Use of Upadacitinib as Salvage Therapy for Ulcerative Colitis in Pregnancy: A Case Report.

Upadacitinib, a selective JAK-1 inhibitor, was used as rescue therapy for ulcerative colitis in the setting of pregnancy following use of mesalamine, vedolizumab, infliximab, and corticosteroids. This resulted in an uncomplicated live full birth without need for surgical intervention.

Consensus Statement: Technical Standards for Thoracoabdominal Normothermic Regional Perfusion.

BACKGROUND: Thoracoabdominal normothermic regional perfusion (TA-NRP) has emerged as a powerful technique for optimizing organ procurement from donation after circulatory death donors. Despite its rapid adoption, standardized guidelines for TA-NRP implementation are lacking, prompting the need for consensus recommendations to ensure safe and effective utilization of this technique. METHODS: A working group composed of members from The American Society of Transplant Surgeons, The International Society of Heart and Lung Transplantation, The Society of Thoracic Surgeons, and The American Association for Thoracic Surgery was convened to develop technical guidelines for TA-NRP. The group systematically reviewed existing literature, consensus statements, and expert opinions to identify key areas requiring standardization, including predonation evaluation, intraoperative management, postdonation procedures, and future research directions. RESULTS: The working group formulated recommendations encompassing donor evaluation and selection criteria, premortem testing and therapeutic interventions, communication protocols, and procedural guidelines for TA-NRP implementation. These recommendations aim to facilitate coordination among transplant teams, minimize variability in practice, and promote transparency and accountability throughout the TA-NRP process. CONCLUSIONS: The consensus guidelines presented herein serve as a comprehensive framework for the successful and ethical implementation of TA-NRP programs in organ procurement from donation after circulatory death donors. By providing standardized recommendations and addressing areas of uncertainty, these guidelines aim to enhance the quality, safety, and efficiency of TA-NRP procedures, ultimately contributing to improved outcomes for transplant recipients.

Characterization of Synthetic Peptides by Mass Spectrometry.

In the quality control of synthetic peptides, mass spectroscopy (MS) serves as an optimal method for evaluating authenticity and integrity. Typically, the sequence of a synthetic peptide is already established, thereby directing the focus of analysis towards validating its identity and purity. This chapter outlines straightforward methodologies for conducting MS analyses specifically tailored for synthetic peptides.

Consensus Statement: Technical Standards for Thoracoabdominal Normothermic Regional Perfusion.

BACKGROUND: Thoracoabdominal normothermic regional perfusion (TA-NRP) has emerged as a powerful technique for optimizing organ procurement from donation after circulatory death donors. Despite its rapid adoption, standardized guidelines for TA-NRP implementation are lacking, prompting the need for consensus recommendations to ensure safe and effective utilization of this technique. METHODS: A working group composed of members from The American Society of Transplant Surgeons, The International Society of Heart and Lung Transplantation, The Society of Thoracic Surgeons, and The American Association for Thoracic Surgery was convened to develop technical guidelines for TA-NRP. The group systematically reviewed existing literature, consensus statements, and expert opinions to identify key areas requiring standardization, including predonation evaluation, intraoperative management, postdonation procedures, and future research directions. RESULTS: The working group formulated recommendations encompassing donor evaluation and selection criteria, premortem testing and therapeutic interventions, communication protocols, and procedural guidelines for TA-NRP implementation. These recommendations aim to facilitate coordination among transplant teams, minimize variability in practice, and promote transparency and accountability throughout the TA-NRP process. CONCLUSIONS: The consensus guidelines presented herein serve as a comprehensive framework for the successful and ethical implementation of TA-NRP programs in organ procurement from donation after circulatory death donors. By providing standardized recommendations and addressing areas of uncertainty, these guidelines aim to enhance the quality, safety, and efficiency of TA-NRP procedures, ultimately contributing to improved outcomes for transplant recipients.

Pigmented Villonodular Synovitis: A Metastatic Melanoma Imitator.

ABSTRACT: A 45-year-old woman with a history of previously treated left plantar foot melanoma presented with a left thigh mass. Fine needle aspiration findings were concerning for metastatic melanoma (MM). Imaging was remarkable for PET-avidity of both the biopsied thigh mass and of a left posterior knee nodule. The knee nodule was also enhancing on MRI, concerning for a site of metastasis. Resection of the thigh mass and intra-articular nodule was performed. The thigh lesion was positive for MM. The specimen obtained from the knee demonstrated a proliferation of spindle and epithelioid cells associated with focal fibrosis and scattered giant cells with brown pigment, raising the possibility of melanoma metastasis with treatment effect. Additional immunohistochemical studies with anti-SOX10 failed to demonstrate melanoma cells in the lesion. The final diagnosis for the knee nodule was pigmented villonodular synovitis. This case highlights the potential for pigmented villonodular synovitis to mimic MM, requiring additional pathologic analysis to yield an accurate diagnosis.

In Operando Imaging Electrostatic-Driven Disassembly and Reassembly of Collagen Nanostructures.

Collagen is the most abundant protein in tissue scaffolds in live organisms. Collagen can self-assemble in vitro, which has led to a number of biotechnological and biomedical applications. To understand the dominant factors that participate in the formation of collagen nanostructures, here we study in real time and with nanoscale resolution the disassembly and reassembly of collagens. We implement a high-speed force microscope, which provides in situ high spatiotemporal resolution images of collagen nanostructures under changing pH conditions. The disassembly and reassembly are dominated by the electrostatic interactions among amino-acid residues of different molecules. Acidic conditions favor disassembly by neutralizing negatively charged residues. The process sets a net repulsive force between collagen molecules. A neutral pH favors the presence of negative and positively charged residues along the collagen molecules, which promotes their electrostatic attraction. Molecular dynamics simulations reproduce the experimental behavior and validate the electrostatic-based model of the disassembly and reassembly processes.

Dissemination and implementation research coordination and training to improve cardiovascular health in people living with HIV in sub-Saharan Africa: the research coordinating center of the HLB-SIMPLe Alliance.

As global adoption of antiretroviral therapy extends the lifespan of People Living with HIV (PLHIV) through viral suppression, the risk of comorbid conditions such as hypertension has risen, creating a need for effective, scalable interventions to manage comorbidities in PLHIV. The Heart, Lung, and Blood Co-morbiditieS Implementation Models in People Living with HIV (HLB-SIMPLe) Alliance has been funded by the National Heart, Lung, and Blood Institute (NHLBI) and the Fogarty International Center (FIC) since September 2020. The Alliance was created to conduct late-stage implementation research to contextualize, implement, and evaluate evidence-based strategies to integrate the diagnosis, treatment, and control of cardiovascular diseases, particularly hypertension, in PLHIV in low- and middle-income countries (LMICs).The Alliance consists of six individually-funded clinical trial cooperative agreement research projects based in Botswana, Mozambique, Nigeria, South Africa, Uganda, and Zambia; the Research Coordinating Center; and personnel from NIH, NHLBI, and FIC (the Federal Team). The Federal Team works together with the members of the seven cooperative agreements which comprise the alliance. The Federal Team includes program officials, project scientists, grant management officials and clinical trial specialists. This Alliance of research scientists, trainees, and administrators works collaboratively to provide and support venues for ongoing information sharing within and across the clinical trials, training and capacity building in research methods, publications, data harmonization, and community engagement. The goal is to leverage shared learning to achieve collective success, where the resulting science and training are greater with an Alliance structure rather than what would be expected from isolated and unconnected individual research projects.In this manuscript, we describe how the Research Coordinating Center performs the role of providing organizational efficiencies, scientific technical assistance, research capacity building, operational coordination, and leadership to support research and training activities in this multi-project cooperative research Alliance. We outline challenges and opportunities during the initial phases of coordinating research and training in the HLB-SIMPLe Alliance, including those most relevant to dissemination and implementation researchers.

Decreased postpartum exercise capacity after a diagnosis of pre-eclampsia: Implications for CVD risk prediction.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are associated with increased long-term risk for cardiometabolic risk factors (chronic hypertension [HTN], obesity, diabetes) and heart failure. Exercise capacity is a known predictor of heart failure in patients with normal resting cardiac filling pressures. In this prospective observational cohort study, we sought to identify predictors of reduced postpartum exercise capacity in participants with normotensive vs. preeclamptic pregnancies. METHODS: Preeclampsia (PreE) and normotensive subjects were enrolled to undergo bedside echocardiography within 48 hours of delivery, and rest/exercise echocardiography 12 weeks postpartum. RESULTS: Recruited subjects (n=68) were grouped according to their blood pressure as: a) normotensive pregnancy n=15; b) PreE with normotensive postpartum (PreE-Resolved, n=36); c) PreE with persistent postpartum HTN (PreE-HTN, n=17). At enrollment, a significantly higher percentage of subjects in the PreE-HTN group were Black. Compared to normotensive and PreE-Resolved subjects, those with PreE-HTN demonstrated higher resting systolic blood pressure (SBP, 112 [normotensive] vs 112 [PreE-Resolved] vs 134 [PreE-HTN], p<0.001) and diastolic blood pressure (DBP, 70.0 vs 72.5 vs 85.0, p<0.001), and significantly less postpartum weight loss (9.6% vs 13.6% vs 3.8%, p<0.001). Following Bruce protocol stress testing, PreE-HTN subjects demonstrated achieved significantly lower exercise duration (10.4 vs 10.2 vs 7.9 minutes, p = 0.001). Subjects with PreE-HTN also demonstrated evidence of exercise-induced diastolic dysfunction as assessed by peak exercise lateral e' (18.0 vs 18.0 vs 13.5, p=0.045) and peak exercise tricuspid regurgitation velocity (TR Vm, 2.4 vs 3.0 vs 3.1, p = 0.045). Exercise duration was negatively associated with gravidity (R=-0.27, p=0.029) and postpartum LV mass index (R=-0.45, p<0.001), resting average E/e' (R=-0.51, p<0.001), BMI (R=-0.6, p<0.001) and resting SBP (R=-0.51, p<0.001). CONCLUSIONS: Postpartum exercise stress testing capacity is related to readily available clinical markers including pregnancy factors, echocardiographic parameters and unresolved cardiometabolic risk factors.

Spitz Melanoma With SLC20A1::ALK Fusion: A Novel Fusion Previously Undescribed in Spitz Melanocytic Neoplasm.

ABSTRACT: Spitz melanocytic neoplasms exhibit frequent chromosomal rearrangements leading to recurring gene fusions, such as ALK fusions. TPM3 and DCTN1 emerge as the predominant fusion partners of ALK, although less common partners such as NPM1, TPR, CLIP1, GTF3C2, MLPH, EEF2, MYO5A, and KANK1 have also been documented. Although ALK fusions are primarily associated with Spitz nevi or atypical Spitz tumors, instances of Spitz melanoma with ALK fusions documented in the English literature are exceedingly rare. Here, we present a case of Spitz melanoma harboring SLC20A1::ALK fusion, highlighting a novel fusion transcript not previously reported in Spitz melanocytic neoplasms, including Spitz melanomas. In addition, the tumor exhibits multiple aberrant chromosomal alterations characteristic of melanoma, along with a somatic mutation in GRM3.

Neurotrophin-3 Rescues Striatal Synaptic Plasticity in Model of Neurodegeneration by PLC Signaling Activation.

BACKGROUND: Neurotrophins are essential factors for neural growth and function; they play a crucial role in neurodegenerative diseases where their expression levels are altered. Our previous research has demonstrated changes in synaptic plasticity and neurotrophin expression levels in a pharmacological model of Huntington's disease induced by 3-nitropropionic acid (3-NP). In the 3- NP-induced HD model, corticostriatal Long Term Depression (LTD) was impaired, but neurotrophin-3 (NT-3) restored striatal LTD. This study delves into the NT-3-induced signaling pathways involved in modulating and restoring striatal synaptic plasticity in cerebral slices from 3-NPinduced striatal degeneration in mice in vivo. METHODS: Phospholipase C (PLC), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways activated by NT-3 were analyzed by means of field electrophysiological recordings in brain slices from control and 3-NP treated in the presence of specific inhibitors of the signaling pathways. RESULTS: Using specific inhibitors, PLC, PI3K, and MEK/ERK signaling pathways contribute to NT3-mediated plasticity modulation in striatal tissue slices recorded from control animals. However, in the neurodegeneration model induced by 3-NP, the recovery of striatal LTD induced by NT-3 was prevented only by the PLC inhibitor. Moreover, the PLC signaling pathway appeared to trigger downstream activation of the endocannabinoid system, evidenced by AM 251, an inhibitor of the CB1 receptor, also hindered NT-3 plasticity recovery. CONCLUSION: Our finding highlights the specific involvement of the PLC pathway in the neuroprotective effects of NT-3 in mitigating synaptic dysfunction under neurodegenerative conditions.

Keratosis Pilaris-Like Reaction Associated With Chromatin Remodeling Complex Inhibition in Uveal Melanoma.

This case series describes a constellation of novel adverse reactions in 3 of 9 patients with uveal melanoma receiving treatment targeting activity of the Brahma-associated factor chromatin remodeling complex.

Locomotion and morphological adaptations in the glass lizard Ophiodes cf. fragilis (Raddi, 1820) (Squamata: Anguidae).

There are few studies related to the biological and ecological aspects of the glass snake, a limbless lizard and with a wide geographic distribution. The aim of this study was to analyze the locomotion mode of specimens of Ophiodes cf. fragilis in different substrates and to investigate the morphological adaptations associated with this type of behavior. We observed that the analyzed specimens presented slide-push locomotion modes and lateral undulation in different substrates, using their hind limbs to aid locomotion in three of the four substrates analyzed. The bones of the hind limbs (proximal - femur - and distal - tibia and fibula) were present and highly reduced and the femur is connected to a thin pelvic girdle. Our data support that hind limbs observed in species of this genus are reduced rather than vestigial. The costocutaneous musculature was macroscopically absent. This is the first study of locomotor behavior and morphology associated with locomotion in Ophiodes, providing important information for studies on morphological evolution in the genus.

Handedness and its Impact on a Career in Medicine.

ABSTRACT: Left-handedness in a world of right lateral bias can be an invisible barrier both in every-day life as well as in medical career development, and throughout a medical career. Common every-day life actions, including screwing in lightbulbs, inserting a screw, or any action that requires a clockwise rotation, is designed for "righties," making life for "lefties" a challenge. Other examples include writing without a slant, or without smudging. In medicine, the physical examination of a patient is taught using the right hand and standing on the right side of the patient, an awkward situation for left handers. Another major concern in medicine, specifically, is handwriting-notoriously poor in lefties-impacting legibility in progress notes, prescriptions, and medical records. In surgery and other procedural specialties in particular, using instruments intended for right-handed individuals, including suturing and positioning at the operating room table, presents left-handed individuals with particular challenges. Left-handed medical students and residents are especially vulnerable, as they may feel uncomfortable requesting special accommodations for their "handedness." The significance and impact of handedness often goes unrecognized, yet it may play a substantial role in career choices: the difficulties of being left-handed may dissuade students from pursuing their desired career. Solutions are available, including using instruments designed for left-handers (or learning to use "righty" instruments), and positioning at the operating room or procedure table as preferred by the left-handed individual. These solutions often require a cooperative attitude by colleagues. The authors describe the significance of handedness, including their own personal experiences, and offer some solutions for left-handed individuals who struggle to adapt to a right-handed world.

The eTEP/eTEP-TAR Repair of Ventral Hernias a Study From One Center/ One Surgeon-The First Five Years of Experience.

Objective: The objective of this study is analyze the outcomes of retro-muscular repair techniques for ventral hernias performed by a single surgeon in a renowned hernia surgery center. Method: This study involved 197 patients who underwent surgery between May 2016 and December 2021 under the care of a single surgeon (VR). Respecting the indication/contraindications of the eTEP procedure, 197 of 212 patients with ventral hernias underwent eTEP/eTEP-TAR surgery during this period. The cohort consisted of diverse hernia types, including median, lateral, and multiple-site defects. The safety of this approach was evaluated based on postoperative occurrences, where the number of complications accounted for 5% of the cases. Results of the study indicated that there was a significant improvement in the quality of life of patients following the procedure. The assessment, which measured postoperative pain, normal activity, and aesthetics on a 0-10 scale, showed improvement at 2 weeks and 3 months after surgery compared to the preoperative level. However, after a mean of 51.11 months, only one case of recurrence was reported. This recurrence occurred on top of the mesh, 18 months after the initial operation. The follow-up period lasted between 24 and 90 months. Patient monitoring was conducted either in person or over the phone, focusing on quality of life, postoperative pain, and the occurrence of recurrence. In conclusion, the laparo-endoscopic retro-muscular repair of ventral hernias, whether primary or incisional, has shown to yield excellent results in medium and long-term follow-up. The eTEP technique combines the benefits of the Rives-Stoppa technique (considered the gold standard in open ventral hernia repair) with the advantages of minimally invasive surgery.

Edge Functionalization of Bulk γ-Graphyne Facilitates Mechanical Exfoliation and Modulates the Mode of Sheet Stacking.

We have successfully achieved selective and efficient functionalization of sheet edges in microcrystalline multilayer γ-graphyne through two methods: cross-coupling with residual bromide edge groups and copper-catalyzed azide-alkyne cycloaddition (CuAAC) with edge terminal alkyne groups. This modification significantly enhances the ease of mechanical exfoliation and dispersibility of the sheets of γ-graphyne. Specifically, C18-grafted γ-graphyne forms stable dispersions in compatible organic solvents, allowing for the imaging of atomically thin layers of γ-graphyne for the first time. Additionally, we have discovered that phenylacetylide edge groups alter the preferred stacking mode of γ-graphyne sheets. Few-layer flakes of Ph-edge γ-graphyne exhibit a preference for the R3m space group, contrasting with the aperiodic stacking of Br-edge γ-graphyne. These results open the door for scalable exfoliation of few-layer flakes of γ-graphyne with a high aspect ratio, enabling potential applications in carbon electronics.

MicroRNA Expression Profiles in Human Samples and Cell Lines Revealed Nine miRNAs Associated with Cisplatin Resistance in High-Grade Serous Ovarian Cancer.

Metastasis and drug resistance are major contributors to cancer-related fatalities worldwide. In ovarian cancer (OC), a staggering 70% develop resistance to the front-line therapy, cisplatin. Despite proposed mechanisms, the molecular events driving cisplatin resistance remain unclear. Dysregulated microRNAs (miRNAs) play a role in OC initiation, progression, and chemoresistance, yet few studies have compared miRNA expression in OC samples and cell lines. This study aimed to identify key miRNAs involved in the cisplatin resistance of high-grade-serous-ovarian-cancer (HGSOC), the most common gynecological malignancy. MiRNA expression profiles were conducted on RNA isolated from formalin-fixed-paraffin-embedded human ovarian tumor samples and HGSOC cell lines. Nine miRNAs were identified in both sample types. Targeting these with oligonucleotide miRNA inhibitors (OMIs) reduced proliferation by more than 50% for miR-203a, miR-96-5p, miR-10a-5p, miR-141-3p, miR-200c-3p, miR-182-5p, miR-183-5p, and miR-1206. OMIs significantly reduced migration for miR-183-5p, miR-203a, miR-296-5p, and miR-1206. Molecular pathway analysis revealed that the nine miRNAs regulate pathways associated with proliferation, invasion, and chemoresistance through PTEN, ZEB1, FOXO1, and SNAI2. High expression of miR-1206, miR-10a-5p, miR-141-3p, and miR-96-5p correlated with poor prognosis in OC patients according to the KM plotter database. These nine miRNAs could be used as targets for therapy and as markers of cisplatin response.

Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity.

There is considerable heterogeneity in the cardiometabolic abnormalities associated with obesity. We evaluated multi-organ system metabolic function in 20 adults with metabolically healthy obesity (MHO; normal fasting glucose and triglycerides, oral glucose tolerance, intrahepatic triglyceride content, and whole-body insulin sensitivity), 20 adults with metabolically unhealthy obesity (MUO; prediabetes, hepatic steatosis, and whole-body insulin resistance), and 15 adults who were metabolically healthy lean. Compared with MUO, people with MHO had (1) altered skeletal muscle biology (decreased ceramide content and increased expression of genes involved in BCAA catabolism and mitochondrial structure/function); (2) altered adipose tissue biology (decreased expression of genes involved in inflammation and extracellular matrix remodeling and increased expression of genes involved in lipogenesis); (3) lower 24-h plasma glucose, insulin, non-esterified fatty acids, and triglycerides; (4) higher plasma adiponectin and lower plasma PAI-1 concentrations; and (5) decreased oxidative stress. These findings provide a framework of potential mechanisms responsible for MHO and the metabolic heterogeneity of obesity. This study was registered at ClinicalTrials.gov (NCT02706262).

Comprehensive Ocular and Systemic Safety Evaluation of Polysialic Acid-Decorated Immune Modulating Therapeutic Nanoparticles (PolySia-NPs) to Support Entry into First-in-Human Clinical Trials.

An inflammation-resolving polysialic acid-decorated PLGA nanoparticle (PolySia-NP) has been developed to treat geographic atrophy/age-related macular degeneration and other conditions caused by macrophage and complement over-activation. While PolySia-NPs have demonstrated pre-clinical efficacy, this study evaluated its systemic and intraocular safety. PolySia-NPs were evaluated in vitro for mutagenic activity using Salmonella strains and E. coli, with and without metabolic activation; cytotoxicity was evaluated based on its interference with normal mitosis. PolySia-NPs were administered intravenously in CD-1 mice and Sprague Dawley rats and assessed for survival and toxicity. Intravitreal (IVT) administration in Dutch Belted rabbits and non-human primates was assessed for ocular or systemic toxicity. In vitro results indicate that PolySia-NPs did not induce mutagenicity or cytotoxicity. Intravenous administration did not show clastogenic activity, effects on survival, or toxicity. A single intravitreal (IVT) injection and two elevated repeat IVT doses of PolySia-NPs separated by 7 days in rabbits showed no signs of systemic or ocular toxicity. A single IVT inoculation of PolySia-NPs in non-human primates demonstrated no adverse clinical or ophthalmological effects. The demonstration of systemic and ocular safety of PolySia-NPs supports its advancement into human clinical trials as a promising therapeutic approach for systemic and retinal degenerative diseases caused by chronic immune activation.

Interplay Between Ni and Brønsted and Lewis Acid Sites in the Hydrodesulfurization of Dibenzothiophene.

Ni-MoS2/γ-Al2O3 catalysts are commonly used in hydrotreating to enhance fossil fuel quality. The extensive research on these catalysts reveals a gap in understanding the role of Ni, often underestimated as an inactive sulfide phase or just a MoS2 promoter. In this work, we focused on analyzing whether well-dispersed supported nickel nanoparticles can be active in the hydrodesulfurization of dibenzothiophene. We dispersed Ni by Strong Electrostatic Adsorption (SEA) method across four supports with different types of acidity: silica (~ neutral acidity), γ-Al2O3 (Lewis acidity), H+-Y zeolite, and microporous-mesoporous H+-Y zeolite (both with Brønsted-Lewis acidity). Our findings reveal that Ni is indeed active in dibenzothiophene hydrodesulfurization, even with alumina and silica as supports, although their catalytic activity declines abruptly in the first hours. Contrastingly, the acid nature of zeolites imparts sustained stability and performance, attributed to robust metal-support interactions. The efficacy of the SEA method and the added mesoporosity in zeolites further amplify catalytic efficiency. Overall, we demonstrate that Ni nanoparticles may perform as a hydrogenating metal in the same manner as noble metals such as Pt and Pd perform in hydrodesulfurization. We discuss some of the probable reasons for such performance and remark on the role of Ni in hydrotreatment.