Microbiome signature suggestive of lactose-intolerance in rhesus macaques (Macaca mulatta) with intermittent chronic diarrhea.

BACKGROUND: Chronic diarrhea is a common cause of mortality and morbidity in captive rhesus macaques (Macaca mulatta). The exact etiology of chronic diarrhea in macaques remains unidentified. The occurrence of diarrhea is frequently linked to dysbiosis within the gut microbiome. Research into microbiome signatures correlated with diarrhea in macaques have predominantly been conducted with single sample collections. Our analysis was based on the metagenomic composition of longitudinally acquired fecal samples from rhesus macaques with chronic diarrhea and clinically healthy rhesus macaques that were obtained over the course of two years. We aimed to investigate potential relationships between the macaque gut microbiome, the presence of diarrhea and diet interventions with a selection of commercially available monkey diets. RESULTS: The microbiome signature of macaques with intermittent chronic diarrhea showed a significant increase in lactate producing bacteria e.g. lactobacilli, and an increase in fermenters of lactate and succinate. Strikingly, two lactose free diets were associated with a lower incidence of diarrhea. CONCLUSION: A lactose intolerance mechanism is suggested in these animals by the bloom of Lactobacillus in the presence of lactose resulting in an overproduction of intermediate fermentation products likely led to osmotically induced diarrhea. This study provides new insights into suspected microbiome-lactose intolerance relationship in rhesus macaques with intermittent chronic diarrhea. The integration of machine learning with metagenomic data analysis holds potential for developing targeted dietary interventions and therapeutic strategies and therefore ensuring a healthier and more resilient primate population.

High radiative forcing climate scenario relevance analyzed with a ten-million-member ensemble.

Developing future climate projections begins with choosing future emissions scenarios. While scenarios are often based on storylines, here instead we produce a probabilistic multi-million-member ensemble of radiative forcing trajectories to assess the relevance of future forcing thresholds. We coupled a probabilistic database of future greenhouse gas emission scenarios with a probabilistically calibrated reduced complexity climate model. In 2100, we project median forcings of 5.1 watt per square meters (5th to 95th percentiles of 3.3 to 7.1), with roughly 0.5% probability of exceeding 8.5 watt per square meters, and a 1% probability of being lower than 2.6 watt per square meters. Although the probability of 8.5 watt per square meters scenarios is low, our results support their continued utility for calibrating damage functions, characterizing climate in the 22nd century (the probability of exceeding 8.5 watt per square meters increases to about 7% by 2150), and assessing low-probability/high-impact futures.

A Novel Luciferase-Based Reporter Gene Technology for Simultaneous Optical and Radionuclide Imaging of Cells.

Multimodality reporter gene imaging combines the sensitivity, resolution and translational potential of two or more signals. The approach has not been widely adopted by the animal imaging community, mainly because its utility in this area is unproven. We developed a new complementation-based reporter gene system where the large component of split NanoLuc luciferase (LgBiT) presented on the surface of cells (TM-LgBiT) interacts with a radiotracer consisting of the high-affinity complementary HiBiT peptide labeled with a radionuclide. Radiotracer uptake could be imaged in mice using SPECT/CT and bioluminescence within two hours of implanting reporter-gene-expressing cells. Imaging data were validated by ex vivo biodistribution studies. Following the demonstration of complementation between the TM-LgBiT protein and HiBiT radiotracer, we validated the use of the technology in the highly specific in vivo multimodal imaging of cells. These findings highlight the potential of this new approach to facilitate the advancement of cell and gene therapies from bench to clinic.

Dreams interrupted: characteristics of REM sleep-associated seizures and status epilepticus.

STUDY OBJECTIVES: Seizures are rare in rapid eye movement sleep (REM). However; seizures sometimes occur in REM, and a small number of focal epilepsy patients display their maximum rate of interictal epileptiform discharges in REM. We sought to systematically identify and characterize seizures in REM. METHODS: We reviewed all admissions to the Epilepsy Monitoring Unit (EMU) at the Winnipeg Health Sciences Centre over 12-months in 2014-2015. American Academy of Sleep Medicine sleep-stage scoring was initially applied in the standard 30-second epochs. Then, to capture sudden changes in sleep-wake state on shorter timescales that are associated with seizure formation and propagation, we re-scored ictal and peri-ictal EEG epochs every 1 second. Patients found to have seizures in REM were subject to chart review spanning three years pre- and post-admission. RESULTS: REM seizures occurred in 3/63 EMU patients. Notably, one patient exhibited continuous epileptiform activity, consistent with focal nonconvulsive electrographic status epilepticus, throughout REM cycles for each night of her admission. Otherwise, discrete REM seizures constituted a small fraction of the other patients' total seizures (range 5.0-8.3%), occurred shortly after REM onset from non-REM 2, and were manifest as minor epileptic arousals. CONCLUSIONS: Our results confirm that REM seizures are rare, while highlighting outliers who widen the known spectrum of heterogeneous sleep effects on seizures/epilepsy. We also report the first case of paradoxical status epilepticus in REM.

Total Joint Arthroplasty in the Patient with Inflammatory Arthritis: A Review.

Inflammatory arthritis is a family of conditions including rheumatoid arthritis, juvenile inflammatory arthritis, and spondyloarthropathies affecting both the large and small joints. Total joint arthroplasty is commonly used for surgical management of end-stage disease. Preoperative and postoperative considerations as well as perioperative medical management and intraoperative treatment of patients with inflammatory arthritis undergoing total joint arthroplasty are reviewed. Although individualized, multidisciplinary approaches to treatment are necessary due to the complex nature of the disease and the varying levels of severity, patients generally have favorable outcomes with respect to pain scores and functional outcomes.

Follow-up of Cystic Pineal Glands in Retinoblastoma Patients Does Not Increase Detection of Pineal Trilateral Retinoblastoma.

PURPOSE: To evaluate the effectiveness of baseline screening and follow-up with magnetic resonance imaging (MRI) for detecting trilateral retinoblastoma (TRb) and assessing the risk of TRb development. DESIGN: Prospective multicenter cohort study. METHODS: A total of 607 retinoblastoma patients from 2012 through 2022 were included and followed up until September 1, 2023. At each center, a neuroradiologist categorized pineal glands on baseline and follow-up scans into 4 groups: (A) normal, (B) cystic gland, (C) suspicious gland, or (D) TRb. Different follow-up schedules were assigned to each category. Categories B and C were followed up with MRI after approximately 3 months and repeated 3 months later if suspicion remained. On each MRI, they measured the height and width, evaluated the aspect (solid, partly cystic, and completely cystic) of the pineal gland, and evaluated radiologic features suspicious of pineal TRb. The effectiveness of the current TRb screening method was assessed by evaluating its sensitivity and specificity to detect TRb. Determining the TRb incidence was a secondary outcome measure. RESULTS: Heritable retinoblastoma patients had a risk of 3.78% to develop TRb. One of 4 pineal TRbs was detected during a follow-up scan and 4 of 5 nonpineal TRbs were detected on the baseline MRI. Screening for pineal TRb had a sensitivity of 25% and specificity of 100%; for nonpineal TRb, the sensitivity was 80%. It required 494 follow-up scans to detect 1 pineal TRb. However, when restricting the follow-up to solely suspicious glands, only 22 scans were required to detect 1 pineal TRb. CONCLUSION: During extended follow-up after baseline MRI, only 1 pineal trilateral retinoblastoma was detected in our study. Follow-up after 3 months should be restricted to patients with a suspicious pineal gland defined as irregular thickening of the cyst wall (>2 mm), fine nodular aspect of the cyst wall, or when a solid or cystic gland exceeds the upper 99% prediction interval for size; patients with an unsuspicious cystic gland should not be followed up. Baseline MRI screening was able to detect most nonpineal trilateral retinoblastomas.

Case report: Treatment response of NF-1-associated bladder ganglioneuroma to trametinib.

We present the clinical course of a 4-year-old girl with neurofibromatosis type 1-associated, unresectable, symptomatic urinary bladder ganglioneuroma. She was initially trialed on sirolimus without response and subsequently responded to MEK inhibitor trametinib, with improvement clinically and radiographically over 10 months. This report broadens the repertoire of therapeutic strategies for MEK inhibition in diseases related to the MAPK pathway.

Co-shared genomic alterations within tumors from patients with both myeloproliferative neoplasms and lymphoma.

Not available.

Transcriptome-wide association study and Mendelian randomization in pancreatic cancer identifies susceptibility genes and causal relationships with type 2 diabetes and venous thromboembolism.

BACKGROUND: Two important questions regarding the genetics of pancreatic adenocarcinoma (PDAC) are 1. Which germline genetic variants influence the incidence of this cancer; and 2. Whether PDAC causally predisposes to associated non-malignant phenotypes, such as type 2 diabetes (T2D) and venous thromboembolism (VTE). METHODS: In this study of 8803 patients with PDAC and 67,523 controls, we first performed a large-scale transcriptome-wide association study to investigate the association between genetically determined gene expression in normal pancreas tissue and PDAC risk. Secondly, we used Mendelian Randomization (MR) to analyse the causal relationships among PDAC, T2D (74,124 cases and 824,006 controls) and VTE (30,234 cases and 172,122 controls). FINDINGS: Sixteen genes showed an association with PDAC risk (FDR <0.10), including six genes not yet reported for PDAC risk (PPIP5K2, TFR2, HNF4G, LRRC10B, PRC1 and FBXL20) and ten previously reported genes (INHBA, SMC2, ABO, PDX1, MTMR6, ACOT2, PGAP3, STARD3, GSDMB, ADAM33). MR provided support for a causal effect of PDAC on T2D using genetic instruments in the HNF4G and PDX1 loci, and unidirectional causality of VTE on PDAC involving the ABO locus (OR 2.12, P < 1e-7). No evidence of a causal effect of PDAC on VTE was found. INTERPRETATION: These analyses identified candidate susceptibility genes and disease relationships for PDAC that warrant further investigation. HNF4G and PDX1 may induce PDAC-associated diabetes, whereas ABO may induce the causative effect of VTE on PDAC. FUNDING: National Institutes of Health (USA).

An integrated analysis of bile acid metabolism in humans with severe obesity.

BACKGROUND AND AIMS: Bile acids (BA) are vital regulators of metabolism. BAs are AQ6 secreted in the small intestine, reabsorbed, and transported back to the liver, where they can modulate metabolic functions. There is a paucity of data regarding the portal BA composition in humans. This study aimed to address this knowledge gap by investigating portal BA composition and the relation with peripheral and fecal BA dynamics in conjunction with the gut microbiome. APPROACH AND RESULTS: Thirty-three individuals from the BARIA cohort were included. Portal plasma, peripheral plasma, and feces were collected. BA and C4 levels were measured employing mass spectrometry. FGF19 was measured using ELISA. Gut microbiota composition was determined through metagenomics analysis on stool samples. Considerable diversity in the portal BA composition was observed. The majority (n = 26) of individuals had a 9-fold higher portal than peripheral BA concentration. In contrast, 8 individuals showed lower portal BA concentration compared with peripheral and had higher levels of unconjugated and secondary BA in this compartment, suggesting more distal origin. The altered portal BA profile was associated with altered gut microbiota composition. In particular, taxa within Bacteroides were reduced in abundance in the feces of these individuals. CONCLUSIONS: Characterization of the portal BA composition in relation to peripheral and fecal BA increased insight into the dynamics of BA metabolism in individuals with obesity. Peripheral BA composition was much more diverse due to microbial metabolism. About 24% of the portal samples was surprisingly low in total BA; the underlying mechanism requires further exploration.

Linking nursing students' professional identity, clinical learning environment, financial incentives, and career opportunities with migration intent: Structural equation modeling.

AIMS: To investigate how nursing students' professional identity, clinical learning environment, financial incentives, and career opportunities influence their intention to migrate. BACKGROUND: There is a preponderance of studies about nurse migration and its impact on the global nursing workforce. However, a critical gap remains about nursing students' intentions to migrate, particularly among developing countries like the Philippines. METHODS: Using a cross-sectional design, third- and fourth-year nursing students (n = 316) from the largest comprehensive university in Manila were conveniently recruited. Data were collected from November to December 2023 using five validated self-report scales. Descriptive (e.g., mean, standard deviation) and inferential statistics (e.g., Spearman rho, covariance-based structural equation modeling) were used to analyze data. RESULTS: The emerging model demonstrated acceptable model fit indices. Nursing students' professional identity (ß = 0.18, p = 0.043) and financial incentives (ß = 0.10, p = 0.046) significantly and positively influence the intention to migrate. The satisfaction with future career opportunities (ß = -0.12, p = 0.038) and clinical learning environment perception (ß = -0.15, p = 0.048) negatively influence the intention to migrate. These four predictors accounted for 4.60% of the total variance of intention to migrate. CONCLUSION: Nursing students' professional identity and financial incentives directly impact intent to migrate, whereas future career opportunities satisfaction and clinical learning environment inversely affect intent to migrate. IMPLICATIONS FOR NURSING PRACTICE AND POLICY: This study underscores the imperative for nursing colleges and faculty to promote positive professional identity and provide a conducive clinical learning environment to develop sustainable nurses' migration policies.

Fractional-Order Robust Control Design under parametric uncertain approach.

This paper presents a novel methodology that combines fractional-order control theory with robust control under a parametric uncertainty approach to enhance the performance of linear time-invariant uncertain systems with integer or fractional order, referred to as Fractional-Order Robust Control (FORC). In contrast to traditional approaches, the proposed methodology introduces a novel formulation of inequalities-based design, thus expanding the potential for discovering improved solutions through linear programming optimization. As a result, fractional order controllers are designed to guarantee desired transient and steady-state performance in a closed-loop system. To enable the digital implementation of the designed controller, an impulse response invariant discretization of fractional-order differentiators (IRID-FOD) is employed to approximate the fractional-order controllers to an integer-order transfer function. Additionally, Hankel's reduction order method is applied, thus making it suitable for hardware deployment. Experimental tests carried out in a thermal system and the assessment results, based on time-domain responses and robustness analysis supported by performance indices and set value analysis in a thermal system test-bed, demonstrate the improved and robust performance of the proposed FORC methodology compared to classical robust control under parametric uncertainty.

The challenges of treating status epilepticus in rural Canada.

Though unified by challenges in the treatment of status epilepticus (SE), rural Canada is simultaneously massive and diverse, spanning the Pacific, Atlantic, and Arctic Oceans. According to the national statistical agency, the most rural jurisdiction in Canada is the Arctic territory of Nunavut. In particular, the Kivalliq region of Nunavut represents a unique epidemiologic SE space because any treatment beyond typical first-line lorazepam and second-line phenytoin by a non-neurologist locum tenens requires airborne evacuation over a thousand kilometers away to a single hospital with a single electroencephalographic (EEG) laboratory. This distinctive mode of healthcare delivery affords unique insights into the challenges of treating SE in rural Canada, such as lack of EEG infrastructure, a markedly high incidence of SE, the struggles of enduring cultural and socioeconomic trauma, and a relative lack of local epilepsy care as recommended by the World Health Organization. For example, despite empiric treatment and waiting over 2 days on average for EEG, 1 in 5 patients still had ongoing or possible electrographic seizures. At the same time, Kivalliq experiences routine dramatic changes in light-dark exposure each year to afford unique insights into circannual SE chronobiology in relation to the chief human zeitgeber of sunlight. This shows that challenges may also represent opportunities, such as for existing and emerging technologies to synergistically address enormous treatment gaps to improve SE care for the people of Kivalliq, while providing novel insights that may also help improve SE clinical care around the world.

2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of Plasmodium falciparum Phosphatidylinositol-4-kinase and Hemozoin Formation with In Vivo Efficacy.

Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of Plasmodium falciparum (Pf) phosphatidylinositol-4-kinase ß (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained Plasmodium PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PfPI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of Pf. It was efficacious in the humanized NSG mouse malaria infection model at a single oral dose of 32 mg/kg. This compound was nonteratogenic in the zebrafish embryo model of teratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate for malaria.

Chemical cyclization of tyrosine-containing peptides via in situ generated triazolinedione peptides.

Tyr-derived cyclic peptide natural products are formed by enzymatic manifolds that oxidatively cross-link embedded phenolic side chains of tyrosine (Tyr) and 4-hydroxyphenylglycine residues during their controlled production. Bioactive Tyr-derived cyclic peptides, such as the arylomycins and vancomycins, continue to motivate the development of enzymatic and chemical strategies for their de novo assembly and modification. However, chemical access to these structurally diverse natural cycles can be challenging and step intensive. Therefore, we developed an oxidative procedure to selectively convert Tyr-containing N4-substituted 1,2,4-triazolidine-3,5-dione peptides (urazole peptides) into stable Tyr-linked cyclic peptides. We show that Tyr-containing urazole peptides are simple to prepare and convert into reactive N4-substituted 1,2,4-triazoline-3,5-dione peptides by oxidation, which then undergo spontaneous cyclization under mildly basic aqueous conditions to form a cross-linkage with the phenol side chain of embedded Tyr residues. Using this approach, we have demonstrated access to over 25 Tyr-linked cyclic peptides (3- to 11-residue cycles) with good tolerance of native residue side chain functionalities. Importantly, this method is simple to perform, and product formation can be quickly confirmed by mass spectrometric and 1H NMR spectroscopic analyses.

MR Imaging of Adverse Effects and Ocular Growth Decline after Selective Intra-Arterial Chemotherapy for Retinoblastoma.

This retrospective multicenter study examines therapy-induced orbital and ocular MRI findings in retinoblastoma patients following selective intra-arterial chemotherapy (SIAC) and quantifies the impact of SIAC on ocular and optic nerve growth. Patients were selected based on medical chart review, with inclusion criteria requiring the availability of posttreatment MR imaging encompassing T2-weighted and T1-weighted images (pre- and post-intravenous gadolinium administration). Qualitative features and quantitative measurements were independently scored by experienced radiologists, with deep learning segmentation aiding total eye volume assessment. Eyes were categorized into three groups: eyes receiving SIAC (Rb-SIAC), eyes treated with other eye-saving methods (Rb-control), and healthy eyes. The most prevalent adverse effects post-SIAC were inflammatory and vascular features, with therapy-induced contrast enhancement observed in the intraorbital optic nerve segment in 6% of patients. Quantitative analysis revealed significant growth arrest in Rb-SIAC eyes, particularly when treatment commenced ≤ 12 months of age. Optic nerve atrophy was a significant complication in Rb-SIAC eyes. In conclusion, this study highlights the vascular and inflammatory adverse effects observed post-SIAC in retinoblastoma patients and demonstrates a negative impact on eye and optic nerve growth, particularly in children treated ≤ 12 months of age, providing crucial insights for clinical management and future research.

Acute response to pathogens in the early human placenta at single-cell resolution.

The placenta is a selective maternal-fetal barrier that provides nourishment and protection from infections. However, certain pathogens can attach to and even cross the placenta, causing pregnancy complications with potential lifelong impacts on the child's health. Here, we profiled at the single-cell level the placental responses to three pathogens associated with intrauterine complications-Plasmodium falciparum, Listeria monocytogenes, and Toxoplasma gondii. We found that upon exposure to the pathogens, all placental lineages trigger inflammatory responses that may compromise placental function. Additionally, we characterized the responses of fetal macrophages known as Hofbauer cells (HBCs) to each pathogen and propose that they are the probable niche for T. gondii. Finally, we revealed how P. falciparum adapts to the placental microenvironment by modulating protein export into the host erythrocyte and nutrient uptake pathways. Altogether, we have defined the cellular networks and signaling pathways mediating acute placental inflammatory responses that could contribute to pregnancy complications.

Quinoxaline-Based Anti-Schistosomal Compounds Have Potent Anti-Malarial Activity.

The human pathogens Plasmodium and Schistosoma are each responsible for over 200 million infections annually, being particularly problematic in low- and middle-income countries. There is a pressing need for new drug targets for these diseases, driven by emergence of drug-resistance in Plasmodium and the overall dearth of new drug targets for Schistosoma. Here, we explored the opportunity for pathogen-hopping by evaluating a series of quinoxaline-based anti-schistosomal compounds for activity against P. falciparum. We identified compounds with low nanomolar potency against 3D7 and multidrug-resistant strains. Evolution of resistance using a mutator P. falciparum line revealed a low propensity for resistance. Only one of the series, compound 22, yielded resistance mutations, including point mutations in a non-essential putative hydrolase pfqrp1, as well as copy-number amplification of a phospholipid-translocating ATPase, pfatp2, a potential target. Notably, independently generated CRISPR-edited mutants in pfqrp1 also showed resistance to compound 22 and a related analogue. Moreover, previous lines with pfatp2 copy-number variations were similarly less susceptible to challenge with the new compounds. Finally, we examined whether the predicted hydrolase activity of PfQRP1 underlies its mechanism of resistance, showing that both mutation of the putative catalytic triad and a more severe loss of function mutation elicited resistance. Collectively, we describe a compound series with potent activity against two important pathogens and their potential target in P. falciparum.

High-definition transcranial direct current stimulation desynchronizes refractory status epilepticus.

Recently, we showed that high-definition transcranial direct current stimulation (hd-tDCS) can acutely reduce epileptic spike rates during and after stimulation in refractory status epilepticus (RSE), with a greater likelihood of patient discharge from the intensive care unit compared to historical controls. We investigate whether electroencephalographic (EEG) desynchronization during hd-tDCS can help account for observed anti-epileptic effects. Defining desynchronization as greater power in higher frequencies such as above 30 â€‹Hz ("gamma") and lesser power in frequency bands lower than 30 â€‹Hz, we analyzed 27 EEG sessions from 10 RSE patients who had received 20-minute session(s) of 2-milliamperes of transcranial direct current custom-targeted at the epileptic focus as previously determined by a clinical EEGer monitoring the EEG in real-time. During hd-tDCS, median relative power change over the EEG electrode chains in which power changes were maximal was +4.84%, -5.25%, -1.88%, -1.94%, and +4.99% for respective delta, theta, alpha, beta, and gamma frequency bands in the bipolar longitudinal montage (p â€‹= â€‹0.0001); and +4.13%, -5.44%, -1.81%, -3.23%, and +5.41% in the referential Laplacian montage (p â€‹= â€‹0.0012). After hd-tDCS, median relative power changes reversed over the EEG electrode chains in which power changes were maximal: -2.74%, +4.20%, +1.74%, +1.75%, and -4.68% for the respective delta, theta, alpha, beta, and gamma frequency bands in the bipolar longitudinal montage (p â€‹= â€‹0.0001); and +1.59%, +5.07%, +1.74%, +2.40%, and -5.12% in the referential Laplacian montage (p â€‹= â€‹0.0004). These findings are consistent with EEG desynchronization through theta-alpha-beta-gamma bands during hd-tDCS, helping account for the efficacy of hd-tDCS as an emerging novel anti-epileptic therapy against RSE.

Technical Considerations in Laparoscopic-Assisted Endoscopic Retrograde Cholangiography.

The use of endoscopic retrograde cholangiography (ERCP) for diagnostic and therapeutic interventions on the pancreaticobiliary system has steadily increased, but the standard approach through the oropharynx is prohibited after Roux-en-Y (RYGB) gastric bypass surgery. Laparoscopic access to the gastric remnant allows for the completion of ERCP using the standard side-viewing duodenoscope to facilitate the completion of standard and advanced endoscopic maneuvers. Here, we describe our experience with the technical aspects of safe and effective performance of laparoscopic-assisted ERCP.