The ribotoxic stress response drives UV-mediated cell death.

While ultraviolet (UV) radiation damages DNA, eliciting the DNA damage response (DDR), it also damages RNA, triggering transcriptome-wide ribosomal collisions and eliciting a ribotoxic stress response (RSR). However, the relative contributions, timing, and regulation of these pathways in determining cell fate is unclear. Here we use time-resolved phosphoproteomic, chemical-genetic, single-cell imaging, and biochemical approaches to create a chronological atlas of signaling events activated in cells responding to UV damage. We discover that UV-induced apoptosis is mediated by the RSR kinase ZAK and not through the DDR. We identify two negative-feedback modules that regulate ZAK-mediated apoptosis: (1) GCN2 activation limits ribosomal collisions and attenuates ZAK-mediated RSR and (2) ZAK activity leads to phosphodegron autophosphorylation and its subsequent degradation. These events tune ZAK's activity to collision levels to establish regimes of homeostasis, tolerance, and death, revealing its key role as the cellular sentinel for nucleic acid damage.

Comparing Peer-Taught Student Tutors to Faculty-Taught Student Tutors in Educating Medical Students on Musculoskeletal Ultrasound.

INTRODUCTION: In recent years, medical education has witnessed a shift in the integration of ultrasound into the preclinical years of medical school. Given the exponential increase in accessibility to ultrasound technology, students now have the opportunity to create peer learning groups in which ultrasound concepts can be taught from peer to peer, empowering students to work together to integrate ultrasound concepts early in their preclinical education. This project investigates the efficacy of peer-taught student tutors (PTSTs) in imparting the fundamentals of basic ultrasound techniques to first-year medical students in the setting of identifying and labeling upper extremity musculoskeletal (MSK) anatomy.  Methods: First-year medical students were instructed to identify volar forearm structures with an ultrasound probe. Students and instructors were given access to an ultrasound probe, ultrasound gel, an iPad, and a standardized patient. Students were taught either by an ultrasound instructor (UI) or PTST. After a hands-on demonstration by a UI or PTST, participating students were told to take screenshots and label their images as accurately as possible, identifying the aforementioned volar structures on a standardized patient without any feedback. The labeled screenshot images of volar structures were graded based on the ability to clearly visualize the intended structures.  Results: The results of this study compare the efficacy of PTSTs as educators of basic sonographic identification techniques with that of UI faculty members. A chi-square analysis was performed between the images obtained by the UI and PTST students, and there was no statistically significant difference in identification accuracy between the groups (p = 0.7538, 0.1977, 0.1812, 0.301). When using the Mann-Whitney U rank test, there remained no statistically significant difference between the accuracy of the students taught by STs compared to students taught by UIs (p = 0.7744, 0.09538, 0.07547, 0.1846). Another finding showed that students belonging to both teaching groups were generally not able to infer the pathology of volar wrist structures when given pathology identification questions regarding upper extremity ultrasound. Using chi-square with Yates correction, there is no sufficient evidence to justify an association between the ability to answer pathology-based ultrasound questions and instructor type (p = p = 0.6299, 0.8725). CONCLUSIONS: This study supports the interpretation that the capability of first-year medical students to learn novice MSK sonographic identification is independent of whether the educator is a PTST or UI. This interpretation reveals a promising avenue toward the integration of the fundamentals of ultrasound identification early in medical education with little to no concern for the exhaustion of institutional resources. Along with the other well-documented benefits of the utilization of STs in medical school, a peer tutoring system centered on ultrasound skills designed in the way this study describes can be an effective, resource-sparing system that enhances medical students' sonographic capabilities early in their preclinical years.

3D bioprinting: a review and potential applications for Mohs micrographic surgery.

Mohs Micrographic Surgery (MMS) is effective for treating common cutaneous malignancies, but complex repairs may often present challenges for reconstruction. This paper explores the potential of three-dimensional (3D) bioprinting in MMS, offering superior outcomes compared to traditional methods. 3D printing technologies show promise in advancing skin regeneration and refining surgical techniques in dermatologic surgery. A PubMed search was conducted using the following keywords: "Three-dimensional bioprinting" OR "3-D printing" AND "Mohs" OR "Mohs surgery" OR "Surgery." Peer-reviewed English articles discussing medical applications of 3D bioprinting were included, while non-peer-reviewed and non-English articles were excluded. Patients using 3D MMS models had lower anxiety scores (3.00 to 1.7, p < 0.0001) and higher knowledge assessment scores (5.59 or 93.25% correct responses), indicating better understanding of their procedure. Surgical residents using 3D models demonstrated improved proficiency in flap reconstructions (p = 0.002) and knowledge assessment (p = 0.001). Additionally, 3D printing offers personalized patient care through tailored surgical guides and anatomical models, reducing intraoperative time while enhancing surgical. Concurrently, efforts in tissue engineering and regenerative medicine are being explored as potential alternatives to address organ donor shortages, eliminating autografting needs. However, challenges like limited training and technological constraints persist. Integrating optical coherence tomography with 3D bioprinting may expedite grafting, but challenges remain in pre-printing grafts for complex cases. Regulatory and ethical considerations are paramount for patient safety, and further research is needed to understand long-term effects and cost-effectiveness. While promising, significant advancements are necessary for full utilization in MMS.

Immune checkpoint inhibitor associated epidermal necrosis, beyond SJS and TEN: a review of 98 cases.

Immune checkpoint inhibitor (ICI) therapies carry the risk of major immune-related adverse events (irAEs). Among the most severe irAEs is epidermal necrosis that may clinically mimic Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The aim of this study was to provide a summary of the clinical and histological features of ICI-associated epidermal necrosis, with a special focus on factors associated with fatal outcomes in cases of extensive disease. A total of 98 cases, 2 new cases and 96 reported on PubMed and in the literature, of ICI-associated epidermal necrosis were assessed. Development of epidermal necrosis occurred between 1 day and 3 years after starting ICI therapy, with an average onset of 13.8 weeks for patients with limited (< 30% BSA) and 11.3 weeks for those with extensive (≥ 30% BSA) involvement, and a median onset of 5.8 weeks and 4 weeks respectively. A preceding rash was seen in 52 cases and was more common in extensive cases. Mucosal involvement was only reported in 65% of extensive cases but was significantly associated with fatal reactions. Co-administration of cytotoxic chemotherapy was associated with more extensive disease. Recovery was observed in 96% and 65% of those with limited and extensive involvement respectively and no specific therapy was associated with improved survival. Young age was significantly associated with poor outcomes in extensive disease, the average age of surviving patients was 64.5 years old versus 55.1 years old for deceased patients, p < 0.01. Both superficial perivascular and interface/lichenoid inflammatory infiltrates were commonly seen. These findings suggest that ICI-associated epidermal necrosis should be considered a distinct clinical entity from drug-induced SJS/TEN.

Antiviral fibrils of self-assembled peptides with tunable compositions.

The lasting threat of viral pandemics necessitates the development of tailorable first-response antivirals with specific but adaptive architectures for treatment of novel viral infections. Here, such an antiviral platform has been developed based on a mixture of hetero-peptides self-assembled into functionalized ß-sheets capable of specific multivalent binding to viral protein complexes. One domain of each hetero-peptide is designed to specifically bind to certain viral proteins, while another domain self-assembles into fibrils with epitope binding characteristics determined by the types of peptides and their molar fractions. The self-assembled fibrils maintain enhanced binding to viral protein complexes and retain high resilience to viral mutations. This method is experimentally and computationally tested using short peptides that specifically bind to Spike proteins of SARS-CoV-2. This platform is efficacious, inexpensive, and stable with excellent tolerability.

CODA: an open-source platform for federated analysis and machine learning on distributed healthcare data.

OBJECTIVES: Distributed computations facilitate multi-institutional data analysis while avoiding the costs and complexity of data pooling. Existing approaches lack crucial features, such as built-in medical standards and terminologies, no-code data visualizations, explicit disclosure control mechanisms, and support for basic statistical computations, in addition to gradient-based optimization capabilities. MATERIALS AND METHODS: We describe the development of the Collaborative Data Analysis (CODA) platform, and the design choices undertaken to address the key needs identified during our survey of stakeholders. We use a public dataset (MIMIC-IV) to demonstrate end-to-end multi-modal FL using CODA. We assessed the technical feasibility of deploying the CODA platform at 9 hospitals in Canada, describe implementation challenges, and evaluate its scalability on large patient populations. RESULTS: The CODA platform was designed, developed, and deployed between January 2020 and January 2023. Software code, documentation, and technical documents were released under an open-source license. Multi-modal federated averaging is illustrated using the MIMIC-IV and MIMIC-CXR datasets. To date, 8 out of the 9 participating sites have successfully deployed the platform, with a total enrolment of >1M patients. Mapping data from legacy systems to FHIR was the biggest barrier to implementation. DISCUSSION AND CONCLUSION: The CODA platform was developed and successfully deployed in a public healthcare setting in Canada, with heterogeneous information technology systems and capabilities. Ongoing efforts will use the platform to develop and prospectively validate models for risk assessment, proactive monitoring, and resource usage. Further work will also make tools available to facilitate migration from legacy formats to FHIR and DICOM.

The Effectiveness of Student-Led Musculoskeletal and Vascular Ultrasound Workshops at a Single Institution: A Retrospective Survey Analysis.

Introduction Point-of-care ultrasound (POCUS) is a rapidly evolving field of diagnostic medicine as its low cost, portability, and versatility have made handheld ultrasound (US) probes an invaluable tool for many modern physicians. Despite US's benefits as a bedside evaluative tool, many medical schools have not integrated POCUS into their pre-clerkship medical education due to a lack of equipment and faculty. The first objective of our study was to determine whether student tutors (STs) would be effective resources to teach musculoskeletal (MSK) and vascular US to preclinical medical students. The second objective of our study was to determine whether students who previously attended ST-run MSK US workshops perform better in vascular US than those who did not. Methods Six POCUS workshops were led by STs after approval from experienced US faculty. These included US workshops on gastrointestinal structures, forearm structures, joint structures, basic echocardiography, and US-guided IV access. We collected data from two of our six workshops. We developed surveys to gauge the confidence and ability of students to perform US after an MSK workshop and US-guided IV access workshop led by STs. We also measured students' US abilities and collected student feedback after our US-guided IV access workshop. We evaluated students' US competency in US-guided IV access via their ability to correctly position the US probe, angle the needle of insertion, move the probe with the needle, and access the vein based on the accuracy of the movements. We divided student results into two groups: students who previously attended the MSK workshop before attending the US-guided IV access workshop and students who did not attend the MSK workshop before attending the US-guided IV access workshop. We used averages, frequencies, and two-tailed t-tests to analyze the survey responses and US-guided IV access skill assessments. Results Fifty percent of first- and second-year surveyed students "agreed," and 32.4% "strongly agreed" that they felt confident using US after an ST-run MSK workshop. About 29.4% of surveyed students "agreed" and 41.2% "strongly agreed" that they felt comfortable explaining basic US concepts, such as proper probe positioning and echogenicity. The group of students who attended the MSK workshop prior to the peripheral IV workshop scored similarly to the students who did not attend the MSK workshop (14.33±1.03 versus 14.20±0.84 points). Both groups of students had an average of over 94% accuracy in technique, positioning, angling, moving the US probe, and achieving US-guided venous access after being taught by STs. Qualitative surveying noted positive student feedback, such as "Teacher was great at guiding us through the procedure." Survey responses also included suggestions on adding and diversifying equipment, such as "[It would be useful to have a] different type of needle to see the difference on ultrasound." Conclusion Based on the high percentages of accuracy and confidence, we found that STs were effective resources to teach MSK and vascular POCUS and that students who attended previous MSK ST-run US workshops had stronger vascular US ability over time compared to those who did not. Our data support the use of STs as US educational resources, especially in institutions without an existing pre-clerkship US curriculum and limited US resources.

Phytanic Acid Intake and Lifestyle Modifications on Quality of Life in Individuals with Adult Refsum Disease: A Retrospective Survey Analysis.

Adult Refsum disease (ARD) is a rare peroxisomal biogenesis disorder inherited in an autosomal recessive fashion and is often characterized by retinitis pigmentosa, cerebellar ataxia, and polyneuropathy. Many patients with ARD require diet modification, psychosocial support, and various specialist visits to manage their symptoms. In this study, we explored the quality of life in individuals with ARD by analyzing retrospective survey data collected by the Coordination of Rare Diseases at Sanford (CoRDS) Registry and Global Defeat Adult Refsum Everywhere (DARE) Foundation. Statistical tests used were frequencies, mean, and median. There were 32 respondents, ranging between 11 and 32 responses for each question. The mean age at diagnosis was 35.5 ± 14.5 years (range 6-64) with 36.4% male and 63.6% female respondents. The average age for retinitis pigmentosa diagnosis was 22.8 ± 15.7 years (range 2-61). Dieticians were the most frequently seen (41.7%) for management of low-phytanic-acid diets. Most participants exercise at least once per week (92.5%). Depression symptoms were reported in 86.2% of the participants. Early diagnosis of ARD is important for managing symptoms and preventing progression of visual impairment due to phytanic acid buildup. Interdisciplinary approach should be used for patients to address physical and psychosocial impairments of ARD.

PESPIP: Software to fit complex molecular and many-body potential energy surfaces with permutationally invariant polynomials.

We wish to describe a potential energy surface by using a basis of permutationally invariant polynomials whose coefficients will be determined by numerical regression so as to smoothly fit a dataset of electronic energies as well as, perhaps, gradients. The polynomials will be powers of transformed internuclear distances, usually either Morse variables, exp(-ri,j/λ), where λ is a constant range hyperparameter, or reciprocals of the distances, 1/ri,j. The question we address is how to create the most efficient basis, including (a) which polynomials to keep or discard, (b) how many polynomials will be needed, (c) how to make sure the polynomials correctly reproduce the zero interaction at a large distance, (d) how to ensure special symmetries, and (e) how to calculate gradients efficiently. This article discusses how these questions can be answered by using a set of programs to choose and manipulate the polynomials as well as to write efficient Fortran programs for the calculation of energies and gradients. A user-friendly interface for access to monomial symmetrization approach results is also described. The software for these programs is now publicly available.

Central Diabetes Insipidus in the Background of Lithium Use: Consider Central Causes Despite Nephrogenic as the Most Common.

BACKGROUND Nephrogenic diabetes insipidus is a well-known adverse effect of lithium use. Albeit rare, there have also been documented cases of central diabetes insipidus (CDI) associated with lithium use. CASE REPORT A 31-year-old woman with a past medical history of bipolar disorder, managed with lithium 300 mg by mouth every day for 3 years, was assessed for a 1-year history of polyuria with accompanying polydipsia. During her initial hospital stay, her estimated urine output was more than 4 L per day. Initial labs showed elevated serum sodium (149 mmol/L; reference range 135-145), elevated serum osmolality (304 mOsm/kg; reference range 275-295), urine osmolality of 99 mOsm/kg (reference range 50-1200), and urine specific gravity (1.005; reference range 1.005-1.030). Lithium was at a subtherapeutic level of 0.05 mEq/L (reference range 0.6-1.2). Magnetic resonance imaging of the brain revealed no abnormalities of the pituitary gland. Two different occasions of desmopressin administration resulted in >50% increase in urine osmolality, confirming the diagnosis of CDI. Common causes of CDI, including trauma, tumors, and familial CDI, were ruled out and chronic lithium use was determined as the most probable cause for the patient's CDI. CONCLUSIONS CDI in the background of chronic lithium use is rarely reported. We present this case to consider CDI as a differential diagnosis when evaluating polyuria and hypernatremia in patients with long-term lithium use. These presentations warrant the consideration of both types of diabetes insipidus in the differential diagnoses.

Paradoxical Hyperreflexia in a Patient With Classic Guillain-Barré Syndrome.

BACKGROUND: Guillain-Barré syndrome (GBS) is a rare entity with characteristic features, including progressive ascending paralysis. Patients typically present with progressive symmetrical weakness with areflexia in bilateral lower extremities, which can be confounded by psychiatric comorbidities. This case is unusual in that the patient had paradoxical hyperreflexia and normal CSF protein levels during her initial presentation, later confirmed to be GBS. CASE PRESENTATION: Here, we describe the case of a young female with bipolar disorder who presented to the hospital with complaints of week-long bilateral lower leg weakness that started abruptly about a month after an episode of multiple stools of bloody diarrhea. The initial neurological exam revealed 4/5 bilateral lower extremity strength and near global areflexia, excluding a 3+ right patellar reflex, and CSF studies returned normal CSF protein levels.  Based on the clinical presentation of worsening ascending paralysis, electromyography (EMG) findings, and nerve conduction studies (NCS) consistent with an axonal and demyelinating neuropathy, we diagnosed her with the classic form of Guillain-Barré syndrome with paradoxical hyperreflexia. Imaging results, laboratory findings, treatment decisions, and outcomes of this case are presented.

Vaccine-associated corneal graft rejection following SARS-CoV-2 vaccination: a CDC-VAERS database analysis.

PURPOSE: To evaluate the cases of corneal graft rejection following SARS-CoV-2 vaccination reported to Centers for Disease Control and Prevention Vaccine Adverse Event Reporting System. METHODS: A descriptive analysis of the demographics, clinical history and presentation was performed. We evaluated the correlation between the vaccines and duration of vaccine-associated graft rejection (VAR) onset following vaccination using a one-way analysis of variance test. A post hoc analysis was performed between VAR onset-interval following vaccination dose and vaccine type. Finally, a 30-day cumulative incidence analysis was performed to assess the risk of VAR in short term following different doses, vaccines and type of corneal transplantation. RESULTS: A total of 55 eyes of 46 patients were diagnosed with VAR following vaccination with BNT162b2 (73.91%) and mRNA-1273 (26.09%). The mean age of the patients was 62.76±15.83 years, and 28 (60.87%) were female. The patients diagnosed with VAR had undergone penetrating keratoplasty (61.82%), Descemet membrane endothelial keratoplasty (12.73%), descemet stripping endothelial keratoplasty (18.18%), anterior lamellar keratoplasty (3.64%) and corneal limbal allograft transplantation (1.82%). The mean time for VAR since penetrating and endothelial keratoplasty was 8.42±9.23 years and 4.18±4.40 years, respectively. 45.65% of the cases of VAR were reported after the second dose of vaccine. The duration of VAR onset was significantly shorter after the second dose compared with the first and booster doses (p=0.0165) and in patients who underwent endothelial keratoplasty compared with penetrating keratoplasty (p=0.041). CONCLUSIONS: This study outlines a possible temporal relationship between corneal graft rejection and SARS-CoV-2 vaccination. An earlier onset of VAR was observed in patients who had a history of endothelial keratoplasty and following the second dose of vaccination.

Targeting PTEN but not SOCS3 resists an age-dependent decline in promoting axon sprouting.

Axonal repair is critical for functional recovery after injury of the CNS. We previously reported that neuronal PTEN deletion exhibits an age-dependent decline in promoting axon regeneration from the corticospinal tract (CST). How sprouting of uninjured axons, a naturally occurring form of axonal repair, is impacted by age is unknown. We assessed CST sprouting after unilateral pyramidotomy in PTEN and/or SOCS3-deleted mice at different ages. While PTEN deletion enhances sprouting independently of age, SOCS3 deletion loses its sprouting-promoting effect with age. The synergistic effect of PTEN/SOCS3 co-deletion on CST sprouting is rapidly lost with increased age. Overall, promoting sprouting appears more robust across age than regeneration, yet distinct molecular pathways are differentially impacted by age. Importantly, six-week delayed PTEN deletion promotes CST sprouting across age groups, supporting a clinically relevant time frame for this neural repair strategy independently of age.

Comparing the Effectiveness and Image Quality of Musculoskeletal Ultrasound of First-Year Medical Students After Training by Student Tutors Versus Ultrasound Instructors: A Pilot Study.

Background Ultrasound is a vital part in many medical schools' curriculum. Although there is strong support for the use of student tutors (STs), there is a lack in gauging their effectiveness with more difficult organ systems such as the musculoskeletal (MSK) system. We aim to determine the effectiveness of using STs versus expert ultrasound instructors (UIs) when teaching MSK ultrasound. Methodology Medical students were recruited to participate in an MSK workshop to identify superficial volar arm structures (radial nerve, radial artery, median nerve, ulnar artery, ulnar nerve) using Butterfly iQ. In total, 14 participants were taught by STs and 10 participants were taught by UIs. Participants imaged the five structures and answered surveys gauging their confidence via five-point Likert scales. Results There was no significant difference in confidence or identification accuracy for all five structures between the two groups. However, there was a significant difference in confidence in the understanding of basic ultrasound concepts in favor of the UI group (p < 0.05). A greater number of students were more confident in identifying all five structures when taught by STs, but more students correctly identified the structures when taught by UIs. Conclusions The results on confidence could be due to positive peer perception. Both groups scored relatively high in their identification accuracies, promoting the successful use of STs. The successful use of STs in teaching MSK ultrasound opens the possibility to developing peer-led ultrasound curriculum on more complex ultrasound topics in the future.

pyXPCSviewer: an open-source interactive tool for X-ray photon correlation spectroscopy visualization and analysis.

pyXPCSviewer, a Python-based graphical user interface that is deployed at beamline 8-ID-I of the Advanced Photon Source for interactive visualization of XPCS results, is introduced. pyXPCSviewer parses rich X-ray photon correlation spectroscopy (XPCS) results into independent PyQt widgets that are both interactive and easy to maintain. pyXPCSviewer is open-source and is open to customization by the XPCS community for ingestion of diversified data structures and inclusion of novel XPCS techniques, both of which are growing demands particularly with the dawn of near-diffraction-limited synchrotron sources and their dedicated XPCS beamlines.

Flavivirus NS1 Triggers Tissue-Specific Disassembly of Intercellular Junctions Leading to Barrier Dysfunction and Vascular Leak in a GSK-3ß-Dependent Manner.

The flavivirus nonstructural protein 1 (NS1) is secreted from infected cells and contributes to endothelial barrier dysfunction and vascular leak in a tissue-dependent manner. This phenomenon occurs in part via disruption of the endothelial glycocalyx layer (EGL) lining the endothelium. Additionally, we and others have shown that soluble DENV NS1 induces disassembly of intercellular junctions (IJCs), a group of cellular proteins critical for maintaining endothelial homeostasis and regulating vascular permeability; however, the specific mechanisms by which NS1 mediates IJC disruption remain unclear. Here, we investigated the relative contribution of five flavivirus NS1 proteins, from dengue (DENV), Zika (ZIKV), West Nile (WNV), Japanese encephalitis (JEV), and yellow fever (YFV) viruses, to the expression and localization of the intercellular junction proteins ß-catenin and VE-cadherin in endothelial cells from human umbilical vein and brain tissues. We found that flavivirus NS1 induced the mislocalization of ß-catenin and VE-cadherin in a tissue-dependent manner, reflecting flavivirus disease tropism. Mechanistically, we observed that NS1 treatment of cells triggered internalization of VE-cadherin, likely via clathrin-mediated endocytosis, and phosphorylation of ß-catenin, part of a canonical IJC remodeling pathway during breakdown of endothelial barriers that activates glycogen synthase kinase-3ß (GSK-3ß). Supporting this model, we found that a chemical inhibitor of GSK-3ß reduced both NS1-induced permeability of human umbilical vein and brain microvascular endothelial cell monolayers in vitro and vascular leakage in a mouse dorsal intradermal model. These findings provide insight into the molecular mechanisms regulating NS1-mediated endothelial dysfunction and identify GSK-3ß as a potential therapeutic target for treatment of vascular leakage during severe dengue disease.