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Abstract Recently, biotechnology and pharmaceutical industries have made strides to adopt and implement Natural Language Processing (NLP) to address challenges faced when extracting and synthesizing high volumes of information found in unstructured and semistructured text. Here we present, and provide a summary of the findings from, a use case where NLP and text mining methodologies were used to extract clinical trial data from ClinicalTrials.gov for mRNA cancer vaccines.

Skill in generating inferences predicts reading comprehension for students in the elementary and intermediate grades even after taking into account word reading, vocabulary knowledge, and cognitive ability (Cain et al., "Journal of Educational Psychology, 96," 671-81, 2004; Kendeou et al., "Journal of Research in Reading, 31," 259-72, 2008; Oakhill and Cain, "Scientific Studies of Reading, 16"(2), 91-121, 2012; Oakhill et al., "Language and Cognitive Processes, 18," 443-468, 2003). While research shows that struggling readers are less likely than proficient readers to make inferences when reading text (Cain et al., "Memory and Cognition, 29," 850-859, 2001; "Oakhill, British Journal of Educational Psychology, 54," 31-39, 1984), struggling readers may also benefit more from inference instruction than do proficient readers (Hansen and Pearson, "Journal of Educational Psychology, 75"(6), 821-829, 1983; McGee and Johnson, "Educational Psychology, 23"(1), 49-59, 2003; Raphael and Pearson, "American Educational Research Journal, 22"(2), 217-235, 1985; Yuill and Oakhill, "Applied Cognitive Psychology, 2," 33-45, 1988). This synthesis assessed (a) the effectiveness of inference instruction in improving reading outcomes for struggling readers and (b) the features of instructional interventions (e.g., duration, type of instruction) that were associated with improved outcomes. One single-case design and eight experimental group design studies were synthesized. Mean effect sizes for group design studies ranged from g=0.72* to g=1.85* for researcher-developed measures of inferential reading comprehension and from g=-0.03 to g=1.96* for standardized measures of reading comprehension. The percentage of non-overlapping data for the study that employed a single-case design was 100% for all measures.

Abstract The success of antibodies targeting Programmed cell death protein 1 (PD-1) and its ligand L1 (PD-L1) in cancer treatment and the need for improving response rates has led to an increased demand for the development of combination therapies with anti-PD-1/PD-L1 blockers as a backbone. As more and more drugs with translational potential are identified, the number of clinical trials evaluating combinations has increased considerably and the demand to prioritize combinations having potential for success over the ones that are unlikely to be successful is rising. This review aims to address the unmet need to prioritize cancer immunotherapy combinations through comprehensive search of potential drugs and ranking them based on their mechanism of action, clinical efficacy and safety. As lung cancer is one of the most frequently studied cancer types, combinations that showed potential for the treatment of lung cancer were prioritized. A literature search was performed to identify drugs with potential in combination with PD-1/PD-L1 blockers and the drugs were ranked based on their mechanism of action and known clinical efficacy. Nineteen drugs or drug classes were identified from an internal list of lead molecules and were scored for their clinical potential. Efficacy and safety data from pivotal studies was summarized for the selected drugs. Further, overlap of mechanisms of action and adverse events was visualized using a heat map illustration to help screen drugs for combinations. The quantitative scoring methodology provided in this review could serve as a template for preliminary ranking of novel combinations.

Background: Atezolizumab has been studied in multiple indications for both pediatric and adult patient populations. Generally, clinical studies enrolling pediatric patients may not collect sufficient pharmacokinetic data to characterize the drug exposure and disposition because of operational, ethical, and logistical challenges including burden to children and blood sample volume limitations. Therefore, mechanistic modeling and simulation may serve as a tool to predict and understand the drug exposure in pediatric patients.Objective: To use mechanistic physiologically-based pharmacokinetic (PBPK) modeling to predict atezolizumab exposure at a dose of 15 mg/kg (max 1,200 mg) in pediatric patients to support dose rationalization and label recommendations.Methods: A minimal mechanistic PBPK model was used which incorporated age-dependent changes in physiology and biochemistry that are related to atezolizumab disposition such as endogenous IgG concentration and lymph flow. The PBPK model was developed using both in vitro data and clinically observed data in adults and was verified across dose levels obtained from a phase I and multiple phase III studies in both pediatric patients and adults. The verified model was then used to generate PK predictions for pediatric and adult subjects ranging from 2- to 29-year-old.Results: Individualized verification in children and in adults showed that the simulated concentrations of atezolizumab were comparable (76% within two-fold and 90% within three-fold, respectively) to the observed data with no bias for either over- or under-prediction. Applying the verified model, the predicted exposure metrics including Cmin, Cmax, and AUCtau were consistent between pediatric and adult patients with a geometric mean of pediatric exposure metrics between 0.8- to 1.25-fold of the values in adults.Conclusion: The results show that a 15 mg/kg (max 1,200 mg) atezolizumab dose administered intravenously in pediatric patients provides comparable atezolizumab exposure to a dose of 1,200 mg in adults. This suggests that a dose of 15 mg/kg will provide adequate and effective atezolizumab exposure in pediatric patients from 2- to 18-year-old.

Introduction: Phase 1b GO30140 and phase 3 IMbrave150 studies evaluated first-line atezolizumab + bevacizumab for unresectable hepatocellular carcinoma (HCC). Here, we evaluated pharmacokinetics (PK) and safety by hepatic impairment status and geographic region. Methods: Patients received atezolizumab 1,200 mg + bevacizumab 15 mg/kg IV every 3 weeks. Drug concentrations were evaluated by descriptive statistics and population PK. PK and adverse event frequencies were evaluated by hepatic impairment status and region. Results: 323 IMbrave150 patients and 162 GO30140 patients were PK evaluable. Compared with IMbrave150 patients who had normal hepatic function per the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (n = 123), patients with mild impairment (n = 171) had a geometric mean ratio (GMR) of 0.92 for cycle 1 atezolizumab area under the concentration-time curve (AUC); patients with moderate impairment (n = 27) had a GMR of 0.88. Patients in Asia ([n = 162] vs. outside [n = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [n = 61]), patients with mild impairment (n = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (n = 9) had a GMR of 0.94. Patients in Asia (n = 111) versus outside Asia (n = 51) had a GMR of 0.94 for cycle 1 peak bevacizumab concentration. PK results were generally comparable when evaluated based on additional hepatic functional definitions (Child-Pugh or albumin/bilirubin criteria) or study enrollment in Japan. No associations between atezolizumab PK and HCC etiology were seen. Adverse event frequencies were similar across evaluated groups. Conclusions: IMbrave150 and GO30140 patients with unresectable HCC had varying baseline hepatic impairment and high enrollment from Asia. PK data demonstrated considerable exposure overlap across groups. Treatment was tolerable across groups. No need for dose adjustment based on mild or moderate hepatic impairment or region is recommended based on this analysis.

Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules—water and carbon dioxide—to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generated in this enzyme to create a catalyst for the reduction of aryl ketones. Dialkyl ketones are more challenging to reduce, and the enantioselective reduction of dialkyl ketones with two alkyl groups that are similar in size and electronic properties, is a particularly challenging transformation to achieve with high activity and selectivity. Here, we show that hCAII, as well as a double mutant of it, catalyzes the enantioselective reduction of dialkyl ketones with high yields and enantioselectivities, even when the two alkyl groups are similar in size. We also show that variants of hCAII catalyze the site‐selective reduction of one ketone over the other in an unsymmetrical aliphatic diketone. Computational docking of a dialkyl ketone to variants of hCAII containing the zinc hydride provides insights into the origins of the reactivity of various substrates and the high enantioselectivity of the transformations and show how a confined environment can control the enantioselectivity of an abiological intermediate. [ABSTRACT FROM AUTHOR]

Introduction The United States Army has shifted doctrine to focus on large-scale combat operations against peer to near-peer adversaries. Future conflicts could result in a limited supply chain, leaving medical providers with only expired blood products for treatment of hemorrhagic shock. This study evaluated quality, function, and safety metrics of whole blood stored for 1 week past regulated expiration (i.e. 35 days, in CPDA-1). Materials and Methods Whole blood units (n  = 6) were collected in citrate phosphate dextrose adenine-1 (CPDA-1) anticoagulant and stored refrigerated for up to 42 days. Units were sampled on days 35, 37, 39, and 42 of storage and evaluated for the following: complete blood count, blood metabolism and chemistries, clotting dynamics, and presence of bacteria. Results The majority of evaluated parameters fell outside of normal clinical ranges beginning at day 35 of storage. At 42 days, blood pH was 6.58 ± 0.038, hemolysis was significantly increased (P  = .037 vs day 35), and bacterial contamination was not evident. Glucose levels continuously dropped during extended storage. K+ was significantly increased at day 42 compared to day 35 (P  = .010). A significant reduction in clot strength, factor V activity, and factor VIII activity was evident beginning at day 39 of storage. Conclusions Storage of whole blood out to 42 days results in a continuous decline in function, but further in vivo safety studies should be performed to determine if the benefits of expired blood outweigh the risks. Other methods to safely extend storage of whole blood that maintain hemostatic function and preserve safety should be investigated, with emphasis placed on methods that reduce potassium leak and/or hemolysis. [ABSTRACT FROM AUTHOR]

UnlabelledEpidemiological studies suggest a dose-response relationship exists between physical activity and cognitive outcomes. However, no direct data from randomized trials exists to support these indirect observations. The purpose of this study was to explore the possible relationship of aerobic exercise dose on cognition. Underactive or sedentary participants without cognitive impairment were randomized to one of four groups: no-change control, 75, 150, and 225 minutes per week of moderate-intensity semi-supervised aerobic exercise for 26-weeks in a community setting. Cognitive outcomes were latent residual scores derived from a battery of 16 cognitive tests: Verbal Memory, Visuospatial Processing, Simple Attention, Set Maintenance and Shifting, and Reasoning. Other outcome measures were cardiorespiratory fitness (peak oxygen consumption) and measures of function functional health. In intent-to-treat (ITT) analyses (n = 101), cardiorespiratory fitness increased and perceived disability decreased in a dose-dependent manner across the 4 groups. No other exercise-related effects were observed in ITT analyses. Analyses restricted to individuals who exercised per-protocol (n = 77) demonstrated that Simple Attention improved equivalently across all exercise groups compared to controls and a dose-response relationship was present for Visuospatial Processing. A clear dose-response relationship exists between exercise and cardiorespiratory fitness. Cognitive benefits were apparent at low doses with possible increased benefits in visuospatial function at higher doses but only in those who adhered to the exercise protocol. An individual’s cardiorespiratory fitness response was a better predictor of cognitive gains than exercise dose (i.e., duration) and thus maximizing an individual’s cardiorespiratory fitness may be an important therapeutic target for achieving cognitive benefits.Trial registrationClinicalTrials.gov NCT01129115.

Introduction: Strategies to identify high-risk emergency department (ED) patients often use markedly abnormal vital signs and serum lactate levels. Risk stratifying such patients without using the presence of shock is challenging. The objective of the study is to identify independent predictors of in-hospital adverse outcomes in ED patients with abnormal vital signs or lactate levels, but who are not in shock.Methods: We performed a prospective observational study of patients with abnormal vital signs or lactate level defined as heart rate ≥130 beats/min, respiratory rate ≥24 breaths/min, shock index ≥1, systolic blood pressure 4.0mmol/L (OR 5.1, 95% CI [2.1–12.2]), age ≥80 yrs (OR 1.9, CI [1.0–3.7]), bicarbonate

A two‐analyte integrated population pharmacokinetic (PK) model that simultaneously describes concentrations of antibody‐conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE following repeated administrations of polatuzumab vedotin (pola) was developed based on data from four clinical studies of pola in patients with non‐Hodgkin lymphoma. A two‐compartment model with a nonspecific, time‐dependent linear clearance, a linear time‐dependent exponentially declining clearance, and a Michaelis–Menten clearance provided a good fit of the acMMAE plasma PK profiles. All three acMMAE elimination pathways contributed to the input to the central compartment of unconjugated MMAE, which was also described by a two‐compartment model. Population PK parameters, covariate effects, and interindividual variability of model parameters were estimated. The impact of clinically relevant covariates on PK exposures of each analyte were quantified and reported to support key label claims.

Purpose: Tiragolumab is an immunoglobulin G1 monoclonal antibody targeting the immune checkpoint T cell immunoreceptor with immunoglobulin and immunoreceptor ITIM domains. Targeting multiple immune pathways may improve anti-tumor responses. The phase I YP42514 study assessed the pharmacokinetics (PK), safety, and preliminary efficacy of tiragolumab plus atezolizumab in Chinese patients with advanced solid tumors. Methods: Adult patients from mainland China with Eastern Cooperative Oncology Group performance score 0/1, life expectancy of ≥ 12 weeks, and adequate hematologic/end organ function were eligible. Patients received tiragolumab 600 mg and atezolizumab 1200 mg intravenous every 3 weeks. Key endpoints were PK (serum concentrations of tiragolumab and atezolizumab) and safety. Results from this study were compared with the global phase I study, GO30103 (NCT02794571). Results: In this study, 20 patients received a median of five doses of tiragolumab plus atezolizumab. Median age was 57.5 years, 85.0% of patients were male and the most common tumor type was non-small cell lung cancer. Exposures in Chinese patients were comparable to the global GO30103 population: geometric mean ratio was 1.07 for Cycle 1 tiragolumab area under the concentration–time curve0–21 and 0.92 and 0.93 for Cycle 1 peak and trough atezolizumab exposure, respectively. Treatment-related adverse events were consistent across the Chinese and global populations. Two patients (10.0%) in this study achieved a partial response. Conclusion: In this study, tiragolumab plus atezolizumab was tolerable and demonstrated preliminary anti-tumor activity. There were no meaningful differences in the PK or safety of tiragolumab plus atezolizumab between the Chinese and global populations. Clinical trial registration number: China Clinical Trial Registry Identifier CTR20210219/YP42514. Date of registration 16 March 2021. [ABSTRACT FROM AUTHOR]

Abstract Background The iMATRIX-atezolizumab study was a phase I/II, multicenter, open-label study designed to assess the safety and pharmacokinetics of atezolizumab in pediatric and young adult patients. We describe the pharmacokinetics (PK), exposure-safety, and immunogenicity of atezolizumab in pediatric and young adults with metastatic solid tumors or hematologic malignancies enrolled in this study. Methods Patients aged

Abstract We retrospectively investigated the pharmacokinetics and exposure‐efficacy/safety relationships of single‐agent atezolizumab based on tissue tumor mutational burden (tTMB) status (high vs low [≥16 vs

Tiragolumab is a first‐in‐class, fully human IgG1/kappa anti‐TIGIT monoclonal antibody that blocks the binding of TIGIT to CD155 (the poliovirus receptor). We summarize the pharmacokinetics (PK) data from the phase 1a/1b GO30103 study of Q3W (every 3 weeks) sequential dosing of tiragolumab (2, 8, 30, 100, 400, 600, or 1200 mg) followed by atezolizumab (1200 mg), Q4W (every 4 weeks) sequential dosing (tiragolumab 840 mg followed by atezolizumab 1680 mg), and Q4W co‐infusion (tiragolumab 840 mg plus atezolizumab 1680 mg). Serum samples were collected at multiple time points following tiragolumab and atezolizumab intravenous infusion in patients with solid tumors for PK and immunogenicity assessment. The serum PK profile of tiragolumab appeared to be biphasic, with a rapid distribution phase followed by a slower elimination phase when administered alone or in combination with atezolizumab. In phase 1a, across doses of tiragolumab ranging from 2 to 1200 mg (cycle 1), the geometric mean (GM), coefficient of variation (CV%), serum tiragolumab Cmax ranged from 0.682 to 270 µg/mL (18.6% to 36.5%) and Cmin ranged from 0.0125 to 75.3 µg/mL (0.0% to 24.2%). The GM systemic exposure (area under the plasma drug concentration‐time curve, AUC0‐21) ranged from 310 to 2670 µg day/mL (20.5% to 27.0%); interindividual variability in AUC0‐21 ranged from 20.5% to 43.9%. Tiragolumab exposure increased in an approximately dose‐proportional manner when administered alone or with atezolizumab at doses ≥100 mg. Postbaseline, 4/207 patients (1.9%) were positive for treatment‐emergent antidrug antibodies (ADA) against tiragolumab, each at a single time point. Tiragolumab combined with atezolizumab demonstrated desirable PK properties, with no drug‐drug interactions or immunogenicity liability. There were no meaningful differences in tiragolumab or atezolizumab exposure between the Q4W co‐infusion and sequential dosing cohorts. ClinicalTrials.gov: NCT02794571 (date of registration June 6, 2016). [ABSTRACT FROM AUTHOR]

Background: Depressed mood and Substance misuse are prevalent during adolescence, but rates differ between males and females. Little is known regarding how depressed mood influences response to substance use interventions and interacts with gender in connection with subsequent drinking. This study explores the relationship of depressed mood and gender to treatment response in adolescents admitted to an Emergency Department (ED). for alcohol-related incidents. Methods: Adolescents treated at an ED were randomly assigned to a Motivational Interviewing condition or to standard hospital care. Participants (N = 268; ages 13 to 19) were followed for 6 months with detailed measures of alcohol involvement and depressed mood. Results: Depressed mood at the time of the ED visit predicted less drinking at 6-month follow-up for 13- to 17-year-old girls, but predicted more follow-up drinking for 13- to 17-year-old boys and for 18- to 19-year-old females, above and beyond effects of baseline drinking. Depressed mood did not moderate the relationship between treatment condition and drinking outcome. Conclusions: Depressed mood as reported at the time of an ED visit appears to motivate drinking reductions in early- to mid-adolescent girls. Depressive symptoms may indicate an adaptive distress response to the event that precipitated the ED visit, which clinicians could capitalize on by heightening awareness of adverse risks and collaborating to set goals. In contrast, depression may be a liability in teenage boys and older teenage girls, and mood symptoms could be an additional target for intervention.