Primary Intraosseous Spindle Cell Rhabdomyosarcoma: A Case Report in an Unusual Location.

Spindle cell/sclerosing rhabdomyosarcoma is an infrequent subtype of rhabdomyosarcoma according to the World Health Organization Classification of Soft Tissue and Bone Tumours, which includes a novel category of intraosseous spindle-cell rhabdomyosarcomas (ISCRMS) with EWSR1:: or FUS::TFCP2 fusions. We report a case of ISCRMS with EWSR1::TFCP2 fusion presenting in the femur mimicking osteosarcoma in this unusual primary location. We present an 18-year-old male with relapsed widely metastatic sarcoma, morphologically identical to osteosarcoma responding poorly to chemotherapy, initially presenting in the distal femur. Sections showed a high-grade malignant neoplasm with sheets of epithelioid and spindled cells without obvious rhabdomyoblastic differentiation morphologically containing focal areas resembling new bone/osteoid formation. Molecular sequencing identified t(12;22) EWSR1::TFCP2. The tumor cells were diffusely positive for pancytokeratin, MyoD1, and ALK by retrospective immunohistochemistry. Desmin and SATB2 were focally positive. Myogenin was negative, and INI-1 expression was retained. ISCRMS commonly involves craniofacial and pelvic bones, but rarely originates in long bones, as in this case. Initially, osteosarcoma was the primary diagnostic consideration based on distal long bone location, patient age, and evidence of osteoid formation. Distinction between the two entities may be nearly impossible on morphologic grounds alone, which presents a diagnostic pitfall without molecular or extensive immunoprofiling data.

The birth of pediatric urology in the United States: From pioneers to subcertification.

INTRODUCTION: Pediatric urology is a subspecialty of urology that emerged from a culture in which children with urological disorders were cared for by general urologists and general pediatric surgeons. The development of pediatric urology as a subspecialty was years in the making, highlighted by individuals who recognized that children with urological conditions were not just "small adults," but required special experience and training. Subspecialization was initiated by persistent visionaries who recognized the need for a trained cadre of experts to provide better care for children. It took the coordinated effort of all subgroups and leaderships in pediatric urology to push these efforts over the goal line. The focus of this review is to highlight certain individuals who played major roles in this vision and to document the efforts of many to coordinate the pathways to sub-specialization. METHODS: The careers of Meredith F. Campbell and Frank B. Bicknell were researched to identify their rationale and roles in developing pediatric urology as a distinct medical specialty in the United States. In addition, the minutes of the meetings of the Pediatric Urology Advisory Council (PUAC) with the American Board of Urology (ABU) were reviewed. The origins of the Society for Pediatric Urology (SPU) and the American Academy of Pediatrics Section of Urology (AAP-SOU) were researched. The contributions of each to the certification of pediatric urology as a distinct subspecialty was delineated. RESULTS: Campbell was Chair of Urology at the New York University (NYU) School of Medicine and wrote prolifically about pediatric urology. He published one of the first practical textbooks in pediatric urology, almost completely self-written, in 1937. Bicknell, a general urologist in Michigan on the faculty at Wayne State University School of Medicine, led the initiative to create the Society for Pediatric Urology (SPU) that first met at the 1951 annual American Urological Association (AUA) meeting in Chicago and included nine attendees. Subsequently, John Lattimer (College of Physicians and Surgeons at Columbia University) organized a well-attended meeting of urologists interested in pediatrics at the 1964 annual AAP meeting in New York City. This led to the formation of the AAP Section on Urology. Integral to the justification for the development of a subspecialty was evidence of a published corpus of content. In addition to published textbooks devoted exclusively to pediatric urology, this was further fulfilled by the AAP Section on Urology Pediatric Supplement to the Journal of Urology, first published in 1986, and later with the Journal of Pediatric Urology in 2005. The SPU and the AAP Section on Urology came together to form the Pediatric Urology Advisory Council (PUAC) in 2000, which worked with the ABU to create subspecialty certification in pediatric urology with an independent exam, first administered in 2008 to 176 applicants. CONCLUSION: The metaphor "We have stood on the shoulders of giants" is apt for pediatric urology: Meredith Campbell, Frank Bicknell, David Innes Williams (Hospital for Sick Children, London), and J. Herbert Johnston (Alder Hay Hospital, Liverpool) come to mind among the first generation of pediatric urology pioneers, and others among their colleagues also had significant impact. Clearly this is a story of persistence and attention to detail on the part of those giants and those who followed. Pediatric urology became a distinct discipline after the SPU and AAP-SOU came together to create a robust cohort of pediatric urologists who through education and negotiation were able to help the ABU and the American Board of Medical Specialties (ABMS) recognize that subspecialization would lead to better care for children with urologic disorders. This benchmark set a high bar for future subspecialization in urology and other fields.

The economic case for scaling up health research and development: Lessons from the COVID-19 pandemic.

In response to the COVID-19 pandemic, governments directly funded vaccine research and development (R&D), quickly leading to multiple effective vaccines and resulting in enormous health and economic benefits to society. We develop a simple economic model showing this feat could potentially be repeated for other health challenges. Based on inputs from the economic and medical literatures, the model yields estimates of optimal R&D spending on treatments and vaccines for known diseases. Taking a global and societal perspective, we estimate the social benefits of such spending and a corresponding rate of return. Applications to Streptococcus A vaccines and Alzheimer's disease treatments demonstrate the potential of enhanced research and development funding to unlock massive global health and health-related benefits. We estimate that these benefits range from 2 to 60 trillion (2020 US$) and that the corresponding rates of return on R&D spending range from 12% to 23% per year for 30 y. We discuss the current shortfall in R&D spending and public policies that can move current funding closer to the optimal level.

Return to athletics after total knee arthroplasty: a survey study of 784 recreational athletes across 12 sports.

BACKGROUND: Postoperative return to recreational activity is a common concern among the increasingly active total knee arthroplasty (TKA) patient population, though there is a paucity of research characterizing sport-specific return and function. This study aimed to assess participation level, postoperative return to activity, sport function, and limitations for recreational athletes undergoing TKA. METHODS: A survey of recreational sports participation among primary, elective TKA patients from a single academic center between June 2011 and January 2022 was conducted. Of the 10,777 surveys administered, responses were received from 1,063 (9.9%) patients, among whom 784 indicated being active in cycling (273 [34.8%]), running (33 [4.2%]), jogging (68 [8.7%]), swimming (228 [29.1%]), tennis (63 [8.0%]), skiing (55 [7.0%]), or high-impact team sports (64 [8.2%]) between two years preoperatively and time of survey administration, and were included for analyses. RESULTS: Cycling (62.3% at two years preoperatively vs. 59.0% at latest follow-up) and swimming (62.7% at two years preoperatively vs. 63.6% at latest follow-up) demonstrated the most favorable participation rate changes, while running (84.0% at two years preoperatively vs. 48.5% at latest follow-up) and skiing (72.7% at two years preoperatively vs. 45.5% at latest follow-up) demonstrated the least favorable participation rate changes. The majority of respondents were "satisfied" or "very satisfied" with their return across all sports, though dissatisfaction was highest among runners and joggers. For cycling, running, jogging, and swimming, respondents most commonly reported no change in speed or distance capacity, though among these cyclists reported the highest rates of improved speed and distance. The majority of returning skiers reported improved balance, form, and ability to put on skis. CONCLUSION: Return to sport is feasible following TKA with high satisfaction. Swimming and cycling represent manageable postoperative activities with high return-rates, while runners and joggers face increased difficulty returning to equal or better activity levels. Patients should receive individualized, sports-specific counseling regarding their expected postoperative course based on their goals of treatment.

Very Broadly Effective Hemagglutinin-Directed Influenza Vaccines with Anti-Herpetic Activity.

A universal vaccine that generally prevents influenza virus infection and/or illness remains elusive. We have been exploring a novel approach to vaccination involving replication-competent controlled herpesviruses (RCCVs) that can be deliberately activated to replicate efficiently but only transiently in an administration site in the skin of a subject. The RCCVs are derived from a virulent wild-type herpesvirus strain that has been engineered to contain a heat shock promoter-based gene switch that controls the expression of, typically, two replication-essential viral genes. Additional safety against inadvertent replication is provided by an appropriate secondary mechanism. Our first-generation RCCVs can be activated at the administration site by a mild local heat treatment in the presence of an antiprogestin. Here, we report that epidermal vaccination with such RCCVs expressing a hemagglutinin or neuraminidase of an H1N1 influenza virus strain protected mice against lethal challenges by H1N1 virus strains representing 75 years of evolution. Moreover, immunization with an RCCV expressing a subtype H1 hemagglutinin afforded full protection against a lethal challenge by an H3N2 influenza strain, and an RCCV expressing a subtype H3 hemagglutinin protected against a lethal challenge by an H1N1 strain. Vaccinated animals continued to gain weight normally after the challenge. Protective effects were even observed in a lethal influenza B virus challenge. The RCCV-based vaccines induced robust titers of in-group, cross-group and even cross-type neutralizing antibodies. Passive immunization suggested that observed vaccine effects were at least partially antibody-mediated. In summary, RCCVs expressing a hemagglutinin induce robust and very broad cross-protective immunity against influenza.

Vaccination for healthy aging.

As the world's population grows older, vaccination is becoming a key strategy for promoting healthy aging. Despite scientific progress in adult vaccine development, obstacles such as immunosenescence and vaccine hesitancy remain. To unlock the potential of adult vaccines fully, we must enhance immunization programs, dispel misinformation, and invest in research that deepens our understanding of aging and immunity.

Superior Pain Reduction with Anteromedialization Tibial Tubercle Osteotomy Versus Non-Operative Management for Patellofemoral Osteoarthritis.

PURPOSE: The purpose of this study was to compare the clinical outcomes of patients with patellofemoral osteoar-thritis (PFOA) treated non-operatively with those treated operatively with an unloading anteromedialization tibial tubercle osteotomy (TTO). METHODS: A retrospective chart review was performed to identify patients with isolated PFOA who were either managed non-operatively or surgically with a TTO and who had a minimum follow-up of 2 years. Patients were surveyed with the visual analog scale (VAS) for pain, Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR), Anterior Knee Pain scale (Kujala), and Tegner Activity scale. Statistical analysis included two-sample t-testing, one-way ANOVA, and bivariate analysis. RESULTS: The clinical outcomes of 49 non-operatively managed patients (mean age: 52.7 ± 11.3 years; mean follow-up: 1.7 ± 1.0 years) and 35 operatively managed patients (mean age: 31.8 ± 9.4 years; mean follow-up: 3.5 ± 1.7 years) were assessed. The mean VAS improved sig-nificantly in both groups [6.12 to 4.22 (non-operative), p < 0.0001; 6.94 to 2.45 (TTO); p < 0.0001], with operatively treated patients having significantly lower postoperative pain than non-operatively managed patients at the time of final follow-up [2.45 (TTO) vs. 4.22 (non-operative), p < 0.001]. The mean KOOS-JR score was significantly greater in the operative group at time of final follow-up [78.7 ± 11.6 (TTO) vs. 71.7 ± 17.8 (non-operative), p = 0.035]. There was no significant difference in Kujala or Tegner scores between the treatment groups. Additionally, there was no sig-nificant relationship between the number of intra-articular injections, duration of NSAID use, and number of physical therapy sessions on clinical outcomes in the non-operatively treated group (p > 0.05). CONCLUSIONS: An unloading anteromedialization TTO provides significantly better pain relief and restoration of function compared to non-operative management in the treatment of symptomatic PFOA.

Arctos: Community-driven innovations for managing natural and cultural history collections.

More than tools for managing physical and digital objects, museum collection management systems (CMS) serve as platforms for structuring, integrating, and making accessible the rich data embodied by natural history collections. Here we describe Arctos, a scalable community solution for managing and publishing global biological, geological, and cultural collections data for research and education. Specific goals are to: (1) Describe the core features and implementation of Arctos for a broad audience with respect to the biodiversity informatics principles that enable high quality research; (2) Highlight the unique aspects of Arctos; (3) Illustrate Arctos as a model for supporting and enhancing the Digital Extended Specimen concept; and (4) Emphasize the role of the Arctos community for improving data discovery and enabling cross-disciplinary, integrative studies within a sustainable governance model. In addition to detailing Arctos as both a community of museum professionals and a collection database platform, we discuss how Arctos achieves its richly annotated data by creating a web of knowledge with deep connections between catalog records and derived or associated data. We also highlight the value of Arctos as an educational resource. Finally, we present the financial model of fiscal sponsorship by a nonprofit organization, implemented in 2022, to ensure the long-term success and sustainability of Arctos.

Evaluation of Preoperative Variables that Improve the Predictive Accuracy of the Risk Assessment and Prediction Tool in Primary Total Hip Arthroplasty.

INTRODUCTION: Discharge disposition after total joint arthroplasty may be predictable. Previous literature has attempted to improve upon models such as the Risk Assessment and Prediction Tool (RAPT) in an effort to optimize postoperative planning. The purpose of this study was to determine whether preoperative laboratory values and other previously unstudied demographic factors could improve the predictive accuracy of the RAPT. METHODS: All patients included had RAPT scores in addition to the following preoperative laboratory values: red blood cell count, albumin, and vitamin D. All values were recorded within 90 days of surgery. Demographic variables including marital status, American Society of Anesthesiologists (ASA) scores, body mass index, Charlson Comorbidity Index, and depression were also evaluated. Binary logistic regression was used to determine the significance of each factor in association with discharge disposition. RESULTS: Univariate logistic regression found significant associations between discharge disposition and all original RAPT factors as well as nonmarried patients (P < 0.001), ASA class 3 to 4 (P < 0.001), body mass index >30 kg/m2 (P = 0.065), red blood cell count <4 million/mm3 (P < 0.001), albumin <3.5 g/dL (P < 0.001), Charlson Comorbidity Index (P < 0.001), and a history of depression (P < 0.001). All notable univariate models were used to create a multivariate model with an overall predictive accuracy of 90.1%. CONCLUSIONS: The addition of preoperative laboratory values and additional demographic data to the RAPT may improve its PA. Orthopaedic surgeons could benefit from incorporating these values as part of their discharge planning in THA. Machine learning may be able to identify other factors to make the model even more predictive.

Strep A: challenges, opportunities, vaccine-based solutions, and economics.

This collection of articles focuses on Streptococcus pyogenes (Strep A) vaccine research and innovation, with a focus on emerging efforts to understand and estimate the full societal value of Strep A vaccination.

Health and Economic Growth: Reconciling the Micro and Macro Evidence.

Economists use micro-based and macro-based approaches to assess the macroeconomic return to population health. The macro-based approach tends to yield estimates that are either negative and close to zero or positive and an order of magnitude larger than the range of estimates derived from the micro-based approach. This presents a micro-macro puzzle regarding the macroeconomic return to health. We reconcile the two approaches by controlling for the indirect effects of health on income per capita, which macro-based approaches usually include but micro-based approaches deliberately omit when isolating the direct income effects of health. Our results show that the macroeconomic return to health lies in the range of plausible microeconomic estimates, demonstrating that both approaches are in fact consistent with one another.

RNA-Seq time-course analysis of neural precursor cell transcriptome in response to herpes simplex Virus-1 infection.

The neurogenic niches within the central nervous system serve as essential reservoirs for neural precursor cells (NPCs), playing a crucial role in neurogenesis. However, these NPCs are particularly vulnerable to infection by the herpes simplex virus 1 (HSV-1). In the present study, we investigated the changes in the transcriptome of NPCs in response to HSV-1 infection using bulk RNA-Seq, compared to those of uninfected samples, at different time points post infection and in the presence or absence of antivirals. The results showed that NPCs upon HSV-1 infection undergo a significant dysregulation of genes playing a crucial role in aspects of neurogenesis, including genes affecting NPC proliferation, migration, and differentiation. Our analysis revealed that the CREB signaling, which plays a crucial role in the regulation of neurogenesis and memory consolidation, was the most consistantly downregulated pathway, even in the presence of antivirals. Additionally, cholesterol biosynthesis was significantly downregulated in HSV-1-infected NPCs. The findings from this study, for the first time, offer insights into the intricate molecular mechanisms that underlie the neurogenesis impairment associated with HSV-1 infection.

Cost of care for Alzheimer's disease and related dementias in the United States: 2016 to 2060.

Medical and long-term care for Alzheimer's disease and related dementias (ADRDs) can impose a large economic burden on individuals and societies. We estimated the per capita cost of ADRDs care in the in the United States in 2016 and projected future aggregate care costs during 2020-2060. Based on a previously published methodology, we used U.S. Health and Retirement Survey (2010-2016) longitudinal data to estimate formal and informal care costs. In 2016, the estimated per patient cost of formal care was $28,078 (95% confidence interval [CI]: $25,893-$30,433), and informal care cost valued in terms of replacement cost and forgone wages was $36,667 ($34,025-$39,473) and $15,792 ($12,980-$18,713), respectively. Aggregate formal care cost and formal plus informal care cost using replacement cost and forgone wage methods were $196 billion (95% uncertainty range [UR]: $179-$213 billion), $450 billion ($424-$478 billion), and $305 billion ($278-$333 billion), respectively, in 2020. These were projected to increase to $1.4 trillion ($837 billion-$2.2 trillion), $3.3 trillion ($1.9-$5.1 trillion), and $2.2 trillion ($1.3-$3.5 trillion), respectively, in 2060.

Lifecycle model-based evaluation of infant 4CMenB vaccination in the UK.

OBJECTIVES: Invasive meningococcal disease, an uncommon but severe disease, imposes catastrophic health and economic burdens. Cost-utility analysis (CUA) assumes separability in lifetime health and economic variables and cannot capture the full value of preventing such burdens. We overcome these limitations with a retrospective societal perspective cost-benefit analysis (CBA) of meningococcal serogroup B vaccination (4CMenB) of one infant cohort in the United Kingdom using a health-augmented lifecycle model (HALM) incorporating health's interactions with consumption, earnings, non-market time and financial risk. METHODS: We used a static Markov model of vaccination's health impact and an HALM to estimate the private willingness to pay (PWTP) for the intrinsic and instrumental value of health under perfect capital markets, financial risk protection in the absence of insurance against permanent disability, parental spillovers, and acute phase disability. We estimated social WTP (SWTP) incorporating social severity preferences. We estimated rates of return that inform health payer reimbursement decisions, finance ministry budgeting decisions, and legislature taxation decisions. An expert Advisory Board investigated the validity of applying the HALM to infant 4CMenB. RESULTS: The PWTP for a 2 + 1 vaccination schedule is £395, comprising £166 of disability insurance value, £79 of positive parental spillover value, £28 in the value of averting acute phase disability, and £122 in residual intrinsic and instrumental value of health. SWTP is £969. CONCLUSIONS: HALM-based CBA provides an empirically richer, more utility-theoretically grounded approach to vaccine evaluation than CUA, demonstrating good value for money for legislatures (based on private values) and for all decision-makers (based on social values).

White matter and literacy: A dynamic system in flux.

Cross-sectional studies have linked differences in white matter tissue properties to reading skills. However, past studies have reported a range of, sometimes conflicting, results. Some studies suggest that white matter properties act as individual-level traits predictive of reading skill, whereas others suggest that reading skill and white matter develop as a function of an individual's educational experience. In the present study, we tested two hypotheses: a) that diffusion properties of the white matter reflect stable brain characteristics that relate to stable individual differences in reading ability or b) that white matter is a dynamic system, linked with learning over time. To answer these questions, we examined the relationship between white matter and reading in a five-year longitudinal dataset and a series of large-scale, single-observation, cross-sectional datasets (N = 14,249 total participants). We find that gains in reading skill correspond to longitudinal changes in the white matter. However, in the cross-sectional datasets, we find no evidence for the hypothesis that individual differences in white matter predict reading skill. These findings highlight the link between dynamic processes in the white matter and learning.

Trajectories and correlates of poor mental health in India over the course of the COVID-19 pandemic: a nationwide survey.

INTRODUCTION: The COVID-19 pandemic had large impacts on mental health; however, most existing evidence is focused on the initial lockdown period and high-income contexts. By assessing trajectories of mental health symptoms in India over 2 years, we aim to understand the effect of later time periods and pandemic characteristics on mental health in a lower-middle income context. METHODS: We used data from the Real-Time Insights of COVID-19 in India cohort study (N=3709). We used covariate-adjusted linear regression models with generalised estimating equations to assess associations between mental health (Patient Health Questionnaire (PHQ-4) score; range 0-12) and pandemic periods as well as pandemic characteristics (COVID-19 cases and deaths, government stringency, self-reported financial impact, COVID-19 infection in the household) and explored effect modification by age, gender and rural/urban residence. RESULTS: Mental health symptoms dropped immediately following the lockdown period but rose again during the delta and omicron waves. Associations between mental health and later pandemic stages were stronger for adults 45 years of age and older (p<0.001). PHQ-4 scores were significantly associated with all pandemic characteristics considered, including estimated COVID-19 deaths (PHQ-4 difference of 0.10 units; 95% CI 0.06 to 0.13), government stringency index (0.14 units; 95% CI 0.11 to 0.18), self-reported major financial impacts (1.20 units; 95% CI 1.09 to 1.32) and COVID-19 infection in the household (0.36 units; 95% CI 0.23 to 0.50). CONCLUSION: While the lockdown period and associated financial stress had the largest mental health impacts on Indian adults, the effects of the pandemic on mental health persisted over time, especially among middle-aged and older adults. Results highlight the importance of investments in mental health supports and services to address the consequences of cyclical waves of infections and disease burden due to COVID-19 or other emerging pandemics.

Meningococcal Disease in the Post-COVID-19 Era: A Time to Prepare.

The global invasive meningococcal disease (IMD) landscape changed considerably during the COVID-19 pandemic, as evidenced by decreased incidence rates due to COVID-19 mitigation measures, such as limited social contact, physical distancing, mask wearing, and hand washing. Vaccination rates were also lower during the pandemic relative to pre-pandemic levels. Although policymakers may have shifted their focus away from IMD vaccination programs to COVID-19 vaccination programs, strong arguments support implementation and prioritization of IMD vaccination programs; IMD cases have increased in some countries and IMD rates may even have exceeded pre-pandemic levels. Additional concerns include increased susceptibility due to vaccination coverage gaps, increased incidence of other respiratory pathogens, immunity debt from lockdown restrictions, and increased IMD epidemiologic variability. The full range of benefits of widely available and effective meningococcal vaccines needs to be considered, especially in health technology assessments, where the broad benefits of these vaccines are neither accurately quantified nor captured in implementation policy decisions. Importantly, implementation of meningococcal vaccination programs in the current IMD climate also appeals to broader healthcare principles, including preparedness rather than reactive approaches, generally accepted benefit-risk approaches to vaccination, historical precedent, and the World Health Organization's goal of defeating meningitis by 2030. Countries should therefore act swiftly to bolster existing meningococcal vaccination strategies to provide broad coverage across age groups and serogroups given the recent increases in IMD incidence.