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: Introduction: New South Wales (NSW) has one of the world's highest uptake rates of HIV pre‐exposure prophylaxis (PrEP). This uptake has been credited with sharp declines in HIV transmission, particularly among Australian‐born gay and bisexual men. Concerns have been raised around the potential for the emergence of tenofovir (TFV) and XTC (lamivudine/emtricitabine) resistance in settings of high PrEP use. Such an emergence could also increase treatment failure and associated clinical outcomes among people living with HIV (PLHIV). Despite low levels of nucleoside reverse‐transcriptase inhibitor (NRTI) resistance relating to PrEP use in clinical settings, there are few published studies describing the prevalence of NRTI resistance among people newly diagnosed with HIV in a setting of high PrEP use. Methods: Using HIV antiretroviral drug resistance data linked to NSW HIV notifications records of people diagnosed from 1 January 2015 to 31 December 2021 and with HIV attributed to male‐to‐male sex, we described trends in TFV and XTC resistance. Resistance was identified using the Stanford HIV Drug Resistance genotypic resistance interpretation system. To focus on transmitted drug resistance, resistance prevalence estimates were generated using sequences taken less than 3 months post‐HIV diagnosis. These estimates were stratified by timing of sequencing relative to the date of diagnosis, year of sequencing, birthplace, likely place of HIV acquisition, and stage of HIV at diagnosis. Results: Among 1119 diagnoses linked to HIV genomes sequenced less than 3 months following diagnosis, overall XTC resistance prevalence was 1.3%. Between 2015 and 2021, XTC resistance fluctuated between 0.5% to 2.9% and was 1.0% in 2021. No TFV resistance was found over the study period in any of the sequences analysed. Higher XTC resistance prevalence was observed among people with newly acquired HIV (evidence of HIV acquisition in the 12 months prior to diagnosis; 2.9%, p = 0.008). Conclusions: In this Australian setting, TFV and XTC resistance prevalence in new HIV diagnoses remained low. Our findings offer further evidence for the safe scale‐up of PrEP in high‐income settings, without jeopardizing the treatment of those living with HIV., INTRODUCTION Australia has made remarkable progress in its effort to meet the UNAIDS 2030 target of ending AIDS as a public health threat with HIV diagnoses attributed to male‐to‐male sex [...]

Introduction: Due to a lack of robust population denominators, Australia is unable to accurately monitor changes in the HIV epidemic for some populations. The ratio of HIV transmission relative to the number of people with HIV (an incidence prevalence ratio, or IPR) can measure such changes. The IPR is measured against an IPR benchmark derived from post‐HIV acquisition life expectancy, to indicate whether an HIV epidemic is shrinking or growing. Using IPRs and Australia‐specific IPR benchmarks, this study aims to describe the Australian HIV epidemic among three groups: men with HIV attributed to male‐to‐male sex, women with HIV and people with HIV attributed to injection drug use. Methods: Using mathematical modelling derived from HIV notifications, cohort and administrative data, IPRs were generated for each of the three groups. These IPRs were compared with IPR benchmarks derived from post‐HIV acquisition mortality estimates using abridged life tables for men, women and people who inject drugs. The IPR benchmark for men was applied to people with HIV attributed to male‐to‐male sex. Trends in the IPR over time were described for each reported population from 2015 to 2022. Results: Overall, the IPR fell by 80%, from 0.040 (range: 0.034−0.045) in 2015 to 0.008 (range: 0.003−0.013) in 2022 and fell below the benchmark (0.022) in 2020. Among people with HIV attributed to male‐to‐male sex, the IPR fell by 85%, from 0.041 (range: 0.034−0.047) in 2015 to 0.006 (range: 0.003−0.024) in 2022 and fell below the benchmark (0.022) in 2020. Among women with HIV, the IPR fell by 56%, from 0.032 (range: 0.026−0.039) in 2015 to 0.014 (range: 0.003−0.029) in 2022 and fell below the benchmark (0.022) in 2019. Among people with HIV attributed to injection drug use, the IPR fell by 61%, from 0.036 (range: 0.022−0.047) in 2015 to 0.014 (range: 0.002−0.057) in 2022 and fell below the benchmark (0.028) in 2019. Conclusions: Australian IPRs in all populations examined have dropped below the level required to sustain the HIV epidemic at current levels. By applying this method in other contexts, the changing scale of HIV epidemics may be better described for populations lacking robust population denominators. [ABSTRACT FROM AUTHOR]

Introduction: Decentralized molecular testing for infectious disease diagnosis at the point-of-care (POC) is critical to address inequities in access to timely, informed health care. The COVID-19 pandemic accelerated the demand, development and adoption of POC tests for infectious diseases globally. This has provided opportunities to maximize the individual benefits and public health impact of POC testing, particularly in remote and resource-limited primary care settings. Despite this, there remains a lack of harmonized, regulatory compliance and quality management frameworks for the delivery of molecular POC testing networks outside the laboratory setting. Areas Covered: This Perspective describes real-world lessons and experiences of delivering a fit-for-purpose, quality framework for one of the world's largest decentralized molecular POC testing programs for infectious disease across rural and remote Australian communities. Here we detail unique, key considerations to ensure the quality of POC testing in primary health settings with global application. Expert Opinion: There is an ethical and public health imperative to provide sustained access to decentralized POC testing for infectious disease in primary care. Genuine partnerships across stakeholders and disciplines are essential to deliver well governed, fit-for-purpose quality management POC testing frameworks and increase equitable access to timely, high-quality person-centered care. [ABSTRACT FROM AUTHOR]

: Introduction: Australia has set the goal for the virtual elimination of HIV transmission by the end of 2022, yet accurate information is lacking on the level of HIV transmission occurring among residents. We developed a method for estimating the timing of HIV acquisition among migrants, relative to their arrival in Australia. We then applied this method to surveillance data from the Australian National HIV Registry with the aim of ascertaining the level of HIV transmission among migrants to Australia occurring before and after migration, and to inform appropriate local public health interventions. Methods: We developed an algorithm incorporating CD4[sup.+] T‐cell decline back‐projection and enhanced variables (clinical presentation, past HIV testing history and clinician estimate of the place of HIV acquisition) and compared it to a standard algorithm which uses CD4[sup.+] T‐cell back‐projection only. We applied both algorithms to all new HIV diagnoses among migrants to estimate whether HIV infection occurred before or after arrival in Australia. Results: Between 1 January 2016 and 31 December 2020, 1909 migrants were newly diagnosed with HIV in Australia, 85% were men, and the median age was 33 years. Using the enhanced algorithm, 932 (49%) were estimated to have acquired HIV after arrival in Australia, 629 (33%) before arrival (from overseas), 250 (13%) close to arrival and 98 (5%) were unable to be classified. Using the standard algorithm, 622 (33%) were estimated to have acquired HIV in Australia, 472 (25%) before arrival, 321 (17%) close to arrival and 494 (26%) were unable to be classified. Conclusions: Using our algorithm, close to half of migrants diagnosed with HIV were estimated to have acquired HIV after arrival in Australia, highlighting the need for tailored culturally appropriate testing and prevention programmes to limit HIV transmission and achieve elimination targets. Our method reduced the proportion of HIV cases unable to be classified and can be adopted in other countries with similar HIV surveillance protocols, to inform epidemiology and elimination efforts., INTRODUCTION UNAIDS has set the ambitious target to eliminate the global transmission of HIV by 2030 [1] and Australia is aiming for “virtual elimination” by the end of 2022 [2]. [...]

Introduction: Elevations in serum ferritin and serum iron occur during pediatric extracorporeal membrane oxygenation (ECMO). Previous reports attribute the elevation to frequent red blood cell transfusions and/or hemolysis. Chronic transfusion can cause iron deposition in tissues leading to multisystem organ dysfunction. This study aims identify clinical factors associated with elevated ferritin and iron in pediatric ECMO patients, along with post-decannulation magnetic resonance imaging (MRI) assessment of iron deposition in liver and brain. Methods: Prospective, pilot study, using descriptive statistics to investigate potential associations between patient characteristics, serum ferritin and iron levels, and post-decannulation hepatic and basal ganglia iron deposition. Results: In this study, nine patients (100%) had elevated serum ferritin levels during ECMO. High ferritin levels were more common with veno-arterial than with veno-venous cannulation (p = 0.026) and were also associated with high plasma free hemoglobin levels (p < 0.001). Five patients presented with elevated serum iron levels. High serum iron levels were associated with higher daily (p = 0.016) and cumulative transfusion volumes (p = 0.013) as well ECMO duration beyond 7 days. MRI scans were performed on three patients with no evidence of abnormal iron deposition detected in the liver or brain. Conclusions: This pilot study shows that during pediatric ECMO, elevations in serum ferritin and serum iron occur and those elevations may be related to the cannulation modality, ECMO duration, amount of hemolysis, and volume of red blood cell transfusions. Further investigation is warranted to fully understand the implications of elevated serum iron and ferritin in pediatric ECMO. [ABSTRACT FROM AUTHOR]

Paleoclimate data assimilation (DA) is a novel tool for reconstructing past climates that directly integrates proxy records with climate model output. Despite the potential for DA to expand the scope of quantitative paleoclimatology, these methods remain difficult to implement in practice due to the multi-faceted requirements and data handling necessary for DA reconstructions, the diversity of DA methods, and the need for computationally efficient algorithms. Here, we present DASH, a MATLAB toolbox designed to facilitate paleoclimate DA analyses. DASH provides command line and scripting tools that implement common tasks in DA workflows. The toolbox is highly modular and is not built around any specific analysis, and thus DASH supports paleoclimate DA for a wide variety of time periods, spatial regions, proxy networks, and algorithms. DASH includes tools for integrating and cataloguing data stored in disparate formats, building state vector ensembles, and running proxy (system) forward models. The toolbox also provides optimized algorithms for implementing ensemble Kalman filters, particle filters, and optimal sensor analyses with variable and modular parameters. This paper reviews the key components of the DASH toolbox and presents examples illustrating DASH's use for paleoclimate DA applications. [ABSTRACT FROM AUTHOR]

Since both parties committed to adding women to the federal bench in the 1970s, Democratic and Republican presidents have sought out qualified women for judgeships. Diversifying the bench offers symbolic and substantive benefits to both parties, but those benefits come at the cost of finding non-traditional nominees. Presidents can take one of two different approaches to diversification: maintain existing diversity by anchoring women to a seat, or increase diversity by considering women for every opening. Given presidents consider many factors, including electoral benefits, when selecting potential judges, we expect partisan politics influence approach. Examining all lower court nominations made between 1981 and 2022, we find that Republican presidents tend to anchor while Democratic presidents expand diversity. Additionally, Senate diversity influences diversification, as women are more likely to get nominated when the relevant state Senate delegation includes a woman. Overall, we offer new perspectives on the mechanisms of judicial diversification. [ABSTRACT FROM AUTHOR]

New presidents now commonly inherit a backlog of judicial vacancies. Lifetime judicial appointments provide presidents with lasting policy influence, but time and energy are rarely more valuable than after transitions while the selection and vetting of new judicial nominations are costly. Attempting to alter the ideological character of the courts could yield opposition that further increases the cost of each nomination. How then do new presidents prioritize vacancies? We use a unique data set of all district court vacancies that exist at the start of a new presidency to investigate. We find significant variation in the time to nominate within administrations and that presidents tend to prioritize necessity and expediency when filling transition vacancies. [ABSTRACT FROM AUTHOR]

Background: Potentially preventable hospitalizations (PPH) are defined as unplanned hospital admissions which could potentially have been prevented with the provision of effective, timely outpatient care. To better understand and ultimately reduce rates of PPH, a means of identifying those which are actually preventable is required. The Preventability Assessment Tool (PAT) was designed for use by hospital clinicians to assess the preventability of unplanned admissions for chronic conditions.Objective: The present study examined the ability of the PAT to distinguish between those unplanned admissions which are preventable and those which are not, compared to the assessments of an Expert Panel.Methods: Data were collected between November 2014 and June 2017 at three hospitals in NSW, Australia. Participants were community-dwelling patients with unplanned hospital admissions for congestive heart failure, chronic obstructive pulmonary disease, diabetes complications or angina pectoris. A nurse and a doctor caring for the patient made assessments of the preventability of the admission using the PAT. Expert Panels made assessments of the preventability of each admission based on a comprehensive case report and consensus process.Results: There was little concordance between the hospital doctors and nurses regarding the preventability of admissions, nor between the assessments of the Expert Panel and the hospital nurse or the Expert Panel and the hospital doctor.Conclusions: The PAT demonstrated poor concurrent validity and is not a valid tool for assessing the preventability of unplanned hospital admissions. The use of Expert Panels provides a more rigorous approach to assessing the preventability of such admissions. [ABSTRACT FROM AUTHOR]

A multireaction chemical equilibria geothermometry (MEG) model applicable to high-temperature geothermal systems has been developed over the past three decades. Given sufficient data, this model provides more constraint on calculated reservoir temperatures than classical chemical geothermometers that are based on either the concentration of silica (SiO 2 ), or the ratios of cation concentrations. A set of 23 chemical analyses from Ojo Caliente Spring and 22 analyses from other thermal features in the Lower Geyser Basin of Yellowstone National Park are used to examine the sensitivity of calculated reservoir temperatures using the GeoT MEG code (Spycher et al. 2013, 2014) to quantify the effects of solute concentrations, degassing, and mineral assemblages on calculated reservoir temperatures. Results of our analysis demonstrate that the MEG model can resolve reservoir temperatures within approximately ± 15 °C, and that natural variation in fluid compositions represents a greater source of variance in calculated reservoir temperatures than variations caused by analytical uncertainty (assuming ~ 5% for major elements). The analysis also suggests that MEG calculations are particularly sensitive to variations in silica concentration, the concentrations of the redox species Fe(II) and H 2 S, and that the parameters defining steam separation and CO 2 degassing from the liquid may be adequately determined by numerical optimization. Results from this study can provide guidance for future applications of MEG models, and thus provide more reliable information on geothermal energy resources during exploration. [ABSTRACT FROM AUTHOR]

The EBIT calorimeter spectrometer (ECS) is a new high-resolution, broadband x-ray spectrometer that has recently been installed at the Electron Beam Ion Trap Facility (EBIT) at the Lawrence Livermore National Laboratory. The ECS is an entirely new production class spectrometer that replaces the XRS/EBIT spectrometer that has been operating at EBIT since 2000. The ECS utilizes a 32-pixel x-ray calorimeter array from the XRS instrument on the Suzaku x-ray observatory. Eighteen of the pixels are optimized for the 0.1–10 keV band and yield 4.5 eV full width at half maximum energy resolution and 95% quantum efficiency at 6 keV. In addition, the ECS includes 14 detector pixels that are optimized for the high-energy band with a bandpass from 0.5 to over 100 keV with 34 eV resolution and 32% quantum efficiency at 60 keV. The ECS detector array is operated at 50 mK using a five stage cryogenic system that is entirely automated. The instrument takes data continuously for over 65 h with a 2.5 h recycle time. The ECS is a nondispersive, broadband, highly efficient spectrometer that is one of the prime instruments at the EBIT facility. The instrument is used for studies of absolute cross sections, charge exchange recombination, and x-ray emission from nonequilibrium plasmas, among other measurements in our laboratory astrophysics program. [ABSTRACT FROM AUTHOR]

Background: Elevated matrix metalloproteinase-9 production during inflammation may be deleterious to epithelial barrier function. Therefore we examined the effect of proinflammatory cytokines on the expression and regulation of matrix metalloproteinase-9 in a model renal epithelial cell system. Tight junctions limit diffusion between compartments and permit directional transport of solutes. Impairment of these junctional complexes by proteolysis may contribute to renal failure through loss of barrier function. Methods: The renal epithelial cell model, MDCK cells were employed to examine metalloproteinase activity and mRNA expression. Epithelial barrier function was determined using paracellular flux studies. Results: We found that matrix metalloproteinase-9 expression (MMP-9) and activity is markedly elevated in response to tumor necrosis factor-? exposure through a mitogen-activated protein kinase dependent pathway. The MMP-9 is predominately secreted into the apical compartment and elevated MMP-9 expression correlates with impaired cell barrier function that was restored using a specific inhibitor of MMP activity. Addition of recombinant MMP-9 to the apical compartment of MDCK cultures significantly elevated paracellular flux rate. Conclusions: We provide direct evidence for a MMP-9-mediated mechanism that produces junctional disruption. Collectively, these findings support the hypothesis that impaired epithelial barrier function due to activation of tissue/matrix degrading mechanisms occurs in response to specific inflammatory cues. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article presents the study to characterize the response of Madin-Darby canine kidney (MDCK) cells to the combination of tumor necrosis factor-α (TNFα ) and interferon-ϒ (INFϒ). The researchers have hypothesized that TNFα/INFϒ would impar MDCK cell tight junction function, and determined the percentage of apoptotic cells. Data suggested that downstream effectors of MAP kinase mediated the TNFα/INFϒ-induced junctional reorganization.

Infants undergoing ECMO may have elevated serum ferritin and iron levels, raising concerns about iron overload. Recent studies question the utility of these markers for acute vs. chronic iron overload during ECMO. This study evaluates iron content and localization in autopsy tissues from deceased infants who received or were considered for ECMO.This retrospective single-center case-control study analyzed paraffin-embedded tissues from the basal ganglia, liver, spleen, pancreas, and kidney. Tissue sections were stained to quantify iron deposition and an independent pathologist reviewed samples for iron accumulation.Eighteen deceased infants' tissues were analyzed: nine underwent ECMO, and nine were considered for it. Both groups showed multi-organ iron accumulation with no significant difference between ECMO and non-ECMO cohorts. Red blood cell transfusions were linked to increased iron content in adrenal (p = 0.004), hepatic (p = 0.042), and splenic (p = 0.013) tissues.ECMO exposure alone does not independently increase iron content in infants' organs. Multi-organ iron accumulation in both groups suggests iron deposition in critically ill pediatric patients irrespective of ECMO exposure. Further research is needed to understand the mechanisms and implications. [ABSTRACT FROM AUTHOR]

Oxidative stress has been linked to many disease processes, including ischemia-reperfusion injury and toxicant damage. Loss of barrier function in renal epithelial cells due to alterations in the tight junction (TJ) may complicate the effects of oxidative stress. The mitogen-activated protein kinase (MAPK) pathway has been shown to be an early cellular signal during hydrogen peroxide exposure oxidant injury and may be linked to TJ protein alterations. In this study, we are interested in effects on cell barrier function due to a brief exposure to hydrogen peroxide and the ensuing recovery period. Transepithelial electrical resistance and paracellular flux were used as a measure of barrier integrity, while the lactate dehydrogenase activity assay was used to assess cytotoxicity. Protein expression was determined via Western blot analysis, and immunofluorescent staining was used for localization of TJ proteins and examination of the actin cytoskeleton. A positive relationship between dose of hydrogen peroxide and cytotoxicity was observed. Low doses of hydrogen peroxide perturb TJ function without exhibiting a cytotoxic effect. ERK-1/2, an enzyme of the MAPK pathway, was activated within minutes of exposure to hydrogen peroxide as determined by phospho-ERK content. Exposure to hydrogen peroxide with subsequent recovery was also associated with changes in expression and localization of the TJ proteins occludin and claudin-1. These findings demonstrate that the TJ in MDCK cells is altered by exposure to hydrogen peroxide and these changes are preceded by activation of the MAPK pathway. [ABSTRACT FROM AUTHOR]

ECMO plays a crucial role in treating severe respiratory and cardiac failure in pediatric patients. However, its impact on the regulation of erythropoietin (EPO) and erythropoiesis remains poorly understood. Factors such as improved oxygenation, inflammation, and hemodilution associated with ECMO treatment may influence EPO production and erythropoiesis. This study aimed to examine the effects of ECMO on EPO regulation and erythropoiesis in pediatric patients.This retrospective study serially quantified EPO serum levels, measured markers of erythropoiesis, and tabulated clinical outcomes of pediatric ECMO patients. Descriptive statistics and Pearson correlation coefficients were used to identify associations between biomarkers and clinical care parameters.Preliminary findings suggest a disconnection between elevated EPO levels and reduced markers of erythropoiesis or iron metabolism, indicating ineffective erythropoiesis. Patients receiving more than 10 mL/kg/day of RBC transfusions had higher reticulocyte counts. Non-survivors had sustained elevations of EPO serum levels but reduced erythropoietic activity.In ECMO-treated pediatric patients, ineffective erythropoiesis is a significant concern and may be associated with higher mortality rates. Understanding the mechanisms behind this pathology could better inform clinical approaches and optimize management strategies. Further research is imperative to uncover the factors resulting in ineffective erythropoiesis in these patients and to develop targeted interventions. [ABSTRACT FROM AUTHOR]

Background: HIV pre-exposure prophylaxis (PrEP) is highly effective and has been government subsidised in Australia since April, 2018. We examined HIV incidence over 5 years in a retrospective observational cohort of people who had received subsidised PrEP., Methods: Linked de-identified dispensing records for all government-subsidised oral PrEP, HIV antiretroviral therapy (ART), and hepatitis C treatment were used. We included all people dispensed subsidised PrEP from April 1, 2018, to March 31, 2023, and examined records up to Sept 30, 2023. Exposure was measured from date of first PrEP prescription and days covered by PrEP calculated for individuals based on quantity and date supplied. Assuming that HIV was diagnosed 30 days before ART initiation, we imputed the date of acquisition as the midpoint between the diagnosis and the later of the last PrEP prescription or 6 months before the diagnosis. We calculated HIV incidence and its predictors using Poisson regression., Findings: We included 66 206 people dispensed PrEP: 64 757 (97·8%) were men; median age was 33 years (IQR 27-43). 207 people acquired HIV, with an overall incidence of 1·07 per 1000 person-years (95% CI 0·93-1·23). Incidence was 2·61 per 1000 person-years among those dispensed PrEP once only. Using this group as a comparator, those with 60% or more days covered by PrEP had a 78·5% reduction in incidence (0·56 per 1000 person-years, p<0·0001) and those with less than 60% days covered had a 61·6% reduction (0·99 per 1000 person-years, p=0·0045). Independent predictors of HIV acquisition were a record of hepatitis C treatment (9·83 per 1000 person-years, adjusted incident rate ratio [aIRR] 8·70, 95% CI 4·86-15·56), only attending prescribers outside of areas with a high estimated prevalence of gay men (1·66 per 1000 person-years, aIRR 1·50, 1·08-2·09), age 18-29 years (1·33 per 1000 person-years, aIRR 1·56, 1·11-2·21), and earlier year of first PrEP., Interpretation: The low observed incidence of HIV among people receiving government-subsidised PrEP highlights the success of a national programme of oral PrEP scale-up in achieving sustained reduction in community HIV transmission. However, incidence varied greatly, indicating that more research is needed to understand why people were not taking PrEP at times of risk and emphasising the need for new interventions focused on this population to achieve elimination of HIV transmission. Individuals dispensed PrEP once only and less frequent users might benefit from more support., Funding: None., Competing Interests: Declaration of interests NAM and RJG have received funding to their institution for investigator-initiated research unrelated to this work from Gilead Sciences. NAM and BRB have unpaid leadership and governance roles with ASHM and ACON, respectively. BRB has received funding to his institution for research unrelated to this work from ViiV Healthcare and Gilead Sciences, and payment, honoraria, or support for attending meetings from FHI 360, Gilead Sciences, Virology Education, and ViiV Healthcare. MWT has received funding to his institution for investigator-initiated research unrelated to this work and speaker's honoraria from Gilead Sciences. AEG has received funding to his institution for investigator-initiated research unrelated to this work from GSK and ViiV Healthcare, payment or honoraria from Clinical Care Options and Sequiris, and support for attending meetings from ViiV Healthcare. MAS has received funding to his institution for investigator-initiated research unrelated to this work from Gilead Sciences and AbbVie, and consulting fees for activities unrelated to this work from Gilead Sciences. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The tight junction is a dynamic structure that is regulated by a number of cellular signaling processes. Occludin, claudin-1, claudin-2 and claudin-3 are integral membrane proteins found in the tight junction of MDCK cells. These proteins are restricted to this region of the membrane by a complex array of intracellular proteins which are tethered to the cytoskeleton. Alteration of these tight junction protein complexes during pathological events leads to impaired epithelial barrier function that perturbs water and electrolyte homeostasis. We examined MDCK cell barrier function in response to challenge by the proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma)., Results: Exposure of MDCK cells to TNFalpha/IFNgamma resulted in a marked sustained elevation of transepithelial electrical resistance (TER) as well as elevated paracellular permeability. We demonstrate that the combination of TNFalpha/IFNgamma at doses used in this study do not significantly induce MDCK cell apoptosis. We observed significant alterations in occludin, claudin-1 and claudin-2 protein expression, junctional localization and substantial cytoskeletal reorganization. Pharmacological inhibition of ERK1/2 and p38 signaling blocked the deleterious effects of the proinflammatory cytokines on barrier function., Conclusion: These data strongly suggest that downstream effectors of MAP kinase signaling pathways mediate the TNFalpha/IFNgamma-induced junctional reorganization that modulates MDCK cell barrier function.