Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations.

Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific "emergent" biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets. SIGNIFICANCE: We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of "emergent" combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses. This article is featured in Selected Articles from This Issue, p. 695.

Development of a Series of Pyrrolopyridone MAT2A Inhibitors.

The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

Examining Patterns and Predictors of ADHD Teens' Skill-Learning Trajectories During Enhanced FOrward Concentration and Attention Learning (FOCAL+) Training.

OBJECTIVE: Examine patterns and predictors of skill learning during multisession Enhanced FOrward Concentration and Attention Learning (FOCAL+) training. BACKGROUND: FOCAL+ teaches teens to reduce the duration of off-road glances using real-time error learning. In a randomized controlled trial, teens with ADHD received five sessions of FOCAL+ training and demonstrated significant reductions in extended glances (>2-s) away from the roadway (i.e., long-glances) and a 40% reduced risk of a crash/near-crash event. Teens' improvement in limiting long-glances as assessed after each FOCAL+ training session has not been examined. METHOD: Licensed teen (ages 16-19) drivers with ADHD (n = 152) were randomly assigned to five sessions of either FOCAL+ or modified standard driver training. Teens completed driving simulation assessments at baseline, after each training session, and 1 month and 6 months posttraining. Naturalistic driving was monitored for one year. RESULTS: FOCAL+ training produced a 53% maximal reduction in long-glances during postsession simulated driving. The number of sessions needed to achieve maximum performance varied across participants. However, after five FOCAL+ training sessions, number of long-glances was comparable irrespective of when teens achieved their maximum performance. The magnitude of reduction in long-glances predicted levels of long-glances during simulated driving at 1 month and 6 months posttraining but not naturalistic driving outcomes. FOCAL+ training provided the most benefit during training to teens who were younger and had less driving experience. CONCLUSION: FOCAL+ training significantly reduces long-glances beginning at the 1st training session. APPLICATION: Providing five FOCAL+ training sessions early on during teen driving may maximize benefit.

Differences between parent- and teacher-reported executive functioning behaviors after traumatic injuries.

Deficits in executive functioning (EF) behaviors are very common following pediatric traumatic brain injury (TBI) and can linger well after acute injury recovery. Raters from multiple settings provide information that may not be appreciated otherwise. We examined differences between parent and teacher ratings of EF using data examining longitudinal outcomes following pediatric TBI in comparison to orthopedic injury (OI). We used linear mixed models to determine the association of rater type and injury type with scores on the Behavior Rating Inventory of Executive Functioning (BRIEF). After controlling for demographic variables, rater type and injury type accounted for a small but significant proportion of the variance in EF. Teachers' ratings on the BRIEF were significantly higher than parent ratings for global EF and metacognition, but not for behavior regulation, regardless of injury type, indicating greater EF concerns. All BRIEF ratings, whether from teachers or parents, were higher for children with TBI than for those with OI. Results suggest that parents and teachers provide unique information regarding EF following traumatic injuries and that obtaining ratings from persons who observe children at school as well as at home can result in a better understanding of situation-specific variability in outcomes.

Differences Between Black and White Caregivers in the Association Between Autism Diagnostic Process Satisfaction and Service Use.

BACKGROUND: Black families of children with autism spectrum disorder have less access to high quality, culturally responsive care for their children. METHOD: We assessed satisfaction and service utilization among fifty (29%) Black caregivers and 124 (71%) White caregivers of children with autism spectrum disorder. We also examined whether race moderated the association between satisfaction and service utilization. RESULTS: We did not identify racial differences in satisfaction or service utilization. Race moderated the association between satisfaction and total service use, F(170) = 5.29, p =.02, therapy service use, F(163) = 3.59, p =.046, and community service use, F(169) = 4.76, p =.046. For Black families, there was a positive association between satisfaction and service use. There was no association between satisfaction and service use among White families. DISCUSSION: Satisfaction may be particularly important among Black families, who have been mistreated by the healthcare system and frequently face discrimination. Our results suggest the importance of culturally responsive care for Black families.

Diuretics use in the management of bronchopulmonary dysplasia in preterm infants: A systematic review.

AIM: Bronchopulmonary dysplasia (BPD), a respiratory complication associated with neonatal prematurity, presents opportunities for pharmacological intervention due to its contributing risk factors. Despite diuretics' controversial usage in BPD treatment and varying institutional practices, this review aims to consolidate evidence from clinical trials regarding diuretic use in BPD. METHODS: We conducted a systematic review following PRISMA guidelines, searching EMBASE, Medline, Web of Science and CINAHL databases (PROSPERO 2022: CRD42022328292). Covidence facilitated screening and data extraction, followed by analysis and formatting in Microsoft Excel. RESULTS: Among 430 screened records, 13 were included for analysis. Three studies assessed spironolactone and chlorothiazide combinations, two studied spironolactone and hydrochlorothiazide, while eight examined furosemide. All studies evaluated drug effects on dynamic pulmonary compliance and pulmonary resistance, serving as comparative measures in our review. CONCLUSION: Diuretics' effectiveness in treating bronchopulmonary dysplasia remains uncertain. The limited number of identified randomised controlled trials (RCTs) hampers high-level evidence-based conclusions when applying the Population, Intervention, Comparison, Outcome (PICO) approach. Conducting large prospective studies of good quality could provide more definitive insights, but the rarity of outcomes and eligible patients poses challenges. Further research, primarily focusing on RCTs assessing diuretics' safety and efficacy in this population, is warranted.

Diagnostic suspicion bias and machine learning: Breaking the awareness deadlock for sepsis detection.

Many early warning algorithms are downstream of clinical evaluation and diagnostic testing, which means that they may not be useful when clinicians fail to suspect illness and fail to order appropriate tests. Depending on how such algorithms handle missing data, they could even indicate "low risk" simply because the testing data were never ordered. We considered predictive methodologies to identify sepsis at triage, before diagnostic tests are ordered, in a busy Emergency Department (ED). One algorithm used "bland clinical data" (data available at triage for nearly every patient). The second algorithm added three yes/no questions to be answered after the triage interview. Retrospectively, we studied adult patients from a single ED between 2014-16, separated into training (70%) and testing (30%) cohorts, and a final validation cohort of patients from four EDs between 2016-2018. Sepsis was defined per the Rhee criteria. Investigational predictors were demographics and triage vital signs (downloaded from the hospital EMR); past medical history; and the auxiliary queries (answered by chart reviewers who were blinded to all data except the triage note and initial HPI). We developed L2-regularized logistic regression models using a greedy forward feature selection. There were 1164, 499, and 784 patients in the training, testing, and validation cohorts, respectively. The bland clinical data model yielded ROC AUC's 0.78 (0.76-0.81) and 0.77 (0.73-0.81), for training and testing, respectively, and ranged from 0.74-0.79 in four hospital validation. The second model which included auxiliary queries yielded 0.84 (0.82-0.87) and 0.83 (0.79-0.86), and ranged from 0.78-0.83 in four hospital validation. The first algorithm did not require clinician input but yielded middling performance. The second showed a trend towards superior performance, though required additional user effort. These methods are alternatives to predictive algorithms downstream of clinical evaluation and diagnostic testing. For hospital early warning algorithms, consideration should be given to bias and usability of various methods.

Bridging two insect flight modes in evolution, physiology and robophysics.

Since taking flight, insects have undergone repeated evolutionary transitions between two seemingly distinct flight modes1-3. Some insects neurally activate their muscles synchronously with each wingstroke. However, many insects have achieved wingbeat frequencies beyond the speed limit of typical neuromuscular systems by evolving flight muscles that are asynchronous with neural activation and activate in response to mechanical stretch2-8. These modes reflect the two fundamental ways of generating rhythmic movement: time-periodic forcing versus emergent oscillations from self-excitation8-10. How repeated evolutionary transitions have occurred and what governs the switching between these distinct modes remain unknown. Here we find that, despite widespread asynchronous actuation in insects across the phylogeny3,6, asynchrony probably evolved only once at the order level, with many reversions to the ancestral, synchronous mode. A synchronous moth species, evolved from an asynchronous ancestor, still preserves the stretch-activated muscle physiology. Numerical and robophysical analyses of a unified biophysical framework reveal that rather than a dichotomy, these two modes are two regimes of the same dynamics. Insects can transition between flight modes across a bridge in physiological parameter space. Finally, we integrate these two actuation modes into an insect-scale robot11-13 that enables transitions between modes and unlocks a new self-excited wingstroke strategy for engineered flight. Together, this framework accounts for repeated transitions in insect flight evolution and shows how flight modes can flip with changes in physiological parameters.

Examining bidirectional associations between sleep and behavior among children with attention-deficit/hyperactivity disorder.

Background: Children with attention-deficit/hyperactivity disorder (ADHD) have more sleep problems than their peers which contribute to behavioral and functional impairments. This study examines the bidirectional relationship between nightly sleep (i.e., total sleep time and sleep efficiency) and daily behavior of children with ADHD. Method: Forty-three children (ages 6-13 [mean = 9.05, 54% male, 77% medicated]) participated in a 2-week study during an ADHD Summer Treatment Program (STP). Sleep was measured with actigraphy. Behavior was assessed using STP clinical data and daily parent and counselor ratings of ADHD symptoms, oppositional defiant disorder behaviors, and emotion regulation (e.g., difficulty regulating emotional disposition and controlling emotions). We hypothesized that healthier night's sleep measured by actigraphy (i.e., sleep efficiency and total sleep time [TST]) would relate to less ADHD symptoms, less emotional dysregulation, and better academic performance the next day. Additionally, we hypothesized that less ADHD symptoms, less emotional dysregulation, and greater academic performance would relate to healthier sleep that night. Results: Higher nightly sleep efficiency was related to improved parent-ratings of ADHD the next day (R 2 = 0.04, p = 0.04) and improved parent-ratings of ADHD during the day lead to higher sleep efficiency that night (R 2 = 0.002, p = 0.02). Higher rates of daily assignment completion were related to higher sleep efficiency at night (R 2 = 0.035, p = 0.03). TST was not related to any behavioral outcomes. Conclusion: Sleep efficiency may be more relevant than TST to behavioral performance the next day. Additionally, a bidirectional relationship exists between sleep efficiency and parent ratings of ADHD. Findings highlight the importance of assessing for manifestations of poor sleep efficiency, waking minutes, and wakings after sleep onset when diagnosing and treating ADHD.

Executive Functioning as a Predictor of Adverse Driving Outcomes in Teen Drivers With ADHD.

OBJECTIVE: The present study examined the association between executive functioning (EF) and risky driving behaviors in teens with ADHD. METHOD: Teens diagnosed with ADHD (n = 179; Mage = 17.4 years) completed two 15-min drives in a fixed-base driving simulator. EF was assessed using parent- and self-report Behavior Rating Inventory of Executive Functioning (BRIEF-2), a temporal reproduction task, and a Go/No-Go task (GNG). Driving outcomes included known predictors of crashes: count of long (>2 s) off-road glances, standard deviation (SD) of lane position (SDLP), mean speed, and SD speed. Generalized linear mixed models, controlling for intelligence and driving experience, were conducted. RESULTS: Higher rates of GNG commission errors predicted higher rates of long off-road glances. Lower parent-rated EF and increased rates of GNG omission errors predicted SDLP. Higher rates of GNG commission errors also predicted faster average driving speed. CONCLUSION: Heterogeneity in EF is associated with differences in teen ADHD risky driving behaviors.

Environmental predictors of children's executive functioning development.

Executive functioning (EF) abilities develop through childhood, but this development can be impacted by various psychosocial environmental influences. Using longitudinal data from the Health Outcome and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort study, we examined if psychosocial environmental factors were significant predictors of EF development. Study participants comprised 271 children and their primary caregivers (98.5% mothers) followed from birth to age 12. We identified four distinct EF developmental trajectory groups comprising a consistently impaired group (13.3%), a descending impairment group (27.7%), an ascending impairment group (9.95%), and a consistently not impaired group (49.1%). Higher levels of maternal ADHD and relational frustration appear to be risk factors for increased EF difficulty over time, while higher family income may serve as a protective factor delaying predisposed EF impairment. Important intervention targets might include teaching positive and effective parenting strategies to mothers whose children are at risk for EF dysfunction.

Stellate Ganglion Block Reduces Anxiety Symptoms by Half: A Case Series of 285 Patients.

The stellate ganglion block (SGB) procedure has been used successfully for over twelve years to treat thousands of patients suffering from posttraumatic stress disorder (PTSD). Level 1b evidence supports this use of SGB, but no studies to date have reported specifically on anxiety symptom improvements following SGB. We collected Generalized Anxiety Disorder questionnaire (GAD-7) scores pre-procedure and at 1-week and 1-month post-procedure from 285 patients. The mean baseline GAD-7 score of 15.9 (indicating severe anxiety) declined significantly following SGB treatment. Changes in GAD-7 scores ≥ 4 were considered clinically meaningful. From baseline to 1 week, the GAD-7 scores dropped by 9.0 points (95% CI = 8.3-9.7, p < 0.001, d = 1.8), with 211 (79.6%) patients demonstrating clinically meaningful improvement. Furthermore, from baseline to 1 month, the GAD-7 scores dropped by 8.3 points (95% CI = 7.6-9.0, p < 0.001, d = 1.7), with 200 (75.5%) patients demonstrating clinically meaningful improvement. The stellate ganglion block treatment resulted in a decrease of GAD-7 scores of over twice the minimal clinically important difference in treating anxiety for at least 1 month following SGB. Given the results from this retrospective observational study, larger prospective studies should be conducted to determine the effects of SGB treatment as a novel therapeutic treatment for generalized anxiety disorder and other anxiety disorders.

Bubble-PAPR: a phase 1 clinical evaluation of the comfort and perception of a prototype powered air-purifying respirator for use by healthcare workers in an acute hospital setting.

OBJECTIVES: We aimed to design and produce a low-cost, ergonomic, hood-integrated powered air-purifying respirator (Bubble-PAPR) for pandemic healthcare use, offering optimal and equitable protection to all staff. We hypothesised that participants would rate Bubble-PAPR more highly than current filtering face piece (FFP3) face mask respiratory protective equipment (RPE) in the domains of comfort, perceived safety and communication. DESIGN: Rapid design and evaluation cycles occurred based on the identified user needs. We conducted diary card and focus group exercises to identify relevant tasks requiring RPE. Lab-based safety standards established against British Standard BS-EN-12941 and EU2016/425 covering materials; inward particulate leakage; breathing resistance; clean air filtration and supply; carbon dioxide elimination; exhalation means and electrical safety. Questionnaire-based usability data from participating front-line healthcare staff before (usual RPE) and after using Bubble-PAPR. SETTING: Overseen by a trial safety committee, evaluation progressed sequentially through laboratory, simulated, low-risk, then high-risk clinical environments of a single tertiary National Health Service hospital. PARTICIPANTS: 15 staff completed diary cards and focus groups. 91 staff from a range of clinical and non-clinical roles completed the study, wearing Bubble-PAPR for a median of 45 min (IQR 30-80 (15-120)). Participants self-reported a range of heights (mean 1.7 m (SD 0.1, range 1.5-2.0)), weights (72.4 kg (16.0, 47-127)) and body mass indices (25.3 (4.7, 16.7-42.9)). OUTCOME MEASURES: Preuse particulometer 'fit testing' and evaluation against standards by an independent biomedical engineer.Primary:Perceived comfort (Likert scale).Secondary: Perceived safety, communication. RESULTS: Mean fit factor 16 961 (10 participants). Bubble-PAPR mean comfort score 5.64 (SD 1.55) vs usual FFP3 2.96 (1.44) (mean difference 2.68 (95% CI 2.23 to 3.14, p<0.001). Secondary outcomes, Bubble-PAPR mean (SD) versus FFP3 mean (SD), (mean difference (95% CI)) were: how safe do you feel? 6.2 (0.9) vs 5.4 (1.0), (0.73 (0.45 to 0.99)); speaking to other staff 7.5 (2.4) vs 5.1 (2.4), (2.38 (1.66 to 3.11)); heard by other staff 7.1 (2.3) vs 4.9 (2.3), (2.16 (1.45 to 2.88)); speaking to patients 7.8 (2.1) vs 4.8 (2.4), (2.99 (2.36 to 3.62)); heard by patients 7.4 (2.4) vs 4.7 (2.5), (2.7 (1.97 to 3.43)); all p<0.01. CONCLUSIONS: Bubble-PAPR achieved its primary purpose of keeping staff safe from airborne particulate material while improving comfort and the user experience when compared with usual FFP3 masks. The design and development of Bubble-PAPR were conducted using a careful evaluation strategy addressing key regulatory and safety steps. TRIAL REGISTRATION NUMBER: NCT04681365.

Structural damping renders the hawkmoth exoskeleton mechanically insensitive to non-sinusoidal deformations.

Muscles act through elastic and dissipative elements to mediate movement, which can introduce dissipation and filtering which are important for energetics and control. The high power requirements of flapping flight can be reduced by an insect's exoskeleton, which acts as a spring with frequency-independent material properties under purely sinusoidal deformation. However, this purely sinusoidal dynamic regime does not encompass the asymmetric wing strokes of many insects or non-periodic deformations induced by external perturbations. As such, it remains unknown whether a frequency-independent model applies broadly and what implications it has for control. We used a vibration testing system to measure the mechanical properties of isolated Manduca sexta thoraces under symmetric, asymmetric and band-limited white noise deformations. The asymmetric and white noise conditions represent two types of generalized, multi-frequency deformations that may be encountered during steady-state and perturbed flight. Power savings and dissipation were indistinguishable between symmetric and asymmetric conditions, demonstrating that no additional energy is required to deform the thorax non-sinusoidally. Under white noise conditions, stiffness and damping were invariant with frequency, suggesting that the thorax has no frequency-dependent filtering properties. A simple flat frequency response function fits our measured frequency response. This work demonstrates the potential of materials with frequency-independent damping to simplify motor control by eliminating any velocity-dependent filtering that viscoelastic elements usually impose between muscle and wing.

Introduction to the Special Issue on COVID-19.

The COVID-19 pandemic has been a global event affecting all aspects of human life and society, including acoustic aspects. In this Special Issue on COVID-19 and acoustics, we present 48 papers discussing the acoustical impacts of the pandemic and how we deal with it. The papers are divided into seven categories which include: physical masking and speech production, speech perception, noise, the underwater soundscape, the urban soundscape, pathogen transmissibility, and medical diagnosis.

A systematic review examining caregivers' of color experiences with the diagnostic process of autism spectrum disorder.

LAY ABSTRACT: Children of color are diagnosed with autism later than White children. Caregivers of color are also more likely than White caregivers to report that their child's healthcare providers do not treat them as a partner, spend enough time with them, or respect their culture and values. We wanted to better understand the experiences of caregivers of color with the diagnostic process of autism spectrum disorder, from the time they discuss developmental concerns with their child's primary care provider to when the diagnosis is shared with them. We systematically reviewed the literature and found 15 articles that explored the experiences of caregivers of color. Caregivers of color described that they faced large-scale barriers, such as the cost of appointments, transportation, and long wait lists. They also reported negative experiences with providers, including providers not taking their concerns seriously, making assumptions about caregivers, and delaying referrals for an evaluation. Caregivers stated that their own lack of knowledge of autism spectrum disorder, stigma, their family's thoughts and opinions, and cultural differences between providers and caregivers served as barriers during the diagnostic process. Communication challenges were discussed and included use of medical and technical jargon, a lack of follow-up, language barriers, and difficulty obtaining high-quality interpreters. Some families described providers, other individuals, community networks, and self-advocacy as helpful during the diagnostic process. Large-scale changes are needed, such as increases in the number of providers who are trained in diagnosing Autism. Provider-level changes (e.g. implicit bias training) are also important for improving caregivers' experiences.

mTOR inhibition amplifies the anti-lymphoma effect of PI3Kß/δ blockage in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic B-cell receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3Kß/δ inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3Kß/δ inhibition decreased the pro-survival NF-κB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K/AKT/mTOR pathway following PI3Kß/δ inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kß/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kß/δ signaling and thus identifies a previously unappreciated role of the PI3Kß isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kß/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.