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Background: Management of acromioclavicular (AC) joint injuries has been an ongoing source of debate, with over 150 variations of surgery described in the literature. Without a consensus on surgical technique, patients are seeking answers to common questions through internet resources. This study investigates the most common online patient questions pertaining to AC joint injuries and the quality of the websites providing information. Hypothesis: 1) Question topics will pertain to surgical indications, pain management, and success of surgery and 2) the quality and transparency of online information are largely heterogenous. Methods: Three AC joint search queries were entered into the Google Web Search. Questions under the “People also ask” tab were expanded in order and 100 results for each query were included (300 total). Questions were categorized based on Rothwell’s classification. Websites were categorized by source. Website quality was evaluated by the Journal of the American Medical Association (JAMA) Benchmark Criteria. Results: Most questions fell into the Rothwell Fact category (48.0%). The most common question topics were surgical indications (28.0%), timeline of recovery (13.0%), and diagnosis/evaluation (12.0%). The least common question topics were anatomy/function (3.3%), evaluation of surgery (3.3%), injury comparison (1.0%), and cost (1.0%). The most common websites were medical practice (44.0%), academic (22.3%), and single surgeon personal (12.3%). The average JAMA score for all websites was 1.0 ± 1.3. Government websites had the highest JAMA score (4.0 ± 0.0) and constituted 45.8% of all websites with a score of 4/4. PubMed articles constituted 63.6% (7/11) of government website. Comparatively, medical practice websites had the lowest JAMA score (0.3 ± 0.7, range [0-3]). Conclusion: Online patient AC joint injury questions pertain to surgical indications, timeline of recovery, and diagnosis/evaluation. Government websites and PubMed articles provide the highest-quality sources of reliable, up-to-date information but constitute the smallest proportion of resources. In contrast, medical practice represents the most visited websites, however, recorded the lowest quality score. Physicians should utilize this information to answer frequently asked questions, guide patient expectations, and help provide and identify reliable online resources.

Rationale & Objective: The majority of patients with kidney failure receiving dialysis own mobile devices, but the use of mobile health (mHealth) technologies to conduct surveys in this population is limited. We assessed the reach and acceptability of a short message service (SMS) text message-based survey that assessed coronavirus disease 2019 (COVID-19) vaccine hesitancy among patients receiving dialysis. Study Design & Exposure: A cross-sectional SMS-based survey conducted in January 2021. Setting & Participants: Patients receiving in-center hemodialysis, peritoneal dialysis, or home hemodialysis in a nonprofit dialysis organization in New York City. Outcomes: (1) Reach of the SMS survey, (2) Acceptability using the 4-item Acceptability of Intervention Measure, and (3) Patient preferences for modes of survey administration. Analytical Approach: We used Fisher exact tests and multivariable logistic regression to assess sociodemographic and clinical predictors of SMS survey response. Qualitative methods were used to analyze open-ended responses capturing patient preferences. Results: Among 1,008 patients, 310 responded to the SMS survey (response rate 31%). In multivariable adjusted analyses, participants who were age 80 years and above (aOR, 0.49; 95% CI, 0.25-0.96) were less likely to respond to the SMS survey compared with those aged 18 to 44 years. Non-Hispanic Black (aOR, 0.58; 95% CI, 0.39-0.86), Hispanic (aOR, 0.31; 95% CI, 0.19-0.51), and Asian or Pacific Islander (aOR, 0.46; 95% CI, 0.28-0.74) individuals were less likely to respond compared with non-Hispanic White participants. Participants residing in census tracts with higher Social Vulnerability Index, indicating greater neighborhood-level social vulnerability, were less likely to respond to the SMS survey (fifth vs first quintile aOR, 0.61; 95% CI, 0.37-0.99). Over 80% of a sample of survey respondents and nonrespondents completely agreed or agreed with the Acceptability of Intervention Measure. Qualitative analysis identified 4 drivers of patient preferences for survey administration: (1) convenience (subtopics: efficiency, multitasking, comfort, and synchronicity); (2) privacy; (3) interpersonal interaction; and (4) accessibility (subtopics: vision, language, and fatigue). Limitations: Generalizability, length of survey. Conclusions: An SMS text message-based survey had moderate reach among patients receiving dialysis and was highly acceptable, but response rates were lower in older (age ≥ 80), non-White individuals and those with greater neighborhood-level social vulnerability. Future research should examine barriers and facilitators to mHealth among patients receiving dialysis to ensure equitable implementation of mHealth-based technologies. Plain-Language Summary: We conducted a short message service (SMS) text message-based survey that assessed coronavirus disease 2019 (COVID-19) vaccine hesitancy among patients receiving dialysis in New York City. Overall response rate was 31%, and those with age ≥ 80, non-White individuals, and participants with greater neighborhood-level social vulnerability were less likely to respond to the survey. Over 80% of participants found SMS-based surveys to be highly acceptable. Qualitative analysis showed that participants cared about the convenience, privacy, interpersonal interaction, and accessibility of surveys. Our results suggest that SMS text message surveys are a promising strategy to collect patient-reported data among patients receiving dialysis.

Background: This study aims to determine the effect of time and imaging modality (three-dimensional (3D) CT vs. 3D magnetic resonance imaging (MRI)) on the surgical procedure indicated for shoulder instability. The hypothesis is there will be no clinical difference in procedure selection between time and imaging modality. Methods: Eleven shoulder surgeons were surveyed with the same ten shoulder instability clinical scenarios at three time points. All time points included history of present illness, musculoskeletal exam, radiographs, and standard two-dimensional MRI. To assess the effect of imaging modality, survey 1 included 3D MRI while survey 2 included a two-dimensional and 3D CT scan. To assess the effect of time, a retest was performed with survey 3 which was identical to survey 2. The outcome measured was whether surgeons made a “major” or “minor” surgical change between surveys. Results: The average major change rate was 14.1% (standard deviation: 7.6%). The average minor change rate was 12.6% (standard deviation: 7.5%). Between survey 1 to the survey 2, the major change rate was 15.2%, compared to 13.1% when going from the second to the third survey (P = .68). The minior change rate between the first and second surveys was 12.1% and between the second to third interview was 13.1% (P = .8). Discussion: The findings suggest that the major factor related to procedural changes was time between reviewing patient information. Furthermore, this study demonstrates that there remains significant intrasurgeon variability in selecting surgical procedures for shoulder instability. Lastly, the findings in this study suggest that 3D MRI is clinically equivalent to 3D CT in guiding shoulder instability surgical management. Conclusion: This study demonstrates that there is significant variability in surgical procedure selection driven by time alone in shoulder instability. Surgical decision making with 3D MRI was similar to 3D CT scans and may be used by surgeons for preoperative planning.

Pharmacies are currently unable to stock proper oral dosage forms for pediatric populations. This leads to manipulation of medications or the need to compound specialized medications, which can be a time-consuming process. Using Semisolid Extrusion (SSE) additive manufacturing (AM), specialized medications can be produced in an expedited process from off-the shelf medication in a hospital or outpatient pharmacy setting. In this study, tablets with a desired dose of 5 mg of metoprolol tartrate derived from commercial Seloken™ 50 mg tablets were 3D printed in a hospital setting. Validation testing was done on five batches, highlighting tablets with a high uniformity in mass and dimension, drug content, acceptable microbial assays, and prolonged release during in-vitro analysis. The average drug content found for the tablets was within ±6% of 5 mg for all batches produced. Comparisons were done between the SSE tablets and capsules produced in an external compounding facility, highlighting several positive aspects of SSE-produced tablets beyond simply shortening the production timeline. The SSE tablets printed in this study are characterized by their smaller size, enhanced prolonged release properties, and more uniform drug content across the tested samples. Additionally, interviews with pharmaceutical professionals were conducted to determine the positive aspects of SSE and further improvements to bring this technique as seamlessly as possible into the pharmacy. This study underscores the feasibility of employing SSE in the production of specialized medications within a hospital environment. Furthermore, it highlights the methodological advantages SSE offers over existing production standards, demonstrating its potential to improve pharmaceutical manufacturing in healthcare settings.

Recurrence of cardiac sarcoidosis (CS) in post-transplant patients presents a rare but potentially life-threatening form of graft dysfunction and poses challenges due to varying clinical presentations, limited diagnostic modalities, and treatments based on anecdotal evidence. We discuss the case of a 46-year-old woman with CS, who developed cardiogenic shock necessitating orthotopic heart transplant. She subsequently developed likely recurrent CS in the transplanted heart. We discuss the rarity of this scenario as well as diagnostic modalities and management principles to consider.

Summary: Dysregulated host immune responses contribute to disease severity and worsened prognosis in COVID-19 infection and the underlying mechanisms are not fully understood. In this study, we observed that IL-33, a damage-associated molecular pattern molecule, is significantly increased in COVID-19 patients and in SARS-CoV-2-infected mice. Using IL-33−/− mice, we demonstrated that IL-33 deficiency resulted in significant decreases in bodyweight loss, tissue viral burdens, and lung pathology. These improved outcomes in IL-33−/− mice also correlated with a reduction in innate immune cell infiltrates, i.e., neutrophils, macrophages, natural killer cells, and activated T cells in inflamed lungs. Lung RNA-seq results revealed that IL-33 signaling enhances activation of inflammatory pathways, including interferon signaling, pathogen phagocytosis, macrophage activation, and cytokine/chemokine signals. Overall, these findings demonstrate that the alarmin IL-33 plays a pathogenic role in SARS-CoV-2 infection and provides new insights that will inform the development of effective therapeutic strategies for COVID-19.

Study region: Floodplain ecosystem region at the confluence of the Morava and Thaya Rivers, the Czech Republic. Study focus: Accurate determination of actual evapotranspiration (ETa) is essential for understanding surface hydrological conditions. The aim of this study was to evaluate two remote sensing models, METRIC and TSEB, for estimating ETa and energy fluxes in two ecosystems using the eddy covariance (EC) as a reference. New hydrological insights for the region: Both models demonstrate the ability to quantify ETa across the region. Compared with the METRIC, which had a mean bias error (MBE) = 0.12 mm/day, the TSEB better detected ETa in the forest test site (MBETSEB = −0.03 mm/day). In contrast, the METRIC improved detection of ETa (MBEMETRIC = −0.03 mm/day) in grassland test site, where the TSEB overestimate daily ETa (MBETSEB = 0.52 mm/day). The models and EC indicate similar seasonal dynamics of the evaporative fraction and Bowen ratio throughout the growing season. Despite the overall agreement between the models and EC, selected spatial outputs indicate some disagreement among them in terms of the spatial patterns of ETa. This disagreement is related to the sensitivity of TSEB to canopy height/roughness, as well as the a priori Priestley–Taylor coefficient in forests. Despite these shortcomings, this study highlights the applicability of remote sensing energy balance-based diagnostic models for studying hydrological processes in a spatially distributed manner.

Purpose: To report the findings supported by multimodal imaging in a case of secondary vitreoretinal lymphoma presenting with inner retina and optic nerve head infiltration. Observations: A 64-year-old man with systemic diffuse large B-cell lymphoma presented with reduced visual acuity. Moderate anterior chamber and vitreous cell were present. Fundus exam showed bilateral disc edema and diffuse opaque macular infiltrates with a pseudo cherry-red spot in the left eye. Optical coherence tomography showed inner retinal infiltration and loss of normal architecture. Surgery for tissue biopsy was discussed and declined due to risk. Instead, multimodal imaging and anterior chamber fluid sampling were used as a surrogate for tissue biopsy and helped rule out infectious uveitis and retinal vascular disease. The patient was empirically treated with intravitreal methotrexate with rapid improvement in vision, exam, and quality of life. Conclusions and importance: Multimodal imaging can support a presumed diagnosis of secondary vitreoretinal lymphoma in order to proceed with intravitreal methotrexate treatment, which can result in rapid clinical and visual improvement.

Summary: Background: No study has compared the virological and immunological status of young people with perinatally-acquired HIV infection (P-HIV) with that of people with HIV adulthood (A-HIV) having a similar duration of infection. Methods: 5 French cohorts of P-HIV and A-HIV patients with a known date of HIV-infection and receiving antiretroviral treatment (ART), were used to compare the following proportions of: virological failure (VF) defined as plasma HIV RNA ≥ 50 copies/mL, CD4 cell percentages and CD4:CD8 ratios, at the time of the most recent visit since 2012. The analysis was stratified on time since infection, and multivariate models were adjusted for demographics and treatment history. Findings: 310 P-HIV were compared to 1515 A-HIV (median current ages 20.9 [IQR:14.4–25.5] and 45.9 [IQR:37.9–53.5] respectively). VF at the time of the most recent evaluation was significantly higher among P-HIV (22.6%, 69/306) than A-HIV (3.3%, 50/1514); p ≤ 0.0001. The risk of VF was particularly high among the youngest children (2–5 years), adolescents (13–17 years) and young adults (18–24 years), compared to A-HIV with a similar duration of infection: adjusted Odds-Ratio (aOR) 7.0 [95% CI: 1.7; 30.0], 11.4 [4.2; 31.2] and 3.3 [1.0; 10.8] respectively. The level of CD4 cell percentages did not differ between P-HIV and A-HIV. P-HIV aged 6–12 and 13–17 were more likely than A-HIV to have a CD4:CD8 ratio ≥ 1: 84.1% vs. 58.8% (aOR = 3.5 [1.5; 8.3]), and 60.9% vs. 54.7% (aOR = 1.9 [0.9; 4.2]) respectively. Interpretation: P-HIV were at a higher risk of VF than A-HIV with a similar duration of infection, even after adjusting for treatment history, whereas they were not at a higher risk of immunological impairment. Exposure to viral replication among young patients living with HIV since birth or a very early age, probably because of lower adherence, could have an impact on health, raising major concerns about the selection of resistance mutations and the risk of HIV transmission. Funding: Inserm - ANRS MIE.

The COVID-19 pandemic and associated need for social isolation left in-person youth mentoring programs scrambling to keep mentees and mentors connected, and many programs turned to e-mentoring. To better understand the transition period and to inform e-mentoring practice in a post-COVID world, this study explored the experience of mentoring programs shifting to e-mentoring during the first year of the pandemic. Seven remote focus group discussions were conducted with twenty-three staff members from twenty U.S. youth mentoring organizations that used the iCouldBe e-mentoring platform during Spring/summer 2020 or Fall/Winter 2020–2021. Thematic content analysis was used to uncover insights from the data. E-mentoring was successful overall for keeping mentees and mentors in touch, especially for matches with a strong connection before the pandemic. Zoom and text messaging were the most used virtual communication methods. Programs faced many challenges but also experienced unexpected positives, including a strong interest in future e-mentoring implementation. Participants recommended that programs interested in e-mentoring start small and with intention; they also requested a central website with e-mentoring support and ways to connect with other programs and mentors. Although the literature on e-mentoring remains limited, this study contributes a picture of e-mentoring success even during a global crisis.

Purpose: To review the evidence for imaging modalities in assessing the vascular component of diabetic retinal disease (DRD), to inform updates to the DRD staging system. Design: Standardized narrative review of the literature by an international expert workgroup, as part of the DRD Staging System Update Effort, a project of the Mary Tyler Moore Vision Initiative. Overall, there were 6 workgroups: Vascular Retina, Neural Retina, Systemic Health, Basic and Cellular Mechanisms, Visual Function, and Quality of Life. Participants: The Vascular Retina workgroup, including 16 participants from 4 countries. Methods: Literature review was conducted using standardized evidence grids for 5 modalities: standard color fundus photography (CFP), widefield color photography (WFCP), standard fluorescein angiography (FA), widefield FA (WFFA), and OCT angiography (OCTA). Summary levels of evidence were determined on a validated scale from I (highest) to V (lowest). Five virtual workshops were held for discussion and consensus. Main Outcome Measures: Level of evidence for each modality. Results: Levels of evidence for standard CFP, WFCP, standard FA, WFFA, and OCTA were I, II, I, I, and II respectively. Traditional vascular lesions on standard CFP should continue to be included in an updated staging system, but more studies are required before they can be used in posttreatment eyes. Widefield color photographs can be used for severity grading within the area covered by standard CFPs, although these gradings may not be directly interchangeable with each other. Evaluation of the peripheral retina on WFCP can be considered, but the method of grading needs to be clarified and validated. Standard FA and WFFA provide independent prognostic value, but the need for dye administration should be considered. OCT angiography has significant potential for inclusion in the DRD staging system, but various barriers need to be addressed first. Conclusions: This study provides evidence-based recommendations on the utility of various imaging modalities for assessment of the vascular component of DRD, which can inform future updates to the DRD staging system. Although new imaging modalities offer a wealth of information, there are still major gaps and unmet research needs that need to be addressed before this potential can be realized. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Summary: Precise regulation of Type I interferon signaling is crucial for combating infection and cancer while avoiding autoimmunity. Type I interferon signaling is negatively regulated by USP18. USP18 cleaves ISG15, an interferon-induced ubiquitin-like modification, via its canonical catalytic function, and inhibits Type I interferon receptor activity through its scaffold role. USP18 loss-of-function dramatically impacts immune regulation, pathogen susceptibility, and tumor growth. However, prior studies have reached conflicting conclusions regarding the relative importance of catalytic versus scaffold function. Here, we develop biochemical and cellular methods to systematically define the physiological role of USP18. By comparing a patient-derived mutation impairing scaffold function (I60N) to a mutation disrupting catalytic activity (C64S), we demonstrate that scaffold function is critical for cancer cell vulnerability to Type I interferon. Surprisingly, we discovered that human USP18 exhibits minimal catalytic activity, in stark contrast to mouse USP18. These findings resolve human USP18's mechanism-of-action and enable USP18-targeted therapeutics.

The 2023 report represents a full decade of published annual reports of the American Joint Replacement Registry (AJRR). The number of cases being captured continues to rapidly grow, as are over 3.2 million patients included in AJRR. Matched-pair primary and revision data is more robust with 10-year survivorship being available. Similarly, implant-specific survivorship has been included for common implants being used in the United States. The data mined from the AJRR have led to numerous publications and presentations. Numerous trends have emerged, and others have been reinforced with the most recent data. The authors encourage readers to more thoroughly review the full report at the following link: https://www.aaos.org/registries/publications/ajrr-annual-report/.

Summary: The evolution of gene expression programs underlying the development of vertebrates remains poorly characterized. Here, we present a comprehensive proteome atlas of the model chordate Ciona, covering eight developmental stages and ∼7,000 translated genes, accompanied by a multi-omics analysis of co-evolution with the vertebrate Xenopus. Quantitative proteome comparisons argue against the widely held hourglass model, based solely on transcriptomic profiles, whereby peak conservation is observed during mid-developmental stages. Our analysis reveals maximal divergence at these stages, particularly gastrulation and neurulation. Together, our work provides a valuable resource for evaluating conservation and divergence of multi-omics profiles underlying the diversification of vertebrates.

Background: Seasonal patterns in measured exposure biomarkers can cause measurement error in epidemiological studies. There is little research about the seasonality of metals and trace elements when assessed in toenail samples. Adjusting for such patterns in models for estimating associations between long-term exposures and health outcomes can potentially improve precision and reduce bias. Objectives: Assess and describe seasonal patterns in toenail measurements of trace elements. Methods: The Sister Study enrolled women residing in the US, including Puerto Rico, whose sister had been diagnosed with breast cancer. At the time of enrollment, participants removed nail polish and collected their toenail clippings, which were cleaned before analysis. We considered the following elements: iron, vanadium, aluminum, chromium, manganese, cobalt, nickel, copper, zinc, arsenic, selenium, molybdenum, cadmium, tin, antimony, mercury, and lead. For two subsamples of the cohort, we fit trigonometric regression models with toenail element measures as the outcome, using sine and cosine functions of the collection day (transformed to an angle) to capture seasonal patterns. These models can estimate the amplitude and timing of the peaks in measures. We evaluated the evidence for a seasonal effect by comparing for each measured element the trigonometric model to a model that was constant across time. Results: There was a seasonal trend in toenail element concentration for iron, aluminum, vanadium, chromium, manganese, cobalt, arsenic, molybdenum, cadmium, tin, and lead, all of which peaked near mid-August. Seasonal patterns were concordant across two non-overlapping samples of women, analyzed in different labs. Discussion: Given the evidence supporting seasonal patterns for 11 of the 17 elements measured in toenails, correcting for seasonality of toenail levels of those trace elements in models estimating the association between those exposures and health outcomes is important. The basis for higher concentrations in toenails collected during the summer remains unknown.

Objective: The impact of previous aortic root replacement (True-Redo) versus any previous operation (Any-Redo) on outcomes after reoperative aortic root replacement (redo-ROOT) is largely unknown. In this first multi-institutional study, the clinical impact True-Redo versus Any-Redo in the setting of redo-ROOT was reviewed. Methods: From 2004 to 2021, 822 patients underwent redo-ROOT at 2 major academic centers: 638 Any-Redo and 184 True-Redo. Matching based on preoperative demographics and concomitant operations resulted in 174 matched pairs. An independent risk factor analysis was performed to determine risk factors for early and late mortality. Results: Patients in the True-Redo group were younger, at 49.9 ± 15.1 versus 55.3 ± 14.7 years, P .05. Median cardiopulmonary bypass time (P

Objectives: Interpreting real-time reverse transcription-polymerase chain reaction (rRT-PCR) results for human avian influenza A virus (AIV) detection in contaminated settings like live bird markets (LBMs) without serology or viral culture poses a challenge. Methods: During February-March 2012 and November 2012-February 2013, we screened workers at nine LBMs in Dhaka, Bangladesh, to confirm molecular detections of AIV RNA in respiratory specimens with serology. We tested nasopharyngeal (NP) and throat swabs from workers with influenza-like illness (ILI) and NP, throat, and arm swabs from asymptomatic workers for influenza virus by rRT-PCR and sera for seroconversion and antibodies against HPAI A(H5N1) and A(H9N2) viruses. Results: Among 1273 ILI cases, 34 (2.6%) had A(H5), 56 (4%) had A(H9), and six (0.4%) had both A(H5) and A(H9) detected by rRT-PCR. Of 192 asymptomatic workers, A(H5) was detected in eight (4%) NP and 38 (20%) arm swabs. Of 28 ILI cases with A(H5) or A(H9) detected, none had evidence of seroconversion, but one (3.5%) and 12 (43%) were seropositive for A(H5) and A(H9), respectively. Conclusion: Detection of AIV RNA in respiratory specimens from symptomatic and asymptomatic LBM workers without evidence of seroconversion or virus isolation suggests environmental contamination, emphasizing caution in interpreting rRT-PCR results in high viral load settings.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Given the tubal origin of high-grade serous ovarian cancer (HGSC), we sought to investigate intrauterine lavage (IUL) as a novel method of biomarker detection. IUL and serum samples were collected from patients with HGSC or benign pathology. Although CA-125 and HE4 concentrations were significantly higher in IUL samples compared to serum, they were similar between IUL samples from patients with HGSC vs benign conditions. In contrast, CA-125 and HE4 serum concentrations differed between HGSC and benign pathology (P =.002 for both). IUL and tumor samples from patients with HGSC were subjected to targeted panel sequencing and droplet digital PCR (ddPCR). Tumor mutations were found in 75 % of matched IUL samples. Serum CA-125 and HE4 biomarker levels allowed for better differentiation of HGSC and benign pathology compared to IUL samples. We believe using IUL for early detection of HGSC requires optimization, and current strategies should focus on prevention until early detection strategies improve.

Purpose: To analyze epidemiology, mechanisms, and diagnoses of upper extremity volleyball injuries in youth who present to United States emergency departments. Methods: Data from the National Electronic Injury Surveillance System were analyzed for upper extremity volleyball injuries in patients ≤18 years old from January 1, 2012, to December 31, 2022. Data were collected for body part, diagnosis, mechanism of injury, and disposition. Weighted national estimates were calculated using the hospitals’ corresponding statistical sample weights. Linear regressions were used to analyze annual trends. χ2 tests were used to analyze categorical variables. Results: A weighted national estimate of 131,624 upper extremity volleyball-related injuries occurred in the study period. Average age was 13.9 ± 2.3 years. Female patients constituted 77.6% of patients; 99.3% of patients did not require admission. The most common body parts injured were fingers (43.0%), wrists (22.8%), and shoulders (12.2%). The most common identifiable mechanisms of injury were impacts with the floor (19.4%), impacts with the ball (14.7%), and spikes/serves (5.7%). Most common diagnoses were strains/sprains (42.6%) and fractures (19.5%). Most common locations of fracture were fingers (57.4% of all fractures), wrists (16.6%), and lower arms (12.4%). There was a decrease of 544 overall injuries per year (P = .03, 95% confidence interval [CI] –1031 to –58). Female players experienced more contusions/abrasions (16.0% vs 9.9%, P < .001) and strains/sprains (46.1% vs 30.4%, P < .001) compared with male players. Female patients had decreases of 513 overall injuries (P = .01, 95% CI –881 to –144), 349 strains/sprains (P = .002, 95% CI –530 to –168), 102 contusions/abrasions (P = .008, 95% CI 170 to –34), and 92 fractures per year (P = .03, 95% CI –175 to –10). Conclusions: Youth volleyball players are at risk of upper extremity injury, particularly involving the fingers, wrist, and shoulder. Despite increasing national participation in youth volleyball, there is a decreasing incidence of upper extremity injuries. Level of Evidence: Level IV, prognostic case series.

To use public transit, riders must complete first and last mile trip segments. However, transportation planning measures of access to opportunity often assume that transit riders can complete first and last mile trips with ease. This paper contributes to the understanding of how disabled transit riders experience the first and last mile of public transit trips. Using a mobility justice framework, interviews with disabled transit riders reveal accessibility challenges along the first and last mile in Austin, TX and Seattle, WA. Participants in both Austin and Seattle faced myriad accessibility challenges along the first and last mile, indicating that transit network size and local politics did not influence travel experiences. Findings indicate disproportionate and intersectional barriers to accessing public transit in both cities, especially among female transit riders. I find that gender, social conditions, built environment quality, connectivity, and public engagement experiences influence access to transit for disabled people along the first and last mile. This work reveals how planners can better engage with disabled transit riders about their experiences and incorporate mobility justice goals to improve first and last mile accessibility.

Summary: The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis.

Substance use disorders (SUDs) have an enormous impact on public health. With classic psychedelic-assisted therapies showing initial promise in treating multiple SUDs, it is possible that these treatments will become legally available options for patients with SUDs in the future. This article highlights how classic psychedelic-assisted therapies might be integrated into current clinical practice. We first describe contemporary evidence-based treatments for SUDs and highlight how classic psychedelic-assisted therapies might fit within each treatment. We suggest that classic psychedelic-assisted therapies can be integrated into most mainstream evidence-based SUD treatments that are currently used in clinical settings, indicating broad compatibility of classic psychedelics with contemporary SUD treatment paradigms.

Background: Epithelial-to-mesenchymal transition (EMT) is a developmental program that consists of the loss of epithelial features concomitant with the acquisition of mesenchymal features. Activation of EMT in cancer facilitates the acquisition of aggressive traits and cancer invasion. EMT plasticity (EMP), the dynamic transition between multiple hybrid states in which cancer cells display both epithelial and mesenchymal markers, confers survival advantages for cancer cells in constantly changing environments during metastasis. Methods: RNAseq analysis was performed to assess genome-wide transcriptional changes in cancer cells depleted for histone regulators FLASH, NPAT, and SLBP. Quantitative PCR and Western blot were used for the detection of mRNA and protein levels. Computational analysis was performed on distinct sets of genes to determine the epithelial and mesenchymal score in cancer cells and to correlate FLASH expression with EMT markers in the CCLE collection. Results: We demonstrate that loss of FLASH in cancer cells gives rise to a hybrid E/M phenotype with high epithelial scores even in the presence of TGFβ, as determined by computational methods using expression of predetermined sets of epithelial and mesenchymal genes. Multiple genes involved in cell-cell junction formation are similarly specifically upregulated in FLASH-depleted cells, suggesting that FLASH acts as a repressor of the epithelial phenotype. Further, FLASH expression in cancer lines is inversely correlated with the epithelial score. Nonetheless, subsets of mesenchymal markers were distinctly up-regulated in FLASH, NPAT, or SLBP-depleted cells. Conclusions: The ZEB1low/SNAILhigh/E-cadherinhigh phenotype described in FLASH-depleted cancer cells is driving a hybrid E/M phenotype in which epithelial and mesenchymal markers coexist.

Summary: Pathogenic or likely pathogenic (P/LP) germline TP53 variants are the primary cause of Li-Fraumeni syndrome (LFS), a hereditary cancer predisposition disorder characterized by early-onset cancers. The population prevalence of P/LP germline TP53 variants is estimated to be approximately one in every 3,500 to 20,000 individuals. However, these estimates are likely impacted by ascertainment biases and lack of clinical and genetic data to account for potential confounding factors, such as clonal hematopoiesis. Genome-first approaches of cohorts linked to phenotype data can further refine these estimates by identifying individuals with variants of interest and then assessing their phenotypes. This study evaluated P/LP germline (variant allele fraction ≥30%) TP53 variants in three cohorts: UK Biobank (UKB, n = 200,590), Geisinger (n = 170,503), and Penn Medicine Biobank (PMBB, n = 43,731). A total of 109 individuals were identified with P/LP germline TP53 variants across the three databases. The TP53 p.R181H variant was the most frequently identified (9 of 109 individuals, 8%). A total of 110 cancers, including 47 hematologic cancers (47 of 110, 43%), were reported in 71 individuals. The prevalence of P/LP germline TP53 variants was conservatively estimated as 1:10,439 in UKB, 1:3,790 in Geisinger, and 1:2,983 in PMBB. These estimates were calculated after excluding related individuals and accounting for the potential impact of clonal hematopoiesis by excluding heterozygotes who ever developed a hematologic cancer. These varying estimates likely reflect intrinsic selection biases of each database, such as healthcare or population-based contexts. Prospective studies of diverse, young cohorts are required to better understand the population prevalence of germline TP53 variants and their associated cancer penetrance.

Background: Artificial intelligence (AI) aims to simulate human intelligence using automated computer algorithms. There has been a rapid increase in research applying AI to various subspecialties of orthopedic surgery, including shoulder surgery. The purpose of this review is to assess the scope and validity of current clinical AI applications in shoulder surgery literature. Methods: A systematic literature review was conducted using PubMed for all articles published between January 1, 2010 and June 10, 2022. The search query used the terms as follows: (artificial intelligence OR machine learning OR deep learning) AND (shoulder OR shoulder surgery OR rotator cuff). All studies that examined AI application models in shoulder surgery were included and evaluated for model performance and validation (internal, external, or both). Results: A total of 45 studies were included in the final analysis. Eighteen studies involved shoulder arthroplasty, 13 rotator cuff, and 14 other areas. Studies applying AI to shoulder surgery primarily involved (1) automated imaging analysis including identifying rotator cuff tears and shoulder implants (2) risk prediction analyses including perioperative complications, functional outcomes, and patient satisfaction. Highest model performance area under the curve ranged from 0.681 (poor) to 1.00 (perfect). Only 2 studies reported external validation. Conclusion: Applications of AI in the field of shoulder surgery are expanding rapidly and offer patient-specific risk stratification for shared decision-making and process automation for resource preservation. However, model performance is modest and external validation remains to be demonstrated, suggesting increased scientific rigor is warranted prior to deploying AI-based clinical applications.

Bone mineral density (BMD), which is used to assess bone health, is often diminished in chronic disease states, such as diabetes, which increases the risk of bone fracture. The circulating vitamin C and 25-hydroxy-vitamin D levels are commonly lower in diabetic patients. Vitamin D is implicated in bone formation, while vitamin C has been shown to inhibit osteoclastic activity. Vascular cell adhesion molecule-1 (VCAM-1) promotes osteoclastic activity and bone loss. This study investigated whether any association exists between vitamin C and vitamin D status and BMD and VCAM-1 levels in female diabetic subjects (n = 65). 25-hydroxy-vitamin D had no significant relationship with either BMD or VCAM-1 levels. However, vitamin C showed a significant positive association with BMD and a negative association with VCAM-1. This suggests that combined supplementation with vitamin D and vitamin C, rather than supplementation with vitamin D alone, could be a better strategy for the improvement of bone health and thus deserves further investigation.

The aim of this study is to investigate the influence of polymer chemistry on the properties of oral dosage forms produced using selective laser sintering (SLS). The dosage forms were printed using different grades of polyvinyl alcohol or copovidone in combination with indomethacin as the active pharmaceutical ingredient. The properties of the printed structures were assessed according to European Pharmacopoeia guidelines at different printing temperatures and laser scanning speeds in order to determine the suitable printing parameters.The results of the study indicate that the chemical properties of the polymers, such as dynamic viscosity, degree of hydrolyzation, and molecular weight, have significant impact on drug release and kinetics. Drug release rate and supersaturation can be modulated by selecting the appropriate polymer type. Furthermore, the physical properties of the dosage forms printed under the same settings are influenced by the selected polymer type, which determines the ideal manufacturing settings.This study demonstrates how the chemical properties of the polymer can determine the appropriate choice of manufacturing settings and the final properties of oral dosage forms produced using SLS.

Objective: Detection of diabetic retinopathy (DR) outside of specialized eye care settings is an important means of access to vision-preserving health maintenance. Remote interpretation of fundus photographs acquired in a primary care or other nonophthalmic setting in a store-and-forward manner is a predominant paradigm of teleophthalmology screening programs. Artificial intelligence (AI)-based image interpretation offers an alternative means of DR detection. IDx-DR (Digital Diagnostics Inc) is a Food and Drug Administration-authorized autonomous testing device for DR. We evaluated the diagnostic performance of IDx-DR compared with human-based teleophthalmology over 2 and a half years. Additionally, we evaluated an AI-human hybrid workflow that combines AI-system evaluation with human expert-based assessment for referable cases. Design: Prospective cohort study and retrospective analysis. Participants: Diabetic patients ≥ 18 years old without a prior DR diagnosis or DR examination in the past year presenting for routine DR screening in a primary care clinic. Methods: Macula-centered and optic nerve-centered fundus photographs were evaluated by an AI algorithm followed by consensus-based overreading by retina specialists at the Stanford Ophthalmic Reading Center. Detection of more-than-mild diabetic retinopathy (MTMDR) was compared with in-person examination by a retina specialist. Main Outcome Measures: Sensitivity, specificity, accuracy, positive predictive value, and gradability achieved by the AI algorithm and retina specialists. Results: The AI algorithm had higher sensitivity (95.5% sensitivity; 95% confidence interval [CI], 86.7%–100%) but lower specificity (60.3% specificity; 95% CI, 47.7%–72.9%) for detection of MTMDR compared with remote image interpretation by retina specialists (69.5% sensitivity; 95% CI, 50.7%–88.3%; 96.9% specificity; 95% CI, 93.5%–100%). Gradability of encounters was also lower for the AI algorithm (62.5%) compared with retina specialists (93.1%). A 2-step AI-human hybrid workflow in which the AI algorithm initially rendered an assessment followed by overread by a retina specialist of MTMDR-positive encounters resulted in a sensitivity of 95.5% (95% CI, 86.7%–100%) and a specificity of 98.2% (95% CI, 94.6%–100%). Similarly, a 2-step overread by retina specialists of AI-ungradable encounters improved gradability from 63.5% to 95.6% of encounters. Conclusions: Implementation of an AI-human hybrid teleophthalmology workflow may both decrease reliance on human specialist effort and improve diagnostic accuracy. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Many popular tourist attractions and trekking routes in Bhutan and Nepal are situated between 3000 and 6000 m in elevation. High-altitude emergencies are becoming more common and medical providers must be aware of the practical and medical issues in managing these disorders. We reflect on the challenges in providing high-altitude emergency medical services in Bhutan and Nepal.

Background: Noise has been reported to occur with relatively high frequency after conventional total knee arthroplasty (C-TKA), and this may impact the incidence of patient satisfaction and function. The purpose of this study was to compare the rate of patient-reported prosthetic noise generation after robotically-assisted TKA (RA-TKA) and C-TKA. Methods: A retrospective study was conducted of unilateral primary RA-TKAs and C-TKAs performed between 2018 and 2021. Patients completed a survey consisting of 4 Likert scale questions related to prosthetic noise generation and Knee Injury and Osteoarthritis Score Joint Replacement and Forgotten Joint Score were assessed prospectively preoperatively and at a minimum of 1-year of clinical follow-up. Statistical analysis was done utilizing T-tests and chi-square tests, with statistical significance defined as a P-value < .05. Results: One hundred sixty-two RA-TKAs and 320 C-TKAs with similar baseline characteristics and functions were included. There were no significant differences in hearing or feeling grinding, popping, clicking, or clunking (40.7% vs 38.1%; P = .647) between groups. Most RA-TKAs and C-TKAs were not dissatisfied regarding noise generation (70.4% vs 73.1%; P = .596). In both cohorts, patients who reported noise generation had lower average Forgotten Joint Scores (45.5 vs 66.1; P < .001) and lower postoperative Knee Injury and Osteoarthritis Score Joint Replacement scores (72.0 vs 81.4; P < .001) than those who did not experience noise generation. Conclusions: While RA-TKA may facilitate soft tissue balancing, there were no differences in prosthetic noise generation between RA-TKA and C-TKA. However, those who experience implant-generated noise have lower functional outcome scores.

Tuberculosis (TB) is a leading cause of infectious death worldwide, with nearly 2 billion currently infected globally. While the largest burden of active TB resides in low to middle-income countries, the US contributes to the global epidemic and can play a significant role in interrupting the spread of TB by recognizing and treating latent TB infection (LTBI). The vast majority of active TB in the US originates from the reactivation of LTBI.This cross-sectional study examines the prevalence of LTBI in a general medicine practice and explores the efficacy of a primary care nurse-run electronic directly observed therapy (eDOT) treatment program. 1221 patients were screened for the presence of historical risk factors for LTBI. Of those screened, 192 were offered QuantiFERON-TB Gold Plus (QFT-Plus) testing and a CXR if indicated, resulting in 35 being offered treatment for LTBI. After an initial provider visit to decide on the treatment regimen, patients received weekly nurse calls to verify adherence, assess for side effects and answer additional patient questions. Provider follow-up appointments occurred at the midpoint and completion of treatment.33 (94%) of patients with LTBI completed treatment. Patients found the nurse calls very helpful to reassure them about their treatment and to address treatment concerns.Primary care providers are particularly well-positioned to identify and treat LTBI. Screening is simple and treatment is generally well tolerated. Utilization of a nurse-run eDOT) program can be quite helpful in facilitating adherence and treatment completion.

Background: Most metastatic recurrences of triple negative breast cancer (TNBC) occur within five years of diagnosis, yet late relapses of TNBC (lrTNBC) do occur. Our objective was to develop a risk prediction model of lrTNBC using readily available clinicopathologic and sociodemographic features. Methods: We included patients diagnosed with stage I–III TNBC between 1998 and 2012 at ten academic cancer centers. lrTNBC was defined as relapse or mortality greater than 5 years from diagnosis. Features associated with lrTNBC were included in a multivariable logistic model using backward elimination with a p

Thallium is a heavy metal that is known to induce a broad spectrum of adverse health effects in humans including alopecia, neurotoxicity, and mortality following high dose acute poisoning events. Widespread human exposure to thallium may occur via consumption of contaminated drinking water; limited toxicity data are available to evaluate the corresponding public health risk. To address this data gap, the Division of Translational Toxicology conducted short-term toxicity studies of a monovalent thallium salt, thallium (I) sulfate. Thallium (I) sulfate was administered via dosed drinking water to time-mated Sprague Dawley (Hsd:Sprague Dawley® SD®) rats (F0 dams) and their offspring (F1) from gestation day (GD) 6 until up to postnatal day (PND) 28 at concentrations of 0, 3.13, 6.25, 12.5, 25, or 50 mg/L, and adult male and female B6C3F1/N mice for up to 2 weeks at concentrations of 0, 6.25, 12.5, 25, 50, or 100 mg/L. Rat dams in the 50 mg/L exposure group were removed during gestation, and dams and offspring in the 25 mg/L exposure group were removed on or before PND 0 due to overt toxicity. Exposure to thallium (I) sulfate at concentrations ≤ 12.5 mg/L did not impact F0 dam body weights, maintenance of pregnancy, littering parameters, or F1 survival (PND 4–28). However, in F1 pups, exposure to 12.5 mg/L thallium (I) sulfate resulted in decreased body weight gains relative to control rats and onset of whole-body alopecia. Measurement of thallium concentrations in dam plasma, amniotic fluid, fetuses (GD 18), and pup plasma (PND 4) indicated marked maternal transfer of thallium to offspring during gestation and lactation. Mice exposed to 100 mg/L thallium (I) sulfate were removed early due to overt toxicity, and mice exposed to ≥ 25 mg/L exhibited exposure concentration-related decreases in body weight. Lowest-observed-effect levels of 12.5 mg/L (rats) and 25 mg/L (mice) were determined based on the increased incidence of clinical signs of alopecia in F1 rat pups and significantly decreased body weights for both rats and mice.