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Background There is substantial corroborating evidence that orthopaedic surgery has historically been the least diverse of all medical and surgical specialties in terms of race, ethnicity, and sex. Growing recognition of this deficit and the benefits of a diverse healthcare workforce has motivated policy changes to improve diversity. To measure progress with these efforts, it is important to understand the existing representation of sexual and gender minorities among orthopaedic professionals. Questions/purposes (1) What proportion of American Academy of Orthopaedic Surgeons (AAOS) members reported their identity as a sexual or gender minority? (2) What demographic factors are associated with the self-reporting of one’s sexual orientation and gender identity? Methods The AAOS published the updated membership questionnaire in January 2022 to collect information from new and existing society members regarding age and race or ethnicity and newly added categories of gender identity, sexual orientation, and pronouns. The questionnaire was updated with input from a committee of orthopaedic surgeons and researchers to ensure face validity. The AAOS provided a deidentified dataset that included the variables of interest: membership type, gender identity, sexual orientation, pronouns, age, race, and ethnicity. Of 35,427 active AAOS members, 47% (16,652) updated their membership questionnaire. To answer our first study question, we calculated the prevalence of participants who self-reported as lesbian, gay, bisexual, transgender, queer, or another sexual or gender minority identity (LGBTQ+) and other demographic characteristics of the 16,652 respondents. Categorical demographic data are described using frequencies and proportions. Median and IQR were used to describe the central tendency and variability. To answer our second study question, we conducted a stratified analysis to compare demographic characteristics between those who self-reported LGBTQ+ identity and those who did not. Visual methods (quantile-quantile plots) and statistical tests (Kolmogorov-Smirnov and Shapiro Wilk) confirmed that the age of AAOS member was not normally distributed. Therefore, a Kruskal Wallis test was used to determine the statistical associations between age and self-reported LGBTQ+ status. Chi-square tests were used to determine bivariate statistical associations between categorical demographic characteristics and self-reported LGBTQ+ status. A multivariable logistic regression model was developed to identify the independent demographic characteristics associated with respondents who self-reported LGBTQ+ identity. Further stratified analyses were not conducted to protect the anonymity of AAOS members. An alpha level of 5% was established a priori to define statistical significance. Results Overall, 3% (109 of 3679) and fewer than 1% (3 of 16,182) of the AAOS members (surgeons, clinicians, allied healthcare providers, and researchers) who updated their membership profiles reported identifying as a sexual (lesbian, gay, bisexual, queer) or gender minority (nonbinary or transgender), respectively. No individual self-identified as transgender. Five percent (33 of 603) of women and 3% (80 of 3042) of men self-identified as a sexual minority (such as lesbian, gay, bisexual, or queer). AAOS members who self-identified as LGBTQ+ were younger (OR 0.99 [95% confidence interval (CI) 0.98 to 0.99]; p < 0.001), less likely to self-identify as women (OR 0.86 [95% CI 0.767 to 0.954]; p < 0.001), less likely to be underrepresented in medicine (OR 0.49 [95% CI 0.405 to 0.599]; p < 0.001), and less likely to be an emeritus or honorary member (OR 0.75 [95% CI 0.641 to 0.883]; p < 0.003). Conclusion The proportion of self-reported LGBTQ+ AAOS members is lower than the 7% of the general US population. The greater proportion of younger AAOS members reporting this information suggests progress in the pursuit of a more-diverse field. Clinical Relevance The study findings support standardized collection of sexual orientation and gender identity data to better identify and address diversity gaps. As orthopaedic surgery continues to transform to reflect the diversity of musculoskeletal patients, all orthopaedic professionals (surgeons, clinicians, allied healthcare providers, and researchers), regardless of their identities, are essential in the mission to provide equitable and informed orthopaedic care. Sexual and gender minority individuals may serve as important mentors to the next generations of orthopaedic professionals; individuals from nonminority groups should serve as important allies in achieving this goal.

Background: Arsenic is a well-known toxin which may contaminate household water. It is harmful when ingested over prolonged periods of time. As a result, public health experts recommend that water should be screened and treated to prevent arsenic ingestion. In the United States, the responsibility of testing and treatment of private wells falls on homeowners. Despite recommendations for routine screening, this is rarely done. Objectives: To assess the prevalence of well water use in a Midwestern patient population, how patients and clinicians perceive the risks of arsenic in well water, and whether additional resources on well water testing are desired. These findings will be used to influence tools for clinicians regarding symptom and examination findings of chronic arsenic exposure and potentiate the distribution of informational resources on well water testing. Methods: Surveys were sent via email to all actively practicing primary care clinicians at the Mayo Clinic in the United States Midwest, and all active adult patients at the Mayo Clinic in the same region. Our team analyzed survey data to determine whether both patients and clinicians are aware of the health effects of chronic arsenic toxicity from well water, the need for routine well water testing and whether each group wants more information on the associated risks. Results: Both patients and primary care clinicians worry about arsenic exposure. Patients with well water are concerned about their water safety yet feel uninformed about testing options. Clinicians do not know how prevalent well water use is among their patients, feel uninformed about the chronic risks of arsenic exposure and the physical examination associated with it. Both groups unanimously want more information on testing options. Conclusions: Our findings show a significant reliance on well water use in the American Midwest, and unanimous support for the need for further well water testing information and resources for patients and their clinicians.

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type– and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

ABSTRACT Background: Inorganic polyphosphate (polyP) is a procoagulant polyanion. We assessed the impact of polyP inhibition on thrombin generation after trauma using the novel polyP antagonists, macromolecular polyanion inhibitor 8 (MPI 8), and universal heparin reversal agent 8 (UHRA-8). Methods: Plasma thrombin generation (calibrated automated thrombogram, CAT), in 56 trauma patients and 39 controls +/− MPI 8 and UHRA-8 (50 μg/mL), was expressed as lag time (LT, minutes), peak height (PH, nM), and time to peak (ttPeak, minutes), with change in LT (ΔLT) and change in ttPeak (ΔttPeak) quantified. Results expressed in median and quartiles [Q1, Q3], Wilcoxon matched-pairs testing, P < 0.05 significant. Results: Trauma patients had greater baseline PH than controls (182.9 [121.0, 255.2]; 120.5 [62.1, 174.8], P < 0.001). MPI 8 treatment prolonged LT and ttPeak in trauma (7.20 [5.88, 8.75]; 6.46 [5.45, 8.93], P = 0.020; 11.28 [8.96, 13.14]; 11.00 [8.95, 12.94], P = 0.029) and controls (7.67 [6.67, 10.50]; 6.33 [5.33, 8.00], P < 0.001; 13.33 [11.67, 15.33]; 11.67 [10.33, 13.33], P < 0.001). UHRA-8 treatment prolonged LT and ttPeak and decreased PH in trauma (9.09 [7.45, 11.33]; 6.46 [5.45, 8.93]; 14.02 [11.78, 17.08]; 11.00 [8.95, 12.94]; 117.4 [74.5, 178.6]; 182.9 [121.0, 255.2]) and controls (9.83 [8.00, 12.33]; 6.33 [5.33, 8.00]; 16.67 [14.33, 20.00]; 11.67 [10.33, 13.33]; 55.3 [30.2, 95.9]; 120.5 [62.1, 174.8]), all P < 0.001. Inhibitor effects were greater for controls (greater ΔLT and ΔttPeak for both inhibitors, P < 0.001). Conclusion: PolyP inhibition attenuates thrombin generation, though to a lesser degree in trauma than in controls, suggesting that polyP contributes to accelerated thrombin generation after trauma.

Introduction: Hydrochlorothiazide (HCTZ) is among the most commonly prescribed antihypertensives in the US, yet <50% of HCTZ treated patients achieve blood pressure (BP) control. Hypothesis: Integrating metabolomic and genomic profiles of HCTZ treated patients could identify novel pathways/biomarkers for optimizing the use of HCTZ. Methods: Primary analysis included 228 white hypertensives treated with HCTZ from the Pharmacogenomic Evaluation of Antihypertensive Response (PEAR) study. Genotyping was determined via Illumina Omni 1M-Quad Chip and untargeted metabolomics was performed on baseline fasting plasma samples using a GC-TOF MS platform. Pathway analysis was used to integrate metabolites significantly associated with HCTZ BP response (FDR<.05) and genetic signals at p<5x10-5 from HCTZ BP genome-wide analysis. Replication was conducted in another 212 white HCTZ treated patients. Replicated genetic signals were used to create a BP response score by summing their BP lowering alleles. We validated this score by testing it in 196 white HCTZ treated patients in the Genetic Epidemiology of Responses to Antihypertensives (GERA) study. Results: Thirteen metabolites were significantly associated with HCTZ systolic BP (SBP) and diastolic BP (DBP) responses (FDR<.05). Metabolomics-genomics integration revealed significant metabolites along with rs2727563 PRKAG2, rs12604940 DCC, and rs13262930 EPHX2, in the netrin signalling pathway (p=1x10-5), as potential markers significantly influencing HCTZ BP response. We successfully replicated those 3 genetic signals and added their alleles to create a response score which explained 11.3% and 11.9% of the variability to HCTZ SBP and DBP responses, respectively. We found that patients carrying one “response” allele had a significantly worse response than carriers of six alleles (ΔSBP/ΔDBP: -1.5/1.2 vs -16.3/-10.4 mmHg, respectively, SBP score p=1x10-8 and DBP score p=3x10-9). We further validated this response score by testing it in the GERA (DBP score p=0.03, SBP score p=0.07). Conclusion: This study highlights the power of using different omics to identify novel pathways/biomarkers of drug response, and suggests that PRKAG2, DCC and EPHX2 might be important determinants of HCTZ BP response.

Abstract Introduction Insomnia is a common sleep disorder in pediatric patients with neurodevelopmental disabilities. There are no FDA approved medications for insomnia in the pediatric population, and treatment can be challenging. We present a case of successful treatment of sleep maintenance insomnia in a 15-year-old male with doxepin with supportive actigraphy data. Report of case(s) A 15-year-old male with a past history pertinent for a genetic neurodevelopmental disorder, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) was evaluated in Pediatric Sleep Medicine Clinic for long standing difficulties with sleep maintenance. He experienced frequent, prolonged nocturnal awakenings and early morning awakenings. Previous polysomnogram was negative for sleep disordered breathing. He previously trialed clonidine, guanfacine, trazodone, melatonin, and mirtazapine without significant benefit. Baseline actigraphy demonstrated frequent and prolonged nocturnal awakenings and early morning awakenings. He was initiated on doxepin 3 mg at bedtime, and it was subsequently increased to 6 mg at bedtime. Parental report and repeat actigraphy 4 months later (on doxepin 6 mg) demonstrated improvement in nocturnal awakenings and early morning awakenings. Conclusion Up to now, there are no FDA approved medications for the treatment of insomnia in the pediatric population. A prior study of patients with ASD and ADHD demonstrated the use of doxepin provided clinical improvement in sleep onset and maintenance insomnia based on subjective evidence with parental report. In this case, doxepin improved subjective report of insomnia and correlated with objective findings on actigraphy. Support (if any) NA

Abstract Introduction The definition of respiratory events has evolved over decades. The current American Academy of Sleep Medicine scoring manual recommends hypopneas be defined by a ≥ 30% airflow reduction with either ≥ 3% desaturation or an arousal, while the prior “recommended” criteria of a ≥ 30% airflow reduction and associated ≥ 4% oxygen desaturation (with no requirement of arousal) was changed to “optional”. Consequently, events previously characterized as a respiratory effort related arousal (RERA) may now be defined as a 3% hypopnea. We hypothesized that while the 3% apnea-hypopnea index (3%AHI) will be higher than the 4%AHI, the 3%AHI will be similar to the 4% respiratory disturbance index (4%RDI), and that the measurement of RERAs under 3% scoring criteria will be clinically insignificant. Methods We prospectively collected 70 consecutive in-lab polysomnography results in 4 adult age groups. We re-scored the respiratory events utilizing the 3% hypopnea rule, and compared the differences between 3% and 4% scoring criteria. Results Among the 70 studies (mean age 50, males 46%), the 3%AHI was significantly higher than the 4%AHI (+9.247 ± 1.161, p&lt; 0.001). This was mainly due to increased hypopnea events (+10.313 ± 1.617, p&lt; 0.001). The 3%AHI was significantly different from the 4%RDI (+7.096 ± 1.133, p&lt; 0.001). There were no significant differences between the 3% and 4% RERA indices, with both values being minimal. Results were similar in both diagnostic and titration phases of testing. Conclusion As previously shown, utilizing the 3% hypopnea rule results in an increased AHI. Most of this difference is related to hypopneas with negligible influence of RERAs. This may lead to increased diagnosis and severity of sleep-disordered breathing in the adult population, and potentially be associated with payer ramifications. Our findings demonstrated negligible RERA indices on average with either rule, thus calling into question the clinical significance of this index in most patients. Support (if any) NA

Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (T PHEX ), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ + T PHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ + T PHEX . We also observed IFN-γ + T PHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19 + leukemia cells. An IFN-γ + T PHEX gene signature was recapitulated in T EX cells from human cancers, including myeloma and lymphoma. Here, we characterize a T EX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional T EX found in chronic viral infections. Thus, IFN-γ + T PHEX represent a potential target for immunotherapy of blood cancers.

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator–activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.