Citations

Abstract Background: Trial recruitment of Black, indigenous, and people of color (BIPOC) is key for interventions that interact with socioeconomic factors and cultural norms, preferences, and values. We report on our experience enrolling BIPOC participants into a multicenter trial of a shared decision-making intervention about anticoagulation to prevent strokes, in patients with atrial fibrillation (AF). Methods: We enrolled patients with AF and their clinicians in 5 healthcare systems (three academic medical centers, an urban/suburban community medical center, and a safety-net inner-city medical center) located in three states (Minnesota, Alabama, and Mississippi) in the United States. Clinical encounters were randomized to usual care with or without a shared decision-making tool about anticoagulation. Analysis: We analyzed BIPOC patient enrollment by site, categorized reasons for non-enrollment, and examined how enrollment of BIPOC patients was promoted across sites.Results: Of 2247 patients assessed, 922 were enrolled of which 147 (16%) were BIPOC patients. In comparison to trial-eligible White participants, eligible Black participants more frequently did not enroll (102 (11%) vs. 185 (15%); p <.001). The rate of BIPOC patients enrollment varied substantially by site and was generally reflective of the population served at each participating site. Enrollment of BIPOC patients benefited most from including and prioritizing practices most likely to care for BIPOC patients, with lower yield from specific efforts to reach BIPOC clinic attendees and enrolling BIPOC patients first when possible. Conclusions: Enrollment from practices that have implemented policies that favor the care of BIPOC patients can contribute to generate trustworthy estimates of the effect of these interventions in clinical practice that are applicable to BIPOC populations. Best practices to optimize the enrollment of BIPOC participants into trials that examined complex and culturally sensitive interventions remain to be developed.Clinical trial registration: ClinicalTrials.gov (NCT02905032)

Abstract Breast cancer risk is increased in parous women in the period following childbirth, peaking at five years. After weaning or in the absence of lactation, the breast undergoes postpartum involution (PPI), a process characterized by epithelial cell death and tissue remodeling that returns the mammary gland to a baseline state, and has previously been associated with increased inflammation and breast cancer development and progression in preclinical models. Features of PPI and determinants of related inflammation have been incompletely characterized among women. In this study, we performed visual and AI analysis of 725 digitized H&E images of normal breast tissues donated to the Komen Tissue Bank (KTB) by parous and nulliparous women ≤45 years, and further investigated the immune microenvironment in specimens from 23 women (also from KTB, 13 parous, 10 nulliparous) using NanoString RNA immuno oncology (IO) 360 panels and immune protein biomarkers by NanoString GeoMx Digital Spatial Profiling (DSP). We found that recently parous women (≤5 years of a last birth) had higher numbers of terminal duct lobular units (TDLUs), immune cells, and plasma cells as compared with nulliparous women, and that beyond 5 years of a last birth, TDLU numbers were still higher in parous women, but the immune and plasma cell content of the breast of parous and nulliparous women were not significantly different. Our gene expression analysis revealed differential expression of genes that clustered according to parity status, with interferon stimulated genes; STAT1 and IFITM1, and interferon alpha receptor 1 (IFNAR1), and MHC class II genes (HLA-DMA, HLA-DPA,HLA-DPB1, and HLA-DRA) elevated in parous women. Our DSP analysis revealed that immune biomarkers with immunosuppressive functions, including ARG1, VISTA, CTLA-4, and CD68 were significantly higher in parous women as compared with nulliparous women. Breast tissues of parous women show lobular expansion and alterations in immune cell components compared with nulliparous tissues. Further research is needed to assess how these alterations may impact risk. Citation Format: Joshua Were Ogony, Thomas De Bel, Derek Radisky, Jeroen VanderLaak, Mark Sherman. Pathology AI features and immune biomarkers of postpartum involution: Implications for postpartum breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-11-14.

Abstract Antibiotic-associated diarrhea (AAD) is a common side effect of antibiotics. We examined the gastrointestinal microbiota in children treated with β-lactams for community-acquired pneumonia. Data were from 66 children (n = 198 samples), aged 6–71 months, enrolled in the SCOUT-CAP trial (NCT02891915). AAD was defined as ≥1 day of diarrhea. Stool samples were collected on study days 1, 6–10, and 19–25. Samples were analyzed using 16S ribosomal RNA gene sequencing to identify associations between patient characteristics, microbiota characteristics, and AAD (yes/no). Nineteen (29%) children developed AAD. Microbiota compositional profiles differed between AAD groups (permutational multivariate analysis of variance, P &lt; .03) and across visits (P &lt; .001). Children with higher baseline relative abundances of 2 Bacteroides species were less likely to experience AAD. Higher baseline abundance of Lachnospiraceae and amino acid biosynthesis pathways were associated with AAD. Children in the AAD group experienced prolonged dysbiosis (P &lt; .05). Specific gastrointestinal microbiota profiles are associated with AAD in children.

A woman in her 30s was referred to our neurology outpatient clinic following an incidental finding of significant bilateral and symmetric basal ganglia, thalamic, cerebellar and subcortical white matter calcification on brain CT and MRI. A diagnosis of asymptomatic primary familial brain calcification (PFBC) was made. Targeted genetic testing revealed a likely pathogenic variant in the SLC20A2 gene, the most common gene in which pathogenic variants have been implicated in PFBC. These findings prompted genetic testing and brain CT of our patient’s asymptomatic 64-year-old father. These tests revealed the same variant in SLC20A2 and similar brain calcification on CT in the patient’s father.

Abstract Background:Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described.Methods: Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors <45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean “capillary” area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fisher’s exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [ recent birth: ≤5 years versus remote birth: >5 years]) using multivariable regression models.Results:Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p<0.001). Differences in TDLU counts and average acini size persisted for >5 years postpartum whereas increases in immune cells were most marked <5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration. Conclusions:Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.

Background: The purpose of this study was to examine the complications and outcomes after maxillofacial reconstruction using the free fibular flap in the pediatric population. Methods: A systematic review and descriptive analysis were conducted using data variables, including study characteristics; patient characteristics; postoperative complications (major and minor); surgical revision; and dental rehabilitation. Results: The systematic review resulted in 1622 articles, 55 of which met inclusion criteria for this study. The 55 articles consisted of 17 case series and 38 case reports with level III/IV and level V of evidence, respectively. Of the 155 identified pediatric patients, the rate of major complications was 13.5% and minor complications was 24.5%. The most common complication was mild growth distortion (n = 7) at the recipient site. Complications at the donor site were less common. During follow-up, 29 patients (18.7%) underwent or awaited surgical revision, and 43 patients (27.7%) underwent or awaited dental rehabilitation. Conclusions: Our study suggests that the free fibular flap for pediatric maxillofacial reconstruction is safe and reliable. Additionally, surgical revision to correct the functional impairments resulting from primary reconstruction using the free fibular flap is relatively common.

Background: Dynamic supination is a well-recognized cause of congenital clubfoot deformity relapse. However, there is no consensus on how to diagnose it and there are varied approaches in its management. This study aims to define dynamic supination and indications for treatment by presenting consensus from an international panel of experts using a modified Delphi panel approach. Methods: An international panel of 15 pediatric orthopaedic surgeons with clinical and research expertise in childhood foot disorders participated in a modified Delphi panel on dynamic supination in congenital clubfoot. Panelists voted on 51 statements using a 4-point Likert scale on dynamic supination, clinical indications for treatment, operative techniques, and postoperative casting and bracing. All panelists participated in 2 voting rounds with an interim meeting for discussion. Responses were classified as unanimous consensus (100%), consensus (80% or above), near-consensus (70% to 79%), and indeterminate (69% or less). Results: Consensus was achieved for 34 of 51 statements. Panelists agreed dynamic supination is present when the forefoot is supinated during swing phase of gait with initial contact on the lateral border of the foot. There was also agreement that dynamic supination results from muscle imbalance between the tibialis anterior and the peroneus longus and brevis. There was no consensus on observation of hindfoot varus in dynamic supination, operative indications for posterior release of the ankle joint, or incisional approach for tibialis anterior tendon transfer. Reference to the calcaneopedal unit concept, planes of movement, and phases of gait were deemed important factors for consideration when evaluating dynamic supination. Conclusions: Consensus statements from the Delphi panel can guide diagnosis and treatment of dynamic supination in clubfoot deformity relapse, including clinical decision making regarding preoperative casting, surgical approach, and postoperative immobilization. Near-consensus and indeterminate statements may be used to direct future areas of investigation. Level of Evidence: Level V.

Background: Visual impairment secondary to orbital and periorbital dysmorphology is frequent in Pfeiffer syndrome patients. The etiopathogenesis of this aberrancy, however, remains unclear. Methods: Untreated Pfeiffer syndrome patients (n = 31) and normal control subjects (n = 43) were compared. Craniometric and volumetric analyses related to the orbital and periorbital anatomy were performed using Materialise (Leuven, Belgium) software. Results: Overall, orbital cavity volume of Pfeiffer patients is reduced by 28 percent (p < 0.001), compared to normal, starting before 3 months of age (p = 0.004). Globe volume was diminished by 10 percent (p = 0.041) before 3 months of age, yet tended to catch up thereafter. However, the retrobulbar soft-tissue volume remained smaller beyond 1 year of age (17 percent, p = 0.003). Globe volume projection beyond the bony orbit increased in all observed ages (82 percent, p < 0.001). The volumes of sphenoid bone, maxilla, and mandible proportionately were restricted by 24 to 25 percent (p = 0.003 to 0.035) before 3 months of age. The volume of maxilla and mandible gradually approximate normal; however, the sphenoid bone volume in Pfeiffer patients remains less than normal (p = 0.002) into childhood. The anteroposterior length of both the zygoma and the maxilla was reduced by 14 percent (p < 0.001). Anterior positioning of the zygoma is less by 23 percent (p < 0.001) in Pfeiffer patients overall, with anterior positioning of maxilla reduced similarly by 23 percent (p < 0.001). Conclusions: Pfeiffer syndrome patients develop decreased retrobulbar soft-tissue and globe volume, along with a restricted orbital cavity volume in infancy. Significant hypoplasia of the sphenoid bone is associated with more severe central facial (maxilla) retrusion, compared to lateral facial structures (zygoma). CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Ureaplasma -induced hyperammonemia is a deadly complication affecting around 4% of lung transplant recipients and, to a lesser extent, other solid organ transplant patients. Understanding the underlying mechanisms will inform patient management, potentially decreasing mortality and morbidity. Here, it is shown that uremia is a plausible contributing factor to the pathophysiology of the condition.