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•Celecoxib-tramadol co-crystal (CTC) is a first-in-class API-API co-crystal.•Celecoxib absorption is inhibited when co-administered with tramadol.•Celecoxib absorption interference is minimized with CTC.•CTC do not result in higher systemic exposure compared to tramadol or celecoxib.•This study validates the dosing regimen for a subsequent factorial Phase 3 study. Celecoxib-tramadol co-crystal (CTC) is a first-in-class co-crystal of celecoxib and racemic tramadol. This Phase 1 bioavailability study compared single-dose pharmacokinetic (PK) parameters of CTC with those of the individual reference products from the United States, immediate-release celecoxib and tramadol, taken alone and simultaneously to determine their systemic exposure. This was a single-center, randomized, single-dose, open-label, 4-period, 4-sequence, crossover study conducted in healthy subjects between October and December 2016. Study treatments included 200-mg CTC (equivalent to 112-mg celecoxib and 88-mg tramadol; Treatment-1); 100-mg tramadol (Treatment-2); 100-mg celecoxib (Treatment-3); and 100-mg celecoxib plus 100-mg tramadol (Treatment-4). The PK parameters of interest were Cmax, AUC0–T, and AUC0–∞, which were also calculated normalized to the dose. Tmax was only considered as supportive. The statistical analysis was based on a parametric analysis of variance model of the PK parameters; the two-sided 90% CI of the ratio of geometric mean values for the Cmax, AUC0–T, and AUC0–∞ was based on ln-transformed data, and Tmax was rank-transformed. Thirty-six subjects aged 18 to 55 years (21 male subjects, 15 female subjects; mean age, 35 years) participated in the study. Celecoxib from CTC presented a lower Cmax, reduced AUCs, and a faster Tmax. The interference in celecoxib absorption when celecoxib and tramadol are administered together was minimized with the CTC. For Treatment-1, -3, and -4, celecoxib PK parameters were 259, 318, and 165 ng/mL (Cmax), respectively; 1930, 2348, and 1929 ng • h/mL (AUC0–T); and 1.5, 3.0, and 2.5 hours (Tmax). Tramadol and its active metabolite O-desmethyl tramadol from CTC presented lower Cmax and AUCs as well as a longer Tmax. Tramadol/O-desmethyl tramadol PK parameters for Treatment-1, -2, and -4 were 214/55, 305/78, and 312/78 ng/mL for Cmax; 2507/846, 2709/965, and 2888/1010 ng • h/mL for AUC0–T; and 3.0/4.0, 2.0/2.5, and 1.9/2.5 hours for Tmax. Reported adverse events (none unexpected) occurred more frequently with Treatment-2 and Treatment-4. The aim of this study was to compare the PK profile of the US-marketed tramadol and celecoxib products with CTC to determine their systemic exposure and to validate the dosing regimen for a subsequent pivotal factorial Phase 3study. PK parameters of each active component in CTC were favorably modified by co-crystallization and did not result in higher systemic exposure compared with US-marketed celecoxib, tramadol, and their concomitant administration. © 2021 Elsevier HS Journals, Inc.

[...]if CFIUS has concerns that are not resolved through mitigation agreements, the President has fifteen days to announce whether he will suspend or prohibit the transaction.10 Not all voluntary notices filed with CFIUS are truly voluntary. The tension between Iran and the international community stems from disagreement over Iran's obligations to implement nuclear safeguards under the so-called Safeguards Agreement,26 six UN Security Council Resolutions,27 and eleven International Atomic Energy Agency (IAEA) resolutions.\"114 Members of Congress from both political parties voiced concerns that the State Department was granting visas to numerous Cuban officials suspected of espionage and of having links to global terrorist organizations.

The moduli space of cubic threefolds in $\\mathbb{C}P^4$, with some minor birational modifications, is the Baily-Borel compactification of the quotient of the complex 10-ball by a discrete group. The authors describe both the birational modifications and the discrete group explicitly.|The moduli space of cubic threefolds in $\\mathbb{C}P^4$, with some minor birational modifications, is the Baily-Borel compactification of the quotient of the complex 10-ball by a discrete group. The authors describe both the birational modifications and the discrete group explicitly.

The authors assessed transmission of SARS-CoV-2 and evaluated the adequacy of symptom-based screening in a skilled nursing facility. More than half of residents with positive test results were asymptomatic at the time of testing. Infection-control strategies focused solely on symptomatic residents were not sufficient to prevent transmission.

Statistical control is widely used in correlational studies with the intent of providing more accurate estimates of relationships among variables, more conservative tests of hypotheses, or ruling out alternative explanations for empirical findings. However, the use of control variables can produce uninterpretable parameter estimates, erroneous inferences, irreplicable results, and other barriers to scientific progress. As a result, methodologists have provided a great deal of advice regarding the use of statistical control, to the point that researchers might have difficulties sifting through and prioritizing the available suggestions. We integrate and condense this literature into a set of 10 essential recommendations that are generally applicable and which, if followed, would substantially enhance the quality of published organizational research. We provide explanations, qualifications, and examples following each recommendation.

The objective of our study was to examine the effects of isometric resistance training (IRT) on resting blood pressure in adults. We conducted a systematic review and meta-analysis of randomized-controlled trials lasting ⩾2 weeks, investigating the effects of isometric exercise on blood pressure in healthy adults (aged ⩾18 years), published in a peer-reviewed journal between 1 January 1966 to 31 January 2015. We included 11 randomized trials, totaling 302 participants. The following reductions were observed after isometric exercise training; systolic blood pressure (SBP) mean difference (MD) -5.20 mm Hg (95% confidence interval (CI) -6.08 to -4.33, P<0.00001); diastolic blood pressure (DBP) MD -3.91 mm Hg (95% CI -5.68 to -2.14, P<0.0001); and mean arterial blood pressure (MAP) MD -3.33 mm Hg (95% CI -4.01 to -2.66, P<0.00001). Sub-analyses showed males tended to reduce MAP MD -4.13 mm Hg (95% CI -5.08 to -3.18) more than females. Subjects aged ⩾45 years demonstrated larger reductions in MAP MD -5.51 mm Hg (95% CI -6.95 to -4.06) than those <45 years. Subjects undertaking ⩾8 weeks of IRT demonstrated a larger reduction in SBP MD -7.26 mm Hg (95% CI -8.47 to -6.04) and MAP MD -4.22 mm Hg (95% CI -5.08 to -3.37) than those undertaking<8 weeks. Hypertensive participants in IRT demonstrated a larger reduction in MAP MD -5.91 mm Hg (95% CI -7.94 to -3.87) than normotensive participants MD -3.01 mm Hg (95% CI -3.73 to -2.29). Our study indicated that IRT lowers SBP, DBP and MAP. The magnitude of effect may be larger in hypertensive males aged ⩾45 years, using unilateral arm IRT for >8 weeks.

To improve cancer therapy, it is critical to target metastasizing cells. Circulating tumor cells (CTCs) are rare cells found in the blood of patients with solid tumors and may play a key role in cancer dissemination. Uncovering CTC phenotypes offers a potential avenue to inform treatment. However, CTC transcriptional profiling is limited by leukocyte contamination; an approach to surmount this problem is single cell analysis. Here we demonstrate feasibility of performing high dimensional single CTC profiling, providing early insight into CTC heterogeneity and allowing comparisons to breast cancer cell lines widely used for drug discovery. We purified CTCs using the MagSweeper, an immunomagnetic enrichment device that isolates live tumor cells from unfractionated blood. CTCs that met stringent criteria for further analysis were obtained from 70% (14/20) of primary and 70% (21/30) of metastatic breast cancer patients; none were captured from patients with non-epithelial cancer (n = 20) or healthy subjects (n = 25). Microfluidic-based single cell transcriptional profiling of 87 cancer-associated and reference genes showed heterogeneity among individual CTCs, separating them into two major subgroups, based on 31 highly expressed genes. In contrast, single cells from seven breast cancer cell lines were tightly clustered together by sample ID and ER status. CTC profiles were distinct from those of cancer cell lines, questioning the suitability of such lines for drug discovery efforts for late stage cancer therapy. For the first time, we directly measured high dimensional gene expression in individual CTCs without the common practice of pooling such cells. Elevated transcript levels of genes associated with metastasis NPTN, S100A4, S100A9, and with epithelial mesenchymal transition: VIM, TGFß1, ZEB2, FOXC1, CXCR4, were striking compared to cell lines. Our findings demonstrate that profiling CTCs on a cell-by-cell basis is possible and may facilitate the application of 'liquid biopsies' to better model drug discovery.

Achieving sustainable global food security is one of humanity's contemporary challenges. Here we present an analysis identifying key \"global leverage points\" that offer the best opportunities to improve both global food security and environmental sustainability. We find that a relatively small set of places and actions could provide enough new calories to meet the basic needs for more than 3 billion people, address many environmental impacts with global consequences, and focus food waste reduction on the commodities with the greatest impact on food security. These leverage points in the global food system can help guide how nongovernmental organizations, foundations, governments, citizens' groups, and businesses prioritize actions.

Changes in the distribution and abundance of invasive species can have far-reaching ecological consequences. Programs to control invaders are common but gauging the effectiveness of such programs using carefully controlled, large-scale field experiments is rare, especially at higher trophic levels. Experimental manipulations coupled with long-term demographic monitoring can reveal the mechanistic underpinnings of interspecific competition among apex predators and suggest mitigation options for invasive species. We used a large-scale before–after control–impact removal experiment to investigate the effects of an invasive competitor, the barred owl (Strix varia), on the population dynamics of an iconic old-forest native species, the northern spotted owl (Strix occidentalis caurina). Removal of barred owls had a strong, positive effect on survival of sympatric spotted owls and a weaker but positive effect on spotted owl dispersal and recruitment. After removals, the estimated mean annual rate of population change for spotted owls stabilized in areas with removals (0.2% decline per year), but continued to decline sharply in areas without removals (12.1% decline per year). The results demonstrated that the most substantial changes in population dynamics of northern spotted owls over the past two decades were associated with the invasion, population expansion, and subsequent removal of barred owls. Our study provides experimental evidence of the demographic consequences of competitive release, where a threatened avian predator was freed from restrictions imposed on its population dynamics with the removal of a competitively dominant invasive species.

Companies spend billions of dollars annually on sales force training, often carried out as off-site, multiday training events. However, the numerous challenges involved in training an entire sales group force many retailers to selectively train only a subset of their salespeople. It is crucial to know when selective training can be more effective and what composition of salespeople should be trained to benefit the entire group. This study addresses these questions using data from several stores of a retailer with different sales force training policies (full, selective, and no training [control]). The authors track the degree to which salespeople applied a customer relationship—building strategy taught in the training, along with more than 30 store- and salesperson-level covariates, and perform various analyses to correct for selection issues. They find that (1) selective training can be highly effective in stores with low performance diversity, (2) training salespeople with diverse tenures helps the spillover of training to the untrained, and (3) untrained salespeople with performance that is similar to the trained group are more likely to adopt the training-related behavior.