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Abstract Efficient and site‐specific delivery of therapeutics drugs remains a critical challenge in cancer treatment. Traditional drug nanocarriers such as antibody‐drug conjugates are not generally accessible due to their high cost and can lead to serious side effects including life‐threatening allergic reactions. Here, these problems are overcome via the engineering of supramolecular agents that are manufactured with an innovative double imprinting approach. The developed molecularly imprinted nanoparticles (nanoMIPs) are targeted toward a linear epitope of estrogen receptor alfa (ERα) and loaded with the chemotherapeutic drug doxorubicin. These nanoMIPs are cost‐effective and rival the affinity of commercial antibodies for ERα. Upon specific binding of the materials to ERα, which is overexpressed in most breast cancers (BCs), nuclear drug delivery is achieved via receptor‐mediated endocytosis. Consequentially, significantly enhanced cytotoxicity is elicited in BC cell lines overexpressing ERα, paving the way for precision treatment of BC. Proof‐of‐concept for the clinical use of the nanoMIPs is provided by evaluating their drug efficacy in sophisticated three‐dimensional (3D) cancer models, which capture the complexity of the tumor microenvironment in vivo without requiring animal models. Thus, these findings highlight the potential of nanoMIPs as a promising class of novel drug compounds for use in cancer treatment.

Reinforcement learning has been used extensively to learn the low-level tactical choices during gameplay; however, less effort is invested in the strategic decisions governing the effective engagement of a diverse set of opponents. In this paper, a two-tier reinforcement learning model is created to play competitive games and effectively engage in matches with different opponents to maximize earnings. The multi-agent environment has four types of learners, which vary in their ability to learn gameplay directly (tactics) and their ability to learn to bet or withdraw from gameplay (strategy). The players are tested in three different competitive games: Connect 4, Dots and Boxes, and Tic-Tac-Toe. Analyzing the behavior of players as they progress from naivety to game mastery reveals some interesting features: (1) learners who optimize strategy and tactics outperform all learners, (2) learners who initially optimize their strategy to engage in matches outperform those who focus on optimizing tactical gameplay, and (3) the advantage of strategy optimization versus tactical gameplay optimization diminishes as more games are played. A reinforcement learning model with a dual learning scheme presents possible applications in adversarial scenarios where both strategic and tactical learning are critical. We present detailed results in a systematic manner, providing strong support for our claim.

A versatile strategy for synthesizing tailored peptide based biradicals is presented. By labeling the protected amino acid hydroxyproline with PROXYL via the OH functionality and using this building block in solid phase peptide synthesis (SPPS), the obtained peptides become polarization agents for DNP enhanced solid-state NMR in biotolerant media. To analyze the effect of the radical position on the enhancement factor, three different biradicals are synthesized. The PROXYL spin-label is inserted in a collagen inspired artificial peptide sequence by binding through the OH group of the hydroxyproline moieties at specific position in the chain. This labeling strategy is universally applicable for any hydroxyproline position in a peptide sequence since solid-phase peptide synthesis is used to insert the building block. High performance liquid chromatography (HPLC) and mass spectrometry (MS) analyses show the successful introduction of the spin label in the peptide chain and electron paramagnetic resonance (EPR) spectroscopy confirms its activity. Dynamic nuclear polarization (DNP) enhanced solid-state nuclear magnetic resonance (NMR) experiments performed on frozen aqueous glycerol-d8 solutions containing these peptide radicals show significantly higher enhancement factors of up to 45 in 1H→13C cross polarization magic angle spinning (CP MAS) experiments compared to an analogous mono-radical peptide including this building block (ε ≈ 14). Compared to commercial biradicals such as AMUPol for which enhancement factors > 100 have been obtained in the past and which have been optimized in their structure, the obtained enhancement up to 45 for our biradicals presents a significant progress in radical design.

Abstract Etizolam is a thienodiazepine derivative which produces an anxiolytic effect similar to benzodiazepines such as alprazolam (Xanax). Like classic benzodiazepines, etizolam has a high affinity towards the GABAA receptor, and allosterically potentiates the effects of GABA resulting in neuronal hyperpolarization related to chloride influx. When taken in therapeutic doses, etizolam produces a similar effect to Xanax. Counterfeit Xanax tablets contain variable amounts of etizolam. Tablets with high amounts of etizolam can cause toxicity if ingested, especially when combined with other substances. When toxic symptoms occur in patients, they may include severe sedation, unconsciousness, and depression of the medullary respiratory center. In this regard, there is the potential for death. Additionally, the rise in fake Xanax tablets containing etizolam and other counterfeit medications has been exacerbated by the difference in regulations regarding these substances in different countries as well as the illegal drug trade. Healthcare providers may also play a role through the over- or underprescribing of certain medications. Thus, in order to combat the rise in counterfeit medications such as fake Xanax, international cooperation, regulation, and enforcement of laws pertaining to the manufacture, prescription, and distribution of these substances are needed.

Abstract Purpose The addition of intrathecal morphine to general anesthesia for laparoscopic colorectal surgery is an effective method of providing analgesia. However, the analgesia duration of approximately 24 hours poses the risk of rebound pain on the second postoperative day. Therefore, this study aimed to investigate the patients' perception on postoperative pain management using the International Pain Outcomes questionnaire on both the first and second postoperative day. Methods This prospective single-center cohort study was conducted between November 2020 and March 2021 and included forty patients. The primary outcome was a difference in postoperative pain on the first and second postoperative day. Secondary outcomes included opioid consumption, interference of pain with activities, side effects, and patients’ perception and satisfaction with pain treatment. Results The intensity of postoperative pain did not increase on the second postoperative day NRS [numeric rating scale] 5 (2–7 [0–10]) vs 5 (3–7 [1–10]), p=0.414), but the percentage of time spent in severe pain increased (20% (10-40 [0-90]) vs 30% (20-50 [0-80]), p=0.010). There was no difference in opioid consumption (6 mg (0–12) [0–42] vs 6 mg (0–12) [0–29], p=0.914). Pruritis (NRS 2 (0–6 [0–10]) vs 0 (0–3 [0–8]), p=0.001) and dizziness (NRS 2 (0–7 [0–10]) vs 0 (0–2 [0–9]), p=0.002) decreased on the second postoperative day. Patients reported high satisfaction during the first two days after surgery (NRS 8 (7–9) [0–10] vs 8 (7–9) [0–10], p=0.395). Conclusion Intrathecal morphine is a suitable analgesic modality in laparoscopic colorectal surgery within an enhanced recovery after surgery program, without causing important rebound pain. Pain scores, however, may be further reduced by adding non-opioid analgesics.

Abstract Purpose/objective(s) Treatment related lymphopenia is a known toxicity for glioblastoma (GBM) patients and several single-institution studies have linked lymphopenia with poor survival outcomes. We performed a systematic review and pooled analysis to evaluate the association between lymphopenia and overall survival (OS) for GBM patients undergoing chemotherapy and radiation therapy (RT). Materials/methods Following PRISMA guidelines, a systematic literature review of the MEDLINE database and abstracts from ASTRO, ASCO, and SNO annual meetings was conducted. A pooled analysis was performed using inverse variance-weighted random effects to generate a pooled estimate of the hazard ratio of association between lymphopenia and OS. Results Ten of 104 identified studies met inclusion criteria, representing 1,718 patients. The lymphopenia cutoff value varied (400–1100 cells/uL) and as well as the timing of its onset. Studies were grouped as time-point (i.e., lymphopenia at approximately 2-months post-RT) or time-range (any lymphopenia occurrence from treatment-start to approximately 2-months post-RT. The mean overall pooled incidence of lymphopenia for all studies was 31.8%, and 11.8% vs. 39.9% for time-point vs. time-range studies, respectively. Lymphopenia was associated with increased risk of death, with a pooled HR of 1.78 (95% CI 1.46–2.17, P

Abstract Drivers and dynamics of initial human migrations across individual islands and archipelagos are poorly understood, hampering assessments of subsequent modification of island biodiversity. We developed and tested a new statistical-simulation approach for reconstructing the pattern and pace of human migration across islands at high spatiotemporal resolutions. Using Polynesian colonisation of New Zealand as an example, we show that process-explicit models, informed by archaeological records and spatiotemporal reconstructions of past climates and environments, can provide new and important insights into the patterns and mechanisms of arrival and establishment of people on islands. We find that colonisation of New Zealand required there to have been a single founding population of approximately 500 people, arriving between 1233 and 1257 AD, settling multiple areas, and expanding rapidly over both North and South Islands. These verified spatiotemporal reconstructions of colonisation dynamics provide new opportunities to explore more extensively the potential ecological impacts of human colonisation on New Zealand’s native biota and ecosystems.

The globally endangered oceanic manta ray Mobula birostris is believed to spend significantly more time in the open ocean than in coastal areas. Nonetheless, the Bird's Head Seascape (BHS) in eastern Indonesia hosts a large population of this species (over 850 individuals), frequently sighted at coral reef cleaning stations and forming a vital asset for marine tourism in the region. Despite this, detailed understanding of the movements and habitat use of this wide-ranging species within shallow (< 30 m) coral reef ecosystems remains limited. Addressing this knowledge gap is urgently required for the sustainable management of oceanic manta ray-focused tourism in the region. Here, we report the results of an initial passive acoustic telemetry study investigating the use of coral reef cleaning stations by oceanic manta rays. Forty-one rays were acoustically tracked from February 2016 to August 2019 in an array of 28 acoustic receivers deployed at known cleaning stations and hypothesized transit points across the BHS (including the regions of Raja Ampat, Fakfak, and Kaimana). A total of 5,822 detections were recorded by 16 of the 28 receivers from all tagged individuals, and 421 visitation events were documented from 37 out of the 41 tagged individuals, providing valuable insights into their visitation patterns at cleaning stations. Tagged individuals were detected at receiver stations for durations ranging from 0.2 to 427.0 min (mean ± SD = 48 ± 64 min). Notably, 94% of detections were recorded during daylight hours (reaching a peak at noon), underscoring an apparent diurnal pattern in time spent around cleaning stations. The study documented frequent short-range movements between adjacent receivers (5–12 km apart), with two-thirds of all 191 tracked movements occurring between neighboring stations in southern Raja Ampat. Notably, tagged individuals were detected repeatedly at three cleaning stations which were previously only known for hosting reef manta rays, suggesting oceanic manta rays likely also utilize these cleaning stations. Our study provides important insights into the visitations and local movements of oceanic manta rays between coral reef cleaning stations, which will inform effective oceanic manta ray conservation efforts and tourism management in the BHS.

Abstract Marine heatwaves (MHWs) cause disruption to marine ecosystems, deleteriously impacting macroflora and fauna. However, effects on microorganisms are relatively unknown despite ocean temperature being a major determinant of assemblage structure. Using data from thousands of Southern Hemisphere samples, we reveal that during an “unprecedented” 2015/16 Tasman Sea MHW, temperatures approached or surpassed the upper thermal boundary of many endemic taxa. Temperate microbial assemblages underwent a profound transition to niche states aligned with sites over 1000 km equatorward, adapting to higher temperatures and lower nutrient conditions bought on by the MHW. MHW conditions also modulate seasonal patterns of microbial diversity and support novel assemblage compositions. The most significant affects of MHWs on microbial assemblages occurred during warmer months, when temperatures exceeded the upper climatological bounds. Trends in microbial response across several MHWs in different locations suggest these are emergent properties of temperate ocean warming, which may facilitate monitoring, prediction and adaptation efforts.

Abstract Isolated indigenous societies who actively avoid sustained peaceful contact with the outside world are critically endangered. Last year, “Tanaru”, the lone surviving man of his tribe for at least 35 years, died in Southwest Amazonia, marking the latest cultural extinction event in a long history of massacres, enslavement, and epidemics. Yet in the upper reaches of the Amazon Basin, dozens of resilient isolated tribes still manage to survive. Remote sensing is a reliable method of monitoring the population dynamics of uncontacted populations by quantifying the area cleared for gardens and villages, along with the fire detections associated with the burning of those clearings. Remote sensing also provides a method to document the number of residential structures and village fissioning. Only with these longitudinal assessments can we better evaluate the current no-contact policies by the United Nations and governments, along with the prospects for the long-term survival of isolated tribes. While the world’s largest isolated indigenous metapopulation, Pano speakers in Acre, Brazil, appears to be thriving, other smaller isolated populations disconnected from metapopulations continue to be extremely vulnerable to external threats. Our applied anthropological conservation approach is to provide analyses of publicly available remote sensing datasets to help inform policies that enhance the survival and well-being of isolated cultural groups.

Abstract BackgroundWith the increasing availability of data, computing resources, and easier-to-use software libraries, machine learning (ML) is increasingly used in disease detection and prediction, including for Parkinson disease (PD). Despite the large number of studies published every year, very few ML systems have been adopted for real-world use. In particular, a lack of external validity may result in poor performance of these systems in clinical practice. Additional methodological issues in ML design and reporting can also hinder clinical adoption, even for applications that would benefit from such data-driven systems. ObjectiveTo sample the current ML practices in PD applications, we conducted a systematic review of studies published in 2020 and 2021 that used ML models to diagnose PD or track PD progression. MethodsWe conducted a systematic literature review in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines in PubMed between January 2020 and April 2021, using the following exact string: “Parkinson’s” AND (“ML” OR “prediction” OR “classification” OR “detection” or “artificial intelligence” OR “AI”). The search resulted in 1085 publications. After a search query and review, we found 113 publications that used ML for the classification or regression-based prediction of PD or PD-related symptoms. ResultsOnly 65.5% (74/113) of studies used a holdout test set to avoid potentially inflated accuracies, and approximately half (25/46, 54%) of the studies without a holdout test set did not state this as a potential concern. Surprisingly, 38.9% (44/113) of studies did not report on how or if models were tuned, and an additional 27.4% (31/113) used ad hoc model tuning, which is generally frowned upon in ML model optimization. Only 15% (17/113) of studies performed direct comparisons of results with other models, severely limiting the interpretation of results. ConclusionsThis review highlights the notable limitations of current ML systems and techniques that may contribute to a gap between reported performance in research and the real-life applicability of ML models aiming to detect and predict diseases such as PD.

The reef manta ray Mobula alfredi is present throughout most island groups that form the Raja Ampat archipelago, Indonesia. The species is protected regionally and nationally and is currently managed as a single homogeneous population within the 6.7 million ha archipelago. However, scientific evidence is currently lacking regarding the spatial connectivity and population structure of M. alfredi within this archipelago. Using network analysis and an array of 34 acoustic receivers deployed throughout Raja Ampat between February 2016 and September 2021, we examined the movements of 72 subadult and adult M. alfredi tagged in seven regions of Raja Ampat. A total of 1094 M. alfredi movements were recorded and were primarily concentrated between nearby receiver stations, highlighting frequent local movements within, and limited long-distance movements between regional acoustic receiver arrays. Network analysis revealed highly connected nodes acting as hubs important for M. alfredi movements. A community detection algorithm further indicated clusters within the network. Our results suggest the existence of a metapopulation comprising three demographically and geographically distinct subpopulations within the archipelago. They also reveal the importance of Eagle Rock as a critical node in the M. alfredi movement network, justifying the urgent inclusion of this site within the Raja Ampat marine protected area network.

Abstract In this review, we explore the growing role of artificial intelligence (AI) in advancing the biomedical applications of human pluripotent stem cell (hPSC)‐derived organoids. Stem cell‐derived organoids, these miniature organ replicas, have become essential tools for disease modeling, drug discovery, and regenerative medicine. However, analyzing the vast and intricate datasets generated from these organoids can be inefficient and error‐prone. AI techniques offer a promising solution to efficiently extract insights and make predictions from diverse data types generated from microscopy images, transcriptomics, metabolomics, and proteomics. This review offers a brief overview of organoid characterization and fundamental concepts in AI while focusing on a comprehensive exploration of AI applications in organoid‐based disease modeling and drug evaluation. It provides insights into the future possibilities of AI in enhancing the quality control of organoid fabrication, label‐free organoid recognition, and three‐dimensional image reconstruction of complex organoid structures. This review presents the challenges and potential solutions in AI‐organoid integration, focusing on the establishment of reliable AI model decision‐making processes and the standardization of organoid research.

Introduction: Hypertension affects approximately 50 % of patients with hypertrophic cardiomyopathy (HCM) but clinical course in adults with co-occurring HCM and hypertension is underexplored. Management may be challenging as routine anti-hypertensive medications may worsen obstructive HCM, the most common HCM phenotype. In this scoping review, we sought to synthesize the available literature related to clinical course and outcomes in adults with both conditions and to highlight knowledge gaps to inform future research directions. Methods: We searched 5 electronic databases (PubMed, CINAHL, Scopus, Embase, Web of Science) to identify peer-reviewed articles, 2011–2023. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Scoping Review (PRISMA-ScR) guideline. Results: Eleven articles met eligibility. Adults with both conditions were older and had higher rates of obesity and diabetes than adults with HCM alone. Results related to functional class and arrhythmia were equivocal in cross-sectional studies. Only 1 article investigated changes in medical therapy among adults with both conditions. Hypertension was a predictor of worse functional class, but was not associated with all-cause mortality, heart failure-related mortality, or sudden-death. No data was found that related to common hypertension-related outcomes, including renal disease progression, nor patient-reported outcomes, including quality of life. Conclusions: Our results highlight areas for future research to improve understanding of co-occurring HCM and hypertension. These include a need for tailored approaches to medical management to optimize outcomes, evaluation of symptom burden and quality of life, and investigation of hypertension-related outcomes, like renal disease and ischemic stroke, to inform cardiovascular risk mitigation strategies.

Abstract Glansreginin A has been reported to be an indicator of the quality of walnuts (Juglans spp.). However, bioactive properties of glansreginin A have not been adequately explored. In the present study, we quantified concentrations of glansreginin A in black walnuts (Juglans nigra) using high performance liquid chromatography-tandem mass spectrometry (HPLC–MS/MS) and performed an array of in vitro bioassays to characterize biological activities (e.g., antibacterial, antioxidant, anticancer capacities) of this compound. Results from HPLC–MS/MS analysis indicated that glansreginin A was presented in all 12 black cultivars examined and its contents were variable among black walnut cultivars, ranged from 6.8 mg/kg (Jackson) to 47.0 mg/kg (Hay). Glansreginin A possessed moderate antibacterial activities against Gram-positive pathogens (Staphylococcus aureus and Bacillus anthracis). This compound exhibited no antioxidant activities, did not induce the activity of antioxidant response element signaling pathways, and exerted no antiproliferative effects on tumorigenic alveolar epithelial cells and non-tumorigenic lung fibroblast cells.

Optimizing forest plantation management has become imperative due to increasing forest product demand, higher fertilization and management costs, declining land availability, increased competition for land use, and the growing demands for carbon sequestration. Precision forestry refers to the ability to use data acquired with technology to support the forest management decision-making process. LiDAR can be used to assess forest metrics such as tree height, topographical position, soil surface attributes, and their combined effects on individual tree growth. LiDAR opens the door to precision silviculture applied at the tree level and can inform precise treatments such as fertilization, thinning, and herbicide application for individual trees. This study uses ALS LiDAR and other ancillary data to assess the effect of scale (i.e., stand, soil type, and microtopography) on dominant height and site index measures within loblolly pine plantations across the southeastern United States. This study shows differences in dominant height and site index across soil types, with even greater differences observed when the interactions of microtopography were considered. These results highlight how precision forestry may provide a unique opportunity for assessing soil and microtopographic information to optimize resource allocation and forest management at an individual tree scale in a scarce higher-priced fertilizer scenario.

Abstract Reliable information on population size is fundamental to the management of threatened species. For wild species, mark-recapture methods are a cornerstone of abundance estimation. Here, we show the first application of the close-kin mark-recapture (CKMR) method to a terrestrial species of high conservation value; the Christmas Island flying-fox (CIFF). The CIFF is the island's last remaining native terrestrial mammal and was recently listed as critically endangered. CKMR is a powerful tool for estimating the demographic parameters central to CIFF management and circumvents the complications arising from the species’ cryptic nature, mobility, and difficult-to-survey habitat. To this end, we used genetic data from 450 CIFFs captured between 2015 and 2019 to detect kin pairs. We implemented a novel CKMR model that estimates sex-specific abundance, trend, and mortality and accommodates observations from the kin-pair distribution of male reproductive skew and mate persistence. CKMR estimated CIFF total adult female abundance to be approximately 2050 individuals (95% CI (950, 4300)). We showed that on average only 23% of the adult male population contributed to annual reproduction and strong evidence for between-year mate fidelity, an observation not previously quantified for a Pteropus species in the wild. Critically, our population estimates provide the most robust understanding of the status of this critically endangered population, informing immediate and future conservation initiatives.

Abstract Background Because of high demand on hospital beds, hospitals seek to reduce patients’ length of stay (LOS) while preserving the quality of care. In addition to usual intermittent vital sign monitoring, continuous monitoring might help to assess the patient’s risk of deterioration, in order to improve the discharge process and reduce LOS. The primary aim of this monocenter randomized controlled trial is to assess the effect of continuous monitoring in an acute admission ward (AAW) on the percentage of patients who are discharged safely. Methods A total of 800 patients admitted to the AAW, for whom it is equivocal whether they can be discharged directly after their AAW stay, will be randomized to either receive usual care without (control group) or with additional continuous monitoring of heart rate, respiratory rate, posture, and activity, using a wearable sensor (sensor group). Continuous monitoring data are provided to healthcare professionals and used in the discharge decision. The wearable sensor keeps collecting data for 14 days. After 14 days, all patients fill in a questionnaire to assess healthcare use after discharge and, if applicable, their experience with the wearable sensor. The primary outcome is the difference in the percentage of patients who are safely discharged home directly from the AAW between the control and sensor group. Secondary outcomes include hospital LOS, AAW LOS, intensive care unit (ICU) admissions, Rapid Response Team calls, and unplanned readmissions within 30 days. Furthermore, facilitators and barriers for implementing continuous monitoring in the AAW and at home will be investigated. Discussion Clinical effects of continuous monitoring have already been investigated in specific patient populations for multiple purposes, e.g., in reducing the number of ICU admissions. However, to our knowledge, this is the first Randomized Controlled Trial to investigate effects of continuous monitoring in a broad patient population in the AAW. Trial registration https://clinicaltrials.gov/ct2/show/NCT05181111 . Registered on 6 January 2022. Start of recruitment: 7 December 2021.

Introduction: Cities located in lower income countries are global flood risk hotspots. Assessment and management of these risks forms a key part of global climate adaptation efforts. City scale flood risk assessments necessitate flood hazard information, which is challenging to obtain in these localities because of data quality/scarcity issues, and the complex multi-source nature of urban flood dynamics. A growing array of global datasets provide an attractive means of closing these data gaps, but their suitability for this context remains relatively unknown.Methods: Here, we test the use of relevant global terrain, rainfall, and flood hazard data products in a flood hazard and exposure assessment framework covering Addis Ababa, Ethiopia. To conduct the tests, we first developed a city scale rain-on-grid hydrodynamic flood model based on local data and used the model results to identify buildings exposed to flooding. We then observed how the results of this flood exposure assessment changed when each of the global datasets are used in turn to drive the hydrodynamic model in place of its local counterpart.Results and discussion: Results are evaluated in terms of both the total number of exposed buildings, and the spatial distribution of exposure across Addis Ababa. Our results show that of the datasets tested, the FABDEM global terrain and the PXR global rainfall data products provide the most promise for use at the city scale in lower income countries.

Candida auris recently emerged as an urgent public health threat, causing outbreaks of invasive infections in healthcare settings throughout the world. This fungal pathogen persists on the skin of patients and on abiotic surfaces despite antiseptic and decolonization attempts. The heightened capacity for skin colonization and environmental persistence promotes rapid nosocomial spread. Following skin colonization, C. auris can gain entrance to the bloodstream and deeper tissues, often through a wound or an inserted medical device, such as a catheter. C. auris possesses a variety of virulence traits, including the capacity for biofilm formation, production of adhesins and proteases, and evasion of innate immune responses. In this review, we highlight the interactions of C. auris with the host, emphasizing the intersection of laboratory studies and clinical observations.

Objective: The purpose of this study was to identify barriers and design interventions to promote adherence to 2017 Guideline for Syncope Evaluation and Management. Methods: Focus groups and interviews were conducted to understand preferences, needs and barriers from patients and providers. Educational materials for patients were developed following a co-design, iterative process with patients, providers and hospital staff. The academic medical center's (AMC) Patient Education Department and Patient & Family Advisory Council reviewed materials to ensure health literacy. We piloted usability and feasibility of delivering the materials to a small cohort of patients. Results: From Feb to March 2020, 24 patients were asked to watch the video. Twenty-two watched the intake video; of those 8 watched the discharge video. 95% of participants found the intake video informational and 86% would recommend it to others; 100% found the discharge video informational and would recommend it to others. Patients who watched both videos reported the videos improved their overall stay. Conclusion: Our study described a patient-clinician-researcher codesign process and demonstrated feasibility of tools developed to communicate risk and uncertainty with patients and facilitate shared decision making in syncope evaluation. Innovation: Engaging end users in developing interventions is critical for sustained practice change.

Abstract Background Analgesia after robot assisted radical cystectomy aims to reduce postoperative pain and opioid consumption, while facilitating early mobilization and enteral nutrition and minimizing complications. Epidural analgesia is currently recommended for an open radical cystectomy, but it is unclear if intrathecal morphine is a suiting, less-invasive alternative for a robot-assisted radical cystectomy. Methods The analgesic method of choice changed from epidural anesthesia to intrathecal anesthesia for patients undergoing a robot-assisted radical cystectomy. This single-center retrospective study aims to investigate if there is a difference between epidural and intrathecal analgesia in postoperative pain scores, opioid consumption, length of hospital stays and postoperative complications. An Propensity Matched Analysis was added to conventional analysis to consolidate the findings. Results The study population consisted of 153 patients of whom 114 received an epidural catheter with bupivacaine/sufentanil and 39 received a single shot of intrathecal bupivacaine/morphine. Mean pain scores on the first two postoperative days (POD) were slightly higher in the intrathecal analgesia group (epidural versus intrathecal analgesia, NRS POD0: 0(0–2)[0–8] versus 1(0–3)[0–5], p = 0.050; POD1: 2(1–3)[0–8] versus 3(1–4)[0–7], p = 0.058; POD2: 2(0–3)[0–8] versus 3(2–4)[0–7], p = 0.010). Total postoperative morphine consumption was similar over the first seven days: 15 mg (5–35)[0–148] in the epidural group versus 11 mg (0–35)[0–148] in the intrathecal morphine group, p = 0.167. Length of hospital stay and time until fit for discharge where slightly higher in the epidural group (respectively 7 days (5–9)[4–42] versus 6 days (5–7)[4–38], p = 0.006, and 5 days (4–8)[3–30]) versus 5 days (4–6)[3–34], p = 0.018). There was no further difference in postoperative course. Conclusions This study showed that the effects of epidural analgesia and intrathecal morphine are comparable and that intrathecal morphine may be a suiting alternative for epidural analgesia.

Abstract Background There has been an increased significance on patient-reported outcomes in clinical settings. We aimed to evaluate the feasibility of administering patient-reported outcome measures by computerized adaptive testing (CAT) using a tablet computer with rehabilitation inpatients, assess workload demands on staff, and estimate the extent to which rehabilitation inpatients have elevated T-scores on six Patient Reported Outcomes Measurement Information System® (PROMIS®) measures. Methods Patients (N = 108) with stroke, spinal cord injury, traumatic brain injury, and other neurological disorders participated in this study. PROMIS computerized adaptive tests (CAT) were administered via a web-based platform. Summary scores were calculated for six measures: Pain Interference, Sleep Disruption, Anxiety, Depression, Illness Impact Positive, and Illness Impact Negative. We calculated the percent of patients with T-scores equivalent to 2 standard deviations or greater above the mean. Results During the first phase, we collected data from 19 of 49 patients; of the remainder, 61% were not available or had cognitive or expressive language impairments. In the second phase of the study, 40 of 59 patients participated to complete the assessment. The mean PROMIS T-scores were in the low 50 s, indicating an average symptom level, but 19–31% of patients had elevated T-scores where the patients needed clinical action. Conclusions The study demonstrated that PROMIS assessment using a CAT administration during an inpatient rehabilitation setting is feasible with the presence of a research staff member to complete PROMIS assessment.

Muscle flaps must have a strong vascular network to support a large tissue volume and ensure successful engraftment. We developed porcine stomach musculofascial flap matrix (PDSF) comprising extracellular matrix (ECM) and intact vasculature. PDSF had a dominant vascular pedicle, microcirculatory vessels, a nerve network, well-retained 3-dimensional (3D) nanofibrous ECM structures, and no allo- or xenoantigenicity. In-depth proteomic analysis demonstrated that PDSF was composed of core matrisome proteins (e.g., collagens, glycoproteins, proteoglycans, and ECM regulators) that, as shown by Gene Ontology term enrichment analysis, are functionally related to musculofascial biological processes. Moreover, PDSF−human adipose-derived stem cell (hASC) synergy not only induced monocytes towards IL-10−producing M2 macrophage polarization through the enhancement of hASCs' paracrine effect but also promoted the proliferation and interconnection of both human skeletal muscle myoblasts (HSMMs) and human umbilical vein endothelial cells (HUVECs) in static triculture conditions. Furthermore, PDSF was successfully prevascularized through a dynamic perfusion coculture of hASCs and HUVECs, which integrated with PDSF and induced the maturation of vascular networks in vitro. In a xenotransplantation model, PDSF demonstrated myoconductive and immunomodulatory properties associated with the predominance of M2 macrophages and regulatory T cells. In a volumetric muscle loss (VML) model, prevascularized PDSF augmented neovascularization and constructive remodeling, which was characterized by the predominant infiltration of M2 macrophages and significant musculofascial tissue formation. These results indicate that hASCs' integration with PDSF enhances the cells’ dual function in immunomodulation and angiogenesis. Owing in part to this PDSF-hASC synergy, our platform shows promise for vascularized muscle flap engineering for VML reconstruction.

Climate change poses a significant threat to the resilience and sustainability of forest ecosystems. This study examines the performance of white oak (Quercus alba, L.) across a range of provenances in a common garden planting, focusing on the species’ response to climatic variables and the potential role of assisted migration in forest management. We evaluated the survival and growth rates of white oak provenances originating from various points along a latitudinal gradient over a period of 40 years. These provenances were planted in a common garden situated near the midpoint of this latitudinal gradient, where we also monitored their phenological traits, such as budburst and leaf senescence. The results revealed substantial variation in phenological responses and growth patterns among the provenances, with southern provenances demonstrating faster growth and later senescence relative to local sources, with limited impact on survival. In contrast, the northern provenances demonstrated slower growth, resulting in later-aged competition-induced mortality. The findings highlight the necessity of incorporating genetic diversity into white oak reforestation and conservation strategies, as the local provenance may no longer be the most suitable option for current and future conditions. We advocate for a nuanced approach to forest management that leverages genetic insights to optimize seed source selection for reforestation, fostering resilient forest landscapes in the face of ongoing climate shifts.

While some research supports utilizing plain radiography for measuring biomechanical alignment of the spine for prognosis and treatment, there are contrasting viewpoints regarding both the value and utilization of these procedures in conservative care. Evaluation of both conservative and non-conservative approaches to spinal care revealed vast differences in radiographic utilization and interpretation between orthopedic surgeons, primary care physicians, chiropractic physicians, and physical therapists, which may account for the different viewpoints and rationales in the literature. A research summary is provided to explore any unique biomechanical parameters identified with plain radiography of the spine (PROTS) and how these measurements may relate to patient health. Understanding any unique value provided through biomechanical assessment utilizing PROTS may help chiropractic physicians determine the appropriate use of radiographic procedures in clinical practice and how to coordinate efforts with other conservative and non-conservative spinal healthcare professions to improve patient health.

Currently, there are 2 proposed causes of acute left ventricular ballooning. The first is the most cited hypothesis that ballooning is caused by direct catecholamine toxicity on cardiomyocytes or by microvascular ischemia. We refer to this pathogenesis as Takotsubo syndrome. More recently, a second cause has emerged: that in some patients with underlying hypertrophic cardiomyopathy, left ventricular ballooning is caused by the sudden onset of latent left ventricular outflow tract obstruction. When it becomes severe and unrelenting, severe afterload mismatch and acute supply–demand ischemia appear and result in ballooning. In the context of 2 causes, presentations might overlap and cause confusion. Knowing the pathophysiology of each mechanism and how to determine a correct diagnosis might guide treatment.

Background & Aims: Cholestatic liver injury is associated with c-Jun N-terminal kinases (JNK) activation in distinct cell types. Its hepatocyte-specific function during cholestasis, however, has not yet been established. Therefore, in our present study, we investigated the role of JNK1/2 during cholestasis and dissected its hepatocyte-specific function. Methods: A cohort of patients with primary biliary cholangitis (n = 29) and primary sclerosing cholangitis (n = 37) was examined. Wild-type, hepatocyte-specific knockout mice for Jnk2 (Jnk2Δhepa) or Jnk1 and Jnk2 (Jnk1Δhepa/2Δhepa) were generated. Mice were subjected to bile duct ligation (BDL) or carbon tetrachloride (CCl4) treatment. Finally, Apelin signalling was blocked using a specific inhibitor. As an interventional approach, Jnk1/2 were silenced in wild-type mice using lipid nanoparticles for small interfering RNA delivery. Results: JNK activation was increased in liver specimens from patients with chronic cholestasis (primary biliary cholangitis and primary sclerosing cholangitis) and in livers of Mdr2-/- and BDL-treated animals. In Jnk1Δhepa/2Δhepa animals, serum transaminases increased after BDL, and liver histology demonstrated enhanced cell death, compensatory proliferation, hepatic fibrogenesis, and inflammation. Furthermore, microarray analysis revealed that hepatocytic Jnk1/2 ablation induces JNK-target genes involved in oxidative stress and Apelin signalling after BDL. Consequently, blocking Apelin signalling attenuated BDL-induced liver injury and fibrosis in Jnk1Δhepa/2Δhepa mice. Finally, we established an interventional small interfering RNA approach of selective Jnk1/2 targeting in hepatocytes in vivo, further demonstrating the essential protective role of Jnk1/2 during cholestasis. Conclusions: Jnk1 and Jnk2 work together to protect hepatocytes from cholestatic liver disease by controlling Apelin signalling. Dual modification of JNK signalling in hepatocytes is feasible, and enhancing its expression might be an attractive therapeutic approach for cholestatic liver disease. Impact and Implications: The cell-specific function of Jnk genes during cholestasis has not been explicitly explored. In this study, we showed that combined Jnk1/2, but not Jnk2 deficiency, in hepatocytes exacerbates liver damage and fibrosis by enhancing Apelin signalling, which contributes to cholestasis progression. Combined cell-specific Jnk targeting may be a new molecular strategy for treating cholestatic liver disease.

Background: Surgical treatment of proximal femur fractures is complicated by postoperative delirium in about one-third of patients. Pain and opioid consumption are modifiable factors that may influence the incidence of delirium.1 An intrathecal injection of morphine may lead to a reduction in postoperative pain and reduced systemic opioid consumption. In current practice, the addition of morphine to intrathecal anaesthesia is commonly used but depends on the anaesthesiologist's preference. Recently, a retrospective study found that intrathecal morphine was independently associated with a lower incidence of delirium. However, this has to be confirmed in a prospective, randomised study. We hypothesise that using intrathecal morphine reduces postoperative pain and opioid consumption during the first 48 h after surgery and reduces the incidence of delirium during hospital admission. We also seek additional evidence of the association between neuronal injury (delirium) and neurofilament light in serum of patients with proximal femur fractures. Objective: The primary objective is to compare the incidence of delirium. The secondary objectives are to compare pain scores, systemic opioid consumption, and (opioid-related) side-effects. The tertiary objective is to test the association between intrathecal morphine and neurofilament light as a marker of neuronal injury. Study design: A double-blind, randomised, placebo-controlled intervention study is proposed. Study population: All patients with a proximal femur fracture who are scheduled for surgery under spinal anaesthesia. Intervention: The intervention is the addition of morphine 100 μg to the intrathecal injection for spinal anaesthesia. The intervention group will receive a mixture of bupivacaine 10 mg and morphine 100 μg. The control group will receive bupivacaine 10 mg. Clinical trial registration: EU Clinical Trials Register: EudraCT number 2020-002143-27.

The article highlights data on the first sighting of Bearded Vulture Gypaetus barbatuson the territory of the Ustyurt State Nature Reserve (Kazakhstan) after 2013. It has been suggested that the bearded vulture is periodically visiting from the Great Balkan Range (Western Turkmenistan) and the subspecies of the bird encountered.

Abstract Background Healthcare organizations made major adjustments to deliver care during the COVID pandemic, yet little is known about how these adjustments shaped ongoing quality and safety improvement efforts. We aimed to understand how COVID affected four U.S. hospitals’ prospective implementation efforts in an ongoing quality improvement initiative, the RE designing S yst E ms to Improve T eamwork and Quality for Hospitalized Patients (RESET) project, which implemented complementary interventions to redesign systems of care for medical patients. Methods We conducted individual semi-structured interviews with 40 healthcare professionals to determine how COVID influenced RESET implementation. We used conventional qualitative content analysis to inductively code transcripts and identify themes in MAXQDA 2020. Results We identified three overarching themes and nine sub-themes. The three themes were (1) COVID exacerbated existing problems and created new ones. (2) RESET and other quality improvement efforts were not the priority during the pandemic. (3) Fidelity of RESET implementation regressed. Conclusion COVID had a profound impact on the implementation of a multifaceted intervention to improve quality and teamwork in four hospitals. Notably, COVID led to a diversion of attention and effort away from quality improvement efforts, like RESET, and sites varied in their ability to renew efforts over time. Our findings help explain how COVID adversely affected hospitals’ quality improvement efforts throughout the pandemic and support the need for research to identify elements important for fostering hospital resilience.

Objective: To review the literature to assess best practices for counseling transgender men who desire gender-affirming surgery on fertility preservation options. Design: A scoping review of articles published through July 2021. Setting: None. Patient(s): Articles published in Cochrane, Web of Science, PubMed, Science Direct, SCOPUS, and Psychinfo. Intervention(s): None. Main Outcome Measure(s): Papers discussing transgender men, fertility preservation (FP), and FP counseling. Result(s): The primary search yielded 1,067 publications. After assessing eligibility and evaluating with a quality assessment tool, 25 articles remained, including 8 reviews, 5 surveys, 4 consensus studies, 3 retrospective studies, 3 committee opinions, and 2 guidelines. Publications highlighted the importance of including the following topics during counseling: (1) FP and family building options; (2) FP outcomes; (3) effects of testosterone therapy on fertility; (4) contraception counseling; (5) attitudes toward family building; (6) consequences of transgender parenting; and (7) barriers to success. Conclusion(s): Currently, there is a lack of standardization for comprehensive counseling about FP for transgender men. Standardized approaches can facilitate conversation between physicians and transgender men and ensure patients are making informed decisions regarding pelvic surgery and future family building plans.

Abstract Virus recognition has been driven to the forefront of molecular recognition research due to the COVID‐19 pandemic. Development of highly sensitive recognition elements, both natural and synthetic is critical to facing such a global issue. However, as viruses mutate, it is possible for their recognition to wane through changes in the target substrate, which can lead to detection avoidance and increased false negatives. Likewise, the ability to detect specific variants is of great interest for clinical analysis of all viruses. Here, a hybrid aptamer‐molecularly imprinted polymer (aptaMIP), that maintains selective recognition for the spike protein template across various mutations, while improving performance over individual aptamer or MIP components (which themselves demonstrate excellent performance). The aptaMIP exhibits an equilibrium dissociation constant of 1.61 nM toward its template which matches or exceeds published examples of imprinting of the spike protein. The work here demonstrates that “fixing” the aptamer within a polymeric scaffold increases its capability to selectivity recognize its original target and points toward a methodology that will allow variant selective molecular recognition with exceptional affinity.

Introduction: Malrotation of the intestinal tract is a congenital malformation commonly found either incidentally or after affected individuals develop signs and symptoms of intestinal obstruction. Malrotation is prone to midgut volvulus that can cause intestinal obstruction and lead to ischemia and necrosis requiring emergent surgical intervention. Rare instances of in utero midgut volvulus have been reported in the literature and carry a high mortality given the difficulty in establishing a diagnosis prior to development of signs of intestinal ischemia and necrosis. Advancements in imaging have made it possible to diagnose in utero malrotation earlier, raising the question of optimal timing of delivery, especially in cases of prenatally diagnosed midgut volvulus. In these cases, the risks of premature birth must be weighed against the risks of fetal intestinal ischemia and potential fetal demise. Case presentation: This case report details an interesting presentation of intestinal malrotation with suspected midgut volvulus found on prenatal imaging at 33 weeks and 4 days' gestation. This prompted delivery of the infant at 34 weeks and 2 days’ gestation with urgent operative management, within 3 hours of life, after diagnosis was confirmed postnatally. Intraoperatively, the infant was confirmed to have midgut volvulus without bowel ischemia, the intestines were reduced, and a Ladd procedure was performed without incident. The infant recovered post-operatively without complication, tolerated advancement to full volume feeds and was discharged on day of life 18. Conclusion: Successful management of fetal malrotation with midgut volvulus may be accomplished by early access to a multi-disciplinary team of professionals, prompt postnatal confirmation of diagnosis, and urgent correction to minimize the risk of complications.

Background: Obesity is prevalent among patients with hypertrophic cardiomyopathy (HCM). Obese HCM patients have greater wall thickness, LV mass, worse hemodynamic function and NYHA class. Weight loss may favorably influence the HCM phenotype. Case summary: We describe six patients with hypertrophic cardiomyopathy who lost weight through diet and lifestyle changes (n = 4) or bariatric surgery (n = 2). Radiographic imaging, with cardiac MRI or CT scan, was performed before and after their weight loss. There was a mean decrease in LV mass and indexed LV mass, and a mean numerical decrease in mean wall thickness in up to 14 out of 18 LV segments. There was also NYHA class reduction in symptoms. Discussion: In this case series, we have shown that substantial weight loss in HCM patients can be associated with a decrease in LV mass, wall thickness and improvement in symptoms. These observations indicate the potential for positive remodeling of the heart by weight loss. Prospective studies of the benefits of weight loss in HCM are needed.

This work presents the synthesis of a new compound, 1-[aryl-(diphenylphosphono)methyl]-3,4,6-trimethylglycolurils, via the interaction of benzaldehyde and its mononitro- and monohydroxyderivatives with 1,3,4-trimethylglycoluril and triphenylphosphite. By varying the reaction conditions and the catalysts, the obtained product yields ranged from satisfactory to good. The diastereomers formed during the reaction were separated by semipreparative HPLC on the C18 stationary phase. The isolated diastereomers were characterized by 1H, 13C, and 31P NMR, and the structures of the diastereomers were confirmed using a single-crystal X-ray crystal structure analysis and quantum chemical calculations.

Details of the endolymphatic structures are described for the first time in the headshields of the osteostracan genus Tremataspis from the Silurian of Estonia. Tiny platelets, here termed covering platelets, are located within the openings of the endolymphatic duct. The details of their shapes and arrangements differ among the four studied species. In Tremataspis schmidti Rohon and Tremataspis milleri Patten, the covering platelets are usually arranged in an oval or circular shape around the opening of the endolymphatic duct. These species can have smooth, flat covering platelets at the mouth of an irregularly funnel-shaped aperture in the dorsal shield; the funnel often has a posterior extension. In Tremataspis rohoni Robertson and Tremataspis mammillata Patten, a distinct circular arrangement of platelets does not occur; instead, their funnel was capped with a few (2â3) smooth, flat covering platelets. The funnel of T. milleri sometimes has a long postero-lateral extension, while that of T. mammillata can have a short extension; no extensions of the funnel have been observed in T. schmidti or T. rohoni. The diameter of the pores in the covering platelets is larger than that of the pores in the superficial layer of the headshield and much larger than the diameter of the pores in the porous fields (these are thin perforated bony septa subdividing the sensory canals horizontally into lower and upper parts). In T. milleri, the larger pores are located on the side of the covering platelets that is closer to the body midline. The discovered system of covering platelets possibly functioned as a sieve for allowing in suitable grains of material and preventing material that is too fine or too coarse, or not sufficiently dense, from entering the inner ear.

Abstract Background Falls are a common complication experienced after a stroke and can cause serious detriments to physical health and social mobility, necessitating a dire need for intervention. Among recent advancements, wearable airbag technology has been designed to detect and mitigate fall impact. However, these devices have not been designed nor validated for the stroke population and thus, may inadequately detect falls in individuals with stroke-related motor impairments. To address this gap, we investigated whether population-specific training data and modeling parameters are required to pre-detect falls in a chronic stroke population. Methods We collected data from a wearable airbag’s inertial measurement units (IMUs) from individuals with (n = 20 stroke) and without (n = 15 control) history of stroke while performing a series of falls (842 falls total) and non-falls (961 non-falls total) in a laboratory setting. A leave-one-subject-out crossvalidation was used to compare the performance of two identical machine learned models (adaptive boosting classifier) trained on cohort-dependent data (control or stroke) to pre-detect falls in the stroke cohort. Results The average performance of the model trained on stroke data (recall = 0.905, precision = 0.900) had statistically significantly better recall (P = 0.0035) than the model trained on control data (recall = 0.800, precision = 0.944), while precision was not statistically significantly different. Stratifying models trained on specific fall types revealed differences in pre-detecting anterior–posterior (AP) falls (stroke-trained model’s F1-score was 35% higher, P = 0.019). Using activities of daily living as non-falls training data (compared to near-falls) significantly increased the AUC (Area under the receiver operating characteristic) for classifying AP falls for both models (P

Background: Tracheal reconstruction presents a challenge because of the difficulty in maintaining the rigidity of the trachea to ensure an open lumen and in achieving an intact luminal lining that secretes mucus to protect against infection.Methods: On the basis of the finding that tracheal cartilage has immune privilege, researchers recently started subjecting tracheal allografts to “partial decellularization” (in which only the epithelium and its antigenicity are removed), rather than complete decellularization, to maintain the tracheal cartilage as an ideal scaffold for tracheal tissue engineering and reconstruction. In the present study, we combined a bioengineering approach and a cryopreservation technique to fabricate a neo-trachea using pre-epithelialized cryopreserved tracheal allograft (ReCTA).Results: Our findings in rat heterotopic and orthotopic implantation models confirmed that tracheal cartilage has sufficient mechanical properties to bear neck movement and compression; indicated that pre-epithelialization with respiratory epithelial cells can prevent fibrosis obliteration and maintain lumen/airway patency; and showed that a pedicled adipose tissue flap can be easily integrated with a tracheal construct to achieve neovascularization.Conclusion: ReCTA can be pre-epithelialized and pre-vascularized using a 2-stage bioengineering approach and thus provides a promising strategy for tracheal tissue engineering.

Introduction:. In 2014, 56 Illinois hospitals came together to form a unique learning collaborative, the Illinois Surgical Quality Improvement Collaborative (ISQIC). Our objectives are to provide an overview of the first 3 years of ISQIC focused on (1) how the collaborative was formed and funded, (2) the 21 strategies implemented to support quality improvement (QI), (3) collaborative sustainment, and (4) how the collaborative acts as a platform for innovative QI research. Methods:. ISQIC includes 21 components to facilitate QI that target the hospital, the surgical QI team, and the perioperative microsystem. The components were developed from available evidence, a detailed needs assessment of the hospitals, reviewing experiences from prior surgical and nonsurgical QI Collaboratives, and interviews with QI experts. The components comprise 5 domains: guided implementation (eg, mentors, coaches, statewide QI projects), education (eg, process improvement [PI] curriculum), hospital- and surgeon-level comparative performance reports (eg, process, outcomes, costs), networking (eg, forums to share QI experiences and best practices), and funding (eg, for the overall program, pilot grants, and bonus payments for improvement). Results:. Through implementation of the 21 novel ISQIC components, hospitals were equipped to use their data to successfully implement QI initiatives and improve care. Formal (QI/PI) training, mentoring, and coaching were undertaken by the hospitals as they worked to implement solutions. Hospitals received funding for the program and were able to work together on statewide quality initiatives. Lessons learned at 1 hospital were shared with all participating hospitals through conferences, webinars, and toolkits to facilitate learning from each other with a common goal of making care better and safer for the surgical patient in Illinois. Over the first 3 years, surgical outcomes improved in Illinois. Discussion:. The first 3 years of ISQIC improved care for surgical patients across Illinois and allowed hospitals to see the value of participating in a surgical QI learning collaborative without having to make the initial financial investment themselves. Given the strong support and buy-in from the hospitals, ISQIC has continued beyond the initial 3 years and continues to support QI across Illinois hospitals.

The article discusses the problems of effectiveness of established network relations and communication in tertiary education are discussed. The university’s role in academic and professional network functioning is analyzed in detail. There are given the recommendationsfor a university to become effective as a network actor as well as a subject of training specialists representing integrated professionally oriented educational product.

Objective: To examine the relationship of preconception hemoglobin A1c, a marker of cumulative exposure to glucose over the preceding 2–3 months, with time to pregnancy, pregnancy loss, and live birth among fecund women without diagnosed diabetes or other medical diseases. Design: A secondary analysis of a prospective cohort of women participating in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial. Setting: Four US academic medical centers. Patient(s): A total of 1,194 healthy women aged 18–40 years with a history of one or two pregnancy losses attempting spontaneous conception were observed for up to six cycles while attempting pregnancy and throughout pregnancy if they conceived. Intervention(s): Not applicable. Main Outcome Measure(s): Time to pregnancy, human chorionic gonadotropin pregnancy, clinical pregnancy, pregnancy loss, and live birth. Result(s): Although increasing preconception A1c level was associated with reduced fecundability (fecundability odds ratio [FOR] per unit increase in A1c 0.74; 95% confidence interval [CI] 0.57, 0.96) in unadjusted models and models adjusted for age, race, smoking and treatment arm (FOR 0.79; 95% CI 0.60, 1.04), results were attenuated after further adjustment for body mass index (FOR 0.91; 95% CI 0.68, 1.21). Preconception A1c levels among women without diagnosed diabetes were not associated with live birth or pregnancy loss. Conclusions(s): Among healthy women without diagnosed diabetes, we observed no association of A1c with live birth or pregnancy loss. The association between A1c and fecundability was influenced by body mass index, a strong risk factor for both diabetes and infertility. These data support current recommendations that preconception A1c screening should be reserved for patients with risk factors for diabetes. Clinical Trial Registration Number: ClinicalTrials.gov: NCT00467363.

The effects of hypothermia on neonatal encephalopathy may vary topographically and cytopathologically in the neocortex with manifestations potentially influenced by seizures that alter the severity, distribution, and type of neuropathology. We developed a neonatal piglet survival model of hypoxic-ischemic (HI) encephalopathy and hypothermia (HT) with continuous electroencephalography (cEEG) for seizures. Neonatal male piglets received HI-normothermia (NT), HI-HT, sham-NT, or sham-HT treatments. Randomized unmedicated sham and HI piglets underwent cEEG during recovery. Survival was 2–7 days. Normal and pathological neurons were counted in different neocortical areas, identified by cytoarchitecture and connectomics, using hematoxylin and eosin staining and immunohistochemistry for RNA-binding FOX-1 homolog 3 (Rbfox3/NeuN). Seizure burden was determined. HI-NT piglets had a reduced normal/total neuron ratio and increased ischemic-necrotic/total neuron ratio relative to sham-NT and sham-HT piglets with differing severities in the anterior and posterior motor, somatosensory, and frontal cortices. Neocortical neuropathology was attenuated by HT. HT protection was prominent in layer III of the inferior parietal cortex. Rbfox3 immunoreactivity distinguished cortical neurons as: Rbfox3-positive/normal, Rbfox3-positive/ischemic-necrotic, and Rbfox3-depleted. HI piglets had an increased Rbfox3-depleted/total neuron ratio in layers II and III compared to sham-NT piglets. Neuronal Rbfox3 depletion was partly rescued by HT. Seizure burdens in HI-NT and HI-HT piglets were similar. We conclude that the neonatal HI piglet neocortex has: (1) suprasylvian vulnerability to HI and seizures; (2) a limited neuronal cytopathological repertoire in functionally different regions that engages protective mechanisms with HT; (3) higher seizure burden, insensitive to HT, that is correlated with more panlaminar ischemic-necrotic neurons in the somatosensory cortex; and (4) pathological RNA splicing protein nuclear depletion that is sensitive to HT. This work demonstrates that HT protection of the neocortex in neonatal HI is topographic and laminar, seizure unmitigating, and restores neuronal depletion of RNA splicing factor.

Speckle tracking echocardiography (STE) has been utilized to evaluate independent spatial alterations in the diabetic heart, but the progressive manifestation of regional and segmental cardiac dysfunction in the type 2 diabetic (T2DM) heart remains understudied. Therefore, the objective of this study was to elucidate if machine learning could be utilized to reliably describe patterns of the progressive regional and segmental dysfunction that are associated with the development of cardiac contractile dysfunction in the T2DM heart. Non-invasive conventional echocardiography and STE datasets were utilized to segregate mice into two pre-determined groups, wild-type and Db/Db, at 5, 12, 20, and 25 weeks. A support vector machine model, which classifies data using a single line, or hyperplane, that best separates each class, and a ReliefF algorithm, which ranks features by how well each feature lends to the classification of data, were used to identify and rank cardiac regions, segments, and features by their ability to identify cardiac dysfunction. STE features more accurately segregated animals as diabetic or non-diabetic when compared with conventional echocardiography, and the ReliefF algorithm efficiently ranked STE features by their ability to identify cardiac dysfunction. The Septal region, and the AntSeptum segment, best identified cardiac dysfunction at 5, 20, and 25 weeks, with the AntSeptum also containing the greatest number of features which differed between diabetic and non-diabetic mice. Cardiac dysfunction manifests in a spatial and temporal fashion, and is defined by patterns of regional and segmental dysfunction in the T2DM heart which are identifiable using machine learning methodologies. Further, machine learning identified the Septal region and AntSeptum segment as locales of interest for therapeutic interventions aimed at ameliorating cardiac dysfunction in T2DM, suggesting that machine learning may provide a more thorough approach to managing contractile data with the intention of identifying experimental and therapeutic targets.

BackgroundHealthcare simulators have been demonstrated to be a valuable resource for training several technical and nontechnical skills. A gap in the fidelity of tissues has been acknowledged as a barrier to application for current simulators; especially for interventional procedures. Inaccurate or unrealistic mechanical response of a simulated tissue to a given surgical tool motion may result in negative training transfer and/or prevents the "suspension of disbelief" necessary for a trainee to engage in the activity. Thus, where it is relevant to training outcomes, there should be an effort to create healthcare simulators with simulated tissue mechanical responses that match or represent those of biological tissues. Historically, this data is most often gathered from preserved (post mortem) tissue; however, there is a concern that the mechanical properties of preserved tissue, that lacks blood flow, may lack adequate accuracy to provide the necessary training efficacy of simulators.Methods and findingsThis work explores the effect of the "state" of the tissue testing status on liver and peritoneal tissue by using a customized handheld grasper to measure the mechanical responses of representative porcine (Sus domesticus) tissues in n = 5 animals across five test conditions: in vivo, post mortem (in-situ), ex vivo (immediately removed from fresh porcine cadaver), post-refrigeration, and post-freeze-thaw cycle spanning up to 72 hours after death. No statistically significant difference was observed in the mechanical responses due to grasping between in vivo and post-freeze conditions for porcine liver and peritoneum tissue samples (p = 0.05 for derived stiffness at grasping force values F = 5N and 6.5N). Furthermore, variance between in vivo and post-freeze conditions within each animal, was comparable to the variance of the in vivo condition between animals.ConclusionsResults of this study further validate the use of preserved tissue in the design of medical simulators via observing tissue mechanical responses of post-freeze tissue comparable to in vivo tissue. Therefore, the use of thawed preserved tissue for the further study and emulation of mechanical perturbation of the liver and peritoneum can be considered. Further work in this area should investigate these trends further, particularly in regard to other tissues and the potential effects varying preservation methods may yield.

This report presents the results of survey of a 46-kilometer section of the overhead line (OHL) powering the cathodic protection of the Bukhara – Ural Gas Pipeline within the Aktobe Region of the Republicof Kazakhstan. 7 kilometersof this section were previously equipped with bird protection devices (BPDs), which are now totally lost due to destruction of their fastening elements. Inspection of the 46-km section of this OHL has revealed deaths of 2 eagles (Aquilasp.), 1 Common Kestrel (Falco tinnunculus), 1 Black Kite (Milvus migrans), and 3 Greater Flamingo (Phoenicopterus roseus). The conclusion was made that the BPDs of this OHL needed renewal. It was also concluded that instead of OHLs laid along the pipeline route it was advisable to consider other options, including stations of cathodic protection fed from modular-packaged electrical power plants with self-contained micro-turbine units, such as used at the Beineu – Bozoy – Shymkent Gas Pipeline.

Abstract Background Air pollution is a complex mixture of particles and gases, yet current regulations are based on single toxicant levels failing to consider potential interactive outcomes of co-exposures. We examined transcriptomic changes after inhalation co-exposure to a particulate and a gaseous component of air pollution and hypothesized that co-exposure would induce significantly greater impairments to mitochondrial bioenergetics. A whole-body inhalation exposure to ultrafine carbon black (CB), and ozone (O3) was performed, and the impact of single and multiple exposures was studied at relevant deposition levels. C57BL/6 mice were exposed to CB (10 mg/m3) and/or O3 (2 ppm) for 3 h (either a single exposure or four independent exposures). RNA was isolated from lungs and mRNA sequencing performed using the Illumina HiSeq. Lung pathology was evaluated by histology and immunohistochemistry. Electron transport chain (ETC) activities, electron flow, hydrogen peroxide production, and ATP content were assessed. Results Compared to individual exposure groups, co-exposure induced significantly greater neutrophils and protein levels in broncho-alveolar lavage fluid as well as a significant increase in mRNA expression of oxidative stress and inflammation related genes. Similarly, a significant increase in hydrogen peroxide production was observed after co-exposure. After single and four exposures, co-exposure revealed a greater number of differentially expressed genes (2251 and 4072, respectively). Of these genes, 1188 (single exposure) and 2061 (four exposures) were uniquely differentially expressed, with 35 mitochondrial ETC mRNA transcripts significantly impacted after four exposures. Both O3 and co-exposure treatment significantly reduced ETC maximal activity for complexes I (− 39.3% and − 36.2%, respectively) and IV (− 55.1% and − 57.1%, respectively). Only co-exposure reduced ATP Synthase activity (− 35.7%) and total ATP content (30%). Further, the ability for ATP Synthase to function is limited by reduced electron flow (− 25%) and translation of subunits, such as ATP5F1, following co-exposure. Conclusions CB and O3 co-exposure cause unique transcriptomic changes in the lungs that are characterized by functional deficits to mitochondrial bioenergetics. Alterations to ATP Synthase function and mitochondrial electron flow underly a pathological adaptation to lung injury induced by co-exposure.

The discussion about the changes in teaching is shaped by the ideas of what impact digitalization has on the development and socialization of the younger generation. These processes are closely related to personal development training. Personal development training is under ever expanding influence of digitalization, and researchers notice the gap between traditional teaching methods and work models and their poor reproducibility under such conditions. The aim of the study is twofold: to analyze how personal development training tasks are implemented in the current climate of digitalization, and to determine the major tendencies of the changes in personal development training. The methodology of the study is based on the provisions of the following theories: the theory of social education in the context of socialization (A. V. Mudrik), theories of personal development training systems (L. I. Novikova, N. L. Selivanova), and the network approach. Apparently, in the modern post-industrial digital society, a virtual community can become the space for personal development training. There emerge new subjects of personal development training (digital technologies, subcultural communities, network groups, voluntary assistants, volunteers, parents, etc.). This will “require” a change in the professional language and teacher’s professional functions. The intention to enable productive behavior of an individual to solve their own problems should remain an important component of personal development training. In order to do this, the life of an educational organization should be enriched with a variety of social practices that encourage interaction and joint productive activities; an educational organization should develop forms of self- and co-management, and introduce a variety of extracurricular activities. The search for forms of personal development training relevant to the needs of the modern teenager is being reinforced. Moreover, globalization raises the issue of how global and eternal values are compatible with the values of digital culture, i.e. the culture of the virtual augmented world. The authors note that in the current climate of the digital world, the boundaries of personal development training are constantly changing geographically, organizationally, meaningfully. As a result, the task of creating, developing and retaining the personal development training environment acquires significance not only at the content level, but also at the organizational level, including the virtual one.