Augmentation of Endothelial S1PR1 Attenuates Postviral Pulmonary Fibrosis.

Respiratory viral infections are frequent causes of acute respiratory distress syndrome (ARDS), a disabling condition with a mortality of up to 46%. The pulmonary endothelium plays an important role in the development of ARDS as well as the pathogenesis of pulmonary fibrosis; however, the therapeutic potential to modulate endothelium-dependent signaling to prevent deleterious consequences has not been well explored. Here, we used a clinically relevant influenza A virus infection model, endothelial cell-specific transgenic gain-of-function and loss-of-function mice as well as pharmacologic approaches and in vitro modeling, to define the mechanism by which S1PR1 expression is dampened during influenza virus infection and determine whether therapeutic augmentation of S1PR1 has the potential to reduce long-term postviral fibrotic complications. We found that the influenza virus-induced inflammatory milieu promoted internalization of S1PR1, which was pharmacologically inhibited with paroxetine, an inhibitor of GRK2. Moreover, genetic overexpression or administration of paroxetine days after influenza virus infection was sufficient to reduce postviral pulmonary fibrosis. Taken together, our data suggest that endothelial S1PR1 signaling provides critical protection against long-term fibrotic complications after pulmonary viral infection. These findings support the development of antifibrotic strategies that augment S1PR1 expression in virus-induced ARDS to improve long-term patient outcomes.

Tissue of origin detection for cancer tumor using low-depth cfDNA samples through combination of tumor-specific methylation atlas and genome-wide methylation density in graph convolutional neural networks.

BACKGROUND: Cell free DNA (cfDNA)-based assays hold great potential in detecting early cancer signals yet determining the tissue-of-origin (TOO) for cancer signals remains a challenging task. Here, we investigated the contribution of a methylation atlas to TOO detection in low depth cfDNA samples. METHODS: We constructed a tumor-specific methylation atlas (TSMA) using whole-genome bisulfite sequencing (WGBS) data from five types of tumor tissues (breast, colorectal, gastric, liver and lung cancer) and paired white blood cells (WBC). TSMA was used with a non-negative least square matrix factorization (NNLS) deconvolution algorithm to identify the abundance of tumor tissue types in a WGBS sample. We showed that TSMA worked well with tumor tissue but struggled with cfDNA samples due to the overwhelming amount of WBC-derived DNA. To construct a model for TOO, we adopted the multi-modal strategy and used as inputs the combination of deconvolution scores from TSMA with other features of cfDNA. RESULTS: Our final model comprised of a graph convolutional neural network using deconvolution scores and genome-wide methylation density features, which achieved an accuracy of 69% in a held-out validation dataset of 239 low-depth cfDNA samples. CONCLUSIONS: In conclusion, we have demonstrated that our TSMA in combination with other cfDNA features can improve TOO detection in low-depth cfDNA samples.

A20 promoted the phagocytosis of lymphoma cells by dendritic cells from activated B-cell-like non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) is a lymphoproliferative disorder derived from either B or T lymphocytes. Among NHL, activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) and T cell non-Hodgkin lymphomas (T-NHL) are poor prognosis and aggressive subtypes. Macrophages are professional phagocytic cells and dendritic cells (DCs) are professional antigen-presenting cells in immune system. Doxorubicin (Dox) and Etoposide (ET) are the most effective anti-cancer drugs. A20 and CYLD are negative regulators of NF-κB-dependent functions in many cell types. Little is known about the roles of A20 and CYLD in regulating functions of DCs and macrophages from NHL. The present study, therefore, explored whether A20/CYLD expression contributes to functions of DCs and macrophages from NHL. To this end, blood samples of seventy-nine patients with ABC DLBCL and T-NHL were examined. Gene expression profile was determined by quantitative RT-PCR and immunophenotype, cell apoptosis and phagocytosis by flow cytometry. As a result, immunophenotypic analysis showed that the numbers of CD13+CD117-, CD56+CD40+ and CD23+CD40+ expressing cells were significantly elevated in ABC DLBCL cases compared to healthy individuals and T-NHL patients. Interestingly, upon treatment of Dox and ET, the phagocytosis of lymphoma cells was significantly reduced by CD11c+CD123- DCs and the percentage of CD56+ mature DCs was significantly enhanced in ABC DLBCL patients only in the presence of A20 siRNA, but not CYLD siRNA. In conclusion, ABC DLBCL patients with low A20 expression were defective in elimination of lymphoma cells by DCs and linked to killer DC expansion in circulation.

Knowledge, attitudes and self-confidence with skills required for providing dementia care in physicians at primary healthcare settings in Vietnam.

BACKGROUND: Dementia is a global public health priority. The World Health Organization adopted a Global Action Plan on Dementia, with dementia awareness a priority. This study examined the knowledge, attitudes, and self-confidence with skills required for providing dementia care among primary health care providers in Vietnam. METHODS: A cross-sectional study was conducted with 405 primary health care providers who worked at commune health stations and district health centers in eight provinces across Vietnam. RESULTS: The results showed that primary health care providers had poor knowledge and little confidence but more positive attitudes toward dementia care and management. CONCLUSIONS: The results suggest the training needs for building capacity amongst primary health care providers, which will be critical as Vietnam's population ages.

Genome-wide association study of resistance to Mycobacterium tuberculosis infection identifies a locus at 10q26.2 in three distinct populations.

The natural history of tuberculosis (TB) is characterized by a large inter-individual outcome variability after exposure to Mycobacterium tuberculosis. Specifically, some highly exposed individuals remain resistant to M. tuberculosis infection, as inferred by tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). We performed a genome-wide association study of resistance to M. tuberculosis infection in an endemic region of Southern Vietnam. We enrolled household contacts (HHC) of pulmonary TB cases and compared subjects who were negative for both TST and IGRA (n = 185) with infected individuals (n = 353) who were either positive for both TST and IGRA or had a diagnosis of TB. We found a genome-wide significant locus on chromosome 10q26.2 with a cluster of variants associated with strong protection against M. tuberculosis infection (OR = 0.42, 95%CI 0.35-0.49, P = 3.71×10-8, for the genotyped variant rs17155120). The locus was replicated in a French multi-ethnic HHC cohort and a familial admixed cohort from a hyper-endemic area of South Africa, with an overall OR for rs17155120 estimated at 0.50 (95%CI 0.45-0.55, P = 1.26×10-9). The variants are located in intronic regions and upstream of C10orf90, a tumor suppressor gene which encodes an ubiquitin ligase activating the transcription factor p53. In silico analysis showed that the protective alleles were associated with a decreased expression in monocytes of the nearby gene ADAM12 which could lead to an enhanced response of Th17 lymphocytes. Our results reveal a novel locus controlling resistance to M. tuberculosis infection across different populations.

Shoulder external rotation contracture following neonatal brachial plexus injury.

BACKGROUND: Glenohumeral posterior external rotation contractures and scapular winging are frequently overlooked problems in residual neonatal brachial plexus injury (NBPI). Recent attention has emphasized their impact on vital functions such as feeding and hygiene. This study aims to present the epidemiology of posterior glenohumeral (GH) contractures in a significant pediatric NBPI population and explore contributing factors. METHODS: We conducted a retrospective analysis of data collected from January 2019 to November 2022, involving a case series of 262 children with residual NBPI. The data included demographics, palsy level, prior surgical history, and the modified Mallet scale. Glenohumeral passive internal rotation in abduction (IRABD) and cross-body adduction (CBADD) angles were measured bilaterally. Subjects were categorized into 'Belly-' (Mallet Hand-to-Belly <3) and 'Belly+' (Mallet Hand-to-Belly ≥3) groups. RESULTS: Median participant age was 7.9 years (range: 3.5 - 21 years). Extension injury patterns included Erb's palsy (56.5%), extended Erb's palsy (28.6%), and global palsy (14.9%). Contractures exceeding 10, 20, and 30 degrees were prevalent in both IRABD and CBADD angles. The 'Belly-' group (9.5%) demonstrated a significant reduction in both angles compared to the 'Belly+' group. Weak correlations were found between IRABD (r=0.390, p<0.0001) or CBADD (r=0.163, p=0.0083) angles and Mallet hand-to-abdomen item. Glenohumeral reduction and Hoffer procedures led to a notable decrease in CBADD angle, without affecting 'Belly-' prevalence. Global injuries exhibited decreased angles compared to Erb's group. CONCLUSIONS: External rotation glenohumeral contractures are prevalent in residual NBPI, impacting midline access. Surprisingly, history of glenohumeral procedures or extensive injuries did not increase the likelihood of losing the ability to reach the belly. ROC analysis suggests specific thresholds for maintaining this ability.

Spontaneous Resolution of Congenital Insufficiency of the Extensor Tendon Central Slip.

BACKGROUND: The congenital insufficiency of the extensor tendon central slip of the fingers is a relatively rare condition, with only a few reported cases in pediatric patients, as described in 2 clinical series. In this study, we aimed to present the natural history of a significant number of untreated patients with this deformity. METHODS: This study has received institutional review board approval, and parents provided informed consent following the Declaration of Helsinki guidelines for biomedical research involving humans. A retrospective analysis of children with this deformity, ranging from June 2008 to July 2021, was collected by 1 surgeon. The inclusion criteria included children with a supple PIP flexion deformity, characterized by MP hyperextension and PIP extension lag, which had been present since birth. Complete passive PIP extension and the absence of volar skin webbing differentiated this condition from camptodactyly. RESULTS: The mean age of 24 children with 57 involved digits at diagnosis was 7 months (range, 1 to 17) and the mean follow-up was 6 years to 9 months (2 yr to 1 mo to 13 yr). Six patients had an incorrect previous diagnosis of camptodactyly.Active PIP extension recovered progressively. At the final follow-up, complete PIP extension occurred in all except 4 cases in which a residual 10° extension lag. The mean time for a complete active PIP extension was 2 years to 7 months (20 mo to 3 yr to 9 mo). Nineteen cases (79%) showed a mild FDS contracture of the involved digits at the final follow-up.The deformity was bilateral in 15 children (62.5%) and involved only 1 finger (unilaterally or bilaterally) in 15 cases (62.5%), and 2 fingers in 6 (25%). Little and ring fingers were most commonly involved. In 7 cases, there was a family history of finger deformity. CONCLUSIONS: Congenital insufficiency of the extensor tendon central slip typically resolves spontaneously within the first 4 years of life. Literature suggests that splinting can expedite the correction of the deformity and thus, if possible, it can be used. In most cases, a residual, clinically insignificant FDS contracture may be present. This condition is often misdiagnosed as camptodactyly. LEVEL OF EVIDENCE: IV.

Dietary glycemic index and glycemic load predict longitudinal change in glycemic and cardio-metabolic biomarkers among old diabetic adults living in a resource-poor country.

This study aims to investigate longitudinal associations between the dietary glycemic index (GI) and glycemic load (GL) and changes in glycemic and cardio-metabolic outcomes. A 28-month retrospective cohort study included 110 Vietnamese diabetic patients, collecting their dietary GI and GL values along with blood biochemical data from baseline 24-h dietary recall and medical records. Latent class growth modelling identified three distinct HbA1c trajectories during the follow-up period, with 51% of patients achieving good glycemic control. The adjusted linear mixed-effect model showed that 1 unit increase in logarithms in dietary GL was associated with a 0.14% increase in the log-HbA1c. Among poorly controlled diabetic patients, baseline GL values were positively correlated with increases in HbA1c; GI showed effects on changes in fasting plasma glucose and the triglyceride-glucose (TyG) index. No significant association was observed in patients with good glycemic control.

A comparison between the enzymatic oxidation method and headspace gas chromatography with a flame ionization detector in the determination of postmortem blood ethanol.

Ethanol is the most commonly encountered substance in forensic toxicology. Determining blood alcohol concentration (BAC) in autopsies accounts for the majority of work in forensic diagnosis. The most common method to assess BAC is the enzymatic oxidation method because of its low cost, easy operation, and high throughput. Still, the elevated lactate and lactate dehydrogenase (LDH) levels in postmortem blood may affect accuracy. This study uses headspace gas chromatography with a flame ionization detector (HS-GC/FID) to assess the interference of lactate and LDH levels on BAC in 110 autopsied blood samples determined by the enzymatic oxidation method. The results showed that lactate and LDH levels in postmortem blood were higher than in normal blood. There was a weak correlation between the lactate levels and BAC difference (r = 0.23, p < 0.05) and a strong correlation between LDH levels and BAC difference (r = 0.67, p < 0.001). The differentiation of BAC between the enzymatic oxidation method and HS-GC/FID was significant (p < 0.001), confirming the interference significantly. All postmortem blood samples with lactate and LDH levels higher than regular lead to a positive error in determining BAC by enzymatic oxidation method. The study results suggest that the HS-GC/FID method should be used to determine BAC in postmortem blood samples instead of the enzymatic oxidation method to avoid mistakes in forensic diagnosis.

Drug-induced aseptic meningitis after an interlaminar lumbar epidural steroid injection.

BACKGROUND: This case report describes a rare instance of drug-induced aseptic meningitis after an interlaminar lumbar epidural steroid injection. CASE PRESENTATION: A 74 year-old female patient presented to the ED post-procedure day three after an L4-L5 interlaminar lumbar epidural steroid injection with fever, nausea, and vomiting. The patient had previously undergone numerous lumbar epidurals without complications and used identical medications, which included 1% lidocaine, iohexol contrast, methylprednisolone (Depo-medrol), and normal saline. Pertinent labs included a WBC of 15,000 cells/µL. Lumbar MRI revealed L4-S1 aseptic arachnoiditis. Two bone scans with Gallium and T-99 confirmed no infectious process. The patient then had a second admission months later with similar presenting symptoms and hospital course after repeating the lumbar epidural steroid injection. Lumbar MRI and CSF studies confirmed aseptic meningitis. CONCLUSION: This patient's repeated admissions from aseptic meningitis were likely caused by irritation of the meningeal layers from a medication used during the procedure.

Heroin Use Is Associated With Vascular Inflammation in Human Immunodeficiency Virus.

BACKGROUND: Heroin use may work synergistically with human immunodeficiency virus (HIV) infection to cause greater immune dysregulation than either factor alone. Unraveling how this affects end-organ disease is key as it may play a role in the excess mortality seen in people with HIV (PWH) who use heroin despite access to care and antiretroviral therapy. METHODS: This is a prospectively enrolled, cross-sectional study of adults with and without HIV who use and do not use heroin using (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to compare tissue-specific inflammation including aortic (target-to-background ratio [TBR]), splenic, and bone marrow (standardized uptake value [SUV]). RESULTS: A total of 120 participants were enrolled. The unadjusted mean difference in aortic TBR was 0.43 between HIV-positive [HIV+] heroin+ and HIV+ heroin-negative [heroin-] (P = .02); however, among HIV-, aortic TBR was similar regardless of heroin-use status. Further, HIV-by-heroin-use status interaction was significant (P = .02), indicating that the relationship between heroin use and higher aortic TBR depended on HIV status. On the other hand, both HIV (1.54 vs 1.68; P = .04, unadjusted estimated means for HIV+ vs HIV-) and heroin use were associated with lower bone marrow SUV, although the effect of heroin depended on sex (heroin-use-by-sex interaction, P = .03). HIV-by-heroin-use interaction was not significant for splenic or bone marrow SUV. CONCLUSIONS: Aortic inflammation was greatest in PWH who use heroin, but paradoxically, bone marrow activity was the least in this group, suggesting complex and possibly divergent pathophysiology within these different end organs.

Myofibroblast-specific inhibition of the Rho kinase-MRTF-SRF pathway using nanotechnology for the prevention of pulmonary fibrosis.

Pulmonary fibrosis is characterized by the accumulation of myofibroblasts in the lung and progressive tissue scarring. Fibroblasts exist across a spectrum of states, from quiescence in health to activated myofibroblasts in the setting of injury. Highly activated myofibroblasts have a critical role in the establishment of fibrosis as the predominant source of type 1 collagen and profibrotic mediators. Myofibroblasts are also highly contractile cells and can alter lung biomechanical properties through tissue contraction. Inhibiting signaling pathways involved in myofibroblast activation could therefore have significant therapeutic value. One of the ways myofibroblast activation occurs is through activation of the Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF) pathway, which signals through intracellular actin polymerization. However, concerns surrounding the pleiotropic and ubiquitous nature of these signaling pathways have limited the translation of inhibitory drugs. Herein, we demonstrate a novel therapeutic antifibrotic strategy using myofibroblast-targeted nanoparticles containing a MTRF/SRF pathway inhibitor (CCG-1423), which has been shown to block myofibroblast activation in vitro. Myofibroblasts were preferentially targeted via the angiotensin 2 receptor, which has been shown to be selectively upregulated in animal and human studies. These nanoparticles were nontoxic and accumulated in lung myofibroblasts in the bleomycin-induced mouse model of pulmonary fibrosis, reducing the number of these activated cells and their production of profibrotic mediators. Ultimately, in a murine model of lung fibrosis, a single injection of these drugs containing targeted nanoagents reduced fibrosis as compared with control mice. This approach has the potential to deliver personalized therapy by precisely targeting signaling pathways in a cell-specific manner, allowing increased efficacy with reduced deleterious off-target effects.

Patterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS).

BACKGROUND: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. METHODS AND FINDINGS: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. CONCLUSION: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT03721302).

Efficacy, safety, and immunogenicity of an inactivated, adjuvanted enterovirus 71 vaccine in infants and children: a multiregion, double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Children are susceptible to severe or fatal enterovirus 71 (EV71) infections. We aimed to evaluate the efficacy, safety, and immunogenicity of EV71vac, an aluminium phosphate-adjuvanted inactivated EV71 vaccine in children aged 2-71 months. METHODS: We did a randomised, double-blinded, placebo-controlled, phase 3 trial at five hospitals in Taiwan and two in Vietnam. Children aged 2-71 months were stratified by country and age, and randomly assigned (1:1) to receive two doses of EV71vac or placebo via intramuscular injection 56 days apart. Children aged 2-23 months received a third booster dose on day 366. The primary endpoint was the clinical efficacy of the total vaccinated cohort against EV71-associated diseases during the follow-up period, from 14 days after the second dose to when 15 cases of EV71 infections were confirmed in the per-protocol population. Our safety analysis included all participants who received at least one dose of EV71vac. This trial is registered with ClinicalTrials.gov, NCT03865238, and is complete. FINDINGS: Between April 23 and Dec 25, 2019, of 3663 children assessed, 3061 were randomly assigned, of whom 3049 were vaccinated: 1521 children in the EV71vac group and 1528 in the placebo group. By May 20, 2021, our primary efficacy analysis included 2959 children, with 1476 children in the EV71vac group and 1483 children in the placebo group. The vaccine efficacy of EV71vac was 96·8% (95% CI 85·5-100) against EV71 associated diseases (p<0·0001). The percentage of participants who reported solicited adverse events were similar in both groups: 865 (56·9%) in the EV71vac group and 852 (55·8%) in the placebo group. Almost all reported solicited adverse events were mild and self-limited. INTERPRETATION: EV71vac is safe, well-tolerated, and highly effective in preventing EV71 associated diseases in children aged 2-71 months. FUNDING: Medigen Vaccine Biologics and A+ Industrial Innovative R&D Program of the Ministry of Economic Affairs, Taiwan.

Clinical validation of a ctDNA-Based Assay for Multi-Cancer Detection: An Interim Report from a Vietnamese Longitudinal Prospective Cohort Study of 2795 Participants.

The SPOT-MAS assay "Screening for the Presence Of Tumor by Methylation And Size" detects the five most common cancers in Vietnam by evaluating circulating tumor DNA in the blood. Here, we validated its performance in a prospective multi-center clinical trial, K-DETEK. Our analysis of 2795 participants from 14 sites across Vietnam demonstrates its ability to detect cancers in asymptomatic individuals with a positive predictive value of 60%, with 83.3% accuracy in detecting tumor location. We present a case report to support further using SPOT-MAS as a complementary method to achieve early cancer detection and provide the opportunity for early treatment.

Fragment length profiles of cancer mutations enhance detection of circulating tumor DNA in patients with early-stage hepatocellular carcinoma.

BACKGROUND: Late detection of hepatocellular carcinoma (HCC) results in an overall 5-year survival rate of less than 16%. Liquid biopsy (LB) assays based on detecting circulating tumor DNA (ctDNA) might provide an opportunity to detect HCC early noninvasively. Increasing evidence indicates that ctDNA detection using mutation-based assays is significantly challenged by the abundance of white blood cell-derived mutations, non-tumor tissue-derived somatic mutations in plasma, and the mutational tumor heterogeneity. METHODS: Here, we employed concurrent analysis of cancer-related mutations, and their fragment length profiles to differentiate mutations from different sources. To distinguish persons with HCC (PwHCC) from healthy participants, we built a classification model using three fragmentomic features of ctDNA through deep sequencing of thirteen genes associated with HCC. RESULTS: Our model achieved an area under the curve (AUC) of 0.88, a sensitivity of 89%, and a specificity of 82% in the discovery cohort consisting of 55 PwHCC and 55 healthy participants. In an independent validation cohort of 54 PwHCC and 53 healthy participants, the established model achieved comparable classification performance with an AUC of 0.86 and yielded a sensitivity and specificity of 81%. CONCLUSIONS: Our study provides a rationale for subsequent clinical evaluation of our assay performance in a large-scale prospective study.

Astrocytic NKCC1 inhibits seizures by buffering Cl- and antagonizing neuronal NKCC1 at GABAergic synapses.

OBJECTIVE: A pathological excitatory action of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) has been observed in epilepsy. Blocking the Cl- importer NKCC1 with bumetanide is expected to reduce the neuronal intracellular Cl- concentration ([Cl- ]i ) and thereby attenuate the excitatory GABA response. Accordingly, several clinical trials of bumetanide for epilepsy were conducted. Although NKCC1 is expressed in both neurons and glial cells, an involvement of glial NKCC1 in seizures has not yet been reported. Astrocytes maintain high [Cl- ]i with NKCC1, and this gradient promotes Cl- efflux via the astrocytic GABAA receptor (GABAA R). This Cl- efflux buffers the synaptic cleft Cl- concentration to maintain the postsynaptic Cl- gradient during intense firing of GABAergic neurons, thereby sustaining its inhibitory action during seizure. In this study, we investigated the function of astrocytic NKCC1 in modulating the postsynaptic action of GABA in acute seizure models. METHODS: We used the astrocyte-specific conditional NKCC1 knockout (AstroNKCC1KO) mice. The seizurelike events (SLEs) in CA1 pyramidal neurons were triggered by tetanic stimulation of stratum radiatum in acute hippocampus slices. The SLE underlying GABAA R-mediated depolarization was evaluated by applying the GABAA R antagonist bicuculline. The pilocarpine-induced seizure in vivo was monitored in adult mice by the Racine scale. The SLE duration and tetanus stimulation intensity threshold and seizure behavior in AstroNKCC1KO mice and wild-type (WT) mice were compared. RESULTS: The AstroNKCC1KO mice were prone to seizures with lower threshold and longer duration of SLEs and larger GABAA R-mediated depolarization underlying the SLEs, accompanied by higher Racine-scored seizures. Bumetanide reduced these indicators of seizure in AstroNKCC1KO mice (which still express neuronal NKCC1), but not in the WT, both in vitro and in vivo. SIGNIFICANCE: Astrocytic NKCC1 inhibits GABA-mediated excitatory action during seizures, whereas neuronal NKCC1 has the converse effect, suggesting opposing actions of bumetanide on these cells.

Spatial metapopulation dynamics with local and global colonization.

We revisit a spatial metapopulation model on continuous space as a stochastic point pattern dynamics. In the model, local patches as points are distributed with a certain spatial configuration and status of each patch changes stochastically between occupied and empty: an occupied patch becomes empty by local extinction and an empty patch becomes occupied both by local and global colonization. We carry out simulation analysis and derive an analytical model in terms of singlet, pair and triplet probabilities that describe the stochastic dynamics. Using a simple closure that approximates triplet probabilities by singlet and pair probabilities, we show that equilibrium singlet and pair probabilities can be analytically derived. The derived equilibrium properties successfully describe simulation results under a certain condition where the range of local colonization and the proportion of global colonization play key roles. Our model is an extension of the classical non-spatial Levins model to a spatially explicit metapopulation model. We appeal the advantage of point pattern approach to study spatial dynamics in general ecology and call for the need to deepen our understanding of mathematical tools to explore point pattern dynamics.

Extensor carpi radialis brevis motor branch transfer to the deep branch of the ulnar nerve to repair intrinsic hand palsy in neonatal lower brachial plexus and spinal cord injury: A case report.

Concomitant lower neonatal brachial plexus palsy (Klumpke) and spinal cord injury is extremely rare but with a clearly established mechanism of injury pattern. No successful surgical techniques have been reported to date to restore intrinsic hand function. We report a case of successful transfer of the extensor carpi radialis brevis motor branch to the deep branch of the ulnar nerve to repair intrinsic hand palsy. Three-month-old boy with the diagnosis of left Klumpke paralysis and thoracic spinal cord injury associating left Horner's sign, intrinsic minus deformity of all the digits, and thenar muscle paralysis in the upper limb. Both lower limbs were fully paralyzed. Cervical magnetic resonance imaging (MRI) revealed spinal cord narrowing from T1 to T5 and pseudo-meningoceles involving the left C8 through T3 roots. Since no spontaneous recovery was apparent by 6.5 months and surgical exploration showed pronator quadratus denervation, the ECRB motor branch deep branch was transferred to the ulnar nerve (DBUN) with interposed a 7.5 cm-long sural nerve graft. By 18 months post-operatively, all the digits showed complete active IP extension. Thirty-six months after surgery, no signs of first dorsal interosseous nerve or thenar muscle reinnervation were present, thus an extensor carpi ulnaris opponensplasty was performed. ECRB motor branch might be a valuable tool to restore finger intrinsic function in these uncommon cases.

StethAid: A Digital Auscultation Platform for Pediatrics.

(1) Background: Mastery of auscultation can be challenging for many healthcare providers. Artificial intelligence (AI)-powered digital support is emerging as an aid to assist with the interpretation of auscultated sounds. A few AI-augmented digital stethoscopes exist but none are dedicated to pediatrics. Our goal was to develop a digital auscultation platform for pediatric medicine. (2) Methods: We developed StethAid-a digital platform for artificial intelligence-assisted auscultation and telehealth in pediatrics-that consists of a wireless digital stethoscope, mobile applications, customized patient-provider portals, and deep learning algorithms. To validate the StethAid platform, we characterized our stethoscope and used the platform in two clinical applications: (1) Still's murmur identification and (2) wheeze detection. The platform has been deployed in four children's medical centers to build the first and largest pediatric cardiopulmonary datasets, to our knowledge. We have trained and tested deep-learning models using these datasets. (3) Results: The frequency response of the StethAid stethoscope was comparable to those of the commercially available Eko Core, Thinklabs One, and Littman 3200 stethoscopes. The labels provided by our expert physician offline were in concordance with the labels of providers at the bedside using their acoustic stethoscopes for 79.3% of lungs cases and 98.3% of heart cases. Our deep learning algorithms achieved high sensitivity and specificity for both Still's murmur identification (sensitivity of 91.9% and specificity of 92.6%) and wheeze detection (sensitivity of 83.7% and specificity of 84.4%). (4) Conclusions: Our team has created a technically and clinically validated pediatric digital AI-enabled auscultation platform. Use of our platform could improve efficacy and efficiency of clinical care for pediatric patients, reduce parental anxiety, and result in cost savings.