Diagnostic and Practical Challenges in Applying National Comprehensive Cancer Network Guidelines for Suspected Pathogenic TP53 Mosaicism.

Benefits and limitations in using NCCN guidelines to distinguish TP53 CH from mosaic LFS.

Body Size Perceptions Associated with Body Mass Index and Weight Loss Intentions Among Two Immigrant Populations.

BACKGROUND: The rates of obesity among immigrant populations within the USA rise with increasing duration of residency. The aims of this study were to examine weight self-perception and body image discrepancy within a large community sample of Hispanic and Somali predominantly immigrant adults. METHODS: Utilizing a community-based participatory research (CBPR) approach to collect survey data from a sample of adults who self-identified as Hispanic, Latino, or Somali in Southeast Minnesota. Correlations among actual body mass index (BMI), perceived weight category, and perceived body size were assessed with Spearman rank correlation coefficients. Associations of weight loss intentions with actual BMI, perceived weight category, perceived body size, and body image discrepancy were assessed using Kruskal-Wallis nonparametric tests. RESULTS: A total of 1256 adults completed the survey and biometric measurements (610 Hispanic, 646 Somali); 81% (457) and 50% (328) had a BMI in the overweight or obese category in the Hispanic and Somali cohorts, respectively. Among participants with a BMI of > 25, more participants reported a perceived body size that was overweight or obese than a perceived weight category that was in the overweight or obese category (79% vs. 48%, p = < 0.0001). Body image discrepancy, but not actual BMI, was associated with weight loss intentions for both groups. Perceived body size and perceived weight category were associated with weight loss intentions for Hispanic participants only. CONCLUSIONS: Perceived body size is a more accurate self-report proxy of BMI-defined weight status compared with the perceived weight category among Hispanic and Somali immigrant groups. Body image discrepancy may be more predictive of weight loss intentions than actual BMI.

The reparative immunologic consequences of stem cell transplantation as a cellular therapy for refractory Crohn's disease.

Background: Treatment strategies for Crohn's disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell transplantation (SCT) has emerged as a therapy for medically refractory CD. SCT was developed to rescue cancer patients from myelosuppressive chemotherapy but its use for CD and other immune diseases necessitates reimagining SCT as a cellular therapy that restores appropriately responsive immune cell populations from hematopoietic progenitors in the stem cell autograft (i.e. immune "reset"). Here we present a paradigm to understand SCT as a cellular therapy for immune diseases and reveal how SCT re-establishes cellular immunity utilizing high-dimensional cellular phenotyping and functional studies of the stem cell grafts. Methods: Immunophenotyping using CyTOF, single cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing was performed on peripheral blood and intestinal tissue samples from refractory CD patients who underwent SCT. The stem cell graft from these patients was analyzed using flow cytometry and functionally interrogated using a murine model for engraftment. Results: Our study revealed a remodeling of intestinal macrophages capable of supporting mucosal healing that was independently validated using multimodal studies of immune reconstitution events including CyTOF and scRNA-seq. Functional interrogation of hematopoietic stem cells (HSCs) using a xenograft model demonstrated that HSCs shape the timing of immune reconstitution, the selected reconstitution of specific cell lineages and potentially the clinical efficacy of SCT. Conclusions: These studies indicate that SCT serves as a myeloid-directed cellular therapy re-establishing homeostatic intestinal macrophages that support intestinal healing and suggest refractory CD evolves from impairment of restorative functions in myeloid cells. Furthermore, we report heterogeneity among HSCs from CD patients which may drive SCT outcomes and suggests an unrecognized impact of CD pathophysiology on HSC in the marrow niche.

Parent-coached exposure therapy versus cognitive behavior therapy for childhood anxiety disorders.

Cognitive-behavioral therapy (CBT) is the strongest evidenced-based therapy for childhood anxiety disorders (CADs). However, CBT's impact is limited by its lack of clear superiority over treatment as usual, excessive length, and greater than 50% of patients remaining symptomatic. Parent-coached exposure therapy (PCET) is designed to treat CADs more effectively and efficiently through a focus on exposure and working with parents and youth together. In a randomized controlled trial, 78 patients (78% female) aged 7 to 17 with CADs were assigned to PCET or the gold-standard CBT. The primary outcome was independent evaluator ratings of anxiety severity at mid- and post-treatment. Secondary outcomes were parent- and child-reported symptoms. Patients receiving PCET had significantly lower mean scores than those receiving CBT on the primary outcome measure at mid-treatment (3.03 ± 0.14, 95% CI, 2.75-3.32 vs. 3.77 ± 0.16 95% CI, 3.45-4.08, p = 0.0010) and post-treatment (2.79 ± 0.14, 95% CI, 2.50-3.07 vs. 3.33 ± 0.16, 95% CI, 2.02-3.64, p = 0.0153). Similar significant results were found with the secondary parent- and child-reported outcomes. These superior results were achieved in PCET with fewer sessions (6.62, SD = 2.8) than those in CBT (8.00, SD = 3.1), p = 0.041. The superior effectiveness and efficiency of PCET likely results from the greater focus on implementing exposure exercises compared to traditional CBT.

Leflunomide with prednisone or nonsteroidal anti-inflammatory drug therapy is safe and tolerated for long-term treatment of immune-mediated polyarthritis in 27 dogs.

OBJECTIVE: To retrospectively evaluate safety and tolerance of leflunomide for long-term treatment of canine idiopathic immune-mediated polyarthritis (IMPA). ANIMALS: 27 dogs with clinical signs and synovial fluid cytology supportive of IMPA with ≥ 6 months' follow-up after starting leflunomide. METHODS: Medical records were reviewed to identify dogs prescribed leflunomide for treatment of IMPA from February 2012 to May 2022. Initial leflunomide doses of 2 to 4 mg/kg once daily were prescribed and were titrated to the lowest effective dose with concurrent anti-inflammatory therapy. Complete blood count, serum chemistry, and clinical signs were monitored throughout the course of treatment. RESULTS: Adverse effects potentially attributable to leflunomide noted in 9 of 27 dogs (33%) included vomiting, diarrhea, lethargy, decreased or absent appetite, polyuria and polydipsia, and secondary antibiotic responsive infection and were self-limiting or resolved with outpatient therapy. Alkaline phosphatase (ALP) and alanine aminotransferase (ALT) elevation were documented in all dogs prescribed leflunomide plus prednisone, with persistent liver enzyme elevation in 6 of 9 dogs (67%) and normalization after antibiotic therapy in 3 of 9 dogs (33%). The majority of dogs prescribed leflunomide plus NSAID (11/17 [65%] dogs) did not experience liver enzyme elevation; 2 of 17 (12%) dogs developed transient antibiotic-responsive liver enzyme elevations, and 4 of 17 (23%) dogs had persistent liver enzyme elevation. CLINICAL RELEVANCE: Leflunomide was well tolerated for long-term management of IMPA. A significant difference in liver enzyme elevation was identified between dogs prescribed prednisone versus NSAID in combination with leflunomide. Leflunomide with NSAID therapy resulted in less hepatotoxicity compared with leflunomide with prednisone.

Myeloid neoplasms in inflammatory bowel disease: A case series and review of the literature.

Patients with inflammatory bowel disease (IBD) are exposed to chronic systemic inflammation and are at risk for secondary malignancies. Here we review the literature on the risk of myeloid neoplasms (MN) in IBD and present the disease profiles of patients at a single institution with IBD who later developed MN, comparing them to those in the literature. No IBD characteristic was found to associate with MN disease severity, including the previously-identified association between MNs and thiopurine exposure. Of the somatic mutations identified in out cohort's MN, mutations in TET2 were most prevalent, followed by FLT3-ITD, BCR-ABL, and NPM1 mutations.

Natural Compounds Oridonin and Shikonin Exhibit Potentially Beneficial Regulatory Effects on Select Functions of Microglia.

Accumulating evidence indicates that the adverse neuroimmune activation of microglia, brain immunocytes that support neurons, contributes to a range of neuroinflammatory disorders, including Alzheimer's disease. Correcting the abnormal functions of microglia is a potential therapeutic strategy for these diseases. Nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor (NLRP) 3 inflammasomes are implicated in adverse microglial activation and their inhibitors, such as the natural compounds oridonin and shikonin, reduce microglial immune responses. We hypothesized that some of the beneficial effects of oridonin and shikonin on microglia are independent of their suppression of NLRP3 inflammasomes. Murine and human microglia-like cells were stimulated with bacterial lipopolysaccharide (LPS) only, which did not induce NLRP3 inflammasome activation or the resulting secretion of interleukin (IL)-1ß, allowing for the identification of other anti-inflammatory effects. Under these experimental conditions, both oridonin and shikonin reduced nitric oxide (NO) secretion and the cytotoxicity of BV-2 murine microglia towards HT-22 murine neuronal cells, but upregulated BV-2 cell phagocytic activity. Only oridonin inhibited the secretion of tumor necrosis factor (TNF) by stimulated BV-2 microglia, while only shikonin suppressed the respiratory burst response of human HL-60 microglia-like cells. This observed discrepancy indicates that these natural compounds may have different molecular targets in microglia. Overall, our results suggest that oridonin and shikonin should be further investigated as pharmacological agents capable of correcting dysfunctional microglia, supporting their potential use in neuroinflammatory disorders.

Neighborhood-scale lead (Pb) speciation in Akron, Ohio (USA) soils: primary sources, post-deposition diagenesis, and high concentrations of labile Pb.

Lead (Pb) poses a significant risk to infants and children through exposure to contaminated soil and dust. However, there is a lack of information on Pb speciation and distribution at the neighborhood-scale. This work aimed to determine: (1) the distribution of acid-extractable (labile) Pb and other metals ([M]AE) in two neighborhoods in Akron, Ohio (USA) (Summit Lake and West Akron; n = 82 samples); and (2) Pb speciation and potential sources. Total metal concentration ([M]T) and [M]AE was strongly correlated for Pb and Zn (R2 of 0.66 and 0.55, respectively), corresponding to 35% and 33% acid-extractability. Lead and Zn exhibited a strong positive correlation with each other (R2 = 0.56 for MT and 0.68 for MAE). Three types of Pb-bearing phases were observed by electron microscopy: (1) galena (PbS)-like (5-10 µm); (2) paint chip residuals (10-20 µm); and (3) Pb-bearing Fe-oxides (20 µm). Isotope ratio values for PbAE were 1.159 to 1.245 for 206Pb/207Pb, and 1.999 to 2.098 for 208Pb/206Pb, and there was a statistically significant difference between the two neighborhoods (p = 0.010 for 206Pb/207Pb and p = 0.009 for 208Pb/206Pb). Paint and petrol are the dominant sources of Pb, with some from coal and fly ash. Lead speciation and distribution is variable and reflects a complex relationship between the input of primary sources and post-deposition transformations. This work highlights the importance of community science collaborations to expand the reach of soil sampling and establish areas most at risk based on neighborhood-dependent Pb speciation and distribution for targeted remediation.

Physiological Synchrony During Partnered Sexual Activity.

Physiological synchrony (PS) refers to the coordination of bodily responses in close relationships. It seems to be linked to relational well-being, satisfaction, closeness, and empathy. Recent research extends these findings to sexual relationships as well, with evidence suggesting that PS may predict attraction and sexual satisfaction. The current study focuses on PS during sexual activity within established couples. Results suggest that PS develops during sexual activity, in certain contexts, and tends to be greater in magnitude during sexual encounters than during non-sexual interactions. Results may shed light on the dyadic psychophysiological factors relevant to sexual experiences.

Intraoperative Epiphyseal Perfusion Monitoring Does Not Reliably Predict Osteonecrosis Following Treatment of Unstable SCFE.

BACKGROUND: Avascular necrosis (AVN) remains the most dreaded complication of unstable slipped capital femoral epiphysis (SCFE) treatment. Newer closed reduction techniques (with perfusion monitoring) have emerged as a technically straightforward means to address residual SCFE deformity while still minimizing the risk of osteonecrosis. However, limited data exists regarding the reliability of intraoperative epiphyseal perfusion monitoring to predict the development of AVN. The purpose of this study was to evaluate its reliability. METHODS: We retrospectively reviewed all patients with unstable SCFE who underwent closed or open reduction with epiphyseal perfusion monitoring using an intracranial pressure (ICP) probe from 2015 to 2023 at a single institution with a minimum 6-month radiographic follow-up. Demographic, clinical, and radiographic data were recorded, including duration of symptoms, type of reduction, capsulotomy performed, presence of a waveform on ICP monitoring after epiphyseal fixation, and development of AVN on follow-up radiographs. RESULTS: Our cohort included 33 hips (32 patients), of which 60.6% (n=20) were male. The average age was 12.5±1.8 years, with a median follow-up of 15.8 months. Eleven hips were treated with open reduction using the modified Dunn technique (10 hips) or anterior approach (1 hip), and 22 hips were treated with inadvertent (5 hips) or purposeful closed reduction using the Leadbetter technique (17 hips). Overall, 8 of the 33 hips in our series (24.2%) developed AVN, 6 of which (20%) had a pulsatile waveform on intraoperative epiphyseal perfusion monitoring. The overall rate of AVN after closed reductions was 31.8% (7 of 22 hips); the incidence of AVN after closed reduction with a detectable waveform was 30% (6 of 20 hips). There was no significant association between time to surgery ( P =0.416) or type of reduction ( P =0.218) and the incidence of AVN. CONCLUSIONS: In this series, intraoperative epiphyseal perfusion monitoring did not reliably predict the development of osteonecrosis. To our knowledge, this is the first study to report AVN after demonstrable intraoperative epiphyseal perfusion following closed reduction of unstable slips. LEVEL OF EVIDENCE: Level IV: case series-therapeutic study.

KD025 Is a Casein Kinase 2 Inhibitor That Protects Against Glucolipotoxicity in ß-Cells.

Glucolipotoxicity (GLT), in which elevated levels of glucose and fatty acids have deleterious effects on ß-cell biology, is thought to be one of the major contributors in progression of type 2 diabetes. In search of novel small molecules that protect ß-cells against GLT, we previously discovered KD025, an inhibitor of Rho-associated coiled-coil-containing kinase isoform 2 (ROCK2), as a GLT-protective compound in INS-1E cells and dissociated human islets. To further understand the mechanism of action of KD025, we found that pharmacological and genetic inhibition of ROCK2 was not responsible for the protective effects of KD025 against GLT. Instead, kinase profiling revealed that KD025 potently inhibits catalytic subunits of casein kinase 2 (CK2), a constitutively active serine/threonine kinase. We experimentally verified that the inhibition of one of the catalytic subunits of casein kinase 2, CK2A1, but not CK2A2, improved cell viability when challenged with GLT. We conclude that KD025 inhibits CK2 to protect ß-cells from GLT.

Promoting Safe and Supportive Health Care Spaces for Youth Experiencing Racism.

OBJECTIVE: This qualitative study applies a community-based participatory research approach to elicit formative data on pediatric patient experiences of racism in the health care setting and to explore clinic-based opportunities for supporting pediatric patients experiencing racism. METHODS: The study is situated within the outpatient practice of a large tertiary academic medical center in a midsize Midwestern city. Community partners were involved in all aspects of the research, including research protocol design, recruitment, data analysis, community dissemination, and manuscript preparation. Participants were youth between 11 and 18 years, in middle or high school, self-identifying as a person of color, Latinx or Indigenous who answered yes to the question "have you ever experienced race-related prejudice and discrimination?" Parent/guardians of youth meeting inclusion criteria participated in separate focus groups. Data were analyzed using an interpretative phenomenological analysis approach. RESULTS: Major findings were divided into 2 categories: 1) racism-related experiences in the health care setting; and 2) patient and parent/guardian recommendations to support pediatric patients experiencing racism. Among health care setting experiences, primary emerging themes included racism experienced in the health care setting, patient-clinician communication around racism, patient-clinician concordance, and high-quality clinical care. Recommendations were presented within the 4 domains of racism: intrapersonal, interpersonal, structural, and institutional. CONCLUSIONS: Racism experiences worsen child biological, psychological, and behavioral functioning, yet research is lacking on how health care professionals may best support pediatric patients experiencing racism. Study findings suggest opportunities for providing safer and more supportive health care spaces for youth experiencing racism.

Who Cares? Unpaid Caregiving by Sexual Identity, Gender, and Partnership Status Among U.S. Adults.

Recent scholarship indicates that sexual minority adults have higher caregiving rates than heterosexuals and that women are more likely to be caregivers than men. However, little research has addressed how gender and sexuality intersect in shaping caregiving status. This study uses data from the Behavioral Risk Factor Surveillance System and aggregates a probability-based sample of adults living in 36 U.S. states between 2015 and 2021. We examine who provides care among adult heterosexual, lesbian, gay, and bisexual men and women. Results reveal that women are more likely to be caregivers than men, but only among heterosexuals. We find little variation in caregiving by sexuality among women, but bisexual men are more likely than heterosexual men to be caregivers; the latter result appears to be driven by unpartnered, bisexual men. Lastly, we contextualize caregivers' experiences and reveal selected descriptive differences in patterns of care recipient-caregiver relationships across gender and sexual identity groups. Our findings advance understanding of caregiving and changing family ties in an era of population aging and increasing diversity in sexual identities.

Discontinuation Syndrome With JAK2 Selective Agents: Case Presentation and Mechanistic Insights.

We report the first case of pacritinib-withdrawal syndrome with in vitro elucidation of underlying mechanisms.

Psychometric Evaluation and Adaptation of the Five-Factor Sexual Satisfaction Scale (SSS-W) for Use in Men: The Sexual Satisfaction Scale (SSS).

The Sexual Satisfaction Scale for Women (SSS-W) is a psychometrically sound, widely used instrument for assessing sexual satisfaction and distress in women. Because the majority of scale items are gender nonspecific, numerous researchers have adapted this scale for use in male samples. The goal of the current study was to assess the reliability and validity of a slightly modified version of the SSS-W in a male sample (N = 268). A Confirmatory Factor Analysis of five previously established factors provided evidence for consistency of internal structure in men. The adapted scale (SSS) exhibited acceptable test-retest reliability, as well as evidence for validity based on relationships with theoretically predicted variables. Taken together, there is evidence to suggest that the SSS may be a reliable and valid psychometric tool for the measurement of sexual satisfaction and distress in both men and women.

Stepwise lengthening of quadriceps extensor mechanism for severe obligatory and fixed patella dislocators: Four-year clinical and surgical outcomes.

OBJECTIVES: The purpose of this study was to report clinical and surgical outcomes of medial patellofemoral ligament reconstruction (MPFLR) and concomitant quadriceps lengthening to treat fixed and obligatory patellofemoral instability (PFI) in the pediatric population. METHODS: Patients with obligatory or fixed PFI who underwent simultaneous MPFLR and quadriceps lengthening from 2008 to 2020 were reviewed. Of the 413 records, 24 fit the inclusion criteria. Demographic information, surgical details, associated diagnoses, and outcome measures were collected for each knee. Complications and additional surgeries were also obtained. RESULTS: The final cohort included 20 patients (10 male, 10 female), with a total of 24 knees. The average age at the time of surgery was 11.9 â€‹± â€‹3.1 (5.4-17.3). Seventeen were obligatory dislocators in flexion and 7 were fixed dislocators. Average follow-up was 4.3 â€‹± â€‹2.4 (1.3-9.4) years. One patient was lost to follow-up and excluded from the study. The mean outcome measures were as followed; KOOS 82, HSS Pedi-FABS 9, IKDC 76, Kujala 78, BPII 67, and SANE 90. Six patients had subsequent instability episodes. Ten patients had a subsequent surgery. CONCLUSIONS: Reports on quadriceps lengthening to treat PFI in the pediatric population are rare. Six (25 â€‹%) of the 24 knees included had subsequent PFI. Although this is a high rate of recurrent instability, no second surgeries were indicated for infection, extensor mechanism weakness, or contracture. The authors conclude that simultaneous MPFLR and stepwise quadriceps lengthening can be used to effectively manage fixed and obligatory PFI in this difficult patient population. LEVEL OF EVIDENCE: IV.

Early Prelicensure Nursing Students' Perceptions of Case Studies Through the Lens of the Clinical Judgment Measurement Model.

BACKGROUND: Research indicates new nursing graduates struggle with clinical reasoning, despite some related skill development throughout their education. The question remains, "Could an earlier focus on clinical reasoning in nursing programs enhance nursing students' clinical reasoning?" PURPOSE: This pilot study investigated how first-semester nursing students perceive the use of case studies in clinical reasoning skill development and the perceived benefits of case studies related to the NCSBN Clinical Judgment Measurement Model (NCJMM). METHODS: Case studies and written reflections were introduced to a convenience sample (n = 45) of first-semester nursing students. Qualitative analysis was conducted on written reflections. RESULTS: Students found case studies enhanced their knowledge and prepared them for clinical practice as a nurse. CONCLUSIONS: Findings suggest early introduction of case studies is a meaningful teaching strategy to develop clinical reasoning aligned with the NCJMM.

Femoral Head Remodeling After Surgical Reduction of Developmental Hip Dislocations.

OBJECTIVE: Developmental dysplasia of the hip is prevalent and is associated with dysplasia of both the femoral head and acetabulum. There is a paucity of literature describing femoral head remodeling after surgical reduction of developmentally dislocated hips. The purpose of this study was to describe and quantify changes in femoral head sphericity after closed or open reduction for developmental dysplasia of the hip. METHODS: A retrospective cohort study was performed including patients with typical developmental hip dislocations who underwent closed or open reduction from 2009 to 2022 at a single institution and had immediate postoperative and average 3-week follow-up magnetic resonance imaging (MRI) scans. A subset of patients also had 3-year follow-up MRI scans. Patients with insufficient imaging or bony procedures at the time of reduction were excluded. We developed a technique to quantify femoral head "sphericity" by comparing differences in measured radii of the femoral head on axial and coronal plane MRI slices. We then calculated the variance of the radii for each plane and averaged these to calculate a combined variance. The variance was used to represent "sphericity," with a larger variance indicating a wider distribution of radii and thus a less spherical shape. RESULTS: A total of 74 patients (69 females) with 96 hips were included in this series. The median age of the child at the time of reduction was 8.7 months [interquartile range (IQR): 2.2]. Over half (58.3%) of the hips had a closed reduction, whereas the remaining were open reduced (41.7%). Immediately postoperatively, at the 3-week time point, and at the 3-year time point the median combined variance was 1.1 (IQR: 3.93), 0.51 (IQR: 1.32), and 0.31 (IQR: 0.50), respectively, indicating improved sphericity over time. CONCLUSIONS: Sphericity of the femoral head in developmental hip dislocations improves in both the immediate postoperative period, as well as the first few years after reduction. Further research is needed to evaluate the mechanism of remodeling, the ideal timing of reduction, and the relationship between femoral head and acetabular remodeling. LEVEL OF EVIDENCE: Level IV-case series, therapeutic study.