Navigating the spectrum of pediatric sialorrhea management: A narrative review.

OBJECTIVE: This review summarizes the approaches to pediatric sialorrhea management from least-to-most invasive: non-pharmacological management, anticholinergic medications, botulinum neurotoxin, non-invasive surgery, and invasive surgical intervention. REVIEW METHODS: An electronic literature review identified English-language articles on sialorrhea management in pediatric patients. Publications between 1982 and 2022 were used, with a focus on articles published from 2012 to 2022. Additional augmentation of pharmacologic information was obtained from the latest editions of medical textbooks supplemented with official package inserts of investigated medications. CONCLUSIONS: Sialorrhea is abnormal in patients greater than four years of age. Severe cases warrant intervention to improve patient quality of life and reduce caregiver burden. Management starts with conservative approaches. Viable candidates begin with non-pharmacological management options. Anticholinergic medications can decrease saliva production, but adverse side effects may outweigh benefits. Botulinum neurotoxin injection of the salivary glands decreases salivary flow rate; however, relief is transient and thus multiple treatments are required. Non-invasive sclerotherapy is an emerging treatment option showing promising results for sialorrhea. In contrast, surgical intervention is reserved as a last-resort treatment for patients with severe symptoms, due to its higher risk for adverse consequences. IMPLICATIONS FOR PRACTICE: Physicians should be familiar with the different pediatric sialorrhea management options, including advantages and disadvantages, to adequately facilitate shared decision making with caretakers of pediatric patients who require treatment.

Parity Quantum Computing as yz-Plane Measurement-Based Quantum Computing.

We show that universal parity quantum computing employing a recently introduced constant depth decoding procedure is equivalent to measurement-based quantum computation (MBQC) on a bipartite graph using only yz-plane measurements. We further show that any unitary MBQC using only yz-plane measurements must occur on a bipartite graph. These results have a number of consequences and open new research avenues for both frameworks.

Evaluating Factors Associated With Telehealth Appropriateness in Outpatient Rheumatoid Arthritis Encounters Using the Encounter Appropriateness Score for You (EASY).

OBJECTIVE: Telehealth has been proposed as a safe and effective alternative to in-person care for rheumatoid arthritis (RA). The purpose of this study was to evaluate factors associated with telehealth appropriateness in outpatient RA encounters. METHODS: A prospective cohort study (January 1, 2021, to August 31, 2021) was conducted using electronic health record data from outpatient RA encounters in a single academic rheumatology practice. Rheumatology providers rated the telehealth appropriateness of their own encounters using the Encounter Appropriateness Score for You (EASY) immediately following each encounter. Robust Poisson regression with generalized estimating equations modeling was used to evaluate the association of telehealth appropriateness with patient demographics, RA clinical characteristics, comorbid noninflammatory causes of joint pain, previous and current encounter characteristics, and provider characteristics. RESULTS: During the study period, 1823 outpatient encounters with 1177 unique patients with RA received an EASY score from 25 rheumatology providers. In the final multivariate model, factors associated with increased telehealth appropriateness included higher average provider preference for telehealth in prior encounters (relative risk [RR] 1.26, 95% CI 1.21-1.31), telehealth as the current encounter modality (RR 2.27, 95% CI 1.95-2.64), and increased patient age (RR 1.05, 95% CI 1.01-1.09). Factors associated with decreased telehealth appropriateness included moderate (RR 0.81, 95% CI 0.68-0.96) and high (RR 0.57, 95% CI 0.46-0.70) RA disease activity and if the previous encounters were conducted by telehealth (RR 0.83, 95% CI 0.73-0.95). CONCLUSION: In this study, telehealth appropriateness was most associated with provider preference, the current and previous encounter modality, and RA disease activity. Other factors like patient demographics, RA medications, and comorbid noninflammatory causes of joint pain were not associated with telehealth appropriateness.

Thin Profunda Artery Perforator Flap for Hand and Upper Extremity Coverage.

The profunda artery perforator (PAP) flap provides a good option for hand and upper extremity reconstruction. The reliable quality, caliber, and number of perforators in the posteromedial thigh support large flaps with long pedicles. The PAP flap has been widely used for breast reconstruction, although its use in the extremities has been slower to catch on due to the bulk and thickness of the subcutaneous tissue. The authors discuss evolution of thin flaps and our application of the thin and superthin PAP flap for upper extremity reconstruction.

Do Self-Processes and Parenting Mediate the Effects of Anxious Parents' Psychopathology on Youth Depression and Suicidality?

To understand how anxious parents' global psychopathology increases children's risks for depression and suicidality, we tested mediational pathways through which parent global psychopathology was associated with youth depression and suicidality over a six-year period. Parents (n = 136) who had an anxiety disorder at baseline reported global psychopathology and youth internalizing problems. Youth did not have any psychiatric disorder at baseline and they reported self-esteem, perceived control, and perceived parental warmth and rejection at baseline and 1-year follow-up. At 6-year follow-up, youth depression and suicidality were assessed via multiple reporters including the self, parent, and/or an independent evaluator. Results showed that parental psychopathology had an indirect but not direct effect on youth depression and suicidality via perceived control. No associations were found for the other hypothesized mediators. Perceived control might be a transdiagnostic intervention target in depression and suicide prevention programs for youth exposed to parental anxiety.

Evaluating Provider Perceptions of Telehealth Utility in Outpatient Rheumatology Telehealth Encounters.

OBJECTIVE: This study aims to explore the factors associated with rheumatology providers' perceptions of telehealth utility in real-world telehealth encounters. METHODS: From September 14, 2020 to January 31, 2021, 6 providers at an academic medical center rated their telehealth visits according to perceived utility in making treatment decisions using the following Telehealth Utility Score (TUS) (1 = very low utility to 5 = very high utility). Modified Poisson regression models were used to assess the association between TUS scores and encounter diagnoses, disease activity measures, and immunomodulatory therapy changes during the encounter. RESULTS: A total of 481 telehealth encounters were examined, of which 191 (39.7%) were rated as "low telehealth utility" (TUS 1-3) and 290 (60.3%) were rated as "high telehealth utility" (TUS 4-5). Encounters with a diagnosis of inflammatory arthritis were significantly less likely to be rated as high telehealth utility (adjusted relative risk [aRR], 0.8061; p = 0.004), especially in those with a concurrent noninflammatory musculoskeletal diagnosis (aRR, 0.54; p = 0.006). Other factors significantly associated with low telehealth utility included higher disease activity according to current and prior RAPID3 scores (aRR, 0.87 and aRR, 0.89, respectively; p < 0.001) and provider global scores (aRR, 0.83; p < 0.001), as well as an increase in immunomodulatory therapy (aRR, 0.70; p = 0.015). CONCLUSIONS: Provider perceptions of telehealth utility in real-world encounters are significantly associated with patient diagnoses, current and prior disease activity, and the need for changes in immunomodulatory therapy. These findings inform efforts to optimize the appropriate utilization of telehealth in rheumatology.

Encounter Appropriateness Score for You Model: Development and Pilot Implementation of a Predictive Model to Identify Visits Appropriate for Telehealth in Rheumatology.

OBJECTIVE: We aimed to develop a decision-making tool to predict telehealth appropriateness for future rheumatology visits and expand telehealth care access. METHODS: The model was developed using the Encounter Appropriateness Score for You (EASY) and electronic health record data at a single academic rheumatology practice from January 1, 2021, to December 31, 2021. The EASY model is a logistic regression model that includes encounter characteristics, patient sociodemographic and clinical characteristics, and provider characteristics. The goal of pilot implementation was to determine if model recommendations align with provider preferences and influence telehealth scheduling. Four providers were presented with future encounters that the model identified as candidates for a change in encounter modality (true changes), along with an equal number of artificial (false) recommendations. Providers and patients could accept or reject proposed changes. RESULTS: The model performs well, with an area under the curve from 0.831 to 0.855 in 21,679 encounters across multiple validation sets. Covariates that contributed most to model performance were provider preference for and frequency of telehealth encounters. Other significant contributors included encounter characteristics (current scheduled encounter modality) and patient factors (age, Routine Assessment of Patient Index Data 3 scores, diagnoses, and medications). The pilot included 201 encounters. Providers were more likely to agree with true versus artificial recommendations (Cohen's κ = 0.45, P < 0.001), and the model increased the number of appropriate telehealth visits. CONCLUSION: The EASY model accurately identifies future visits that are appropriate for telehealth. This tool can support shared decision-making between patients and providers in deciding the most appropriate follow-up encounter modality.

Caregiver skills training for caregivers of individuals with neurodevelopmental disorders: A systematic review and meta-analysis.

AIM: To systematically review the effectiveness of caregiver and parent skills training programs, including caregiver-mediated interventions, for caregivers of individuals with neurodevelopmental disorders. METHOD: We conducted a systematic review with a random-effects meta-analysis. We searched 11 electronic databases through July 2021 and used a snowball methodology to locate relevant articles of randomized controlled trials. Effect size estimates were pooled using Hedges' g from data extracted from study reports and through author requests using random-effects meta-analyses for three child outcome categories (child development, adaptive behavior, and problem behavior) and three caregiver outcome categories (parenting skills and knowledge, psychological well-being, and interpersonal family relations). RESULTS: We located 44 910 records, from which 75 randomized controlled trials involving 4746 individuals with neurodevelopmental disorders and their caregivers were included. Random-effects meta-analyses showed improvements in child development (g = 0.30; 99% confidence interval [CI] = 0.07-0.53) and reduction in reported problem behaviors (g = 0.41; 99% CI = 0.24-0.59), but not a statistically significant improvement in adaptive behavior (g = 0.28; 99% CI = -0.42 to 0.98). Caregivers showed improvements in parenting skills and knowledge (g = 0.72; 99% CI = 0.53-0.90), psychological well-being (g = 0.52; 99% CI = 0.34-0.71), and interpersonal family relations (g = 0.76; 99% CI = 0.32-1.20). INTERPRETATION: Caregiver skills training programs benefit both caregivers and children with neurodevelopmental disorders. Skills training programs improve child development and behavior, improve parenting skills, reduce caregiver mental health issues, and improve family functioning. Programs using culturally appropriate training material to improve the development, functioning, and participation of children within families and communities should be considered when caring for children with neurodevelopmental disorders.

Use of Structured Electronic Health Records Data Elements for the Development of Computable Phenotypes to Identify Potential Adverse Events Associated with Intravenous Immunoglobulin Infusion.

INTRODUCTION: Detection of adverse reactions to drugs and biologic agents is an important component of regulatory approval and post-market safety evaluation. Real-world data, including insurance claims and electronic health records data, are increasingly used for the evaluation of potential safety outcomes; however, there are different types of data elements available within these data resources, impacting the development and performance of computable phenotypes for the identification of adverse events (AEs) associated with a given therapy. OBJECTIVE: To evaluate the utility of different types of data elements to the performance of computable phenotypes for AEs. METHODS: We used intravenous immunoglobulin (IVIG) as a model therapeutic agent and conducted a single-center, retrospective study of 3897 individuals who had at least one IVIG administration between 1 January 2014 and 31 December 2019. We identified the potential occurrence of four different AEs, including two proximal AEs (anaphylaxis and heart rate alterations) and two distal AEs (thrombosis and hemolysis). We considered three different computable phenotypes: (1) an International Classification of Disease (ICD)-based phenotype; (2) a phenotype-based on EHR-derived contextual information based on structured data elements, including laboratory values, medication administrations, or vital signs; and (3) a compound phenotype that required both an ICD code for the AE in combination with additional EHR-derived structured data elements. We evaluated the performance of each of these computable phenotypes compared with chart review-based identification of AEs, assessing the positive predictive value (PPV), specificity, and estimated sensitivity of each computable phenotype method. RESULTS: Compound computable phenotypes had a high positive predictive value for acute AEs such as anaphylaxis and bradycardia or tachycardia; however, few patients had both ICD codes and the relevant contextual data, which decreased the sensitivity of these computable phenotypes. In contrast, computable phenotypes for distal AEs (i.e., thrombotic events or hemolysis) frequently had ICD codes for these conditions in the absence of an AE due to a prior history of such events, suggesting that patient medical history of AEs negatively impacted the PPV of computable phenotypes based on ICD codes. CONCLUSIONS: These data provide evidence for the utility of different structured data elements in computable phenotypes for AEs. Such computable phenotypes can be used across different data sources for the detection of infusion-related adverse events.

Emotion Regulation and Executive Function: Associations with Depression and Anxiety in Autism.

Background: Adolescents and young adults with autism spectrum disorder (ASD) are prone to experience co-occurring mental health conditions such as mood or anxiety disorders, as well as impairments in emotion regulation and executive functioning. However, little research has examined inter-relationships among these constructs, despite evidence of additional stressors and increased risk of internalizing disorders at this age, relative to non-autistic individuals. If either emotion regulation or executive functioning are shown to have patterns of association with mental health, this can inform mechanism-based intervention. Method: Fifty-seven autistic adolescents and adults (16-25 years) with ASD in a transition intervention completed questionnaires and clinician-administered measures at baseline. Analyses assessed whether executive functioning impairment, above and beyond emotion regulation impairment, were associated with depression and anxiety symptoms. Results: ASD characteristics, emotion regulation, anxiety, and depression were significantly correlated. ASD characteristics was a significant contributor to depression and emotion regulation impairments were significant contributors to anxiety and depression. Findings indicated that inhibition difficulties did not uniquely contribute to depression or anxiety above emotion regulation impairment. Difficulties in cognitive flexibility were associated with depression above and beyond ASD characteristics, IQ, and emotion regulation, but not associated with anxiety. Conclusions: Although preliminary, findings suggest that inflexibility and regulatory impairment should be considered in depression remediation approaches. Improving ER, on the other hand, may have broader transdiagnostic impact across both mood and anxiety symptoms in ASD.

Youth stress generation: an examination of the role of anxiety, anxiety symptoms and cognitive distortions.

INTRODUCTION: Stress generation suggests a reciprocal relationship between depression and prospective stressful life events. However, the applicability of stress generation to anxiety disorders has been understudied, particularly among youth. We address this gap by examining stress generation in youth at high-risk of developing anxiety disorders. METHODS: Participants were one-hundred thirty-six at-risk youth (M age = 8.69, 84.6% Caucasian; 55.9% female), each of whom had a parent with an anxiety disorder. We examined the role of an anxiety disorder diagnosis, anxiety symptoms, and cognitive distortions in youth's prospective one and six-year stressful life events (i.e., stress generation). RESULTS: Anxiety symptoms and cognitive distortions were significant predictors of one-year total dependent stress. Anxiety diagnosis and anxiety symptoms were significant predictors of one-year dependent interpersonal stress. Anxiety diagnosis and anxiety symptoms were significant predictors of six-year independent stress. CONCLUSION: Support for the stress generation model was found in high-risk youth, but only over a one-year period. This suggests important effects of anxiety and cognitive distortions on stress generation, though their implications might be time-capped.

Five-Year Review of a Pediatric Pharmacy Internship Program.

Pharmacy internship programs improve job readiness for pharmacy learners. Pediatric-focused programs are not well described in the literature and represent only a small subset of pharmacy internships; furthermore, they offer unique experiences for learners with a strong interest in pediatrics. To better meet this need, a paid pediatric pharmacy internship was implemented in 2017 for rising second- and third-year professional pharmacy students. The program provides high-quality inpatient experience to pharmacy students with a strong interest in pediatrics via a 10-week, full-time summer program and ongoing weekend shifts throughout the academic year. Key focus areas of the internship include clinical shadowing and topic discussions, completing medication histories, research activities, and inpatient pharmacy triage. This program offers a multifaceted approach to providing interns with health-system experience and prepares learners for future careers in clinical and health-system pharmacy. To date, 100% of the 6 former interns who have graduated from pharmacy school have obtained residency positions. Furthermore, a permanent medication history technician role was created secondary to the positive response to interns providing this service.

Subconcussion, Concussion, and Cognitive Decline: The Impact of Sports Related Collisions.

Subconcussion can cause long-term consequences for patients. Increasing understanding of what causes the injury and how it can be assessed is important. This paper focuses on the pathophysiology, epidemiology, and assessment tools. Specific emphasis is placed on early diagnosis to implement treatment. Current research is targeting improved pharmaceutic and biomechanic innovations. Enhanced understanding of subconcussion will improve outcomes for patients and allow clinicians to implement treatments earlier.

Effects of total knee arthroplasty on skeletal muscle structure and function at the cellular, organellar, and molecular levels.

Total knee arthroplasty (TKA) is an important treatment option for knee osteoarthritis (OA) that improves self-reported pain and physical function, but objectively measured physical function typically remains reduced for years after surgery due, in part, to precipitous reductions in lower extremity neuromuscular function early after surgery. The present study examined intrinsic skeletal muscle adaptations during the first 5 weeks post-TKA to identify skeletal muscle attributes that may contribute to functional disability. Patients with advanced stage knee OA were evaluated prior to TKA and 5 weeks after surgery. Biopsies of the vastus lateralis were performed to assess muscle fiber size, contractility, and mitochondrial content, along with assessments of whole muscle size and function. TKA was accompanied by marked reductions in whole muscle size and strength. At the fiber (i.e., cellular) level, TKA caused profound muscle atrophy that was approximately twofold higher than that observed at the whole muscle level. TKA markedly reduced muscle fiber force production, contractile velocity, and power production, with force deficits persisting in myosin heavy chain (MHC) II fibers after expression relative to fiber size. Molecular level assessments suggest reduced strongly bound myosin-actin cross bridges and myofilament lattice stiffness as a mechanism underlying reduced force per unit fiber size. Finally, marked reductions in mitochondrial content were apparent and more prominent in the subsarcolemmal compartment. Our study represents the most comprehensive evaluation of skeletal muscle cellular adaptations to TKA and uncovers novel effects of TKA on muscle fiber size and intrinsic contractility early after surgery that may contribute to functional disability.NEW & NOTEWORTHY We report the first evaluation of the effects of total knee arthroplasty (TKA) on skeletal muscle at the cellular and subcellular levels. We found marked effects of TKA to cause skeletal muscle fiber atrophy and contractile dysfunction in older adults, as well as molecular mechanisms underlying impaired contractility. Our results reveal profound effects of TKA on muscle fiber size and intrinsic contractility early after surgery that may contribute to functional disability.

Telehealth Made EASY: Understanding Provider Perceptions of Telehealth Appropriateness in Outpatient Rheumatology Encounters.

OBJECTIVE: The purpose of this study was to evaluate a novel scoring system, the Encounter Appropriateness Score for You (EASY), to assess provider perceptions of telehealth appropriateness in rheumatology encounters. METHODS: The EASY scoring system prompts providers to rate their own encounters as follows: in-person or telehealth acceptable, EASY = 1; in-person preferred, EASY = 2; or telehealth preferred, EASY = 3. Assessment of the EASY scoring system occurred at a single academic institution from January 1, 2021, to August 31, 2021. Data were collected in three rounds: 1) initial survey (31 providers) assessing EASY responsiveness to five hypothetical scenarios, 2) follow-up survey (34 providers) exploring EASY responsiveness to 11 scenario modifications, and 3) assessment of EASYs documented in clinic care. RESULTS: The initial and follow-up surveys demonstrated responsiveness of EASYs to different clinical and nonclinical factors. For instance, less than 20% of providers accepted telehealth when starting a biologic for active rheumatoid arthritis, although more than 35% accepted telehealth in the same scenario if the patient lived far away or was well known to the provider. Regarding EASY documentation, 27 providers provided EASYs for 12,381 encounters. According to these scores, telehealth was acceptable or preferred for 29.7% of all encounters, including 21.4% of in-person encounters. Conversely, 24.4% of telehealth encounters were scored as in-person preferred. CONCLUSION: EASY is simple, understandable, and responsive to changes in the clinical scenario. We have successfully accumulated 12,381 EASYs that can be studied in future work to better understand telehealth utility and optimize telehealth triage.

Alcohol consumption and the risk of mortality and myocardial infarction in patients with rheumatoid arthritis.

OBJECTIVES: Many studies have found that moderate alcohol consumption is associated with lower risks of mortality and myocardial infarction (MI). Our aim was to examine the potential effects of alcohol on all-cause mortality and MI in rheumatoid arthritis (RA), a risk factor condition. METHODS: A cohort study (1995-2017) was conducted using medical records of RA patients from The Health Improvement Network in the United Kingdom (UK). Alcohol exposure was divided into non-drinkers, mild (1-7 UK units/week), moderate (8-14 UK units/week), moderate-high (15-21 UK units/week), and high (>21 UK units/week) consumption levels. We calculated hazard ratios (HRs) for the relation of alcohol consumption to all-cause mortality and MI, adjusting for covariates. RESULTS: Of 30,320 RA patients, 5,994 deaths and 1,098 MI cases occurred over 236,188 person-years. Mild-to-moderate alcohol use was associated with lower all-cause mortality in RA patients, including those taking methotrexate. The multivariable HRs (95% CI) for mortality by alcohol use category were non-drinkers 1.0, mild 0.80 (0.75-0.85), moderate 0.74 (0.67-0.82), moderate-high 0.84 (0.72-0.98), and high 0.99 (0.86-1.15). Mild, moderate-high, and high levels of alcohol use were associated with lower risk of MI among RA patients. The HRs MI risk by alcohol use category were non-drinkers 1.0, mild 0.81 (0.70-0.94), moderate 0.84 (0.68-1.04), moderate-high 0.51 (0.35-0.74), and high 0.59 (0.42-0.84). CONCLUSIONS: These findings suggest that mild-to-moderate alcohol use is associated with a lower mortality risk and overall alcohol use is associated with a lower MI risk in RA patients, similar to the general population.

Postoperative Hemorrhage After Lidocaine-Epinephrine Field Block in Cutaneous Surgery: A Letter to the Editor.

Introduction: Epinephrine is used in field block anesthesia for cutaneous surgery to enhance the effect of lidocaine and reduce its systemic effects. It has been hypothesized that the use of epinephrine increases the risk for postoperative hemorrhage in cutaneous surgery. Case: An elderly male was seen in the clinic for excision of a basal cell carcinoma (BCC) in the right upper trapezius area. A field block was performed by injecting lidocaine 1% with epinephrine 1:200,000 (3 mL) circumferentially around the margins of the excision. Adequate hemostasis was achieved during the procedure and the wound was closed without complication. Approximately 45 min post-excision, the patient returned with profuse active bleeding from the wound. The sutures were removed, and an active arterial bleed was identified. The artery was tied off on the lateral side of the wound to achieve hemostasis. Conclusion: A wearing-off effect of epinephrine may increase the risk for postoperative hemorrhage in cutaneous surgery, wherein an intraoperative arterial nick, masked by localized vasoconstriction, is revealed by a relative postoperative vasodilation. Practitioners should be aware of this potential complication.

Brief Report: The Influence of Autism Severity and Depression on Self-Determination Among Young Adults with Autism Spectrum Disorder.

Self-determination (SD) is linked to autonomy and better adult outcomes. Adults with autism spectrum disorder (ASD) are often less independent than cognitively matched peers. Given the frequency with which depression co-occurs in ASD and the established association between depression and SD, we sought to evaluate the influence of both ASD severity and depression on SD among cognitively able emerging adults with ASD. Emerging adults (n = 59) with ASD completed measures of SD, ASD severity, and depression. Both ASD severity and depression were moderately correlated with SD (r = - 0.473; - 0.423, respectively) and with each other (r = 0.625). After controlling for ASD severity, depression did not significantly predict SD. Strengthening SD should be considered in programming to promote independence.

daf-16/FOXO blocks adult cell fate in Caenorhabditis elegans dauer larvae via lin-41/TRIM71.

Many tissue-specific stem cells maintain the ability to produce multiple cell types during long periods of non-division, or quiescence. FOXO transcription factors promote quiescence and stem cell maintenance, but the mechanisms by which FOXO proteins promote multipotency during quiescence are still emerging. The single FOXO ortholog in C. elegans, daf-16, promotes entry into a quiescent and stress-resistant larval stage called dauer in response to adverse environmental cues. During dauer, stem and progenitor cells maintain or re-establish multipotency to allow normal development to resume after dauer. We find that during dauer, daf-16/FOXO prevents epidermal stem cells (seam cells) from prematurely adopting differentiated, adult characteristics. In particular, dauer larvae that lack daf-16 misexpress collagens that are normally adult-enriched. Using col-19p::gfp as an adult cell fate marker, we find that all major daf-16 isoforms contribute to opposing col-19p::gfp expression during dauer. By contrast, daf-16(0) larvae that undergo non-dauer development do not misexpress col-19p::gfp. Adult cell fate and the timing of col-19p::gfp expression are regulated by the heterochronic gene network, including lin-41 and lin-29. lin-41 encodes an RNA-binding protein orthologous to LIN41/TRIM71 in mammals, and lin-29 encodes a conserved zinc finger transcription factor. In non-dauer development, lin-41 opposes adult cell fate by inhibiting the translation of lin-29, which directly activates col-19 transcription and promotes adult cell fate. We find that during dauer, lin-41 blocks col-19p::gfp expression, but surprisingly, lin-29 is not required in this context. Additionally, daf-16 promotes the expression of lin-41 in dauer larvae. The col-19p::gfp misexpression phenotype observed in dauer larvae with reduced daf-16 requires the downregulation of lin-41, but does not require lin-29. Taken together, this work demonstrates a novel role for daf-16/FOXO as a heterochronic gene that promotes expression of lin-41/TRIM71 to contribute to multipotent cell fate in a quiescent stem cell model.

Germline and Somatic Genetic Variants in the p53 Pathway Interact to Affect Cancer Risk, Progression, and Drug Response.

Insights into oncogenesis derived from cancer susceptibility loci (SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, although both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of prosurvival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacologic inhibition of the prosurvival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies. SIGNIFICANCE: These results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and present novel therapeutic targets.