Citations

INTRODUCTION: Little is known about the impact of gender-affirming hormone therapy (GAHT) on transgender and gender diverse adults with inflammatory bowel disease (IBD). The primary aim was to evaluate the incidence of IBD flare in the year before and after GAHT initiation. METHODS: A retrospective study across 5 IBD centers. Flare was defined as need for steroids, IBD-associated emergency department visit, or need for IBD medication change. Factors associated with IBD flare were assessed with univariate analysis and multivariable logistic regression controlling for age and IBD type. RESULTS: A total of 85 transgender and gender diverse adults with IBD who initiated GAHT were included in this study. Forty-six (54.1%) received estrogen and 39 (45.9%) received testosterone. In the year before GAHT, 42 (49%) flared compared with 32 (38%) in the year after, P = 0.06. There was no statistically significant difference in incidence of flare by age, IBD type, or IBD therapy type. Individuals with active IBD at GAHT initiation were more likely to flare in univariate (58% vs 24%, P = 0.003) and multivariable analyses (adjusted odds ratio 5.1, 95% confidence interval 1.7–15.2). In both univariate and multivariable analyses, individuals who received testosterone were more likely to flare in the year after starting GAHT, testosterone: 51% vs estrogen: 26%, P = 0.02 with an adjusted odds ratio 3.1 (95% confidence interval 1.2–8.1). DISCUSSION: Although there was no overall increased risk of flare in the year after GAHT start, those with active IBD before hormone start and those who received testosterone were more likely to experience an IBD flare.

ABSTRACT Objective There is limited consensus on endoscopic skull base surgery (ESBS) reconstruction principles. This study aims to generate comprehensive themes regarding ESBS reconstruction by pooling the experiences of ESBS experts, with comparison to a literature review of current published evidence. Methods Structured qualitative interviews of ESBS experts regarding postoperative management and reconstruction of various defect locations were conducted. Results A total of 68 experts comprising 40 academic teams across 13 countries with an average of 18 years of ESBS experience were included. We propose 10 stepwise algorithms for common skull base reconstruction scenarios based on these expert interviews. When available, the nasoseptal flap is used for all high_flow cerebrospinal leak defects. Multilayered reconstruction is favored at all anatomical subsites with increasing number of layers for increasing defect size and complexity. Heterogeneity exists in terms of inlay technique and materials, free grafting versus various pedicled flap options for low‐flow defects or in the absence of a nasal septum, nasal packing, tissue sealant, lumbar drain use, and postoperative management. Commonalities and discrepancies between experts were summarized. Conclusion Skull base reconstruction and post‐ESBS management is highly complex with a wide variety of practice patterns and expert strategies. Further research of higher quality evidence is warranted to identify optimal management patterns, though the current work aims to inform surgeons on these controversial areas by drawing from numerous experiences.

Purpose The aim of part-one of this EU-US consensus was to combine literature research and expertise to provide recommendations for the usage of rehabilitation (including physical therapy) of patients undergoing surgical treatment for degenerative meniscus lesions or acute meniscus tears (including meniscectomy, repair, or reconstruction). Prevention programs, non-operative treatment of acute tears and degenerative lesions, return to sports and patient-reported outcome measures (PROMS) will be presented in a part-II article. Methods This consensus followed ESSKA “formal consensus” methodology. For this combined ESSKA (European Society for Sports Traumatology and Arthroscopy), AOSSM (American Orthopedic Society for Sports Medicine), ASSPT (American Academy of Sports Physical Therapy) initiative, 67 experts (26 in the steering group and 41 in the rating group) from 14 countries (USA and 13 European countries) including orthopedic surgeons, sports medicine doctors and physiotherapists were involved. Steering group members established guiding questions, searched the literature, proposed statements. Rating group members assessed the statements according to a Likert scale and provided grades of recommendations reaching final agreement about rehabilitation of the knee after meniscus surgery. Final documents were then assessed by a peer review group to adress the geographical adaptability. Results The overall level of evidence of the literature was low. Of the 19 questions (leading to 29 statements), one received a grade A of recommendation, two a grade B, nine a grade C and 17 a Grade D. Nevertheless, the mean median rating of all questions was 8.2/9 (9 being the highest rating on a scale of 1-9) and the global mean rating was 8.4+/-0.2, indicating a high agreement. Rehabilitation depends on the type of lesion, the treatment performed and is the same after medial or lateral meniscus surgery. Rehabilitation after meniscectomy should follow a criterion-based rehabilitation protocol, based on milestones rather than a time-based protocol. After meniscus repair and reconstruction, rehabilitation should be progressed according to both time and criterion-based milestones. Conclusion Rehabilitation after meniscus surgery is a debated topic that may influence surgical outcomes if not optimally performed. This international formal consensus established clear, updated, and structured recommendations for both surgeons and physiotherapists treating patients after meniscus surgery. Level of Evidence I, Consensus.

Abstract Purpose The aim of part one of this EU‐US consensus was to combine literature research and expertise to provide recommendations for the usage of rehabilitation (including physical therapy) of patients undergoing surgical treatment for degenerative meniscus lesions or acute meniscus tears (including meniscectomy, repair, or reconstruction). Prevention programmes, non‐operative treatment of acute tears and degenerative lesions, return to sports and patient‐reported outcome measures will be presented in a part II article. Methods This consensus followed the European Society for Sports Traumatology and Arthroscopy (ESSKA)'s ‘formal consensus’ methodology. For this combined ESSKA, American Orthopedic Society for Sports Medicine and American Academy of Sports Physical Therapy initiative, 67 experts (26 in the steering group and 41 in the rating group) from 14 countries (US and 13 European countries), including orthopaedic surgeons, sports medicine doctors and physiotherapists were involved. Steering group members established guiding questions, searched the literature and proposed statements. Rating group members assessed the statements according to a Likert scale and provided grades of recommendations, reaching a final agreement about rehabilitation of the knee after meniscus surgery. Final documents were then assessed by a peer review group to address the geographical adaptability. Results The overall level of evidence in the literature was low. Of the 19 questions (leading to 29 statements), 1 received a Grade A of recommendation, 2 a Grade B, 9 a Grade C and 17 a Grade D. Nevertheless, the mean median rating of all questions was 8.2/9 (9 being the highest rating on a scale of 1–9). The global mean rating was 8.4 ± 0.2, indicating a high agreement. Rehabilitation depends on the type of lesion, the treatment performed and is the same after medial or lateral meniscus surgery. Rehabilitation after meniscectomy should follow a criterion‐based rehabilitation protocol, based on milestones rather than a time‐based protocol. After meniscus repair and reconstruction, rehabilitation should be progressed according to both time and criterion‐based milestones. Conclusion Rehabilitation after meniscus surgery is a debated topic that may influence surgical outcomes if not optimally performed. This international formal consensus established clear, updated and structured recommendations for both surgeons and physiotherapists treating patients after meniscus surgery. Level of Evidence Level I, consensus.

AbstractThe sliding filament theory explains skeletal muscle fibre force change as a function of length based on the overlap of actin and myosin filaments. Although this length‐tension (LT) relationship has been well investigated in animal models, it is not known whether this microscopic sarcomere LT property can be scaled up five orders of magnitude to explain the LT behaviour of a long human muscle such as the gracilis. The goal of this study is to validate the sarcomere LT curve in humans based on human filament length combined with in vivo experimental data. Intraoperative measurements of maximal tetanic force and muscle‐tendon unit length at four different joint configurations (JC) were obtained from 19 patients undergoing free functioning muscle transfer surgery. With physiologically measured fibre length and estimated sarcomere shortening resulting from tendon compliance, we show that 79.7% variance in isometric force data is explained by a simple human sarcomere LT model. This study demonstrates that the human whole muscle LT relationship can be modelled by the sliding filament theory given patient‐specific fibre length, filament length, tendon compliance and sarcomere shortening. imageKey points Whole human gracilis muscle isometric length‐tension relationships were measured in the operating room. Grouped whole muscle raw length‐tension curves showed no obvious form. The width of each experimental length‐tension curve was highly variable across subjects and used to predict fibre length (serial sarcomere number). After whole muscle length‐tension curves were normalized to each patient's serial sarcomere number, the whole human muscle length‐tension curve was well predicted by the sliding filament theory.

Abstract Rationale: The 1-year double-blind period of the MANDARA trial (NCT04157348) demonstrated non-inferiority of benralizumab to mepolizumab for achieving remission, in adults with relapsing/refractory eosinophilic granulomatosis with polyangiitis (EGPA). Here, we report the 2-year combined double-blind and ongoing open-label extension (OLE) data. Methods: On completion of the double-blind period (n=136/140) comparing benralizumab 1x30mg versus mepolizumab 3x100mg subcutaneously every 4 weeks, patients were invited to enter the OLE where they continued benralizumab (benra/benra) or switched from mepolizumab to benralizumab (mepo/benra). Endpoints included remission (Birmingham Vasculitis Activity Score=0 and oral glucocorticoid [OGC[ dose ≤4 mg/day), OGC use, relapse, blood eosinophil count (bEOS), Asthma Control Questionnaire (ACQ-6), pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV1), and safety. Results: In total, 128 patients entered the OLE (n=66 benra/benra, n=62 mepo/benra; mean age 52.8 years; 60.2% female), and 119 completed OLE Year 1. Baseline characteristics of those entering the OLE were similar to the double-blind period. At Week 104, over 60% in both groups (41 [62.1%] benra/benra and 42 [67.7%] mepo/benra patients) achieved remission. During the OLE, 51 (77.3%) benra/benra and 42 (67.7%) mepo/benra patients had no relapses. The percentage of benra/benra patients who discontinued OGCs was similar at Weeks 49-52 (27 [40.9%]) and Weeks 101-104 (29 [43.9%]), while the percentage increased for mepo/benra patients between Weeks 49-52 (16 [25.8%]) and Weeks 101-104 (27 [43.5%]; Figure). The median (IQR) OGC dose at Weeks 101-104 was 0.5 (0,5) in benra/benra and 1.36 (0,5) mg/day in mepo/benra patients. The median (IQR) bEOS in benra/benra patients was 20 (10,40) cells/µL at both Weeks 52 and 100; bEOS were depleted in mepo/benra patients from 70 (40,90) cells/µL to 20 (10,50) cells/µL by 4 weeks after switching. Mean (SD) ACQ-6 scores were 0.64 (0.78) in benra/benra patients and 0.60 (0.76) in mepo/benra patients at Week 104 compared with 1.39 (1.18) and 1.11 (0.95) at baseline. Mean (SD) pre-BD FEV1 was 2.59 (0.90) L versus 2.62 (0.84) L in benra/benra versus mepo/benra patients at Week 52, and 2.61 (0.90) versus 2.63 (0.81) L, at Week 100. Safety of mepolizumab and benralizumab was consistent with their known profiles. Conclusions: In patients with EGPA receiving benralizumab, remission rates, OGC discontinuation, and bEOS depletion were durable over 104 weeks with low relapse rates, and without loss of asthma control or lung function decline. Additional bEOS depletion and OGC sparing was observed in patients switching from mepolizumab to benralizumab.

Abstract RATIONALE: Airway-to-lung ratio (AirLR), calculated as the mean of airway lumen diameters at standard anatomic locations divided by the cube-root of total lung volume, is associated with COPD risk regardless of smoking status, and we have previously shown an association between total-pulmonary-vascular-volume-to-lung-size relationship with AirLR. [PMCID: PMC11284327] Using dual energy computed tomography (DECT), we recently developed a deep learning-based algorithm for pulmonary arterial segmentation to compute pulmonary-arterial-to-lung ratio (ArtLR) which correlated significantly with AirLR and markers COPD. Here we automate image processing in a larger cohort to estimate ArtLR, introduce an alternative ArtLR standardization and correlate it to COPD-related measures of lung structure and function. METHODS: Using a SPIROMICS sub-cohort (110 participants), imaged via contrast enhanced DECT at functional residual capacity (FRC), an automatic deep learning pipeline segmented the arteries from the pulmonary vascular tree. Another pipeline automatically extracted the centerlines and calculated average arterial segment diameters. A paired non-contrast total lung capacity (TLC) scan was registered to the DECT FRC scan to transfer airway segment labels from the TLC to FRC domain. AirLR was calculated as the mean of airway lumen diameters at standard anatomic locations (trachea-to-subsegments) divided by cube root of lung volume [TLC or FRC]. A simple Long Short-Term Memory (LSTM) network was used to find corresponding anatomic arterial segments. Associations between ArtLR and %Emphysema, AirLR, pre- and post-bronchodilator FEV1/FVC, and a texture-based (AMFM) measure of %broncho-vascular bundles was assessed using linear regression to adjust for age, sex and BMI. RESULTS: In adjusted analyses, a 1-SD decrement in ArtLR-TLC was associated with 4.198 units increase in %Emphysema-910 (95%CI: 1.360-7.037; p = 0.0041), and 0.8198 units decrease in %Bronchovascular (95%CI: 0.5037-1.136; p < 0.0001). A 1-SD increment in ArtLR-TLC was associated with 0.2515 SD increase in AirLR-Outer (95%CI: 0.04947SD-0.4536SD; p = 0.0152), and 0.02083 units increase in PreBronch-FEV1FVC (95%CI: 0.001814-0.03984; p = 0.0321). Sex and BMI show significant associations with ArtLR-TLC, where female is associated with 1.068 SD decrease in ArtLR, and a unit increase in BMI is associated with 0.05788 SD increase in ArtLR (both p-values < 0.0001), and age was not association with ArtLR. CONCLUSIONS: An automated pipeline for pulmonary arterial tree segmentation and standardization from contrast enhanced DECT FRC scans demonstrates a significant relationship between ArtLR and AirLR as well as between ArtLR and %emphysema, and FEV1/FVC. A standardized method of arterial tree size assessment provides for expanded exploration of vascular vs airway disease etiologies.

Abstract Rationale Chronic obstructive pulmonary disease (COPD) manifests later in life and is a leading cause of death worldwide. While smoking-related lung pathology is a long-recognized COPD etiotype, emerging evidence suggests that early-life growth conditions also play an important role. A recently-developed index of early-life growth conditions – the difference between attained height and genotype-predicted height (height-GaP) – has been validated against prospectevely ascertained adverse early-life growth conditions. This study used height-GaP to evaluate the association of early-life growth conditions with COPD phenotype and prognosis later in life. Methods Among current and former smokers with spirometry-defined COPD in the SubPopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS), we computed height-GaP as the difference between attained height and genotype-predicted height. Regression models were fit for respiratory mortality (defined by primary diagnostic code), dyspnea prevalence (Medical Research Council dyspnea rating >1), chronic bronchitis prevalence, airflow obstruction severity as quantified by FEV1Q, and functional capacity (six-minute walk distance), adjusting for age, age2, sex, race-ethnicity, genotype-predicted height, cigarette smoking status and pack-years. Sensitivity analyses accounted for competing risks of death (Fine-Gray subdistribution hazard model) and accounted for later-life height loss (restricting sample to participants under 50 years). Results Among 1,258 participants with COPD (mean±SD age: 65.4±8.0 years, 42.4% female, mean±SD pack-years: 53.6±28.2, mean±SD FEV1%: 63.3±23.9%), there were 202 respiratory deaths over a median 7.5 years of follow-up (Figure). Larger height-GaP deficit was associated with higher respiratory mortality (adjusted hazard ratio [aHR]: 1.30 [95%CI: 1.12 to 1.50] per 1-SD increment in height-GaP deficit). This association remained significant after accounting for competing events (p=0.001) and when restricted to participants under 50 years (p=0.032). Larger height-GaP deficit was associated with higher dyspnea prevalence (adjusted prevalence ratio: 1.13 [95%CI: 1.02 to 1.25] per 1-SD increment in height-GaP deficit), lower FEV1Q (adjusted mean difference: -0.37 [95%CI: -0.45 to -0.29] per 1-SD height-GaP deficit), and shorter 6-minute walk (adjusted mean difference: -16.6 m [95%CI: -23.1 m to -10.0 m] per 1-SD increment in height-GaP deficit), but not chronic bronchitis or CAT score ≥10 (p>0.05 for each). Conclusions Among current and former smokers with COPD, a quantitative index of early-life conditions was associated with higher respiratory mortality, in addition to dyspnea, airflow obstruction severity and reduced functional capacity. These results suggest that early-life growth conditions may influence COPD phenotype and prognosis later in life.

Abstract Rationale. Bronchoscopy can directly assess cells in airway epithelium in participants with COPD, but it is invasive, expensive, difficult to perform at scale, and contraindicated in severe disease. Blood is much more easily available but contains only a limited subset of cell types, many of which are less relevant to lung biology. Recent advances in RNA-sequencing technology have allowed for reliable measurement of transcriptomics in a wider variety of more accessible tissues, including hair follicle cells. We collected and performed bulk RNA-seq on hair follicles as an ancillary study within the NIH-funded SubPopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) and investigated their cell type composition to better understand the opportunities and limitations of this tissue for the study of lung disease. Methods. SPIROMICS recruited individuals with and without COPD aged 40-80 years with ≥ 20 pack-years smoking history. Participant at several sites underwent collection of approximately 10 hair follicles from the head, which were immediately frozen at -80ºC in 2018-21. mRNA in hair follicles was measured by bulk RNA-seq, and cell type deconvolution was performed using GEDIT v1.7 with the provided BlueCodeV1.0.tsv reference matrix. Cell types were collapsed into broader categories by summing the estimated cell type proportions. Results. The cell type deconvolution of the hair follicle bulk RNA-seq from 80 participants with and without COPD estimated that the tissue was largely composed of immune cells (median 36%, including B cells, T cells, neutrophils, macrophages, NK cells, and monocytes) and epithelial cell types (median 31%), with the largest subgroup of epithelial cell types identified as hair follicular keratinocytes (Figure 1). The next largest component was fibroblasts (median 9%), followed by endothelial cells (median 8%). Signals for myocytes (median 5%), melanocytes (median 5%), and chondrocytes (median 5%) were also present. Conclusion. This initial study demonstrated promising signals for a variety of lung-relevant cell types in hair follicles in SPIROMICS, including immune and epithelial cells in addition to fibroblasts and endothelial cells that are not otherwise easily accessible. Hair follicle gene expression profiling shows promise for understanding numerous facets of lung biology and disease that both complements and exceeds that of other noninvasive tissues such as blood.

Abstract Primary ciliary dyskinesia (PCD) results from mutations in over 50 genes that affect motile cilia (PMID: 29905515). PCD incidence is at least 1:7600 (PMID: 35051411). Asthma may be a PCD comorbidity (PMID: 36431268); and antigen stasis on the airway surface in PCD may predispose to asthma (PMID: 3831866). Methods. We analyzed the association between PCD and asthma in children ≤ 18 years old in two large electronic health record (EHR)-based databases: the Indiana Network for Patient Care Research (INPCR) cohort of 20 million EHRs and, in a validation cohort, TriNetX, with 112 million EHRs. We needed to address two issues. First, there is no ICD 10 code for PCD. Secondly, clinicians may confuse asthma and PCD in assessment. Therefore, we analyzed two diagnoses that, together, are unlikely to occur together in the absence of PCD: bronchiectasis (ICD10:J47) and situs inversus totalis (Q89.3) together (B-SIT). We asked whether subjects with B-SIT also had an asthma diagnosis ( ICD10 J45). We matched cases to controls, 1:3 in INPCR; and 1:1 in TriNetX, controlling for age, sex and race. We used conditional logistic regression adjusted for the matching strategy. For INPCR, we performed a conditional exact test: numbers were too small for adjusted models. This study was approved by the Indiana University and Case Western Reserve University IRBs. Results. In the initial INPCR study, 100% of children with B-SIT had an asthma diagnosis (p < 0.001). In the TriNetX validation cohort (Matched 1:1, n = 115 each), 84 children with B-SIT had asthma and 31 did not; in the controls, 12 had asthma and 103 did not (p = 2.2 x 10-16). The adjusted OR for B-SIT patients having asthma was 22.26 (95%CI: 10.80 – 45.91; p <0.001). Discussion. In two large EHR data sets, we found that most children with likely PCD (B-SIT) had a diagnosis of asthma. Local antigen stasis in PCD could contribute to the asthma phenotype in PCD, or perhaps even to asthma among patients heterozygous for PCD genes (PMID: 38457400). Additional studies are needed to understand the immunology, and this study is that it will need to be validated prospectively using airway reactivity testing after drug with-hold. In summary, children with PCD may need evaluation for airway reactivity. Further, providers should be alert to whether there are cardinal features of PCD among any of the children cared for with a diagnosis of asthma.