VISIBL-MS: A bilingual educational framework to increase awareness of early multiple sclerosis.

BACKGROUND: Despite advancements in treatments of multiple sclerosis (MS), there is a lack of awareness of early MS symptoms, especially in students and the public, contributing to delays in diagnosis and treatment. This review aims to identify gaps in tools to increase awareness and to provide a bilingual framework to facilitate recognition of early MS symptoms. METHODS: We performed a literature review to determine the use of English and Spanish mnemonics in MS education for medical students and patients. RESULTS: There is no educational tool to help remember the early signs of MS at present. Here we present a framework for early awareness encompassed in the bilingual mnemonics VISIBLY (English) and VISIBLE (Spanish). VISIBLY stands for (1) Vision changes: Painful vision loss, loss of color vision or double vision; (2) Belly or Back numbness and Balance issues; (3) Limb weakness or Numbness; (4), Young people. Spanish version is included in the manuscript. CONCLUSION: We posit that VISIBL-MS provides a framework for MS awareness that addresses the interconnection between language, culture, health literacy, and health outcomes and can be a useful educational tool to tackle the effects of health literacy on diverse communities.

ACEGEN: Reinforcement Learning of Generative Chemical Agents for Drug Discovery.

In recent years, reinforcement learning (RL) has emerged as a valuable tool in drug design, offering the potential to propose and optimize molecules with desired properties. However, striking a balance between capabilities, flexibility, reliability, and efficiency remains challenging due to the complexity of advanced RL algorithms and the significant reliance on specialized code. In this work, we introduce ACEGEN, a comprehensive and streamlined toolkit tailored for generative drug design, built using TorchRL, a modern RL library that offers thoroughly tested reusable components. We validate ACEGEN by benchmarking against other published generative modeling algorithms and show comparable or improved performance. We also show examples of ACEGEN applied in multiple drug discovery case studies. ACEGEN is accessible at https://github.com/acellera/acegen-open and available for use under the MIT license.

A sensory neuron-specific long non-coding RNA reduces neuropathic pain by rescuing KCNN1 expression.

Nerve injury to peripheral somatosensory system causes refractory neuropathic pain. Maladaptive changes of gene expression in primary sensory neurons are considered molecular basis of this disorder. Long non-coding RNAs (lncRNAs) are key regulators of gene transcription; however, their significance in neuropathic pain remains largely elusive.Here, we reported a novel lncRNA, named sensory neuron-specific lncRNA (SS-lncRNA), for its expression exclusively in dorsal root ganglion (DRG) and trigeminal ganglion. SS-lncRNA was predominantly expressed in small DRG neurons and significantly downregulated due to a reduction of early B cell transcription factor 1 in injured DRG after nerve injury. Rescuing this downregulation reversed a decrease of the calcium-activated potassium channel subfamily N member 1 (KCNN1) in injured DRG and alleviated nerve injury-induced nociceptive hypersensitivity. Conversely, DRG downregulation of SS-lncRNA reduced the expression of KCNN1, decreased total potassium currents and afterhyperpolarization currents and increased excitability in DRG neurons and produced neuropathic pain symptoms.Mechanistically, downregulated SS-lncRNA resulted in the reductions of its binding to Kcnn1 promoter and heterogeneous nuclear ribonucleoprotein M (hnRNPM), consequent recruitment of less hnRNPM to the Kcnn1 promoter and silence of Kcnn1 gene transcription in injured DRG.These findings indicate that SS-lncRNA may relieve neuropathic pain through hnRNPM-mediated KCNN1 rescue in injured DRG and offer a novel therapeutic strategy specific for this disorder.

Outcomes of same-day discharge in bariatric surgery.

BACKGROUND: Restrictions during the COVID-19 pandemic influenced a shift to same-day discharge in bariatric surgery. Current studies show conflicting findings regarding morbidity and mortality. We aim to compare outcomes for same-day discharge versus admission after bariatric surgery. METHODS: Subjects included patients who underwent primary laparoscopic or robotic-assisted sleeve gastrectomy or Roux-En-Y gastric bypass at an academic center. The inpatient group included patients discharged postoperative day one, and the outpatient group included patients discharged on the day of surgery. Primary outcomes included the number of emergency room visits, reoperations, IV fluid treatments, readmissions, and mortality within 30 days. Secondary outcomes were morbidity, including skin and soft tissue infection, pulmonary embolism, and acute kidney injury. RESULTS: 1225 patients met the inclusion criteria. In the gastric sleeve group, 852 subjects were outpatients and 227 inpatients. In the gastric bypass group, 70 subjects were outpatients, and 40 were inpatients. The mean age was 44.63 (17.38-85.31) years, and the mean preoperative BMI was 46.07 ± 8.14 kg/m2. The subjects in the outpatient group had lower BMI with fewer comorbidities. The groups differed significantly in age, BMI, and presence of several chronic comorbidities. The inpatient and outpatient groups for each surgery type did not differ significantly regarding reoperations, IV fluid treatments, or 30-day mortality. The inpatient sleeve group demonstrated a significantly higher readmission percentage than the outpatient group (4.6% vs 2.1%; p = 0.02882). The inpatient bypass group showed significantly greater ER visits (21.7% vs 10%; p = 0.0108). The incidence of adverse events regarding the secondary outcomes was not statistically different. CONCLUSION: Same-day discharge after bariatric surgery is a safe and reasonable option for patients with few comorbidities.

One-hundred Consecutive Physician-Modified Fenestrated Endovascular Aneurysm Repair of Pararenal and Thoracoabdominal Aortic Aneurysms Using the Terumo TREO Stent Graft.

BACKGROUND: Fenestrated endovascular aortic aneurysm repair (FEVAR) has been widely applied for the treatment of pararenal (PAA) and thoracoabdominal aortic aneurysms (TAAA). If custom-made devices or off-the-shelf devices are not available, physician-modified endografts (PMEGs) are an alternative device option. Several different endograft platforms have been used for PMEG; however, minimal data exists on utilizing the Terumo TREO abdominal stent graft system in this setting. The purpose of this study was to evaluate our single-center experience treating PAA and TAAA, with a physician-modified FEVAR, using the Terumo TREO platform. METHODS: A prospective database of consecutive patients with PAA and TAAA treated at a single center, with a FEVAR, utilizing a PMEG device between March 2021 and September 2023 was queried for those having a Terumo TREO device implanted. The demographics, operative details, and postoperative complications were analyzed. The rates of technical success, type I or III endoleak, branch vessel status, reintervention, and 2-year survival were also assessed. RESULTS: Of the 153 patients who underwent FEVAR with a PMEG device during the study period, 100 had repair using a Terumo TREO stent graft. The mean age of the cohort was 73.7 ± 7.0 years with the majority suffering from hypertension (n = 94, 94%), coronary artery disease (n = 51, 51%), and chronic obstructive pulmonary disease (n = 40, 40%). Thirty-four patients (34%) had a prior failed EVAR device in place. The mean aneurysm size was 66.0 ± 13.7 mm, with 58 (50%) patients classified as PAA and 30 (30%) patients as an extent IV TAAA. Six (6%) patients presented with symptomatic/ruptured aneurysms. The average number of target arteries incorporated per patient was 3.8 ± 0.6. The overall technical success was 99%, procedure time was 218 ± 116 min, contrast volume was 82 ± 21 mL, and cumulative air kerma was 3,054 ± 1,560 mGy. Postoperative complications were present in 20 patients (20%), and 2 patients (2%) died within 30 days. Rates of type I or III endoleak, branch vessel stenosis or occlusion, and reintervention were 2%, 1%, and 7%, respectively. The two-year overall survival was 87%. CONCLUSIONS: Treatment of PAA and the extent IV TAAA using a physician-modified fenestrated Terumo TREO endograft is safe and effective. This large, early experience using the Terumo TREO platform supports preferential use of this device in this setting due to the device design and low likelihood of type I or III endoleak.

Expansion of the genetic code through reassignment of redundant sense codons using fully modified tRNA.

Breaking codon degeneracy for the introduction of non-canonical amino acids offers many opportunities in synthetic biology. Yet, despite the existence of 64 codons, the code has only been expanded to 25 amino acids in vitro. A limiting factor could be the over-reliance on synthetic tRNAs which lack the post-transcriptional modifications that improve translational fidelity. To determine whether modified, wild-type tRNA could improve sense codon reassignment, we developed a new fluorous method for tRNA capture and applied it to the isolation of roughly half of the Escherichia coli tRNA isoacceptors. We then performed codon competition experiments between the five captured wild-type leucyl-tRNAs and their synthetic counterparts, revealing a strong preference for wild-type tRNA in an in vitro translation system. Finally, we compared the ability of wild-type and synthetic leucyl-tRNA to break the degeneracy of the leucine codon box, showing that only captured wild-type tRNAs are discriminated with enough fidelity to accurately split the leucine codon box for the encoding of three separate amino acids. Wild-type tRNAs are therefore enabling reagents for maximizing the reassignment potential of the genetic code.

Exploring Infant Feeding Experiences and Maternity Care Practices in Appalachia.

OBJECTIVES: Our aim was to explore postpartum individuals' experiences and perceptions of breastfeeding and International Board Certified Lactation Consultants' (IBCLC) knowledge and perceptions of maternity care practices and perceived barriers to breastfeeding among their patient populations in Appalachia. METHODS: Semistructured interviews were conducted with seven IBCLCs and seven postpartum individuals. Interviews were recorded and transcribed. Thematic analysis was conducted to determine emergent themes and subthemes related to knowledge/perceptions, experiences, and barriers to breastfeeding among postpartum individuals, as well as emergent themes associated with the knowledge and perceptions of maternity care practices, easy-/difficult-to-implement Baby-Friendly Hospital Initiative maternity care practices, and perceived barriers to breastfeeding among IBCLCs. RESULTS: Postpartum individuals recruited from an Appalachian obstetrics/gynecology clinic were aware of the benefits of breastfeeding, but their infant feeding journeys were more stressful than they expected, and they had limited access to lactation support and breastfeeding education/information. IBCLCs identified the benefits of the Baby-Friendly maternity care practices but mentioned some risks, especially when there is a lack of communication and coordination among providers. Environmental and informational barriers were identified by both postpartum individuals and IBCLCs as breastfeeding challenges potentially amenable to change. CONCLUSIONS: To support postpartum mothers in the Appalachian region, environmental barriers (eg, lack of lactation support) and informational barriers (eg, lack of prenatal education) need to be addressed.

Cell numbers, cell ratios, and developmental plasticity in the rod pathway of the mouse retina.

The precise specification of cellular fate is thought to ensure the production of the correct number of neurons within a population. Programmed cell death may be an additional mechanism controlling cell number, believed to refine the proper ratio of pre- to post-synaptic neurons for a given species. Here, we consider the size of three different neuronal populations in the rod pathway of the mouse retina: rod photoreceptors, rod bipolar cells, and AII amacrine cells. Across a collection of 28 different strains of mice, large variation in the numbers of all three cell types is present. The variation in their numbers is not correlated, so that the ratio of rods to rod bipolar cells, as well as rod bipolar cells to AII amacrine cells, varies as well. Establishing connectivity between such variable pre- and post-synaptic populations relies upon plasticity that modulates process outgrowth and morphological differentiation, which we explore experimentally for both rod bipolar and AII amacrine cells in a mouse retina with elevated numbers of each cell type. While both rod bipolar dendritic and axonal arbors, along with AII lobular arbors, modulate their areal size in relation to local homotypic cell densities, the dendritic appendages of the AII amacrine cells do not. Rather, these processes exhibit a different form of plasticity, regulating the branching density of their overlapping arbors. Each form of plasticity should ensure uniformity in retinal coverage in the presence of the independent specification of afferent and target cell number.

Impact of essential amino acid intake, resistance exercise, and aging on the concentration of Achilles peritendinous amino acids and procollagen Iα1 in humans.

Recent studies have shown that consuming amino acid-rich compounds improves tendon collagen content and biomechanical properties. Yet, it is unclear if the consumption of amino acids alters local (peritendinous) amino acid concentrations. If aging or exercise influence local amino acid concentrations in conjunction with an amino acid bolus is also not known. We conducted two studies. In Study 1, young women (n = 7, 25 ± 2 years) completed two identical resistance training sessions with either essential amino acid (EAA) or placebo consumption. In Study 2, an EAA bolus identical to Study 1 was given to younger (n = 7; 27 ± 1 year) and older adults (n = 6; 68 ± 2 years). Microdialysis was used to determine Achilles peritendinous amino acid and pro-collagen Iα1 (a marker of collagen synthesis) concentrations. In Study 1, amino acid consumption increased peritendinous concentrations of all EAA except histidine (p < 0.05). In Study 2, the peritendinous concentration of EAAs except for methionine, histidine, and lysine (p > 0.05) increased with time (p < 0.05). Further, the concentrations of most measured amino acids were greater in older adults (p < 0.05). Pro-collagen Iα1 concentration (p > 0.05) was unaffected by exercise, EAA, or aging (p > 0.05). Our findings demonstrate the following: (1) when not combined with exercise, an oral EAA bolus leads to only modest increases in Achilles peritendinous amino acid concentrations; (2) when combined with resistance exercise, EAA consumption resulted in greater peritendinous amino acid concentrations compared to no exercise; (3) the basal concentrations of most amino acids were greater in older adults, and (4) neither the EAA bolus nor exercise altered peritendinous pro-collagen concentrations.

Impact of elevated serum advanced glycation end products and exercise on intact and injured murine tendons.

OVERVIEW: Delayed tendon healing is a significant clinical challenge for those with diabetes. We explored the role of advanced glycation end-products (AGEs), a protein modification present at elevated levels in serum of individuals with diabetes, on injured and intact tendons using a mouse model. Cell proliferation following tissue injury is a vital component of healing. Based on our previous work demonstrating that AGEs limit cell proliferation, we proposed that AGEs are responsible for the delayed healing process commonly observed in diabetic patients. Further, in pursuit of interventional strategies, we suggested that moderate treadmill exercise may support a healing environment in the presence of AGEs as exercise has been shown to stimulate cell proliferation in tendon tissue. MATERIALS AND METHODS: Mice began receiving daily intraperitoneal injections of bovine serum albumin (BSA)-Control or AGE-BSA injections (200µg/ml) at 16-weeks of age. A tendon injury was created in the central third of both patellar tendons. Animals assigned to an exercise group began a moderate treadmill protocol one week following injury. The intact Achilles tendon and soleus muscle were also evaluated to assess the effect of BSA and AGE-BSA on un-injured muscle and tendon. RESULTS: We demonstrate that our injection dosing and schedule lead to an increase in serum AGEs. Our findings imply that AGEs indeed modulate gene expression following a patellar tendon injury and have modest effects on gene expression in intact muscle and tendon. CONCLUSIONS: While additional biomechanical analysis is warranted, these data suggest that elevated serum AGEs in persons with diabetes may impact tendon health.

Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods.

The therapeutic approach of targeted protein degradation (TPD) is gaining momentum due to its potentially superior effects compared with protein inhibition. Recent advancements in the biotech and pharmaceutical sectors have led to the development of compounds that are currently in human trials, with some showing promising clinical results. However, the use of computational tools in TPD is still limited, as it has distinct characteristics compared with traditional computational drug design methods. TPD involves creating a ternary structure (protein-degrader-ligase) responsible for the biological function, such as ubiquitination and subsequent proteasomal degradation, which depends on the spatial orientation of the protein of interest (POI) relative to E2-loaded ubiquitin. Modeling this structure necessitates a unique blend of tools initially developed for small molecules (e.g., docking) and biologics (e.g., protein-protein interaction modeling). Additionally, degrader molecules, particularly heterobifunctional degraders, are generally larger than conventional small molecule drugs, leading to challenges in determining drug-like properties like solubility and permeability. Furthermore, the catalytic nature of TPD makes occupancy-based modeling insufficient. TPD consists of multiple interconnected yet distinct steps, such as POI binding, E3 ligase binding, ternary structure interactions, ubiquitination, and degradation, along with traditional small molecule properties. A comprehensive set of tools is needed to address the dynamic nature of the induced proximity ternary complex and its implications for ubiquitination. In this Perspective, we discuss the current state of computational tools for TPD. We start by describing the series of steps involved in the degradation process and the experimental methods used to characterize them. Then, we delve into a detailed analysis of the computational tools employed in TPD. We also present an integrative approach that has proven successful for degrader design and its impact on project decisions. Finally, we examine the future prospects of computational methods in TPD and the areas with the greatest potential for impact.

More than meets the eye: emotional stimuli enhance boundary extension effects for both depressed and never-depressed individuals.

Boundary extension is a memory phenomenon in which an individual reports seeing more of a scene than they actually did. We provide the first examination of boundary extension in individuals diagnosed with depression, hypothesising that an overemphasis on pre-existing schema may enhance boundary extension effects on emotional photographs. The relationship between boundary extension and overgeneralisation in autobiographical memory was also explored. Individuals with (n = 42) and without (n = 41) Major Depressive Disorder completed a camera paradigm task utilising positive, negative, and neutral stimuli. Across all participants, positive (d = 0.37) and negative (d = 0.66) stimuli were extended more than neutral stimuli. This effect did not differ between depressed and never-depressed participants. Across all participants, images containing objects were extended more than images containing faces. An association was also evident between extension effects in memory for perceptual space and extensions of autobiographical memory across time.

A Surgeon's Armamentarium for Ocular Management in Facial Paralysis: A Comprehensive Review.

OBJECTIVE: To review the current management paradigm of the eye in patients with facial paralysis. METHODS: A PubMed and Cochrane search was done with no date restrictions for English-language literature on facial synkinesis. The search terms used were "ocular," "facial," "synkinesis," "palsy," "neurotization," and various combinations of the terms. A total of 65 articles were included. RESULTS: Facial paralysis may result in devastating ocular sequelae. Therefore, assessment of the eye in facial paralysis is a critical component of patient management. Although the management should be individualized to the patient, the primary objective should include an ophthalmologic evaluation to implement measures to protect the ocular surface and preserve visual acuity. The degree of facial paralysis, lacrimal secretion, corneal sensation, and position of the eyelids should be assessed thoroughly. Patients with the anticipated recovery of facial nerve function may respond to more conservative temporizing measures to protect the ocular surface. Conversely, patients with expected prolonged paralysis should be appropriately identified as they will benefit from surgical reconstruction and rehabilitation of the periorbital complex. The majority of reconstructive measures within a facial surgeon's armamentarium augment coverage of the eye but are unable to restore blink. Eyelid reanimation restores the esthetic proportionality of the eye with blinking and reestablishes protective functions necessary for ocular preservation and function. CONCLUSIONS: Ocular preservation is the primary priority in the initial management of the patient with facial paralysis. An accurate assessment is a critical component in identifying the type of paralysis and developing an individualized treatment plan.

Symptomatic Hammertoes Treatment Comparison: Peg-in-Hole Arthrodesis Versus End-to-End Screw Fixation.

Proximal interphalangeal (PIP) arthrodesis technique utilizing the peg-in-hole arthrodesis was founded to avoid the use of retained internal fixation implants and thereby potentially decrease the concern of hardware complication. The specific aim of this study was to report the complication rates of the modified peg-in-hole arthrodesis technique and the end-to-end arthrodesis with single screw fixation technique for correcting symptomatic hammertoe deformities in lesser digits. This retrospective chart review included patients who underwent surgical hammertoe correction of lesser digits between the dates of January 2012 and December 2019. Patient demographic data and charts were reviewed to evaluate need for revision including screw/pin removal and complications related to corrective surgery. Five hundred ninety-three symptomatic hammertoe deformity cases (443 female, 150 male) were identified, with 113 cases (88 female, 25 male) treated with peg-in-hole arthrodesis technique and 480 cases (355 female, 125 male) treated with end-to-end arthrodesis with a single screw technique. The deformity recurrence rate was not significantly different between the two techniques (peg-in-hole: 10%, end-to-end: 13%, p = .428). There were 97 cases with postoperative complications that required re-operation (peg-in-hole: 7 cases, end-to-end: 90 cases) with the majority detected at <6 months. There was no statistically significant difference in reoperation rate between the peg-in-hole technique and the end-to-end arthrodesis technique reoperated with reasons excluding simple screw removal (p = .068). This study tended to show these two arthrodesis techniques have equivalent risks and similar success in bone healing; however, the peg-in-hole arthrodesis technique offers an advantage that does not result in retained hardware.

Biologics and acellular dermal matrices in head and neck reconstruction: A comprehensive review.

Acellular dermal matrices (ADMs) have been studied extensively in the literature and have gained popularity for various reconstructive and aesthetic purposes. ADMs are composed of a basement membrane and acellular dermal layer of collagen and provide a platform for mucosal epithelization and neovascularization. Combining dermal collagen and essential growth factors allows ADMs to support adequate wound healing and bolster soft-tissue repairs. These dermal matrices can be derived from human cadaveric donor skin (allogenic) or mammalian donor sources (xenogeneic). These dermal substitutes provide the benefit of reducing or eliminating the need for autologous tissue grafts and subsequently minimize donor site morbidity. Many ADMs are currently available in the market, each with variations in processing, manufacturing, storage, preparation, and use. The literature validating ADMs in the head and neck for both cosmetic and reconstructive purposes is evolving rapidly. This review aims to provide an up-to-date and comprehensive overview of the principles of acellular dermal matrices (ADMs), the different types of ADMs, and evaluate common indications, techniques, and outcomes pertaining to select anatomic sites in the head and neck reconstruction.

Adult tonsillectomy: An evaluation of indications and complications.

OBJECTIVE: This study aimed to evaluate current adult tonsillectomy indications along with risk factors associated with postoperative complications. METHODS: In this retrospective chart review, demographic, clinical, and surgical data were collected from 2004 to 2020 of adult patients who underwent tonsillectomy. Indications for surgery were categorized as infectious etiology, biopsy, obstructive sleep apnea (OSA), and tonsillar stones. Data regarding postoperative hemorrhage, emergency department (ED) visits, and readmissions were collected. Multivariable logistic regression models were used to evaluate factors associated with postoperative complications. RESULTS: 574 adults (mean age 32 years, 69.9% F vs. 30.1% M) were included. The most common indication was infections (62.2%), followed by biopsy (26.5%), tonsillar stones (6.8%), and OSA (4.5%). The highest frequency of postoperative bleeds (17.9%) occurred in the tonsillar stones cohort; however, the indication for surgery was not a significant predictor on multivariate analysis. Male sex and younger age were independent predictors of postoperative bleeding, while younger age was a significant predictor of postoperative ED visits. There was a significant linear trend of an increasing proportion of tonsillectomies performed for tonsillar stones compared to other indications for 2011-2019. CONCLUSION: Infectious etiology was the most common indication for tonsillectomy. Indication for surgery was not a significant predictor of postoperative bleeding; however, male sex and younger age had higher odds of postoperative bleeding. The proportion of tonsillectomies performed for tonsillar stones was steadily increasing.

Optical clearing reveals TNBS-induced morphological changes of VGLUT2-positive nerve fibers in mouse colorectum.

Colorectal hypersensitivity and sensitization of both mechanosensitive and mechanically insensitive afferents develop after intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) in the mouse, a model of postinfectious irritable bowel syndrome. In mice in which ∼80% of extrinsic colorectal afferents were labeled genetically using the promotor for vesicular glutamate transporter type 2 (VGLUT2), we systematically quantified the morphology of VGLUT2-positive axons in mouse colorectum 7-28 days following intracolonic TNBS treatment. After removal, the colorectum was distended (20 mmHg), fixed with paraformaldehyde, and optically cleared to image VGLUT2-positive axons throughout the colorectal wall thickness. We conducted vector path tracing of individual axons to allow systematic quantification of nerve fiber density and shape. Abundant VGLUT2-positive nerve fibers were present in most layers of the colorectum, except the serosal and longitudinal muscular layers. A small percentage of VGLUT2-positive myenteric plexus neurons was also detected. Intracolonic TNBS treatment significantly reduced the number of VGLUT2-positive nerve fibers in submucosal, myenteric plexus, and mucosal layers at day 7 post-TNBS, which mostly recovered by day 28. We also found that almost all fibers in the submucosa were meandering and curvy, with ∼10% showing pronounced curviness (quantified by the linearity index). TNBS treatment resulted in a significant reduction of the proportions of pronounced curvy fibers in the rectal region at 28 days post-TNBS. Altogether, the present morphological study reveals profound changes in the distribution of VGLUT2-positive fibers in mouse colorectum undergoing TNBS-induced colitis and draws attention to curvy fibers in the submucosa with potential roles in visceral nociception.NEW & NOTEWORTHY We conducted genetic labeling and optical clearing to visualize extrinsic sensory nerve fibers in whole-mount colorectum, which revealed widespread presence of axons in the submucosal layer. Remarkably, axons in the submucosa were meandering and curvy, in contrast to axons in other layers generally aligned with the basal tissues. Intracolonic TNBS treatment led to pronounced changes of nerve fiber density and curviness, suggesting nerve fiber morphologies as potentially contributing factors to sensory sensitization.

Pembrolizumab-induced severe rejection and graft intolerance syndrome resulting in renal allograft nephrectomy.

INTRODUCTION: Pembrolizumab is a selective anti-programmed cell death protein-1 (PD-1) humanized monoclonal antibody that inhibits PD-1 activity by binding to the PD-1 receptor that is found on activated T-cells. The goal of the treatment is to allow the immune system to target and destroy cancer cells by preventing cancer cells from binding to PD-1 receptors, leading to decreased tumor growth. The activation of T-cells by pembrolizumab not only leads to the destruction of malignant cells but also attacks the donor alloantigens that are present in a renal transplant, resulting in graft rejection. CASE REPORT: We present a case of a 46-year-old African American female with history of renal transplant who was treated with pembrolizumab for stage IV B endometrial adenocarcinoma and experienced renal transplant rejection and severe graft intolerance syndrome.Management and outcome: Due to ongoing graft intolerance, a transplant nephrectomy was performed. Allograft pathology was consistent with non-viable kidney with tubulitis, interstitial fibrosis and necrosis consistent with transplant rejection without any evidence of malignancy. DISCUSSION: As emphasized in our case, there is a very high risk of graft rejection in patients who need to be placed on immunomodulators such as pembrolizumab, so the risk versus benefit needs to be assessed and discussed. Our case is unique because pembrolizumab not only caused graft rejection but also severe graft intolerance syndrome which led to transplant nephrectomy. Further guidelines are needed in renal transplant patients requiring PD-1 inhibitors to establish the ideal treatment plan of immunosuppression management and anti-cancer treatments.

Changes of blood pressure following initiation of physical inactivity and after external addition of pulses to circulation.

PURPOSE: To determine whether an innovative, motorized, wellness device that effortlessly produces physical activity (JD) can mitigate the hypertensive effects of prolonged sitting or lying down. METHODS: Twenty-two normotensive and hypertensive adults of both genders gave informed consent to participate in a randomized controlled crossover study of a passive simulated jogging device (JD) in both supine and seated postures. Each study participant was monitored with a continuous non-invasive arterial pressure monitoring device (CNAP) over 60 min. The initial 10 min served as baseline for each posture. The subjects were randomized to begin with either JD or SHAM control for 30 min, and monitoring was continued for an additional 10 min in one posture; three days later posture and order of JD or SHAM were changed. RESULTS: In both seated and supine postures, SHAM was associated with a significant rise in blood pressure (BP) which was observed within 5-10 min; it continued to rise or remain elevated for over a 40-min observation period. In contrast, JD produced a significant decrease in both systolic and diastolic blood pressure in both postures. During recovery in seated posture JD decreased systolic and diastolic BP by - 8.1 and - 7.6 mmHg, respectively. In supine posture, a similar decrease in BP occurred. CONCLUSIONS: There is rapid onset of increase in systolic and diastolic BP with physical inactivity in both supine and seated postures. Administration of JD significantly decreased BP in both postures. Further studies are needed to assess long-term effectiveness.

Dietary material properties shape cranial suture morphology in the mouse calvarium.

Cranial sutures are fibrous connective tissue articulations found between intramembranous bones of the vertebrate cranium. Growth and remodeling of these tissues is partially regulated by biomechanical loading patterns that include stresses related to chewing. Advances in oral processing structure and function of the cranium that enabled mammalian-style chewing is commonly tied to the origins and evolution of this group. To what degree masticatory overuse or underuse shapes the complexity and ossification around these articulations can be predicted based on prior experimental and comparative work. Here, we report on a mouse model system that has been used to experimentally manipulate dietary material properties in order to investigate cranial suture morphology. Experimental groups were fed diets of contrasting material properties. A masticatory overuse group was fed pelleted rodent chow, nuts with shells, and given access to cotton bedding squares. An underuse group was deprived of cotton bedding as well as diverse textured food, and instead received gelatinized food continuously. Animals were raised from weaning to adulthood on these diets, and sagittal, coronal and lambdoid suture morphology was compared between groups. Predicted intergroup variation was observed in mandibular corpus size and calvarial suture morphology, suggesting that masticatory overuse is associated with jaw and suture growth. The anterior region of the sagittal suture where it intersects with the coronal suture (bregma) showed no effect from the experiment. The posterior sagittal suture where it intersects with the lambdoid sutures (lambda) was more complex in the overuse group. In other words, the posterior calvarium was responsive to dietary material property demands while the anterior calvarium was not. This probably resulted from the different strain magnitudes and/or strain frequencies that occurred during overuse diets with diverse material properties as compared with underuse diets deprived of such enrichment. This work highlights the contrasting pattern of the sutural response to loading differences within the calvarium as a result of diet.