Cherenkov imaging combined with scintillation dosimetry provides real-time positional and dose monitoring for radiotherapy patients with cardiac implanted electronic devices.

Background and purpose: Cardiac implanted electronic devices (CIED) require dose monitoring during each fraction of radiotherapy, which can be time consuming and may have delayed read-out times. This study explores the potential of Cherenkov imaging combined with scintillation dosimetry as an alternative verification system. Methods and materials: Time-gated, complementary metal-oxide-semiconductor (iCMOS) cameras were used to collect video images of anthropomorphic phantoms and patients undergoing radiation treatment near chest wall cardiac devices. Scintillator discs and optically stimulated luminescence dosimeters (OSLDs) were used for dose measurement. Accuracy of spatial delivery was assessed by overlaying predicted surface dose outlines derived from the treatment planning system (TPS) with the Cherenkov images. Dose measurements from OSLDs and scintillators were compared. Results: In phantom studies, Cherenkov images visibly indicated when dose was delivered to the CIED as compared to non-overlapping dose deliveries. Comparison with dose overlays revealed congruence at the planned position and non-congruence when the phantom was shifted from the initial position. Absolute doses derived from scintillator discs aligned well with the OSLD measurements and TPS predictions for three different positions, measuring within 10 % for in-field positions and within 5 % for out-of-field positions. For two patients with CIEDs imaged over 18 fractions, Cherenkov imaging confirmed positional accuracy for all fractions, and dose measured by scintillator discs deviated by <0.015 Gy from the OSLD measurements. Conclusions: Cherenkov imaging combined with scintillation dosimetry presents an alternative methodology for CIED monitoring with the added benefit of instantly detecting deviations, enabling timely corrective actions or proper patient triage.

Design and Rationale of the V-Wave Shunt MitraClip Study.

Heart failure (HF) and moderate-to-severe mitral regurgitation (MR) with residual elevations in left atrial pressure (LAP) after MitraClip may remain symptomatic and experience subsequent HF readmissions. The V-Wave interatrial shunt system is a permanent interatrial septal implant that shunts blood from the left-to-right atrium and serves to continuously unload the left atrium. Although the V-Wave shunt has previously been studied in patients with HF, the safety and feasibility of its deployment at the time of the MitraClip procedure is unknown. The V-Wave Shunt MitraClip Study (NCT04729933) is an early feasibility study that aims to demonstrate the safety and efficacy of implantation of the V-Wave shunt device at the time of MitraClip procedure. Patients with moderate-to-severe secondary MR with left ventricular ejection fraction 20% to 50% and New York Heart Association functional class III/IV symptoms despite optimal medical therapy, residual mean LAP ≥20 mm Hg after MitraClip, and mean LAP-right atrial pressure difference ≥5 mm Hg are included. The primary safety end point is a composite outcome of all-cause death, stroke, myocardial infarction device embolization, cardiac tamponade, or device-related re-intervention or surgery at 30 days. Patients will be followed up to 5 years. Enrollment is ongoing, with 30-day results expected by the end of 2024. The V-Wave Shunt Mitraclip Study aims to demonstrate the safety and efficacy of the implantation of the V-Wave interatrial shunt device at the time of index MitraClip placement which may serve as an adjunctive method by which continuous left atrial unloading may be achieved.

Imputation of ancient canid genomes reveals inbreeding history over the past 10,000 years.

The multi-millenia long history between dogs and humans has placed them at the forefront of archeological and genomic research. Despite ongoing efforts including the analysis of ancient dog and wolf genomes, many questions remain regarding their geographic and temporal origins, and the microevolutionary processes that led to the diversity of breeds today. Although ancient genomes provide valuable information, their use is hindered by low depth of coverage and post-mortem damage, which inhibits confident genotype calling. In the present study, we assess how genotype imputation of ancient dog and wolf genomes, utilising a large reference panel, can improve the resolution provided by ancient datasets. Imputation accuracy was evaluated by down-sampling high coverage dog and wolf genomes to 0.05-2x coverage and comparing concordance between imputed and high coverage genotypes. We measured the impact of imputation on principal component analyses and runs of homozygosity. Our findings show high (R2>0.9) imputation accuracy for dogs with coverage as low as 0.5x and for wolves as low as 1.0x. We then imputed a dataset of 90 ancient dog and wolf genomes, to assess changes in inbreeding during the last 10,000 years of dog evolution. Ancient dog and wolf populations generally exhibited lower inbreeding levels than present-day individuals. Interestingly, regions with low ROH density maintained across ancient and present-day samples were significantly associated with genes related to olfaction and immune response. Our study indicates that imputing ancient canine genomes is a viable strategy that allows for the use of analytical methods previously limited to high-quality genetic data.

Deep mutational scanning of influenza A virus NEP reveals pleiotropic mutations in its N-terminal domain.

The influenza A virus nuclear export protein (NEP) is a multifunctional protein that is essential for the viral life cycle and has very high sequence conservation. However, since the open reading frame of NEP largely overlaps with that of another influenza viral protein, non-structural protein 1, it is difficult to infer the functional constraints of NEP based on sequence conservation analysis. Besides, the N-terminal of NEP is structurally disordered, which further complicates the understanding of its function. Here, we systematically measured the replication fitness effects of >1,800 mutations of NEP. Our results show that the N-terminal domain has high mutational tolerance. Additional experiments demonstrate that N-terminal domain mutations pleiotropically affect viral transcription and replication dynamics, host cellular responses, and mammalian adaptation of avian influenza virus. Overall, our study not only advances the functional understanding of NEP, but also provides insights into its evolutionary constraints.

Effect of Three-Dimensional-Printed Thermoplastics Used in Sensor Housings on Common Atmospheric Trace Gasses.

Low-cost air quality sensors (LCSs) are becoming more ubiquitous as individuals and communities seek to reduce their exposure to poor air quality. Compact, efficient, and aesthetically designed sensor housings that do not interfere with the target air quality measurements are a necessary component of a low-cost sensing system. The selection of appropriate housing material can be an important factor in air quality applications employing LCSs. Three-dimensional printing, specifically fused deposition modeling (FDM), is a standard for prototyping and small-scale custom plastics production because of its low cost and ability for rapid iteration. However, little information exists about whether FDM-printed thermoplastics affect measurements of trace atmospheric gasses. This study investigates how five different FDM-printed thermoplastics (ABS, PETG, PLA, PC, and PVDF) affect the concentration of five common atmospheric trace gasses (CO, CO2, NO, NO2, and VOCs). The laboratory results show that the thermoplastics, except for PVDF, exhibit VOC off-gassing. The results also indicate no to limited interaction between all of the thermoplastics and CO and CO2 and a small interaction between all of the thermoplastics and NO and NO2.

Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.

Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.

Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations.

Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment.

MBD2 couples DNA methylation to transposable element silencing during male gametogenesis.

DNA methylation is an essential component of transposable element (TE) silencing, yet the mechanism by which methylation causes transcriptional repression remains poorly understood1-5. Here we study the Arabidopsis thaliana Methyl-CpG Binding Domain (MBD) proteins MBD1, MBD2 and MBD4 and show that MBD2 acts as a TE repressor during male gametogenesis. MBD2 bound chromatin regions containing high levels of CG methylation, and MBD2 was capable of silencing the FWA gene when tethered to its promoter. MBD2 loss caused activation at a small subset of TEs in the vegetative cell of mature pollen without affecting DNA methylation levels, demonstrating that MBD2-mediated silencing acts strictly downstream of DNA methylation. TE activation in mbd2 became more significant in the mbd5 mbd6 and adcp1 mutant backgrounds, suggesting that MBD2 acts redundantly with other silencing pathways to repress TEs. Overall, our study identifies MBD2 as a methyl reader that acts downstream of DNA methylation to silence TEs during male gametogenesis.

100 ancient genomes show repeated population turnovers in Neolithic Denmark.

Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1-4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5-7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.

The selection landscape and genetic legacy of ancient Eurasians.

The Holocene (beginning around 12,000 years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical and mental health of present-day populations. Using a dataset of more than 1,600 imputed ancient genomes1, we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify key selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in over 400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, whereas risk alleles for diabetes and Alzheimer's disease are enriched for Western hunter-gatherer ancestry. Our results indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans.

Population genomics of post-glacial western Eurasia.

Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

Preradiosurgical Embolization of Arteriovenous Malformations Reduces Target Volume - The Main Determinant for Complete Obliteration.

BACKGROUND: Embolization and stereotactic radiosurgery (SRS) have increasingly been used to treat complex arteriovenous malformations (AVMs). We studied outcomes of AVM patients treated through a multidisciplinary approach, examined the effect of embolization on SRS success, and analyzed predictors of treatment failure. METHODS: We retrospectively reviewed a prospectively maintained database of patients with AVMs treated with Gamma Knife (Leksell) SRS over an 11-year period. Patients with incomplete medical records and follow-up <2 years were excluded. Demographics, clinical presentation, previous rupture history, angiographic nidus size, Spetzler-Martin (S-M) grade, adjunctive endovascular embolization and microsurgical resection, radiologic evidence of obliteration and hemorrhage, and clinical outcomes (modified Rankin Scale [mRS] scores) were recorded. Radiosurgery-related details including nidus volume and number of sessions and radiosurgery-, embolization-, and resection-associated complications were also recorded. RESULTS: Eighty-three patients (mean age, 41.0 ± 21.3 years) were included. Mean reduction in AVM nidus target volume with endovascular embolization was 66.0 ± 19.7%. S-M grade reduction was achieved in 51.6% cases. Total obliteration after SRS was achieved in 56 AVMs (67.5%) after 2 years, and in 38 (86.4%) after 4 years. Two (2.4%) patients had rehemorrhage after SRS. Overall complication rate was 3.6%. Median angiographic follow-up was 55.5 months. Favorable outcomes (mRS = 0-2) were seen in 77.1%. SRS target volume was an independent predictor of treatment failure regardless of pre-SRS embolization. CONCLUSIONS: High AVM obliteration rates were achieved with judicious use of radiosurgery alone or with embolization. Embolization reduced target nidus volume by an average of 66%. SRS target volume was an independent predictor of treatment failure.

Compliance with U.S. Government Nutrition Advice and Concurrent Obesity Trends Using Nurses' Health Study Data, 1980-2011.

BACKGROUND: Beginning in 1977, the U.S. Government began formally issuing dietary advice, a main objective of which was to reduce and prevent the prevalence of obesity in the American population. Concurrently, the Harvard School of Public Health began conducting dietary intake surveys and collecting body mass index (BMI) (kg/m2) data on female nurses in the Nurses' Health Study I (NHSI) and II (NHSII). OBJECTIVES: We aimed to assess whether compliance with the nutrition guidance from the U.S. Government to restrict dietary intake regarding total fat, saturated fat, and cholesterol was meaningfully associated with the prevalence of obesity. METHODS: We analyzed nutrition survey data from 1980 to 2011, grouping the sample into "compliers," those who complied with guidance on the intake of total fat, saturated fat, and cholesterol, and "noncompliers," those who did not. We then compared the means, medians, and distributions of BMI for compliers and noncompliers over the period for both the full survey population and an age-controlled sample. Finally, we plotted raw NHS data to examine respondents' Fat Proportion intake of energy and concurrent BMI. RESULTS: The mean and median BMI for both compliers and noncompliers increased throughout the sample period, and the BMI distributions shifted toward obese and severely obese overall and for an age-controlled subset compared with the 1980 NHSI and 1990 NHSII baselines. Compliers had slightly lower mean BMI increases than noncompliers but saw a relatively higher increase in the growth of the prevalence of those with BMI >30. We also found no linear relationship between Fat Proportion of energy intake and concurrent BMI. CONCLUSIONS: Guidance from the U.S. Government to limit fat, saturated fat, and cholesterol consumption was widely adopted by American female nurses during the study period. Our results show that compliance with this guidance had little if any effect in mitigating population-wide BMI increases during our study period.

Metabolic partitioning in the brain and its hijacking by glioblastoma.

The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron-astrocyte glutamate-glutamine cycle. An emerging theme in glioblastoma (GBM) biology is that malignant cells integrate into or "hijack" brain metabolism, co-opting neurons and glia for the supply of nutrients and recycling of waste products. Moreover, GBM cells communicate via signaling metabolites in the tumor microenvironment to promote tumor growth and induce immune suppression. Recent findings in this field point toward new therapeutic strategies to target the metabolic exchange processes that fuel tumorigenesis and suppress the anticancer immune response in GBM. Here, we provide an overview of the intercellular division of metabolic labor that occurs in both the normal brain and the GBM tumor microenvironment and then discuss the implications of these interactions for GBM therapy.

Postoperative Complications of True Dropless Cataract Surgery versus Standard Topical Drops.

Purpose Compare postoperative outcomes in cataract surgery between eyes with standard drop regimen versus dropless protocol by residents. Design Retrospective cohort study between April 1, 2018 and March 31, 2020. Methods The study was performed at Lyndon B. Johnson General Hospital in Houston, Harris County, Texas. A total of 547 eyes (234 dropless vs. 313 standard) with phacoemulsification cataract surgery and minimum of 1-month follow-up with best-corrected visual acuity (BCVA) were included. Dropless received 40 mg sub-Tenon's triamcinolone and intracameral moxifloxacin. Patients were followed at postoperative day 1 (POD1), week 1 (POW1), and month 1 (POM1). Postoperative rate of BCVA better than 20/40 (Good vision) and rate of complications were compared between groups. Results Good vision on POM1 in dropless (77.8%) was noninferior to standard (75.1%, p = 0.80). Complication rate in dropless (28.6%) was noninferior to standard (24.0%, p = 0.13). Intraocular pressure (IOP) elevation on POD1 ( p = 0.041) and anterior chamber (AC) cells on POW1 and POM1 ( p < 0.001) were more frequent in dropless. Mean spherical equivalent at POM1 was better in dropless (-0.37 D [±0.81 D]) compared with standard (-0.61D [±0.77 D], p = 0.001). Early posterior capsular opacification (early PCO) was more frequent in dropless ( p = 0.042). Conclusions Postoperative rate of BCVA better than 20/40 and rate of postoperative complications were noninferior, although dropless had higher rates of AC inflammation, IOP elevation, and early PCO.

The Effects of Safe Zone Badges in Physicians' Online Biographies: Evidence from an Experimental Study.

Earning digital badges to showcase a person's expertise or knowledge are becoming increasingly popular. A healthcare provider's displaying of a Safe Zone badge within their online profile may offer prospective patients a cue as to the kind of care they might receive if they selected that particular provider. Prior research indicates LGBTQ+ individuals are looking for these types of cues within providers' biographies to make their selections. A between subjects, 2 (Safe Zone badge present/absent) x 2 (male/female doctor) online experiment was conducted (n = 658). Results revealed a main effect for the presence of the Safe Zone badge. Participants had greater anticipated satisfaction, liking, were more likely to view the provider as approachable, and were more willing to schedule an appointment with the provider displaying a Safe Zone badge.

Qualitative feasibility study of the mobile app Destroke for clinical stroke monitoring based on the NIH stroke scale.

Background: Stroke is a leading cause of severe disability in the United States, but there is no effective method for patients to accurately detect the signs of stroke at home. We developed a mobile app, Destroke, that allows remote performance of a modified NIH stroke scale (NIHSS) by patients. Aims: To assess the feasibility of a mobile app for stroke monitoring and education by patients with a history of stroke. Materials and methods: We enrolled 25 patients with a history of stroke in a prospective open-label study to evaluate the feasibility of the Destroke app in patients with stroke. Nineteen patients completed all study assessments, with a median time from stroke onset to enrollment of 5.6 years (range 0.1-12 years). We designed a modified NIHSS that assessed 12 out of 16 tasks on the NIHSS. Patients completed this test eight times over a 28-day period. We conducted pre-study surveys that assessed demographic information, stroke and cardiovascular history, baseline NIHSS, and experience using mobile technologies, and mid- and post-study surveys that assessed patient satisfaction on app usage and confidence in stroke detection. Results: Ten men and nine women participated in this study (median age of 64 (33-76)), representing ten US states and Washington D.C. Median baseline NIHSS was 0 (0-4). 15 patients reported using health apps. On a 5-point Likert scale, patients rated the app as 4.2 on being able to understand and use the app and 4.3 on using the app when instructed by their doctor. For eight patients with poor confidence in detecting the signs of a stroke before the study, six showed higher confidence after the study. Conclusions: The use of an at-home stroke monitoring app is feasible by patients with a history of stroke and improves confidence in detecting the signs of stroke.