An artificial intelligence-generated model predicts 90-day survival in alcohol-associated hepatitis: A global cohort study.

BACKGROUND AND AIMS: Alcohol-associated hepatitis (AH) poses significant short-term mortality. Existing prognostic models lack precision for 90-day mortality. Utilizing artificial intelligence in a global cohort, we sought to derive and validate an enhanced prognostic model. APPROACH AND RESULTS: The Global AlcHep initiative, a retrospective study across 23 centers in 12 countries, enrolled patients with AH per National Institute for Alcohol Abuse and Alcoholism criteria. Centers were partitioned into derivation (11 centers, 860 patients) and validation cohorts (12 centers, 859 patients). Focusing on 30 and 90-day postadmission mortality, 3 artificial intelligence algorithms (Random Forest, Gradient Boosting Machines, and eXtreme Gradient Boosting) informed an ensemble model, subsequently refined through Bayesian updating, integrating the derivation cohort's average 90-day mortality with each center's approximate mortality rate to produce posttest probabilities. The ALCoholic Hepatitis Artificial INtelligence Ensemble score integrated age, gender, cirrhosis, and 9 laboratory values, with center-specific mortality rates. Mortality was 18.7% (30 d) and 27.9% (90 d) in the derivation cohort versus 21.7% and 32.5% in the validation cohort. Validation cohort 30 and 90-day AUCs were 0.811 (0.779-0.844) and 0.799 (0.769-0.830), significantly surpassing legacy models like Maddrey's Discriminant Function, Model for End-Stage Liver Disease variations, age-serum bilirubin-international normalized ratio-serum Creatinine score, Glasgow, and modified Glasgow Scores ( p < 0.001). ALCoholic Hepatitis Artificial INtelligence Ensemble score also showcased superior calibration against MELD and its variants. Steroid use improved 30-day survival for those with an ALCoholic Hepatitis Artificial INtelligence Ensemble score > 0.20 in both derivation and validation cohorts. CONCLUSIONS: Harnessing artificial intelligence within a global consortium, we pioneered a scoring system excelling over traditional models for 30 and 90-day AH mortality predictions. Beneficial for clinical trials, steroid therapy, and transplant indications, it's accessible at: https://aihepatology.shinyapps.io/ALCHAIN/ .

Toward data-driven, dynamical complex systems approaches to disaster resilience.

With rapid urbanization and increasing climate risks, enhancing the resilience of urban systems has never been more important. Despite the availability of massive datasets of human behavior (e.g., mobile phone data, satellite imagery), studies on disaster resilience have been limited to using static measures as proxies for resilience. However, static metrics have significant drawbacks such as their inability to capture the effects of compounding and accumulating disaster shocks; dynamic interdependencies of social, economic, and infrastructure systems; and critical transitions and regime shifts, which are essential components of the complex disaster resilience process. In this article, we argue that the disaster resilience literature needs to take the opportunities of big data and move toward a different research direction, which is to develop data-driven, dynamical complex systems models of disaster resilience. Data-driven complex systems modeling approaches could overcome the drawbacks of static measures and allow us to quantitatively model the dynamic recovery trajectories and intrinsic resilience characteristics of communities in a generic manner by leveraging large-scale and granular observations. This approach brings a paradigm shift in modeling the disaster resilience process and its linkage with the recovery process, paving the way to answering important questions for policy applications via counterfactual analysis and simulations.

Creatine mapping of the brain at 3T by CEST MRI.

PURPOSE: To assess the feasibility of CEST-based creatine (Cr) mapping in brain at 3T using the guanidino (Guan) proton resonance. METHODS: Wild type and knockout mice with guanidinoacetate N-methyltransferase deficiency and low Cr and phosphocreatine (PCr) concentrations in the brain were used to assign the Cr and protein-based arginine contributions to the GuanCEST signal at 2.0 ppm. To quantify the Cr proton exchange rate, two-step Bloch-McConnell fitting was used to fit the extracted CrCEST line-shape and multi-B1 Z-spectral data. The pH response of GuanCEST was simulated to demonstrate its potential for pH mapping. RESULTS: Brain Z-spectra of wild type and guanidinoacetate N-methyltransferase deficiency mice show a clear Guan proton peak at 2.0 ppm at 3T. The CrCEST signal contributes ∼23% to the GuanCEST signal at B1 = 0.8 µT, where a maximum CrCEST effect of 0.007 was detected. An exchange rate range of 200-300 s-1 was estimated for the Cr Guan protons. As revealed by the simulation, an elevated GuanCEST in the brain is observed when B1 is less than 0.4 µT at 3T, when intracellular pH reduces by 0.2. Conversely, the GuanCEST decreases when B1 is greater than 0.4 µT with the same pH drop. CONCLUSIONS: CrCEST mapping is possible at 3T, which has potential for detecting intracellular pH and Cr concentration in brain.

Influence of the calcium voltage-gated channel auxiliary subunit (CACNA2D1) absence on intraocular pressure in mice.

The etiology of elevated intraocular pressure (IOP), a major risk factor for glaucoma (optic nerve atrophy), is poorly understood despite continued efforts. Although the gene variant of CACNA2D1 (encoding α2δ1), a calcium voltage-gated channel auxiliary subunit, has been reported to be associated with primary open-angle glaucoma, and the pharmacological mitigation of α2δ1 activity by pregabalin lowers IOP, the cellular basis for α2δ1 role in the modulation of IOP remains unclear. Our recent findings reveled readily detectable levels of α2δ1 and its ligand thrombospondin in the cytoskeletome fraction of human trabecular meshwork (TM) cells. To understand the direct role of α2δ1 in the modulation of IOP, we evaluated α2δ1 null mice for changes in IOP and found a moderate (∼10%) but significant decrease in IOP compared to littermate wild type control mice. Additionally, to gain cellular insights into α2δ1 antagonist (pregabalin) induced IOP changes, we assessed pregabalin's effects on human TM cell actin cytoskeletal organization and cell adhesive interactions in comparison with a Rho kinase inhibitor (Y27632), a known ocular hypotensive agent. Unlike Y27632, pregabalin did not have overt effects on cell morphology, actin cytoskeletal organization, or cell adhesion in human TM cells. These results reveal a modest but significant decrease in IOP in α2δ1 deficient mice, and this response appears to be not associated with the contractile and cell adhesive characteristics of TM cells based on the findings of pregabalin effects on isolated TM cells. Therefore, the mechanism by which pregabalin lowers IOP remains elusive.

Simultaneous Measurement of GABA, Glutathione, and Glutamate-Glutamine in the Thalamus using Edited MR Spectroscopy: Feasibility and Applications in Traumatic Brain Injury.

BACKGROUND: MR spectroscopy (MRS) is a noninvasive tool for evaluating biochemical alterations, such as glutamate (Glu)/gamma-aminobutyric acid (GABA) imbalance and depletion of antioxidative glutathione (GSH) after traumatic brain injury (TBI). Thalamus, a critical and vulnerable region post-TBI, is challenging for MRS acquisitions, necessitating optimization to simultaneously measure GABA/Glu and GSH. PURPOSE: To assess the feasibility and optimize acquisition and processing approaches for simultaneously measuring GABA, Glx (Glu + glutamine (Gln)), and GSH in the thalamus, employing Hadamard encoding and reconstruction of MEscher-GArwood (MEGA)-edited spectroscopy (HERMES). STUDY TYPE: Prospective. SUBJECTS: 28 control subjects (age: 35.9 ± 15.1 years), and 17 mild TBI (mTBI) patients (age: 32.4 ± 11.3 years). FIELD STRENGTH/SEQUENCE: 3T/T1-weighted magnetization-prepared rapid gradient-echo (MP-RAGE), HERMES. ASSESSMENT: We evaluated the impact of acquisition with spatial saturation bands and post-processing with spectral alignment on HERMES performance in the thalamus among controls. Within-subject variability was examined in five controls through repeated scans within a week. The HERMES spectra in the posterior cingulate cortex (PCC) of controls were used as a reference for assessing HERMES performance in a reliable target. Furthermore, we compared metabolite levels and fitting quality in the thalamus between mTBI patients and controls. STATISTICAL TESTS: Unpaired t-tests and within-subject coefficient-of-variation (CV). A P-value <0.05 was deemed significant. RESULTS: HERMES spectra, acquired with saturation bands and processed with spectral alignment, yielded reliable metabolite measurements in the thalamus. The mean within-subject CV for GABA, Glx, and GSH levels were 18%, 10%, and 16% in the thalamus (7%, 9%, and 16% in the PCC). GABA (3.20 ± 0.60 vs 2.51 ± 0.55, P < 0.01) and Glx (8.69 ± 1.23 vs 7.72 ± 1.19, P = 0.03) levels in the thalamus were significantly higher in mTBI patients than in controls, with GSH (1.27 ± 0.35 vs 1.22 ± 0.28, P = 0.65) levels showing no significant difference. DATA CONCLUSION: Simultaneous measuring GABA/Glx and GSH using HERMES is feasible in the thalamus, providing valuable insight into TBI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Enhanced control over size, areal density, and shape of substrate-supported Au and Ag nanoparticles by solid-state dewetting and alloying.

The ability to manipulate the dimensions, areal density, and form of substrate-supported Au and Ag nanoparticles (NPs) is highly desirable for utilizing their plasmonic properties in biosensing, photovoltaics, and nanophotonic applications. The transformation of thin films into the substrate-supported nanostructures by solid-state dewetting (SSD), provides an avenue to manipulate the dimensional aspects of nanostructures simply and cost-effectively on a large scale. However, spontaneous agglomeration of the film produces randomly distributed and non-uniform nanostructures that must be controlled. Here, we have systematically studied the effect of annealing temperature, between 200 °C and 750 °C, on the dewetting morphology evolution of Au, Ag, and Au-Ag bilayer ultrathin films sputter deposited on thec-plane (0001) sapphire substrates. Regardless of the film thickness, Ag films dewet faster than Au films and produce spherical NPs, compared to faceted Au NPs, with broader size distribution. Whereas, by the SSD of Au-Ag bilayer ultrathin films, highly spherical and monodisperse AuAg bimetallic NPs can be fabricated. Furthermore, we have shown the possibility of fabricating the AuAg bimetallic NPs of varying compositions by adjusting the thickness of individual layers, thus enabling us to smoothly tune the spectral location of plasmonic resonance within the visible range.

Rescue splenic artery embolization in an adult patient of sickle cell disease presented with acute splenic sequestration crisis.

BACKGROUND: Splenic sequestration crisis is a potentially fatal complication of sickle cell disease, mainly seen in young children. Only a few case series describe the acute splenic sequestration crisis in adults and its management, which primarily consists of supportive care and, in some cases, splenectomy. Splenic artery embolization has seldom been described in sickle cell disease. This is probably the first case in which an adult with sickle cell disease presented with an acute splenic sequestration crisis was managed successfully through splenic artery embolization. RESULTS: This 22-year-old female, a known case of sickle cell disease, presented with severe pain in the abdomen and low-grade intermittent fever for two days, secondary to an acute splenic sequestration crisis. The diagnosis of acute splenic sequestration was made based on clinical and blood parameters, ultrasonography, and computed tomography. Even with adequate supportive care and blood transfusions, the patient's condition worsened with a rapid fall in the hemoglobin and total platelet count. Considering splenectomy to be a high-risk procedure for this patient, a decision of rescue splenic artery embolization was taken, which was successful. CONCLUSION: Splenic artery embolization may be considered a lifesaving procedure in patients with acute splenic sequestration, where the risk of splenectomy can be high. Adequate post-procedure supportive care is vital for preventing complications.

A CROSS-SECTIONAL STUDY ON COVID-19 VACCINATION HESITATION AMONG UNIVERSITY STUDENTS.

Students serve as ambassadors, conveying effective messages to encourage the adoption of promotes healthy behaviors. Recognizing their consciousness about corona illness 2019 (COVID-19), desires to utilize the COVID-19 vaccines, and other associated variables will aid in developing viable vaccination promotion tactics for the present COVID-19 pandemic. A transverse-segment internet poll of university students in the healthcare and non-healthcare industries was conducted to analyze their motivations to be vaccinated against the coronavirus. To recruit research participants, a random snowball sampling approach was utilized using digital media sites and mails. The contestants were chosen from throughout India, including several main geographic areas, between Nov-2020 and Jan-2021, prior to the release of the COVID-19 vaccination. There were descriptive metrics utilized to illustrate the research participants' socio-demographics and vaccine-related behaviors. Using logistic regression modeling, key characteristics that are expected to influence vaccination uptake among students were modeled. p 0.06 was judged substantial in each study. 656 students participated in the study, with 48.4% coming from the healthcare sector & 51.5% from other fields. Of these 655 students, 43.6 and 22.4% came from India's northern and eastern areas. Graduate students accounted for 41.1% of the total population, and graduates for around 43.2%. The age range of 56.0% of the students was 18 to 25. Women made up 62% of the population, and 69.5% of them were unmarried. Seventy-eight percent of the students were from the medium socioeconomic level. Concerns about side effects and safety, distrust of government officials, and questions about the vaccine's efficacy were among the reasons given by students in this study for their reluctance to get vaccinated. It is essential to remember that these investigations were carried out at various times and in various nations; thus, the conclusions may not apply to all college students throughout the globe. According to the findings of this research, Indian university students showed rather a great deal of motivating desire to acquire COVID-19 immunizations. The people were either doubtful or reluctant to get the vaccination, which suggests possible vaccine aversion. There is a need for information campaigns and other actions to lessen vaccine hesitancy in order to promote the usage of COVID-19 vaccines.

A phase I trial of LXS196, a protein kinase C (PKC) inhibitor, for metastatic uveal melanoma.

BACKGROUND: Up to 50% of patients with uveal melanoma develop metastases (MUM) with a poor prognosis and median overall survival of approximately 1 year. METHODS: This phase I study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the oral protein kinase C inhibitor LXS196 in 68 patients with MUM (NCT02601378). Patients received LXS196 doses ranging from 100-1000 mg once daily (QD; n = 38) and 200-400 mg twice daily (BID; n = 30). RESULTS: First cycle dose-limiting toxicities (DLTs) were observed in 7/38 (18.4%) QD and 2/17 (11.8%) BID patients. Hypotension was the most common DLT, occurring at doses ≥500 mg/day, and manageable with LXS196 interruption and dose reduction. Median duration of exposure to LXS196 was 3.71 months (range: 1.81-15.28) for QD and 4.6 months (range: 0.33-58.32) for BID dosing. Clinical activity was observed in 6/66 (9.1%) evaluable patients achieving response (CR/PR), with a median duration of response of 10.15 months (range: 2.99-41.95); 45/66 had stable disease (SD) per RECIST v1.1. At 300 mg BID, the recommended dose for expansion, 2/18 (11.1%) evaluable patients achieved PR and 12/18 (66.7%) had SD. CONCLUSION: These results suggest manageable toxicity and encouraging clinical activity of single-agent LXS196 in patients with MUM.

Toward vendor-independent measurement of cerebral venous oxygenation: Comparison of TRUST MRI across three major MRI manufacturers and association with end-tidal CO2.

Cerebral venous oxygenation (Yv ) is a valuable biomarker for a variety of brain diseases. T2 relaxation under spin tagging (TRUST) MRI is a widely used method for Yv quantification. In this work, there were two main objectives. The first was to evaluate the reproducibility of TRUST Yv measurements across MRI scanners from different vendors. The second was to examine the correlation between Yv and end-tidal CO2 (EtCO2 ) in a multisite, multivendor setting and determine the usefulness of this correlation to account for variations in Yv caused by normal variations and physiological fluctuations. Standardized TRUST pulse sequences were implemented on three scanners from major MRI vendors (GE, Siemens, Philips). These scanners were located at two research institutions. Ten healthy subjects were scanned. On each scanner, the subject underwent two scan sessions, each of which included three TRUST scans, to evaluate the intrasession and intersession reproducibility of Yv . Each scanner was also equipped with a capnograph device to record the EtCO2 of the subject during the MRI scan. We found no significant bias in Yv measurements across the three scanners (P = 0.18). The measured Yv values on the three scanners were also strongly correlated with each other (intraclass correlation coefficients > 0.85, P < 0.001). The intrasession and intersession coefficients of variation of Yv were less than 4% and showed no significant difference among the scanners. In addition, our results revealed that (1) within the same subject, Yv increased with EtCO2 at a rate of 1.24 ± 0.17%/mmHg (P < 0.0001), and (2) across different subjects, individuals with a higher EtCO2 had a higher Yv , at a rate of 0.94 ± 0.36%/mmHg (P = 0.01). These results suggest that (1) the standardized TRUST sequences had similar accuracies and reproducibilities for the quantification of Yv across the scanners, and (2) recording of EtCO2 may be a useful complement to Yv measurement to account for CO2 -related physiological fluctuations in Yv in multisite, multivendor studies.

Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity.

Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.

A Multi-Stage Faster RCNN-Based iSPLInception for Skin Disease Classification Using Novel Optimization.

Nowadays, skin cancer is considered a serious disorder in which early identification and treatment of the disease are essential to ensure the stability of the patients. Several existing skin cancer detection methods are introduced by employing deep learning (DL) to perform skin disease classification. Convolutional neural networks (CNNs) can classify melanoma skin cancer images. But, it suffers from an overfitting problem. Therefore, to overcome this problem and to classify both benign and malignant tumors efficiently, the multi-stage faster RCNN-based iSPLInception (MFRCNN-iSPLI) method is proposed. Then, the test dataset is used for evaluating the proposed model performance. The faster RCNN is employed directly to perform image classification. This may heavily raise computation time and network complications. So, the iSPLInception model is applied in the multi-stage classification. In this, the iSPLInception model is formulated using the Inception-ResNet design. For candidate box deletion, the prairie dog optimization algorithm is utilized. We have utilized two skin disease datasets, namely, ISIC 2019 Skin lesion image classification and the HAM10000 dataset for conducting experimental results. The methods' accuracy, precision, recall, and F1 score values are calculated, and the results are compared with the existing methods such as CNN, hybrid DL, Inception v3, and VGG19. With 95.82% accuracy, 96.85% precision, 96.52% recall, and 0.95% F1 score values, the output analysis of each measure verified the prediction and classification effectiveness of the method.

A comparison of ultrasonic, ozone, and enzyme pre-treatments on cheese whey degradation for enhancement of anaerobic digestion.

Lactose in cheese whey wastewater (CWW) makes it difficult to degrade under normal conditions. The effect of ultra-sonication (US), ozonation and enzymatic hydrolysis on increasing the bioavailability of organic matter in CWW and biogas production were evaluated. The pre-treatment conditions were: specific energy input varied from 2130 to 8773KJ/KgTS for a sonication time of 4.5-18.5 min, Ozone (O3) dosages ranging from 0.03 to 0.045gO3/gTS were applied for 4-16 min, pH (3.8-7.1), temperature (35°C-55°C), enzyme dosage (0.18-0.52%), was operated from 7.75 to 53 min for enzymatic hydrolysis by ß-galactosidase. The results of the US reported a maximum sCOD solubilisation of 77.15% after 18.5 min of operation, while the corresponding values for ozonation and enzymatic methods were 64.8% at 16 min and 54.79%, respectively. The organic matter degradation rates evaluated in terms of protein and lactose hydrolysis were 68.78%,46.03%; 47.83%,16.15% and 54.22%,86.2%respectively, for US, ozonation and enzymatic methods. The cumulative methane yield for sonicated, ozonised and enzymatically hydrolysed samples were 412.4 ml/g VS, 361.2 ml/g VS and 432.3mlCH4/gVS, respectively. Regardless of the lower COD solubilisation rates attained, enzymatic pre-treatment showed maximum methane generation compared to US and ozonation. This could be attributable to the increased activity of ß-galactosidase in hydrolysing whey lactose. The energy calculations revealed that the pre-conditioning of organic-rich CWW with enzymatic hydrolysis is more effective and efficient, yielding a net energy gain (gross output energy-input energy) of 9166.7 KJ and an energy factor (ratio of output to input energy) of 6.67. The modified Gompertz model well simulated all experimental values.

Rice mill wastewater management in the era of circular economy.

Several nations around the world use rice as their primary food staple because of its tremendous nutritional value. India's expanding population has sparked a proliferation of rice mills as a result of the country's growing rice demand. However, small and medium-scale industries lack adequate facilities for processing effluents and other waste generated. Paddy is typically processed by parboiling, which involves soaking it in water, boiling it with steam, and then drying and milling. Around 1-1.5 L of water is necessary to partially cook 1 kg of unhusked rice, with approximately half of this water being discharged as effluent. Disposal of rice mill effluent (RME) in water bodies or on the land causes severe damage to soil and water. An inclusive examination of diverse approaches for the treatment and stabilization of partially cooked rice milling effluents is provided. Moreover, the document provides a concise overview of contemporary and environmentally friendly technologies for treating RME. Adsorption, electrocoagulation, chemical coagulation, and bioremediation using microbes, plants, and microalgae are all included in these methods. This manuscript discusses the concept of a circular economy, which is focused on enhancing environmental sustainability through the recycling and repurposing of generated waste into raw materials for the creation of new products. In addition, this review aims to focus on the impact of RME on soils and water species and the status of sustainable management at the point of circular economy with RME bioenergy production (bioelectricity, biomethane, and bio-hydrogen).

A nonlinear mathematical model on the Covid-19 transmission pattern among diabetic and non-diabetic population.

In this paper, a three tier mathematical model describing the interactions between susceptible population, Covid-19 infected, diabetic population and Covid-19 infected, non diabetic population is proposed. Basic properties of such a dynamic model, namely, non negativity, boundedness of solutions, existence of disease-free and disease equilibria are studied and sufficient conditions are obtained. Basic reproduction number for the system is derived. Sufficient conditions on functionals and parameters of the system are obtained for the local as well as global stability of equilibria, thus, establishing the conditions for eventual prevalence of disease free or disease environment, as the case may be. The stability aspects are discussed in the context of basic reproduction number and vice versa. An important contribution of this article is that a novel technique is presented to estimate some key, influencing parameters of the system so that a pre-specified, assumed equilibrium state is approached eventually. This enables the society to prepare itself with the help of these key, influencing parameters so estimated. Several examples are provided to illustrate the results established and simulations are provided to visualize the examples.

Targeting primary and metastatic uveal melanoma with a G protein inhibitor.

Uveal melanoma (UM) is the most common intraocular tumor in adults. Nearly half of UM patients develop metastatic disease and often succumb within months because effective therapy is lacking. A novel therapeutic approach has been suggested by the discovery that UM cell lines driven by mutant constitutively active Gq or G11 can be targeted by FR900359 (FR) or YM-254890, which are bioavailable, selective inhibitors of the Gq/11/14 subfamily of heterotrimeric G proteins. Here, we have addressed the therapeutic potential of FR for UM. We found that FR inhibited all oncogenic Gq/11 mutants reported in UM. FR arrested growth of all Gq/11-driven UM cell lines tested, but induced apoptosis only in a few. Similarly, FR inhibited growth of, but did not efficiently kill, UM tumor cells from biopsies of primary or metastatic tumors. FR evoked melanocytic redifferentiation of UM tumor cells with low (class 1), but not high (class 2), metastatic potential. FR administered systemically below its LD50 strongly inhibited growth of PDX-derived class 1 and class 2 UM tumors in mouse xenograft models and reduced blood pressure transiently. FR did not regress xenografted UM tumors or significantly affect heart rate, liver function, hematopoiesis, or behavior. These results indicated the existence of a therapeutic window in which FR can be explored for treating UM and potentially other diseases caused by constitutively active Gq/11.

Tonic pain alters functional connectivity of the descending pain modulatory network involving amygdala, periaqueductal gray, parabrachial nucleus and anterior cingulate cortex.

INTRODUCTION: Resting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN). METHODS: In 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN. RESULTS: Of all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free>pain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection's FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction CONCLUSION: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions.

Alterations in motor functional connectivity in Neonatal Hypoxic Ischemic Encephalopathy.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) is the result of global hypoxic-ischemic brain injury in neonates due to asphyxia during birth and is one of the most common causes of severe, long-term neurologic deficits in children. Methods: Resting state fMRI (rs-fMRI) was used to assess potential functional disruptions in the primary and association motor areas in HIE neonates (n = 16) compared to healthy controls (n = 11). RESULTS: Results demonstrate reduced intra-hemispheric resting state functional connectivity (rs-FC) between primary motor regions (upper extremity and facial motor regions) as well as reduced inter-hemispheric rs-FC in the HIE group. In addition, HIE neonates demonstrated increased rs-FC between motor regions and frontal, temporal and parietal cortices but decreased rs-FC with the cerebellum. DISCUSSION: These preliminary results provide initial evidence for the disruption of functional communication with the motor network in neonates with HIE. Further studies are necessary to both validate these findings in a larger dataset as well as to determine if rs-fMRI measurements collected at birth may have the potential to serve as a prognostic marker in addition to the traditional combination of clinical measurements and conventional MRI.

Anaerobic co-digestion of cheese whey and septage: Effect of substrate and inoculum on biogas production.

Cheese whey is an industrial waste generated from the cheese processing unit of the dairy industry and requires treatment before its disposal. The present study investigated the possibilities of improving the digestibility from anaerobic digestion of lipid rich dairy by-product, cheese whey using septage as the co-substrate with different inoculum. Biochemical methane potential assays were conducted under mesophilic temperature conditions and results were validated using Modified Gompertz Model. Two sets of BMP tests were done; to assess the individual and combined digestion abilities of septage in anaerobic co-digestion of whey and to assess the ability of 3 inoculum sources (cattle manure, sewage sludge, and acclimatized anaerobic sludge) in the co-digestion process. The results indicated that septage is an excellent co-substrate that has better adaptability with cheese whey and the optimum mix ratio was found as 40:60 (SCW: SSP). BMP tests were also conducted with inoculum at S/I ratio of 1 and statistical analysis was performed to study the synergistic effect of both co-digestion and inoculum. The tests revealed that the cattle manure resulted in the highest biogas production (342.22mL/gVS) at 60% whey fraction. Modified Gompertz model fitted the experimental data well and identified an increase in lag phase times when whey fraction is increased. Comparatively higher lag phase times ranging from 1.98 to 4.35 days were obtained for sewage sludge inoculated samples. The maximum methane production (Pmax) was obtained at 60% whey fraction (369.63 ± 4.05mL/gVS) at a very short lag time of 0.76 ± 0.17days for cattle manure inoculated mixture.

Isolation of a Melanoblast Stimulator from Dimocarpus longan, Its Structural Modification, and Structure-Activity Relationships for Vitiligo.

A novel melanoblast stimulator (1) was isolated from Dimocarpus longan. Its analogs were also synthesized to support a new furan-based melanoblast stimulator scaffold for treating vitiligo. Isolated 5-(hydroxymethyl)furfural (HMF, 1) is a well-known compound in the food industry. Surprisingly, the melanogenic activity of HMF (1) was discovered here for the first time. Both HMF and its synthetic analog (16) promote the differentiation and migration of melanoblasts in vitro. Typically, stimulator (1) upregulated MMP2 expression, which promoted the migration of melanoblasts in vitro.