Corneal Epithelial Hyperplasia Related to Chronic Eye Rubbing Mimicking Keratoconus.

ABSTRACT: We report a case of corneal epithelial hyperplasia associated with chronic eye rubbing mimicking keratoconus. A 32-year-old man was presented with a 3-year history of suboptimal vision and astigmatism in his left eye. His history was significant for chronic left eye rubbing. The anterior corneal curvature map showed inferior steepening in the left eye; however, other features of ectasia were absent. Corneal epithelium thickness mapping with optical coherence tomography was significant for corresponding epithelial thickening. His corneal imaging remained stable at a 6-month follow-up examination. At month 15-and after cessation of eye rubbing behavior-the vision symptoms, refraction, and corneal imaging had normalized. In conclusion, chronic eye rubbing may cause reversible corneal epithelial hypertrophy. Eye rubbing should be considered in the evaluation of patients presenting with unexplained vision symptoms and changes in astigmatism that are not consistent with ectasia on corneal imaging.

Elevated total mercury (THg) levels in water sources under the influence of artisanal and small-scale gold mining (ASGM) in Tanzania.

This study investigated the presence and distribution of mercury in water bodies under the influence of artisanal and small-scale mining (ASGM) activities in Tanzania, which continue to predominantly rely on mercury for gold extraction. Various water bodies available for domestic and animal use in mining communities were sampled from surface water sources in ASGM settlements during the rainy and dry seasons. Water samples were analysed using cold vapour atomic fluorescence spectrophotometer (CVAFS). The results indicate that most of water sources had THg levels above the WHO guideline of 1.0 µg/L (1000 ng/L) for safe drinking water. The levels were significantly higher during the wet season ranging from 3.4 to 96.3 µg/L, whereas the range was from 0.84 to 2.12 µg/L during the dry period. The higher THg values during the wet season are likely a result of increased lateral transport (e.g. via enhanced runoff) and physical properties of the waterways. Transportation and resuspension of matrix-bound mercury from surface soils and inflow of contaminated water from unprotected tailings were also observed to be potential means of lateral mercury transport. The lowest concentrations (0.846 µg/L) were observed in water samples from the Mabubi River, upstream of a mining village. Downstream of the mining village in the same river, higher concentrations were observed in the Nungwe Bay region of Lake Victoria. In other surveyed mining settlements where there were no nearby rivers, pool water indicated high concentrations of THg, including levels above thresholds for safe human use. Immediate stringent measures are needed in order to ensure human and animal safety at ASGM mining settlements. Future investigation is suggested to focus on the distribution of mercury in different media, assessing the prevalence of different mercury species, and investigating the influence of weather and hydrological conditions on the impacts of mercury to organisms as part of the strategies to mitigate mercury pollution.

Optimizing IOL Calculators with Deep Learning Prediction of Total Corneal Astigmatism.

Background/Objectives: This study aims to identify the most accurate regression model for predicting total corneal astigmatism (TCA) from anterior corneal astigmatism (ACA) and to fine-tune the best model's architecture to further optimize predictive accuracy. Methods: A retrospective review of 19,468 eyes screened for refractive surgery was conducted using electronic medical records. Corneal topography data were acquired using the Pentacam HR. Various types (7) and subtypes (21) of regression learners were tested, with a deep neural network (DNN) emerging as the most suitable. The DNN was further refined, experimenting with 23 different architectures. Model performance was evaluated using root mean squared error (RMSE), R2, average residual error, and circular error. The final model only used age, ACA magnitude, and ACA axis to predict TCA magnitude and axis. Results were compared to predictions from one of the leading TCA prediction formulas. Results: Our model achieved higher performance for TCA magnitude prediction (R2 = 0.9740, RMSE = 0.0963 D, and average residual error = 0.0733 D) compared to the leading formula (R2 = 0.8590, RMSE = 0.2257 D, and average residual error = 0.1928 D). Axis prediction error also improved by an average of 8.1° (average axis prediction error = 4.74° versus 12.8°). The deep learning approach consistently demonstrated smaller errors and tighter clustering around actual values compared to the traditional formula. Conclusion: Deep learning techniques significantly outperformed traditional methods for TCA prediction accuracy using the Pentacam HR. This approach may lead to more precise TCA calculations and better IOL selection, potentially enhancing surgical outcomes.

Octogenarians unable to return home by postoperative-day 30.

BACKGROUND: For older adults undergoing surgery, returning home is instrumental for functional independence. We quantified octogenarians unable to return home by POD-30, assessed geriatric factors in a predictive model, and identified risk factors to inform decision-making and quality improvement. METHODS: This retrospective cohort study examined patients ≥80 years old from the ACS NSQIP Geriatric Surgery Pilot, using sequential logistic regression modelling. The primary outcome was non-home living location at POD-30. RESULTS: Of 4946 patients, 19.8 â€‹% lived in non-home facilities at POD-30. Increased odds of non-home living location were seen in patients with preoperative fall history (OR 2.92, 95%CI 2.06-4.14) and new postoperative pressure ulcer (OR 2.66, 95%CI 1.50-4.71) Other significant geriatric-specific risk factors included mobility aid use, surrogate-signed consent, and postoperative delirium, with odds ratios ranging from 1.42 (1.19-1.68) to 1.97 (1.53-2.53). CONCLUSIONS: These geriatric-specific risk factors highlight the importance of preoperative vulnerability screening and intervention to inform surgical decision-making.

The incidence and decompression rates of median and ulnar neuropathies following shoulder surgery.

Background: Upper extremity peripheral neuropathy is a known, but uncommon complication that can occur after shoulder surgery. The incidence rate is well documented, and most of these cases historically have been treated conservatively. However, we hypothesize peripheral compression neuropathy requires a much higher need for surgical decompression than originally reported. The purpose of this study was to evaluate the incidence, decompression rates, and prognostic factors for developing median and ulnar neuropathies following shoulder surgery. Methods: A retrospective chart review was performed examining patients who underwent open and arthroscopic shoulder surgery from a multisurgeon, single-institution database. Perioperative data and functional outcomes were recorded. Symptom resolution was assessed with both conservative and surgical management of compression peripheral neuropathy. Further analysis was made to compare open and arthroscopic procedures, the type of neuropathy developed, and electromyographic (EMG) severity. Results: The incidence rates of compression peripheral neuropathy following open arthroplasty and arthroscopic procedures was 1.80% (31/1722) and 0.54% (44/8150), respectively. 73.33% (55/75) of patients developed ipsilateral disease, while 20.00% (15/75) of patients had bilateral disease. Amongst the 75 included patients, there were 99 cases of neuropathy. Carpal tunnel syndrome was more common than cubital tunnel syndrome, comprising 61.61% (61/99) cases of neuropathy. 12.00% (9/75) of patients developed both carpal tunnel syndrome and cubital tunnel syndrome. Four patients were lost to follow-up. Decompression surgery was performed for 36.84% (35/95) cases of neuropathy with >90% obtaining symptom resolution with surgery. 63.16% (60/95) cases of neuropathy were managed conservatively, 71.67% (43/60) of which had persistent symptoms. When comparing arthroscopic versus open procedures, patients who underwent open procedures were significantly older (68.62 vs. 49.78 years, P < .001) and developed peripheral neuropathy significantly faster after the index procedure (87.24 vs. 125.58 days, P = .008). EMG severity did not correlate with decompression rates or symptom resolution. There were no differences in the subgroup analyses between beach chair and lateral positioning in regard to the type of neuropathy, laterality of symptoms, and/or treatment received. Conclusion: The overall incidence of peripheral neuropathy after shoulder surgery was 0.76% (75/9872). The development of peripheral neuropathy is multifactorial, with older patients undergoing open arthroplasty more at risk. Neuropathy symptoms were refractory to conservative management despite the type of shoulder surgery, type of neuropathy, or EMG severity. Decompression consistently led to resolution of symptoms.

Within-hospital Temporal Clustering of Postoperative Complications and Implications for Safety Monitoring and Benchmarking Using ACS-NSQIP Data.

Objective: To determine the extent to which within-hospital temporal clustering of postoperative complications is observed in the American College of Surgeons, National Surgical Quality Improvement Program (ACS-NSQIP). Background: ACS-NSQIP relies on periodic and on-demand reports for quality benchmarking. However, if rapid increases in postoperative complication rates (clusters) are common, other reporting methods might be valuable additions to the program. This article focuses on estimating the incidence of within-hospital temporal clusters. Methods: ACS-NSQIP data from 1,547,440 patients, in 425 hospitals, over a 2-year period was examined. Hospital-specific Cox proportional hazards regression was used to estimate the incidence of mortality, morbidity, and surgical site infection (SSI) over a 30-day postoperative period, with risk adjustment for patient and procedure and with additional adjustments for linear trend, day-of-week, and season. Clusters were identified using scan statistics, and cluster counts were compared, using unpaired and paired t tests, for different levels of adjustment and when randomization of cases across time eliminated all temporal influences. Results: Temporal clusters were rarely observed. When clustering was adjusted only for patient and procedure risk, an annual average of 0.31, 0.85, and 0.51 clusters were observed per hospital for mortality, morbidity, and SSI, respectively. The number of clusters dropped after adjustment for linear trend, day-of-week, and season (0.31-0.24; P = 0.012; 0.85-0.80; P = 0.034; and 0.51-0.36; P < 0.001; using paired t tests) for mortality, morbidity, and SSI, respectively. There was 1 significant difference in the number of clusters when comparing data with all adjustments and after data were randomized (0.24 and 0.25 for mortality; P = 0.853; 0.80 and 0.82 for morbidity; P = 0.529; and 0.36 and 0.46 [randomized data had more clusters] for SSI; P = 0.001; using paired t tests) for mortality, morbidity, and SSI, respectively. Conclusions: Temporal clusters of postoperative complications were rarely observed in ACS-NSQIP data. The described methodology may be useful in assessing clustering in other surgical arenas.

Recomendaciones ALAT para el uso de vacunas respiratorias. Guía de práctica clínica basada en evidencias / ALAT Recommendations for the Use of Respiratory VaccinesEvidence-Based Clinical Practice Guideline

Introducción: Las infecciones respiratorias son las enfermedades respiratorias con mayor mortalidad en el mundo. Las causadas por Streptococcus pneumoniae, virus de influenza, Bordetella pertussis, SARS-CoV-2 y el Virus Sincitial Respiratorio, cuentan hoy día con vacunas seguras y efectivas. Este documento representa una guía de práctica clínica (GPC) de la Asociación Latinoamericana de Tórax (ALAT), elaborada por iniciativa de los departamentos de enfermedades infecciosas y pediatría, con el objetivo de establecer recomendaciones sobre vacunas respiratorias, utilizando la evidencia disponible. Método: Se estableció un grupo de desarrollo de las guías conformado por cinco médicos responsables globales del proyecto, se crearon cinco subgrupos de trabajo, uno por cada vacuna, con expertos neumólogos de adulto, pediatras e infectólogos invitados, que generaron preguntas clínicas. Se trabajó con un grupo de expertos metodólogos que transformaron preguntas clínicas en preguntas PICO, seleccionándose nueve preguntas por método DELPHI. Luego, se utilizó el sistema GRADE (Grading of Recommendations Assessment, Development and Evaluation) para evaluar la evidencia disponible. Resultados: Se obtuvieron recomendaciones para población adulta y pediátrica de las vacunas de neumococo, influenza, tos ferina, COVID-19 y Virus Respiratorio Sincitial basadas en preguntas PICO. También se agregaron recomendaciones basadas en preguntas narrativas relacionadas al uso de vacunas respiratorias en población con enfermedades respiratorias crónicas como asma, EPOC y fibrosis pulmonar.

Introduction: Respiratory infections are the leading cause of respiratory disease-related mortality worldwide. Infections caused by Streptococcus pneumoniae, influenza virus, Bordetella pertussis, SARS-CoV-2 and Respiratory Syncytial Virus (RSV) now have safe and effective vaccines available.This document represents a Clinical Practice Guideline (CPG) by the Latin American Thoracic Association (ALAT), developed through the initiative of the departments of in-fectious diseases and pediatrics, with the goal of establishing recommendations on respiratory vaccines using the available evidence. Method: A guideline development group was established, composed of five lead physicians responsible for the overall project. Five working subgroups were created, one for each vaccine, involving invited experts in adult pulmonology, pediatrics, and infectious diseases, who formulated clinical questions. A group of expert methodologists then transformed these clinical questions into PICO questions, with nine questions selected using the DELPHI method. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was then used to assess the available evidence. Results: Recommendations were obtained for the adult and pediatric populations for pneumococcal, influenza, pertussis, COVID-19 and Respiratory Syncytial Virus vaccines based on PICO questions. Additionally, recommendations based on narrative questions related to the use of respiratory vaccines in populations with chronic respiratory diseases such as asthma, COPD, and pulmonary fibrosis were included.

The Investigation of Hsp90 C-terminal inhibitors containing Amide bioisosteres.

Heat Shock Protein 90 (Hsp90) is responsible for the proper folding and maturation of ~400 client protein substrates, many of which are directly associated with the ten hallmarks of cancer. Hsp90 is a great target for cancer therapy including melanoma, since Hsp90 inhibition can disrupt multiple oncogenic pathways simultaneously. In this study, we report the synthesis and anti-proliferative activity manifested by a series of Hsp90 C-terminal inhibitors against mutant BRAF and wild-type BRAF melanoma cells. Furthermore, we explored structure-activity relationships (SAR) for the amide moiety of 6 (B1), a novel Hsp90 C-terminal inhibitor via introduction of amide bioisosteres. Compound 6 displayed an IC50 of 1.01 µM, 0.782 µM, 0.607 µM and 1.413 µM against SKMel173, SKMel103, SKMel19 and A375 cells, respectively.

Recalcitrant Lateral Epicondylitis: A Systematic Review on Current Nonoperative and Operative Treatment Modalities.

BACKGROUND: Lateral epicondylitis is a common cause of elbow pain that is generally self-limiting. For patients who have persistent symptoms refractory to conservative treatment, there is still no clear consensus on the most favorable treatment modality. The purpose of this systematic review was to synthesize the available literature regarding both nonoperative and operative treatment modalities for recalcitrant lateral epicondylitis (RLE) to provide insight into the efficacy of treatment options. METHODS: A systematic review was performed in accordance with the 2020 Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines, where the PubMed, MEDLINE/Ovid, CINAHL, Cochrane, and Scopus databases were queried to identify studies evaluating treatment options for RLE. RESULTS: A total of 27 studies with 1,958 patients were included. Of the reviewed studies, there were a wide variety of treatments including platelet-rich plasma injections, percutaneous tenotomies, and various arthroscopic and open procedures. CONCLUSION: There are a wide variety of treatment modalities available for RLE that have promising efficacy in the short, medium, and long terms. A comprehensive approach combining evidence-based and patient-centered care is critical for effective management of refractory symptoms. LEVEL OF EVIDENCE: Level IV. See Instructions for Authors for a complete description of levels of evidence.

Sexually dimorphic computational histopathological signatures prognostic of overall survival in high-grade gliomas via deep learning.

High-grade glioma (HGG) is an aggressive brain tumor. Sex is an important factor that differentially affects survival outcomes in HGG. We used an end-to-end deep learning approach on hematoxylin and eosin (H&E) scans to (i) identify sex-specific histopathological attributes of the tumor microenvironment (TME), and (ii) create sex-specific risk profiles to prognosticate overall survival. Surgically resected H&E-stained tissue slides were analyzed in a two-stage approach using ResNet18 deep learning models, first, to segment the viable tumor regions and second, to build sex-specific prognostic models for prediction of overall survival. Our mResNet-Cox model yielded C-index (0.696, 0.736, 0.731, and 0.729) for the female cohort and C-index (0.729, 0.738, 0.724, and 0.696) for the male cohort across training and three independent validation cohorts, respectively. End-to-end deep learning approaches using routine H&E-stained slides, trained separately on male and female patients with HGG, may allow for identifying sex-specific histopathological attributes of the TME associated with survival and, ultimately, build patient-centric prognostic risk assessment models.

Neuropathologically-directed profiling of PRNP somatic and germline variants in sporadic human prion disease.

Creutzfeldt-Jakob Disease (CJD), the most common human prion disease, is associated with pathologic misfolding of the prion protein (PrP), encoded by the PRNP gene. Of human prion disease cases, ~1% were transmitted by misfolded PrP, ~15% are inherited, and ~85% are sporadic (sCJD). While familial cases are inherited through germline mutations in PRNP, the cause of sCJD is unknown. Somatic mutations have been hypothesized as a cause of sCJD, and recent studies have revealed that somatic mutations accumulate in neurons during aging. To investigate the hypothesis that somatic mutations in PRNP may underlie sCJD, we performed deep DNA sequencing of PRNP in 205 sCJD cases and 170 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate focal initiation of prion formation, and examined multiple regions across the brain including in the affected occipital cortex. We employed Multiple Independent Primer PCR Sequencing (MIPP-Seq) with a median depth of >5,000X across the PRNP coding region and analyzed for variants using MosaicHunter. An allele mixing experiment showed positive detection of variants in bulk DNA at a variant allele fraction (VAF) as low as 0.2%. We observed multiple polymorphic germline variants among individuals in our cohort. However, we did not identify bona fide somatic variants in sCJD, including across multiple affected regions in H-sCJD, nor in control individuals. Beyond our stringent variant-identification pipeline, we also analyzed VAFs from raw sequencing data, and observed no evidence of prion disease enrichment for the known germline pathogenic variants P102L, D178N, and E200K. The lack of PRNP pathogenic somatic mutations in H-sCJD or the broader cohort of sCJD suggests that clonal somatic mutations may not play a major role in sporadic prion disease. With H-sCJD representing a focal presentation of neurodegeneration, this serves as a test of the potential role of clonal somatic mutations in genes known to cause familial neurodegeneration.

Neuropathologically directed profiling of PRNP somatic and germline variants in sporadic human prion disease.

Creutzfeldt-Jakob Disease (CJD), the most common human prion disease, is associated with pathologic misfolding of the prion protein (PrP), encoded by the PRNP gene. Of human prion disease cases, < 1% were transmitted by misfolded PrP, ~ 15% are inherited, and ~ 85% are sporadic (sCJD). While familial cases are inherited through germline mutations in PRNP, the cause of sCJD is unknown. Somatic mutations have been hypothesized as a cause of sCJD, and recent studies have revealed that somatic mutations accumulate in neurons during aging. To investigate the hypothesis that somatic mutations in PRNP may underlie sCJD, we performed deep DNA sequencing of PRNP in 205 sCJD cases and 170 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate localized initiation of prion formation, and examined multiple regions across the brain including in the affected occipital cortex. We employed Multiple Independent Primer PCR Sequencing (MIPP-Seq) with a median depth of > 5000× across the PRNP coding region and analyzed for variants using MosaicHunter. An allele mixing experiment showed positive detection of variants in bulk DNA at a variant allele fraction (VAF) as low as 0.2%. We observed multiple polymorphic germline variants among individuals in our cohort. However, we did not identify bona fide somatic variants in sCJD, including across multiple affected regions in H-sCJD, nor in control individuals. Beyond our stringent variant-identification pipeline, we also analyzed VAFs from raw sequencing data, and observed no evidence of prion disease enrichment for the known germline pathogenic variants P102L, D178N, and E200K. The lack of PRNP pathogenic somatic mutations in H-sCJD or the broader cohort of sCJD suggests that clonal somatic mutations may not play a major role in sporadic prion disease. With H-sCJD representing a localized presentation of neurodegeneration, this serves as a test of the potential role of clonal somatic mutations in genes known to cause familial neurodegeneration.

Laparoscopic Total Pancreatectomy After Laparoscopic Whipple.

BACKGROUND: The incidence of a second de novo pancreatic ductal adenocarcinoma (PDAC) among patients with prior cancer has been reported to be 6%.1,2 however, as survival increases through improvements in systemic therapy, this incidence of a de novo PDAC after prior PDAC may become more prevalent.3-8 In this context, a structured and stepwise approach to a total pancreatectomy for a second de novo PDAC after a prior PDAC treated with a pancreaticoduodenectomy is detailed. PATIENTS: We present two similar cases. The first patient was a 71-year-old female with de novo body PDAC, and the second was a 50-year-old female with de novo tail PDAC. To rule out recurrence, immunohistochemical staining as well as the review of biopsies by two experienced pathologists were employed. Both patients had undergone a laparoscopic pancreatoduodenectomy for PDAC 4 and 3 years prior. Each patient received four cycles of neoadjuvant chemotherapy and underwent a safe laparoscopic total pancreatectomy. TECHNIQUE: Prior to surgery, three-dimensional anatomic and port site modeling is performed to optimize the understanding of the spatial relationship between the tumor, blood vessels, and adjacent organs involved. The port site modeling (including pneumoperitoneum simulation) focuses on the optimal port set-up for dissecting the biliopancreatic limb off the portal vein. Following complete mobilization of the biliopancreatic limb, the biliopancreatic limb is staple-divided between the hepatico- and pancreaticojejunostomy. Great care must be taken to avoid accidental staple injury to the hepatic artery or celiac trunk. The remainder of the dissection is akin to a standard distal pancreaticosplenectomy. CONCLUSION: Virtual pancreatectomy modeling facilitates an optimal set-up for the critical step of this case, i.e. dissection of the pancreaticojejunostomy off the portal vein. Early division of the biliopancreatic limb between hepatico- and pancreatojejunostomy is crucial to facilitating the remainder of the dissection. Laparoscopic total pancreatectomy for a de novo PDAC after laparoscopic pancreaticoduodenectomy may become more common as survival of patients with prior PDAC improves over time.

Identifying Population-Level and Within-Hospital Disparities in Surgical Care.

BACKGROUND: The lack of consensus on equity measurement and its incorporation into quality-assessment programs at the hospital and system levels may be a barrier to addressing disparities in surgical care. This study aimed to identify population-level and within-hospital differences in the quality of surgical care provision. STUDY DESIGN: The analysis included 657 NSQIP participating hospitals with more than 4 million patients (2014 to 2018). Multilevel random slope, random intercept modeling was used to examine for population-level and in-hospital disparities. Disparities in surgical care by Area Deprivation Index (ADI), race, and ethnicity were analyzed for 5 measures: all-case inpatient mortality, all-case urgent readmission, all-case postoperative surgical site infection, colectomy mortality, and spine surgery complications. RESULTS: Population-level disparities were identified across all measures by ADI, 2 measures for Black race (all-case readmissions and spine surgery complications), and none for Hispanic ethnicity. Disparities remained significant in the adjusted models. Before risk adjustment, in all measures examined, within-hospital disparities were detected in: 25.8% to 99.8% of hospitals for ADI, 0% to 6.1% of hospitals for Black race, and 0% to 0.8% of hospitals for Hispanic ethnicity. After risk adjustment, in all measures examined, less than 1.1% of hospitals demonstrated disparities by ADI, race, or ethnicity. CONCLUSIONS: After risk adjustment, very few hospitals demonstrated significant disparities in care. Disparities were more frequently detected by ADI than by race and ethnicity. The lack of substantial in-hospital disparities may be due to the use of postoperative metrics, small sample sizes, the risk adjustment methodology, and healthcare segregation. Further work should examine surgical access and healthcare segregation.

Addressing the Rhino in the Room: ChatGPT Creates "Novel" Patent Ideas for Rhinoplasty.

Background: OpenAI's ChatGPT can generate novel ideas for a number of applications. The aim of this study was to prompt the chatbot to generate possible innovations in aesthetic surgery relating to rhinoplasty. Methods: ChatGPT was prompted to develop rhinoplasty patents. The resulting outputs were tabulated and categorized based on technology domain and anatomic location. A Google Patents search was conducted to find uses of the term "rhinoplasty" between 2021 and 2023. Patents not pertaining to rhinoplasty were excluded. Filed patents were compared with those generated by ChatGPT to determine predictive power. Results: A total of 40 patents resulted from ChatGPT and 42 Google Patents from 2021 to 2023 were included. Patents generated without a detailed description command were related to preoperative planning (35%), intraoperative tools (30%), functional evaluation (15%), and 3D printing and implants (10%). Patents with a detailed description command resulted in the majority being postoperative tools (40%), followed by intraoperative tools (30%), 3D printing and implants (10%), and nonsurgical (10%) categories. The anatomic locations included the airway, dorsum, septum, and nasal tip. ChatGPT's predictive power yielded 45% for the detailed prompting, which was higher than the prompt without the detail command. Conclusions: ChatGPT has reasonable potential to generate ideas for innovations in plastic surgery with the assistance of an experienced surgeon-innovator. With new artificial intelligence generations and updates, chatbots will continue to improve. Determining whether these technologies can assist in the later portions of the patent process beyond idea generation will be crucial.

Development of Hsp90 C-terminal inhibitors with noviomimetics that manifest anti-proliferative activities.

Inhibition of the Hsp90 C-terminal domain offers a promising opportunity to treat numerous diseases/indications. Furthermore, the development of Hsp90 C-terminal inhibitors (CTIs) is advantageous over N-terminal inhibitors because it avoids the detriments associated with induction of the heat shock response (HSR). However, the lack of co-crystal structures of small molecules bound to the C-terminus have hindered their development. Therefore, structure-activity relationship (SAR) studies have been pursued to optimize such inhibitors. Noviose sugar surrogates, also known as noviomimetics have been prepared to investigate the size and nature of the C-terminal domain binding pocket. Herein, we report the synthesis and anti-proliferative activity manifested by this new series of Hsp90 C-terminal inhibitors.

Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases.

Definitive diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) relies on the examination of brain tissues for the pathological prion protein (PrPSc). Our previous study revealed that PrPSc-seeding activity (PrPSc-SA) is detectable in skin of sCJD patients by an ultrasensitive PrPSc seed amplification assay (PrPSc-SAA) known as real-time quaking-induced conversion (RT-QuIC). A total of 875 skin samples were collected from 2 cohorts (1 and 2) at autopsy from 2-3 body areas of 339 cases with neuropathologically confirmed prion diseases and non-sCJD controls. The skin samples were analyzed for PrPSc-SA by RT-QuIC assay. The results were compared with demographic information, clinical manifestations, cerebrospinal fluid (CSF) PrPSc-SA, other laboratory tests, subtypes of prion diseases defined by the methionine (M) or valine (V) polymorphism at residue 129 of PrP, PrPSc types (#1 or #2), and gene mutations in deceased patients. RT-QuIC assays of the cohort #1 by two independent laboratories gave 87.3% or 91.3% sensitivity and 94.7% or 100% specificity, respectively. The cohort #2 showed sensitivity of 89.4% and specificity of 95.5%. RT-QuIC of CSF available from 212 cases gave 89.7% sensitivity and 94.1% specificity. The sensitivity of skin RT-QuIC was subtype dependent, being highest in sCJDVV1-2 subtype, followed by VV2, MV1-2, MV1, MV2, MM1, MM1-2, MM2, and VV1. The skin area next to the ear gave highest sensitivity, followed by lower back and apex of the head. Although no difference in brain PrPSc-SA was detected between the cases with false negative and true positive skin RT-QuIC results, the disease duration was significantly longer with the false negatives [12.0 ± 13.3 (months, SD) vs. 6.5 ± 6.4, p < 0.001]. Our study validates skin PrPSc-SA as a biomarker for the detection of prion diseases, which is influenced by the PrPSc types, PRNP 129 polymorphisms, dermatome sampled, and disease duration.

Genome-wide association studies identify novel loci in rapidly progressive Alzheimer's disease.

INTRODUCTION: Recent data suggest that distinct prion-like amyloid beta and tau strains are associated with rapidly progressive Alzheimer's disease (rpAD). The role of genetic factors in rpAD is largely unknown. METHODS: Previously known AD risk loci were examined in rpAD cases. Genome-wide association studies (GWAS) were performed to identify variants that influence rpAD. RESULTS: We identified 115 pathology-confirmed rpAD cases and 193 clinical rpAD cases, 80% and 69% were of non-Hispanic European ancestry. Compared to the clinical cohort, pathology-confirmed rpAD had higher frequencies of apolipoprotein E (APOE) ε4 and rare missense variants in AD risk genes. A novel genome-wide significant locus (P < 5×10-8 ) was observed for clinical rpAD on chromosome 21 (rs2832546); 102 loci showed suggestive associations with pathology-confirmed rpAD (P < 1×10-5 ). DISCUSSION rpAD constitutes an extreme subtype of AD with distinct features. GWAS found previously known and novel loci associated with rpAD. Highlights Rapidly progressive Alzheimer's disease (rpAD) was defined with different criteria. Whole genome sequencing identified rare missense variants in rpAD. Novel variants were identified for clinical rpAD on chromosome 21.

Pathological findings in autoimmune encephalitis autopsy specimens from cases of suspected prion disease.

OBJECTIVE: The underlying pathology of autoimmune encephalitis is not well characterized due to the limited opportunities to study tissue specimens. Autopsy specimens available at prion surveillance centers from patients with suspected Creutzfeldt-Jakob disease offer a unique opportunity to study the pathology of autoimmune encephalitis. Our objective was to describe pathological findings of autoimmune encephalitis specimens submitted to the U.S. National Prion Disease Pathology Surveillance Center. METHODS: Pathology reports were obtained from the National Prion Center. Specimens negative for prion disease were screened for inflammatory pathology and those suggestive of autoimmune encephalitis were analyzed. Cases identified on autopsy were compared to institutional cases with fatal seronegative autoimmune encephalitis and available brain biopsy. RESULTS: Between 1998 and 2022, 7934 specimens were evaluated of which 2998 (38%) were negative for prion protein. Querying the database for alternative diagnoses of encephalitis/encephalopathy yielded 43 cases that were screened by an experienced neuropathologist yielding 14 (0.5%) cases consistent with autoimmune encephalitis. Most specimens showed diffuse inflammation involving the limbic system (86%), basal ganglia (86%), cortex (71%), diencephalon (71%), and in some cases the brainstem (43%) and cerebellum (43%). Lymphocytic inflammatory infiltrate was predominantly perivascular with parenchymal extension in 64%. Microglial activation/nodules were seen in 64% of cases. Neuronal loss was present only in 50%. Pathological findings were identical to biopsy specimens from our institutional cohort. DISCUSSION: Seronegative AE may have consistent pathology with diffuse or multifocal perivascular inflammation and microglial activation. Half the patients do not have neuronal loss suggesting a potential for neurological recovery. These findings are preliminary and require further confirmation.