should advance mechanistic modeling of the human SI microbiota and its role in disease and dietary responses.

Drivers and implications of alternative routes to fuels decarbonization in net-zero energy systems.

Energy transition scenarios are characterized by increasing electrification and improving efficiency of energy end uses, rapid decarbonization of the electric power sector, and deployment of carbon dioxide removal (CDR) technologies to offset remaining emissions. Although hydrocarbon fuels typically decline in such scenarios, significant volumes remain in many scenarios even at the time of net-zero emissions. While scenarios rely on different approaches for decarbonizing remaining fuels, the underlying drivers for these differences are unclear. Here we develop several illustrative net-zero systems in a simple structural energy model and show that, for a given set of final energy demands, assumptions about the use of biomass and CO2 sequestration drive key differences in how emissions from remaining fuels are mitigated. Limiting one resource may increase reliance on another, implying that decisions about using or restricting resources in pursuit of net-zero objectives could have significant tradeoffs that will need to be evaluated and managed.

Accurate automated segmentation of autophagic bodies in yeast vacuoles using cellpose 2.0.

Segmenting autophagic bodies in yeast TEM images is a key technique for measuring changes in autophagosome size and number in order to better understand macroautophagy/autophagy. Manual segmentation of these images can be very time consuming, particularly because hundreds of images are needed for accurate measurements. Here we describe a validated Cellpose 2.0 model that can segment these images with accuracy comparable to that of human experts. This model can be used for fully automated segmentation, eliminating the need for manual body outlining, or for model-assisted segmentation, which allows human oversight but is still five times as fast as the current manual method. The model is specific to segmentation of autophagic bodies in yeast TEM images, but researchers working in other systems can use a similar process to generate their own Cellpose 2.0 models to attempt automated segmentations. Our model and instructions for its use are presented here for the autophagy community.Abbreviations: AB, autophagic body; AvP, average precision; GUI, graphical user interface; IoU, intersection over union; MVB, multivesicular body; ROI, region of interest; TEM, transmission electron microscopy; WT,wild type.

Echocardiographic assessment of cardiovascular physiology of preterm miniature piglets supported with a pumped artificial placenta system.

OBJECTIVES: We evaluated fetal cardiovascular physiology and mode of cardiac failure in premature miniature piglets on a pumped artificial placenta (AP) circuit. METHODS: Fetal pigs were cannulated via the umbilical vessels and transitioned to an AP circuit composed of a centrifugal pump and neonatal oxygenator and maintained in a fluid-filled biobag. Echocardiographic studies were conducted to measure ventricular function, umbilical blood flow, and fluid status. In utero scans were used as control data. RESULTS: AP fetuses (n = 13; 102±4d gestational age [term 115d]; 616 ± 139 g [g]; survival 46.4 ± 46.8 h) were tachycardic and hypertensive with initially supraphysiologic circuit flows. Increased myocardial wall thickness was observed. Signs of fetal hydrops were present in all piglets. Global longitudinal strain (GLS) measurements increased in the left ventricle (LV) after transition to the circuit. Right ventricle (RV) and LV strain rate decreased early during AP support compared with in utero measurements but recovered toward the end of the experiment. Fetuses supported for >24 h had similar RV GLS to in utero controls and significantly higher GLS compared to piglets surviving only up to 24 h. CONCLUSIONS: Fetuses on a pump-supported AP circuit experienced an increase in afterload, and redistribution of blood flow between the AP and systemic circulations, associated with elevated end-diastolic filling pressures. This resulted in heart failure and hydrops. These preterm fetuses were unable to tolerate the hemodynamic changes associated with connection to the current AP circuit. To better mimic the physiology of the native placenta and preserve normal fetal cardiovascular physiology, further optimization of the circuit will be required.

VDX-111 targets proliferative pathways in canine cancer cell lines.

VDX-111 (also identified as AMPI-109) is a vitamin D derivative which has shown anticancer activity. To further assess the function of this compound against multiple cancer types, we examined the efficacy of VDX-111 against a panel of 30 well characterized canine cancer cell lines. Across a variety of cancer types, VDX-111 induced widely variable growth inhibition, cell death, and migration inhibition, at concentrations ranging from 10 nM to 1 µM. Growth inhibition sensitivity did not correlate strongly with tumor cell histotype; however, it was significantly correlated with the expression of genes in multiple cell signaling pathways, including the MAPK and PI3K-AKT pathways. We confirmed inhibition of these signaling pathways as likely participants in the effects of VDX-111. These results suggest that a subset of canine tumors may be sensitive to treatment with VDX-111, and suggests possible predictive markers of drug sensitivity and pharmacodynamic biomarkers of drug exposure that could be employed in future clinical trials.

Functional dissection of complex and molecular trait variants at single nucleotide resolution.

Identifying the causal variants and mechanisms that drive complex traits and diseases remains a core problem in human genetics. The majority of these variants have individually weak effects and lie in non-coding gene-regulatory elements where we lack a complete understanding of how single nucleotide alterations modulate transcriptional processes to affect human phenotypes. To address this, we measured the activity of 221,412 trait-associated variants that had been statistically fine-mapped using a Massively Parallel Reporter Assay (MPRA) in 5 diverse cell-types. We show that MPRA is able to discriminate between likely causal variants and controls, identifying 12,025 regulatory variants with high precision. Although the effects of these variants largely agree with orthogonal measures of function, only 69% can plausibly be explained by the disruption of a known transcription factor (TF) binding motif. We dissect the mechanisms of 136 variants using saturation mutagenesis and assign impacted TFs for 91% of variants without a clear canonical mechanism. Finally, we provide evidence that epistasis is prevalent for variants in close proximity and identify multiple functional variants on the same haplotype at a small, but important, subset of trait-associated loci. Overall, our study provides a systematic functional characterization of likely causal common variants underlying complex and molecular human traits, enabling new insights into the regulatory grammar underlying disease risk.

Adiposity, immunity, and inflammation: interrelationships in health and disease: a report from 24th Annual Harvard Nutrition Obesity Symposium, June 2023.

The rapidly evolving field of immunometabolism explores how changes in local immune environments may affect key metabolic and cellular processes, including that of adipose tissue. Importantly, these changes may contribute to low-grade systemic inflammation. In turn, chronic low-grade inflammation affecting adipose tissue may exacerbate the outcome of metabolic diseases. Novel advances in our understanding of immunometabolic processes may critically lead to interventions to reduce disease severity and progression. An important example in this regard relates to obesity, which has a multifaceted effect on immunity, activating the proinflammatory pathways such as the inflammasome and disrupting cellular homeostasis. This multifaceted effect of obesity can be investigated through study of downstream conditions using cellular and systemic investigative techniques. To further explore this field, the National Institutes of Health P30 Nutrition Obesity Research Center at Harvard, in partnership with Harvard Medical School, assembled experts to present at its 24th Annual Symposium entitled "Adiposity, Immunity, and Inflammation: Interrelationships in Health and Disease" on 7 June, 2023. This manuscript seeks to synthesize and present key findings from the symposium, highlighting new research and novel disease-specific advances in the field. Better understanding the interaction between metabolism and immunity offers promising preventative and treatment therapies for obesity-related immunometabolic diseases.

Gender differences in risk and resilience for suicidal thoughts and behaviors: A national longitudinal survey study of United States veterans with a recent suicide attempt.

BACKGROUND: This study reports on gender differences in psychosocial symptoms and suicidal thoughts and behaviors from the first longitudinal, national survey of veterans with a recent nonfatal suicide attempt to inform women-tailored suicide prevention. METHODS: We recruited all female veterans with a documented nonfatal suicide attempt between October 2018 and September 2019 and a stratified matched sample of males. Surveys were administered at baseline, month 6, and month 12; 968 veterans completed the baseline survey with valid gender data. Surveys assessed psychosocial constructs, suicidal ideation severity, and suicidal behavior. Administrative datasets provided healthcare and suicide attempt data during the one year follow up. RESULTS: Women retained higher social rejection and institutional betrayal, and lower self-compassion and autonomy than men over follow up. Higher overall self-compassion was associated with lower baseline suicide ideation for both women and men; however, this association was stronger for women (Δ = -0.19; 95 % CI = -0.31, -0.07; d = -0.15). Individuals with higher overall psychological distress had greater odds of a subsequent suicide attempt (AOR = 2.20, 95 % CI = 1.56, 3.11). Social rejection had the strongest association with worsening psychological distress, both within individuals (b = 0.18; 95 % CI = 0.14, 0.23; d = 0.23) and between individuals (b = 0.07; 95 % CI = 0.04, 0.10; d = 0.09). LIMITATIONS: Results may not generalize beyond a VHA-utilizing veteran population. CONCLUSIONS: Findings from this study inform potential therapeutic targets and topics for future research on tailoring suicide prevention for women veterans. While all veterans may need support reducing distress, women may need additional support in multiple other areas.

Coronary Microvascular Dysfunction Is Present Among Well-Treated Asymptomatic Persons With HIV and Similar to Those With Diabetes.

Background: Coronary microvascular dysfunction (CMD) could be a potential underlying mechanism for myocardial disease in HIV. Methods: Comparisons of coronary flow reserve corrected for heart rate-blood pressure product (CFRCOR) were made among people with HIV (PWH) with no known history of cardiovascular disease (CVD) or diabetes mellitus, persons without HIV (PWOH), and persons with diabetes (PWDM) and no known history of CVD or HIV. Results: PWH (n = 39, 74% male, age 55 [7] years, body mass index [BMI] 32.3 (26.8-34.9) kg/m2, duration of antiretroviral therapy 13 [5] years, CD4+ count 754 [598-961] cells/µL) were similar to PWOH (n = 69, 74% male, age 55 [8] years, BMI 32.2[25.6-36.5] kg/m2) and PWDM (n = 63, 63% male, age 55 [8] years, BMI 31.5 [28.6-35.6] kg/m2). CFRCOR was different among groups: PWOH 2.76 (2.37-3.36), PWH 2.47 (1.92-2.93), and PWDM 2.31 (1.98-2.84); overall P = .003. CFRCOR was reduced comparing PWH to PWOH (P = .04) and PWDM to PWOH (P = .007) but did not differ when comparing PWH to PWDM (P = .98). A total 31% of PWH had CFRCOR < 2.0, a critical cutoff for CMD, compared to 14% of PWOH and 27% with PWDM. A total 40% of women with HIV had a CFRCOR < 2.0 compared to 6% of women without HIV (P = .02). Conclusions: Subclinical CMD is present among chronically infected and well-treated, asymptomatic PWH who are immunologically controlled. This study demonstrates CFR is reduced in PWH compared to PWOH and comparable to PWDM, further highlighting that well-treated HIV infection is a CVD-risk enhancing factor for CMD similar to diabetes. Clinical Trials Registration: NCT02740179.

The Impact of Financial Education on Stress Among Orthopaedic Surgeons.

BACKGROUND: Financial stress has been an increasing area of concern for residents and attendings. The primary goal of this study was to determine the financial education level and differentiate financial outcome measures of orthopaedic surgery residents and attendings. METHODS: A survey of all residents and attendings of the 201 Accreditation Council for Graduate Medical Education (ACGME)-accredited orthopaedic surgery programs in the United States. RESULTS: Total participation in the study was 118 residents (postgraduate year (PGY) 1-5), three fellows (PGY 6), and 57 attending orthopaedic surgeons. A significant difference existed between average current financial stress scores between residents versus attending (2.32 vs 1.17), but not Doctor of Medicine (MD) versus Doctor of Osteopathic Medicine (DO) attendings (0.96 vs 1.67) and MD versus DO residents (2.25 vs 2.50). There was a significant difference in average future financial stress scores between residents and attendings (1.85 vs 1.44) and MD vs DO residents (1.61 vs 2.25) but no difference between MD vs DO attending (1.31 vs 1.63). Residents' confidence in financial knowledge compared to college graduates had a significantly negative Pearson coefficient with current financial stress score, while the attending group was not significant. CONCLUSIONS: Orthopaedic residents and attending physicians' financial stress levels are positively correlated with the amount of student debt they hold. Most residents who currently have no personal finance education offered in their residency would likely attend a personal finance course if offered. Decreasing the amount of debt held by residents, increasing their financial knowledge, and helping them develop good financial habits would likely lead to a decrease in financial stress.