On Demand Bioorthogonal Switching of an Antibody-Conjugated SPECT Probe to a Cytotoxic Payload: from Imaging to Therapy.

Antibody-drug conjugates (ADCs) for the treatment of cancer aim to achieve selective delivery of a cytotoxic payload to tumor cells while sparing normal tissue. In vivo, multiple tumor-dependent and -independent processes act on ADCs and their released payloads to impact tumor-versus-normal delivery, often resulting in a poor therapeutic window. An ADC with a labeled payload would make synchronous correlations between distribution and tissue-specific pharmacological effects possible, empowering preclinical and clinical efforts to improve tumor-selective delivery; however, few methods to label small molecules without destroying their pharmacological activity exist. Herein, we present a bioorthogonal switch approach that allows a radiolabel attached to an ADC payload to be removed tracelessly at will. We exemplify this approach with a potent DNA-damaging agent, the pyrrolobenzodiazepine (PBD) dimer, delivered as an antibody conjugate targeted to lung tumor cells. The radiometal chelating group, DOTA, was attached via a novel trans-cyclooctene (TCO)-caged self-immolative para-aminobenzyl (PAB) linker to the PBD, stably attenuating payload activity and allowing tracking of biodistribution in tumor-bearing mice via SPECT-CT imaging (live) or gamma counting (post-mortem). Following TCO-PAB-DOTA reaction with tetrazines optimized for extra- and intracellular reactivity, the label was removed to reveal the unmodified PBD dimer capable of inducing potent tumor cell killing in vitro and in mouse xenografts. The switchable antibody radio-drug conjugate (ArDC) we describe integrates, but decouples, the two functions of a theranostic given that it can serve as a diagnostic for payload delivery in the labeled state, but can be switched on demand to a therapeutic agent (an ADC).

The Importance of Social Support in the Management of Hypertension in Brazil.

BACKGROUND: The prevalence of hypertension (HTN) is high in Brazil, and control rates are low. Little is known about the factors that contribute to HTN control from a family-based perspective. OBJECTIVES: Guided by the family management style framework, specific aims were to (1) describe the prevalence of adequate blood pressure (BP) control in individuals cared for the Family Health Strategy, (2) identify facilitators and barriers to HTN management, and (3) identify individual contextual sociocultural influences (sociocultural context and social and Family Health Strategy support), definition of the situation, and management behaviors that help or interfere with individual functioning (BP control in the individual with HTN). METHODS: This descriptive, cross-sectional study included 213 individuals with HTN randomly selected from 3 Family Health Strategy units from July 2016 until July 2017. RESULTS: Most of the individuals were female (n = 139, 65.3%), retired (n = 129, 60.5%), and White (n = 129, 60.2%) and had less than a high school education (n = 123, 57.6%). Family income (n = 166, 77.8%) was less than 5500 reals (US $1117/month). Mean (SD) systolic BP was 137.1 (±24.1) mm Hg, and mean (SD) diastolic BP was 83.8 (±18.6) mm Hg, with 47.9% (n = 102) having uncontrolled BP. In the multivariate logistic model, only high levels of perceived social support were significantly associated (odds ratio, 3.29; 95% confidence interval, 1.44-7.5; P = .005) with controlled BP. CONCLUSIONS: Social support is strongly associated with BP control. Optimizing support may play an important role in BP control and preventing HTN-related complications.

Children use disagreement to infer what happened.

In a rapidly changing and diverse world, the ability to reason about conflicting perspectives is critical for effective communication, collaboration, and critical thinking. The current pre-registered experiments with children ages 7 to 11 years investigated the developmental foundations of this ability through a novel social reasoning paradigm and a computational approach. In the inference task, children were asked to figure out what happened based on whether two speakers agreed or disagreed in their interpretation. In the prediction task, children were provided information about what happened and asked to predict whether two speakers will agree or disagree. Together, these experiments assessed children's understanding that disagreement often results from ambiguity about what happened, and that ambiguity about what happened is often predictive of disagreement. Experiment 1 (N = 52) showed that children are more likely to infer that an ambiguous utterance occurred after learning that people disagreed (versus agreed) about what happened and found that these inferences become stronger with age. Experiment 2 (N = 110) similarly found age-related change in children's inferences and also showed that children could reason in the forward direction, predicting that an ambiguous utterance would lead to disagreement. A computational model indicated that although children's ability to predict when disagreements might arise may be critical for making the reverse inferences, it did not fully account for age-related change.

How barriers become invisible: Children are less sensitive to constraints that are stable over time.

When making inferences about the mental lives of others (e.g., others' preferences), it is critical to consider the extent to which the choices we observe are constrained. Prior research on the development of this tendency indicates a contradictory pattern: Children show remarkable sensitivity to constraints in traditional experimental paradigms, yet often fail to consider real-world constraints and privilege inherent causes instead. We propose that one explanation for this discrepancy may be that real-world constraints are often stable over time and lose their salience. The present research tested whether children (N = 133, 5- to 12-year-old mostly US children; 55% female, 45% male) become less sensitive to an actor's constraints after first observing two constrained actors (Stable condition) versus after first observing two actors in contexts with greater choice (Not Stable condition). We crossed the stability of the constraint with the type of constraint: either the constraint was deterministic such that there was only one option available (No Other Option constraint) or, in line with many real-world constraints, the constraint was probabilistic such that there was another option, but it was difficult to access (Hard to Access constraint). Results indicated that children in the Stable condition became less sensitive to the probabilistic Hard to Access constraint across trials. Notably, we also found that children's sensitivity to constraints was enhanced in the Not Stable condition regardless of whether the constraint was probabilistic or deterministic. We discuss implications for children's sensitivity to real-world constraints. RESEARCH HIGHLIGHTS: This research addresses the apparent contradiction that children are sensitive to constraints in experimental paradigms but are often insensitive to constraints in the real world. One explanation for this discrepancy is that constraints in the real world tend to be stable over time and may lose their salience. When probabilistic constraints (i.e., when a second option is available but hard to access) are stable, children become de-sensitized to constraints across trials. First observing contexts with greater choice increases children's sensitivity to both probabilistic and deterministic constraints.

Orthopaedic Manual Physical Therapy: A Modern Definition and Description.

Currently, orthopaedic manual physical therapy (OMPT) lacks a description of practice that reflects contemporary thinking and embraces advances across the scientific, clinical, and educational arms of the profession. The absence of a clear definition of OMPT reduces understanding of the approach across health care professions and potentially limits OMPT from inclusion in scientific reviews and clinical practice guidelines. For example, it is often incorrectly classified as passive care or incorrectly contrasted with exercise-therapy approaches. This perspective aims to provide clinicians, researchers, and stakeholders a modern definition of OMPT that improves the understanding of this approach both inside and outside the physical therapist profession. The authors also aim to outline the unique and essential aspects of advanced OMPT training with the corresponding examination and treatment competencies. This definition of practice and illustration of its defining characteristics is necessary to improve the understanding of this approach and to help classify it correctly for study in the scientific literature. This perspective provides a current definition and conceptual model of OMPT, defining the distinguishing characteristics and key elements of this systematic and active patient-centered approach to improve understanding and help classify it correctly for study in the scientific literature.

Don't be a rat: An investigation of the taboo against reporting other students for cheating.

This research examines barriers to reporting academic dishonesty in early adulthood (Study 1; N = 92) and adolescence (Study 2; N = 137). Participants were asked to describe a recent time they observed a peer cheating and to reflect on their decision about whether to report the cheating. They also responded to hypothetical scenarios about observing typical cheating actions, and the presence of social motives (e.g., whether people who report tend to gain reputations for being snitches) was manipulated in each scenario. Even though participants judged reporting to be the morally right thing to do, doing so was rare and approval for it was low, especially in adolescence. Participants also tended to say they would rather be friends with people who do not report cheaters than with those who do. Participants reasoned about a variety of social concerns to support their judgments about reporting (e.g., concern about their relationship with the cheater, concerns for others' welfare), and the manipulated social motives in the hypothetical scenarios significantly influenced judgments about reporting. These findings inform our understanding of the social dynamics that contribute to decisions about policing academic honesty.

Factors Associated With the Cardiovascular Health of Black and Latino Adults With Type 2 Diabetes.

AIMS: The purpose of this study was to assess the levels of cardiovascular health (CVH) of Black and Latino adults with type 2 diabetes (T2D) and examine the association of individual and microsystem level factors with their CVH score. METHODS: This was a cross-sectional design in 60 Black and Latino Adults aged 18-40 with T2D. Data were collected on sociodemographic, individual (sociodemographic, diabetes self-management, sleep disturbance, depressive symptoms, quality of life, and the inflammatory biomarkers IL-6 and hs-CRP) and microsystem factors (family functioning), and American Heart Association's Life's Simple 7 metrics of CVH. Factors significantly associated with the CVH score in the bivariate analyses were entered into a linear regression model. RESULTS: The sample had a mean age 34 ± 5 years and was primarily female (75%) with a mean CVH score was 8.6 ± 2.2 (possible range of 0-14). The sample achieved these CVH factors at ideal levels: body mass index <25 kg/m2 (8%); blood pressure <120/80 (42%); hemoglobin A1c < 7% (57%); total cholesterol <200 mg/dL (83%); healthy diet (18%); never or former smoker > one year (95%); and physical activity (150 moderate-to-vigorous minutes/week; 45%). In the multivariable model, two factors were significantly associated with cardiovascular health: hs-CRP (B = -0.11621, p < .0001) and the general health scale (B = 0.45127, p = .0013). CONCLUSIONS: This sample had an intermediate level of CVH, with inflammation and general health associated with overall CVH score.

Calculated Comparisons: Manufacturing Societal Causal Judgments by Implying Different Counterfactual Outcomes.

How do people come to opposite causal judgments about societal problems, such as whether a public health policy reduced COVID-19 cases? The current research tests an understudied cognitive mechanism in which people may agree about what actually happened (e.g., that a public health policy was implemented and COVID-19 cases declined), but can be made to disagree about the counterfactual, or what would have happened otherwise (e.g., whether COVID-19 cases would have declined naturally without intervention) via comparison cases. Across two preregistered studies (total N = 480), participants reasoned about the implementation of a public policy that was followed by an immediate decline in novel virus cases. Study 1 shows that people's judgments about the causal impact of the policy could be pushed in opposite directions by emphasizing comparison cases that imply different counterfactual outcomes. Study 2 finds that people recognize they can use such information to influence others. Specifically, in service of persuading others to support or reject a public health policy, people systematically showed comparison cases implying the counterfactual outcome that aligned with their position. These findings were robust across samples of U.S. college students and politically and socioeconomically diverse U.S. adults. Together, these studies suggest that implied counterfactuals are a powerful tool that individuals can use to manufacture others' causal judgments and warrant further investigation as a mechanism contributing to belief polarization.

Lying to recommend unqualified friends: Diverging implications for interpersonal and epistemic trust inferences.

When people are asked to recommend individuals they care about, they often grapple with conflicts regarding the level of honesty they should maintain when being truthful could potentially hinder those individuals' chances of receiving beneficial opportunities. In the current study, we examined how adolescents evaluate people based on how they respond to such dilemmas, with a focus on how it affects judgments of interpersonal and epistemic trustworthiness. We tested a sample of high school students in the southwestern United States (N = 78; Mage = 16.45 years), who were asked about a moral dilemma in which a story character needed to decide whether to recommend an unqualified friend. We experimentally manipulated whether the friend was very close to the standard (requiring a small exaggeration) or was far from the standard (requiring a large exaggeration) between participants. Across both exaggeration conditions, we observed a dissociation in judgments of epistemic and interpersonal trustworthiness: Lie-tellers were judged to be more interpersonally trustworthy than epistemically trustworthy, whereas truth-tellers were judged to be more epistemically trustworthy than interpersonally trustworthy. These results show that adolescents are capable of using information about an individual's lie-telling versus truth-telling decisions to make highly nuanced social inferences.

Parenting by Lying.

Parenting by lying is a practice in which parents lie to their children to influence their emotions or behavior. Recently, researchers have tried to document the nature of this phenomenon and to understand its causes and consequences. The present research provides an overview of the research in the emerging field, describes some key theoretical and methodological challenges in studying this topic, and proposes a theoretical framework for understanding parenting by lying and for guiding future research to advance our knowledge about this understudied parenting practice.

The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results.

Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. In our study, the PBD dimer is modified to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrates in vivo efficacy in models of HER2-positive and HER2-low cancers and is well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial.

BIPOC experiences of (anti-)racist patient engagement in adolescent and young adult oncology research: an electronic Delphi study.

Aims: To characterize Black, Indigenous and People of Color (BIPOC) adolescent and young adult (AYA) cancer patients' experiences of patient engagement in AYA oncology and derive best practices that are co-developed by BIPOC AYAs and oncology professionals. Materials & methods: Following a previous call to action from AYA oncology professionals, a panel of experts composed exclusively of BIPOC AYA cancer patients (n = 32) participated in an electronic Delphi study. Results: Emergent themes described BIPOC AYA cancer patients' direct experiences and consensus opinion on recommendations to advance antiracist patient engagement from BIPOC AYA cancer patients and oncology professionals. Conclusion: The findings reveal high-priority practices across all phases of research and are instructional for advancing health equity.

Site-Specific Dolasynthen Antibody-Drug Conjugates Exhibit Consistent Pharmacokinetic Profiles across a Wide Range of Drug-to-Antibody Ratios.

Key defining attributes of an antibody-drug conjugate (ADC) include the choice of the targeting antibody, linker, payload, and the drug-to-antibody ratio (DAR). Historically, most ADC platforms have used the same DAR for all targets, regardless of target characteristics. However, recent studies and modeling suggest that the optimal DAR can depend on target expression level and intratumoral heterogeneity, target internalization and trafficking, and characteristics of the linker and payload. An ADC platform that enables DAR optimization could improve the success rate of clinical candidates. Here we report a systematic exploration of DAR across a wide range, by combining THIOMAB protein engineering technology with Dolasynthen, an auristatin-based platform with monomeric and trimeric variants. This approach enabled the generation of homogeneous, site-specific ADCs spanning a discrete range of DARs 2, 4, 6, 12, and 18 by conjugation of trastuzumab IgG1 THIOMAB constructs with 1, 2, or 3 engineered cysteines to monomeric or trimeric Dolasynthen. All ADCs had physicochemical properties that translated to excellent in vivo pharmacology. Following a single dose of ADCs in a HER2 xenograft model with moderate antigen expression, our data demonstrated comparable pharmacokinetics for the conjugates across all DARs and dose-dependent efficacy of all test articles. These results demonstrate that the Dolasynthen platform enables the generation of ADCs with a broad range of DAR values and with comparable physiochemical, pharmacologic, and pharmacokinetics profiles; thus, the Dolasynthen platform enables the empirical determination of the optimal DAR for a clinical candidate for a given target.

Feasibility, Acceptability, and Preliminary Effectiveness of a Sleep Intervention in Adults at Risk for Metabolic Syndrome With Short Sleep Duration.

BACKGROUND: The prevalence of short sleep duration is rising and is linked to chronic comorbidities, such as metabolic syndrome (MetS). Sleep extension interventions in adults with MetS comorbidities and short sleep duration are limited and vary widely in terms of approach and duration. OBJECTIVES: This pilot study aimed to test the feasibility and acceptability of a personalized 12-week systematic sleep time extension intervention on post-intervention sleep outcomes in middle-aged adults at risk for MetS with actigraphy-estimated short sleep duration. METHODS: A single-arm, 12-week, 12-session systematic sleep time extension intervention was delivered weekly via videoconferencing. Feasibility and acceptability were assessed using retention rates and mean sleep diary completions. Sleep was estimated for 14 consecutive days prior to and immediately following the 12-week intervention using wrist actigraphy. Daytime sleepiness was assessed using the Epworth Sleepiness Scale. Paired sample t -tests modeled changes in study outcomes. RESULTS: Study participants ( N = 41) had a mean age of 52 years and were mostly female and White; 86% attended >80% of sessions, and mean sleep diary completion was 6.7 diaries/week. Significant improvements in sleep from pre- to post-intervention included increased total sleep time, earlier sleep onsets, more regular sleep onsets, a higher sleep regularity index, and reduced daytime sleepiness. Extending sleep, as well as improving sleep timing and regularity in middle-aged adults with actigraphy-estimated short sleep duration and at risk for MetS, is feasible and acceptable. DISCUSSION: Behavioral sleep characteristics may be modifiable and present a novel behavioral paradigm for mitigating MetS risk. This pilot study provides a proof of concept for the feasibility, acceptability, and preliminary effectiveness of a systematic sleep time extension for middle-aged adults at risk for MetS with actigraphy-estimated short sleep duration.

Taking Mental Health Seriously.

The authors recommend a more proactive approach.

Mechanisms of cardiac collapse at high temperature in a marine teleost (Girella nigrians).

Heat-induced mortality in ectotherms may be attributed to impaired cardiac performance, specifically a collapse in maximum heart rate (fHmax), although the physiological mechanisms driving this phenomenon are still unknown. Here, we tested two proposed factors which may restrict cardiac upper thermal limits: noxious venous blood conditions and oxygen limitation. We hypothesized elevated blood [K+] (hyperkalemia) and low oxygen (hypoxia) would reduce cardiac upper thermal limits in a marine teleost (Girella nigricans), while high oxygen (hyperoxia) would increase thermal limits. We also hypothesized higher acclimation temperatures would exacerbate the harmful effects of an oxygen limitation. Using the Arrhenius breakpoint temperature test, we measured fHmax in acutely warmed fish under control (saline injected) and hyperkalemic conditions (elevated plasma [K+]) while exposed to hyperoxia (200% air saturation), normoxia (100% air saturation), or hypoxia (20% air saturation). We also measured ventricle lactate content and venous blood oxygen partial pressure (PO2) to determine if there were universal thresholds in either metric driving cardiac collapse. Elevated [K+] was not significantly correlated with any cardiac thermal tolerance metric. Hypoxia significantly reduced cardiac upper thermal limits (Arrhenius breakpoint temperature [TAB], peak fHmax, temperature of peak heart rate [TPeak], and temperature at arrhythmia [TARR]). Hyperoxia did not alter cardiac thermal limits compared to normoxia. There was no evidence of a species-wide threshold in ventricular [lactate] or venous PO2. Here, we demonstrate that oxygen limits cardiac thermal tolerance only in instances of hypoxia, but that other physiological processes are responsible for causing temperature-induced heart failure when oxygen is not limited.

If They Won't Know, I Won't Wait: Anticipated Social Consequences Drive Children's Performance on Self-Control Tasks.

This research evaluated the hypothesis that the act of offering an incentive produces anticipated social benefits that are distinct from the benefits associated with the incentive itself. Across three preregistered studies, 3- to 5-year-old children in China (total N = 210) were given an opportunity to wait for an additional sticker (Studies 1 and 3) or an edible treat (Study 2). Rewards were dispensed via a timer-controlled box that allowed the experimenter's apparent ability to learn how long children waited to be manipulated experimentally. Children waited only about half as long when they believed the experimenter would not find out how long they waited. When children were offered three prizes for waiting, anticipated social benefits still drove behavior at least as much as the reward. The findings demonstrate that children as young as 3 years are sensitive to anticipated social rewards when responding to offers of incentives.

Multicenter Clinical Research in Congenital Heart Disease: Leveraging Research Networks to Investigate Important Unanswered Questions.

Congenital heart disease (CHD) is the most common birth defect in the United States. Neonates with CHD are often cared for by neonatologists in addition to cardiologists. However, there is a paucity of rigorous evidence and limited clinical trials regarding the management of neonates with CHD. In this review, we will describe some of the challenges of research in this field. The Pediatric Heart Network serves as an example of how a research network can effectively overcome barriers to conduct and execute well-designed multicenter studies.

A comprehensive review of protein misfolding disorders, underlying mechanism, clinical diagnosis, and therapeutic strategies.

INTRODUCTION: Proteins are the most common biological macromolecules in living system and are building blocks of life. They are extremely dynamic in structure and functions. Due to several modifications, proteins undergo misfolding, leading to aggregation and thereby developing neurodegenerative and systemic diseases. Understanding the pathology of these diseases and the techniques used to diagnose them is therefore crucial for their effective management . There are several techniques, currently being in use to diagnose them and those will be discussed in this review. AIM/OBJECTIVES: Current review aims to discuss an overview of protein aggregation and the underlying mechanisms linked to neurodegeneration and systemic diseases. Also, the review highlights protein misfolding disorders, their clinical diagnosis, and treatment strategies. METHODOLOGY: Literature related to neurodegenerative and systemic diseases was explored through PubMed, Google Scholar, Scopus, and Medline databases. The keywords used for literature survey and analysis are protein aggregation, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, systemic diseases, protein aggregation mechanisms, etc. DISCUSSION /CONCLUSION: This review summarises the pathogenesis of neurodegenerative and systemic disorders caused by protein misfolding and aggregation. The clinical diagnosis and therapeutic strategies adopted for the management of these diseases are also discussed to aid in a better understanding of protein misfolding disorders. Many significant concerns about the role, characteristics, and consequences of protein aggregates in neurodegenerative and systemic diseases are not clearly understood to date. Regardless of technological advancements, there are still great difficulties in the management and cure of these diseases. Therefore, for better understanding, diagnosis, and treatment of neurodegenerative and systemic diseases, more studies to identify novel drugs that may aid in their treatment and management are required.

P3a amplitude to trauma-related stimuli reduced after successful trauma-focused PTSD treatment.

An elevated P3a amplitude to trauma-related stimuli is strongly associated with posttraumatic stress disorder (PTSD), yet little is known about whether this response to trauma-related stimuli is affected by treatment that decreases PTSD symptoms. As an analysis of secondary outcome measures from a randomized controlled trial, we investigated the latency and amplitude changes of the P3a in responses in a three-condition oddball visual task that included trauma-related (combat scenes) and trauma-unrelated (threatening animals) distractors. Fifty-five U.S. veterans diagnosed with combat-related PTSD were randomized to receive either active or sham repetitive transcranial magnetic stimulation (rTMS). All received cognitive processing therapy, CPT+A, which requires a written account of the index trauma. They were tested before and 6 months after protocol completion. P3a amplitude and response time decreases were driven largely by the changes in the responses to the trauma-related stimuli, and this decrease correlated to the decrease in PTSD symptoms. The amplitude changes were greater in those who received rTMS + CPT than in those who received sham rTMS + CPT, suggesting that rTMS plays beneficial role in reducing arousal and threat bias, which may allow for more effective engagement in trauma-focused PTSD treatment.