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AbstractWe consider the problem of constructing bounds on the average treatment effect (ATE) when unmeasured confounders exist but have bounded influence. Specifically, we assume that omitted confounders could not change the odds of treatment for any unit by more than a fixed factor. We derive the sharp partial identification bounds implied by this assumption by leveraging distributionally robust optimization, and we propose estimators of these bounds with several novel robustness properties. The first is double sharpness: our estimators consistently estimate the sharp ATE bounds when one of two nuisance parameters is misspecified and achieve semiparametric efficiency when all nuisance parameters are suitably consistent. The second and more novel property is double validity: even when most nuisance parameters are misspecified, our estimators still provide valid but possibly conservative bounds for the ATE and our Wald confidence intervals remain valid even when our estimators are not asymptotically normal. As a result, our estimators provide a highly credible method for sensitivity analysis of causal inferences. Supplementary materials for this article are available online including a standardized description of the materials available for reproducing the work. [ABSTRACT FROM AUTHOR]

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]

We have developed a new isotope labeling method, based on the use of isotope-coded p-dimethylaminophenacyl (DmPA) bromide as a reagent, combined with liquid chromatography--mass spectrometry (LC--MS) for high-performance metabolome analysis with a focus on profiling carboxylic acid-containing metabolites. Derivatization is simple, fast (1 h plus 30 min for quenching the reaction), and applicable to a wide range of carboxylic acids with a high yield and little or no side reaction products. This labeling method is demonstrated to be not only effective in introducing an isotope tag for accurate metabolite quantification but also improving the chromatographic retention of the metabolites in reversed-phase (RP) LC, enhancing ESI efficiency by 2-4 orders of magnitude, and facilitating the identification of metabolite peaks in LC--MS. In triplicate experiments of a 1:1 ratio of [sup.13]C-/[sup.12]C-DmPA labeled human urine, we were able to detect 2671, 2546, and 2820 ion pairs from metabolites containing one or more carboxylic acid groups. 10.1021/ac102146g

We report a new quantitative metabolome profiling technique based on differential [sup.12]C-/[sup.13]C-isotope dansylation labeling of metabolites, fast liquid chromatography (LC) separation and electrospray ionization Fourier-transform ion cyclotron resonance mass spectrometry (ESI-FTICR MS) detection. An isotope reagent, [sup.13]C-dansyl chloride, can be readily synthesized. This reagent, along with [sup.12]C-dansyl chloride, provides a simple and robust means of labeling metabolites containing primary amine, secondary amine, or phenolic hydroxyl group(s). It is shown that dansylation labeling offers 1-3 orders of magnitude ESI signal enhancement over the underivatized counterparts. Dansylation alters the chromatographic behaviors of polar and ionic metabolites normally not retainable on a reversed phase (RP) column to an extent that they can be retained and separated by RPLC with high efficiency. There is no isotopic effect on RPLC separation of the differential isotope labeled metabolites, and [sup.12]C-/[sup.13]C-labeled isoforms of metabolites are coeluted and detected by MS for precise and accurate quantification and confident metabolite identification. It is demonstrated that, in the analysis of 20 amino acids, a linear response of over 2 orders of magnitude is achieved for relative metabolite quantification with an average relative standard deviation (RSD) of about 5.3% from replicate experiments. A dansylation standard compound library consisting of 121 known amines and phenols has been constructed and is proven to be useful for absolute metabolite quantification and MS-based metabolite identification in biological samples. As an example, the absolute concentrations of 93 metabolites, ranging from 30 nM to 2510 [micro]M, can be determined from a pooled sample of human urines collected in 5 consecutive days labeled with [sup.12]C-dansylation and spiked with the 121 [sup.13]C-dansylated standards. Relative concentration variations of these metabolites in individual urine samples can also be monitored by mixing the [sup.13]C-dansylated pooled urine sample with the [sup.12]C-dansylated individual sample. With a 12 min fast LC separation combined with FTICR MS, 672 metabolites were detected in a human urine sample with each metabolite peak having a signal-to-noise ratio of greater than 20; the identities of most of the metabolites remain to be determined. This work illustrates that dansylation labeling and fast LC/FTICR MS can be a powerful technique for quantitative profiling of at least 672 metabolites in urine samples in 12 min.

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]

One of the challenges associated with metabolome profiling in complex biological samples is to generate quantitative information on the metabolites of interest. In this work, a targeted metabolome analysis strategy is presented for the quantification of amine-containing metabolites. A dimethylarion reaction is used to introduce a stable isotopic tag onto amine-containing metabolites followed by LC-ESI MS analysis. This labeling reaction employs a common reagent, formaldehyde, to label globally the amine groups through reductive amination. The performance of this strategy was investigated in the analysis of 20 amino acids and 15 amines by LC-ESI MS. It is shown that the labeling chemistry is simple, fast ([less than] 10min reaction rime), specific, and provides high yields under mild reaction conditions. The issue of isotopic effects of the labeled amines on reversed-phase (RP) and hydrophilic interaction (HILIC) LC separations was examined. It was found that deuterium labeling causes an isotope effect on the elution of labeled amines on RPLC but has no effect on HILIC LC. However, [sup.13]C-dimethylation does not show any isotope effect on either RPLC or HILIC LC, indicating that [sup.13]C-labeling is a preferred approach for relative quantification of amine-containing metabolites in different samples. The isotopically labeled 35 amine-containing analogues were found to be stable and proved to be effective in overcoming matrix effects in both relative and absolute quantification of these analytes present in a complicated sample, human urine. Finally, the characteristic mass difference provides additional structural information that reveals the existence of primary or secondary amine functional groups in aminecontaining metabolites. As an example, for a human urine sample, a total of 438 pairs of different amine-containing metabolites were detected, at signal-to-noise ratios of greater than 10, by using the labeling strategy in conjunction with RP LC-ESI Fourier-transform ion cyclotron resonance MS.

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]

A radionuclide, [super 64]Cu, and subsequent fluorescence enhancement upon [super 64]Cu decay to the daughter isotopes [super 64]Ni and [super 64]Zn are used to demonstrate the first evidence of radioactivity-synchronized fluorescence quenching of a near-infrared light-emitting dye. The dynamic switching behavior from high radioactivity and low fluorescence to low radioactivity and high fluorescence exhibited by light-emitting dye could find potential use for development of complementary multimodal image, detection of platforms for chemical, environmental, and biomedical applications as well as understand the mechanisms of metal-induced dynamic fluorescence changes.

We describe a new set of isotope reagents, 12C4-, 12C213C2-, and 13C4-5-diethylamino-naphthalene-1-sulfonyl chloride (DensCl), in combination with liquid chromatography Fourier-transform ion cyclotron resonance mass spectrometry (LC-FTICR-MS), for improved analysis of the amine- and phenol-containing submetabolome. The synthesis of the reagents is reported, and an optimized derivatization protocol for labeling amines and phenols is described. To demonstrate the utility of the triplex reagents for metabolome profiling of biological samples, urine samples collected daily from a healthy volunteer over a period of 14 days were analyzed. The overall workflow is straightforward, including differential isotope labeling of individual samples and a pooled sample that serves a global internal standard, mixing of the isotope differentially labeled samples and LC-MS analysis for relative metabolome quantification. Comparing to the dansyl chloride (DnsCl) duplex isotope reagents, the new triplex DensCl reagents offer the advantages of improved metabolite detectability due to enhanced sensitivity (i.e., about 1000 peak pairs detected by DensCl labeling vs about 600 peak pairs detected by DnsCl labeling) and analysis speed (i.e., simultaneous analysis of two comparative samples by DensCl vs only one comparative sample analyzed by DnsCl). [ABSTRACT FROM AUTHOR]

We demonstrate that the structure of carbocyanine dyes, which are commonly used to label small peptides for molecular imaging and not the bound peptide, controls the rate of extravasation from blood vessels to tissue. By examining several near-infrared (NIR) carbocyanine fluorophores, we demonstrate a quantitative correlation between the binding of a dye to albumin, a model plasma protein, and the rate of extravasation of the probe into tissue. Binding of the dyes was measured by fluorescence quenching of the tryptophans in albumin and was found to be inversely proportional to the rate of extravasation. The rate of extravasation, determined by kurtosis from longitudinal imaging studies using rodent ear models, provided a basis for quantitative measurements. Structure-activity studies aimed at evaluating a representative library of NIR fluorescent cyanine probes showed that hydrophilic dyes with binding constants several orders of magnitude lower than their hydrophobic counterparts have much faster extravasation rate, establishing a foundation for rational probe design. The correlation provides a guideline for dye selection in optical imaging and a method to verify if a certain dye is optimal for a specific molecular imaging application. [ABSTRACT FROM AUTHOR]

We report a new quantitative metabolome profiling technique based on differential 12C-13C-isotope dansylation labeling of metabolites, fast liquid chromatography (LC) separation and electrospray ionization Fourier-transform ion cyclotron resonance mass spectrometry (ESI-FTICR MS) detection. An isotope reagent, 13C-dansyl chloride, can be readily synthesized. This reagent, along with 12C-dansyl chloride, provides a simple and robust means of labeling metabolites containing primary amine, secondary amine, or phenolic hydroxyl group(s). It is shown that dansylation labeling offers 1-3 orders of magnitude ESI signal enhancement over the underivatized counterparts. Dansylation alters the chromatographic behaviors of polar and ionic metabolites normally not retainable on a reversed phase (RP) column to an extent that they can be retained and separated by RPLC with high efficiency. There is no isotopic effect on RPLC separation of the differential isotope labeled metabolites, and 12C-13C-labeled isoforms of metabolites are coeluted and detected by MS for precise and accurate quantification and confident metabolite identification. It is demonstrated that, in the analysis of 20 amino acids, a linear response of over 2 orders of magnitude is achieved for relative metabolite quantification with an average relative standard deviation (RSD) of about 5.3% from replicate experiments. A dansylation standard compound library consisting of 121 known amines and phenols has been constructed and is proven to be useful for absolute metabolite quantification and MS-based metabolite identification in biological samples. As an example, the absolute concentrations of 93 metabolites, ranging from 30 nM to 2510 μM, can be determined from a pooled sample of human urines collected in 5 consecutive days labeled with 12C-dansylation and spiked with the 121 13C-dansylated standards. Relative concentration variations of these metabolites in individual urine samples can also be monitored by mixing the 13C-dansylated pooled urine sample with the 12C-dansylated individual sample. With a 12 min fast LC separation combined with FTICR MS, 672 metabolites were detected in a human urine sample with each metabolite peak having a signal-to-noise ratio of greater than 20; the identities of most of the metabolites remain to be determined. This work illustrates that dansylation labeling and fast LC/FTICR MS can be a powerful technique for quantitative profiling of at least 672 metabolites in urine samples in 12 min. [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]