Search

Abstract Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.

Abstract New strategies for converting signals between optical and microwave domains could play a pivotal role in advancing both classical and quantum technologies. Traditional approaches to optical-to-microwave transduction typically perturb or destroy the information encoded on intensity of the light field, eliminating the possibility for further processing or distribution of these signals. In this paper, we introduce an optical-to-microwave conversion method that allows for both detection and spectral analysis of microwave photonic signals without degradation of their information content. This functionality is demonstrated using an optomechanical waveguide integrated with a piezoelectric transducer. Efficient electromechanical and optomechanical coupling within this system permits bidirectional optical-to-microwave conversion with a quantum efficiency of up to −54.16 dB. Leveraging the preservation of the optical field envelope in intramodal Brillouin scattering, we demonstrate a multi-channel microwave photonic filter by transmitting an optical signal through a series of electro-optomechanical waveguide segments, each with distinct resonance frequencies. Such electro-optomechanical systems could offer flexible strategies for remote sensing, channelization, and spectrum analysis in microwave photonics.

Abstract Duchenne muscular dystrophy (DMD) is characterised by respiratory muscle injury, inflammation, fibrosis and weakness, ultimately culminating in respiratory failure. The dystrophin‐deficient mouse model of DMD (mdx) shows evidence of respiratory muscle remodelling and dysfunction contributing to impaired respiratory system performance. The antioxidant N‐acetylcysteine (NAC) has been shown to exert anti‐inflammatory and anti‐fibrotic effects leading to improved respiratory muscle performance in a range of animal models of muscle dysfunction, including mdx mice, following short‐term administration (2 weeks). We sought to build on previous work by exploring the effects of chronic NAC administration (3 months) on respiratory system performance in mdx mice. One‐month‐old male mdx mice were randomised to receive normal drinking water (n = 30) or 1% NAC in the drinking water (n = 30) for 3 months. At 4 months of age, we assessed breathing in conscious mice by plethysmography followed by ex vivo assessment of diaphragm force‐generating capacity. Additionally, diaphragm histology was performed. In separate studies, in anaesthetised mice, respiratory electromyogram (EMG) activity and inspiratory pressure across a range of behaviours were determined, including assessment of peak inspiratory pressure‐generating capacity. NAC treatment did not affect force‐generating capacity of the mdx diaphragm. Collagen content and immune cell infiltration were unchanged in mdx + NAC compared with mdx diaphragms. Additionally, there was no significant effect of NAC on breathing, ventilatory responsiveness, inspiratory EMG activity or inspiratory pressure across the range of behaviours from basal conditions to peak system performance. We conclude that chronic NAC treatment has no apparent beneficial effects on respiratory system performance in the mdx mouse model of DMD suggesting limited potential of NAC treatment alone for human DMD.

Abstract Herpes zoster (HZ) is caused by reactivation of latent infection of varicella zoster virus (VZV) in sensory (cranial, dorsal root) ganglia. Major risk factors for HZ are increasing age and immunosuppression. HZ ophthalmicus (HZO) is a subset of HZ with involvement of the ophthalmic division of the fifth cranial trigeminal nerve. Approximately 4–20% of patients with HZ develop HZO. Approximately 50% of patients with HZO develop ocular disease, among whom up to 25% develop chronic or recurrent disease. Common manifestations of ocular disease include conjunctivitis, keratitis, and uveitis, whereas optic neuropathy and retinitis are uncommon. Due to the potential for vision impairment, ocular involvement requires urgent ophthalmic consultation. Early recognition and timely treatment with antivirals may prevent ocular complications. HZO is preventable by vaccination against HZ. Vaccine efficacy/effectiveness studies have been largely conducted for HZ with few studies assessing HZO. Both the recombinant adjuvanted vaccine (RZV) and live-attenuated vaccine (ZVL) significantly reduce the incidence of HZ and HZO in older adults. RZV is more effective than ZVL. Data on the effectiveness of vaccines for prevention of recurrent disease in patients with HZO are limited; however, vaccination is recommended. Despite recommendations to vaccinate individuals likely to benefit from an HZ vaccine, coverage for adults remains suboptimal. Barriers to vaccination include patient beliefs about HZ or HZ vaccines, and factors related to healthcare providers. In particular, the lack of a recommendation from their primary care physician is often cited by patients as a reason for remaining unvaccinated. By encouraging vaccination against HZ, physicians not only prevent HZ and HZO but also potential vision loss due to HZO. Graphical abstract available for this article.

Adult degenerative scoliosis (ADS) is a coronal plane deformity often accompanied by sagittal plane malalignment. Surgical correction may involve the major and/or distally-located fractional curves (FCs). Correction of the FC has been increasingly recognized as key to ameliorating radicular pain localized to the FC levels. The present study aims to summarize the literature on the rationale for FC correction in ADS. Three databases were systematically reviewed to identify all primary studies reporting the rationale for correcting the FC in ADS. Articles were included if they were English full-text studies with primary data from ADS (≥ 18 years old) patients. Seventy-four articles were identified, of which 12 were included after full-text review. Findings suggest FC correction with long-segment fusion terminating at L5 increases the risk of distal junctional degeneration as compared to constructs instrumenting the sacrum. Additionally, circumferential fusion offers greater FC correction, lower reoperation risk, and shorter construct length. Minimally invasive surgery (MIS) techniques may offer effective radiographic correction and improve leg pain associated with foraminal stenosis on the FC concavity, though experiences are limited. Open surgery may be necessary to achieve adequate correction of severe, highly rigid deformities. Current data support major curve correction in ASD where the FC concavity and truncal shift are concordant, suggesting that the FC contributes to the patient’s overall deformity. Circumferential fusion and the use of kickstand rods can improve correction and enhance the stability and durability of long constructs. Last, MIS techniques show promise for milder deformities but require further investigation.

Abstract Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts’ increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR.

Intense ionization enhancements in the Earth’s ionosphere, known as sporadic-E (Es), can degrade and severely disrupt the propagation of radio signals. Although many previous studies have analyzed the characteristics and morphologies of sporadic-E, few efforts have attempted to model global Es occurrence rates (ORs) at high time resolutions. This study develops a global empirical model of blanketing sporadic-E occurrence rates using a Karhunen–Loéve Expansion (KLE) of a global OR climatology built with Global Navigation Satellite System radio occultation (GNSS-RO) and ionosonde observations. Using an fbE ≥ threshold of 3 MHz, the model outputs a blanketing sporadic-E OR for a given geomagnetic latitude, longitude, day of year, and local solar time. The model outputs are compared to digisonde observations at four sites with varying geomagnetic latitudes, resulting in correlation coefficients ranging from 0.5 to 0.9 for monthly averaged observations and an uncertainty of 11%. Furthermore, the average uncertainty is estimated to be 12%. This Global Empirical Model of Sporadic-E Occurrence Rates (GEMSOR) is capable of providing blanketing sporadic-E OR estimates for global radio frequency (RF) operations.

IntroductionInadequate ventilation and improper use of personal protective equipment are often observed in many occupational settings with a high risk of dust and other fine particle exposure. Workers who are exposed to dust at work may suffer from respiratory difficulties. Previous systematic reviews on organic dust exposure and its association with respiratory health outcomes did not provide a comprehensive assessment. Therefore, the objective of this systematic review and meta-analysis was to summarize the reported effects of organic dust exposure on lung function parameters among African industrial workers.MethodsA compressive literature search was conducted in PubMed, MEDLINE, Google Scholar, Embase, the Web of Science, African Journals Online, and ScienceDirect databases to identify relevant studies for the review. The Newcastle–Ottawa Scale (NOS) was used to assess the quality of the included studies. The lung function indices including forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), the FEV1/FVC ratio, and peak expiratory flow rate (PEFR) were obtained from primary studies and analyzed using STATA version 17. The I2 test was used to assess the heterogeneity of studies. We used a random-effects model to estimate the pooled standard mean difference in lung function indices between organic dust-exposed and non-exposed industrial workers. To analyze publication bias, funnel plots and Egger’s test were applied.ResultsIn this systematic review and meta-analysis, 32 studies involving 7,085 participants were included from 13,529 identified studies. The estimated mean differences with 95% confidence intervals were as follows: −0.53 [−0.83 to −0.36] L for FVC, −0.60 [−0.77 to −0.43] L for FEV1, −0.43 [−0.57, −0.29] L for FEV1/FVC, and −0.69 [−0.88 to −0.50] L/min for PEFR.ConclusionThis systematic review and meta-analysis revealed that the lung function indices, such as FVC, FEV1, FEV1/FVC, and PEFR, were statistically significantly lower among organic dust-exposed industrial workers compared to non-exposed industrial workers. Therefore, effective dust control measures should be implemented to protect workers from exposure to organic dust.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024527139.

Binary mass transfer can occur at high rates due to rapid expansion of the donor's envelope. In the case where mass transfer is unstable, the binary can rapidly shrink its orbit and lead to a merger. In this work we consider the appearance of the system preceding merger, specifically for the case of a low-mass ($\approx 2.5$-$3~M_\odot$) helium star with a neutron star (NS) companion. Modeling the mass transfer history as well as the wind launched by super-Eddington accretion onto the NS, we find that such systems can power slowly rising transients with timescales as long as years, and luminosities of $\sim 10^{40}$-$10^{41}$ erg s$^{-1}$ from optical to UV. The final explosion following the merger (or core-collapse of the helium star in some cases) leads to an interaction-powered transient with properties resembling Type Ibn supernovae (SNe), possibly with a bright early peak powered by shock cooling emission for merger-powered explosions. We apply our model to the Type Ibn SN 2023fyq, that displayed a long-term precursor activity from years before the terminal explosion.

IntroductionRecent data suggests significant racial disparities in police killings in the United States: Much research finds that Black men are killed by police officers at higher rates than White men, and many individuals killed by police have been unarmed.MethodToward addressing psychological mechanisms at play in these complicated decision contexts, the current study tested the effectiveness of two writing tasks at reducing the unjustified shooting of unarmed targets using a virtual shooting-decision platform. Participants wrote either about their sense of purpose, self-affirming values, or a control topic and then played a first-person shooter video game, which randomly presented pictures of Black and White armed and unarmed targets. Participants were instructed not to shoot unarmed targets and to shoot armed targets.ResultsResults indicated that relative to controls, writing about either purpose or self-affirming values reduced the probability of shooting unarmed targets, without negatively impacting shooting decision reaction time.

Abstract In striated muscle, the sarcomeric protein myosin-binding protein-C (MyBP-C) is bound to the myosin thick filament and is predicted to stabilize myosin heads in a docked position against the thick filament, which limits crossbridge formation. Here, we use the homozygous Mybpc2 knockout (C2-/-) mouse line to remove the fast-isoform MyBP-C from fast skeletal muscle and then conduct mechanical functional studies in parallel with small-angle X-ray diffraction to evaluate the myofilament structure. We report that C2−/− fibers present deficits in force production and calcium sensitivity. Structurally, passive C2-/- fibers present altered sarcomere length-independent and -dependent regulation of myosin head conformations, with a shift of myosin heads towards actin. At shorter sarcomere lengths, the thin filament is axially extended in C2-/-, which we hypothesize is due to increased numbers of low-level crossbridges. These findings provide testable mechanisms to explain the etiology of debilitating diseases associated with MyBP-C.

Abstract Decision-makers objectively commit to a definitive choice, yet at the subjective level, human decisions appear to be associated with a degree of uncertainty. Whether decisions are definitive (i.e., concluding in all-or-none choices), or whether the underlying representations are graded, remains unclear. To answer this question, we recorded intracranial neural signals directly from the brain while human subjects made perceptual decisions. The recordings revealed that broadband gamma activity reflecting each individual’s decision-making process, ramped up gradually while being graded by the accumulated decision evidence. Crucially, this grading effect persisted throughout the decision process without ever reaching a definite bound at the time of choice. This effect was most prominent in the parietal cortex, a brain region traditionally implicated in decision-making. These results provide neural evidence for a graded decision process in humans and an analog framework for flexible choice behavior.

Background: The annual meetings hosted by the American Shoulder and Elbow Surgeons (ASES) present the latest prepublication literature in shoulder and elbow surgery, facilitating early dissemination of novel findings that impact clinical decision-making. Evaluating the publication rate of presented abstracts at ASES conferences becomes crucial in assessing the quality of research showcased, as these presentations often precede the peer-review process. Methods: The ASES conference programs from 2015-2019 were reviewed to identify presented abstracts. For each abstract, the title, author(s), conference year, and meeting type (open vs. closed) were recorded. The names of the author(s) of each abstract were searched in the PubMed and Google Scholar databases to determine if there was an associated published manuscript. For each identified manuscript, the title, author(s), date of publication, publishing journal, impact factor of the publishing journal, level of evidence, and number of citations were recorded. Results: A total of 316 abstracts were presented as podium lectures at ASES open and closed meetings between 2015 and 2019. Within 3 years of presentation, 240 (75.9%) of the presented abstracts resulted in publication. There was an increase in the proportion of abstracts resulting in publication within 3 years of the presentation from 2015-2019 (R = 0.8733, P = .053). Overall, the proportion of presented abstracts that went on to publication in peer-reviewed journals also increased (R = 0.8907, P = .043). Manuscripts of abstracts presented at open meetings had a shorter time to publication (8.78 vs. 11.82 months; P = .0160) and were cited more often (40.89 vs. 30.11, P = .0099) than those presented at closed meetings. Conclusion: There has been an increase in the publication rate of abstracts presented at ASES annual meetings in the study period. Published manuscripts of abstracts presented at ASES open conferences were published faster, and were cited more often, than closed conferences. ASES conferences allow for the presentation of high-quality prepublication literature in shoulder and elbow surgery.

Background: Proximal humerus fractures are the third most common fracture type for patients between the ages of 65 and 89 and occur more frequently in women than men. Given the variety of surgical treatments for proximal humerus fractures, the aim of this study was to (1) report United States national volume and incidence estimates for surgical management of proximal humerus fractures to better understand the changing practice over the past decade and (2) to analyze differences in volume and incidence among age groups, sex, and geographic region. Methods: Using IBM Marketscan national database, all patients that underwent open reduction internal fixation (ORIF), hemiarthroplasty, or reverse total shoulder arthroplasty (RTSA) between 2010 and 2019 were identified with Current Procedural Terminology codes. The dataset was further stratified to identify patients treated for proximal humerus fractures. IBM Marketscan provided discharge weights that were used to determine estimated national annual volumes of each procedure in IBM SPSS Statistics software (IBM Corp., Armonk, NY, USA). Volume and incidence were adjusted per 1,000,000 persons and calculated for subgroups according to age group, sex, and geographical region. The United States Census Bureau annual population data was used for all incidence calculations. Results: Over the past decade, the total volume and incidence of surgically treated proximal humerus fractures increased by 13% and 5%, respectively. Although overall incidence decreased, ORIF remained the most common surgical treatment. The greatest decrease in volume and incidence of ORIF occurred in patients ≥75. The incidence of ORIF treatment increased in the South and West while it decreased in the Northeast and Midwest. Total volume and incidence of HA decreased between 2010 and 2019 and this trend remained among all subgroups. Total volume and incidence of RTSA increased by over 300%. The incidence of males and females receiving RTSA increased by 266% and 320%, respectively. Volume and incidence of RTSA increased across all age groups. Volume and incidence of RTSA increased in the Midwest, South, and Western regions while it remained unchanged in the Northeast. Conclusion: Surgical management trends of proximal humerus fractures have changed greatly over the past decade. ORIF remains the most common surgical treatment for proximal humerus fractures. HA has fallen out of favor while RTSA has seen significant increases in usage across sex, age groups, and geographic regions. These trends represent a change in practice for treating proximal humerus fractures by considering all patient and fracture characteristics when opting for surgical management.

Abstract Muscle contraction is produced via the interaction of myofilaments and is regulated so that muscle performance matches demand. Myosin-binding protein C (MyBP-C) is a long and flexible protein that is tightly bound to the thick filament at its C-terminal end (MyBP-CC8C10), but may be loosely bound at its middle- and N-terminal end (MyBP-CC1C7) to myosin heads and/or the thin filament. MyBP-C is thought to control muscle contraction via the regulation of myosin motors, as mutations lead to debilitating disease. We use a combination of mechanics and small-angle X-ray diffraction to study the immediate and selective removal of the MyBP-CC1C7 domains of fast MyBP-C in permeabilized skeletal muscle. We show that cleavage leads to alterations in crossbridge kinetics and passive structural signatures of myofilaments that are indicative of a shift of myosin heads towards the ON state, highlighting the importance of MyBP-CC1C7 to myofilament force production and regulation.

Abstract We examine the relationship between electric vehicle battery chemistry and supply chain disruption vulnerability for four critical minerals: lithium, cobalt, nickel, and manganese. We compare the nickel manganese cobalt (NMC) and lithium iron phosphate (LFP) cathode chemistries by (1) mapping the supply chains for these four materials, (2) calculating a vulnerability index for each cathode chemistry for various focal countries and (3) using network flow optimization to bound uncertainties. World supply is currently vulnerable to disruptions in China for both chemistries: 80% [71% to 100%] of NMC cathodes and 92% [90% to 93%] of LFP cathodes include minerals that pass through China. NMC has additional risks due to concentrations of nickel, cobalt, and manganese in other countries. The combined vulnerability of multiple supply chain stages is substantially larger than at individual steps alone. Our results suggest that reducing risk requires addressing vulnerabilities across the entire battery supply chain.

Abstract Background Pericytes are multifunctional contractile cells that reside on capillaries. Pericytes are critical regulators of cerebral blood flow and blood–brain barrier function, and pericyte dysfunction may contribute to the pathophysiology of human neurological diseases including Alzheimers disease, multiple sclerosis, and stroke. Induced pluripotent stem cell (iPSC)-derived pericytes (iPericytes) are a promising tool for vascular research. However, it is unclear how iPericytes functionally compare to primary human brain vascular pericytes (HBVPs). Methods We differentiated iPSCs into iPericytes of either the mesoderm or neural crest lineage using established protocols. We compared iPericyte and HBVP morphologies, quantified gene expression by qPCR and bulk RNA sequencing, and visualised pericyte protein markers by immunocytochemistry. To determine whether the gene expression of neural crest iPericytes, mesoderm iPericytes or HBVPs correlated with their functional characteristics in vitro, we quantified EdU incorporation following exposure to the key pericyte mitogen, platelet derived growth factor (PDGF)-BB and, contraction and relaxation in response to the vasoconstrictor endothelin-1 or vasodilator adenosine, respectively. Results iPericytes were morphologically similar to HBVPs and expressed canonical pericyte markers. However, iPericytes had 1864 differentially expressed genes compared to HBVPs, while there were 797 genes differentially expressed between neural crest and mesoderm iPericytes. Consistent with the ability of HBVPs to respond to PDGF-BB signalling, PDGF-BB enhanced and a PDGF receptor-beta inhibitor impaired iPericyte proliferation. Administration of endothelin-1 led to iPericyte contraction and adenosine led to iPericyte relaxation, of a magnitude similar to the response evoked in HBVPs. We determined that neural crest iPericytes were less susceptible to PDGFR beta inhibition, but responded most robustly to vasoconstrictive mediators. Conclusions iPericytes express pericyte-associated genes and proteins and, exhibit an appropriate physiological response upon exposure to a key endogenous mitogen or vasoactive mediators. Therefore, the generation of functional iPericytes would be suitable for use in future investigations exploring pericyte function or dysfunction in neurological diseases.

Objectives: Tissue engineering approaches via repopulation of acellular biological grafts provide an exciting opportunity to generate lung grafts for transplantation. Alveolar type 2 (AT2) cells are a promising cell source for re-epithelialization. There are however inherent limitations with respect to their survival and growth, thus impeding their usability for tissue engineering applications. This study investigates the use of mesenchymal stromal cells to support primary AT2 cells for recellularization of mouse lung scaffolds. Methods: AT2 cells and bone marrow-derived mesenchymal cells (BMC) were co-delivered to decellularized mouse lung scaffolds. Recellularized lungs were evaluated for cell surface coverage, viability, and differentiation at 1 and 4 days after cell seeding. Recellularization was evaluated via histological analysis and immunofluorescence. Results: Simultaneous delivery of AT2 and BMC into acellular lung scaffolds resulted in enhanced cell surface coverage and reduced AT2 cell apoptosis in the recellularized scaffolds at Day 1 but not Day 4. AT2 cell number decreased after 4 days in both of AT2 only and codelivery groups suggesting limited expansion potential in the scaffold. After retention in the scaffold, AT2 cells differentiated into Aqp5-expressing cells. Conclusions: Our results indicate that BMC support AT2 cell survival during the initial attachment and engraftment phase of recellularization. While our findings suggest only a short-term beneficial effect of BMC, our study demonstrates that AT2 cells can be delivered and retained in acellular lung scaffolds; thus with preconditioning and supporting cells, may be used for re-epithelialization. Selection and characterization of appropriate cell sources for use in recellularization, will be critical for ultimate clinical application.

UV light emitting diode (LED) disinfection technologies have advanced over the last decade and expanded the design space for applications in point of use, industrial, and now full-scale water treatment. This literature review examines the progression of UV LED technologies from 2007 to 2023 using key features such as total optical power, price, and wall-plug efficiency. The review found that optical power is increasing while the price per Watt is decreasing; however, the wall plug energy (WPE) is slowly improving over the last decade. These factors govern the feasibility of many UV LEDs applications and establish the current state of the art for these technologies. An analysis of inactivation rate constants for low-pressure, medium-pressure, and UV LED sources was undertaken and provides a comprehensive view of how current UV LED technologies compare to traditional technologies. This comparison found that UV LEDs perform comparably vs conventional UV technologies when disinfecting bacteria and viruses. Furthermore, comparison of reported reduction equivalent fluences for UV LED flow-through reactors at the bench-, pilot-, and full-scale were explored in this review, and it was found that LED treatment is becoming more effective at handling increased flowrates and has been proven to work at full-scale. UV LEDs do however require additional research into the impacts of water matrices at different wavelengths and the impact that each available LED wavelength has on disinfection. Overall, this work provides a broad assessment of UV disinfection technologies and serves as a state-of-the-art reference document for those who are interested in understanding this rapidly developing technology.

Abstract Artificial micro/nanomotors using active particles hold vast potential in applications such as drug delivery and microfabrication. However, upgrading them to micro/nanorobots capable of performing precise tasks with sophisticated functions remains challenging. Bubble microthruster (BMT) is introduced, a variation of the bubble‐driven microrobot, which focuses the energy from a collapsing microbubble to create an inertial impact on nearby target microparticles. Utilizing ultra‐high‐speed imaging, the microparticle mass and density is determined with sub‐nanogram resolution based on the relaxation time characterizing the microparticle's transient response. Master curves of the BMT method are shown to be dependent on the viscosity of the solution. The BMT, controlled by a gamepad with magnetic‐field guidance, precisely manipulates target microparticles, including bioparticles. Validation involves measuring the polystyrene microparticle mass and hollow glass microsphere density, and assessing the mouse embryo mass densities. The BMT technique presents a promising chip‐free, real‐time, highly maneuverable strategy that integrates bubble microrobot‐based manipulation with precise bioparticle mass and density detection, which can facilitate microscale bioparticle characterizations such as embryo growth monitoring.

We present a rare anatomical configuration of a 19-year-old woman, characterized by descending thoracic aortic aneurysm with right aberrant subclavian arteries with a Kommerell's diverticulum in a left aortic arch. The complexity of this vascular anomaly was accompanied by an anomalous origin of left subclavian artery. The patient underwent a single-stage open surgical repair via left thoracotomy under deep hypothermic circulatory arrest. The bilateral aberrant subclavian arteries were separately reconstructed in situ using hand-sewn branched grafts.

The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1G93A mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1G93A mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.

BackgroundSocial media may be a useful method for research centers to deliver health messages, increase their visibility in the local community, and recruit study participants. Sharing examples of social media–based community outreach and educational programs, and evaluating their outcomes in this setting, is important for understanding whether these efforts have a measurable impact. ObjectiveThe aim of this study is to describe one center’s social media activities for community education on topics related to aging, memory loss, and Alzheimer disease and related dementias, and provide metrics related to recruitment into clinical research studies. MethodsSeveral social media platforms were used, including Facebook, X (formerly Twitter), and YouTube. Objective assessments quantified monthly, based on each platform’s native dashboard, included the number of followers, number of posts, post reach and engagement, post impressions, and video views. The number of participants volunteering for research during this period was additionally tracked using a secure database. Educational material posted to social media most frequently included content developed by center staff, content from partner organizations, and news articles or resources featuring center researchers. Multiple educational programs were developed, including social media series, web-based talks, Twitter chats, and webinars. In more recent years, Facebook content was occasionally boosted to increase visibility in the local geographical region. ResultsUp to 4 years of page metrics demonstrated continuing growth in reaching social media audiences, as indicated by increases over time in the numbers of likes or followers on Facebook and X/Twitter and views of YouTube videos (growth trajectories). While Facebook reach and X/Twitter impression rates were reasonable, Facebook engagement rates were more modest. Months that included boosted Facebook posts resulted in a greater change in page followers and page likes, and higher reach and engagement rates (all P≤.002). Recruitment of participants into center-affiliated research studies increased during this time frame, particularly in response to boosted Facebook posts. ConclusionsThese data demonstrate that social media activities can provide meaningful community educational opportunities focused on Alzheimer disease and related dementias and have a measurable impact on the recruitment of participants into research studies. Additionally, this study highlights the importance of tracking outreach program outcomes for evaluating return on investment.

Purpose: Genome-wide association studies have recently uncovered many loci associated with variation in intraocular pressure (IOP). Artificial intelligence (AI) can be used to interrogate the effect of specific genetic knockouts on the morphology of trabecular meshwork cells (TMCs) and thus, IOP regulation. Design: Experimental study. Subjects: Primary TMCs collected from human donors. Methods: Sixty-two genes at 55 loci associated with IOP variation were knocked out in primary TMC lines. All cells underwent high-throughput microscopy imaging after being stained with a 5-channel fluorescent cell staining protocol. A convolutional neural network was trained to distinguish between gene knockout and normal control cell images. The area under the receiver operator curve (AUC) metric was used to quantify morphological variation in gene knockouts to identify potential pathological perturbations. Main Outcome Measures: Degree of morphological variation as measured by deep learning algorithm accuracy of differentiation from normal controls. Results: Cells where LTBP2 or BCAS3 had been perturbed demonstrated the greatest morphological variation from normal TMCs (AUC 0.851, standard deviation [SD] 0.030; and AUC 0.845, SD 0.020, respectively). Of 7 multigene loci, 5 had statistically significant differences in AUC (P

AXL+ Siglec-6+ dendritic cells (ASDC) are novel myeloid DCs which can be subdivided into CD11c+ and CD123+ expressing subsets. We showed for the first time that these two ASDC subsets are present in inflamed human anogenital tissues where HIV transmission occurs. Their presence in inflamed tissues was supported by single cell RNA analysis of public databases of such tissues including psoriasis diseased skin and colorectal cancer. Almost all previous studies have examined ASDCs as a combined population. Our data revealed that the two ASDC subsets differ markedly in their functions when compared with each other and to pDCs. Relative to their cell functions, both subsets of blood ASDCs but not pDCs expressed co-stimulatory and maturation markers which were more prevalent on CD11c+ ASDCs, thus inducing more T cell proliferation and activation than their CD123+ counterparts. There was also a significant polarisation of naïve T cells by both ASDC subsets toward Th2, Th9, Th22, Th17 and Treg but less toward a Th1 phenotype. Furthermore, we investigated the expression of chemokine receptors that facilitate ASDCs and pDCs migration from blood to inflamed tissues, their HIV binding receptors, and their interactions with HIV and CD4 T cells. For HIV infection, within 2 hours of HIV exposure, CD11c+ ASDCs showed a trend in more viral transfer to T cells than CD123+ ASDCs and pDCs for first phase transfer. However, for second phase transfer, CD123+ ASDCs showed a trend in transferring more HIV than CD11c+ ASDCs and there was no viral transfer from pDCs. As anogenital inflammation is a prerequisite for HIV transmission, strategies to inhibit ASDC recruitment into inflamed tissues and their ability to transmit HIV to CD4 T cells should be considered.

Objective The purpose of this study was to apply contemporary consensus criteria developed by the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology to the evaluation of aortic pathology, with the expectation that the additional pathologic information may enhance the understanding and management of aortic diseases. Methods A scoring system was applied to ascending aortic specimens from 42 patients with heritable thoracic aortic disease and known genetic variations and from 86 patients from a single year, including patients with known genetic variations (n = 12) and patients with sporadic disease (n = 74). Results The various types of lesions of medial degeneration and the overall severity of medial degeneration overlapped considerably between those patients with heritable disease and those with sporadic disease; however, patients with heritable thoracic aortic disease had significantly more overall medial degeneration (P = .004) and higher levels of elastic fiber fragmentation (P = .03) and mucoid extracellular matrix accumulation (P = .04) than patients with sporadic thoracic aortic disease. Heritable thoracic aortic disease with known genetic variation was more prevalent in women than in men (27.2% vs 9.8%; P = .04), and women had more severe medial degeneration than men (P = .04). Medial degeneration scores were significantly lower for patients with bicuspid aortic valves than for patients with tricuspid aortic valves (P = .03). Conclusion The study’s findings indicate considerable overlap in the pattern, extent, and severity of medial degeneration between sporadic and hereditary types of thoracic aortic disease. This finding suggests that histopathologic medial degeneration represents the final common outcome of diverse pathogenetic factors and mechanisms.

Lakmali Anthony,1 Madeline Gillies,2 David Goh1 1Department of Vascular Surgery, Northern Health, Epping, Victoria, Australia; 2Department of Surgery, Western Health, Footscray, Victoria, AustraliaCorrespondence: Lakmali Anthony, Email lakmali.anthony610@gmail.comBackground: The advent of endovascular techniques has revolutionised the treatment of abdominal aortic aneurysms (AAA). Many countries have seen a transition from open AAA repair (OAR) to endovascular AAA repair (EVAR) over the past 25 years. The only study done in Australia that describes this change was done in the private sector. Majority of healthcare in Australia is delivered through the public, universal healthcare system. The aim of this study was to evaluate the trends in AAA repair in the Australian public sector over the past two decades.Methods: The Australian Institute of Health and Welfare (AIHW) Procedures Data Cubes from the National Hospitals Data Collection was used to extract data pertaining to AAA repairs from 2000 to 2021. Population data from the Australian Bureau of Statistics was used to calculate incidence of each type of repair per 100,000 population.Results: There were 65,529 AAA repairs performed in the Australian public sector from 2000 to 2021. EVARs accounted for 64.4% (42,205) and OARs accounted for 35.6% (23, 324) of them. EVAR surpassed OAR as the preferred method of AAA repair in 2006. This trend was observed in both males and females and across all age groups.Conclusion: There was a consistent and steady transition from OAR to EVAR over the 21 year period with EVAR surpassing OAR as the preferred method of AAA repair relatively early in Australia compared to other countries. Further research that investigates medium- and long-term outcomes of newer stent grafts is needed to further ascertain the continued viability and effectiveness of this trend in AAA treatment.Keywords: abdominal aortic aneurysm, AAA, endovascular aneurysm repair, EVAR, open surgical repair

Lakmali Anthony,1 Madeline Gillies,2 Vikram Iyer,1 David Goh1,3 1Department of Vascular Surgery, Northern Health, Epping, Victoria, Australia; 2Department of Surgery, Goulburn Valley Health, Shepparton, Victoria, Australia; 3Department of Vascular Surgery, Royal Melbourne Hospital, Parkville, Victoria, AustraliaCorrespondence: Lakmali Anthony, Email lakmali.anthony610@gmail.comBackground: The COVID-19 pandemic has had indirect and deleterious effects on patient health due to interruptions to routine provision of healthcare. This is particularly true for patients with chronic conditions like peripheral vascular disease (PVD). This study aims to evaluate the impact of the pandemic on patients with PVD in Australia by analysing rates of amputation, indications for amputation and urgency of surgery in the pre-pandemic and pandemic periods.Methods: The Australian Vascular Audit was used to capture lower extremity amputation data in Victoria, Australia, in the 22 months before and after the start of the pandemic.Results: The number of total amputations increased from 1770 pre-pandemic to 1850 during the pandemic, a 4.3% increase. This was largely driven by a statistically significant, 19% increase in major amputations. The number of minor amputations remained relatively similar in the two time periods. Amputations due to tissue loss secondary to arterial insufficiency increased from 474 to 526, an 11% increase, potentially indicating disruptions to revascularisation procedures contributing to the rise in amputations. Elective and emergency surgeries fell by 14% and 18%, respectively, while semi-urgent amputations increased by 32%.Conclusion: This study found an increase in the number of amputations overall and a significant increase in major amputations during the pandemic compared to pre-pandemic times. Tissue loss secondary to arterial insufficiency was an increasingly common indication for amputation that was observed in the pandemic group, indicating that disruption to revascularisation likely contributed to this increase in amputations. These findings can inform and direct future vascular surgery service delivery to prepare for the post-pandemic recovery. Additionally, this study further confirms that patients with chronic diseases are often disproportionately disadvantaged when global crises affect routine provision of healthcare and calls for better systems to be developed that can be used in such crises in the future.Keywords: amputation, COVID-19, pandemic, major amputation, minor amputation, peripheral vascular disease

Background Cesarean section is associated with moderate to severe pain and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly employed. The optimal NSAID, however, has not been elucidated. In this network meta-analysis and systematic review, we compared the influence of control and individual NSAIDs on the indices of analgesia, side effects, and quality of recovery. Methods CDSR, CINAHL, CRCT, Embase, LILACS, PubMed, and Web of Science were searched for randomized controlled trials comparing a specific NSAID to either control or another NSAID in elective or emergency cesarean section under general or neuraxial anesthesia. Network plots and league tables were constructed, and the quality of evidence was evaluated with Grading of Recommendations Assessment, Development and Evaluation (GRADE) analysis. Results We included 47 trials. Cumulative intravenous morphine equivalent consumption at 24 h, the primary outcome, was examined in 1,228 patients and 18 trials, and control was found to be inferior to diclofenac, indomethacin, ketorolac, and tenoxicam (very low quality evidence owing to serious limitations, imprecision, and publication bias). Indomethacin was superior to celecoxib for pain score at rest at 8–12 h and celecoxib + parecoxib, diclofenac, and ketorolac for pain score on movement at 48 h. In regard to the need for and time to rescue analgesia COX-2 inhibitors such as celecoxib were inferior to other NSAIDs. Conclusions Our review suggests the presence of minimal differences among the NSAIDs studied. Nonselective NSAIDs may be more effective than selective NSAIDs, and some NSAIDs such as indomethacin might be preferable to other NSAIDs.

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83–0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

The gut microbiota in cattle is essential for protein, energy, and vitamin production and hence, microbiota perturbations can affect cattle performance. This study evaluated the effect of intramammary (IMM) ceftiofur treatment and lactation stage on the functional gut microbiome and metabolome. Forty dairy cows were enrolled at dry-off. Half received IMM ceftiofur and a non-antibiotic teat sealant containing bismuth subnitrate (cases), while the other half received the teat sealant (controls). Fecal samples were collected before treatment at dry off, during the dry period (weeks 1 and 5) and the first week after calving (week 9). Shotgun metagenomic sequencing was applied to predict microbial metabolic pathways whereas untargeted metabolomics was used identify polar and nonpolar metabolites. Compared to controls, long-term changes were observed in the cows given ceftiofur, including a lower abundance of microbial pathways linked to energy production, amino acid biosynthesis, and other vital molecules. The metabolome of treated cows had elevated levels of stachyose, phosphatidylethanolamine diacylglycerol (PE-DAG), and inosine a week after the IMM ceftiofur application, indicating alterations in microbial fermentation, lipid metabolism, energy, and cellular signaling. Differences were also observed by sampling, with cows in late lactation having more diverse metabolic pathways and a unique metabolome containing higher levels of histamine and histamine-producing bacteria. These data illustrate how IMM ceftiofur treatment can alter the functionality of the hindgut metabolome and microbiome. Understanding how antibiotics and lactation stages, which are each characterized by unique diets and physiology, impact the function of resident microbes is critical to define normal gut function in dairy cattle.

There is an increasing desire to study neurodevelopmental disorders (NDDs) together to understand commonalities to develop generic health promotion strategies and improve clinical treatment. Common data elements (CDEs) collected across studies involving children with NDDs afford an opportunity to answer clinically meaningful questions. We undertook a retrospective, secondary analysis of data pertaining to sleep in children with different NDDs collected through various research studies. The objective of this paper is to share lessons learned for data management, collation, and harmonization from a sleep study in children within and across NDDs from large, collaborative research networks in the Ontario Brain Institute (OBI). Three collaborative research networks contributed demographic data and data pertaining to sleep, internalizing symptoms, health-related quality of life, and severity of disorder for children with six different NDDs: autism spectrum disorder; attention deficit/hyperactivity disorder; obsessive compulsive disorder; intellectual disability; cerebral palsy; and epilepsy. Procedures for data harmonization, derivations, and merging were shared and examples pertaining to severity of disorder and sleep disturbances were described in detail. Important lessons emerged from data harmonizing procedures: prioritizing the collection of CDEs to ensure data completeness; ensuring unprocessed data are uploaded for harmonization in order to facilitate timely analytic procedures; the value of maintaining variable naming that is consistent with data dictionaries at time of project validation; and the value of regular meetings with the research networks to discuss and overcome challenges with data harmonization. Buy-in from all research networks involved at study inception and oversight from a centralized infrastructure (OBI) identified the importance of collaboration to collect CDEs and facilitate data harmonization to improve outcomes for children with NDDs.

Hibernation is a period of metabolic suppression utilized by many small and large mammal species to survive during winter periods. As the underlying cellular and molecular mechanisms remain incompletely understood, our study aimed to determine whether skeletal muscle myosin and its metabolic efficiency undergo alterations during hibernation to optimize energy utilization. We isolated muscle fibers from small hibernators, Ictidomys tridecemlineatus and Eliomys quercinus and larger hibernators, Ursus arctos and Ursus americanus. We then conducted loaded Mant-ATP chase experiments alongside X-ray diffraction to measure resting myosin dynamics and its ATP demand. In parallel, we performed multiple proteomics analyses. Our results showed a preservation of myosin structure in U. arctos and U. americanus during hibernation, whilst in I. tridecemlineatus and E. quercinus, changes in myosin metabolic states during torpor unexpectedly led to higher levels in energy expenditure of type II, fast-twitch muscle fibers at ambient lab temperatures (20 °C). Upon repeating loaded Mant-ATP chase experiments at 8 °C (near the body temperature of torpid animals), we found that myosin ATP consumption in type II muscle fibers was reduced by 77–107% during torpor compared to active periods. Additionally, we observed Myh2 hyper-phosphorylation during torpor in I. tridecemilineatus, which was predicted to stabilize the myosin molecule. This may act as a potential molecular mechanism mitigating myosin-associated increases in skeletal muscle energy expenditure during periods of torpor in response to cold exposure. Altogether, we demonstrate that resting myosin is altered in hibernating mammals, contributing to significant changes to the ATP consumption of skeletal muscle. Additionally, we observe that it is further altered in response to cold exposure and highlight myosin as a potentially contributor to skeletal muscle non-shivering thermogenesis.

While enteric pathogens have been widely studied for their roles in causing foodborne infection, their impacts on the gut microbial community have yet to be fully characterized. Previous work has identified notable changes in the gut microbiome related to pathogen invasion, both taxonomically and genetically. Characterization of the metabolic landscape during and after enteric infection, however, has not been explored. Consequently, we investigated the metabolome of paired stools recovered from 60 patients (cases) during and after recovery from enteric bacterial infections (follow-ups). Shotgun metagenomics was applied to predict functional microbial pathways combined with untargeted metametabolomics classified by Liquid Chromatography Mass Spectrometry. Notably, cases had a greater overall metabolic capacity with significantly higher pathway richness and evenness relative to the follow-ups (p

Purpose: Sexual and gender minority (SGM) individuals have an increased risk of poor health outcomes, in part due to knowledge and training gaps in health care education. This study sought to evaluate the knowledge, attitudes, and practice behaviors of various health care role groups within radiation oncology toward SGM patients. Methods and Materials: A 38-item web-based survey was emailed to 1045 staff across 2 large radiation oncology departments. The survey assessed demographics, attitudes, knowledge, and practice behaviors. χ2 tests were performed to explore differences in survey responses by age, political affiliation, religious identity, year since graduation, and role groups. One-way analysis of variance tests were conducted to determine differences between respondents’ confidence in knowledge and performance on the knowledge section of the survey. Thematic analysis was applied to the open discussion section. Results: Of the 223 respondents, 103 clinicians (physicians/advanced practice providers/nurses) and 120 nonclinicians (administrative staff, medical assistants, and other nonmedical staff) participated in the survey (21.3% response rate): 72.6% answered the knowledge questions; 93.5% stated they were comfortable treating sexual minorities, or lesbian, gay, bisexual, and queer + patients; 88% indicated comfort in treating transgender patients; 36.6% stated they were confident in their knowledge of the health needs of transgender patients; and 50.3% expressed confidence in treating lesbian, gay, bisexual, and queer + patients. Fewer nonclinicians than clinicians thought that gender identity, sexual orientation, and sex assigned at birth were important to provide the best care (P < .05). The open comments section identified key themes, including the belief that current educational tools are not helpful, desire for more educational formats (lectures, case-based learning, seminars), and an overall interest in SGM health education. Conclusions: Most staff feel comfortable in treating SGM patients but are less confident in the distinct needs of this population. Knowledge gaps persist for both clinicians and nonclinicians, indicating a need for further training specific to oncology care.

Anxiety is common in neurodevelopmental disorders (NDD). The parent version of the Spence Children’s Anxiety Scale (SCAS-P) is a widely used measure to assess anxiety across a broad range of childhood populations. However, assessment of the measurement properties of the SCAS-P in NDDs have been limited. The present study aimed to assess the psychometric properties of the SCAS-P in children with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) using Rasch Measurement Theory. Data from the Province of Ontario Neurodevelopmental Disorders Network Registry were used in the analysis. Children (ages 6-13 years old) with a primary diagnosis of ADHD (n=146) or ASD (n=104) were administered the SCAS-P. Rasch Measurement Theory was used to assess measurement properties of the SCAS-P, including unidimensionality and item-level fit, category ordering, item targeting, person separation index and reliability and differential item functioning. The SCAS-P fit well to the Rasch model in both ADHD and ASD, including unidimensionality, satisfactory category ordering and goodness-of-fit. However, item-person measures showed poor precision at lower levels of anxiety. Some items showed differential item functioning, including items within the obsessive-compulsive, panic/agoraphobia and physical injury fears domains, suggesting that the presentation of anxiety may differ between ADHD and ASD. Overall, the results generally support the use of the SCAS-P to screen and monitor anxiety symptoms in children with ADHD and ASD. Future studies would benefit from examination of more severely anxious NDD cohort, including those with clinically diagnosed anxiety.

A male patient, 70 years of age, was evaluated for an infected thoracic endovascular aneurysm repair (TEVAR). After presenting with persistent fever, a positron emission tomography scan found an infected aortic stent graft. The patient underwent open repair with explantation of the infected TEVAR, extensive periaortic debridement, graft replacement with a Dacron graft, and complete coverage with a latissimus dorsi muscle flap. Tissue culture revealed Clostridium spp. He was discharged home with long-term ampicillin and sulbactam. A postoperative computed tomography scan showed no recurrence of infection. Open surgery with latissimus muscle flap coverage is an achievable option for infected TEVAR.

Despite increasing alarms over the health impacts of microplastics (MPs) due to their detection in human organs and feces, precise exposure evaluations remain scarce. To comprehend their risks, there is a distinct need to prioritize quantitive estimates in MP exposome, particularly at the environmentally-realistic level. Here we used a method rooted in real-world MP measurements and activity patterns to determine the daily intake of MPs through inhalation and from ground dust/soil ingestion. We found that nearly 80% of this intake comes from residential sectors, with activity intensity and behavioral types significantly affecting the human MP burden. The data showed a peak in MP exposure for those aged 18–64. When compared to dietary MP intake sources like seafood, salt, and water, we identified a previously underestimated exposure from inhalation and dust/soil ingestion, emphasizing the need for more realistic evaluations that incorporate activity factors. This discovery raises questions about the accuracy of past studies and underscores MP's potential health risks. Moreover, our time-based simulations revealed increased MP intake during the COVID-19 lockdown due to more surface dust ingestion, shedding light on how global health crises may inadvertently elevate MP exposure risks.

Abstract Skeletal muscle is the largest metabolic organ making up ∼50% of body mass. Because skeletal muscle has both metabolic and endocrine properties, it can manipulate the microbial populations within the gut. In return, microbes exert considerable influence on skeletal muscle via numerous signalling pathways. Gut bacteria produce metabolites (i.e., short chain fatty acids, secondary bile acids and neurotransmitter substrates) that act as fuel sources and modulators of inflammation, influencing host muscle development, growth and maintenance. The reciprocal interactions between microbes, metabolites and muscle establish a bidirectional gut–muscle axis. The muscular dystrophies constitute a broad range of disorders with varying disabilities. In the profoundly debilitating monogenic disorder Duchenne muscular dystrophy (DMD), skeletal muscle undergoes a reduction in muscle regenerative capacity leading to progressive muscle wasting, resulting in fibrotic remodelling and adipose infiltration. The loss of respiratory muscle in DMD culminates in respiratory insufficiency and eventually premature death. The pathways contributing to aberrant muscle remodelling are potentially modulated by gut microbial metabolites, thus making them plausible targets for pre‐ and probiotic supplementation. Prednisone, the gold standard therapy for DMD, drives gut dysbiosis, inducing a pro‐inflammatory phenotype and leaky gut barrier contributing to several of the well‐known side effects associated with chronic glucocorticoid treatment. Several studies have observed that gut microbial supplementation or transplantation exerts positive effects on muscle, including mitigating the side effects of prednisone. There is growing evidence in support of the potential for an adjunctive microbiota‐directed regimen designed to optimise gut–muscle axis signalling, which could alleviate muscle wasting in DMD.

Infusion-related iatrogenic retinal breaks (IRBs) are a significant complication in vitrectomies, particularly when smaller-gauge cannulas are used during fluid infusion. Using two-dimensional finite element analysis (FEA), we analyzed forces exerted on the retina from different cannulas: traditional 25-gauge, 20-gauge, 23-gauge, and 27-gauge, then investigated four alternative new cannula designs: (A) oblique orifices, (B) external obstruction, (C) side ports, and (D) perpendicular orifices. The analysis revealed that the standard 25-gauge cannula had a force of 0.546 milli-Newtons (mN). Optimized cannulas demonstrated decreased forces: 0.072 mN (A), 0.266 mN (B), 0.417 mN (C), and 0.117 mN (D). While all the designs decrease fluid jet force, each has unique challenges: Design A may complicate manufacturing, B requires unique attachment techniques, C could misdirect fluid toward the lens and peripheral retina, and D requires a sealed trocar/cannula design to prevent unwanted fluid ejection. These four innovative cannula designs, identified with detailed engineering simulations, provide promising strategies to reduce the risk of IRBs during vitrectomy, bridging the gap between engineering insights and clinical application.

Adding 50% vitreous humor to the media surrounding lens explants induces fiber cell differentiation and a significant immune/inflammatory response. While Fgfr loss blocks differentiation in lens epithelial explants, this blockage is partially reversed by deleting Pten. To investigate the functions of the Fgfrs and Pten during lens fiber cell differentiation, we utilized a lens epithelial explant system and conducted RNA sequencing on vitreous humor-exposed explants lacking Fgfrs, or Pten or both Fgfrs and Pten. We found that Fgfr loss impairs both vitreous-induced differentiation and inflammation while the additional loss of Pten restores these responses. Furthermore, transcriptomic analysis suggested that PDGFR-signaling in FGFR-deficient explants is required to mediate the rescue of vitreous-induced fiber differentiation in explants lacking both Fgfrs and Pten. The blockage of β-crystallin induction in explants lacking both Fgfrs and Pten in the presence of a PDGFR inhibitor supports this hypothesis. Our findings demonstrate that a wide array of genes associated with fiber cell differentiation are downstream of FGFR-signaling and that the vitreous-induced immune responses also depend on FGFR-signaling. Our data also demonstrate that many of the vitreous-induced gene-expression changes in Fgfr-deficient explants are rescued in explants lacking both Fgfrs and Pten.

Abstract Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson’s r = 0.794–0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4–9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient’s tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P

Abstract Genetic tools for wildlife monitoring can provide valuable information on spatiotemporal population trends and connectivity, particularly in systems experiencing rapid environmental change. Multiplexed targeted amplicon sequencing techniques, such as genotyping‐in‐thousands by sequencing (GT‐seq), can provide cost‐effective approaches for collecting genetic data from low‐quality and quantity DNA samples, making them potentially useful for long‐term wildlife monitoring using non‐invasive and archival samples. Here, we developed a GT‐seq panel as a potential monitoring tool for the American pika (Ochotona princeps) and evaluated its performance when applied to traditional, non‐invasive, and archival samples, respectively. Specifically, we optimized a GT‐seq panel (307 single nucleotide polymorphisms (SNPs)) that included neutral, sex‐associated, and putatively adaptive SNPs using contemporary tissue samples (n = 77) from the Northern Rocky Mountains lineage of American pikas. The panel demonstrated high genotyping success (94.7%), low genotyping error (0.001%), and excellent performance identifying individuals, sex, relatedness, and population structure. We subsequently applied the GT‐seq panel to archival tissue (n = 17) and contemporary fecal pellet samples (n = 129) collected within the Canadian Rocky Mountains to evaluate its effectiveness. Although the panel demonstrated high efficacy with archival tissue samples (90.5% genotyping success, 0.0% genotyping error), this was not the case for the fecal pellet samples (79.7% genotyping success, 28.4% genotyping error) likely due to the exceptionally low quality/quantity of recovered DNA using the approaches implemented. Overall, our study reinforced GT‐seq as an effective tool using contemporary and archival tissue samples, providing future opportunities for temporal applications using historical specimens. Our results further highlight the need for additional optimization of sample and genetic data collection techniques prior to broader‐scale implementation of a non‐invasive genetic monitoring tool for American pikas.

Summary: The critical role of the intestinal microbiota in human health and disease is well recognized. Nevertheless, there are still large gaps in our understanding of the functions and mechanisms encoded in the genomes of most members of the gut microbiota. Genome-scale libraries of transposon mutants are a powerful tool to help us address this gap. Recent advances in barcoded transposon mutagenesis have dramatically lowered the cost of mutant fitness determination in hundreds of in vitro and in vivo experimental conditions. In an accompanying review, we discuss recent advances and caveats for the construction of pooled and arrayed barcoded transposon mutant libraries in human gut commensals. In this review, we discuss how these libraries can be used across a wide range of applications, the technical aspects involved, and expectations for such screens.

Summary: Randomly barcoded transposon mutant libraries are powerful tools for studying gene function and organization, assessing gene essentiality and pathways, discovering potential therapeutic targets, and understanding the physiology of gut bacteria and their interactions with the host. However, construction of high-quality libraries with uniform representation can be challenging. In this review, we survey various strategies for barcoded library construction, including transposition systems, methods of transposon delivery, optimal library size, and transconjugant selection schemes. We discuss the advantages and limitations of each approach, as well as factors to consider when selecting a strategy. In addition, we highlight experimental and computational advances in arraying condensed libraries from mutant pools. We focus on examples of successful library construction in gut bacteria and their application to gene function studies and drug discovery. Given the need for understanding gene function and organization in gut bacteria, we provide a comprehensive guide for researchers to construct randomly barcoded transposon mutant libraries.

BackgroundHypermobile Ehlers-Danlos syndrome is a heritable connective tissue disorder associated with generalized joint hypermobility but also other multisystem comorbidities, many of which may be exacerbated during a viral illness or after a vaccination. We sought to determine whether individuals with hypermobile Ehlers Danlos syndrome report an increase in adverse events, including cardiovascular events, after COVID-19 illness or vaccination.MethodsA cross-sectional web-based survey was made available from November 22, 2021, through March 15, 2022. 368 respondents primarily from the United States self-reported data including diagnosis. We used a Cox proportional hazards model with time varying indicators for COVID-19 illness or vaccination in the previous 30 days.ResultsWe found a significantly increased rate of new abnormal heart rhythms reported in the 30 days following COVID-19 illness. No additional cardiovascular events were reported after COVID-19 illness. 2.5% of respondents with COVID-19 illness were hospitalized. We did not find a statistically significant increased rate of cardiovascular events in the 30 days following any COVID-19 vaccination dose. Post COVID-19 vaccination, 87.2% of hypermobile Ehlers-Danlos syndrome respondents endorsed an expected adverse event (EAE), and 3.1% reported an emergency department visit/hospitalization, of those who received at least one vaccine dose. Events possibly reflecting exacerbation of orthostasis/dysautonomia were common.ConclusionRespondents did not report an increased rate of any cardiovascular events in the 30 days following COVID-19 vaccination; however, those with hypermobile Ehlers-Danlos syndrome experienced a high rate of expected adverse events after vaccination consistent with a high baseline prevalence of similar symptoms. No cardiovascular events other than new abnormal heart rhythms were reported at any point after a COVID-19 illness.

ABSTRACTAntibody-mediated effector functions are widely considered to unfold according to an associative model of IgG-Fcγ receptor (FcγR) interactions. The associative model presupposes that Fc receptors cannot discriminate antigen-bound IgG from free IgG in solution and have equivalent affinities for each. Therefore, the clustering of Fcγ receptors (FcγR) in the cell membrane, cross-activation of intracellular signaling domains, and the formation of the immune synapse are all the result of avid interactions between the Fc region of IgG and FcγRs that collectively overcome the individually weak, transient interactions between binding partners. Antibody allostery, specifically conformational allostery, is a competing model in which antigen-bound antibody molecules undergo a physical rearrangement that causes them to stand out from the background of free IgG by virtue of greater FcγR affinity. Various evidence exists in support of this model of antibody allostery, but it remains controversial. We report observations from multiplexed, label-free kinetic experiments in which the affinity values of FcγR were characterized for covalently immobilized, captured, and antigen-bound IgG. Across the strategies tested, receptors had greater affinity for the antigen-bound mode of IgG presentation. This phenomenon was observed across multiple FcγRs and generalized to multiple antigens, antibody specificities, and subclasses. Furthermore, the thermodynamic signatures of FcγR binding to free or immune-complexed IgG in solution differed when measured by an orthogonal label-free method, but the failure to recapitulate the trend in overall affinity leaves open questions as to what additional factors may be at play.

Abstract Background The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) (©Blueprint Medicines Corporation), a 12-item daily diary that assesses 11 signs and symptoms of indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM), was psychometrically evaluated among patients with ISM. Additionally, thresholds of the ISM-SAF total symptom score (TSS) to distinguish patients with moderate to severe symptoms from those with mild symptoms were evaluated. Methods The ISM-SAF was completed daily as an electronic diary in a prospective, observational study utilizing an online survey of patients with ISM in the United States. Descriptive statistics, psychometric analyses, and analyses to estimate ISM-SAF TSS clinical cutoff values were conducted. Results A total of 103 patients (81.6% female; mean age = 50.2 [± 12.6]) with a self-reported diagnosis of ISM or SSM (58 of whom also had a medically documented diagnosis) contributed to the analyses. Psychometric analysis supported the trustworthiness of the biweekly TSS, which was reliable (α > 0.8, ICC > 0.9), construct-valid, and able to distinguish among clinically distinct groups as specified by the Patient Global Impression of Severity, 12-item Short-Form Health Survey, and Mastocytosis Quality of Life Questionnaire (p