Citations

Importance Accurate classification and reliability in assessment for lesions of hidradenitis suppurativa (HS) by investigators is critical to the determination of responder status and to overall data quality in clinical trials. Objective To establish consensus-based morphological definitions of HS lesions and guidance statements that standardize investigator lesion assessments for implementation in clinical trials. Evidence Review Health professionals (primarily dermatologists) with expertise in the measurement of HS disease activity as well as novice raters completed a preliminary questionnaire in which participants were asked to assess images of HS lesions and provide qualitative feedback on their decision making. Based on this feedback, detailed morphologic definitions for lesions and guidance statements that standardize lesion assessments were formulated and presented for consensus voting in 2 electronic Delphi surveys. A virtual group discussion after round 1 supported participants in round 2 voting. Findings Response rates were 84.7% (50 of 59), 86.0% (43 of 50), and 90.9% (40 of 44) in the preliminary, electronic Delphi round 1, and electronic Delphi round 2 surveys, respectively. Morphological definitions for 11 lesion types achieved the prespecified 70% consensus threshold, with 9 definitions reaching at least 90% agreement. After 2 electronic Delphi rounds, 16 of 18 guidance statements achieved the prespecified consensus threshold, with 13 statements receiving endorsement from more than 80% of participants. Two guidance statements related to assessment of tunneled plaques with multiple openings and assessment of scalp lesions failed to reach consensus. Conclusions and Relevance Common morphologic definitions and guidance that standardize assessment of HS lesions can be implemented in clinical trial protocols and investigator trainings with the goals of improving accuracy and reliability of investigator ratings.

Objective Mycophenolate mofetil (MMF) can stabilize or improve lung function in systemic sclerosis–related interstitial lung disease (SSc‐ILD). We hypothesized that combining MMF with pirfenidone (PFD) would produce a significantly more rapid and/or greater improvement in lung function. Methods A randomized (1:1), double‐blind, placebo (PLA)‐controlled phase 2 trial was conducted in SSc‐ILD in which patients received PFD or PLA (801 mg three times daily) along with MMF (1,500 mg twice daily) for 18 months. The primary outcome was change in percent predicted forced vital capacity (FVC‐%). Linear mixed‐effects models assessed treatment differences in a modified intention‐to‐treat population. Results Only fifty‐one of 150 intended subjects (34%) were randomized (MMF+PLA, n = 24; MMF+PFD, n = 27). The FVC‐% improved from baseline to 18 months by 2.24 ± 1.35 (least‐squares mean [LSM] ± SEM) in the MMF+PLA group and 2.09 ± 1.28 in the MMF+PFD group (LSM treatment difference −0.14; P = 0.93). Median time to achieve a ≥3% improvement in FVC‐% was numerically faster in the MMF+PFD versus MMF+PLA group (12.3 vs 17.8 months, respectively), but the difference was not significant ( P = 0.33). For secondary outcomes, only the change over 18 months in the Patient‐Reported Outcomes Measurement Information System 29‐item physical function score, favoring MMF+PFD, reached statistical significance ( P = 0.04). Although other related patient‐reported outcomes (PROs) numerically favored the MMF+PFD group, as did quantitative high‐resolution computed tomography measures of ILD, the differences between groups did not reach statistical significance. Early withdrawals from study medication and adverse events of special interest were numerically greater with MMF+PFD (n = 8 vs 2 and n = 20 vs 7, respectively). Conclusion In this underpowered study, there was no statistically significant treatment difference in overall change in FVC‐% between groups. MMF+PFD was not as well tolerated as MMF+PLA.

Importance Assisted ventilation during delayed cord clamping (DCC) may improve the physiologic transition of extremely preterm infants immediately after birth. Objective To determine whether assisted ventilation during 120 seconds of DCC was associated with reduced higher-level resuscitative interventions (intubation, chest compressions, or epinephrine administration) compared with DCC for 30 to 60 seconds followed by resuscitation. Design, Setting, and Participants This was a secondary analysis of the VentFirst randomized clinical trial that was conducted from September 2, 2016, through February 21, 2023, at 12 centers in the US and Canada. Infants born at 23 weeks 0 days’ to 28 weeks 6 days’ gestational age (GA) were included. Intervention Infants randomized to the intervention received either positive-pressure ventilation or continuous positive airway pressure from 30 to 120 seconds after birth, followed by umbilical cord clamping. Those randomized to control received 30 to 60 seconds of DCC followed by assisted ventilation. Main Outcomes and Measures The main outcome was the odds of higher-level resuscitative interventions in the delivery room (DR). Intention-to-treat analyses within 2 a priori cohorts (infants breathing well and not breathing well 30 seconds after birth) used the Cochran-Mantel-Haenszel method to estimate the odds ratios (ORs) of intervention vs control. Results All 570 infants enrolled in the trial were included. Infants had a median (IQR) GA of 26.6 (25.2-27.9) weeks and 273 (47.9%) were female. A total of 271 infants (47.5%) were assessed as not breathing well 30 seconds after birth (150 intervention and 121 control), and 299 (52.5%) were assessed as breathing well 30 seconds after birth (128 intervention and 171 control). In the not-breathing-well cohort, 146 infants (53.9%) were intubated in the DR, 4 received chest compressions (2 intervention and 2 control), and 1 received epinephrine (control). Intubation was less frequent in the intervention group (71 infants [47.3%] vs 75 infants [62.0%]; OR, 0.52; 95% CI, 0.30-0.89). When adjusted by GA strata at randomization, infants in the 26 to 28 weeks’ GA stratum who were in the intervention group were less likely to be intubated in the DR (18 of 79 infants [22.8%] vs 29 of 60 infants [48.3%]; OR, 0.32; 95% CI, 0.15-0.65). However, there was no difference in intubation rates for infants in the 23 to 25 weeks’ GA stratum (53 of 71 infants [74.7%] vs 46 of 61 infants [75.4%]; OR, 0.96; 95% CI, 0.44-2.12). Among infants breathing well at 30 seconds, 74 (24.7%) were intubated in the DR, and none received compressions or epinephrine. Intubation rates were similar between intervention and control in the breathing-well cohort. Conclusions and Relevance While the VentFirst trial did not find a difference in death or intraventricular hemorrhage, this secondary analysis found that assisted ventilation during DCC was associated with less intubation in the DR, primarily among infants born at 26 to 28 weeks’ gestation who were not breathing well 30 seconds after birth. Additional studies are needed before implementing assisted ventilation during DCC in clinical practice. Trial Registration ClinicalTrials.gov Identifier: NCT02742454

OBJECTIVE Lesions of the cerebellopontine angle (CPA) and petroclival region represent a challenging surgical target due to the complex anatomy of the involved neurovascular structures. In this scenario, cranial nerve (CN) VI is particularly exposed to potential injuries due to its deep-seated location and absence of a bony foramen that serves as a reference of its most distal cisternal point, especially when it is encased or displaced by large lesions. This study aimed to provide reliable operative guidance for preventing injuries to CN VI during the retrosigmoid approach to address CPA and petrotentorial lesions. METHODS Four formalin-fixed, latex-injected anatomical specimens were dissected to highlight and investigate the relevant anatomy of the CPA and petroclival region during the retrosigmoid approach. Additionally, 50 sides of noninjected formalin-fixed specimens were dissected for morphometric evaluation. Correlations between the petrotentorial junction (PTJ), porus acusticus (PA), and trigeminal impression (TI) with the entry point of CN VI into Dorello’s canal were evaluated. An illustrative clinical case and a 3D anatomical model generated through the photogrammetry scanning technique were described. RESULTS In the sagittal plane, CN VI entrance into Dorello’s canal was found in a trajectory parallel to the PTJ, passing through the inferior aspect of the PA and 21.5 ± 1.3 mm anteriorly. In the coronal plane, the entry point of CN VI into Dorello’s canal was estimated at 6.2 ± 1.2 mm from the anterior edge of the TI in a trajectory perpendicular to the PTJ in 47 (81%) specimens. CONCLUSIONS The obtained results demonstrated two surgical strategies to locate Dorello’s canal within the retrosigmoid route: 1) approximately 20 mm anterior along the inferior edge of the PA parallel to the PTJ; and 2) approximately 6 mm inferior to the anterior edge of the TI, perpendicular to the PTJ. The defined operative strategies provide reliable anatomical guidance to locate the entrance of CN VI into Dorello’s canal within the retrosigmoid route, potentially reducing the risk of abducens nerve palsy and improving patient outcomes.

Abstract Despite concerns about the toxicity of allogeneic hematopoietic cell transplantation (alloHCT) in older patients, prospective data characterizing prevalence or risk stratification for geriatric morbidity such as disability or frailty are limited. We prospectively assessed the prognostic impact of the novel composite health assessment risk model (CHARM), a score established to predict 1-year nonrelapse mortality (NRM), among 1105 patients aged ≥60 years enrolled on the Bone Marrow Transplant Clinical Trials Network Study 1704. Secondary end points were assessed post-alloHCT at day 100 (D100), D180, and D365 in multivariable models adjusted with predetermined clinical variables. Among alloHCT survivors, the prevalence of disability by instrumental activities of daily living (IADL), frailty by the Physical Frailty Phenotype, and physical function impairment by Patient Reported Measurement Information System (PROMIS) was highest at D100 and lower on D180 and D365. Higher CHARM scores were independently associated with greater disability (coefficient, −0.64; 95% confidence interval [CI], −0.85 to −0.43; P< .001), increased frailty (coefficient, 0.19; CI, 0.081-0.31; P< .001), worse PROMIS physical function, greater PROMIS depression, increased serious organ toxicity by D100, more cognitive decline at D100, and higher mortality after acute graft-versus-host disease (GVHD) but not significantly associated with PROMIS anxiety or acute GVHD. Higher CHARM scores predicted worse disability-free survival (odds ratio [OR], 2.03; CI, 1.66-2.48; P< .001) and lower frailty-free survival (OR, 2.00; CI, 1.61-2.49). In summary, CHARM is an independent prognostic scoring system not only for NRM but also for geriatric morbidity and functional limitation–free survival through 1 year after alloHCT. Pre-alloHCT CHARM is a novel tool to aid shared decision-making for older patients. This trial was registered at www.clinicaltrials.gov as #NCT03992352.

Abstract Description Interactions between ST6GAL1-produced sialic acids and Siglec-2 (CD22) result in immune inactivation. CD22 is a well-characterized regulator of B cell function. We demonstrate that conventional type-2 dendritic cells (cDC2s) and hybrid macrophages express CD22 across the spleen and tumor microenvironment. To understand the function of CD22 on antigen-presenting cells, we generated novel CD22-floxed mice and crossed them with a) Zbtb46-Cre ones (those lacking CD22 on cDC2s and hybrid macrophages) as well as b) CX3CR1-Cre mice (without CD22 on hybrid macrophages nor microglia). From the former cross, we generated subcutaneous flank tumor and colitis-associated colorectal cancer models. CD22 expression on myeloid cells did not impact anti-tumor responses when tumors expressed low CD22 ligand levels. From here, we assess the impact of tumor cell CD22 ligand overexpression on tumor responses. Also, to evaluate CD8 T cell response to CD22, we challenged mice with Theiler’s murine encephalomyelitis virus (TMEV), modeling multiple sclerosis via CD8 T cell hyperactivation. CD22 did not mediate CD8 activation nor infiltration in brains of the latter cross. Thus, CD22 may be functionally redundant across myeloid and B cells. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

Abstract Description The lifetime risk for colorectal cancer in the United States is approximately 4%. Individuals with Inflammatory Bowel Disease, including Ulcerative Colitis and Crohn’s Disease, have a substantially increased risk of developing colorectal cancer. The mechanisms for accelerated tumorigenesis due to enhanced inflammation are not fully characterized. Siglecs (sialic acid immunoglobulin lectin-like proteins) are a family of inhibitory receptors that are negative regulators of the immune response. Siglec-E is an inhibitory receptor that is expressed by innate immune cells, including monocytes, macrophages, neutrophils, and dendritic cells. Interestingly, mice deficient in Siglec-E have accelerated the development of tumors and reduced survival in a spontaneous mouse model of colorectal cancer (TS4-cre LSL-KRasG12D APClox468/wt). Siglec-E knockout mice also have accelerated gut inflammation using the DSS colitis model as compared to WT mice. Using the DSS/AOM model of colitis-associated colorectal cancer, we found that Siglec-E KO mice develop more tumors as compared to wild-type controls. Thus, Siglec-E is an important regulator of gut homeostasis, and the loss of Siglec-E accelerates colon cancer in two murine models. Funding Sources Mayo Clinic Center for Biomedical Discovery NIH R01 CA243545-01A1 to VSS T32 AI170478 Mayo Clinic Graduate School of Biomedical Sciences Deans fellowship: Initiative for maximizing student development (IMSD) R25 GM055252-26 Doyon Foundation Topic Categories Mucosal and Regional Immunology (MUC)

Abstract Description Generation of T cells requires dynamic epigenetic alteration of histones to control gene expression at each developmental stage. The Class I deacetylases HDAC1, HDAC2, and HDAC3 have been shown to have 3 functions: adaptor, decrotonylase, and deacetylase activity. The relative importance of each function in T cells is not known. CD2icre HDAC3 cKO mice develop severe colitis and demonstrate that HDAC3 is required during thymocyte development for positive selection, DP survival, and CD4 lineage commitment. Recently, a mutation was identified in HDAC3 that eradicated deacetylase activity (“VRPP”). We generated a novel mouse model with Cre-mediated deletion of endogenous HDAC3 and linked re-expression of HDAC3 VRPP, which maintained adaptor function but lacks both deacetylase and decrotonylase enzymatic activity. Similar to CD2icre HDAC3 cKO mice, HDAC3 VRPP mice have a block in positive selection due to failure to down regulate RORγt and decreased DP cell survival due to increased expression of P2RX7, demonstrating that HDAC3 enzymatic activity is required for these functions. However, when the positive selection defect is bypassed in HDAC3 VRPP mice, CD4+ lineage commitment is restored. Strikingly, this mouse does not develop spontaneous colitis even up to one year of age, although T cell development is still impaired. Thus, there are different roles for HDAC3 enzymatic vs. adaptor function during T cell development which are made evident in HDAC3 VRPP mice. Funding Sources NIAID RO1 AI150100; T32 AI170478; Mayo Clinic Graduate School of Biomedical Sciences Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)