Oral Insulin Delay of Stage 3 Type 1 Diabetes Revisited in HLA DR4-DQ8 Participants in the TrialNet Oral Insulin Prevention Trial (TN07).

OBJECTIVE: To explore if oral insulin could delay onset of stage 3 type 1 diabetes (T1D) among patients with stage 1/2 who carry HLA DR4-DQ8 and/or have elevated levels of IA-2 autoantibodies (IA-2As). RESEARCH AND METHODS: Next-generation targeted sequencing technology was used to genotype eight HLA class II genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, and DPB1) in 546 participants in the TrialNet oral insulin preventative trial (TN07). Baseline levels of autoantibodies against insulin (IAA), GAD65 (GADA), and IA-2A were determined prior to treatment assignment. Available clinical and demographic covariables from TN07 were used in this post hoc analysis with the Cox regression model to quantify the preventive efficacy of oral insulin. RESULTS: Oral insulin reduced the frequency of T1D onset among participants with elevated IA-2A levels (HR 0.62; P = 0.012) but had no preventive effect among those with low IA-2A levels (HR 1.03; P = 0.91). High IA-2A levels were positively associated with the HLA DR4-DQ8 haplotype (OR 1.63; P = 6.37 × 10-6) and negatively associated with the HLA DR7-containing DRB1*07:01-DRB4*01:01-DQA1*02:01-DQB1*02:02 extended haplotype (OR 0.49; P = 0.037). Among DR4-DQ8 carriers, oral insulin delayed the progression toward stage 3 T1D onset (HR 0.59; P = 0.027), especially if participants also had high IA-2A level (HR 0.50; P = 0.028). CONCLUSIONS: These results suggest the presence of a T1D endotype characterized by HLA DR4-DQ8 and/or elevated IA-2A levels; for those patients with stage 1/2 disease with such an endotype, oral insulin delays the clinical T1D onset.

The effects of explicit morphological analysis instruction in early elementary Spanish speakers.

The purpose of this study was to compare the effects of implicit and explicit morphological analysis instruction in Spanish, a language characterized by high morphological complexity and relatively consistent letter-sound correspondences. For 3 days, 94 Grade 3 Spanish monolingual students (43 girls; Mage = 8.9 years) were trained on target words containing experimenter-designed suffixes consistent in form and meaning (e.g., the suffix -isba refers to a factory in words such as "botisba" [a boot factory] and "cajisba" [a box factory]). Explicit and implicit instruction differed in the attention given to the co-occurrence of the suffixes in the target words. One day (immediate posttest) and 1 week (delayed posttest) after training concluded, participants were tested on their learning of the suffixes' form using a suffix identification task and meaning using a word definition and a multiple-choice task. Results of mixed-effects models showed that explicit instruction yielded better results for the learning of the form of the suffixes. Regarding meaning, across-condition differences were detected only in the word definition task; explicit instruction produced better results for both trained and transfer words. We discuss our findings in the context of the grain-size unit theory and examine the interplay between the language's orthographic and morphological characteristics, considering their impact on classroom instruction.

Impact of Diabetes, Drug-Induced Liver Injury, and Sepsis on Outcomes in MAFLD-Related Acute-on-Chronic Liver Failure.

BACKGROUND: The prevalence of Metabolic dysfunction associated fatty liver disease (MAFLD) and its complication, MAFLD-related acute on chronic liver failure (MAFLD-ACLF), is rising. Yet, factors determining patient outcomes in MAFLD-ACLF remain understudied. METHODS: Patients with MAFLD-ACLF were recruited from the AARC registry. The diagnosis of MAFLD-ACLF was made when the treating unit had identified the etiology of chronic liver disease (CLD) as MAFLD (or previous nomenclature such as NAFLD, NASH, or NASH-cirrhosis). Patients with coexisting other etiologies of CLD (such as alcohol, HBV, HCV, etc.) were excluded. Data was randomly split into derivation (n=258) and validation (n=111) cohorts at a 70:30 ratio. The primary outcome was 90-day mortality. Only the baseline clinical, laboratory features and severity scores were considered. RESULTS: The derivation group had 258 patients; 60% were male, with a mean age of 53. Diabetes was noted in 27%, and hypertension in 29%. The dominant precipitants included viral hepatitis (HAV and HEV, 32%), drug-induced injury (DILI, 29%) and sepsis (23%). MELD-Na and AARC scores upon admission averaged 32±6 and 10.4±1.9. At 90 days, 51% survived. Non-viral precipitant, diabetes, bilirubin, INR, and encephalopathy were independent factors influencing mortality. Adding diabetes and precipitant to MELD-Na and AARC scores, the novel MAFLD-MELD-Na score (+12 for diabetes, +12 for non-viral precipitant) and MAFLD-AARC score (+5 for each) were formed. These outperformed the standard scores in both cohorts. CONCLUSION: Almost half of MAFLD-ACLF patients die within 90 days. Diabetes and non-viral precipitants such as DILI and sepsis lead to adverse outcomes. The new MAFLD-MELD-Na and MAFLD-AARC scores provide reliable 90-day mortality predictions for MAFLD-ACLF patients.

Do Oral and Silent Word-Reading Fluency Rely on the Same Cognitive-Linguistic Skills? Evidence from a Cross-Sectional Study in Greek.

Researchers tend to use oral- and silent-reading fluency measures interchangeably and to generalize research findings across reading modes, especially from oral to silent reading. In this study, we sought to examine if oral and silent word-reading fluency rely on the same cognitive-linguistic skills. Three hundred and forty-five Greek children (80 from Grade 2, 85 from Grade 4, 91 from Grade 6, and 89 from Grade 10) were assessed on measures of general cognitive ability, speed of processing, phonological awareness, rapid automatized naming, orthographic knowledge, articulation rate, and word-reading fluency (oral and silent). Results of hierarchical regression analyses revealed that phonological awareness was a unique predictor of both reading outcomes in Grade 2 and orthographic knowledge was a unique predictor of both reading outcomes in Grades 4, 6, and 10. However, rapid automatized naming predicted only oral word-reading fluency. These findings suggest that silent and oral word-reading fluency do not necessarily rely on the same cognitive-linguistic skills at the same grade level and we need to exercise some caution when we generalize the findings across reading modes.

The Relationship Between the Retromandibular Vein and the Extratemporal Segment of the Facial Nerve: A Prospective Cadaveric Study of 24 Hemifaces.

INTRODUCTION: Anatomical preservation and functional integrity of the facial nerve (FN) are the main concerns of parotid surgery. Even though a variety of anatomical landmarks have been proposed and widely utilized, temporal or permanent postoperative FN palsy is still a significant comorbidity of parotid surgery. Therefore, the literature must fully elucidate the consistency of the anatomical relationship between the FN and the retromandibular vein (RMV). METHODS: We conducted a cadaveric study of 24 hemifaces to map the relationship between the FN and the RMV. Three distinct patterns were identified. Fourteen of the hemifaces were males, and 10 were females. Thirteen cadaveric dissections were performed on the right side and 11 on the left side. RESULTS: Our study found three distinct patterns and proposed a classification system. Type I (66.7%) is when the nerve lies exclusively lateral to the RMV. Type II (29.2%) is when the FN lies superficial to the RMV, but its mandibular branch lies deep to the anterior branch of the RMV, and type III (4.1%) is when the FN lies exclusively medial to the RMV. CONCLUSION: The FN and RMV relationship is not constant, and surgeons should be aware of every anatomical variation. Especially in cases where the FN is estimated to lie more in-depth to the level of the RMV, a retrograde approach may be required to avoid a FN injury.

Individual Variability in Brain Connectivity Patterns and Driving-Fatigue Dynamics.

Mental fatigue during driving poses significant risks to road safety, necessitating accurate assessment methods to mitigate potential hazards. This study explores the impact of individual variability in brain networks on driving fatigue assessment, hypothesizing that subject-specific connectivity patterns play a pivotal role in understanding fatigue dynamics. By conducting a linear regression analysis of subject-specific brain networks in different frequency bands, this research aims to elucidate the relationships between frequency-specific connectivity patterns and driving fatigue. As such, an EEG sustained driving simulation experiment was carried out, estimating individuals' brain networks using the Phase Lag Index (PLI) to capture shared connectivity patterns. The results unveiled notable variability in connectivity patterns across frequency bands, with the alpha band exhibiting heightened sensitivity to driving fatigue. Individualized connectivity analysis underscored the complexity of fatigue assessment and the potential for personalized approaches. These findings emphasize the importance of subject-specific brain networks in comprehending fatigue dynamics, while providing sensor space minimization, advocating for the development of efficient mobile sensor applications for real-time fatigue detection in driving scenarios.

Ongoing Decline in Continuity With GPs in English General Practices: A Longitudinal Study Across the COVID-19 Pandemic.

PURPOSE: Relationship continuity of care has declined across English primary health care, with cross-sectional and longitudinal variations between general practices predicted by population and service factors. We aimed to describe cross-sectional and longitudinal variations across the COVID-19 pandemic and determine whether practice factors predicted the variations. METHODS: We conducted a longitudinal, ecological study of English general practices during 2018-2022 with continuity data, excluding practices with fewer than 750 patients or National Health Service (NHS) payments exceeding £500 per patient. Variables were derived from published data. The continuity measure was the product of weighted responses to 2 General Practice Patient Survey questions. In a multilevel mixed-effects model, the fixed effects were 11 variables' interactions with time: baseline continuity, NHS region, deprivation, location, percentage White ethnicity, list size, general practitioner and nurse numbers, contract type, NHS payments per patient, and percentage of patients seen on the same day as booking. The random effects were practices. RESULTS: Main analyses were based on 6,010 practices (out of 7,190 active practices). During 2018-2022, mean continuity in these practices declined (from 29.3% to 19.0%) and the coefficient of variation across practices increased (from 48.1% to 63.6%). Both slopes were steepest between 2021 and 2022. Practices having more general practitioners and higher percentages of patients seen the same day had slower declines. Practices having higher baseline continuity, located in certain non-London regions, and having higher percentages of White patients had faster declines. The remaining variables were not predictors. CONCLUSIONS: Variables potentially associated with greater appointment availability predicted slower declines in continuity, with worsening declines and relative variability immediately after the COVID-19 lockdown, possibly reflecting surges in demand. To achieve better levels of continuity for those seeking it, practices can increase appointment availability within appointment systems that prioritize continuity.

Testing the Spillover Effect of Intimate Partner Violence Victimization on Emotionally Abusive and Harsh Parenting Practices: The Application of Propensity Score Matching.

Prior research reported a significant association between intimate partner violence (IPV) victimization and negative parenting, but there was an overreliance on U.S. samples and families from low socioeconomic status backgrounds. Therefore, this quasi-experimental study examined the association between recent IPV victimization and abusive parenting practices in a sample of community-based women from Poland. Participants were mothers of children aged 2 to 5 years (N = 610) attending an outpatient clinic located in a city in south-eastern Poland. Mothers were asked about their IPV experiences in the past 12 months and were classed as either IPV positive or IPV negative. Outcome measures assessed emotionally abusive and harsh parenting practices. All data were collected online. To reduce bias in background characteristics (i.e., age, education, employment status, financial distress, self-esteem, childhood violence history, alcohol problems, current mental distress, social support, exposure to COVID-19-pandemic-related stressors, and child sex), we applied the propensity score matching (PSM) technique. Group differences before and after matching were examined using independent samples t-tests. Prematching analyses revealed that IPV-positive mothers used significantly more emotionally abusive and harsh parenting practices than IPV-negative mothers. However, the two samples differed substantially on six background characteristics which are known risk factors for IPV and child maltreatment (financial distress, self-esteem, childhood violence history, current mental distress, social support, and exposure to COVID-19-pandemic-related stressors). PSM was successful in reducing those imbalances. Postmatching group comparisons were statistically nonsignificant for emotionally abusive and harsh parenting, disproving the spillover hypothesis. We conclude that IPV victimization is not related to emotionally abusive and harsh parenting practices when controlling for confounding variables.

A Streamlined and Standardized Procedure for Generating High-Titer, High-Quality Adeno-Associated Virus Vectors Utilizing a Cell Factory Platform.

Preclinical gene therapy research, particularly in rodent and large animal models, necessitates the production of AAV vectors with high yield and purity. Traditional approaches in research laboratories often involve extensive use of cell culture dishes to cultivate HEK293T cells, a process that can be both laborious and problematic. Here, a unique in-house method is presented, which simplifies this process with a specific cell factory (or cell stacks, CF10) platform. An integration of polyethylene glycol/aqueous two-phase partitioning with iodixanol gradient ultracentrifugation improves both the yield and purity of the generated AAV vectors. The purity of the AAV vectors is verified through SDS-PAGE and silver staining, while the ratio of full to empty particles is determined using transmission electron microscopy (TEM). This approach offers an efficient cell factory platform for the production of AAV vectors at high yields, coupled with an improved purification method to meet the quality demands for in vivo studies.

Phosphaturia in HIV-exposed Uninfected Neonates Associated with Maternal Use of Tenofovir Disoproxil Fumarate in Late Pregnancy.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is often used in treating pregnant women living with HIV. Third trimester TDF exposure is associated with a 12% reduction in bone mineral content in HIV-exposed uninfected (HEU) neonates. Potential mechanisms underlying this observation are unknown. METHODS: The TDF study enrolled newborns of gestational age ≥36 weeks from the Surveillance Monitoring for Antiretroviral Therapy and Toxicities study based on in utero TDF exposure (TDF use ≥8 weeks in third trimester versus none). Blood and urine samples were collected cross-sectionally within 30 days of birth to assess renal function (serum creatinine, serum phosphate, eGFR, percent tubular reabsorption of phosphate [PTRP]), and bone turnover (serum parathyroid hormone, 25-OH vitamin D [25(OH)D], and urinary cross-linked N-telopeptide of type 1 collagen). For each biomarker, a LOESS plot was fit using values at age at specimen collection; regression lines over age were fit among samples collected from 4-30 days, to compare slopes by TDF exposure. RESULTS: Among 141 neonates, 77 were TDF-exposed and 64 TDF-unexposed. Between age 4 and 30 days, PTRP decreased more rapidly in the TDF-exposed compared to the unexposed group with slopes of -0.58 versus -0.08/day (difference -0.50/day [95%CI -0.88, -0.11]). Slopes for 25(OH)D were similar in both groups, but serum levels lower in TDF-exposed neonates (median [IQR]: 22 [19, 29] versus 26 [22,37] ng/mL). No differences were observed for other biomarkers. CONCLUSIONS: Third trimester in utero exposure to TDF is associated with increased urinary loss of phosphate and lower serum concentrations of 25(OH)D in HEU neonates.

Clinicosocial determinants of hospital stay following cervical decompression: A public healthcare perspective and machine learning model.

OBJECTIVE: Post-operative length of hospital stay (LOS) is a valuable measure for monitoring quality of care provision, patient recovery, and guiding hospital resource management. But the impact of patient ethnicity, socio-economic deprivation as measured by the indices of multiple deprivation (IMD), and pre-existing health conditions on LOS post-anterior cervical decompression and fusion (ACDF) is under-researched in public healthcare settings. METHODS: From 2013 to 2023, a retrospective study at a single center reviewed all ACDF procedures. We analyzed 14 non-clinical predictors-including demographics, comorbidities, and socio-economic status-to forecast a categorized LOS: short (≤2 days), medium (2-3 days), or long (>3 days). Three machine learning (ML) models were developed and assessed for their prediction reliability. RESULTS: 2033 ACDF patients were analyzed; 79.44 % had a LOS ≤ 2 days. Significant predictors of LOS included patient sex (HR:0.81[0.74-0.88], p < 0.005), IMD decile (HR:1.38[1.24-1.53], p < 0.005), smoking (HR:1.24[1.12-1.38], p < 0.005), DM (HR:0.70[0.59-0.84], p < 0.005), and COPD (HR:0.66, p = 0.01). Asian patients had the highest mean LOS (p = 0.003). Testing on 407 patients, the XGBoost model achieved 80.95 % accuracy, 71.52 % sensitivity, 85.76 % specificity, 71.52 % positive predictive value, and a micro F1 score of 0.715. This model is available at: https://acdflos.streamlit.app. CONCLUSIONS: Utilizing non-clinical pre-operative parameters such as patient ethnicity, socio-economic deprivation index, and baseline comorbidities, our ML model effectively predicts postoperative LOS for patient undergoing ACDF surgeries. Yet, as the healthcare landscape evolves, such tools will require further refinement to integrate peri and post-operative variables, ensuring a holistic decision support tool.

A Novel Role for the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Delta Isoform in Hepatocellular Proliferation.

The phosphatidylinositol-4,5-bisphosphate 3-kinase delta isoform (Pik3cd), usually considered immune-specific, was unexpectedly identified as a gene potentially related to either regeneration and/or differentiation in animals lacking hepatocellular Integrin Linked Kinase (ILK). Since a specific inhibitor (Idelalisib, or CAL101) for the catalytic subunit encoded by Pik3cd (p110δ) has reported hepatotoxicity when used for treating chronic lymphocytic leukemia and other lymphomas, the authors aimed to elucidate whether there is a role for p110δ in normal liver function. To determine the effect on normal liver regeneration, partial hepatectomy (PHx) was performed using mice in which p110δ was first inhibited using CAL101. Inhibition led to over a 50% decrease in proliferating hepatocytes in the first 2 days after PHx. This difference correlated with phosphorylation changes in the HGF and EGF receptors (MET and EGFR, respectively) and NF-κB signaling. Ingenuity Pathway Analyses implicated C/EBPß, HGF, and the EGFR heterodimeric partner, ERBB2, as three of the top 20 regulators downstream of p110δ signaling because their pathways were suppressed in the presence of CAL101 at 1 day post-PHx. A regulatory role for p110δ signaling in mouse and rat hepatocytes through MET and EGFR was further verified using hepatocyte primary cultures, in the presence or absence of CAL101. Combined, these data support a role for p110δ as a downstream regulator of normal hepatocytes when stimulated to proliferate.

Acinar to ß-like cell conversion through inhibition of focal adhesion kinase.

Insufficient functional ß-cell mass causes diabetes; however, an effective cell replacement therapy for curing diabetes is currently not available. Reprogramming of acinar cells toward functional insulin-producing cells would offer an abundant and autologous source of insulin-producing cells. Our lineage tracing studies along with transcriptomic characterization demonstrate that treatment of adult mice with a small molecule that specifically inhibits kinase activity of focal adhesion kinase results in trans-differentiation of a subset of peri-islet acinar cells into insulin producing ß-like cells. The acinar-derived insulin-producing cells infiltrate the pre-existing endocrine islets, partially restore ß-cell mass, and significantly improve glucose homeostasis in diabetic mice. These findings provide evidence that inhibition of the kinase activity of focal adhesion kinase can convert acinar cells into insulin-producing cells and could offer a promising strategy for treating diabetes.

Racial and Ethnic Disparities in Health Care Usage and Death by Neighborhood Poverty Among Individuals With Congenital Heart Defects, 4 US Surveillance Sites, 2011 to 2013.

BACKGROUND: Socioeconomic factors may lead to a disproportionate impact on health care usage and death among individuals with congenital heart defects (CHD) by race, ethnicity, and socioeconomic factors. How neighborhood poverty affects racial and ethnic disparities in health care usage and death among individuals with CHD across the life span is not well described. METHODS AND RESULTS: Individuals aged 1 to 64 years, with at least 1 CHD-related International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code were identified from health care encounters between January 1, 2011, and December 31, 2013, from 4 US sites. Residence was classified into lower- or higher-poverty neighborhoods on the basis of zip code tabulation area from the 2014 American Community Survey 5-year estimates. Multivariable logistic regression models, adjusting for site, sex, CHD anatomic severity, and insurance-evaluated associations between race and ethnicity, and health care usage and death, stratified by neighborhood poverty. Of 31 542 individuals, 22.2% were non-Hispanic Black and 17.0% Hispanic. In high-poverty neighborhoods, non-Hispanic Black (44.4%) and Hispanic (47.7%) individuals, respectively, were more likely to be hospitalized (adjusted odds ratio [aOR], 1.2 [95% CI, 1.1-1.3]; and aOR, 1.3 [95% CI, 1.2-1.5]) and have emergency department visits (aOR, 1.3 [95% CI, 1.2-1.5] and aOR, 1.8 [95% CI, 1.5-2.0]) compared with non-Hispanic White individuals. In high poverty neighborhoods, non-Hispanic Black individuals with CHD had 1.7 times the odds of death compared with non-Hispanic White individuals in high-poverty neighborhoods (95% CI, 1.1-2.7). Racial and ethnic disparities in health care usage were similar in low-poverty neighborhoods, but disparities in death were attenuated (aOR for non-Hispanic Black, 1.2 [95% CI=0.9-1.7]). CONCLUSIONS: Racial and ethnic disparities in health care usage were found among individuals with CHD in low- and high-poverty neighborhoods, but mortality disparities were larger in high-poverty neighborhoods. Understanding individual- and community-level social determinants of health, including access to health care, may help address racial and ethnic inequities in health care usage and death among individuals with CHD.

Applying the Discrepancy Consistency Method on CAS-2: Brief Data in a Sample of Greek-Speaking Children.

This study aimed to examine whether we could use the discrepancy consistency method on CAS-2: Brief data collected in Cyprus. A total of 438 Grade 6 children (201 boys, 237 girls, Mage = 135.75 months, SD = 4.05 months) from Cyprus were assessed on the Cognitive Assessment System-2: Brief that is used to operationalize four neurocognitive processes, namely Planning, Attention, Simultaneous, and Successive (PASS) processing. They were also assessed on two measures of reading (Wordchains and CBM-Maze) and mathematics (Mathematics Achievement Test and Mathematics Reasoning Test). The results showed that 31.5% of our sample had a PASS disorder, and 8% to 10% of our sample had both a PASS disorder and an academic disorder. These numbers are similar to those reported in previous studies that used DCM in North America and suggest that the method can be used to inform instruction, particularly in places where no screening for learning disabilities is available.

Mortality and morbidity after combined heart and liver transplantation in the failing Fontan: An updated dual center retrospective study.

INTRODUCTION: As the adult Fontan population with Fontan associated liver disease continues to increase, more patients are being referred for transplantation, including combined heart and liver transplantation. METHODS: We report updated mortality and morbidity outcomes after combined heart and liver transplant in a retrospective cohort series of 40 patients (age 14 to 49 years) with Fontan circulation across two centers from 2006-2022. RESULTS: The 30-day, 1-year, 5-year and 10-year survival rate was 90%, 80%, 73% and 73% respectively. Sixty percent of patients met a composite comorbidity of needing either post-transplant mechanical circulatory support, renal replacement therapy or tracheostomy. Cardiopulmonary bypass time > 283 min (4.7 h) and meeting the composite comorbidity were associated with mortality by Kaplan Meier analysis. CONCLUSION: Further study to mitigate early mortality and the above comorbidities as well as the high risk of bleeding and vasoplegia in this patient population is warranted.

Where east meets west: Phylogeography of the high Arctic North American brant goose.

Genetic variation in Arctic species is often influenced by vicariance during the Pleistocene, as ice sheets fragmented the landscape and displaced populations to low- and high-latitude refugia. The formation of secondary contact or suture zones during periods of ice sheet retraction has important consequences on genetic diversity by facilitating genetic connectivity between formerly isolated populations. Brant geese (Branta bernicla) are a maritime migratory waterfowl (Anseriformes) species that almost exclusively uses coastal habitats. Within North America, brant geese are characterized by two phenotypically distinct subspecies that utilize disjunct breeding and wintering areas in the northern Pacific and Atlantic. In the Western High Arctic of Canada, brant geese consist of individuals with an intermediate phenotype that are rarely observed nesting outside this region. We examined the genetic structure of brant geese populations from each subspecies and areas consisting of intermediate phenotypes using mitochondrial DNA (mtDNA) control region sequence data and microsatellite loci. We found a strong east-west partition in both marker types consistent with refugial populations. Within subspecies, structure was also observed at mtDNA while microsatellite data suggested the presence of only two distinct genetic clusters. The Western High Arctic (WHA) appears to be a secondary contact zone for both Atlantic and Pacific lineages as mtDNA and nuclear genotypes were assigned to both subspecies, and admixed individuals were observed in this region. The mtDNA sequence data outside WHA suggests no or very restricted intermixing between Atlantic and Pacific wintering populations which is consistent with published banding and telemetry data. Our study indicates that, although brant geese in the WHA are not a genetically distinct lineage, this region may act as a reservoir of genetic diversity and may be an area of high conservation value given the potential of low reproductive output in this species.

Antagonizing Activin A/p15INK4b Signaling as Therapeutic Strategy for Liver Disease.

BACKGROUND/AIM: Activin A is involved in the pathogenesis of human liver diseases, but its therapeutic targeting is not fully explored. Here, we tested the effect of novel, highly specific small-molecule-based activin A antagonists (NUCC-474/555) in improving liver regeneration following partial hepatectomy and halting fibrosis progression in models of chronic liver diseases (CLDs). METHODS: Cell toxicity of antagonists was determined in rat hepatocytes and Huh-7 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Hepatocytes and hepatic stellate cells (HSCs) were treated with activin A and NUCC-555 and analyzed by reverse transcription-polymerase chain reaction and immunohistochemistry. Partial hepatectomized Fisher (F)344 rats were treated with NUCC-555, and bromodeoxyuridine (BrdU) incorporation was determined at 18/24/36/120/240 h. NUCC-555 was administered into thioacetamide- or carbon tetrachloride-treated F344 rats or C57BL/6 mice, and the fibrosis progression was studied. RESULTS: NUCC-474 showed higher cytotoxicity in cultured hepatic cells; therefore, NUCC-555 was used in subsequent studies. Activin A-stimulated overexpression of cell cycle-/senescence-related genes (e.g., p15INK4b, DEC1, Glb1) was near-completely reversed by NUCC-555 in hepatocytes. Activin A-mediated HSC activation was blocked by NUCC-555. In partial hepatectomized rats, antagonizing activin A signaling resulted in a 1.9-fold and 2.3-fold increase in BrdU+ cells at 18 and 24 h, respectively. Administration of NUCC-555 in rats and mice with progressing fibrosis significantly reduced collagen accumulation (7.9-fold), HSC activation indicated by reduced alpha smooth muscle actin+ and vimentin+ cells, and serum aminotransferase activity. CONCLUSIONS: Our studies demonstrate that activin A antagonist NUCC-555 promotes liver regeneration and halts fibrosis progression in CLD models, suggesting that blocking activin A signaling may represent a new approach to treating people with CLD.

Lumbar vertebral diskitis-osteomyelitis with mycotic abdominal aortic aneurysm caused by Streptococcus mitis.

Vertebral osteomyelitis is a well-documented disease entity in literature with various known etiologies. However, vertebral diskitis-osteomyelitis secondary to an infected aortic aneurysm is an uncommon and life-threatening complication. We present the case of a 65-year-old male patient who presented with chronic low back pain that acutely worsened for 1 to 1.5 months and was diagnosed with vertebral diskitis-osteomyelitis secondary to a contiguous infection from an adjacent mycotic aortic aneurysm. To our knowledge, this is one of the few cases reported of vertebral diskitis-osteomyelitis secondary to mycotic aortic aneurysm. We discuss the findings on CT and MRI, as well as the value of imaging in guiding management.