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Inverse propensity weighting (IPW) is a popular method for estimating treatment effects from observational data. However, its correctness relies on the untestable (and frequently implausible) assumption that all confounders have been measured. This article introduces a robust sensitivity analysis for IPW that estimates the range of treatment effects compatible with a given amount of unobserved confounding. The estimated range converges to the narrowest possible interval (under the given assumptions) that must contain the true treatment effect. Our proposal is a refinement of the influential sensitivity analysis by Zhao, Small, and Bhattacharya, which we show gives bounds that are too wide even asymptotically. This analysis is based on new partial identification results for Tan's marginal sensitivity model. for this article are available online. [ABSTRACT FROM AUTHOR]

In observational causal inference, exact covariate matching plays two statistical roles: (i) it effectively controls for bias due to measured confounding; (ii) it justifies assumption-free inference based on randomization tests. In this paper we show that inexact covariate matching does not always play these same roles. We find that inexact matching often leaves behind statistically meaningful bias, and that this bias renders standard randomization tests asymptotically invalid. We therefore recommend additional model-based covariate adjustment after inexact matching. In the framework of local misspecification, we prove that matching makes subsequent parametric analyses less sensitive to model selection or misspecification. We argue that gaining such robustness is the primary statistical role of inexact matching. [ABSTRACT FROM AUTHOR]

After performing a randomized experiment, researchers often use ordinary least-square (OLS) regression to adjust for baseline covariates when estimating the average treatment effect. It is widely known that the resulting confidence interval is valid even if the linear model is misspecified. In this article, we generalize that conclusion to covariate adjustment with nonlinear models. We introduce an intuitive way to use any "simple" nonlinear model to construct a covariate-adjusted confidence interval for the average treatment effect. The confidence interval derives its validity from randomization alone, and when nonlinear models fit the data better than linear models, it is narrower than the usual interval from OLS adjustment. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the kinetics of tumor regression in cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) using computed tomography (CT) and magnetic resonance imaging (MRI), and to correlate rate of regression and residual tumor with progression and survival. Thirty-two patients with stage IB2-IVA cervical cancer were randomly selected from an institutional database with a 2:1 ratio of SCC to AC. All available on-treatment weekly cone beam CT (CBCT) and pre- and postexternal beam MRIs were utilized to generate largest two-dimensional area of tumor and tumor gross tumor volumes (GTV), respectively. Tumor volume regression velocity and percent residual tumor were correlated to 5-year progression-free survival (PFS) and disease-specific survival (DSS) using threshold regression modeling. Kaplan-Meier and Fine-Grey estimators were used for survival and cumulative incidence analysis, respectively. With a median follow-up of 2.9 years, 32 patients were included, 22 (69%) with SCC and 10 (31%) with AC. All received concurrent chemoradiation followed by brachytherapy. The 2-year cumulative incidence (CI) of local progression for both SCC and AC was 10%, and 2-year CI of distant progression was 9% vs. 57% (p = 0.02). Deaths occurred in 3/22 (14%) with SCC and 7/10 (70%) with AC, with a 2-year DSS of 90% versus 60%, respectively. Extent and rate of regression on CBCTs were not correlated with progression or survival; however, consistent rates of tumor regression for both SCC and AC. Thresholds of ≥20% residual disease on post-external beam pre-brachytherapy MRI and regression velocity ≤1.8%/day were associated with worse PFS and DSS. This study showed cervical AC is associated with higher rates of distant progression and worse overall survival than SCC. Cervical AC tends to have a higher initial and residual tumor burden. Our identified thresholds of ≥20% residual tumor and tumor regression of ≤1.8%/day may help identify cases warranting dose escalation. [ABSTRACT FROM AUTHOR]

In Staphylococcus aureus bacteremia, mortality rates in randomized controlled trials (RCTs) are consistently lower than observational studies. Stringent eligibility criteria and omission of early deaths in RCTs contribute to this mortality gap. Clinicians should acknowledge the possibility of a lower treatment effect when applying RCT results to bedside care. [ABSTRACT FROM AUTHOR]

Background Deaths following Staphylococcus aureus bacteremia (SAB) may be related or unrelated to the infection. In SAB therapeutics research, the length of follow-up should be optimized to capture most attributable deaths and minimize nonattributable deaths. We performed a secondary analysis of a systematic review to describe attributable mortality in SAB over time. Methods We systematically searched Medline, Embase, and Cochrane Database of Systematic Reviews from 1 January 1991 to 7 May 2021 for human observational studies of SAB. To be included in this secondary analysis, the study must have reported attributable mortality. Two reviewers extracted study data and assessed risk of bias independently. Pooling of study estimates was not performed due to heterogeneity in the definition of attributable deaths. Results Twenty-four observational cohort studies were included. The median proportion of all-cause deaths that were attributable to SAB was 77% (interquartile range [IQR], 72%–89%) at 1 month and 62% (IQR, 58%–75%) at 3 months. At 1 year, this proportion was 57% in 1 study. In 2 studies that described the rate of increase in mortality over time, 2-week follow-up captured 68 of 79 (86%) and 48 of 57 (84%) attributable deaths that occurred by 3 months. By comparison, 1-month follow-up captured 54 of 57 (95%) and 56 of 60 (93%) attributable deaths that occurred by 3 months in 2 studies. Conclusions The proportion of deaths that are attributable to SAB decreases as follow-up lengthens. Follow-up duration between 1 and 3 months seems optimal if evaluating processes of care that impact SAB mortality. Clinical Trials Registration PROSPERO CRD42021253891. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer is a heterogeneous disease with poorly understood genetic and microenvironmental factors. Mutations in collagen genes are associated with genetic diseases that compromise tissue integrity, but their role in tumor progression has not been extensively reported. Aberrant collagen expression has been long associated with malignant tumor growth, invasion, chemoresistance, and patient outcomes. We hypothesized that somatic mutations in collagens could functionally alter the tumor extracellular matrix.Methods: We used publicly available datasets including The Tumor Cancer Genome Atlas (TCGA) to interrogate somatic mutations in collagens in stomach adenocarcinomas. To demonstrate that collagens were significantly mutated above background mutation rates, we used a moderated Kolmogorov-Smirnov test along with combination analysis with a bootstrap approach to define the background accounting for mutation rates. Association between mutations and clinicopathological features was evaluated by Fisher or chi-squared tests. Association with overall survival was assessed by Kaplan-Meier and the Cox-Proportional Hazards Model. Gene Set Enrichment Analysis was used to interrogate pathways. Immunohistochemistry and in situ hybridization tested expression of COL7A1 in stomach tumors.Results: In stomach adenocarcinomas, we identified individual collagen genes and sets of collagen genes harboring somatic mutations at a high frequency compared to background in both microsatellite stable, and microsatellite instable tumors in TCGA. Many of the missense mutations resemble the same types of loss of function mutations in collagenopathies that disrupt tissue formation and destabilize cells providing guidance to interpret the somatic mutations. We identified combinations of somatic mutations in collagens associated with overall survival, with a distinctive tumor microenvironment marked by lower matrisome expression and immune cell signatures. Truncation mutations were strongly associated with improved outcomes suggesting that loss of expression of secreted collagens impact tumor progression and treatment response. Germline collagenopathy variants guided interpretation of impactful somatic mutations on tumors.Conclusions: These observations highlight that many collagens, expressed in non-physiologically relevant conditions in tumors, harbor impactful somatic mutations in tumors, suggesting new approaches for classification and therapy development in stomach cancer. In sum, these findings demonstrate how classification of tumors by collagen mutations identified strong links between specific genotypes and the tumor environment. [ABSTRACT FROM AUTHOR]

Gold nanoparticles (GNPs) can create heat and free radicals after absorbing high energy photons from radiation. This light absorptive property has been utilized in cancer radiotherapy to produce highly localized heating and destroy cancer cells. For specific tumor accumulation, GNPs can be attached to monoclonal antibodies (mAbs) that recognize cell surface proteins overexpressed in certain types of cancer. One of these surface receptors is HER2, which is overexpressed in 20 - 25% of breast cancers and, therefore, constituted a suitable target for such mAb-driven GNP tumor localization. However, many mAbs cannot cross the cell membrane efficiently. To enable the efficient shuttling of GNPs into cancer cells, protein engineering technology was implemented to fuse penetratin, a cell-penetrating peptide (CPP), to the C-terminus of a wide-type anti-HER2 antibody heavy chain, generating a cell-penetrating mAb specific to the HER2 receptor. One of the recombinant mAbs (mAb-2CPP) completely preserved the HER2-binding activity and could promote the internalization of the antibody into MCF-7 and PC3 cancer cells that express HER2 on the cell surface. Both cell lines were then treated with GNPs conjugated to wild-type mAb (mAb-GNP) or mAb-CPP fusion (mAb-2CPP-GNP). The MAb-2CPP-GNP complex generated a higher mortality rate than mAb-GNP, likely due to more accumulation of GNPs in the cells. The study also investigated the interaction between X-ray radiation and GNPs, demonstrating that GNPs augmented the efficacy of X-ray radiation. Thus, a much lower dose of radiation could be used to generate a similar cell mortality rate. More GNPs were carried by mAb-2CPP into cancer cells and increased the cell mortality rate in a dose-dependent manner. Thus, an effective cell-penetrating antibody could promote the delivery of GNPs into target cancer cells and augment the efficacy of cancer radiotherapy with reduced side effects to patients. [ABSTRACT FROM AUTHOR]

Learning mathematics can be supported by technology in various creative ways. Appliances for 3D digital setups are widely available. They have transcended their intended use as simple in- or output devices and nowadays play a part in many artistic setups. Thus, they change the way we both perceive and create (digital) models. In this paper, we examine the use of gesture-based controllers in the exploration of mathematical content. A user study was conducted as part of the scientific art and education exhibition 'Long Night of Science' including a control group of high school students rating physical models. The participants of the study rated the controllers or the physical models respectively by their individually felt intuitiveness and influence on the perception of the underlying mathematical content. From the answers, a connection between the intuitiveness of the controller and a positive influence on the perception of the presented mathematics is shown. [ABSTRACT FROM AUTHOR]

Mitochondria play a central role in aerobic performance. Studies aimed at elucidating how evolved variation in mitochondrial physiology contributes to adaptive variation in aerobic performance can therefore provide a unique and powerful lens to understanding the evolution of complex physiological traits. Here, we review our ongoing work on the importance of changes in mitochondrial quantity and quality to adaptive variation in aerobic performance in high-altitude deer mice. Whole-organism aerobic capacity in hypoxia (VO2max) increases in response to hypoxia acclimation in this species, but high-altitude populations have evolved consistently greater VO2max than populations from low altitude. The evolved increase in VO2max in highlanders is associated with an evolved increase in the respiratory capacity of the gastrocnemius muscle. This appears to result from highlanders having more mitochondria in this tissue, attributed to a higher proportional abundance of oxidative fiber-types and a greater mitochondrial volume density within oxidative fibers. The latter is primarily caused by an over-abundance of subsarcolemmal mitochondria in high-altitude mice, which is likely advantageous for mitochondrial O2 supply because more mitochondria are situated adjacent to the cell membrane and close to capillaries. Evolved changes in gastrocnemius phenotype appear to be underpinned by population differences in the expression of genes involved in energy metabolism, muscle development, and vascular development. Hypoxia acclimation has relatively little effect on respiratory capacity of the gastrocnemius, but it increases respiratory capacity of the diaphragm. However, the mechanisms responsible for this increase differ between populations: lowlanders appear to adjust mitochondrial quantity and quality (i.e. increases in citrate synthase [CS] activity, and mitochondrial respiration relative to CS activity) and they exhibit higher rates of mitochondrial release of reactive oxygen species, whereas highlanders only increase mitochondrial quantity in response to hypoxia acclimation. In contrast to the variation in skeletal muscles, the respiratory capacity of cardiac muscle does not appear to be affected by hypoxia acclimation and varies little between populations. Therefore, evolved changes in mitochondrial quantity and quality make important tissue-specific contributions to adaptive variation in aerobic performance in high-altitude deer mice. [ABSTRACT FROM AUTHOR]

Vitamin K is a micronutrient necessary for γ-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Recent clinical studies implicate vitamin K in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that mouse β cells lacking γ-carboxylation fail to adapt their insulin secretion in the context of age-related insulin resistance or diet-induced β cell stress. In human islets, γ-carboxylase expression positively correlates with improved insulin secretion in response to glucose. We identify endoplasmic reticulum Gla protein (ERGP) as a γ-carboxylated ER-resident Ca2+-binding protein expressed in β cells. Mechanistically, γ-carboxylation of ERGP protects cells against Ca2+ overfilling by diminishing STIM1 and Orai1 interaction and restraining store-operated Ca2+ entry. These results reveal a critical role of vitamin K-dependent carboxylation in regulation of Ca2+ flux in β cells and in their capacity to adapt to metabolic stress. [Display omitted] • Vitamin K-dependent carboxylation regulates glucose-stimulated insulin secretion • ERGP is a γ-carboxylated protein controlling store-operated calcium entry • ERGP γ-carboxylation reduces STIM1 and Orai1 puncta formation • Decarboxylated ERGP causes calcium overfilling in β cells and hyperinsulinemia Reduced vitamin K (VK) intake is associated with an increased risk of developing type 2 diabetes. Lacombe et al. demonstrate that VK-dependent carboxylation is necessary for β cell adaptation in mice fed a high-fat diet. The underlying mechanism involves ERGP, a carboxylated protein that regulates store-operated calcium entry in β cells. [ABSTRACT FROM AUTHOR]

Background: The CBC is an essential test for assessing the health of rats used in drug development studies. Because of limited blood volume, estimates of cell counts from a blood smear would be valuable when other analytical methods of enumerating cells are not possible or available. Objective: The purpose of this study was to develop a statistical model to accurately estimate WBC, platelet (PLT), and RBC counts in blood smears from rats. Method: Blood smears and quantitative cell counts were obtained from vehicle-treated male and female Fischer 344 rats ( n=65) involved in a variety of studies. The numbers of WBCs, PLTs, and RBCs were estimated in 10 fields in the monolayer of smears using × 20 (WBC) or × 100 (PLT, RBC) objectives. Using a statistical model and the quantitative cell counts obtained on an ADVIA 120 hematology analyzer, formulas were developed to predict the quantitative counts from the estimates. Results: Data were log-transformed before analysis. A formula was derived using the slope and intercept of the regression line between cell estimates and ADVIA counts to predict WBC, PLT, and RBC counts based only on estimates. A second formula was developed for situations in which limited quantitative analyses may be available, and resulted in even more accurately predicted counts from smear estimates. Conclusion: The formulas developed in this study can be a valuable tool in estimating cell counts from a blood smear when cell counting instruments are not available or when an instrument cell count needs to be verified. These formulas may be useful in the assessment of rat blood in discovery and lead optimization studies. [ABSTRACT FROM AUTHOR]

The impacts of the El Niño–Southern Oscillation (ENSO) on the Antarctic region are of special importance in evaluating the variability and change of the climate system in high southern latitudes. In this study, the ENSO signal in modeled precipitation over West Antarctica since 1979 is evaluated using forecast precipitation from several meteorological analyses and reanalyses. Additionally, a dynamical retrieval method (DRM) for precipitation is applied. Over the last two decades, the Southern Oscillation index (SOI) has an overall anticorrelation with precipitation over the West Antarctic sector bounded by 75°–90°S, 120°W–180° while it is positively correlated with precipitation over the South Atlantic sector bounded by 65°–75°S, 30°–60°W. Decadal variations are found as the relationship between the SOI and West Antarctic precipitation is stronger in the 1990s than that in the 1980s. The polar front jet stream, West Antarctic precipitation, and the SOI show a well-ordered correspondence during the 1990s as the jet zonal speed is negatively correlated to the SOI and positively correlated to West Antarctic precipitation. These relationships are weaker during the 1980s, consistent with the change in sign of the correlation between the SOI and West Antarctic precipitation. The decadal variations are apparently related to changes in the quasi-stationary eddies that determine the local onshore and offshore flow over West Antarctica. [ABSTRACT FROM AUTHOR]

The largest outbreak of severe acute respiratory syndrome (SARS) struck Beijing in spring 2003. Multiple importations of SARS to Beijing initiated transmission in several healthcare facilities. Beijing's outbreak began March 5; by late April, daily hospital admissions for SARS exceeded 100 for several days; 2,521 cases of probable SARS occurred. Attack rates were highest in those 20-39 years of age; 1% of cases occurred in children <10 years. The case-fatality rate was highest among patients >65 years (27.7% vs. 4.8% for those 20--64 years, p < 0.001). Healthcare workers accounted for 16% of probable cases. The proportion of case-patients without known contact to a SARS patient increased significantly in May. Implementation of early detection, isolation, contact tracing, quarantine, triage of case-patients to designated SARS hospitals, and community mobilization ended the outbreak. [ABSTRACT FROM AUTHOR]

A new gadolinium chelating NIR fluorescent molecular probe increases T1relaxivity of water protons, facilitating combined optical and magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

Background: As diet-related diseases have increased over the past decades, large food companies have come under scrutiny for contributing to this public health crisis. In response, the food industry has implemented Corporate Social Responsibility (CSR) initiatives related to nutrition and physical activity to emphasize their concern for consumers. This study sought to describe the nature and targeted demographic of physical activity and nutrition-related CSR initiatives of large food companies in Canada and to compare companies who participate in the Canadian Children's Food and Beverage Advertising Initiative (CAI), a self-regulatory initiative aimed at reducing unhealthy food advertising to children, with non-participating companies.Methods: A cross-sectional study was conducted in 2016. Thirty-nine large food companies, including 18 participating in the CAI, were included in the study. The webpages, Facebook pages and corporate reports of these companies were surveyed to identify CSR initiatives related to nutrition and physical activity. Initiatives were then classified by type (as either philanthropic, education-oriented, research-oriented or other) and by targeted demographic (i.e. targeted at children under 18 years or the general population). Differences between CAI and non-CAI companies were tested using chi-square and Mann-Whitney U tests.Results: Overall, 63 CSR initiatives were identified; 39 were nutrition-related while 24 were physical activity-related. Most (70%) initiatives were considered philanthropic activities, followed by education-oriented (20%), research-oriented (8%) and other (2%). Almost half (47%; n = 29) of initiatives targeted children. Examples of child-targeted initiatives included support of school milk programs (n = 2), the sponsorship of children's sports programs (n = 2) and the development of educational resources for teachers (n = 1). There were no statistically significant differences in the number of CSR initiatives per company (CAI: Mdn = 1, IQR = 3; non-CAI: Mdn = 0, IQR = 2; p = .183) or the proportion of child-targeted initiatives (CAI: 42%; non-CAI: 54%; p = .343) between CAI and non-CAI companies.Conclusion: Food companies, including many that largely sell and market unhealthy products, are heavily involved in physical activity and nutrition-related initiatives in Canada, many of which are targeted to children. Government policies aimed at protecting children from unhealthy food marketing should consider including CSR initiatives that expose children to food company branding. [ABSTRACT FROM AUTHOR]

Impaired functional plasma membrane (PM) expression of the hERG K+-channel is associated with Long-QT syndrome type-2 (LQT2) and increased risk of cardiac arrhythmia. Reduced PM-expression is primarily attributed to retention and degradation of misfolded channels by endoplasmic reticulum (ER) protein quality control (QC) systems. However, as the molecular pathogenesis of LQT2 was defined using severely-misfolded hERG variants with limited PM-expression, the potential contribution of post-ER (peripheral) QC pathways to the disease phenotype remains poorly established. Here, we investigate the cellular processing of mildly-misfolded Per-Arnt-Sim (PAS)-domain mutant hERGs, which display incomplete ER-retention and PM-expression defects at physiological temperature. We show that the attenuated PM-expression of hERG is dictated by mutation-specific contributions from both the ER and peripheral QC systems. At the ER, PAS-mutants experience inefficient conformational maturation coupled with rapid ubiquitin-dependent proteasomal degradation. In post-ER compartments, they are rapidly endocytosed from the PM via a ubiquitin-independent mechanism and rapidly targeted for lysosomal degradation. Conformational destabilization underlies aberrant cellular processing at both ER- and post-ER compartments, since conformational correction by a hERG-specific pharmacochaperone or low-temperatures can restore WT-like trafficking. Our results demonstrate that the post-ER QC alone or jointly with the ER QC determines the loss-of-PM-expression phenotype of a subset of LQT2 mutations. [ABSTRACT FROM AUTHOR]