Citations

AbstractBackground and purposePrimary lateral sclerosis (PLS) is a neurodegenerative disorder that primarily affects the central motor system. In rare cases, clinical features of PLS may overlap with those of progressive supranuclear palsy (PSP). We investigate neuroimaging features that can help distinguish PLS with overlapping features of PSP (PLS‐PSP) from PSP.MethodsSix patients with PLS‐PSP were enrolled between 2019 and 2023. We compared their clinical and neuroimaging characteristics with 18 PSP–Richardson syndrome (PSP‐RS) patients and 20 healthy controls. Magnetic resonance imaging, 18F‐flortaucipir positron emission tomography (PET), quantitative susceptibility mapping, and diffusion tensor imaging tractography (DTI) were performed to evaluate eight brain regions of interest. Area under the receiver operating characteristic curve (AUROC) was calculated.ResultsFive of the six PLS‐PSP patients (83.3%) were male. Median age at symptom onset was 61.5 (52.5–63) years, and all had mixed features of PLS and PSP. Volumes of the pallidum, caudate, midbrain, and cerebellar dentate were smaller in PSP‐RS than PLS‐PSP, providing good discrimination (AUROC = 0.75 for all). The susceptibilities in pallidum, midbrain, and cerebellar dentate were greater in PSP‐RS compared to PLS‐PSP, providing excellent discrimination (AUROC ≥ 0.90 for all). On DTI, fractional anisotropy (FA) in the posterior limb of the internal capsule from the corticospinal tract was lower in PLS‐PSP compared to PSP‐RS (AUROC = 0.86), but FA in the superior cerebellar peduncle was lower in PSP‐RS (AUROC = 0.95). Pallidum flortaucipir PET uptake was greater in PSP‐RS compared to PLS‐PSP (AUROC = 0.74).ConclusionsRegional brain volume, tractography, and magnetic susceptibility, but not tau‐PET, are useful in distinguishing PLS‐PSP from PSP.

Background Symptomatic limitations in apical hypertrophic cardiomyopathy may occur because of diastolic dysfunction with resultant elevated left ventricular filling pressures, cardiac output limitation to exercise, pulmonary hypertension (PH), valvular abnormalities, and/or arrhythmias. In this study, the authors aimed to describe invasive cardiac hemodynamics in a cohort of patients with apical hypertrophic cardiomyopathy. Methods and Results Patients presenting to a comprehensive hypertrophic cardiomyopathy center with apical hypertrophic cardiomyopathy were identified (n=542) and those who underwent invasive hemodynamic catheterization (n=47) were included in the study. Of these, 10 were excluded due to postmyectomy status or incomplete hemodynamic data. The mean age was 56±18 years, 16 (43%) were women, and ejection fraction was preserved (≥50%) in 32 (91%) patients. The most common indication for catheterization was dyspnea (48%) followed by suspected PH (13%), and preheart transplant evaluation (10%). Elevated left ventricular filling pressures at rest or exercise were present in 32 (86%) patients. PH was present in 30 (81%) patients, with 6 (20%) also having right‐sided heart failure. Cardiac index was available in 25 (86%) patients with elevated resting filling pressures. Of these, 19 (76%) had reduced cardiac index and all 6 with right‐sided heart failure had reduced cardiac index. Resting hemodynamics were normal in 8 of 37 (22%) patients, with 5 during exercise; 3 of 5 (60%) patients had exercise‐induced elevation in left ventricular filling pressures. Conclusions In patients with apical hypertrophic cardiomyopathy undergoing invasive hemodynamic cardiac catheterization, 86% had elevated left ventricular filling pressures at rest or with exercise, 81% had PH, and 20% of those with PH had concomitant right‐sided heart failure.

Abstract Quadricuspid aortic valve is a rare congenital cardiac anomaly with an incidence of 0.008% to 0.043%. Its clinical course varies depending on cusp anatomy, function, and associated cardiac malformations. It frequently progresses to aortic valve regurgitation that may require surgical valve replacement. Detection has shifted from incidental discovery during autopsies or cardiac surgeries in the early 20th century to various cardiac imaging methods in recent decades. In addition to contributing to the literature, this report supports the use of transesophageal echocardiography more liberally to detect aortic valve abnormalities. The case presents a 48-year-old female patient with an incidentally discovered quadricuspid aortic valve.

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.

INTRODUCTION: Preliminary data suggest that an encapsulated balloon (EsoCheck), coupled with a 2 methylated DNA biomarker panel (EsoGuard), detects Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) with high accuracy. The initial assay requires sample freezing upon collection. The purpose of this study was to assess a next-generation EsoCheck sampling device and EsoGuard assay in a much-enlarged multicenter study clinically enhanced by using a Clinical Laboratory Improvement Amendments of 1988-compliant assay and samples maintained at room temperature. METHODS: Cases with nondysplastic BE (NDBE), dysplastic BE (indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia), EAC, junctional adenocarcinoma, plus endoscopy controls without esophageal intestinal metaplasia, were prospectively enrolled. Medical assistants at 6 institutions delivered the encapsulated balloon per orally with inflation in the stomach. The inflated balloon sampled the distal 5 cm of the esophagus and then was deflated and retracted into the capsule, preventing sample contamination. EsoGuard bisulfite sequencing assayed levels of methylated vimentin and methylated cyclin A1. RESULTS: A total of 243 evaluable patients—88 cases (median age 68 years, 78% men, 92% White) and 155 controls (median age 57 years, 41% men, 88% White)—underwent adequate EsoCheck sampling. The mean procedural time was approximately 3 minutes. Cases included 31 with NDBE, 16 with indefinite for dysplasia/low-grade dysplasia, 23 with high-grade dysplasia, and 18 with EAC/junctional adenocarcinoma. Thirty-seven NDBE and dysplastic BE cases (53%) were short-segment BE (<3 cm). Overall sensitivity was 85% (95% confidence interval 0.78–0.93) and specificity was 85% (95% confidence interval 0.79–0.90). Sensitivity for NDBE was 84%. EsoCheck/EsoGuard detected 100% of cancers (n = 18). DISCUSSION: EsoCheck/EsoGuard demonstrated high sensitivity and specificity in detecting BE and BE-related neoplasia.

Background This study was performed to determine cusp causes of aortic regurgitation in patients with tricuspid aortic valves without significant aortic dilatation and define cusp pathologies amenable to surgical repair (aortic valve repair [AVr]) versus aortic valve replacement. Methods and Results We retrospectively reviewed surgical reports of consecutive adults with tricuspid aortic valves undergoing surgery for clinically significant aortic regurgitation within a prospective registry from January 2005 to September 2019. Valvular mechanisms were determined by systematic in vivo intraoperative quantification methods. Of 516 patients, 287 (56%) underwent repair (AVr; mean±SD age, 59.9±12.4 years; 81% men) and 229 (44%) underwent replacement (aortic valve replacement; mean±SD age, 62.8±13.8 years [ P =0.01 compared to AVr]; 67% men). A single valvular mechanism was present in 454 patients (88%), with cusp prolapse (46%), retraction (24%), and perforation (18%) being the most common. Prolapse involved the right cusp in 86% of cases and was more frequent in men ( P <0.001). Two‐dimensional transesophageal echocardiography accuracy for predicting mechanisms was 73% to 82% for the right cusp, 55% to 61% for the noncoronary cusp, and 0% for the left‐coronary cusp. Cusp prolapse, younger age, and larger patient size were associated with successful AVr (all P <0.03), whereas retraction, perforation, older age, and concomitant mitral repair were associated with aortic valve replacement (all P <0.03). Conclusions Right cusp prolapse is the most frequent single valvular mechanism in patients with tricuspid aortic valve aortic regurgitation, followed by cusp retraction and perforation. The accuracy of 2‐dimensional transesophageal echocardiography is limited for left and noncoronary cusp mechanistic assessment. Prolapse is associated with successful AVr, whereas retraction and perforation are associated with aortic valve replacement. With systematic intraoperative quantification methods and current surgical techniques, more than half of tricuspid aortic valve aortic regurgitation cases may be successfully repaired.

Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.

Traditional definitions of polypharmacy may largely not account for the market proliferation of herbal and dietary supplements, cannabis products, or incorporate the new science of pharmacogenomics (PGx). Polypharmacy is encountered by most pharmacists providing patient care in many settings. The “polypharmacist” can assist patients and providers with solving medication-related problems (MRPs) in this new and challenging environment of supplements and cannabis products by utilizing traditional pharmacology and pharmacokinetic principles, including PGx, broadly across many medical disciplines. One may encounter polypharmacy more in the geriatric population, though in an age of supplements and cannabis proliferation, polypharmacy is increasingly being encountered at younger ages. Not only is polypharmacy training at best fragmented in pharmacy curricula, but it may also not account for the above-mentioned products that may use the same metabolic pathways to increase drug interactions and adverse drug reactions (ADRs) regarding prescription medications. Polypharmacy being more formally prioritized in pharmacist training may better prepare pharmacists for commonly encountered polypharmacy and can be a viable model of practice.