Search Results (37)

Short bowel syndrome (SBS) is characterized by insufficient intestinal length to support absorption causing malnutrition. The bowel adapts to SBS via intestinal dilation and delayed gastric emptying but still often requires long-term parenteral nutrition. Current surgical options to lengthen the bowel pose significant risks and often provide limited expansion. ‘Distraction enterogenesis’ has been proposed as a technique to induce intestinal lengthening for SBS. The deployment of the intestinal expansion sleeve (IES) device is hypothesized to result in significant intestinal lengthening in vivo. A Roux-en-Y was created in the jejunum of seven rats for isolated IES deployment. The IES was precontracted over a Bucatini noodle and inserted into the isolated roux limb. After 4 weeks of deployment, rats were sacrificed, Roux-en-Y length recorded, and histology analyzed. A paired t-test was performed to compare initial and final roux limb lengths and histopathological tissue remodeling. Intestinal distraction evaluated at 4 weeks post deployment of the IES resulted in a significant 30.2% elongation in roux limb length (43.6 ± 14.4 mm to 56.4 ± 20.8 mm (p = 0.043, n = 7). IES samples showed changes in mucosal and submucosal integrity and bowel wall thickness in response to IES lengthening. In samples with partial mucosal erosion, the basal/regenerative layers of the mucosa were preserved. Distraction enterogenesis with significant intestinal lengthening in vivo has been achieved with the IES device. Histologic changes suggest all bowel functional layers and attributes are maintained through distraction enterogenesis. Future constructs of the IES may benefit from the addition of immunomodulators. Increasing intestinal mass with these devices may complement the treatment paradigm for SBS. Full article

Due to constantly evolving technology, a new challenge has entered the relationship landscape: the inclusion of robots as emotional and intimate partners. This article raises the question of the degree to which companionship and intimacy may be fulfilled by robots. Three hundred and fourteen undergraduates, the majority of whom were first- or second-year college students, responded to an online survey on robot acceptance. Factor analysis identified two constructs, which the authors labeled as simulated companionship (e.g., robots as companions/helpful assistants) and simulated intimacy (e.g., robots as intimate partners–emotional and sexual). Data analysis revealed a difference between companionship and intimacy regarding student robot acceptance for home use. Overall, there was greater acceptance of robots as companions than as intimate partners. Group differences for simulated companionship were found for gender, sexual values, commitment to religion, and sexual orientation. While robots may enhance various elements of human life, the data revealed the limits of outsourcing emotional intimacy, companionship, and sex to machines. Full article

Objective: The development of adjacent segment disease or the progression of spondylosis following the surgical treatment of spinal stenosis and spondylolisthesis is well documented and can lead to subsequent functional decline after a successful index surgery. The early detection of negative inflection points during patients’ functional recovery can improve timely intervention. In this study, we developed machine learning (ML) models to predict the occurrence of post-operative decline in patient mobility. Methods: Patients receiving spine surgery for degenerative spinal stenosis or spondylolisthesis were retroactively consented and enrolled. Activity data (steps-per-day) previously recorded across a 4-year peri-operative were collected alongside relevant clinical and demographic variables. Logistic regression (LR), random forest (RF), and extreme gradient boosting (XGBoost) ML models were constructed and trained on 80% of the dataset and validated using the remaining 20%. The study’s primary endpoint was the models’ ability to predict post-operative decline in patient mobility. Results: A total of 75 patients were included. Following training, RF and XGBoost models achieved accuracy values of 86.7% (sensitivity 80%, specificity 90%) and 80% (sensitivity 60%, specificity 90%), respectively, in predicting post-operative functional decline. The LR model was the least effective with an accuracy of 73.3% (sensitivity 50%, specificity 88.8%). Receiver operating characteristic curves showed an area under the curve of 0.80 for RF, 0.70 for XGBoost, and 0.69 for LR. Conclusions: ML models trained on activity data collected from smartphones successfully forecast functional decline in post-operative activity following spine surgery. These results lay the groundwork for the future integration of ML into the surgeon’s toolbox for prognostication and surgical planning. Full article

In the past two decades, students have been more willing to disclose their disability status when entering higher education (HE) in the United Kingdom (UK). Concurrently, higher education institutions (HEIs) have adopted disability policies and service teams for enhancing equality, diversity, and inclusion in the UK. The purpose of this integrative review is to understand the basis of these trends. The article suggests that there have been three major key paradigm shifts that underpin this cultural change. (1) There was a paradigm shift in terms of changing the dominant models for conceptualising disability from a medical model of disability to a social model of disability and to an affirmative model of disability, together with a debate and policy development demonstrating a concern for greater social inclusion and exclusion; (2) with a massive increase in students entering HE and the rising importance of league tables and ranking systems, universities experienced a paradigm shift from teacher-centred learning (TCL) to inclusive student-centred learning and teaching (SCLT); and (3) the increase in autism disclosure in HE signifies a shift in a conceptualisation of autism from a disorder to a disability and an example of neurodiversity. Full article

Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic chordoma, chondrosarcoma, osteosarcoma, Ewing sarcoma with bone involvement, rhabdomyosarcoma (RMS) with bone involvement, or non-RMS soft tissue sarcoma with bone involvement. Treatment arms include (1) CIRT (n = 30) delivered in Europe and Asia, (2) surgical treatment with or without adjuvant radiotherapy (n = 30), and (3) proton therapy (n = 30). Arms two and three will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota. The primary end point is to compare the 1-year change in functional QOL between CIRT and surgical treatment. Additional comparisons among the three arms will be made between treatment sequelae, local control, and other QOL measures. Full article

Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (1). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC₅₀ as well as IC₅₀ values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than 1. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1. Full article

Head and neck squamous cell cancers (HNSCCs) represent a diverse group of tumors emerging within different mucosal surfaces of the oral cavity, nasopharynx, oropharynx, larynx, and hypopharynx. HNSCCs share common clinical risk factors and genomic features, including smoking, alcohol, age, male sex, aneuploidy, and TP53 mutations. Viral initiating and contributing events are increasingly recognized in HNSCCs. While both Epstein–Barr Virus (EBV) and human papilloma virus (HPV) are observed, EBV is more frequently associated with nasopharyngeal cancers whereas HPV is associated with oropharyngeal cancers. HNSCCs are associated with high tumor mutational burden and loss of tumor suppressor gene function, especially in TP53 and X-linked genes. Multiple lines of evidence suggest that HNSCCs are subject to immunologic surveillance and immune-induced evolutionary pressure that correlate with negative clinical outcomes. This review will discuss genomic mechanisms related to immune-mediated pressures and propose prognostic and therapeutic implications of detectable immune escape mechanisms that drive tumorigenesis and disease progression. Full article

Introduction: Pediatric asthma affects 5.5 million US children and is the leading cause of pediatric chronic illness globally. Those with severe asthma have significantly higher healthcare costs compared to those with non-severe disease. Biologics are the newest class of anti-asthma therapy approved for use in patients with severe asthma > 6 years with the eosinophilic phenotype. Objective: The goals of this study were to (1) describe the baseline characteristics of new US pediatric mepolizumab users between 2015 and end dates that varied by data partner (6/30/19–5/31/21), (2) describe asthma medication use in the 12 months preceding and following mepolizumab initiation in this group and (3) assess adherence and persistence to mepolizumab in the 12 months following initiation. Methods: Through an observational cohort study using insurance claim databases, we studied children with a diagnosis of asthma in the preceding 12 months who started mepolizumab and had 12 months of follow-up data. Results: Baseline characteristics of the 72 children who initiated mepolizumab showed variable comorbidities, the most common being allergic rhinitis (88%) and recurrent respiratory infections (71%), as well as varied medication dispensings and patterns of healthcare utilization prior to initiating mepolizumab. Half met the criteria for severe asthma per the GINA guidelines. Comparing weighted averages of treatments dispensed in the 12 months prior to versus following mepolizumab initiation, we observed no significant change in asthma treatments dispensed. Conclusion: This study demonstrates that pediatric patients prescribed mepolizumab have variable previous treatment history and severity of disease, and we found no evidence that mepolizumab alters other asthma medications dispensed in the first 12 months following initiation. Full article

Nuclear factor erythroid factor E2-related factor 2 (Nrf2) transcribes antioxidant genes that reduce the blood pressure (BP), yet its activation with tert-butylhydroquinone (tBHQ) in mice infused with angiotensin II (Ang II) increased mean arterial pressure (MAP) over the first 4 days of the infusion. Since tBHQ enhanced cyclooxygenase (COX) 2 expression in vascular smooth muscle cells (VSMCs), we tested the hypothesis that tBHQ administration during an ongoing Ang II infusion causes an early increase in microvascular COX-dependent reactive oxygen species (ROS) and contractility. Mesenteric microarteriolar contractility was assessed on a myograph, and ROS by RatioMaster™. Three days of oral tBHQ administration during the infusion of Ang II increased the mesenteric microarteriolar mRNA for p47^phox, the endothelin type A receptor and thromboxane A₂ synthase, and increased the excretion of 8-isoprostane F_2α and the microarteriolar ROS and contractions to a thromboxane A₂ (TxA₂) agonist (U-46,619) and endothelin 1 (ET1). These were all prevented in Nrf2 knockout mice. Moreover, the increases in ROS and contractility were prevented in COX1 knockout mice with blockade of COX2 and by blockade of thromboxane prostanoid receptors (TPRs). In conclusion, the activation of Nrf2 over 3 days of Ang II infusion enhances microarteriolar ROS and contractility, which are dependent on COX1, COX2 and TPRs. Therefore, the blockade of these pathways may diminish the early adverse cardiovascular disease events that have been recorded during the initiation of Nrf2 therapy. Full article

Diet impacts the composition of the ruminal microbiota; however, prior to slaughter, cattle are fasted, which may change the ruminal microbial ecosystem structure and lead to dysbiosis. The objective of this study was to determine changes occurring in the rumen after pre-slaughter fasting, which can allow harmful pathogens an opportunity to establish in the rumen. Ruminal samples were collected before and after pre-slaughter fasting from seventeen commercial Angus steers. DNA extraction and 16S rRNA gene sequencing were performed to determine the ruminal microbiota, as well as volatile fatty acid (VFA) concentrations. Microbial richness (Chao 1 index), evenness, and Shannon diversity index all increased after fasting (p ≤ 0.040). During fasting, the two predominant families Prevotellaceae and Ruminococcaceae decreased (p ≤ 0.029), whereas the remaining minor families increased (p < 0.001). Fasting increased Blautia and Methanosphaera (p ≤ 0.003), while Campylobacter and Treponema tended to increase (p ≤ 0.086). Butyrate concentration tended to decrease (p = 0.068) after fasting. The present findings support that fasting causes ruminal nutrient depletion resulting in dysbiosis, allowing opportunistic pathogens to exploit the void in the ruminal ecological niche. Full article

Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid—or NEt-4IB—in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC₅₀ and IC₅₀ values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as 1. Full article

While investigating a signal of adaptive evolution in humans at the gene LARGE, we encountered an intriguing finding by Dr. Stefan Kunz that the gene plays a critical role in Lassa virus binding and entry. This led us to pursue field work to test our hypothesis that natural selection acting on LARGE—detected in the Yoruba population of Nigeria—conferred resistance to Lassa Fever in some West African populations. As we delved further, we conjectured that the “emerging” nature of recently discovered diseases like Lassa fever is related to a newfound capacity for detection, rather than a novel viral presence, and that humans have in fact been exposed to the viruses that cause such diseases for much longer than previously suspected. Dr. Stefan Kunz’s critical efforts not only laid the groundwork for this discovery, but also inspired and catalyzed a series of events that birthed Sentinel, an ambitious and large-scale pandemic prevention effort in West Africa. Sentinel aims to detect and characterize deadly pathogens before they spread across the globe, through implementation of its three fundamental pillars: Detect, Connect, and Empower. More specifically, Sentinel is designed to detect known and novel infections rapidly, connect and share information in real time to identify emerging threats, and empower the public health community to improve pandemic preparedness and response anywhere in the world. We are proud to dedicate this work to Stefan Kunz, and eagerly invite new collaborators, experts, and others to join us in our efforts. Full article

Fused deposition modelling (FDM) is the most extensively employed 3D-printing technique used in pharmaceutical applications, and offers fast and facile formulation development of personalized dosage forms. In the present study, mesoporous materials were incorporated into a thermoplastic filament produced via hot-melt extrusion and used to produce oral dosage forms via FDM. Mesoporous materials are known to be highly effective for the amorphization and stabilization of poorly soluble drugs, and were therefore studied in order to determine their ability to enhance the drug-release properties in 3D-printed tablets. Celecoxib was selected as the model poorly soluble drug, and was loaded into mesoporous silica (MCM-41) or mesoporous magnesium carbonate. In vitro drug release tests showed that the printed tablets produced up to 3.6 and 1.5 times higher drug concentrations, and up to 4.4 and 1.9 times higher release percentages, compared to the crystalline drug or the corresponding plain drug-loaded mesoporous materials, respectively. This novel approach utilizing drug-loaded mesoporous materials in a printed tablet via FDM shows great promise in achieving personalized oral dosage forms for poorly soluble drugs. Full article

Kenyan poultry consists of ~80% free-range indigenous chickens kept in small flocks (~30 birds) on backyard poultry farms (BPFs) and they are traded via live bird markets (LBMs). Newcastle disease virus (NDV) was detected in samples collected from chickens, wild farm birds, and other domestic poultry species during a 2017–2018 survey conducted at 66 BPFs and 21 LBMs in nine Kenyan counties. NDV nucleic acids were detected by rRT-PCR L-test in 39.5% (641/1621) of 1621 analyzed samples, of which 9.67% (62/641) were NDV-positive by both the L-test and a fusion-test designed to identify the virulent virus, with a majority being at LBMs (64.5%; 40/62) compared to BPFs (25.5%; 22/62). Virus isolation and next-generation sequencing (NGS) on a subset of samples resulted in 32 complete NDV genome sequences with 95.8–100% nucleotide identities amongst themselves and 95.7-98.2% identity with other east African isolates from 2010-2016. These isolates were classified as a new sub-genotype, V.3, and shared 86.5–88.9% and 88.5–91.8% nucleotide identities with subgenotypes V.1 and V.2 viruses, respectively. The putative fusion protein cleavage site (¹¹³R-Q-K-R↓F ¹¹⁷) in all 32 isolates, and a 1.86 ICPI score of an isolate from a BPF chicken that had clinical signs consistent with Newcastle disease, confirmed the high virulence of the NDVs. Compared to genotypes V and VI viruses, the attachment (HN) protein of 18 of the 32 vNDVs had amino acid substitutions in the antigenic sites. A time-scaled phylogeographic analysis suggests a west-to-east dispersal of the NDVs via the live chicken trade, but the virus origins remain unconfirmed due to scarcity of continuous and systematic surveillance data. This study reveals the widespread prevalence of vNDVs in Kenyan backyard poultry, the central role of LBMs in the dispersal and possibly generation of new virus variants, and the need for robust molecular epidemiological surveillance in poultry and non-poultry avian species. Full article

The impact of base glass morphology and post heat-treatment protocol on the mechanical properties (Vickers hardness and Young’s modulus) of a multi-component glass-ceramic was examined. Two parent chalcogenide glasses with identical composition but varying morphology (homogeneous and phase separated) were evaluated for their mechanical properties following identical thermal processing to induce crystallization. The nucleation and growth rates of the starting materials were compared for the two glasses, and the resulting crystal phases and phase fractions formed through heat treatment were quantified and related to measured mechanical properties of the glass ceramics. The presence of a Pb-rich amorphous phase with a higher crystal formation tendency in the phase-separated parent glass significantly impacted the volume fraction of the crystal phases formed after heat-treatment. Pb-rich cubic crystal phases were found to be dominant in the resulting glass ceramic, yielding a minor enhancement of the material’s mechanical properties. This was found to be less than a more moderate enhancement of mechanical properties due to the formation of the dominant needle-like As₂Se₃ crystallites resulting from heat treatment of the homogeneous, commercially melted parent glass. The greater enhancement of both Vickers hardness and modulus in this glass ceramic attributable to the high-volume fraction of anisotropic As₂Se₃ crystallites in the post heat-treated commercial melt highlights the important role base glass morphology can play on post heat-treatment microstructure. Full article