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This study aimed to develop a risk prediction model for epilepsy-related death in adults. In this age- and sex-matched case-control study, we compared adults (aged ≥16 years) who had epilepsy-related death between 2009 and 2016 to living adults with epilepsy in Scotland. Cases were identified from validated administrative national datasets linked to mortality records. ICD-10 cause-of-death coding was used to define epilepsy-related death. Controls were recruited from a research database and epilepsy clinics. Clinical data from medical records were abstracted and used to undertake univariable and multivariable conditional logistic regression to develop a risk prediction model consisting of four variables chosen a priori. A weighted sum of the factors present was taken to create a risk index—the Scottish Epilepsy Deaths Study Score. Odds ratios were estimated with 95% confidence intervals (CIs). Here, 224 deceased cases (mean age 48 years, 114 male) and 224 matched living controls were compared. In univariable analysis, predictors of epilepsy-related death were recent epilepsy-related accident and emergency attendance (odds ratio 5.1, 95% CI 3.2–8.3), living in deprived areas (odds ratio 2.5, 95% CI 1.6–4.0), developmental epilepsy (odds ratio 3.1, 95% CI 1.7–5.7), raised Charlson Comorbidity Index score (odds ratio 2.5, 95% CI 1.2–5.2), alcohol abuse (odds ratio 4.4, 95% CI 2.2–9.2), absent recent neurology review (odds ratio 3.8, 95% CI 2.4–6.1) and generalized epilepsy (odds ratio 1.9, 95% CI 1.2–3.0). Scottish Epilepsy Deaths Study Score model variables were derived from the first four listed before, with Charlson Comorbidity Index ≥2 given 1 point, living in the two most deprived areas given 2 points, having an inherited or congenital aetiology or risk factor for developing epilepsy given 2 points and recent epilepsy-related accident and emergency attendance given 3 points. Compared to having a Scottish Epilepsy Deaths Study Score of 0, those with a Scottish Epilepsy Deaths Study Score of 1 remained low risk, with odds ratio 1.6 (95% CI 0.5–4.8). Those with a Scottish Epilepsy Deaths Study Score of 2–3 had moderate risk, with odds ratio 2.8 (95% CI 1.3–6.2). Those with a Scottish Epilepsy Deaths Study Score of 4–5 and 6–8 were high risk, with odds ratio 14.4 (95% CI 5.9–35.2) and 24.0 (95% CI 8.1–71.2), respectively. The Scottish Epilepsy Deaths Study Score may be a helpful tool for identifying adults at high risk of epilepsy-related death and requires external validation.

Further understanding of when to initiate therapies in pulmonary arterial hypertension (PAH) is important to improve long-term outcomes.Post hocanalyses of GRIPHON (NCT01106014) and exploratory analyses of TRITON (NCT02558231) suggested benefit of early selexipag initiation on long-term outcomes, despite no additional benefitversusinitial double combination on haemodynamic and functional parameters in TRITON.Post hocanalyses investigated the effect of early selexipag initiation on disease progression and survival in a large, pooled PAH cohort. Data from newly diagnosed (≤6 months) PAH patients from GRIPHON and TRITON were pooled. Patients on active therapy with selexipag (pooled selexipag group) were compared with those on control therapy with placebo (pooled control group). Disease progression end-points were defined as per the individual studies. Hazard ratios (HR) and 95% CI for time to first disease progression event up to end of double-blind treatment (selexipag/placebo) +7 days and time to all-cause death up to end of study were estimated using Cox regression models. The pooled dataset comprised 649 patients, with 44% on double background therapy. Selexipag reduced the risk of disease progression by 52%versuscontrol (HR: 0.48; 95% CI: 0.35–0.66). HR for risk of all-cause death was 0.70 (95% CI: 0.46–1.10) for the pooled selexipagversuscontrol group. Sensitivity analyses accounting for the impact of PAH background therapy showed consistent results, confirming the appropriateness of data pooling. Thesepost hoc, pooled analyses build on previous insights, further supporting selexipag use within 6 months of diagnosis, including as part of triple therapy, to delay disease progression.

Background: During quit attempts, smokers must overcome smoking urges triggered by environmental cues and nicotine withdrawal symptoms. This study investigates the psychometric properties of the 12-item Tobacco Urge Management Scale (TUMS), a new measure of smoking urge management behaviors. Methods: We analyzed secondary data (n = 327) from a behavioral smoking cessation intervention trial, Kids Safe and Smokefree (KiSS). Results: Confirmatory factor analysis of the TUMS indicated that a one-factor model and a correlated two-factor model had similar model fit indices, and a Chi-square difference test supported the one-factor model. Further study of the parsimonious one-factor scale provided evidence of reliability and construct validity. Known group validity was evidenced by significantly higher TUMS scores in the KiSS intervention arm receiving urge management skills training than in the control arm (p < 0.001). Concurrent validity was evidenced by TUMS’s inverse association with cigarettes smoked per day and positive associations with nonsmoking days, 7-day abstinence, and self-efficacy to control smoking behaviors (p’s < 0.05). Conclusion: The TUMS is a reliable, valid measure of smoking urge management behaviors. The measure can support theory-driven research on smoking-specific coping mechanisms, inform clinical practice by identifying coping strategies that might be under-utilized in treatment-seeking smokers, and function as a measure of treatment adherence in cessation trials that target urge management behaviors.

Although CSI and GS are established prediction metrics in meteorological literature,3-6, 8, 10-12 few texts have translated them into medical literature.9, 13 We provide here the first translation of CSI and GS into epilepsy literature. We suggest CSI may be an appropriate measure to complement Sens, Spec, PPV and NPV, particularly as it allows combined interpretation of PPV and Sens whilst also avoiding the inflation of NPV and Spec when there are many TNs. GS may be a better metric when there are fewer TN and more CH. Based on the current findings, we suggest a CSI of ≥0.8 would be a reasonable threshold score for achieving diagnostic accuracy. Optimal diagnostic thresholds for GS remain to be elucidated.

BCMA bispecific is highly active in vivo.

Supplementary Figure 12 shows the ELISA assay with the dose-dependent C1q binding to plate-adsorbed sasanlimab and the ADCC assay of sasanlimab performed with activated T cells (target cells) and stimulated PBMCs (effector cells).

Supplementary Figure 6 shows the rCGE profile for sasanlimab with two predominant peaks, consistent with L chain and H chain

Supplementary Figure 10 shows the selectivity of sasanlimab binding to human and cynomolgus monkey PD-1 using HEK-293T transiently transfected cells and flow cytometry

Tables show PK kinetics, plasma cell numbers, and patient data. Methods include all supplemental methods.

Supplementary Methods

Supplementary Figure 5 shows the analysis of sasanlimab by SE-HPLC with UV detection at 280 nm

Supplementary Figure 11 shows sasanlimab binding to human and cynomolgus monkey Fcγ receptor and FcRn

BCMA bispecific is activity in the presence of soluble BCMA and APRIL.

BCMA cleavable and non-cleavable ADCs are highly active against xenograft tumors.

Supplementary Figure 3 shows the analysis of the primary structure of sasanlimab by LC-MS peptide mapping.

Supplementary Figure 9 shows the SPR analysis of sasanlimab binding to PD-1 from various species

Supplementary Figure 16 shows the functional blockade of PD-1 receptors in cynomolgus monkeys treated with sasanlimab.

Supplementary Figure 14 shows that sasanlimab blocks the binding of human PD-1 to its ligands, PD-L1 and PD-L2, by SPR analysis.

Antibody analytics and sequences.

Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals. However, broader implementation will require improved precision prevention approaches to identify those most likely to benefit. The major urinary metabolite of PGE2, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), is a biomarker for colorectal cancer risk, but it is unknown whether PGE-M is modifiable by aspirin in individuals at risk for colorectal cancer. Adults (N = 180) who recently underwent adenoma resection and did not regularly use aspirin or NSAIDs were recruited to a double-blind, placebo-controlled, randomized trial of aspirin at 81 or 325 mg/day for 8–12 weeks. The primary outcome was postintervention change in urinary PGE-M as measured by LC/MS. A total of 169 participants provided paired urine samples for analysis. Baseline PGE-M excretion was 15.9 ± 14.6 (mean ± S.D, ng/mg creatinine). Aspirin significantly reduced PGE-M excretion (−4.7 ± 14.8) compared with no decrease (0.8 ± 11.8) in the placebo group (P = 0.015; mean duration of treatment = 68.9 days). Aspirin significantly reduced PGE-M levels in participants receiving either 81 (−15%; P = 0.018) or 325 mg/day (−28%; P < 0.0001) compared with placebo. In 40% and 50% of the individuals randomized to 81 or 325 mg/day aspirin, respectively, PGE-M reduction reached a threshold expected to prevent recurrence in 10% of individuals. These results support that aspirin significantly reduces elevated levels of PGE-M in those at increased colorectal cancer risk to levels consistent with lower risk for recurrent neoplasia and underscore the potential utility of PGE-M as a precision chemoprevention biomarker. The ASPIRED trial is registered as NCT02394769.

ADC in vitro activity

The restricted expression pattern of B-cell maturation antigen (BCMA) makes it an ideal tumor-associated antigen (TAA) for the treatment of myeloma. BCMA has been targeted by both CD3 bispecific antibody and antibody–drug conjugate (ADC) modalities, but a true comparison of modalities has yet to be performed. Here we utilized a single BCMA antibody to develop and characterize both a CD3 bispecific and 2 ADC formats (cleavable and noncleavable) and compared activity both in vitro and in vivo with the aim of generating an optimal therapeutic. Antibody affinity, but not epitope was influential in drug activity and hence a high-affinity BCMA antibody was selected. Both the bispecific and ADCs were potent in vitro and in vivo, causing dose-dependent cell killing of myeloma cell lines and tumor regression in orthotopic myeloma xenograft models. Primary patient cells were effectively lysed by both CD3 bispecific and ADCs, with the bispecific demonstrating improved potency, maximal cell killing, and consistency across patients. Safety was evaluated in cynomolgus monkey toxicity studies and both modalities were active based on on-target elimination of B lineage cells. Distinct nonclinical toxicity profiles were seen for the bispecific and ADC modalities. When taken together, results from this comparison of BCMA CD3 bispecific and ADC modalities suggest better efficacy and an improved toxicity profile might be achieved with the bispecific modality. This led to the advancement of a bispecific candidate into phase I clinical trials.

Development of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function. The binding of sasanlimab to human and cynomolgus PD-1 is associated with the formation of a stable complex, which is likely to be the main driver of this high-affinity interaction. In vitro, sasanlimab significantly augmented T-cell proliferation and cytokine production in mixed lymphocyte reaction and superantigen stimulation assays. In vivo, sasanlimab accelerated the incidence of GvHD by enhancing T-cell proliferation and cytokine secretion in a xenogeneic model of acute GvHD and halted the growth of MC-38 colon adenocarcinoma tumors in human PD-1 knock-in mice. Pharmacokinetic and toxicokinetic findings from cynomolgus monkey showed that sasanlimab was active and well-tolerated. Taken together, the data presented here support the clinical development of sasanlimab for the treatment of patients with advanced cancers as a single agent or in combination with other immunotherapies.

Supplementary Figure 13 shows the structure of sasanlimab bound to human PD-1: Final data collection and refinement statistics and exemplar electron density shown for the reported structure displaying the interface between sasanlimab light chain and hu-PD-1.

Pharmacokinetics of BCMA bispecific and ADC in cynomolgus monkeys.

Supplementary Figure 15 shows no body weight changes in response to sasanlimab treatment in mice.

Supplementary Figure 8 shows the solution binding affinity of sasanlimab to human and cynomolgus monkey PD-1 using the KinExA

T cell dynamics in response to BCMA bispecific and ADCs in cynomolgus monkeys.

Supplementary Figures S1 - S15. Supplementary Figure S1. Effect of obesity on tumor initiation. Supplementary Figure S2. Adipose tissue - tumor interaction. Supplementary Figure S3. Correlation of collagen-I levels with tumor size, co-expression of collagen-I and hyaluronan in PSCs, and impact of obesity on desmoplasia and tumor hyaluronan levels. Supplementary Figure S4. Additional Western blotting data from PAN02 tumors. Supplementary Figure S5. Additional effects of AT-1 inhibition on obesity-aggravated desmoplasia, perfusion and drug delivery. Supplementary Figure S6. Additional data on the effect of obesity on immune cell infiltration in tumors. Supplementary Figure S7. Effects of TAN depletion on vessel perfusion in obese mice. Supplementary Figure S8. Effect of obesity on cytokine profile in AK4.4 tumors. Supplementary Figure S9. Effects of TAN depletion on tumor cytokine expression in obese mice. Supplementary Figure S10. Additional effects of losartan on the tumor immune microenvironment. Supplementary Figure S11. Distribution of PDAC patients according to their BMI. Supplementary Figure S12. Effect of obesity on the expression of AT1, Ly6g, and AT1/Ly6g double positivity in PAN02 tumors. Supplementary Figure S13. Representative picture of AT1 expression in cancer-associated adipocytes (arrows) in PAN02 tumors. Supplementary Figure S14. Additional effects of AT1 inhibition on obesity-aggravated microenvironment. Supplementary Figure S15. Prevalance of hypertesion in PDAC patients.

Supplementary Figure 2 shows the confirmation of the primary structure and multi-chain architecture of intact sasanlimab and the identification of the major and minor product isoforms using ESI MS

Supplementary Figure 1 shows the complete, confirmed amino acid sequence of sasanlimab

Supplemental Methods, References, Figure, and Tables

Supplementary Figure 7 shows the binding of sasanlimab to PD-1 by ELISA

Supplementary Tables S1 - S6. Supplementary Table S1. CT values for demosplasia-related genes in PAN02 tumors. Data obtained from PCR array. Supplementary Table S2. CT values for demosplasia-related genes in AK4.4 tumors. Data obtained from PCR array. Supplementary Table S3. Univariate analysis of prognostic factors for resected pancreatic cancer patients with body mass index (BMI) {less than or equal to}25. Supplementary Table S4. Multivariate analysis of prognostic factors for resected pancreatic cancer patients with body mass index (BMI) {less than or equal to}25. Supplementary Table S5. Univariate analysis of prognostic factors for resected pancreatic cancer patients with body mass index (BMI) >25. Supplementary Table S6. Multivariate analysis of prognostic factors for resected pancreatic cancer patients with body mass index (BMI) >25.

What drives public beliefs about the credibility of a scientific field? This question is increasingly important, with recent discussion of a "reproducibility crisis" affecting many fields. Such discussions are vital in forensic science, a discipline that has experienced severe scrutiny from both the media and large oversight bodies. In this paper, we make three contributions to this discussion. First, we bring together and compare several studies in which laypeople were asked about the reliability of forensic science practices. This review suggests that forensic practices do not enjoy uniformly high reliability ratings from the public and these ratings are not calibrated with the scientific consensus. We then review three empirically-tested ways that other fields are dealing with their own crises, all centred around transparency and openness. Finally, we make recommendations for how forensic science can leverage transparency and openness to improve and maintain its long-term credibility. As part of these recommendations, we find that empirical research supports the Houston Forensic Science Center's recent claims that it has improved its credibility through openness and transparency.

We present a data assimilation package for use with ocean circulation models in analysis, forecasting, and system evaluation applications. The basic functionality of the package is centered on a multivariate linear statistical estimation for a given predicted/background ocean state, observations, and error statistics. Novel features of the package include support for multiple covariance models, and the solution of the least squares normal equations either using the covariance matrix or its inverse—the information matrix. The main focus of this paper, however, is on the solution of the analysis equations using the information matrix, which offers several advantages for solving large problems efficiently. Details of the parameterization of the inverse covariance using Markov random fields are provided and its relationship to finite-difference discretizations of diffusion equations are pointed out. The package can assimilate a variety of observation types from both remote sensing and in situ platforms. The performance of the data assimilation methodology implemented in the package is demonstrated with a yearlong global ocean hindcast with a 1/4° ocean model. The code is implemented in modern Fortran, supports distributed memory, shared memory, multicore architectures, and uses climate and forecasts compliant Network Common Data Form for input/output. The package is freely available with an open source license from www.tendral.com/tsis/.

Supplementary Figure 3 - Expression of VEGFR-1 and IL-1ß in TAMs in PAN02 tumors.

Effects of VEGFR-1 signaling ablation on E0771 tumor growth, vascular and immune environment in lean and obese mice.

Spindle poisons such as paclitaxel are widely used as cancer therapeutics. By interfering with microtubule dynamics, paclitaxel induces mitotic arrest and apoptosis. Targeting the kinesin Eg5, which is required for the formation of a bipolar spindle, is a promising therapeutic alternative to drugs that interfere with microtubule dynamics. Recent data suggest that the spindle checkpoint can determine the response of tumor cells to microtubule poisons. The relationship between checkpoint function and Eg5 inhibition, however, has not yet been fully investigated. Here, we used time-lapse video microscopy and biochemical analysis to study the effect of spindle checkpoint abrogation on the response of HeLa cells to monastrol, a selective Eg5 inhibitor. In HeLa cells, monastrol activated the spindle checkpoint, leading to mitotic arrest and apoptosis. Small interfering RNA–mediated depletion of the spindle checkpoint proteins BubR1 or Mad2 significantly shortened drug-induced arrest, causing premature mitotic exit without cell division. Time-lapse microscopy as well as analysis of caspase activation shows that these checkpoint-deficient cells initiate apoptosis after mitotic exit in response to monastrol. Checkpoint-deficient cells treated with paclitaxel, on the other hand, yielded a higher frequency of cells with >4N DNA content and a decreased incidence of apoptotic events, particularly in Mad2-depleted cells. These results indicate that the immediate fate of postmitotic cells is influenced by both the nature of the checkpoint defect and the type of drug used. Furthermore, these results show that inactivation of the kinesin Eg5 can induce apoptosis in tumor cells in the absence of critical spindle checkpoint components. [Mol Cancer Ther 2006;5(10):2580–91]

Supplementary Figure 5 - Effects of VEGFR-1 signaling ablation on PAN02 tumor progression in body-weight matched mice.

Correlative biomarker analysis: 4A, Shift in balance of tumoral myeloid cells correlates with response. 4B, Baseline circulating AMC and ANC correlate with PFS 4C, High baseline circulating AMC:ALC is associated with disease progression and resistance to immunotherapy 4D, Baseline circulating PMN-MDSC in IOF and ION