Using Item-Response Theory to Improve Interpretation of the Trans Woman Voice Questionnaire.

OBJECTIVE: The Trans Woman Voice Questionnaire (TWVQ) is commonly used to quantify self-perceptions of voice for trans women seeking gender-affirming voice care, but the interpretation of TWVQ scores remains challenging. The objective of this study was to use item-response theory (IRT) to evaluate the relationship between TWVQ items and persons on a common scale and identify improvements to increase the meaningfulness of TWVQ scores. METHODS: A retrospective review of TWVQ scores from trans women patients between 2018-2020 was performed. Rasch-family models were used to generate item-person maps positioning respondent location and item difficulty estimates on a logit scale, which was then converted into a scaled score using linear transformations. RESULTS: TWVQ responses from 86 patients were analyzed. Initial item-person maps demonstrated that the middle response categories ("sometimes" and "often") performed inconsistently across items (poor threshold banding); interpretability improved when these ratings were scored as one category. The models were rerun using revised scoring, which retained high reliability (0.93) and supported a unidimensional construct. Updated item-person maps revealed four scaled score zones (≤54, >54 to ≤101, >101 to ≤140, and >140) that each corresponded to an increasing pattern of item thresholds (probability of selecting one response category vs. others). These ranges can be interpreted as minimal, low, moderate, and high, respectively. CONCLUSIONS: Empiric data from Rasch analysis supports new interval scoring for the TWVQ that advances the clinical and research utility of the instrument and lays the foundation for future improvements in clinical care and outcomes assessment. LEVEL OF EVIDENCE: NA Laryngoscope, 133:1197-1204, 2023.

National perspective on hospital readmissions following adrenalectomy.

Background: Examining risk factors of readmission in adrenalectomy patients and estimated the cost burden of unplanned readmission on the United States' healthcare system. Methods: According to the Nationwide Readmission Database, 20,494 patients underwent adrenalectomy between 2010-2014. Demographics, comorbidities, clinical data, length of stay (LOS), annual case volume, and discharge disposition of 30- and 90-day readmission cohorts were compared to the non-readmitted cohort. Results: A total of 1,463 (7.9%) and 1,959 (12.7%) adrenalectomy patients were readmitted at 30 and 90 days after discharge, respectively. Prolonged initial hospital stays [odds ratio (OR) =1.93; 95% confidence interval (CI): 1.63-2.27] and postoperative complications (OR =4.91; 95% CI: 1.98-12.16) were associated with a higher risk of readmission. Complications were significantly more frequent in patients with a primary or secondary malignancy (OR =1.42; 95% CI: 1.23-1.64) and in patients undergoing a procedure at a low adrenalectomy volume hospital [hazard ratio (HR) =0.75; 95% CI: 0.62-0.91; P=0.003]. Readmission extended overall LOS by an average of 2.06 days, costing an additional $18,529.49 per admission. Conclusions: Readmission adds significantly to the burden of disease after adrenalectomy. Understanding contributing factors may identify strategies to reduce readmissions and improve healthcare for patients.

IL-10 promotes endothelial progenitor cell infiltration and wound healing via STAT3.

Endothelial progenitor cells (EPCs) contribute to de novo angiogenesis, tissue regeneration, and remodeling. Interleukin 10 (IL-10), an anti-inflammatory cytokine that primarily signals via STAT3, has been shown to drive EPC recruitment to injured tissues. Our previous work demonstrated that overexpression of IL-10 in dermal wounds promotes regenerative tissue repair via STAT3-dependent regulation of fibroblast-specific hyaluronan synthesis. However, IL-10's role and specific mode of action on EPC recruitment, particularly in dermal wound healing and neovascularization in both normal and diabetic wounds, remain to be defined. Therefore, inducible skin-specific STAT3 knockdown mice were studied to determine IL-10's impact on EPCs, dermal wound neovascularization and healing, and whether it is STAT3-dependent. We show that IL-10 overexpression significantly elevated EPC counts in the granulating wound bed, which was associated with robust capillary lumen density and enhanced re-epithelialization of both control and diabetic (db/db) wounds at day 7. We noted increased VEGF and high C-X-C motif chemokine 12 (CXCL12) levels in wounds and a favorable CXCL12 gradient at day 3 that may support EPC mobilization and infiltration from bone marrow to wounds, an effect that was abrogated in STAT3 knockdown wounds. These findings were supported in vitro. IL-10 promoted VEGF and CXCL12 synthesis in primary murine dermal fibroblasts, with blunted VEGF expression upon blocking CXCL12 in the media by antibody binding. IL-10-conditioned fibroblast media also significantly promoted endothelial sprouting and network formation. In conclusion, these studies demonstrate that overexpression of IL-10 in dermal wounds recruits EPCs and leads to increased vascular structures and faster re-epithelialization.

Clinical annotations for prostate cancer research: Defining data elements, creating a reproducible analytical pipeline, and assessing data quality.

BACKGROUND: Routine clinical data from clinical charts are indispensable for retrospective and prospective observational studies and clinical trials. Their reproducibility is often not assessed. We developed a prostate cancer-specific database for clinical annotations and evaluated data reproducibility. METHODS: For men with prostate cancer who had clinical-grade paired tumor-normal sequencing at a comprehensive cancer center, we performed team-based retrospective data collection from the electronic medical record using a defined source hierarchy. We developed an open-source R package for data processing. With blinded repeat annotation by a reference medical oncologist, we assessed data completeness, reproducibility of team-based annotations, and impact of measurement error on bias in survival analyses. RESULTS: Data elements on demographics, diagnosis and staging, disease state at the time of procuring a genomically characterized sample, and clinical outcomes were piloted and then abstracted for 2261 patients (with 2631 samples). Completeness of data elements was generally high. Comparing to the repeat annotation by a medical oncologist blinded to the database (100 patients/samples), reproducibility of annotations was high; T stage, metastasis date, and presence and date of castration resistance had lower reproducibility. Impact of measurement error on estimates for strong prognostic factors was modest. CONCLUSIONS: With a prostate cancer-specific data dictionary and quality control measures, manual clinical annotations by a multidisciplinary team can be scalable and reproducible. The data dictionary and the R package for reproducible data processing are freely available to increase data quality and efficiency in clinical prostate cancer research.

Seeking justice amidst chaos: methods to identify and document individuals implicated in crimes against the Rohingya in August 2017.

BACKGROUND: Documenting perpetrators of human rights violations enables effective prosecution and can help prevent future atrocities. Doing so calls for collecting reliable data using verifiable and transparent methodology. We present methods used to document crimes and identify alleged perpetrators implicated in the 2017 attacks against Rohingya civilians in Myanmar. The findings and lessons-learned have relevance to contemporary crises with widespread atrocities. METHODS: A mixed-methods assessment conducted from May to July 2018 included: (1) cross-sectional quantitative surveys among leaders of affected hamlets in northern Rakhine State, (2) qualitative interviews to record hamlet-level accounts, and (3) clinical evaluations of survivors of violence. Survey respondents who reported violence and destruction in each hamlet were asked to identify perpetrators of those acts, including known role or affiliation. The reported names were reviewed for clarity and divergent spellings, repeated references were aggregated, and the names and roles were analyzed and classified by location and affiliation. RESULTS: 143 individuals were implicated in atrocities committed across three Northern Rakhine townships. Each was independently identified by at least three separate survey respondents as directly committing violence or destruction in their hamlet of origin, or as witnessed while fleeing to Bangladesh. Two-thirds (69%) of identified perpetrators were reported by four or more participants and 47% by five or more. Some form of additional identifying information, was provided for 85% of names. The most common affiliations were: Myanmar army (n = 40), Border Guard Police (n = 32), Village Tract Administrators (n = 17), and extremists (n = 25). CONCLUSIONS: The methodology presented here yielded a unique record of individuals purported to have directly committed acts of violence and destruction in Rakhine State in August 2017, forming the most extensive record of individuals implicated in ground-level perpetration of those crimes. This methodology can play a key role in accountability mechanisms for the Rohingya, and in other settings in which perpetrators are many and documentation of their crimes is difficult. The use of survey methods and standardized data collection amongst affected populations to comprehensively characterize crimes committed and to identify individuals implicated in those crimes can serve as a key tool in documentation and an important component of accountability.

Increased Moxifloxacin Dosing Among Patients With Multidrug-Resistant Tuberculosis With Low-Level Resistance to Moxifloxacin Did Not Improve Treatment Outcomes in a Tertiary Care Center in Mumbai, India.

BACKGROUND: Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available. METHODS: We conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5 µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600 mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable Cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes. RESULTS: Of 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200 [56.5%]), which was similar between groups (56.7% vs 54.0%, P = .74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted (hazard ratio [HR], 1.2 [95% confidence interval {CI}, .6-2.4]) or adjusted (HR, 0.8 [95% CI, .5-1.4]) models but was associated with joint pain (HR, 3.2 [95% CI, 1.2-8.8]). CONCLUSIONS: In a large observational cohort, adding high-dose (600 mg) moxifloxacin to a drug susceptibility test-based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin-resistant MDR-TB.

A Systematic Review of Linkage-to-Care and Antiretroviral Initiation Implementation Strategies in Low- and Middle-Income Countries Across Sub-Saharan Africa.

Linkage to care (LTC) and initiation of antiretroviral therapy (ART) are key components in the longitudinal care cascade for people living with HIV. Many strategies to optimize these stages of HIV care have been implemented, though there is a paucity of analyses comparing the outcomes of these efforts in low- and middle-income countries. We conducted a systematic review of studies assessing interventions along all stages of the HIV care continuum published between 2008 and 2020. A comprehensive search strategy reviewed five electronic databases to capture studies assessing HIV testing, LTC, ART initiation, ART adherence, and viral suppression. Of the 388 articles that met the inclusion criteria, 78 described interventions for improving LTC/ART initiation. Efforts focused on empowering patients through integrative approaches generally yielded more substantive results compared to provider-initiated non-adaptive LTC interventions or cash incentives. Specifically, tailoring care and incorporating ART initiation into existing infrastructures, such as maternal clinics, had a high impact across settings. Moreover, strategies such as home-based HIV counseling and testing (HBHCT) appear to be most effective when implemented in tandem with other approaches including motivational counseling and point-of-care CD4 testing.

The birth of quantum mechanics from the spirit of radiation theory.

This paper starts from the observation that the major hallmarks in the history of quantum mechanics centrally involved light and radiation. Consequently, we ask how precisely did concepts and ideas from radiation theory define the creation of quantum mechanics? And why was it a quantum theory of mechanics and not a quantum theory of electrodynamics that was crafted in the years 1925/26? Following these questions, this paper provides a reading of the history of the old quantum theory from the perspective of radiation. We argue that both wave and matrix mechanics, while emerging from widely different trajectories, emerged as spin-offs from nascent, ultimately unsuccessful quantum theories of radiation. We discuss the epistemological implications of this development for the historical and philosophical analysis of quantum mechanics and quantum field theory.

John Wheeler's Desert Island: The conservatism of non-empirical physics.

This paper argues that non-empirical physics, as paradigmatically embodied by string theory, is a conservative research program, in spite of appearances. John Wheeler's 1950s research program of "daring conservatism" is identified as another non-empirical research program that checks all the same boxes as string theory. This case study is used to further analyze the connection between conservatism and a non-empirical approach. It is concluded that the prime difficulty of non-empirical physics is not that it involves unbridled speculation, but that the lack of empirical input prevents it from achieving revolutionary progress.

The Cognitive Load of Inpatient Consults: Development of the Consult Cognitive Load Instrument and Initial Validity Evidence.

PURPOSE: Fellows and residents provide inpatient consultations. Though consults vary considerably, measuring the associated cognitive load (CL) is key to guiding faculty on how to optimize learning during consults. However, existing CL instruments, such as the unidimensional Paas scale, cannot separate the 3 components of CL and may miss the nuances of consult CL. Therefore, the authors developed the Consult Cognitive Load (CCL) instrument to measure the 3 CL components during consults. METHOD: In 2018-2019, the authors developed the CCL at the University of California, San Francisco, using Wilson's constructive approach to measurement. To generate content and response process validity evidence, the authors consulted the literature and experts to generate construct maps, items, and a scoring rubric and conducted cognitive interviews. They administered the CCL to internal medicine and psychiatry trainees across 5 University of California campuses and used Rasch family and linear regression models to assess internal structure validity and relationships to key predictor variables. They compared the CCL with the Paas scale using Wright maps and used latent correlations to support separating CL into 3 components. RESULTS: Analysis revealed appropriate fit statistics, appropriate mean respondent location increases across all levels, threshold banding, and expected relationships with key predictor variables. The CCL provided more coverage of the 3 CL components compared with the Paas scale. Correlations among the 3 CL components were not strong, suggesting that the CCL offers more nuance than a unidimensional measure of CL in the context of consults. CONCLUSIONS: This study generated initial validity evidence to support the CCL's use as a measure of consult CL and supports measuring the 3 CL components separately rather than as a single construct in the context of consults. Learners and faculty could compare learner CCL scores with reference scores to promote reflection, metacognition, and coaching.

Skin-specific knockdown of hyaluronan in mice by an optimized topical 4-methylumbelliferone formulation.

Hyaluronan (HA) is abundant in the skin; while HA can be synthesized by the synthases (HAS1-3), HAS2 is the leading contributor. Dysregulation and accumulation of HA is implicated in the pathogenesis of diseases such as keloid scarring, lymphedema and metastatic melanoma. To understand how HA synthesis contributes to skin physiology, and pathologic and fibrotic disorders, we propose the development of skin-specific HA inhibition model, which tests an optimal delivery system of topical 4-methylumbelliferone (4-MU). A design-of-experiments (DOE) approach was employed to develop an optimal 4-MU skin-delivery formulation comprising propylene glycol, ethanol, and water, topically applied to dorsal skin in male and female C57BL/6J wildtype mice to determine the effect on HAS gene expression and HA inhibition. Serum and skin samples were analyzed for HA content along with analysis of expression of HAS1-3, hyaluronidases (HYAL 1-2), and KIAA1199. Using results from DOE and response surface methodology with genetic algorithm optimization, we developed an optimal topical 4-MU formulation to result in ∼70% reduction of HA in dorsal skin, with validation demonstrating ∼50% reduction in HA in dorsal skin. 4-MU topical application resulted in significant decrease in skin HAS2 expression in female mice only. Histology showed thicker dermis in male mice, whereas female mice had thinner dermal layer with more adiposity; and staining for HA-binding protein showed that topical 4-MU resulted in breakdown in HA. Our data suggest a topical 4-MU formulation-based dermal HA inhibition model that would enable elucidating the skin-specific effects of HA in normal and pathologic states.

High-molecular weight hyaluronan attenuates tubulointerstitial scarring in kidney injury.

Renal fibrosis features exaggerated inflammation, extracellular matrix (ECM) deposition, and peritubular capillary loss. We previously showed that IL-10 stimulates high-molecular weight hyaluronan (HMW-HA) expression by fibroblasts, and we hypothesize that HMW-HA attenuates renal fibrosis by reducing inflammation and ECM remodeling. We studied the effects of IL-10 overexpression on HA production and scarring in mouse models of unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) to investigate whether IL-10 antifibrotic effects are HA dependent. C57BL/6J mice were fed with the HA synthesis inhibitor, 4-methylumbelliferone (4-MU), before UUO. We observed that in vivo injury increased intratubular spaces, ECM deposition, and HA expression at day 7 and onward. IL-10 overexpression reduced renal fibrosis in both models, promoted HMW-HA synthesis and stability in UUO, and regulated cell proliferation in I/R. 4-MU inhibited IL-10-driven antifibrotic effects, indicating that HMW-HA is necessary for cytokine-mediated reduction of fibrosis. We also found that IL-10 induces in vitro HMW-HA production by renal fibroblasts via STAT3-dependent upregulation of HA synthase 2. We propose that IL-10-induced HMW-HA synthesis plays cytoprotective and antifibrotic roles in kidney injury, thereby revealing an effective strategy to attenuate renal fibrosis in obstructive and ischemic pathologies.

T Lymphocytes Attenuate Dermal Scarring by Regulating Inflammation, Neovascularization, and Extracellular Matrix Remodeling.

Objective: While tissue injury and repair are known to involve adaptive immunity, the profile of lymphocytes involved and their contribution to dermal scarring remain unclear. We hypothesized that restoration of T cell deficiency attenuates dermal scarring. Approach: We assessed the temporal-spatial distribution of T lymphocytes and their subtypes during the physiological dermal wound repair process in mice. Also, we compared the scarring outcomes between wild-type (WT) and severe combined immunodeficient (SCID) mice, which are lymphocyte deficient. Complementary gain-of-function experiments were performed by adoptively transferring lymphocyte subsets to validate their contribution to tissue repair in wounded SCID mice. Results: CD4+ T lymphocytes were present within dermal wounds of WT mice beginning on day 1 and remained through day 30. Wounds of SCID mice exhibited accelerated closure, increased inflammation, limited neovascularization, and exacerbated scarring compared with WT mice. Conversely, transfer of either mixed B and T lymphocytes or CD4+ lymphocytes alone into SCID mice resulted in moderated healing with less inflammation, collagen deposition, and scarring than control SCID wounds. In contrast, transfer of other lymphocyte subsets, including helper T lymphocytes (CD3+CD4+CD25-), CD8+ T cells and B cells, or regulatory T lymphocytes (CD4+CD25+CD127low), did not reduce scar. Innovation: The finding that lymphocytes delay wound healing but reduce scar is novel and provides new insights into how dermal scarring is regulated. Conclusion: Our data support a suppressive role for CD4+ T cells against inflammation and collagen deposition, with protective effects in early-stage dermal wound healing. These data implicate adaptive immunity in the regulation of scarring phenotypes.

Preparticipation Evaluation of the Young Athlete: What an Orthopaedic Surgeon Needs to Know.

The preparticipation evaluation (PPE) is a widely used tool for detecting health conditions that may delay or disqualify athletic participation. The medical interview is the most valuable tool for identifying athletes who may be at increased risk for injury. Physical examination is tailored to identifying cardiac abnormalities or factors that may place an athlete at increased risk for injury. Although practiced in Europe, universal cardiac screening with electrocardiography is not currently recommended in the United States largely due to the high rate of false-positive results. Neuropsychological testing for management of concussion and laboratory testing for sickle cell trait may be indicated in select groups of athletes. Health care providers should view the PPE as a chance for anticipatory guidance and athlete-directed health counseling. Despite widespread acceptance of the PPE, the quality of such examinations varies significantly, which is an area for possible improvement and further research.