Citations

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a complex and heterogeneous disease. Given this, we reasoned that differences in genetic profiles may be associated with unique clinical and radiologic features. Computational image analysis, sometimes referred to as radiomics, provides objective, quantitative assessments of radiologic features in subjects with pulmonary fibrosis. Objectives To determine if the genetic risk profile of patients with IPF identifies unique computational imaging phenotypes. Methods Participants with IPF were included in this study if they had genotype data and computed tomography (CT) scans of the chest available for computational image analysis. The extent of lung fibrosis and the likelihood of a usual interstitial pneumonia (UIP) pattern were scored automatically using two separate, previously validated deep learning techniques for CT analysis. UIP pattern was also classified visually by radiologists according to established criteria. Results Among 329 participants with IPF, MUC5B and ZKSCAN1 were independently associated with the deep learning–based UIP score. None of the common variants were associated with fibrosis extent by computational imaging. We did not find an association between MUC5B or ZKSCAN1 and visually assessed UIP pattern. Conclusions Select genetic variants are associated with computer-based classification of UIP on CT in this IPF cohort. Analysis of radiologic features using deep learning may enhance our ability to identify important genotype–phenotype associations in fibrotic lung diseases.

Abstract BACKGROUND Lynch syndrome is caused by pathogenic germline variants in the DNA mismatch repair (MMR) genes, predisposing individuals to malignancies, including glioblastoma (GBM). MMR-deficient tumors are resistant to monofunctional alkylators such as temozolomide but not to bifunctional alkylators such as the nitrosourea lomustine. Anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitor (ICI) pembrolizumab represents another treatment option, which is approved by the United States Food and Drug Administration (FDA) for the treatment of mismatch repair deficient cancers. METHODS We present a patient with multifocal GBM and Lynch syndrome who experienced rapid progression following standard-of-care chemoradiation, followed by durable responses to lomustine and then to pembrolizumab. RESULTS A 58-year-old man with Lynch syndrome (MSH2 mutation) and prior history of colon cancer presented with seizures. Magnetic resonance imaging (MRI) brain identified right frontal and left parietal masses. Right frontal tumor was resected; pathology was consistent with GBM, IDH wildtype, MGMT-unmethylated. Both lesions were treated with radiation therapy (60 Gy, 30 fractions) with concurrent and adjuvant temozolomide. After two cycles of adjuvant temozolomide, his left parietal tumor progressed and was subtotally resected, followed by four cycles of lomustine (stopped due to myelotoxicity). He remained progression-free for 15 months. Surveillance MRI identified new enhancement involving the left frontal lobe, left periventricular white matter, and right internal auditory canal, concerning for leptomeningeal dissemination. MRI spine identified no additional lesions. Cerebrospinal fluid cytology was negative for tumor cells on two occasions. Patient was treated with pembrolizumab. He remains on treatment with stable disease four months after ICI initiation and 31 months after GBM diagnosis. CONCLUSIONS Patients with MMR-deficient GBM resist standard chemoradiation. Alternatives such as nitrosourea or ICI therapy may achieve durable responses. While data is insufficient to administer these agents as upfront therapy in this specific setting, both should be considered as options for recurrent disease.

Introduction/Objectives: We aimed to investigate the effect of family structure on depression program outcomes for adolescents enrolled in a depression-focused, primary care-based collaborative care program. Methods: This was a retrospective study of primary care patients ages 12 to 18 years seen at a Midwestern academic center with data obtained by medical record review. We used logistic regression models to assess the effect of family structure on program graduation and achievement of a single Patient Health Questionnaire 9–Modified for Adolescents (PHQ-9M) score <5 at any time while enrolled. Results: Adolescents were divided into 2 groups, Both Parents in Household (n = 179) and Parents Not Together (n = 161). The Both Parents in Household group had higher rates of graduation (38.0% vs 23.6%, P = .005) and achieving single PHQ-9M scores <5 (64.1% vs 46.2%, P = .002) than the Parents Not Together group. Discussion: Youth residing with both parents had higher rates of successful outcomes in a depression-focused collaborative care program.

Abstract Single‐cell RNA sequencing and spatial transcriptomics enable unprecedented insight into cellular and molecular pathways implicated in human skin aging and regeneration. Senescent cells are individual cells that are irreversibly cell cycle arrested and can accumulate across the human lifespan due to cell‐intrinsic and ‐extrinsic stressors. With an atlas of single‐cell RNA‐sequencing and spatial transcriptomics, epidermal and dermal senescence and its effects were investigated, with a focus on melanocytes and fibroblasts. Photoaging due to ultraviolet light exposure was associated with higher burdens of senescent cells, a sign of biological aging, compared to chronological aging. A skin‐specific cellular senescence gene set, termed SenSkin™, was curated and confirmed to be elevated in the context of photoaging, chronological aging, and non‐replicating CDKN1A + (p21) cells. In the epidermis, senescent melanocytes were associated with elevated melanin synthesis, suggesting haphazard pigmentation, while in the dermis, senescent reticular dermal fibroblasts were associated with decreased collagen and elastic fiber synthesis. Spatial analysis revealed the tendency for senescent cells to cluster, particularly in photoaged skin. This work proposes a strategy for characterizing age‐related skin dysfunction through the lens of cellular senescence and suggests a role for senescent epidermal cells (i.e., melanocytes) and senescent dermal cells (i.e., reticular dermal fibroblasts) in age‐related skin sequelae.

Background: Question prompt lists (QPLs) are structured sets of disease-specific questions intended to encourage question-asking by patients and enhance patient-physician communication. To date, an EoE-specific QPL has not been developed for EoE patients. Aim: To develop a preliminary QPL specific to adults with EoE by incorporating input from international esophageal experts. Methods: Sixteen experts were invited to generate QPL content through a modified Delphi (RAND/University of California, Los Angeles, CA) method consisting of 2 rounds of independent ratings. In round 1, experts provided 5 answers to the prompts “what general questions should patients ask when being seen for EoE?” and “what questions do I not hear patients asking but given my experience, I believe they should be asking?” In round 2, experts rated each question on a 5-point Likert scale, and responses rated as “essential” or “important” (determined by an a priori median threshold of ≥ 4.0) were accepted for the EoE QPL. Results: Ten esophageal experts participated in both rounds. Round 1 generated 100 questions. Questions were combined and modified to reduce redundancy, yielding 57 questions. After round 2, 51 questions (85%) were accepted for inclusion (median value ≥ 4.0) in the final QPL. Questions were then divided into 4 themes based on disease domains: (1) “What is EoE?,” (2) “Treatment Options,” (3) “Follow-up Surveillance and Long-term Risks,” and (4) “Allergy and Genetic Testing.” The largest number of questions covered was “What is EoE?” (16/51 or 31%). Questions with the highest agreement median (5.0) included examples such as “what should I do if I get a food impaction?” and “what are the treatment options?” Conclusion: This is the first preliminary EoE QPL developed in the field of medicine. We hope implementation enhances effective patient-physician communication by encouraging patients to ask relevant questions that experts prioritized. Future studies will aim to modify this communication tool by incorporating patient perspectives

AbstractBackground and ObjectivesCriminal‐legal (CL) referrals to addiction treatment have historically had low utilization of medications for opioid use disorder (MOUD). While state differences have been reported, an in‐depth longitudinal analysis of state‐by‐state differences is lacking.MethodsThe Substance Abuse and Mental Health Services Administration Treatment Episode Dataset‐Admissions 2000–2020 provided data for individuals entering their initial treatment with an opioid as their primary substance. Outcome was planned use of MOUD, assessing odds ratio (OR) of CL referrals relative to non‐CL referrals cumulatively over the 21‐year period and as incremental change (change in relative disparity) using effect sizes, stratified by each state.Results2,187,447 cases met the criteria. Planned MOUD occurred in 37.7% of non‐CL clients versus 6.5% of CL clients (OR = 0.11, 95% confidence interval = 0.11–0.12). For all clients, planned MOUD increased from 2000 (33.9%) to 2020 (44.8%). This increase was blunted within CL clients, increasing from 2000 (6.4%) to 2020 (13.3%). Rhode Island saw the greatest improvements in equity.Discussion and ConclusionsWhile rates of planned MOUD increased over the 21 years, a significant disparity persisted among CL clients in most states. As opioid use disorders and opioid‐related overdoses are more prevalent among those involved with the CL system, improving this has high impact.Scientific SignificanceProvides the most comprehensive analysis of state‐by‐state inequities in MOUD access for CL relative to non‐CL referrals over a 21‐year period through use of a national data set. Positive outliers are used as case examples for others to follow in pursuit of more equitable care.

ImportanceThis is the first population-based study quantifying the incidence of nonsynostotic positional plagiocephaly and/or brachycephaly (PPB) in infancy and its association with developmental disorders.ObjectiveTo report the incidence of PPB before age 1 year, the incidence of craniosynostosis, and the percentage of children with PPB diagnosed with a developmental disorder by age 7 years.Design, Setting, and ParticipantsThis was a retrospective, population-based cohort study of children in the Rochester Epidemiology Project (REP) born in Olmsted County, Minnesota, from January 1, 2008, through December 31, 2012, with follow-up through age 7 years. Data were analyzed from March 2021 to April 2024.ExposurePhysical examination detecting cranial deformity.Main Outcomes and MeasuresThe primary outcome was the incidence of PPB. Secondary outcomes were the incidence of craniosynostosis and the percentage of children with PPB diagnosed with a developmental disorder by age 7 years.ResultsOf 9909 infants (5084 [51.3%] male; 9205 [92.9%] born at term and 704 [7.1%] born preterm) included in the study, 575 had PPB, for a PPB incidence of 5.8% (95% CI, 5.3%-6.3%). The incidence of PPB was 5.3% (95% CI, 4.8%-5.8%) in term infants vs 11.8% (95% CI, 9.4%-14.6%) in preterm infants. The incidence of craniosynostosis was 0.16% (95% CI, 0.09%-0.26%). A developmental disorder was known or suspected in 4.2% (95% CI, 2.7%-6.2%) of infants at the time of PPB diagnosis; among 402 infants with PPB and follow-up through age 7 years, 30 (7.5%; 95% CI, 5.0%-10.7%) had a confirmed developmental disorder by 7 years of age. The prevalence of autism spectrum disorder (ASD) in children with a history of PPB who were followed up to age 7 years was 2.2% (9 of 402 children).Conclusions and RelevanceThis study found that only a small percentage of the infants had positional head deformity significant enough to be documented and/or referred for subspecialty evaluation, and only a small subset of these children went on to have a developmental disorder in childhood. This information is helpful for counseling families about their child’s developmental risk at time of PPB diagnosis.

This scientific commentary refers to ‘NMDA receptor autoantibodies primarily impair the extrasynaptic compartment’ by Jamet et al. (https://doi.org/10.1093/brain/awae163).

BACKGROUND AND OBJECTIVES Efficiently conducting patient- and family-centered rounds (PFCR) is challenging, particularly without a measure of efficiency. In physics, efficiency is the ratio of work output to work input. We sought to evaluate PFCR efficiency via a novel construct rooted in physics. Our objectives were to (1) Establish baseline work output for clinical work (CW), educational effectiveness (EE), and family experience (FE); (2) establish baseline work input for rounds length (RL); and (3) begin preliminary construction of a rounds efficiency index (REI) as a measure of PFCR efficiency. METHODS Four components of rounds efficiency were collected on 5 inpatient acute care teams during a baseline period. CW consisted of the percentage of daily orders placed on rounds. EE was assessed via survey for trainees and FE by families. RL was recorded in minutes per patient. During an 8-week intensive period, the REI (reported as %) was calculated as a ratio of work output/work input using aggregate mean/median ratings for CW, EE, FE, and RL. RESULTS Baseline data included 809 orders, 28 EE ratings, 21 FE ratings, and RL mean of 11.4 minutes per patient. During the intensive period, the median team-specific weekly REI for the end versus beginning of the academic year was 58% and 52.5% (P = .17), respectively. The median REI during the start and end of the block was 49% and 57% (P = .15), respectively. CONCLUSIONS The study assessed 4 components of efficiency (CW, EE, FE, RL) and calculated REI allowing for a preliminary tool to measure rounding efficiency. With this, targeted interventions can improve PFCR efficiency.