Beta-Band power modulation in the human amygdala differentiates between go/no-go responses in an arm reaching task.

Introduction Traditionally known for its involvement in emotional processing, the amygdala's involvement in motor control remains relatively unexplored, with sparse investigation into the neural mechanisms governing amygdaloid motor movement and inhibition. Objective This study aimed to characterize the amygdaloid beta-band (13-30 Hz) power between "Go" and "No-go" trials of an arm reaching task. Methods Ten participants with drug-resistant epilepsy implanted with stereoelectroencephalographic (SEEG) electrodes in the amygdala were enrolled in this study. SEEG data was recorded throughout discrete phases of a Direct Reach Go/No-go task, during which participants reached a touchscreen monitor or withheld movement based on a colored cue. Multitaper power analysis along with Wilcoxon signed-rank and Yates-corrected Z tests were used to assess significant modulations of beta power between the Response and Fixation (baseline) phases in the "Go" and "No-go" conditions. Results In the "Go" condition, nine out of the ten participants showed a significant decrease in relative beta-band power during the Response phase (p ≤ 0.0499). In the "No-go" condition, eight out of the ten participants presented a statistically significant increase in relative beta-band power during the Response phase (p ≤ 0.0494). Four out of the eight participants with electrodes in the contralateral hemisphere and seven out of the eight participants with electrodes in the ipsilateral hemisphere presented significant modulation in beta-band power in both the "Go" and "No-go" conditions. At the group level, no significant differences were found between the contralateral and ipsilateral sides or between genders. Conclusion This study reports beta-band power modulation in the human amygdala during voluntary movement in the setting of motor execution and inhibition. This finding supplements prior research in various brain regions associating beta-band power with motor control. The distinct beta-power modulation observed between these response conditions suggests involvement of amygdaloid oscillations in differentiating between motor inhibition and execution.

Adverse Childhood Experiences (ACEs) in Unhoused Children Increase Odds of Psychiatric Illness, Physical Illness, and Psychiatric Admission.

Unhoused children and adolescents have high rates of adverse childhood experiences (ACEs). The objective of this study was to characterize a large cohort of unhoused children and investigate rates of psychiatric diagnoses, medical diagnoses, and utilization of emergency department (ED) resources depending on the presence of additional documented ACEs. A retrospective cohort of all unhoused children who presented to the ED of a large Midwestern health system from January 2014 to July 2019 were included. Unhoused status was determined by address field or ICD-10 code for homelessness (Z59.0). Demographics and ED visits were extracted from the electronic health record. Past medical history, ACEs, chief complaint (CC), length of stay (LOS), imaging, and labs were extracted by chart review. T-tests, chi square tests, and Fisher's exact tests were completed for each sub-analysis. Unhoused children with at least one additional ACE had higher odds of the following psychiatric disorders: depression (OR = 5.2, 95% CI = 3.4- 7.9), anxiety (OR = 3.4, 95% CI = 32.1-5.5), behavioral disorder (OR = 7.2, 95% CI = 35.1- 10.4), psychoses (OR = 6.0, 1.9-18.4), bipolar disorder (OR = 19.8, 95% CI = 34.6-84.9), suicidal ideation (OR = 8.0, 95% CI = 34.8-13.4), post-traumatic stress disorder (OR = 10.1, 95% CI = 35.4-18.6), and attention deficit hyperactive disorder (OR = 4.1, 3.0-5.7). Patients with additional documented ACEs were also more likely to have a prior psychiatric admission (p < 0.001). Unhoused children and adolescents with exposure to additional documented ACEs are more likely to have some serious psychiatric and medical diagnoses compared to other unhoused children.

Two risk assessments: Evaluating the use of indicator HF183 Bacteroides versus pathogen measurements for modelling recreational illness risks in an urban watershed.

The purpose of this study was to evaluate the performance of HF183 Bacteroides for estimating pathogen exposures during recreational water activities. We compared the use of Bacteroides-based exposure assessment to exposure assessment that relied on pathogen measurements. We considered two types of recreational water sites: those impacted by combined sewer overflows (CSOs) and those not impacted by CSOs. Samples from CSO-impacted and non-CSO-impacted urban creeks were analysed by quantitative polymerase chain reaction (qPCR) for HF183 Bacteroides and eight human gastrointestinal pathogens. Exposure assessment was conducted two ways for each type of site (CSO-impacted vs. non-CSO impacted): 1) by estimating pathogen concentrations from HF183 Bacteroides concentrations using published ratios of HF183 to pathogens in sewage and 2) by estimating pathogen concentrations from qPCR measurements. QMRA (quantitative microbial risk assessment) was then conducted for swimming, wading, and fishing exposures. Overall, mean risk estimates varied from 0.27 to 53 illnesses per 1,000 recreators depending on exposure assessment, site, activity, and norovirus dose-response model. HF183-based exposure assessment identified CSO-impacted sites as higher risk, and the recommended HF183 risk-based threshold of 525 genomic copies per 100 mL was generally protective of public health at the CSO-impacted sites but was not as protective at the non-CSO-impacted sites. In the context of our urban watershed, HF183-based exposure assessment over- and under-estimated risk relative to exposure assessment based on pathogen measurements, and the etiology of predicted pathogen-specific illnesses differed significantly. Across all sites, the HF183 model overestimated risk for norovirus, adenovirus, and Campylobacter jejuni, and it underestimated risk for E. coli and Cryptosporidium. To our knowledge, this study is the first to directly compare health risk estimates using HF183 and empirical pathogen measurements from the same waterways. Our work highlights the importance of site-specific hazard identification and exposure assessment to decide whether HF183 is applicable for monitoring risk.

Electrochemical Generation of Hydroxide and Hydrogen Peroxide for Hydrolysis of Sulfuryl Fluoride Fumigant.

The post-harvest fumigant, sulfuryl fluoride (SO2F2), is a >1000-fold more potent greenhouse gas than carbon dioxide and methane. Pilot studies have shown that SO2F2 fumes vented from fumigation chambers can be captured and hydrolyzed by hydroxide (OH-) and hydrogen peroxide (H2O2) at pH ∼ 12 in a scrubber, producing SO42- and F- as waste salts. To reduce the costs and challenges associated with purchasing and mixing these reagents onsite, this study evaluates the electrochemical generation of OH- and H2O2 within spent scrubbing solution, taking advantage of the waste SO42- and F- as free sources of electrolyte. The study used a gas diffusion electrode constructed from carbon paper coated with carbon black as a catalyst selective for the reduction of O2 to H2O2. Under galvanostatic conditions, the study evaluated the effect of electrochemical conditions, including applied cathodic current density and electrolyte strength. Within an electrolyte containing 200 mM SO42- and 400 mM F-, comparable to the waste salts generated by a SO2F2 scrubbing event, the system produced 250 mM H2O2 at pH 12.6 within 4 h with a Faradaic efficiency of 98.8% for O2 reduction to H2O2. In a scrubbing-water sample from lab-scale fumigation, the system generated ∼200 mM H2O2 at pH 13.5 within 4 h with a Faradaic efficiency of 75.6%. A comparison of the costs to purchase NaOH and H2O2 against the electricity costs for electrochemical treatment indicated that the electrochemical approach could be 38-71% lower, depending on the local cost of electricity.

CUL-6/cullin ubiquitin ligase-mediated degradation of HSP-90 by intestinal lysosomes promotes thermotolerance.

Heat shock can be a lethal stressor. Previously, we described a CUL-6/cullin-ring ubiquitin ligase complex in the nematode Caenorhabditis elegans that is induced by intracellular intestinal infection and proteotoxic stress and that promotes improved survival upon heat shock (thermotolerance). Here, we show that CUL-6 promotes thermotolerance by targeting the heat shock protein HSP-90 for degradation. We show that CUL-6-mediated lowering of HSP-90 protein levels, specifically in the intestine, improves thermotolerance. Furthermore, we show that lysosomal function is required for CUL-6-mediated promotion of thermotolerance and that CUL-6 directs HSP-90 to lysosome-related organelles upon heat shock. Altogether, these results indicate that a CUL-6 ubiquitin ligase promotes organismal survival upon heat shock by promoting HSP-90 degradation in intestinal lysosomes. Thus, HSP-90, a protein commonly associated with protection against heat shock and promoting degradation of other proteins, is itself degraded to protect against heat shock.

Isolated Retinal Neovascularization in Retinopathy of Prematurity: Clinical Associations and Prognostic Implications.

OBJECTIVE: Isolated retinal neovascularization (IRNV) is a common finding in patients with stage 2 and 3 retinopathy of prematurity (ROP). This study aimed to further classify the clinical course and significance of these lesions (previously described as "popcorn" based on clinical appearance) in patients with ROP as visualized with ultrawidefield OCT (UWF-OCT). DESIGN: Single center, retrospective case series. PARTICIPANTS: Images were collected from 136 babies in the Oregon Health and Science University neonatal intensive care unit. METHODS: A prototype UWF-OCT device captured en face scans (>140°), which were reviewed for the presence of IRNV along with standard zone, stage, and plus classification. In a cross-sectional analysis we compared demographics and the clinical course of eyes with and without IRNV. Longitudinally, we compared ROP severity using a clinician-assigned vascular severity score (VSS) and compared the risk of progression among eyes with and without IRNV using multivariable logistic regression. MAIN OUTCOME MEASURES: Differences in clinical demographics and disease progression between patients with and without IRNV. RESULTS: Of the 136 patients, 60 developed stage 2 or worse ROP during their disease course, 22 of whom had IRNV visualized on UWF-OCT (37%). On average, patients with IRNV had lower birth weights (BWs) (660.1 vs. 916.8 g, P = 0.001), gestational age (GA) (24.9 vs. 26.1 weeks, P = 0.01), and were more likely to present with ROP in zone I (63.4% vs. 15.8%, P < 0.001). They were also more likely to progress to stage 3 (68.2% vs. 13.2%, P < 0.001) and receive treatment (54.5% vs. 15.8%, P = 0.002). Eyes with IRNV had a higher peak VSS (5.61 vs. 3.73, P < 0.001) and averaged a higher VSS throughout their disease course. On multivariable logistic regression, IRNV was independently associated with progression to stage 3 (P = 0.02) and requiring treatment (P = 0.03), controlling for GA, BW, and initial zone 1 disease. CONCLUSIONS: In this single center study, we found that IRNV occurs in higher risk babies and was an independent risk factor for ROP progression and treatment. These findings may have implications for OCT-based ROP classifications in the future. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Microsporidia: Pervasive natural pathogens of Caenorhabditis elegans and related nematodes.

The nematode Caenorhabditis elegans is an invaluable host model for studying infections caused by various pathogens, including microsporidia. Microsporidia represent the first natural pathogens identified in C. elegans, revealing the previously unknown Nematocida genus of microsporidia. Following this discovery, the utilization of nematodes as a model host has rapidly expanded our understanding of microsporidia biology and has provided key insights into the cell and molecular mechanisms of antimicrosporidia defenses. Here, we first review the isolation history, morphological characteristics, life cycles, tissue tropism, genetics, and host immune responses for the four most well-characterized Nematocida species that infect C. elegans. We then highlight additional examples of microsporidia that infect related terrestrial and aquatic nematodes, including parasitic nematodes. To conclude, we assess exciting potential applications of the nematode-microsporidia system while addressing the technical advances necessary to facilitate future growth in this field.

The interactive effect of sustained sleep restriction and resistance exercise on skeletal muscle transcriptomics in young females.

INTRODUCTION: Both sleep loss and exercise regulate gene expression in skeletal muscle, yet little is known about how the interaction of these stressors affects the muscle transcriptome. The aim of this study was to investigate the effect of nine nights of sleep restriction, with repeated resistance exercise (REx) sessions, on the skeletal muscle transcriptome of young, trained females. METHODS: Ten healthy females aged 18-35 years undertook a randomised cross-over study of nine nights' sleep restriction (SR; 5-h time in bed) and normal sleep (NS; ≥7 h time in bed) with a minimum 6-week washout. Participants completed four REx sessions per condition (day 3, 5, 7 and 9). Muscle biopsies were collected both pre- and post-REx on days 3 and 9. Gene and protein expression were assessed by RNA sequencing and Western Blot, respectively. RESULTS: Three or nine nights of sleep restriction had no effect on the muscle transcriptome independently of exercise. However, close to 3000 transcripts were differentially regulated (FDR < 0.05) 48 h post the completion of three resistance exercise sessions in both NS and SR conditions. Only 39% of downregulated and 18% of upregulated genes were common between both conditions, indicating a moderating effect of sleep restriction on the response to exercise. CONCLUSION: Sleep restriction and resistance exercise interacted to alter the enrichment of skeletal muscle transcriptomic pathways in young, resistance-trained females. Performing exercise when sleep restricted may not provide the same adaptive response for individuals as if they were fully rested.

Response- and Progression-Based End Points in Trial and Observational Cohorts of Patients With NSCLC.

Importance: Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to assess therapeutic response in clinical trials but not in routine care; thus, RECIST-based end points are difficult to include in observational studies. Clinician-anchored approaches for measuring clinical response have been validated but not widely compared with clinical trial data, limiting their use as evidence for clinical decision-making. Objective: To compare response- and progression-based end points in clinical trial and observational cohorts of patients with non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This retrospective cohort study used patient-level data from the IMpower132 trial (conducted April 7, 2016, to May 31, 2017) and a nationwide electronic health record (EHR)-derived deidentified database (data collected January 1, 2011, to March 31, 2022). Patients in the observational cohort were selected according to the inclusion and exclusion criteria of the IMpower132 trial. All patients in the observational cohort had stage IV NSCLC. Exposure: All patients were randomized to or received first-line carboplatin or cisplatin plus pemetrexed. Main Outcomes and Measures: End points included response rates, duration of response, and progression-free survival, compared between the trial and observational cohorts before and after weighting. Response rates for the observational cohort were derived from the EHR. Results: A total of 769 patients met inclusion criteria, 494 in the observational cohort (median [IQR] age, 67 [60-74] years; 228 [46.2%] female; 45 [9.1%] Black or African American; 352 [71.3%] White; 53 [10.7%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial) and 275 in the trial cohort (median [IQR] age, 63 [56-68] years; 90 [32.7%] female; 4 [1.5%] Black or African American; 194 [70.5%] White; 65 [23.6%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial). All 3 end points were comparable between the study cohorts. Trial patients had a higher number of response assessments compared with patients in the weighted observational cohort. The EHR-derived response rate was numerically higher than the objective response rate after weighting (100.3 of 249.3 [40.2%] vs 105 of 275 [38.2%]) due to higher rates of observed partial response than RECIST-based partial response. Among patients with at least 1 response assessment, the EHR-derived response rate remained higher than the objective response rate (100.3 of 193.4 [51.9%] vs 105 of 256 [41.0%]) due to a higher proportion of patients in the observational cohort with no response assessment. Conclusions and Relevance: In this study, response- and progression-based end points were similar between clinical trial and weighted observational cohorts, which increases confidence in the reliability of observational end points and can inform their interpretation in relation to trial end points. Additionally, the difference observed in response rates (including vs excluding patients with no response assessment) highlights the importance of future research adopting this 2-way approach when evaluating the relationship of EHR-derived and objective response rates.

Microenvironmental reorganization in brain tumors following radiotherapy and recurrence revealed by hyperplexed immunofluorescence imaging.

The tumor microenvironment plays a crucial role in determining response to treatment. This involves a series of interconnected changes in the cellular landscape, spatial organization, and extracellular matrix composition. However, assessing these alterations simultaneously is challenging from a spatial perspective, due to the limitations of current high-dimensional imaging techniques and the extent of intratumoral heterogeneity over large lesion areas. In this study, we introduce a spatial proteomic workflow termed Hyperplexed Immunofluorescence Imaging (HIFI) that overcomes these limitations. HIFI allows for the simultaneous analysis of > 45 markers in fragile tissue sections at high magnification, using a cost-effective high-throughput workflow. We integrate HIFI with machine learning feature detection, graph-based network analysis, and cluster-based neighborhood analysis to analyze the microenvironment response to radiation therapy in a preclinical model of glioblastoma, and compare this response to a mouse model of breast-to-brain metastasis. Here we show that glioblastomas undergo extensive spatial reorganization of immune cell populations and structural architecture in response to treatment, while brain metastases show no comparable reorganization. Our integrated spatial analyses reveal highly divergent responses to radiation therapy between brain tumor models, despite equivalent radiotherapy benefit.

Understanding the human conflict processing network: A review of the literature on direct neural recordings during performance of a modified stroop task.

The Stroop Task is a well-known neuropsychological task developed to investigate conflict processing in the human brain. Our group has utilized direct intracranial neural recordings in various brain regions during performance of a modified color-word Stroop Task to gain a mechanistic understanding of non-emotional human conflict processing. The purpose of this review article is to: 1) synthesize our own studies into a model of human conflict processing, 2) review the current literature on the Stroop Task and other conflict tasks to put our research in context, and 3) describe how these studies define a network in conflict processing. The figures presented are reprinted from our prior publications and key publications referenced in the manuscript. We summarize all studies to date that employ invasive intracranial recordings in humans during performance of conflict-inducing tasks. For our own studies, we analyzed local field potentials (LFPs) from patients with implanted stereotactic electroencephalography (SEEG) electrodes, and we observed intracortical oscillation patterns as well as intercortical temporal relationships in the hippocampus, amygdala, and orbitofrontal cortex (OFC) during the cue-processing phase of a modified Stroop Task. Our findings suggest that non-emotional human conflict processing involves modulation across multiple frequency bands within and between brain structures.

Carbon dioxide shapes parasite-host interactions in a human-infective nematode.

Skin-penetrating nematodes infect nearly one billion people worldwide. The developmentally arrested infective larvae (iL3s) seek out hosts, invade hosts via skin penetration, and resume development inside the host in a process called activation. Activated infective larvae (iL3as) traverse the host body, ending up as parasitic adults in the small intestine. Skin-penetrating nematodes respond to many chemosensory cues, but how chemosensation contributes to host seeking, intra-host development, and intra-host navigation - three crucial steps of the parasite-host interaction - remains poorly understood. Here, we investigate the role of carbon dioxide (CO2) in promoting parasite-host interactions in the human-infective threadworm Strongyloides stercoralis. We show that S. stercoralis exhibits life-stage-specific preferences for CO2: iL3s are repelled, non-infective larvae and adults are neutral, and iL3as are attracted. CO2 repulsion in iL3s may prime them for host seeking by stimulating dispersal from host feces, while CO2 attraction in iL3as may direct worms toward high-CO2 areas of the body such as the lungs and intestine. We also identify sensory neurons that detect CO2; these neurons are depolarized by CO2 in iL3s and iL3as. In addition, we demonstrate that the receptor guanylate cyclase Ss-GCY-9 is expressed specifically in CO2-sensing neurons and is required for CO2-evoked behavior. Ss-GCY-9 also promotes activation, indicating that a single receptor can mediate both behavioral and physiological responses to CO2. Our results illuminate chemosensory mechanisms that shape the interaction between parasitic nematodes and their human hosts and may aid in the design of novel anthelmintics that target the CO2-sensing pathway.

Total fermentable oligo-, di-, monosaccharides and polyols intake, carbohydrate malabsorption and gastrointestinal symptoms during a 56 km trail ultramarathon event.

AIMS: To explore the relationship between nutritional intake, fermentable oligo-, di, monosaccharides and polyols, and carbohydrate malabsorption, with gastrointestinal symptoms during a 56 km trail ultramarathon event and identify differences in nutritional intake between runners with severe and non-severe gastrointestinal symptoms. METHODS: Forty-four ultramarathoners recorded and self-reported dietary intake 3 days before, morning of, and during the ultramarathon with gastrointestinal symptoms obtained retrospectively and nutrient analysis via FoodWorks. Carbohydrate malabsorption was determined via breath hydrogen content pre- and post-race. Spearman's rank-order and Mann-Whitney U-tests were used to identify relationships and differences between groups. RESULTS: Total fermentable oligo-, di, monosaccharides and polyols intake were not associated with gastrointestinal symptoms, but weak associations were observed for lower energy (rs = -0.302, p = 0.044) and fat intake (rs = -0.340, p = 0.024) 3 days before with upper gastrointestinal symptoms and higher caffeine intake 3 days before with overall gastrointestinal symptoms (rs = 0.314, p = 0.038). Total fermentable oligo-, di-, monosaccharides and polyols intake and breath hydrogen were not different between those with severe versus non-severe symptoms (p > 0.05). Although those with severe symptoms had higher caffeine (p = 0.032), and total polyols intake (p = 0.031) 3 days before, and higher % energy from fat (p = 0.043) and sorbitol intake (p = 0.026) during the race, and slower ultramarathon finish times (p = 0.042). CONCLUSION: Total fermentable oligo-, di-, and monosaccharides intake and carbohydrate malabsorption were not associated with gastrointestinal symptoms. Additional research on the effect of fat, caffeine, and polyol intake on exercise-associated gastrointestinal symptoms is warranted and presents new nutritional areas for consideration when planning nutritional intake for ultramarathoners.

Maple samara flight is robust to morphological perturbation and united by a classic drag model.

Winged, autorotating seeds from the genus Acer, have been the subject of study for botanists and aerodynamicists for decades. Despite this attention and the relative simplicity of these winged seeds, there are still considerable gaps in our understanding of how samara dynamics are informed by morphological features. Additionally, questions remain regarding the robustness of their dynamics to morphological alterations such as mass change by moisture or area change by damage. We here challenge the conventional approach of using wing-loading correlations and instead demonstrate the superiority of a classical aerodynamic model. Using allometry, we determine why some species deviate from interspecific aerodynamic behavior. We alter samara mass and wing area and measure corresponding changes to descent velocity, rotation rate, and coning angle, thereby demonstrating their remarkable ability to autorotate despite significant morphological alteration. Samaras endure mass changes greater than 100% while maintaining descent velocity changes of less than 15%, and are thus robust to changes in mass by moisture or damage. Additionally, samaras withstand up to a 40% reduction in wing area before losing their ability to autorotate, with the largest wings more robust to ablation. Thus, samaras are also robust to wing damage in their environment, a fact children joyfully exploit.

Abiotic Small Molecule Inhibitors and Activators of the LasR Quorum Sensing Receptor in Pseudomonas aeruginosa with Potencies Comparable or Surpassing N-Acyl Homoserine Lactones.

The opportunistic pathogen Pseudomonas aeruginosa controls almost 10% of its genome, including myriad virulence genes, via a cell-to-cell chemical communication system called quorum sensing (QS). Small molecules that either inhibit or activate QS in P. aeruginosa represent useful research tools to study the role of this signaling pathway in infection and interrogate its viability as an antivirulence target. However, despite active research in this area over the past 20+ years, there are relatively few synthetic compounds known to strongly inhibit or activate QS in P. aeruginosa. Most reported QS modulators in this pathogen are of low potency or have structural liabilities that limit their application in biologically relevant environments such as mimics of the native N-acyl l-homoserine lactone (AHL) signals. Here, we report the results of a high-throughput screen for abiotic small molecules that target LasR, a key QS regulator in P. aeruginosa. We screened a 25,000-compound library and discovered four new structural classes of abiotic LasR modulators. These compounds include antagonists that surpass the potency of all known AHL-type compounds and mimetics thereof, along with an agonist with potency approaching that of LasR's native ligand. The novel structures of this compound set, along with their anticipated robust physicochemical profiles, underscore their potential value as probe molecules to interrogate the roles of QS in this formidable pathogen.

Proteasome inhibition triggers tissue-specific immune responses against different pathogens in C. elegans.

Protein quality control pathways play important roles in resistance against pathogen infection. For example, the conserved transcription factor SKN-1/NRF up-regulates proteostasis capacity after blockade of the proteasome and also promotes resistance against bacterial infection in the nematode Caenorhabditis elegans. SKN-1/NRF has 3 isoforms, and the SKN-1A/NRF1 isoform, in particular, regulates proteasomal gene expression upon proteasome dysfunction as part of a conserved bounce-back response. We report here that, in contrast to the previously reported role of SKN-1 in promoting resistance against bacterial infection, loss-of-function mutants in skn-1a and its activating enzymes ddi-1 and png-1 show constitutive expression of immune response programs against natural eukaryotic pathogens of C. elegans. These programs are the oomycete recognition response (ORR), which promotes resistance against oomycetes that infect through the epidermis, and the intracellular pathogen response (IPR), which promotes resistance against intestine-infecting microsporidia. Consequently, skn-1a mutants show increased resistance to both oomycete and microsporidia infections. We also report that almost all ORR/IPR genes induced in common between these programs are regulated by the proteasome and interestingly, specific ORR/IPR genes can be induced in distinct tissues depending on the exact trigger. Furthermore, we show that increasing proteasome function significantly reduces oomycete-mediated induction of multiple ORR markers. Altogether, our findings demonstrate that proteasome regulation keeps innate immune responses in check in a tissue-specific manner against natural eukaryotic pathogens of the C. elegans epidermis and intestine.

Feasibility of same-day discharge of robotic-assisted laparoscopic radical prostatectomy with pelvic lymph node dissection.

PURPOSE: Prostate cancer is one of the most common oncologic diseases. Outpatient robotic-assisted laparoscopic radical prostatectomy (RALP) has gained popularity due to its ability to minimize patient costs while maintaining low complication rates. Few studies have analyzed the possibility of performing outpatient RALP specifically in patients undergoing concurrent pelvic lymph node dissections (PLND). METHODS: Using the National Surgical Quality Improvement Program Database (NSQIP), we identified total number of RALP, stratified into inpatient and outpatient groups including those with and without PLND from 2016 to 2021. Baseline characteristics, intraoperative and postoperative complications, and unplanned readmission rates were summarized. Proportions of outpatient procedures were calculated to assess adoption of outpatient protocol. RESULTS: Between 2016 and 2021, a total of 58,527 RALP were performed, 3.7% (2142) outpatient and 96.3% inpatient. Altogether, patients undergoing outpatient RALP without PLND were more likely to have hypertension (52.6% vs. 46.3%, p < 0.01). Patients undergoing outpatient RALP without PLND were more likely to have sepsis or urinary tract infections (3.4% vs. 1.9%, p = 0.04) when compared to outpatient RALP with PLND. Cardiopulmonary, renal, thromboembolic complications, and 30-day events such as unplanned readmission, reoperation rates, and mortality were similar in both groups. However, among multivariate analysis regarding 30-day readmission and complications, there were no significant differences between outpatient RALP with or without PLND. CONCLUSION: Patients undergoing outpatient RALP without PLND were more likely to have baseline hypertension and higher rates of postoperative infection, when compared to outpatient RALP with PLND. No significant differences were seen regarding 30-day readmission or complications on multivariate analysis.

Chorioretinal Anastomosis and Retinal Detachment with Laser Photocoagulation Treated Incontinentia Pigmenti.

PURPOSE: To describe a case of incontinentia pigmenti in which chorioretinal anastomosis occurred after laser photocoagulation, which was ultimately complicated by tractional and rhegmatogenous detachment. METHODS: Observational case report. RESULTS: A 2-month-old was referred to ophthalmology for a rash characteristic of incontinentia pigmenti due to concern for ocular involvement and was found to have peripheral avascular retina with early neovascularization. Following several rounds of panretinal photocoagulation, a chorioretinal anastomosis was noted on follow up fluorescein angiography in the left eye. Subsequently, a tractional retinal detachment formed and was treated initially with a lens sparing pars plana vitrectomy, endolaser, and scleral buckle. Despite treatment, it progressed to a combined tractional/rhegmatogenous detachment and was deemed inoperable. CONCLUSION: Chorioretinal anastomosis is a rare complication of laser photocoagulation.

Development of non-sedating antischistosomal benzodiazepines.

The neglected tropical disease schistosomiasis infects over 200 million people worldwide and is treated with just one broad spectrum antiparasitic drug (praziquantel). Alternative drugs are needed in the event of emerging praziquantel resistance or treatment failure. One promising lead that has shown efficacy in animal models and a human clinical trial is the benzodiazepine meclonazepam, discovered by Roche in the 1970's. Meclonazepam was not brought to market because of dose-limiting sedative side effects. However, the human target of meclonazepam that causes sedation (GABAARs) are not orthologous to the parasite targets that cause worm death. Therefore, we were interested in whether the structure of meclonazepam could be modified to produce antiparasitic benzodiazepines that do not cause host sedation. We synthesized 18 meclonazepam derivatives with modifications at different positions on the benzodiazepine ring system and tested them for in vitro antiparasitic activity. This identified five compounds that progressed to in vivo screening in a murine model, two of which cured parasite infections with comparable potency to meclonazepam. When these two compounds were administered to mice that were run on the rotarod test, both were less sedating than meclonazepam. These findings demonstrate the proof of concept that meclonazepam analogs can be designed with an improved therapeutic index, and point to the C3 position of the benzodiazepine ring system as a logical site for further structure-activity exploration to further optimize this chemical series.