The Legal Landscape for Opioid Treatment Agreements.

Policy Points Opioid treatment agreements (OTAs) are controversial because of the lack of evidence that their use reduces opioid-related harms and the potential risks they pose of stigmatizing patients and undermining the clinician-patient relationship. Even so, their use is now required in most jurisdictions, and their use is influencing the outcomes of civil and criminal lawsuits. More research is needed to evaluate how OTAs are implemented given existing requirements. If additional research does not resolve the current level of uncertainty regarding OTA benefits, then policymakers in jurisdictions where they are required should consider eliminating OTA mandates or providing flexibility in the legal requirements to make room for clinicians and health care institutions to implement best practices. CONTEXT: Opioid treatment agreements (OTAs) are documents that clinicians present to patients when prescribing opioids that describe the risks of opioids and specify requirements that patients must meet to receive their medication. Notwithstanding a lack of evidence that OTAs effectively mitigate opioids' risks, professional organizations recommend that they be implemented, and jurisdictions increasingly require them. We sought to identify the jurisdictions that require OTAs, how OTAs might affect the outcomes of lawsuits that arise when things go wrong, and instances in which the law permits flexibility for clinicians and health care institutions to adopt best practices. METHODS: We surveyed the laws and regulations of all 50 states and the District of Columbia to identify which jurisdictions require the use of OTAs, the circumstances in which OTA use is mandatory, and the terms OTAs must include (if any). We also surveyed criminal and civil judicial decisions in which OTAs were discussed as evidence on which a court relied to make its decision to determine how OTA use influences litigation outcomes. FINDINGS: Results show that a slight majority (27) of jurisdictions now require OTAs. With one exception, the jurisdictions' requirements for OTA use are triggered at least in part by long-term prescribing. There is otherwise substantial variation and flexibility within OTA requirements. Results also show that even in jurisdictions where OTA use is not required by statute or regulation, OTA use can inform courts' reasoning in lawsuits involving patients or clinicians. Sometimes, but not always, OTA use legally protects clinicians from liability. CONCLUSIONS: Our results show that OTA use is entwined with legal obligations in various ways. Clinicians and health care institutions should identify ways for OTAs to enhance clinician-patient relationships and patient care within the bounds of relevant legal requirements and risks.

Principles of Analytic Validation of Immunohistochemical Assays: Guideline Update.

CONTEXT.­: In 2014, the College of American Pathologists developed an evidence-based guideline to address analytic validation of immunohistochemical assays. Fourteen recommendations were offered. Per the National Academy of Medicine standards for developing trustworthy guidelines, guidelines should be updated when new evidence suggests modifications. OBJECTIVE.­: To assess evidence published since the release of the original guideline and develop updated evidence-based recommendations. DESIGN.­: The College of American Pathologists convened an expert panel to perform a systematic review of the literature and update the original guideline recommendations using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS.­: Two strong recommendations, 1 conditional recommendation, and 12 good practice statements are offered in this updated guideline. They address analytic validation or verification of predictive and nonpredictive assays, and recommended revalidation procedures following changes in assay conditions. CONCLUSIONS.­: While many of the original guideline statements remain similar, new recommendations address analytic validation of assays with distinct scoring systems, such as programmed death receptor-1 and analytic verification of US Food and Drug Administration approved/cleared assays; more specific guidance is offered for validating immunohistochemistry performed on cytology specimens.

Getting Wheels: development and evaluation of a psychoeducational resource for parents of children with a neuromuscular condition following recommendation of wheelchair equipment.

PURPOSE: Access to credible information can facilitate parental engagement in wheelchair prescription for their child with a neuromuscular condition (NMC). In this study, we developed and evaluated acceptability, perceived usefulness and emotional responses to a psychoeducational booklet for parents of children with a NMC. METHODS: Australian parents of children who had been recommended a wheelchair and clinicians caring for children with NMCs were invited to evaluate the booklet, Getting Wheels. The booklet included 11 chapters, each covering distinct aspects of wheelchair prescription and supportive care. Participants completed one online survey including validated and study-specific measures. RESULTS: Twenty-seven parents (71% response rate, 78% mothers) and nine clinicians (90% response rate, 89% women) participated. All parents endorsed the booklet as addressing their information and support needs, and 93% agreed it would help parents engage in the wheelchair prescription process. All clinicians endorsed the booklet as addressing parents' information and support needs and agreed they could use the booklet in clinical practice. CONCLUSIONS: Parents and clinicians rate Getting Wheels as acceptable for use in the context of wheelchair recommendation for children with a neuromuscular condition. Next steps include prospective examination of booklet use in clinical practice and adaptation to culturally and linguistically diverse populations.Implications for rehabilitationThe co-designed "Getting Wheels" booklet provides tailored information for use in the context of wheelchair recommendation for children with a neuromuscular condition.The emotions elicited throughout wheelchair prescription endorse the need for integrated psychosocial multidisciplinary care to improve access and support the ongoing emotional needs of this population.Parents of children who receive wheelchair recommendation between zero and two years require greater support from clinicians regarding their thoughts and feelings about wheelchair prescription.Parents of children with a neuromuscular condition and treating clinicians support provision of a tailored psychoeducational resource when a child is recommended a wheelchair.

Training Community Leaders to Serve as Equal Partners in Research: Penn Community Scholars Program, 2015-2023.

An implementation and effectiveness evaluation of the Community Scholars Program was conducted at the University of Pennsylvania to enhance community capacity to collaborate with academics in mutually beneficial, equitable, and transformative research. Mixed methods were employed using administrative data, surveys, and key informant interviews. Participants expressed high satisfaction, valued interactive learning, and identified areas for improvement. The program increased knowledge and self-confidence in research-related skills and trust in the research process. The program serves as an institutional model to create long-term, mutually beneficial community-academic partnerships. (Am J Public Health. 2024;114(3):284-288. https://doi.org/10.2105/AJPH.2023.307549).

Clinician Perspectives on Opioid Treatment Agreements: A Qualitative Analysis of Focus Groups.

BACKGROUND: Patients with chronic pain face significant barriers in finding clinicians to manage long-term opioid therapy (LTOT). For patients on LTOT, it is increasingly common to have them sign opioid treatment agreements (OTAs). OTAs enumerate the risks of opioids, as informed consent documents would, but also the requirements that patients must meet to receive LTOT. While there has been an ongoing scholarly discussion about the practical and ethical implications of OTA use in the abstract, little is known about how clinicians use them and if OTAs themselves modify clinician prescribing practices. OBJECTIVE: To determine how clinicians use OTAs and the potential impacts of OTAs on opioid prescribing. DESIGN: We conducted qualitative analysis of four focus groups of clinicians from a large Midwestern academic medical center. Groups were organized according to self-identified prescribing patterns: two groups for clinicians who identified as prescribers of LTOT, and two who did not. PARTICIPANTS: 17 clinicians from General Internal Medicine, Family Medicine, and Palliative Care were recruited using purposive, convenience sampling. APPROACH: Discussions were recorded, transcribed, and analyzed for themes using reflexive thematic analysis by a multidisciplinary team. KEY RESULTS: Our analysis identified three main themes: (1) OTAs did not influence clinicians' decisions whether to use LTOT generally but did shape clinical decision-making for individual patients; (2) clinicians feel OTAs intensify the power they have over patients, though this was not uniformly judged as harmful; (3) there is a potential misalignment between the intended purposes of OTAs and their implementation. CONCLUSION: This study reveals a complicated relationship between OTAs and access to pain management. While OTAs seem not to impact the clinicians' decisions about whether to use LTOT generally, they do sometimes influence prescribing decisions for individual patients. Clinicians shared complex views about OTAs' purposes, which shows the need for more clarity about how OTAs could be used to promote shared decision-making, joint accountability, informed consent, and patient education.

Pathways and processes to the embodiment of historical trauma secondary to settler colonialism.

AIM(S): This discursive article aims to examine how systemic factors of settler colonialism influence health outcomes among Indigenous peoples in the United States through pathways and processes that may lead to the embodiment of historical trauma. DESIGN: Discursive paper. METHODS: We completed a comprehensive search of empirical and grey literature between September 2022 and January 2023 in PubMed, CINAHL and Google Scholar. Using these articles as a foundation, we explored factors related to the pathways and processes leading to the embodiment of historical trauma rooted in settler colonialism. RESULTS: A conceptual framework of the pathways and processes of the embodiment of historical trauma secondary to settler colonialism was developed, and is presented. CONCLUSION: The societal and historical context for Indigenous peoples includes harmful settler colonial structures and ideologies, resulting in stressors and historical trauma that impact health outcomes and disparities through the phenomenon of the process of embodiment. IMPLICATIONS FOR NURSING: To provide holistic nursing care, nurses must be aware of settler colonialism as a determinant of health. They must be attuned to the pathways and processes through which settler colonial exposures may impact health among Indigenous peoples. Nurses must challenge existing structural inequities to advance health equity and social justice.

Emotional stimuli similarly disrupt attention in both visual fields.

People often need to filter relevant from irrelevant information. Irrelevant emotional distractors interrupt this process. But does the degree to which emotional distractors disrupt attention depend on which visual field they appear in? We thought it might for two reasons: (1) people pay slightly more attention to the left than the right visual field, and (2) some research suggests the right-hemisphere (which, in early visual processing, receives left visual field input) has areas specialised for processing emotion. Participants viewed a rapid image-stream in each visual field and reported the rotation of an embedded neutral target preceded by a negative or neutral distractor. We predicted that the degree to which negative (vs. neutral) distractors impaired target detection would be larger when targets appeared in the left than the right stream. This hypothesis was supported, but only when the distractor and target could appear in the same or opposite stream as each other (Experiments 2a-b), not when they always appeared in the same stream as each other (Experiments 1a-1b). However, this effect was driven by superior left-stream accuracy following neutral distractors, and similar left- and right-stream accuracy following negative distractors. Emotional distractors therefore override visuospatial asymmetries and disrupt attention, regardless of visual field.

Hypertensive Management.

Hypertension affects 1 in 3 Americans and results in nearly 900,000 inpatient admits annually due to ineffective management. As a primary factor in the development of strokes, hypertension management is essential. The approach to effectively manage hypertension should be done from a multipoint approach to ensure the specific elements that impede the effective management of hypertension within various patient populations are addressed accordingly, which includes, personal, physical, and health needs. The robust implementation of lifestyle modifications, medication therapy, and self-efficacy interventions can improve hypertension management by almost 37%.

Genetic subgroups inform on pathobiology in adult and pediatric Burkitt lymphoma.

Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.

Fragment optimization and elaboration strategies - the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits.

Here we describe the early stages of a fragment-based lead discovery (FBLD) project for a recently elucidated synthetic lethal target, the PRMT5/MTA complex, for the treatment of MTAP-deleted cancers. Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment elaboration process encompassing optimization of fragment hits and subsequent fragment growth to increase potency, assess synthetic tractability, and enable structure-based drug design. Two lead series were identified, one of which led to the discovery of the clinical candidate MRTX1719.

[Using the Treatment Passport to stimulate Advance Care Planning]. / Het gebruik van het Behandelpaspoort voor het stimuleren van Proactieve Zorgplanning.

Care recipients are becoming increasingly involved in the decision-making process for suitable treatments. Advance Care Planning (ACP) enables care recipients and healthcare professionals to timely think and discuss wishes and preferences for treatments, before a care recipient becomes limited by disease, cognitive problems or age. The Treatment Passport is developed by geriatric specialist Esther Bertholet and contains supportive questions to think about treatment wishes. This study aimed to evaluate the experiences of civilians and healthcare professionals with the usage of the Treatment Passport during ACP. Involved care organisations distributed the Treatment Passports to healthcare professionals, for example dementia casemanagers. Healthcare professionals then handed the Treatment passports to civilians, for example older persons. Thereafter, healthcare professionals (N=30) and civilians (N=80) filled out a questionnaire about the experiences with usage of the Treatment Passport. 65% of the civilians had a disease and a mean age 75.3 years. The Treatment Passport was considered a helpful tool to think and talk about treatment wishes. 57% of the healthcare professionals wants to keep using the Treatment Passport and 78% of the civilians would recommend it to others. Participants who found the passport of limited added value mostly had their own methods of discussing their treatment wishes.

Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor.

Recent progress in targeting KRASG12C has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRASG12D inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRASG12D with KD and IC50 values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRASG12D as compared to KRASWT. MRTX1133 also demonstrated potent inhibition of activated KRASG12D based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRASG12D-mutant cell lines, with median IC50 values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRASWT cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRASG12D-mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRASG12D with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRASG12D mutation-positive tumors on mutant KRAS for tumor cell growth and survival.

Dental Pain in Care Homes: Is It a Phenomenon? A Systematic Review of the Literature.

BACKGROUND: Evidence suggests that 80% of residents living in nursing homes have moderate to severe pain, could dental causes be an under reported contributory factor. The evidence suggests that this is an under-researched area. Our project aims were to explore and consolidate the current literature and conduct some stakeholder groups with care home managers and dentists. Our stakeholder group will be reported elsewhere. METHODS: We used the SPIDER framework to set out key search terms. Which included "dementia" OR "cognitively-impaired" OR "carehome residents" AND "dental pain" OR "oralfacial pain" OR "mouth pain" AND "pain assessment" OR "pain identification". A literature search was carried out on 8 and 9 March 2022 in the electronic databases: Cochrane, PubMed, Medline, Dental & Oral Sciences Source, CINAHL, Global Health, SocINDEX, Ovid (Medline) and Scopus. Restrictions were placed on dates and language (2012-2022 and English only). RESULTS: The search yielded 775 papers up to the year 2020. After screening and exclusion, we were left with five papers: four quantitative and one qualitative. CONCLUSIONS: This review demonstrates that there has been very little research into oral health and/or dental pain in adults with dementia. Furthermore, the recommendations have yet to be taken forward. Identifying pain in older adults with dementia remains challenging. There is a need to develop an algorithm in conjunction with care home staff and dental practitioners in order to identify and address the pain associated with dental disease in adults with dementia.

Type 1 diabetes knowledge assessment: The KAT-1 validation study.

OBJECTIVE: This study sought to examine the reliability and validity of a novel pediatric type 1 diabetes knowledge assessment (KAT-1) designed for children, adolescents, young adults and their parents/guardians. The instrument was designed to be integrated into the clinic workflow to obtain objective data electronically. RESEARCH DESIGN AND METHODS: KAT-1 was developed by a multidisciplinary team and includes 11 independent topical subscales. Forty children/caregivers participated in a pilot study; their feedback was used to improve item clarity and readability. Subsequently, a validation study was performed in 200 participants (100 children/adolescents/young adults with type 1 diabetes ages 11-21 years and 100 parents/guardians of children with type 1 diabetes ages 1-15 years) to examine correlations between the KAT-1 scores and Revised Diabetes Knowledge Test (DKT2) scores and HbA1c. An item analysis was conducted to determine internal consistency and reliability; topical subscales were evaluated using Cronbach's alpha. RESULTS: Total KAT-1 scores were positively correlated with DKT2 scores r = 0.674, p < 0.001, and negatively correlated with HbA1c, r = -0.3, p < 0.001. All KAT-1 subscales were positively and significantly correlated with one another and with total KAT-1 score. Internal consistency of total KAT-1 score was strong (Cronbach's α = 0.938, mean score 84.6, SD = 16.1) and 9 of 11 independent topical subscales demonstrated strong internal consistency. Completion time for subscales was <5 min. CONCLUSIONS: KAT-1 is a valid instrument to assess type 1 diabetes knowledge. The instrument's short topical subscales can be used to objectively assess specific knowledge and individualize diabetes education. KAT-1 has been integrated into our electronic health record (EPIC) and is available online at no cost.

Design and evaluation of achiral, non-atropisomeric 4-(aminomethyl)phthalazin-1(2H)-one derivatives as novel PRMT5/MTA inhibitors.

MRTX1719 is an inhibitor of the PRMT5/MTA complex and recently entered clinical trials for the treatment of MTAP-deleted cancers. MRTX1719 is a class 3 atropisomeric compound that requires a chiral synthesis or a chiral separation step in its preparation. Here, we report the SAR and medicinal chemistry design strategy, supported by structural insights from X-ray crystallography, to discover a class 1 atropisomeric compound from the same series that does not require a chiral synthesis or a chiral separation step in its preparation.

Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction.

SOS1 is one of the major guanine nucleotide exchange factors that regulates the ability of KRAS to cycle through its "on" and "off" states. Disrupting the SOS1:KRASG12C protein-protein interaction (PPI) can increase the proportion of GDP-loaded KRASG12C, providing a strong mechanistic rationale for combining inhibitors of the SOS1:KRAS complex with inhibitors like MRTX849 that target GDP-loaded KRASG12C. In this report, we detail the design and discovery of MRTX0902─a potent, selective, brain-penetrant, and orally bioavailable SOS1 binder that disrupts the SOS1:KRASG12C PPI. Oral administration of MRTX0902 in combination with MRTX849 results in a significant increase in antitumor activity relative to that of either single agent, including tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model.

The Real Ideal: Misestimation of Body Mass Index.

In Western cultures, the ideal body for women is thin and toned. Idealization of thinness has led many women to desire bodies with an underweight body mass index (BMI). The present study investigated women's knowledge of BMI, particularly relating to their own body ideals, to determine whether women knowingly idealize bodies categorized as "underweight." In August 2020, one-hundred and forty-seven US women aged 18 to 25 completed two online tasks in a repeated-measures design. First, participants estimated the BMIs of a series of bodies. Then, participants selected representations of their own and ideal bodies from a figure rating scale and estimated the BMIs of their selections. Participants generally mis-estimated the BMI of bodies, but did so to a greater extent when viewing bodies as an extension of their own, i.e., following the figure rating scale task. Further, if participants selected an underweight or overweight ideal body, they were likely to estimate this body was within a "normal" weight BMI range, demonstrating that women who idealize underweight-or overweight-bodies do so unknowingly. These findings suggest misperceptions of women's own ideal body size are often greater than misperceptions of other bodies, potentially driving the tendency to idealize underweight bodies.

Molecular Biomarker Testing for the Diagnosis of Diffuse Gliomas.

CONTEXT.­: The diagnosis and clinical management of patients with diffuse gliomas (DGs) have evolved rapidly over the past decade with the emergence of molecular biomarkers that are used to classify, stratify risk, and predict treatment response for optimal clinical care. OBJECTIVE.­: To develop evidence-based recommendations for informing molecular biomarker testing for pediatric and adult patients with DGs and provide guidance for appropriate laboratory test and biomarker selection for optimal diagnosis, risk stratification, and prediction. DESIGN.­: The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. A systematic review of literature was conducted to address the overarching question, "What ancillary tests are needed to classify DGs and sufficiently inform the clinical management of patients?" Recommendations were derived from quality of evidence, open comment feedback, and expert panel consensus. RESULTS.­: Thirteen recommendations and 3 good practice statements were established to guide pathologists and treating physicians on the most appropriate methods and molecular biomarkers to include in laboratory testing to inform clinical management of patients with DGs. CONCLUSIONS.­: Evidence-based incorporation of laboratory results from molecular biomarker testing into integrated diagnoses of DGs provides reproducible and clinically meaningful information for patient management.

The role of social context in own body size estimations: An investigation of the body schema.

Women tend to overestimate their body size, including space needed to pass through gaps/apertures. These results were generated using static apertures resembling doorways. However, body image is influenced by other bodies around us, and how estimations of passability may be influenced by social context is unknown. To investigate, a series of apertures were created comprising two women facing each other, with the space between creating the 'doorway'. The apertures were created using either two larger-bodied or two smaller-bodied women. Non-social versions were generated using the social aperture silhouettes. Thirty-four undergraduate women viewed a series of apertures - varying in width relative to their own size - and judged whether they believed they could pass through them. State and trait body dissatisfaction measurements were also taken. Point of subjective equality (PSE) data suggested that participants did not overestimate the space needed to pass through apertures overall, but showed an overestimation of space for the larger-bodied social doorways. Correlations suggested higher levels of state body dissatisfaction associated with higher PSEs, but only in the social conditions. Results showed that participants may have been engaging in different mechanisms regarding social versus non-social doorways, and the importance of social context when investigating own body size estimations.