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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: 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: 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. [ABSTRACT FROM AUTHOR]

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]

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+ 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+ 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. [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]

President Trump brought judicial appointments to the pinnacle of political salience while campaigning and in office. He was also the first president to inherit Senate rules making it easier to confirm judicial appointments while past partisan obstruction provided his administration with a backlog of vacancies. How then, did President Trump's ability to gain Senate confirmation for judicial nominees compare to recent presidents? We find that he was indeed able to fill an historic number of vacancies. However, the administration was not universally successful as key nominations had to be prioritized at the expense of others. Our findings assess Trump's legacy on judicial appointments and demonstrate the practical tradeoffs newly emerging in appointment politics. [ABSTRACT FROM AUTHOR]

We use the Northern Hemisphere Tree-Ring Network Development (NTREND) tree-ring database to examine the effects of using a small, highly sensitive proxy network for paleotemperature data assimilation over the last millennium. We first evaluate our methods using pseudoproxy experiments. These indicate that spatial assimilations using this network are skillful in the extratropical Northern Hemisphere and improve on previous NTREND reconstructions based on point-by-point regression. We also find our method is sensitive to climate model biases when the number of sites becomes small. Based on these experiments, we then assimilate the real NTREND network. To quantify model prior uncertainty, we produce 10 separate reconstructions, each assimilating a different climate model. These reconstructions are most dissimilar prior to 1100 CE, when the network becomes sparse, but show greater consistency as the network grows. Temporal variability is also underestimated before 1100 CE. Our assimilation method produces spatial uncertainty estimates, and these identify tree-line North America and eastern Siberia as regions that would most benefit from development of new millennial-length temperature-sensitive tree-ring records. We compare our multimodel mean reconstruction to five existing paleotemperature products to examine the range of reconstructed responses to radiative forcing. We find substantial differences in the spatial patterns and magnitudes of reconstructed responses to volcanic eruptions and in the transition between the Medieval epoch and Little Ice Age. These extant uncertainties call for the development of a paleoclimate reconstruction intercomparison framework for systematically examining the consequences of proxy network composition and reconstruction methodology and for continued expansion of tree-ring proxy networks. [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]

Background: Obesity and diabetes mellitus are directly implicated in many adverse health consequences in adults as well as in the offspring of obese and diabetic mothers. Hispanic Americans are particularly at risk for obesity, diabetes, and end-stage renal disease. Maternal obesity and/or diabetes through prenatal programming may alter the fetal epigenome increasing the risk of metabolic disease in their offspring. The aims of this study were to determine if maternal obesity or diabetes mellitus during pregnancy results in a change in infant methylation of CpG islands adjacent to targeted genes specific for obesity or diabetes disease pathways in a largely Hispanic population. Methods: Methylation levels in the cord blood of 69 newborns were determined using the Illumina Infinium MethylationEPIC BeadChip. Over 850,000 different probe sites were analyzed to determine whether maternal obesity and/or diabetes mellitus directly attributed to differential methylation; epigenome-wide and regional analyses were performed for significant CpG sites. Results: Following quality control, agranular leukocyte samples from 69 newborns (23 normal term (NT), 14 diabetes (DM), 23 obese (OB), 9 DM/OB) were analyzed for over 850,000 different probe sites. Contrasts between the NT, DM, OB, and DM/OB were considered. After correction for multiple testing, 15 CpGs showed differential methylation from the NT, associated with 10 differentially methylated genes between the diabetic and non-diabetic subgroups, CCDC110, KALRN, PAG1, GNRH1, SLC2A9, CSRP2BP, HIVEP1, RALGDS, DHX37, and SCNN1D. The effects of diabetes were partly mediated by the altered methylation of HOOK2, LCE3C, and TMEM63B. The effects of obesity were partly mediated by the differential methylation of LTF and DUSP22. Conclusions: The presented data highlights the associated altered methylation patterns potentially mediated by maternal diabetes and/or obesity. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the effects on newborn body composition and future health risk factors for metabolic disease. Additional future consideration should be targeted to the role of Hispanic inheritance. Potential future targeting of transgenerational propagation and developmental programming may reduce population obesity and diabetes risk. [ABSTRACT FROM AUTHOR]

This study aimed to determine the microbial composition of faeces from two groups of caecotrophagic animals; rabbits and guinea pigs. In addition the study aimed to determine the community present in the different organs in the rabbit. DNA was extracted from seven of the organs in wild rabbits (n = 5) and from faecal samples from domesticated rabbits (n = 6) and guinea pigs (n = 6). Partial regions of the small ribosomal sub-unit were amplified by PCR and then the sequences present in each sample were determined by next generation sequencing. Differences were detected between samples from rabbit and guinea pig faeces, suggesting that there is not a microbial community common to caecotrophagic animals. Differences were also detected in the different regions of the rabbits’ digestive tracts. As with previous work, many of the organisms detected were Firmicutes or unclassified species and there was a lack of Fibrobacteres, but for the first time we observed a high number of Bacteroidetes in rabbit samples. This work re-iterates high levels of Firmicutes and unclassified species are present in the rabbit gut, together with low number of Fibrobacteres. This suggests that in the rabbit gut, organisms other than the Fibrobacteres must be responsible for fibre digestion. However observation of high numbers of Bacteroidetes suggests that this phylum may indeed have a role to play in digestion in the rabbit gut. [ABSTRACT FROM AUTHOR]

Tumor-specific deregulated expression of claudins, integral membrane proteins found in tight junctions (TJs), has indicated a possible role for TJ disruption in cancer progression. The current study demonstrates the marked overexpression of claudin-3 protein in two breast cancer cell lines of metastatic origin (MCF-7 and MDA-MB-415). Immunofluorescence and differential detergent fractionation analyses revealed that, although claudin-3 was primarily localized at cell junctions, it was also detected intracellularly. Similarly, the siRNA-mediated suppression of claudin-3 did not considerably affect its pattern of subcellular distribution relative to mock-transfected cells. However, there appeared to be a preferential loss of claudin-3 signal in the cytoskeletal fraction. Wound-healing assays were conducted to assess the effect of endogenous overexpression versus siRNA-mediated suppression of claudin-3 on cellular motility in MCF-7 cells. Suppression of claudin-3 protein levels resulted in a marked decrease in the rate of cellular motility relative to mock-transfected cells. These findings suggest that overexpression of claudin-3 may be important in disrupting TJ integrity and thus contribute to enhanced cellular motility, a key component of tumor progression. [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.

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-α (TNFα) and interferon-γ (IFNγ). Results: Exposure of MDCK cells to TNFα/IFNγ resulted in a marked sustained elevation of transepithelial electrical resistance (TER) as well as elevated paracellular permeability. We demonstrate that the combination of TNFα/IFNγ 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 TNFα/IFNγ-induced junctional reorganization that modulates MDCK cell barrier function. [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]