Disease-specific alterations in the enteric virome in inflammatory bowel disease.

Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn's disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases. We show that the enteric virome is abnormal in CD and UC patients. In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages. The viromes of CD and UC patients were disease and cohort specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations. These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis. We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases.

Molecular profiling of the stroke-induced alterations in the cerebral microvasculature reveals promising therapeutic candidates.

Stroke-induced cerebral microvascular dysfunction contributes to aggravation of neuronal injury and compromises the efficacy of current reperfusion therapies. Understanding the molecular alterations in cerebral microvessels in stroke will provide original opportunities for scientific investigation of novel therapeutic strategies. Toward this goal, using a recently optimized method which minimizes cell activation and preserves endothelial cell interactions and RNA integrity, we conducted a genome-wide transcriptomic analysis of cerebral microvessels in a mouse model of stroke and compared these transcriptomic alterations with the ones observed in human, nonfatal, brain stroke lesions. Results from these unbiased comparative analyses have revealed the common alterations in mouse stroke microvessels and human stroke lesions and identified shared molecular features associated with vascular disease (e.g., Serpine1/Plasminogen Activator Inhibitor-1, Hemoxygenase-1), endothelial activation (e.g., Angiopoietin-2), and alterations in sphingolipid metabolism and signaling (e.g., Sphigosine-1-Phosphate Receptor 2). Sphingolipid profiling of mouse cerebral microvessels validated the transcript data and revealed the enrichment of sphingomyelin and sphingoid species in the cerebral microvasculature compared to brain and the stroke-induced increase in ceramide species. In summary, our study has identified novel molecular alterations in several microvessel-enriched, translationally relevant, and druggable targets, which are potent modulators of endothelial function. Our comparative analyses have revealed the presence of molecular features associated with cerebral microvascular dysfunction in human chronic stroke lesions. The results shared here provide a detailed resource for therapeutic discovery of candidates for neurovascular protection in stroke and potentially, other pathologies exhibiting cerebral microvascular dysfunction.

Phosphorylation of RPT6 Controls Its Ability to Bind DNA and Regulate Gene Expression in the Hippocampus of Male Rats during Memory Formation.

Memory formation requires coordinated control of gene expression, protein synthesis, and ubiquitin-proteasome system (UPS)-mediated protein degradation. The catalytic component of the UPS, the 26S proteasome, contains a 20S catalytic core surrounded by two 19S regulatory caps, and phosphorylation of the 19S cap regulatory subunit RPT6 at serine 120 (pRPT6-S120) has been widely implicated in controlling activity-dependent increases in proteasome activity. Recently, RPT6 was also shown to act outside the proteasome where it has a transcription factor-like role in the hippocampus during memory formation. However, little is known about the proteasome-independent function of "free" RPT6 in the brain or during memory formation and whether phosphorylation of S120 is required for this transcriptional control function. Here, we used RNA-sequencing along with novel genetic approaches and biochemical, molecular, and behavioral assays to test the hypothesis that pRPT6-S120 functions independently of the proteasome to bind DNA and regulate gene expression during memory formation. RNA-sequencing following siRNA-mediated knockdown of free RPT6 revealed 46 gene targets in the dorsal hippocampus of male rats following fear conditioning, where RPT6 was involved in transcriptional activation and repression. Through CRISPR-dCas9-mediated artificial placement of RPT6 at a target gene, we found that RPT6 DNA binding alone may be important for altering gene expression following learning. Further, CRISPR-dCas13-mediated conversion of S120 to glycine on RPT6 revealed that phosphorylation at S120 is necessary for RPT6 to bind DNA and properly regulate transcription during memory formation. Together, we reveal a novel function for phosphorylation of RPT6 in controlling gene transcription during memory formation.

Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism.

Breast adipose tissue is an important contributor to the obesity-breast cancer link. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we find that long-term education of breast cancer cells with EVs obtained from breast adipose tissue of women who are overweight or obese (O-EVs) results in increased proliferation. RNA-seq analysis of O-EV-educated cells demonstrates increased expression of genes involved in oxidative phosphorylation, such as ATP synthase and NADH: ubiquinone oxidoreductase. O-EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. The mitochondrial complex I inhibitor metformin reverses O-EV-induced cell proliferation. Several miRNAs-miR-155-5p, miR-10a-3p, and miR-30a-3p-which promote mitochondrial respiration and proliferation, are enriched in O-EVs relative to EVs from lean women. O-EV-induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity-breast cancer link with human breast adipose tissue-derived EVs causing metabolic reprogramming of breast cancer cells.

Outcomes in Hematopoietic Cell Transplant and Chimeric Antigen Receptor T-Cell Therapy Recipients With Pre-Cellular Therapy SARS-CoV-2 Infection.

BACKGROUND: Hematopoietic cell transplant (HCT) or chimeric antigen receptor (CAR) T-cell therapy recipients have high morbidity from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are limited data on outcomes from SARS-CoV-2 infection shortly before cellular therapy and uncertainty whether to delay therapy. METHODS: We conducted a retrospective cohort study of patients with SARS-CoV-2 infection within 90 days before HCT or CAR-T-cell therapy between January 2020 and November 2022. We characterized the kinetics of SARS-CoV-2 detection, clinical outcomes following cellular therapy, and impact on delays in cellular therapy. RESULTS: We identified 37 patients (n = 15 allogeneic HCT, n = 11 autologous HCT, n = 11 CAR-T-cell therapy) with SARS-CoV-2 infections within 90 days of cellular therapy. Most infections (73%) occurred between March and November 2022, when Omicron strains were prevalent. Most patients had asymptomatic (27%) or mild (68%) coronavirus disease 2019 (COVID-19). SARS-CoV-2 positivity lasted a median of 20.0 days (interquartile range, 12.5-26.25 days). The median time from first positive SARS-CoV-2 test to cellular therapy was 45 days (interquartile range, 37.75-70 days); 1 patient tested positive on the day of infusion. After cellular therapy, no patients had recrudescent SARS-CoV-2 infection or COVID-19-related complications. Cellular therapy delays related to SARS-CoV-2 infection occurred in 70% of patients for a median of 37 days. Delays were more common after allogeneic (73%) and autologous (91%) HCT compared to CAR-T-cell therapy (45%). CONCLUSIONS: Patients with asymptomatic or mild COVID-19 may not require prolonged delays in cellular therapy in the context of contemporary circulating variants and availability of antiviral therapies.

Clinical outcomes and frequency of persistent infection among immunosuppressed patients treated with bebtelovimab for COVID-19 infection at an ambulatory cancer center.

BACKGROUND: There are limited data on clinical outcomes associated with the use of bebtelovimab for the treatment of coronavirus disease 2019 (COVID-19) among cancer patients. We aimed to define the clinical characteristics and outcomes among patients receiving bebtelovimab as part of the COVID-19 therapeutics program at our cancer center. METHODS: This is a retrospective cohort study of immunosuppressed adult patients who received bebtelovimab at Fred Hutchinson Cancer Center between March 2022, and November 2022. We reviewed medical records to capture the date of the first positive COVID-19 test, clinical characteristics, outcomes, and follow-up COVID-19 testing for 60 days after the first positive. Persistent infection was defined as a positive test beyond day 30; these patients were reviewed beyond day 60. RESULTS: Among 93 patients who received bebtelovimab, 64 (69%) had hematologic malignancy. Sixty-nine (74%) patients received bebtelovimab within 2 days after diagnosis. Two (2%) patients were hospitalized, none required ICU care, and one patient died on day 52; although it is unknown if death was directly related to COVID-19. Ten (11%) patients had persistent COVID-19 infection; of these, four received additional COVID-19 therapy with either nirmatrelvir/ritonavir or remdesivir, and five out of six patients with sequencing data available had spike protein mutations associated with bebtelovimab resistance. CONCLUSION: A coordinated systems-based approach led to prompt initiation of bebtelovimab within two days of testing positive in most patients. We observed few hospitalizations or deaths. Persistent infection was noted in 11% of patients with four requiring additional therapies, highlighting a need for novel strategies to manage immunosuppressed patients.

Hemodynamic Renal Reserve Response in Conscious Normotensive and Hypertensive Mice.

INTRODUCTION: Renal function may be compromised following recovery from kidney insults. Renal functional reserve (RFR) is a measure of the difference between the kidney's maximum capacity and its baseline function, which helps identify any areas of the kidney with compromised function. Usually, RFR is evaluated using acute volume expansion (AVE), but this is typically done in anesthetized animals, which may not accurately represent the kidney's complete functional capacity. In this study, we have introduced a novel method that enables AVE to be conducted in conscious mice. METHODS: We have implemented this innovative approach in two animal models representing either intact or impaired renal function, specifically utilizing a lower nephron hypertensive model. Mice were implanted with radio-transmitters for mean artery blood pressure (MAP) monitoring during the experiment. After recovery, half of the mice were induced hypertension by right kidney nephrectomy combined with the ligation of the upper branch of the left kidney. For the AVE, a volume equivalent to 5% of the mouse's body weight was administered via intravenous (IV) or intraperitoneal bolus injection. Subsequently, the mice were individually housed in cages covered with plastic wrap. Urine was collected every hour for a total of 3 h for the measurement of urine and sodium excretion. RESULTS: The MAPs for all normotensive mice were consistent throughout the AVE, but it increased 5-16 mm Hg in the hypertensive mice upon AVE. Remarkably, conscious mice exhibited a significantly stronger response to IV-administered AVE when compared to anesthetized mice. This response was evident in the increase in urinary flow, which was approximately 170% and 145% higher in conscious normotensive and hypertensive mice, respectively, compared to their respective baselines. In contrast, anesthetized normotensive and hypertensive mice showed only around a 130% and 100% increase in urinary flow, respectively. Additionally, upon AVE, conscious normotensive mice excreted approximately 47% more sodium than conscious hypertensive mice. In contrast, anesthetized normotensive mice excreted only about 30% more sodium than their anesthetized hypertensive counterparts. CONCLUSION: Performing a kidney stress test with a significant solution load in conscious mice seems to be a superior method for evaluating RFR compared to conducting the test under anesthesia. Assessing kidney clearance while the mice are conscious has the potential to enhance the precision of diagnosing and predicting both acute and chronic kidney diseases.

Effects of Teprotumumab on Eyelid Retraction in Thyroid Eye Disease.

PURPOSE: This study evaluates the efficacy of teprotumumab in reducing eyelid retraction in thyroid eye disease (TED) patients. METHODS: This retrospective study included patients with active or chronic moderate-to-severe TED who completed at least 4 cycles of teprotumumab. Patients with upper and/or lower eyelid retraction, defined as margin-to-reflex distance (MRD) 1 and/or MRD2 of more than 5 mm, in one or OU were included. The main outcome measure was a change in MRD1 and MRD2 after treatment. Changes in MRD1 and MRD2 were each analyzed for correlation (r) with changes in exophthalmolmetry. Student t test was performed for each comparison, and p values <0.05 were considered significant. RESULTS: The study included 91 patients, predominantly female (87%), with an average age of 52.02 ± 14.6 years. The mean baseline proptosis measurement was 21.8 ± 2.9 OD and 21.7 ± 3.3 OS. The average MRD1 was 5.5 ± 1.5 OD and 5.4 ± 1.7 OS, and the average MRD2 was 6.1 ± 1.1 OD and 6.2 ± 1.1 OS. The follow-up duration post-treatment was 37.5 ± 31.7 weeks. At first follow-up post-treatment, the mean change in proptosis, MRD1, and MRD2 were -2.6 ± 2.0 OD, -2.5 ± 2.1 OS, -0.8.5 ± 1.4 OD, -0.8 ± 1.0 OS, and -0.7 ± 0.9 OD, -0.8 ± 1.0 OS, respectively. Correlation analysis showed that proptosis reduction was positively correlated with MRD1 and MRD2 reduction at the first post-treatment follow-up (MRD1: r = 0.23, p value < 0.01; MRD2: r = 0.17, p = 0.03]. CONCLUSION: Teprotumumab treatment improves upper and lower eyelid retraction. The improvement in MRD correlated positively with proptosis reduction, indicating the influence of globe position on eyelid position.

Is Blepharoplasty Cost-effective? Utility Analysis of Dermatochalasis and Cost-effectiveness Analysis of Upper Eyelid Blepharoplasty.

PURPOSE: This cross-sectional prospective study measured utility values of upper eyelid dermatochalasis to quantify its impact on quality of life and assess cost-effectiveness of upper blepharoplasty. METHODS: Utility of dermatochalasis was assessed using the standard reference gamble and time trade-off methods, with dual anchor points of perfect eye function and perfect health. The utility value obtained was used to create a Markov model and run a cost-effectiveness analysis of blepharoplasty as a treatment for dermatochalasis while utilizing the societal perspective. RESULTS: One hundred three patients with dermatochalasis recruited from an urban outpatient ophthalmology clinic completed the utility survey. The authors determined utility values for dermatochalasis ranging from 0.74 to 0.92 depending on the measurement method (standard reference gamble/time trade-off) and anchor points. The cost-effectiveness analysis yielded an incremental cost-effectiveness ratio of $3,146 per quality-adjusted life year, well under the conventional willingness-to-pay threshold of $50,000 per quality-adjusted life year. Probabilistic sensitivity analysis with Monte Carlo simulation demonstrated that blepharoplasty would be cost-effective in 88.1% of cases at this willingness-to-pay threshold. CONCLUSIONS: Dermatochalasis has an impact on quality of life that is significantly associated with level of perceived functional impairment. Rising health care costs have underscored the importance of providing value-based treatment to patients, and the results of this study suggest that blepharoplasty is a cost-effective treatment option for symptomatic bilateral upper eyelid dermatochalasis.

Evaluating the Accuracy of ChatGPT and Google BARD in Fielding Oculoplastic Patient Queries: A Comparative Study on Artificial versus Human Intelligence.

PURPOSE: This study evaluates and compares the accuracy of responses from 2 artificial intelligence platforms to patients' oculoplastics-related questions. METHODS: Questions directed toward oculoplastic surgeons were collected, rephrased, and input independently into ChatGPT-3.5 and BARD chatbots, using the prompt: "As an oculoplastic surgeon, how can I respond to my patient's question?." Responses were independently evaluated by 4 experienced oculoplastic specialists as comprehensive, correct but inadequate, mixed correct and incorrect/outdated data, and completely incorrect. Additionally, the empathy level, length, and automated readability index of the responses were assessed. RESULTS: A total of 112 patient questions underwent evaluation. The rates of comprehensive, correct but inadequate, mixed, and completely incorrect answers for ChatGPT were 71.4%, 12.9%, 10.5%, and 5.1%, respectively, compared with 53.1%, 18.3%, 18.1%, and 10.5%, respectively, for BARD. ChatGPT showed more empathy (48.9%) than BARD (13.2%). All graders found that ChatGPT outperformed BARD in question categories of postoperative healing, medical eye conditions, and medications. Categorizing questions by anatomy, ChatGPT excelled in answering lacrimal questions (83.8%), while BARD performed best in the eyelid group (60.4%). ChatGPT's answers were longer and potentially more challenging to comprehend than BARD's. CONCLUSION: This study emphasizes the promising role of artificial intelligence-powered chatbots in oculoplastic patient education and support. With continued development, these chatbots may potentially assist physicians and offer patients accurate information, ultimately contributing to improved patient care while alleviating surgeon burnout. However, it is crucial to highlight that artificial intelligence may be good at answering questions, but physician oversight remains essential to ensure the highest standard of care and address complex medical cases.

Reconstruction of Full-Thickness Eyelid Defects Following Tumor Resection: The Bucket Handle Modification.

PURPOSE: To describe a modified approach for full-thickness lower eyelid defect reconstruction. METHODS: This is a retrospective review of 5 patients with large full-thickness lower eyelid defects after tumor resection requiring reconstruction. For these lower eyelid defects, a lateral-based or superior-based tarsoconjunctival pedicle flap from the upper eyelid was used to rebuild the posterior lamella. In all cases, the anterior lamella was supplied from an adjacent myocutaneous flap in a bucket handle configuration. Data collection included tumor type and location, size of eyelid defect, presence of canalicular involvement, postoperative eyelid position, patient satisfaction, and complication rates. RESULTS: Five eyelids of 5 patients underwent Mohs micrographic excision of basal cell carcinoma followed by reconstruction with a bucket handle flap. Age range was 68 to 96 years old (mean of 81 y). Five patients presented with lower eyelid involvement. The defect size ranged from 80% to 100% of the eyelid. Three patients had canalicular involvement and required bicanalicular nasolacrimal stent placement. After reconstruction, all patients showed good eyelid apposition to the globe with excellent esthetic outcome. No revision procedures were done. Average follow-up time was 13 months (range of 8 to 21 mo). CONCLUSION: The bucket handle flap for full-thickness eyelid reconstruction is a simple technique that allows for preservation of all anatomical layers of the anterior lamella. This technique shows promising functional and esthetic outcomes.

Exploring the Molecular Tumor Microenvironment and Translational Biomarkers in Brain Metastases of Non-Small-Cell Lung Cancer.

Brain metastases represent a significant clinical challenge in the treatment of non-small-cell lung cancer (NSCLC), often leading to a severe decline in patient prognosis and survival. Recent advances in imaging and systemic treatments have increased the detection rates of brain metastases, yet clinical outcomes remain dismal due to the complexity of the metastatic tumor microenvironment (TME) and the lack of specific biomarkers for early detection and targeted therapy. The intricate interplay between NSCLC tumor cells and the surrounding TME in brain metastases is pivotal, influencing tumor progression, immune evasion, and response to therapy. This underscores the necessity for a deeper understanding of the molecular underpinnings of brain metastases, tumor microenvironment, and the identification of actionable biomarkers that can inform multimodal treatment approaches. The goal of this review is to synthesize current insights into the TME and elucidate molecular mechanisms in NSCLC brain metastases. Furthermore, we will explore the promising horizon of emerging biomarkers, both tissue- and liquid-based, that hold the potential to radically transform the treatment strategies and the enhancement of patient outcomes.

A comparison of proptosis reduction with teprotumumab versus surgical decompression based on fat-to-muscle ratio in thyroid eye disease.

PURPOSE: To explore if orbital fat-to-muscle ratio (FMR) is predictive of whether surgical decompression or teprotumumab leads to greater proptosis reduction in thyroid eye disease (TED). METHODS: A single-center retrospective cohort study comparing surgical decompression with teprotumumab according to FMR. All TED patients completing an 8-dose course of teprotumumab between January 2020 and September 2022 and all patients undergoing bony orbital decompression from January 2017 to December 2019 were included. Subjects were excluded if they were <18 years, received both surgical decompression and teprotumumab, or lacked orbital imaging. The primary exposure variable was teprotumumab or surgical decompression. The secondary exposure variable was baseline FMR. The primary outcome measure was change in proptosis (mm). RESULTS: Thirty-eight patients, mean age 53.5 years (±11.4), were included in the teprotumumab group and 160 patients, mean age 48 years (±11.1), in the surgical group. Average proptosis reduction after teprotumumab and surgical decompression was 3 mm (±1.44) and 5 mm (±1.75), respectively. The FMR was stratified at the median of 1.80. In subjects with FMR < 1.80, teprotumumab showed equivalent proptosis reduction compared to surgical decompression, -0.33 mm (SE 1.32) p = .802. In subjects with FMR ≥ 1.80, surgical decompression led to significantly more proptosis reduction than teprotumumab, 3.01 mm (SE 0.54), p < .001. CONCLUSIONS: Baseline FMR can be used to counsel patients as to proptosis reduction with teprotumumab versus surgery. Subjects with low FMR obtain comparable proptosis reduction with teprotumumab or surgery, whereas high FMR is associated with more significant proptosis reduction following surgery over teprotumumab.

Transcutaneous retrobulbar amphotericin B for rhino-orbital-cerebral mucormycosis: a multi-center retrospective comparative study.

PURPOSE: To assess whether transcutaneous retrobulbar amphotericin B injections (TRAMB) reduce exenteration rate without increasing mortality in rhino-orbital-cerebral mucormycosis (ROCM). METHODS: In this retrospective case-control study, 46 patients (51 eyes) with biopsy-proven ROCM were evaluated at 9 tertiary care institutions from 1998 to 2021. Patients were stratified by radiographic evidence of local orbital versus extensive involvement at presentation. Extensive involvement was defined by MRI or CT evidence of abnormal or loss of contrast enhancement of the orbital apex with or without cavernous sinus, bilateral orbital, or intracranial extension. Cases (+TRAMB) received TRAMB as adjunctive therapy while controls (-TRAMB) did not. Patient survival, globe survival, and vision/motility loss were compared between +TRAMB and -TRAMB groups. A generalized linear mixed effects model including demographic and clinical covariates was used to evaluate the impact of TRAMB on orbital exenteration and disease-specific mortality. RESULTS: Among eyes with local orbital involvement, exenteration was significantly lower in the +TRAMB group (1/8) versus -TRAMB (8/14) (p = 0.04). No significant difference in mortality was observed between the ±TRAMB groups. Among eyes with extensive involvement, there was no significant difference in exenteration or mortality rates between the ±TRAMB groups. Across all eyes, the number of TRAMB injections correlated with a statistically significant decreased rate of exenteration (p = 0.048); there was no correlation with mortality. CONCLUSIONS: Patients with ROCM with local orbital involvement treated with adjunctive TRAMB demonstrated a lower exenteration rate and no increased risk of mortality. For extensive involvement, adjunctive TRAMB does not improve or worsen these outcomes.

Successful Treatment of Prolonged, Severe Coronavirus Disease 2019 Lower Respiratory Tract Disease in a B cell Acute Lymphoblastic Leukemia Patient With an Extended Course of Remdesivir and Nirmatrelvir/Ritonavir.

A patient with B-cell acute lymphoblastic leukemia (ALL) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had persistent, progressive pneumonia with viremia after 5 months of infection despite monoclonal antibodies, intravenous (IV) remdesivir and prolonged oral steroids. Twenty days of nirmatrelvir/ritonavir and 10 days of IV remdesivir led to full recovery.

Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review.

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections.

The parasitophorous vacuole membrane of Toxoplasma gondii is targeted for disruption by ubiquitin-like conjugation systems of autophagy.

Autophagy is a lysosomal degradation pathway that is important in cellular homeostasis. Prior work showed a key role for the autophagy related 5 (Atg5) in resistance to Toxoplasma gondii. Here we show that the cassette of autophagy proteins involved in the conjugation of microtubule-associated protein 1 light chain 3 (LC3) to phosphatidylethanolamine, including Atg7, Atg3, and the Atg12-Atg5-Atg16L1 complex play crucial roles in the control of T. gondii in vitro and in vivo. In contrast, pharmacologic modulation of the degradative autophagy pathway or genetic deletion of other essential autophagy genes had no substantial effects. Rather the conjugation system was required for targeting of LC3 and interferon-γ effectors onto the vacuolar membrane of T. gondii and its consequent disruption. These data suggest that the ubiquitin-like conjugation systems that reorganize intracellular membranes during canonical autophagy are necessary for proper targeting of immune effectors to the intracellular vacuole membranes utilized by pathogens.

Interrater reliability of motor severity scales for hemifacial spasm.

To compare the inter-rater reliability (IRR) of five clinical rating scales for video-based assessment of hemifacial spasm (HFS) motor severity. We evaluated the video recordings of 45 HFS participants recruited through the Dystonia Coalition. In Round 1, six clinicians with expertise in HFS assessed the participants' motor severity with five scales used to measure motor severity of HFS: the Jankovic rating scale (JRS), Hemifacial Spasm Grading Scale (HSGS), Samsung Medical Center (SMC) grading system for severity of HFS spasms (Lee's scale), clinical grading of spasm intensity (Chen's scale), and a modified version of the Abnormal Involuntary Movement Scale (Tunc's scale). In Round 2, clinicians rated the same cohort with simplified scale wording after consensus training. For each round, we evaluated the IRR using the intraclass correlation coefficient [ICC (2,1) single-rater, absolute-agreement, 2-way random model]. The scales exhibited IRR that ranged from "poor" to "moderate"; the mean ICCs were 0.41, 0.43, 0.47, 0.43, and 0.65 for the JRS, HSGS, Lee's, Chen's, and Tunc's scales, respectively, for Round 1. In Round 2, the corresponding IRRs increased to 0.63, 0.60, 0.59, 0.53, and 0.71. In both rounds, Tunc's scale exhibited the highest IRR. For clinical assessments of HFS motor severity based on video observations, we recommend using Tunc's scale because of its comparative reliability and because clinicians interpret the scale easily without modifications or the need for consensus training.

Low-rank latent matrix-factor prediction modeling for generalized high-dimensional matrix-variate regression.

Motivated by diagnosing the COVID-19 disease using two-dimensional (2D) image biomarkers from computed tomography (CT) scans, we propose a novel latent matrix-factor regression model to predict responses that may come from an exponential distribution family, where covariates include high-dimensional matrix-variate biomarkers. A latent generalized matrix regression (LaGMaR) is formulated, where the latent predictor is a low-dimensional matrix factor score extracted from the low-rank signal of the matrix variate through a cutting-edge matrix factor model. Unlike the general spirit of penalizing vectorization plus the necessity of tuning parameters in the literature, instead, our prediction modeling in LaGMaR conducts dimension reduction that respects the geometric characteristic of intrinsic 2D structure of the matrix covariate and thus avoids iteration. This greatly relieves the computation burden, and meanwhile maintains structural information so that the latent matrix factor feature can perfectly replace the intractable matrix-variate owing to high-dimensionality. The estimation procedure of LaGMaR is subtly derived by transforming the bilinear form matrix factor model onto a high-dimensional vector factor model, so that the method of principle components can be applied. We establish bilinear-form consistency of the estimated matrix coefficient of the latent predictor and consistency of prediction. The proposed approach can be implemented conveniently. Through simulation experiments, the prediction capability of LaGMaR is shown to outperform some existing penalized methods under diverse scenarios of generalized matrix regressions. Through the application to a real COVID-19 dataset, the proposed approach is shown to predict efficiently the COVID-19.

Antimicrobials in patients with hematologic malignancies and recipients of hematopoietic cell transplantation and other cellular therapies.

BACKGROUND: Appropriate use of antimicrobials for hematologic malignancy, hematopoietic stem cell transplant recipients, and other cellular therapies is vital, with infection causing significant morbidity and mortality in this unique population of immunocompromised hosts. However, often in this population the choice and management of antimicrobial therapy is complex. When selecting an antimicrobial agent, key considerations include the need for dose adjustments due to renal or hepatic impairment, managing drug interactions, the potential for additive drug toxicity among those receiving polypharmacy and therapeutic drug monitoring. Other factors include leveraging pharmacodynamic principles to enable optimization of directed therapy against challenging pathogens, as well as judicious use of antimicrobials to limit drug resistance and adverse drug reactions. SUMMARY: This review summarizes the clinical considerations for commonly used antimicrobials in this setting, including antibacterial, antiviral, and antifungal agents.