Outcome and safety of a surveillance biopsy guided personalized immunosuppression program after liver transplantation.

Graft survival beyond year 1 has not changed after orthotopic liver transplantation (OLT) over the last decades. Likewise, OLT causes comorbidities such as infection, renal impairment and cancer. We evaluated our single-center real-world individualized immunosuppression program after OLT, based on 211 baseline surveillance biopsies (svLbx) without any procedural complications. Patients were classified as low, intermediate and high rejection risk based on graft injury in svLbx and anti-HLA donor-specific antibodies. While 32% of patients had minimal histological inflammation, 57% showed histological inflammation and 23% advanced fibrosis (>F2), which was not predicted by lab parameters. IS was modified in 79% of patients after svLbx. After immunosuppression reduction in 69 patients, only 5 patients showed ALT elevations and three of these patients had a biopsy-proven acute rejection, two of them related to lethal comorbidities. The rate of liver enzyme elevation including rejection was not significantly increased compared to a svLbx control cohort prior to the initiation of our structured program. Immunosuppression reduction led to significantly better kidney function compared to this control cohort. In conclusion, a biopsy guided personalized immunosuppression protocol after OLT can identify patients requiring lower immunosuppression or patients with graft injury in which IS should not be further reduced.

Loss of HIF1A From Pancreatic Cancer Cells Increases Expression of PPP1R1B and Degradation of p53 to Promote Invasion and Metastasis.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, resulting in the up-regulation of hypoxia inducible factor 1 alpha (HIF1A), which promotes the survival of cells under low-oxygen conditions. We studied the roles of HIF1A in the development of pancreatic tumors in mice. METHODS: We performed studies with KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx1-Cre (KPC) mice, KPC mice with labeled pancreatic epithelial cells (EKPC), and EKPC mice with pancreas-specific depletion of HIF1A. Pancreatic and other tissues were collected and analyzed by histology and immunohistochemistry. Cancer cells were cultured from PDACs from mice and analyzed in cell migration and invasion assays and by immunoblots, real-time polymerase chain reaction, and liquid chromatography-mass spectrometry. We performed studies with the human pancreatic cancer cell lines PATU-8988T, BxPC-3, PANC-1, and MiaPACA-2, which have no or low metastatic activity, and PATU-8988S, AsPC-1, SUIT-2 and Capan-1, which have high metastatic activity. Expression of genes was knocked down in primary cancer cells and pancreatic cancer cell lines by using small hairpin RNAs; cells were injected intravenously into immune-competent and NOD/SCID mice, and lung metastases were quantified. We compared levels of messenger RNAs in pancreatic tumors and normal pancreas in The Cancer Genome Atlas. RESULTS: EKPC mice with pancreas-specific deletion of HIF1A developed more advanced pancreatic neoplasias and PDACs with more invasion and metastasis, and had significantly shorter survival times, than EKPC mice. Pancreatic cancer cells from these tumors had higher invasive and metastatic activity in culture than cells from tumors of EKPC mice. HIF1A-knockout pancreatic cancer cells had increased expression of protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B). There was an inverse correlation between levels of HIF1A and PPP1R1B in human PDAC tumors; higher expression of PPP1R1B correlated with shorter survival times of patients. Metastatic human pancreatic cancer cell lines had increased levels of PPP1R1B and lower levels of HIF1A compared with nonmetastatic cancer cell lines; knockdown of PPP1R1B significantly reduced the ability of pancreatic cancer cells to form lung metastases in mice. PPP1R1B promoted degradation of p53 by stabilizing phosphorylation of MDM2 at Ser166. CONCLUSIONS: HIF1A can act a tumor suppressor by preventing the expression of PPP1R1B and subsequent degradation of the p53 protein in pancreatic cancer cells. Loss of HIF1A from pancreatic cancer cells increases their invasive and metastatic activity.

Projected ozone trends and changes in the ozone-precursor relationship in the South Coast Air Basin in response to varying reductions of precursor emissions.

UNLABELLED: This study examined the effects of varying future reductions in emissions of oxides of nitrogen (NOx) and volatile organic compounds (VOC) on the location and magnitude of peak ozone levels within California's South Coast Air Basin (SoCAB or Basin). As ozone formation is currently VOC-limited in the Basin, model simulations with 2030 baseline emissions (-61% for NOx and -32% for VOC from 2008) predict 10-20% higher peak ozone levels (i.e., NOx disbenefit) in the western and central SoCAB compared with the 2008 base simulation. With additional NOx reductions of 50% beyond the 2030 baseline emissions (-81% from 2008), the predicted ozone levels are reduced by about 15% in the eastern SoCAB but remain comparable to 2008 levels in the western and central Basin. The Basin maximum ozone site shifts westward to more populated areas of the Basin and will result potentially in greater population-weighted exposure to ozone with even a relatively small shortfall in the required NOx reductions unless accompanied by additional VOC reductions beyond 2030 baseline levels. Once committed to a NOx-focused control strategy, NOx reductions exceeding 90% from 2008 levels will be necessary to attain the ozone National Ambient Air Quality Standards (NAAQS). The findings from this study and other recent work that the current VOC emission estimates are underestimated by about 50% suggest that greater future VOC reductions will be necessary to reach the projected 2030 baseline emissions. Increasing the base year VOC emissions by a factor of 1.5 result in higher 2008 baseline ozone predictions, lower relative response factors, and about 20% lower projected design values. If correct, these findings have important implications for the total and optimum mix of VOC and NOx emission reductions that will be required to attain the ozone NAAQS in the SoCAB. IMPLICATIONS: Results of this study indicate that ozone levels in the western and central SoCAB would remain the same or increase with even a relatively small shortfall in the projected NOx reductions under planned NOx-focused controls. This possibility, therefore, warrants a rigorous analysis of the costs and effects of varying reductions of VOC and NOx on the formation and combined health impacts of ozone and secondary particles. Given the nonlinearity of ozone formation, such analyses should include the implications of gradually increasing global background ozone concentrations and the Basin's topography and meteorology on the practical limits of alternative emission control strategies.

Deaf readers use leftward information to read more efficiently: Evidence from eye tracking.

Little is known about how information to the left of fixation impacts reading and how it may help to integrate what has been read into the context of the sentence. To better understand the role of this leftward information and how it may be beneficial during reading, we compared the sizes of the leftward span for reading-matched deaf signers (n = 32) and hearing adults (n = 40) using a gaze-contingent moving window paradigm with windows of 1, 4, 7, 10, and 13 characters to the left, as well as a no-window condition. All deaf participants were prelingually and profoundly deaf, used American Sign Language (ASL) as a primary means of communication, and were exposed to ASL before age eight. Analysis of reading rates indicated that deaf readers had a leftward span of 10 characters, compared to four characters for hearing readers, and the size of the span was positively related to reading comprehension ability for deaf but not hearing readers. These findings suggest that deaf readers may engage in continued word processing of information obtained to the left of fixation, making reading more efficient, and showing a qualitatively different reading process than hearing readers.

Barriers to perinatal mental health care experiences by midwives and obstetricians and their patients: A rapid review.

INTRODUCTION: While perinatal mental health concerns are common, little attention is paid to noticing or addressing these concerns. Midwives and obstetricians are uniquely positioned to universally screen their patients for mental health conditions during the perinatal period, and provide referrals for additional mental health supports if relevant. Previous studies on perinatal mental health care have focused primarily on midwifery care, excluding perinatal healthcare providers such as obstetricians. This rapid review aims to examine the barriers to accessing mental health care during the perinatal period as experienced by obstetricians, midwives, and their patients. METHODS: A rapid review of literature was conducted on barriers to perinatal mental health care as experienced by patients, midwives, and obstetricians. The search strategy included published literature from PubMed, CINAHL, PsycINFO, and Web of Science published between 2000 and 2020. All documents were screened by two researchers and disagreements were resolved through consensus with a third reviewer. After data from all included articles were extracted, thematic analysis was conducted, and findings were compared with related reviews that focused on mental health access for individuals who accessed midwifery care. RESULTS: Of the 539 references and documents that were screened, 31 articles met the inclusion criteria. In the extraction phase, country, study objective(s), study design, perspective(s), barriers, and the dimension(s) impacted along the pathway to accessing care were retrieved from the 31 included articles. After all barriers were classified using the Supply-Side Dimensions of Access, we developed a classification framework to further examine stigma at the societal, institutional, and individual levels. DISCUSSION: While midwives utilize a more holistic approach to care as compared with obstetricians, the barriers identified through this rapid review indicate that obstetricians and their patients face similar struggles to accessing and providing mental health care. Moreover, stigma plays a large role in the barriers experienced by patients, midwives, and obstetricians - at individual and institutional levels. CONCLUSION: Obstetricians encounter similar stigma-related barriers as midwives in detecting mental health concerns, as well as connecting clients to available mental health resources and supports. Therefore, to effectively eliminate barriers to accessing perinatal mental health care, a systemic change must be enacted throughout all three layers to address the deep-rooted stigma associated with accessing mental health care during the perinatal period.

Rehabilitation Interventions for Physical Capacity and Quality of Life in Adults With Post-COVID-19 Condition: A Systematic Review and Meta-Analysis.

Importance: Current rehabilitation guidelines for patients with post-COVID-19 condition (PCC) are primarily based on expert opinions and observational data, and there is an urgent need for evidence-based rehabilitation interventions to support patients with PCC. Objective: To synthesize the findings of existing studies that report on physical capacity (including functional exercise capacity, muscle function, dyspnea, and respiratory function) and quality of life outcomes following rehabilitation interventions in patients with PCC. Data Sources: A systematic electronic search was performed from January 2020 until February 2023, in MEDLINE, Scopus, CINAHL, and the Clinical Trials Registry. Key terms that were used to identify potentially relevant studies included long-covid, post-covid, sequelae, exercise therapy, rehabilitation, physical activity, physical therapy, and randomized controlled trial. Study Selection: This study included randomized clinical trials that compared respiratory training and exercise-based rehabilitation interventions with either placebo, usual care, waiting list, or control in patients with PCC. Data Extraction and Synthesis: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A pairwise bayesian random-effects meta-analysis was performed using vague prior distributions. Risk of bias was assessed using the Cochrane risk of bias tool version 2, and the certainty of evidence was evaluated using the GRADE system by 2 independent researchers. Main Outcomes and Measures: The primary outcome was functional exercise capacity, measured at the closest postintervention time point by the 6-minute walking test. Secondary outcomes were fatigue, lower limb muscle function, dyspnea, respiratory function, and quality of life. All outcomes were defined a priori. Continuous outcomes were reported as standardized mean differences (SMDs) with 95% credible intervals (CrIs) and binary outcomes were summarized as odds ratios with 95% CrIs. The between-trial heterogeneity was quantified using the between-study variance, τ2, and 95% CrIs. Results: Of 1834 identified records, 1193 were screened, and 14 trials (1244 patients; 45% female participants; median [IQR] age, 50 [47 to 56] years) were included in the analyses. Rehabilitation interventions were associated with improvements in functional exercise capacity (SMD, -0.56; 95% CrI, -0.87 to -0.22) with moderate certainty in 7 trials (389 participants). These improvements had a 99% posterior probability of superiority when compared with current standard care. The value of τ2 (0.04; 95% CrI, 0.00 to 0.60) indicated low statistical heterogeneity. However, there was significant uncertainty and imprecision regarding the probability of experiencing exercise-induced adverse events (odds ratio, 1.68; 95% CrI, 0.32 to 9.94). Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that rehabilitation interventions are associated with improvements in functional exercise capacity, dyspnea, and quality of life, with a high probability of improvement compared with the current standard care; the certainty of evidence was moderate for functional exercise capacity and quality of life and low for other outcomes. Given the uncertainty surrounding the safety outcomes, additional trials with enhanced monitoring of adverse events are necessary.

A Medicaid Statewide Hypertension Quality Improvement Project: Initial Results.

Background Hypertension control is critical to reducing cardiovascular disease, challenging to achieve, and exacerbated by socioeconomic inequities. Few states have established statewide quality improvement (QI) infrastructures to improve blood pressure (BP) control across economically disadvantaged populations. In this study, we aimed to improve BP control by 15% for all Medicaid recipients and by 20% for non-Hispanic Black participants. Methodology This QI study used repeated cross-sections of electronic health record data and, for Medicaid enrollees, linked Medicaid claims data for 17,672 adults with hypertension seen at one of eight high-volume Medicaid primary care practices in Ohio from 2017 to 2019. Evidence-based strategies included (1) accurate BP measurement; (2) timely follow-up; (3) outreach; (4) a standardized treatment algorithm; and (5) effective communication. Payers focused on a 90-day supply (vs. 30-day) of BP medications, home BP monitor access, and outreach. Implementation efforts included an in-person kick-off followed by monthly QI coaching and monthly webinars. Weighted generalized estimating equations were used to estimate the baseline, one-year, and two-year implementation change in the proportion of visits with BP control (<140/90 mm Hg) stratified by race/ethnicity. Results For all practices, the percentage of participants with controlled BP increased from 52% in 2017 to 60% in 2019. Among non-Hispanic Whites, the odds of achieving BP control in year one and year two were 1.24 times (95% confidence interval: 1.14, 1.34) and 1.50 times (1.38, 1.63) higher relative to baseline, respectively. Among non-Hispanic Blacks, the odds for years one and two were 1.18 times (1.10, 1.27) and 1.34 times (1.24, 1.45) higher relative to baseline, respectively. Conclusions A hypertension QI project as part of establishing a statewide QI infrastructure improved BP control in practices with a high volume of disadvantaged patients. Future efforts should investigate ways to reduce inequities in BP control and further explore factors associated with greater BP improvements and sustainability.

Coaching quality improvement in primary care to improve hypertension control.

BACKGROUND: Effective management of hypertension (HTN) is a priority in primary care, necessary to decrease the costs, morbidity, and mortality associated with cardiovascular disease. Strategies to support quality improvement (QI) efforts in primary care are needed to make significant improvements in population health, especially for patients who experience socioeconomic inequalities. LOCAL PROBLEM: To address the high rate (>50%) of uncontrolled HTN in the state of Ohio, a statewide QI project was implemented in high-volume Medicaid practices, aimed at improving blood pressure control and addressing racial disparities. The initiative expanded to include coaching QI to support efforts in primary care practices. METHODS: The Model for Improvement guided development of Plan-Do-Study-Act (PDSA) cycles facilitated by QI coaching and APRN collaboration to implement key components of HTN guidelines: accurate blood pressure measurement, effective treatment, and timely follow-up. INTERVENTIONS: Interventions were implemented after PDSA cycles over 18 months in two practice sites to address HTN control. Linking multiple PDSA test cycles and review of data bimonthly allowed for reflection on the impact of interventions for non-Hispanic Black patients and the overall patient population. RESULTS: The percentage of patients with controlled HTN, repeat blood pressure measurement, and timely follow-up improved in an urban primary care practice associated with an academic medical center and in a rural federally qualified health center. CONCLUSIONS: Primary care practices can benefit from the external support of coaching when implementing QI processes to make meaningful change. APRNs are key collaborators for expanding QI efforts in primary care.

Fossil gaps inferred from phylogenies alter the apparent nature of diversification in dragonflies and their relatives.

BACKGROUND: The fossil record has suggested that clade growth may differ in marine and terrestrial taxa, supporting equilibrial models in the former and expansionist models in the latter. However, incomplete sampling may bias findings based on fossil data alone. To attempt to correct for such bias, we assemble phylogenetic supertrees on one of the oldest clades of insects, the Odonatoidea (dragonflies, damselflies and their extinct relatives), using MRP and MRC. We use the trees to determine when, and in what clades, changes in taxonomic richness have occurred. We then test whether equilibrial or expansionist models are supported by fossil data alone, and whether findings differ when phylogenetic information is used to infer gaps in the fossil record. RESULTS: There is broad agreement in family-level relationships between both supertrees, though with some uncertainty along the backbone of the tree regarding dragonflies (Anisoptera). "Anisozygoptera" are shown to be paraphyletic when fossil information is taken into account. In both trees, decreases in net diversification are associated with species-poor extant families (Neopetaliidae, Hemiphlebiidae), and an upshift is associated with Calopterygidae + Polythoridae. When ghost ranges are inferred from the fossil record, many families are shown to have much earlier origination dates. In a phylogenetic context, the number of family-level lineages is shown to be up to twice as high as the fossil record alone suggests through the Cretaceous and Cenozoic, and a logistic increase in richness is detected in contrast to an exponential increase indicated by fossils alone. CONCLUSIONS: Our analysis supports the notion that taxa, which appear to have diversified exponentially using fossil data, may in fact have diversified more logistically. This in turn suggests that one of the major apparent differences between the marine and terrestrial fossil record may simply be an artifact of incomplete sampling. Our results also support previous notions that adult colouration plays an important role in odonate radiation, and that Anisozygoptera should be grouped in a single inclusive taxon with Anisoptera, separate from Zygoptera.

Description of the NASA GEOS Composition Forecast Modeling System GEOS-CF v1.0.

The Goddard Earth Observing System composition forecast (GEOS-CF) system is a high-resolution (0.25°) global constituent prediction system from NASA's Global Modeling and Assimilation Office (GMAO). GEOS-CF offers a new tool for atmospheric chemistry research, with the goal to supplement NASA's broad range of space-based and in-situ observations. GEOS-CF expands on the GEOS weather and aerosol modeling system by introducing the GEOS-Chem chemistry module to provide hindcasts and 5-days forecasts of atmospheric constituents including ozone (O3), carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), and fine particulate matter (PM2.5). The chemistry module integrated in GEOS-CF is identical to the offline GEOS-Chem model and readily benefits from the innovations provided by the GEOS-Chem community. Evaluation of GEOS-CF against satellite, ozonesonde and surface observations for years 2018-2019 show realistic simulated concentrations of O3, NO2, and CO, with normalized mean biases of -0.1 to 0.3, normalized root mean square errors between 0.1-0.4, and correlations between 0.3-0.8. Comparisons against surface observations highlight the successful representation of air pollutants in many regions of the world and during all seasons, yet also highlight current limitations, such as a global high bias in SO2 and an overprediction of summertime O3 over the Southeast United States. GEOS-CF v1.0 generally overestimates aerosols by 20%-50% due to known issues in GEOS-Chem v12.0.1 that have been addressed in later versions. The 5-days forecasts have skill scores comparable to the 1-day hindcast. Model skills can be improved significantly by applying a bias-correction to the surface model output using a machine-learning approach.

A perspective on the development of gas-phase chemical mechanisms for Eulerian air quality models.

An essential component of a three-dimensional air quality model is its gas-phase mechanism. We present an overview of the necessary atmospheric chemistry and a discussion of the types of mechanisms with some specific examples such as the Master Chemical Mechanism, the Carbon Bond, SAPRC and the Regional Atmospheric Chemistry Mechanism (RACM). The first versions of the Carbon Bond and SAPRC mechanisms were developed through a hierarchy of chemical species approach that relied heavily on chemical environmental chamber data. Now a new approach has been proposed where the first step is to develop a highly detailed explicit mechanism such as the Master Chemical Mechanism and the second step is to test the detailed explicit mechanism against laboratory and field data. Finally, the detailed mechanism is condensed for use in a three-dimensional air quality model. Here it is argued that the development of highly detailed explicit mechanisms is very valuable for research, but we suggest that combining the hierarchy of chemical species and the detailed explicit mechanism approaches would be better than either alone.Implication: Many gas-phase mechanisms are available for urban, regional and global air quality modeling. A "hierarchy of chemical species approach," relying heavily on smog-chamber data was used for the development of the early series of mechanisms. Now the development of large, explicit master mechanisms that may be condensed is a significant, trend. However, a continuing problem with air quality mechanism development is due to the high complexity of atmospheric chemistry and the current availability of laboratory measurements. This problem requires a balance between completeness and speculation so that models maintain their utility for policymakers.

Projected changes in particulate matter concentrations in the South Coast Air Basin due to basin-wide reductions in nitrogen oxides, volatile organic compounds, and ammonia emissions.

An ozone abatement strategy for the South Coast Air Basin (SoCAB) has been proposed by the South Coast Air Quality Management District (SCAQMD) and the California Air Resources Board (ARB). The proposed emissions reduction strategy is focused on the reduction of nitrogen oxide (NOx) emissions by the year 2030. Two high PM2.5 concentration episodes with high ammonium nitrate compositions occurring during September and November 2008 were simulated with the Community Multi-scale Air Quality model (CMAQ). All simulations were made with same meteorological files provided by the SCAQMD to allow them to be more directly compared with their previous modeling studies. Although there was an overall under-prediction bias, the CMAQ simulations were within an overall normalized mean error of 50%; a range that is considered acceptable performance for PM modeling. A range of simulations of these episodes were made to evaluate sensitivity to NOx and ammonia emissions inputs for the future year 2030. It was found that the current ozone control strategy will reduce daily average PM2.5 concentrations. However, the targeted NOx reductions for ozone were not found to be optimal for reducing PM2.5 concentrations. Ammonia emission reductions reduced PM2.5 and this might be considered as part of a PM2.5 control strategy. Implications: The SCAQMD and the ARB have proposed an ozone abatement strategy for the SoCAB that focuses on NOx emission reductions. Their strategy will affect both ozone and PM2.5. Two episodes that occurred during September and November 2008 with high PM2.5 concentrations and high ammonium nitrate composition were selected for simulation with different levels of nitrogen oxide and ammonia emissions for the future year 2030. It was found that the ozone control strategy will reduce maximum daily average PM2.5 concentrations but its effect on PM2.5 concentrations is not optimal.

Linking Air Quality and Human Health Effects Models: An Application to the Los Angeles Air Basin.

Proposed emission control strategies for reducing ozone and particulate matter are evaluated better when air quality and health effects models are used together. The Community Multiscale Air Quality (CMAQ) model is the US Environmental Protection Agency's model for determining public policy and forecasting air quality. CMAQ was used to forecast air quality changes due to several emission control strategies that could be implemented between 2008 and 2030 for the South Coast Air Basin that includes Los Angeles. The Environmental Benefits Mapping and Analysis Program-Community Edition (BenMAP-CE) was used to estimate health and economic impacts of the different emission control strategies based on CMAQ simulations. BenMAP-CE is a computer program based on epidemiologic studies that link human health and air quality. This modeling approach is better for determining optimum public policy than approaches that only examine concentration changes.