Diagnostic and Prognostic Performance of Metabolic Signatures in Pancreatic Ductal Adenocarcinoma: The Clinical Application of Quantitative NextGen Mass Spectrometry.

With 64,050 new diagnoses and 50,550 deaths in the US in 2023, pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all human malignancies. Early detection and improved prognostication remain critical unmet needs. We applied next-generation metabolomics, using quantitative tandem mass spectrometry on plasma, to develop biochemical signatures that identify PDAC. We first compared plasma from 10 PDAC patients to 169 samples from healthy controls. Using metabolomic algorithms and machine learning, we identified ratios that incorporate amino acids, biogenic amines, lysophosphatidylcholines, phosphatidylcholines and acylcarnitines that distinguished PDAC from normal controls. A confirmatory analysis then applied the algorithms to 30 PDACs compared with 60 age- and sex-matched controls. Metabolic signatures were then analyzed to compare survival, measured in months, from date of diagnosis to date of death that identified metabolite ratios that stratified PDACs into distinct survival groups. The results suggest that metabolic signatures could provide PDAC diagnoses earlier than tumor markers or radiographic measures and offer insights into disease severity that could allow more judicious use of therapy by stratifying patients into metabolic-risk subgroups.

William E. Pelham Jr. (1948-2023).

William ("Bill") E. Pelham Jr. was a renowned clinical child psychologist who specialized in the assessment and treatment of children with attention-deficit/hyperactivity disorder (ADHD). Bill was born in 1948 in Atlanta, Georgia, to William E. Pelham Sr. and Kittie Copeland Kay, the eldest of four brothers. Bill is most well-known for the development, study, and advocacy of psychosocial treatments for children with ADHD. While at Florida State University in the 1980s, he developed a comprehensive summer treatment program designed to improve family and classroom functioning, strengthen peer relationships, and boost academic achievement. Bill built the case for the behavioral treatment of ADHD over nearly 50 years of programmatic research. Bill was a leader in the field of clinical child psychology. Bill passed away on October 21, 2023, after a brief illness. He is survived by his wife of 33 years Maureen, son William E. Pelham III, and daughter Caroline. His legacy will live on in their work to support children with ADHD and their families. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Effects of Compliance to a Training Intervention for High School Students with ADHD.

OBJECTIVE: We evaluated the effects of treatment compliance with the Challenging Horizons Program (CHP) for high school aged adolescents with attention-deficit hyperactivity disorder (ADHD). METHOD: Participants were 185 high school aged adolescents (65% non-Hispanic White; 79% male) with a diagnosis of ADHD who were randomly assigned to either CHP or community control. Outcomes included parent-rated academic functioning, parent- and self-rated social-emotional functioning, and GPA. The complier average causal effect (CACE) was estimated using propensity-weighted models for youth engaging in ≥ 30 CHP individual sessions (15-20 min) across the academic year. RESULTS: Most (78%) CHP participants engaged in≥30 CHP sessions. CACE analyses using latent growth curve modeling revealed significant treatment effects among treatment compliers across ratings of academic and social outcomes relative to similar control participants. For most outcomes, CACE estimates were larger than those found in intent-to-treat analyses, especially at 6-months follow-up. CONCLUSIONS: Compliance with 30 or more individual CHP sessions appeared to be an attainable threshold associated with incremental gains across several academic and social outcomes. Effects of compliance were amplified at 6-months follow-up, supporting the hypothesized theory of change of training interventions. Future work should focus on facilitators of treatment engagement and feasibility of the CHP as delivered by high school personnel.

Acceptability and playability of an organization training videogame for young adolescents with ADHD: The development of ATHEMOS.

An estimated 8.7% to 9.8% of school-age children in the United States have attention deficit hyperactivity disorder (ADHD), affecting 4.3 to 4.9 million public school students. ADHD is a costly disorder that often goes untreated, especially among adolescents. Accessible computer-based programs have emerged to address the neurocognitive deficits of ADHD, but results to date have been disappointing. In this study, we tested the acceptability, playability, and user satisfaction of a novel planning/organization skills training game, called "ATHEMOS," based on an established psychosocial treatment package (i.e., Challenging Horizons Program). We conducted eight focus groups during a three-year development period, using feedback from 72 young adolescents with ADHD to iteratively improve the game. Then, during a pilot study in the fourth year, we collected data from 16 young adolescents who played the game as part of a 6- to 16-week school-based intervention. Our findings suggest that the serious game resulted in acceptability and playability ratings only moderately below that of recreational games (δ = -0.40). Critically, average perceptions remained positive when delivered within a school-based ADHD intervention over several weeks or months, with strong overall user satisfaction. Boys found the game more acceptable than girls, with ratings near that of recreational games (δ = -0.23). We conclude that computer-assisted behavior interventions appeal to adolescents with ADHD and offer a potentially promising treatment delivery method in schools.

The Utility of the Behavior Assessment System for Children-2 Behavioral and Emotional Screening System and Strengths and Difficulties Questionnaire in Predicting Mental Disorders in the Project to Learn About Youth-Mental Health.

We examined the predictive utility of the Behavior Assessment System for Children-2 Behavioral and Emotional Screening System (BASC-2-BESS) and Strengths and Difficulties Questionnaire (SDQ) in identifying students with a mental disorder. Data were collected in a two-stage study over 34 months with kindergarten-12th grade (K-12) students (aged 5-19 years) in four U.S. school districts. In Stage 1, teachers completed the BASC-2-BESS and the SDQ. In Stage 2, parents of 1,054 children completed a structured diagnostic interview to determine presence of a mental disorder. Results suggest that teacher versions of the BASC-2-BESS and SDQ have modest utility in identifying children meeting criteria for a mental disorder based on parent report. Area Under the Curve (AUC) statistics representing prediction of any externalizing disorder (.73 for both measures) were higher than the AUCs predicting any internalizing disorder (.58 for both measures). Findings can inform the use of teacher report in mental health screening, specifically the selection of measures when implementing screening procedures.

Social Functioning Outcomes of a High School-Based Treatment Program for Adolescents with ADHD.

OBJECTIVE: We evaluated the extent to which receiving the multi-component treatment of the Challenging Horizons Program (CHP) would lead to significant improvements in social functioning, as well as in inattention, internalizing symptoms, parent stress, and emotion dysregulation for high-school-aged adolescents with attention-deficit hyperactivity disorder (ADHD). METHOD: Participants were 186 high-school-aged adolescents (74% White) with a diagnosis of ADHD who were randomly assigned to either CHP (n = 92; 80% boys; M age = 15.0; SD = 0.8) or Community Care (CC; n = 94; 78% boys; M age = 15.1; SD = 0.9) within each of 12 participating schools. Parent and adolescent reports of social functioning were the primary outcome measures. Secondary outcomes included ratings of symptoms of ADHD and related disorders, parent stress, and emotion regulation. RESULTS: Intent-to-treat analyses using hierarchical linear modeling revealed significant group-by-time interactions of medium magnitude (d range = .40 to .52) on parent-rated social skills. Significant group-by-time benefits were also identified for adolescent self-rated social skills as well as the secondary outcomes of parent-rated inattention symptoms, emotion regulation, and parenting stress. DISCUSSION: CHP appears to benefit social skills along with related characteristics for adolescents with ADHD. Understanding these unique findings for this population informs additional research related to treatment mechanisms and effectiveness trials.

Exploring Intervention Sustainment and Intervention Spread Following a Randomized Clinical Trial of the MOSAIC Program.

The randomized trial of the Making Socially Accepting Inclusive Classrooms (MOSAIC) program included intensive coaching from research staff to support teachers' implementation of MOSAIC strategies and resulted in positive student outcomes (Mikami et al., J. Clin. Child Adolesc. Psychol. 51(6):1039-1052, 2022). However, these intensive procedures are costly (in time, money, and resources) and serve as barriers to intervention adoption under typical school conditions. In this study, we explored the extent to which MOSAIC-trained teachers could sustain practices under typical practice conditions (sustainment), the extent to which teachers who did not participate in the trial could adopt the practices under typical practice conditions (spread), and the extent to which strategy use in the follow-up year was associated with participation in MOSAIC-focused professional learning communities (PLCs). Participants were 30 elementary school teachers, including (a) 13 teachers who received intensive coaching on MOSAIC practices during the previous year (MOSAIC group), and (b) seven teachers who participated in the trial in the control condition, plus 10 new teachers interested in MOSAIC (new-to-MOSAIC group). We assessed MOSAIC strategy use over the school year via monthly observations and biweekly teacher self-report surveys. Observation data revealed high sustainment in the MOSAIC group, with teachers showing less than 20% decline in the use of most strategies between the two years of participation. New-to-MOSAIC teachers implemented some core MOSAIC strategies, although not to the extent as those in the MOSAIC group. Higher strategy use was modestly associated with PLC attendance. We discuss implications for encouraging sustainment and intervention spread after initial, intensive supports are withdrawn. Supplementary Information: The online version contains supplementary material available at 10.1007/s12310-022-09555-w.

Retrospective Report of Academic Motivation Among College Students With Elevated ADHD Symptoms.

OBJECTIVE: Children with ADHD exhibit deficits in academic motivation compared to their peers. Yet conceptualizations of motivation according to prominent motivation theories connected to achievement have not been studied in college-bound youth with ADHD symptoms. METHOD: This study examined motivation according to these theories, differences in motivation by ADHD symptoms, and how the cross-sectional association between motivation and achievement varies by ADHD symptoms. The sample included 461 first-year college students retrospectively reporting their motivation and achievement in their last year of high school. RESULTS: Results indicated differences in motivation by ADHD symptoms. Mastery achievement goal orientation was uniquely associated with achievement and exerted beneficial effects on achievement at moderate to high ADHD symptom levels. CONCLUSION: Motivation may operate differently in association with achievement for college-bound youth with ADHD symptoms compared to youth with no to low symptoms.

Therapeutic Targeting of P53: A Comparative Analysis of APR-246 and COTI-2 in Human Tumor Primary Culture 3-D Explants.

Background:TP53 is the most commonly mutated gene in human cancer with loss of function mutations largely concentrated in "hotspots" affecting DNA binding. APR-246 and COTI-2 are small molecules under investigation in P53 mutated cancers. APR binds to P53 cysteine residues, altering conformation, while COTI-2 showed activity in P53 mutant tumors by a computational platform. We compared APR-246 and COTI-2 activity in human tumor explants from 247 surgical specimens. Methods: Ex vivo analyses of programmed cell death measured drug-induced cell death by delayed-loss-of-membrane integrity and ATP content. The LC50s were compared by Z-Score. Synergy was conducted by the method of Chou and Talalay, and correlations were performed by Pearson moment. Results: APR-246 and COTI-2 activity favored hematologic neoplasms, but solid tumor activity varied by diagnosis. COTI-2 and APR-246 activity did not correlate (R = 0.1028) (NS). COTI-2 activity correlated with nitrogen mustard, cisplatin and gemcitabine, doxorubicin and selumetinib, with a trend for APR-246 with doxorubicin. For ovarian cancer, COTI-2 showed synergy with cisplatin at 25%. Conclusions: COTI-2 and APR-246 activity differ by diagnosis. A lack of correlation supports distinct modes of action. Cisplatin synergy is consistent with P53's role in DNA damage. Different mechanisms of action may underlie disease specificity and offer better disease targeting.

Impairment's Role in the Pathway From Externalizing Psychopathology to Depressive Symptoms in Adolescents With ADHD.

OBJECTIVE: This study examined the role of academic, social, and family impairment in the pathway from externalizing psychopathology to depression among young adolescents with ADHD in a multiple mediation model. METHOD: The sample included adolescents with ADHD enrolled in an intervention trial. Parent ratings of externalizing psychopathology were measured at eligibility assessment, adolescent self-reported depressive symptoms were measured at eligibility and at the end of treatment, and parent-rated impairment was measured in the middle of treatment. A multiple mediation model was used to examine mediating effects of impairment types in the pathway from externalizing psychopathology to depression. RESULTS: Parent-reported family impairment significantly mediated the association between externalizing psychopathology and depressive symptoms. CONCLUSIONS: Results suggest family impairment mediates the association between externalizing psychopathology and depressive symptoms beyond academic and social impairment for youth with ADHD. Findings implicate the importance of targeting family functioning during early adolescence to prevent depression.

Surveillance of ADHD Among Children in the United States: Validity and Reliability of Parent Report of Provider Diagnosis.

OBJECTIVE: To evaluate the appropriateness of parent-reported diagnosis of ADHD as a surveillance tool. METHOD: We assessed agreement over time and concordance of parent-reported diagnosis against Diagnostic and Statistical Manual (DSM)-based criteria. We compared concordance of diagnosis and DSM-based criteria by child characteristics, including treatment. RESULTS: Among parents who reported their child had ADHD, 95.7% reported it again 2 years later. Comparing diagnosis with DSM-based criteria, specificity and negative predictive value were high, sensitivity was moderate, and positive predictive value was low. Most children with an ADHD diagnosis who did not meet DSM-based criteria met sub-threshold criteria or took medication for ADHD. Concordance differed by child characteristics and treatment. CONCLUSION: Parent-reported diagnosed ADHD is reliable over time. Although differences in parent-reported diagnosis and DSM-based criteria were noted, these may reflect children with milder symptoms or treated ADHD. Parent-report of child ADHD ever diagnosis may be a good single-item indicator for prevalence.

Doxycycline-Induced Gastric Perforation.

Esophageal and gastric mucosal injuries are well-documented adverse effects of doxycycline leading to odynophagia, chest pain, and abdominal pain. There are no clear diagnostic criteria for such adverse effects; hence, the diagnosis depends heavily on thorough history. There is a paucity of literature describing life-threatening complications from doxycycline-induced mucosal injury, such as hemorrhage and perforation. We present the first case report describing a gastric perforation from doxycycline use.

Cost-Effectiveness of a Training Intervention for Adolescents with ADHD.

OBJECTIVE: The aim of this study was to examine the costs and cost-effectiveness of a school-based training intervention delivered at varying levels of intensity with adolescents with attention-deficit/hyperactivity disorder (ADHD). Costs were examined in relation to post-treatment and 6-month follow-up effects of the Challenging Horizons Program (CHP), a training intervention for adolescents with ADHD. METHOD: A total of 326 middle-school students (71% male; 77% White) with ADHD were randomized to an after-school version of the CHP (CHP-AS), a less-intensive mentoring version (CHP-M), or routine community care. Detailed time logs were maintained throughout the study and were used to estimate costs associated with each condition. Student grade point average (GPA) and parent-rated ADHD symptoms and organization skills were collected at post-treatment and 6-month follow-up. RESULTS: The cost analysis revealed that CHP-AS was more costly per student than CHP-M, both in terms of overall costs and direct expenses to the school. However, CHP-AS was less costly per hour of intervention provided to the youth than CHP-M. Incremental cost-effectiveness ratios revealed that CHP-M may be the more cost-effective option for post-treatment effects, yet CHP-AS may be the more cost-effective option in the long term for sustained gains in organization skills and GPA. CONCLUSIONS: This study provides stakeholders important information to make decisions regarding allocation of finite monetary resources to meet their prioritized goals.

Intraoperative abobotulinumtoxinA alleviates pain after surgery and improves general wellness in a translational animal model.

Pain after surgery remains a significant healthcare challenge. Here, abobotulinumtoxinA (aboBoNT-A, DYSPORT) was assessed in a post-surgical pain model in pigs. Full-skin-muscle incision and retraction surgery on the lower back was followed by intradermal injections of either aboBoNT-A (100, 200, or 400 U/pig), vehicle (saline), or wound infiltration of extended-release bupivacaine. We assessed mechanical sensitivity, distress behaviors, latency to approach the investigator, and wound inflammation/healing for 5-6 days post-surgery. We followed with immunohistochemical analyses of total and cleaved synaptosomal-associated protein 25 kD (SNAP25), glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor protein-1(Iba1), calcitonin gene-related peptide (CGRP) and substance P (SP) in the skin, dorsal root ganglia (DRG) and the spinal cord of 400 U aboBoNT-A- and saline-treated animals. At Day 1, partial reversal of mechanical allodynia in aboBoNT-A groups was followed by a full reversal from Day 3. Reduced distress and normalized approaching responses were observed with aboBoNT-A from 6 h post-surgery. Bupivacaine reversed mechanical allodynia for 24 h after surgery but did not affect distress or approaching responses. In aboBoNT-A-treated animals cleaved SNAP25 was absent in the skin and DRG, but present in the ipsilateral dorsal horn of the spinal cord. In aboBoNT-A- versus saline-treated animals there were significant reductions in GFAP and Iba1 in the spinal cord, but no changes in CGRP and SP. Analgesic efficacy of aboBoNT-A appears to be mediated by its activity on spinal neurons, microglia and astrocytes. Clinical investigation to support the use of aboBoNT-A as an analgesic drug for post-surgical pain, is warranted.

Bioindustrial manufacturing readiness levels (BioMRLs) as a shared framework for measuring and communicating the maturity of bioproduct manufacturing processes.

Readiness level (RL) frameworks such as technology readiness levels and manufacturing readiness levels describe the status of a technology/manufacturing process on its journey from initial conception to commercial deployment. More importantly, they provide a roadmap to guide technology development and scale-up from a ''totality of system'' approach. Commercialization risks associated with too narrowly focused R&D efforts are mitigated. RLs are defined abstractly so that they can apply to diverse industries and technology sectors. However, differences between technology sectors make necessary the definition of sector specific RL frameworks. Here, we describe bioindustrial manufacturing readiness levels (BioMRLs), a classification system specific to bioindustrial manufacturing. BioMRLs will give program managers, investors, scientists, and engineers a shared vocabulary for prioritizing goals and assessing risks in the development and commercialization of a bioindustrial manufacturing process.

Disparities in Access to Postmastectomy Breast Reconstruction: Does Living in a Specific ZIP Code Determine the Patient's Reconstructive Journey?

BACKGROUND: Postmastectomy breast reconstruction (BR) has been shown to provide long-term quality of life and psychosocial benefits. Despite the policies initiated to improve access to BR, its delivery continues to be inequitable, suggesting that barriers to access have not been fully identified and/or addressed. The purpose of this study was to assess the influence of geographic location, socioeconomic status, and race in access to immediate BR (IBR). METHODS: An institutional review board-approved observational study was conducted. All patients who underwent breast cancer surgery from 2014 to 2019 were queried from our institutional Breast Cancer Registry. A geographical analysis was conducted using demographic characteristics and patient's ZIP codes. Euclidean distance from patient home ZIP code to UPMC Magee Women's Hospital was calculated, and χ2, Student t test, Mann-Whitney, and Kruskal-Wallis tests was used to evaluate differences between groups, as appropriate. Statistical significance was set at P < 0.05. RESULTS: Overall, 5835 patients underwent breast cancer surgery. A total of 56.7% underwent lumpectomy or segmental mastectomy, and 43.3% underwent modified, total, or radical mastectomy. From the latter group, 33.5% patients pursued BR at the time of mastectomy: 28.6% autologous, 48.1% implant-based, 19.4% a combination of autologous and implant-based, and 3.9% unspecified reconstruction. Rates of IBR varied among races: White or European (34.1%), Black or African American (27.7%), and other races (17.8%), P = 0.022. However, no difference was found between type of BR among races (P = 0.38). Moreover, patients who underwent IBR were significantly younger than those who did not pursue reconstruction (P < 0.0001). Patients who underwent reconstruction resided in ZIP codes that had approximately US $2000 more annual income, a higher percentage of White population (8% vs 11% non-White) and lower percentage of Black or African American population (1.8% vs 2.9%) than the patients who did not undergo reconstruction. CONCLUSIONS: While the use of postmastectomy BR has been steadily rising in the United States, racial and socioeconomic status disparities persist. Further efforts are needed to reduce this gap and expand the benefits of IBR to the entire population without distinction.

Comparison of Four Classroom-Based Strategies for Middle School Students With ADHD: A Pilot Randomized Controlled Trial.

Middle school students with ADHD often experience negative academic outcomes. To intervene, schools frequently provide services through special education or section 504. These services include strategies, such as breaks, prompting, and sensory proprioception to remove the impact of construct-irrelevant variance. Student plans rarely include strategies, such as selfmanagement, designed to teach students skills to increase independent functioning. The purpose of this study was to compare the effectiveness of four strategies on engagement, disruptive behavior, and time to initiate tasks. Fifteen sixth and seventh grade students were randomized daily to one of four conditions. Results indicated large statistically significant differences. Social validity data indicated that students found prompting and self-management helpful, but preferred breaks and sensory proprioception. This study builds on a growing empirical base that supports the prioritization of strategies to teach skills over strategies to remove the impact of ADHD on performance.

Promoting Classroom Social and Academic Functioning among Children at Risk for ADHD: The MOSAIC Program.

OBJECTIVE: Social and academic functioning are linked in elementary school, and both are frequently impaired in children with elevated symptoms of attention-deficit/hyperactivity disorder (ADHD). This study evaluated the Making Socially Accepting Inclusive Classrooms (MOSAIC) program, a classroom intervention to support children's social and academic functioning, especially for children at risk for ADHD. Teachers delivered MOSAIC practices to the whole class and applied some strategies more frequently to target children selected for elevated ADHD symptoms and peer impairment. METHOD: Participants were 34 general education teachers (grades K-5) and 558 children in their classrooms, randomized to MOSAIC or to a typical practice control group for one academic year. In the fall and spring, we assessed (a) peers' sociometric judgments of children, (b) children's self-report of supportive relationships with teachers and peers, and (c) teachers' report of children's social and academic competencies and impairments. RESULTS: Regarding whole class effects, relative to control group children, children in MOSAIC classrooms (target and non-target children) were rated by teachers in spring as having better competencies and lower impairment, after controlling for fall functioning. There were no main effects of MOSAIC on peer sociometrics or child perceptions of supportive relationships. Target status moderated some effects such that, in spring, target children in MOSAIC perceived greater support from their teachers but received poorer sociometrics than did target children in control classrooms. CONCLUSIONS: We discuss the difficulty in changing peers' perceptions of children with ADHD symptoms, even in the presence of improvements in other aspects of social and academic functioning.

Understanding the effects of system differences for parameter estimation and scale-up of high throughput chromatographic data.

In this paper, we evaluate how employing fraction collection and multistep gradients with RoboColumns® (Repligen, formally Atoll) affects both comparison to benchtop experimental data and column simulation parameter estimation. These operational differences arise from the RoboColumn® system (operated on an automated liquid handling device) requiring offline analysis for determination of elution profiles rather than the continuous in-line UV curves obtained with larger scale systems. In addition, multistep gradients are used to model the smooth linear gradients of larger scale systems because sequential injections are used to provide liquid flow. Comparisons of two sets of column simulations was first carried out to demonstrate that fraction collection reduced the first moments of the elution peaks by 1/2 of the fraction volumes. Additional column simulations determined that the effect of a multistep gradient approximation on retention volume was dependent upon the gradient step length. An empirical transformation was then developed to correct the first moments obtained from gradient experimental data using the RoboColumn® system. These corrected values provided a more direct comparison of the experimental data at different scales and resulted in a significant improvement in agreement with results obtained using a 20 mL benchtop column. Linear steric mass-action (SMA) parameters were then estimated using the corrected values and employed to successfully predict the performance of the benchtop system data. Finally, these parameters were demonstrated to be well suited for modeling the RoboColumn® gradient data when properly accounting for multistep gradients and fraction collection. This work continues previous investigations into understanding system differences associated with robotic liquid handling devices and proposes a methodology for properly accounting for operational differences to predict operation at larger scales using conventional chromatography systems.