Feasibility of Pharmacy-based Research Opportunity to Enhance Community Testing and Surveillance (PROTECTS).

BACKGROUND: Approximately 89% of the US population lives within five miles of a community pharmacy, which provides a network of geographically distributed recruitment nodes for testing and surveillance of infection and disease. OBJECTIVES: Establish feasibility of Pharmacy-based Research Opportunities To Enhance Community Testing and Surveillance (PROTECTS) in the context of SARS-CoV-2 infection in a community pharmacy setting with University of Kentucky serving as the coordinating center and research hub for sample analysis. METHODS: Two community pharmacies in Kentucky served as community-based recruitment sites to assess SARS-CoV-2 exposure through longitudinal (5 visits over 56 days) collection of nasal swabs and blood samples from subjects. RESULTS: Fifty subjects were recruited between May 2022 and December 2023 for longitudinal sample collection. Three phases of recruitment were investigated by first establishing standard operating procedures in an urban pharmacy, then expanding recruitment at a second pharmacy in a rural setting, and finally increasing recruitment at the urban pharmacy. During the first phase of recruitment, 12 participants were recruited. Of these participants, two never scheduled a visit after the initial screening. The median time for study completion from first to last visit within this phase was 59 days (IQR: 56-68 days). During the second phase of recruitment, eight of nine participants completed all five visits. The median time to complete all visits was 105 days (IQR: 98-112 days). During the ongoing third phase, 29 subjects were recruited, and 19 participants completed all required visits and the remainder continue to schedule follow-up appointments. CONCLUSION: Community pharmacies have a significant role in promoting public health. The geographic distribution of community pharmacies makes them appealing locations for recruitment of outpatient cohorts for local surveillance of infections and chronic inflammatory conditions with opportunities for broad implementation of this project for clinical trials in underserved communities.

Using the ADDIE Model of Instructional Design to Create Programming for Comprehensive ABA Treatment.

ABA research abounds with articles on increasing or decreasing a small set of behaviors. These articles fit nicely within the framework of Focused ABA Treatment in which the goal of treatment centers on only a few behaviors. However, many behavioral practitioners spend most of their time developing Comprehensive ABA Treatment in which a large number of behaviors are systematically changed across multiple developmental domains. Few resources are available to help in designing and implementing such programming. This article presents a model from the field of instructional design for the development of comprehensive programming. Applying the ADDIE model-Analyze, Design, Develop, Implement, Evaluate-the article identifies a consistent process to follow, critical actions to take, and helpful resources to use when developing comprehensive programming for individuals with autism.

Perioperative complications associated with fluoroscopy C1 lateral mass screw fixation (Goel technique) versus computed tomography-guided navigation technique: A review of 202 cases from the German Spine Registry (DWG-Register).

Background: Overview of the literature - Fractures of the C1 constitute 3%-13% of all cervical spine injuries in adults. Most isolated C1 fractures are stable and can be treated nonoperatively with external immobilization. Traditional surgical options for C1 fracture treatment are occiput-to-C2 fusion or C1 with lateral mass screws (LMSs). Purpose - The aim is to assess the management and perioperative complications of C1 fractures undergoing LMS fusion between fluoroscopy and computed tomography (CT)-guided navigation. Methods: This was a retrospective multicenter study of data from the DWG-Register of patients who underwent operative treatment for C1 traumatic fracture with LMSs from January 2017 to September 2022. Inclusion criteria - traumatic injury and age > 18 years old. Results: In total, 202 patients with traumatic C1 fracture requiring spinal surgery were identified in the registry; n = 175 (Group 1) were treated conventionally without CT-guided navigation and n = 27 were treated with CT-guided navigation (Group 2). C1-LMS was principally performed by spine surgeons n = 90 (53.4%) and n = 72 (18.5%) by neurosurgeons in both the groups. Intraoperative adverse events were as follows: dural tear in group 1 n = 0 and in group 2 n = 1, vascular injury, with one case in group 1 and no cases in group 2. General complications were: cardiovasculars in group 1 n = 6 (3.4%) and Group 2 n = 4 (14.8%) (P = 0.03), pulmonary complications in group1 n = 2 (1.1%) and n = 9 in group 2 (33.3%) (P < 0.001), stroke n = 1 (0.57%) in group1 and n = 4 in group 2 (14.8%) (P < 0.001), gastrointestinal bleeding n = 1 (0.57%) in group1 and no cases in group 2, renal insufficiency n = 2 (1.1%) in group 1 and n = 3 (11.1%) in group 2 (P = 0.01). One death was recorded in group 2 (3.7%). Conclusion: This series of 404 screws placed in 202 patients over 5 years who underwent two types of C1 fracture fixation had a considerably lower incidence of screw malposition and vertebral artery injury than has previously been reported in the literature. C1 screws can be safely placed with a low risk of vertebral artery and neurologic injury with and without CT-guided navigation support.

Advancing Primary Care Access: Exploring the Impact of the Virtual Waiting Room on the Quadruple Aim.

BACKGROUND: Community health centers grapple with high no-show rates, posing challenges to patient access and primary care provider (PCP) utilization. AIM: To address these challenges, we implemented a virtual waiting room (VWR) program in April 2023 to enhance patient access and boost PCP utilization. SETTING: Academic community health center in a small urban city in Massachusetts. PARTICIPANTS: Community health patients (n = 8706) and PCP (n = 14). PROGRAM DESCRIPTION: The VWR program, initiated in April 2023, involved nurse triage of same-day visit requests for telehealth appropriateness, then placing patients in a standby pool to fill in as a telehealth visit for no-shows or last-minute cancellations in PCP schedules. PROGRAM EVALUATION: Post-implementation, clinic utilization rates between July and September improved from 75.2% in 2022 to 81.2% in 2023 (p < 0.01). PCP feedback was universally positive. Patients experienced a mean wait time of 1.9 h, offering a timely and convenient alternative to urgent care or the ER. DISCUSSION: The VWR is aligned with the quadruple aim of improving patient experience, population health, cost-effectiveness, and PCP satisfaction through improving same-day access and improving PCP schedule utilization. This innovative and reproducible approach in outpatient offices utilizing telehealth holds the potential for enhancing timely access across various medical disciplines.

Intensity Zones and Intensity Thresholds Used to Quantify External Load in Competitive Basketball: A Systematic Review.

BACKGROUND: Despite widespread use of intensity zones to quantify external load variables in basketball research, the consistency in identifying zones and accompanying intensity thresholds using predominant monitoring approaches in training and games remains unclear. OBJECTIVES: The purpose of this work was to examine the external load intensity zones and thresholds adopted across basketball studies using video-based time-motion analysis (TMA), microsensors, and local positioning systems (LPS). METHODS: PubMed, MEDLINE, and SPORTDiscus databases were searched from inception until 31 January 2023 for studies using intensity zones to quantify external load during basketball training sessions or games. Studies were excluded if they examined players participating in recreational or wheelchair basketball, were reviews or meta-analyses, or utilized monitoring approaches other than video-based TMA, microsensors, or LPS. RESULTS: Following screening, 86 studies were included. Video-based TMA studies consistently classified jogging, running, sprinting, and jumping as intensity zones, but demonstrated considerable variation in classifying low-intensity (standing and walking) and basketball-specific activities. Microsensor studies mostly utilized a single, and rather consistent, threshold to identify only high-intensity activities (> 3.5 m·s-2 for accelerations, decelerations, and changes-in-direction or > 40 cm for jumps), not separately quantifying lower intensity zones. Similarly, LPS studies predominantly quantified only high-intensity activities in a relatively consistent manner for speed (> 18.0 m·s-1) and acceleration/deceleration zones (> 2.0 m·s-2); however, the thresholds adopted for various intensity zones differed greatly to those used in TMA and microsensor research. CONCLUSIONS: Notable inconsistencies were mostly evident for low-intensity activities, basketball-specific activities, and between the different monitoring approaches. Accordingly, we recommend further research to inform the development of consensus guidelines outlining suitable approaches when setting external load intensity zones and accompanying thresholds in research and practice.

Mechanical performance of patient-specific prefabricated temporary shell versus laboratory-fabricated CAD/CAM provisional implant-supported single-tooth restorations: A laboratory study.

OBJECTIVE: To evaluate the mechanical performance of patient-specific prefabricated temporary shell versus laboratory-fabricated CAD/CAM provisional restorations on titanium temporary abutments, with and without thermo-mechanical ageing. MATERIALS AND METHODS: Implants with a conical connection were divided into four groups (n = 24) and restored with temporary shell or laboratory-fabricated central or lateral incisor PMMA restorations that were relined or bonded on titanium temporary abutments. The diameter of the central and lateral incisor groups' implants was regular (ϕ 4.3 mm) or narrow (ϕ 3.5 mm), respectively. Half of each group's specimens were subjected to ageing, simultaneous thermocycling (5-55°C) and chewing simulation (120,000 cycles, 50 N, 1.7 Hz) resulting in eight groups in total (n = 12). The aged specimens were evaluated with optical microscopy, and survival and complication rates were determined according to modified USPHS criteria. The non-aged specimens and those that had survived ageing were loaded until failure, whereupon bending moments were calculated. RESULTS: Survival rates after ageing were 100% for all groups. Apart from wear facets (ϕ 2-3 mm) on the palatal restoration surface, no complications were observed. The mean fracture load and bending moments ranged between 597.6-847.1 N and 433.3-550.6 Ncm, respectively, with no significant differences between the eight groups (p = .25; p = .20). CONCLUSIONS: As patient-specific temporary shell central and lateral incisor provisional implant-supported restorations are mechanically stable enough to withstand clinical bite forces, even after thermo-mechanical ageing, they may serve as an alternative to laboratory-fabricated provisional restorations.

Serum Creatinine as an Independent Predictor of Moderate to Severe Fibrosis in Chinese American Non-obese Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to the obesity epidemic. However, non-obese MASLD (body mass index [BMI] < 25 kg/m2 for Asians) is not uncommon, especially among Asian American populations. Preliminary research has demonstrated sarcopenia, a muscle-wasting syndrome, to be a major risk factor for non-obese Chinese MASLD. This study examined serum creatinine (SCr), a sarcopenia biomarker, and other prominent MASLD biomarkers for their ability to predict moderate to severe fibrosis (≥7.5 kPa or ≥F2 fibrosis) in the Chinese American MASLD population. METHODS: A total of 296 Chinese American MASLD patients were categorized by BMI and fibrosis severity. As per World Health Organization guidelines for Asians, we identified obese MASLD (BMI ≥ 25 kg/m2) in 191 subjects (64.5%) and non-obese MASLD (BMI < 25 kg/m2) in 105 subjects (35.5%). Multivariate logistic regressions were performed to ascertain which biomarkers served as independent predictors of ≥F2 fibrosis. Wilcoxon signed-rank tests were conducted to compare MASLD cohorts (stratified by gender) and the healthy adult population on SCr distribution. RESULTS: The obese MASLD cohorts had higher rates of ≥F2 fibrosis and type 2 diabetes mellitus compared to their older, non-obese counterparts. For obese MASLD patients, higher age (P < 0.05), increased BMI (P < 0.01), increased AST (P < 0.05), and decreased platelets (P < 0.05) independently predicted ≥F2 fibrosis. For non-obese MASLD patients, lowered SCr (P < 0.05) levels served as the main predictor of ≥F2 fibrosis. Female MASLD patients had markedly lower SCr distributions (P < 0.001) compared to the healthy female population, with 26.8% having SCr levels below the normal range. CONCLUSIONS: In summary, SCr was the predominant predictor of moderate to severe fibrosis in non-obese Chinese American MASLD patients. The high rate of decreased SCr levels in Chinese American MASLD women suggests that this population may be at higher risk for muscle mass loss, which can lead to liver fat accumulation.

Mobility-Assisted Pseudo-MS3 Sequencing of Protein Ions.

The sequencing of intact proteins within a mass spectrometer has many benefits but is frequently limited by the fact that tandem mass spectrometry (MS/MS) techniques often generate poor sequence coverages when applied to protein ions. To overcome this limitation, exotic MS/MS techniques that rely on lasers and radical chemistry have been developed. These techniques generate high sequence coverages, but they require specialized instrumentation, create products through multiple dissociation mechanisms, and often require long acquisition times. Recently, we demonstrated that protein ions can be dissociated in a trapped ion mobility spectrometry (TIMS) device prior to mobility separation in a commercial timsTOF. All generated product ions were distributed throughout the mobility dimension, and this separation enabled deconvolution of complex tandem mass spectra and could enable facile pseudo-MS3 interrogation of generated product ions with the downstream quadrupole and collision cell. A second activation step improves sequence coverage because the most labile bonds have been depleted during the first dissociation and subsequent dissociation events are more evenly distributed throughout the product ion backbone. In this work, we explore the potential of this mobility-assisted pseudo-MS3 (MAP) method on a commercial timsTOF and timsTOF Pro 2. We demonstrate that while MAP only generates 92% of the sequence coverage of the most effective MS/MS technique, it accomplished this feat in 1.5 min and could be facilely integrated with liquid chromatographic separations.

Hepatitis C (HCV) Reinfection and Risk Factors among Clients of a Low-Threshold Primary Healthcare Service for People Who Inject Drugs in Sydney, Australia.

Hepatitis C (HCV) reinfection studies have not focused on primary healthcare services in Australia, where priority populations including people who inject drugs (PWID) typically engage in healthcare. We aimed to describe the incidence of HCV reinfection and associated risk factors in a cohort of people most at risk of reinfection in a real-world community setting. We conducted a secondary analysis of routinely collected HCV testing and treatment data from treatment episodes initiated with direct-acting antiviral (DAA) therapy between October 2015 and June 2021. The overall proportion of clients (N = 413) reinfected was 9% (N = 37), and the overall incidence rate of HCV reinfection was 9.5/100PY (95% CI: 6.3-14.3). Reinfection incidence rates varied by sub-group and were highest for Aboriginal and/or Torres Strait Islander people (20.4/100PY; 95% CI: 12.1-34.4). Among PWID (N= 321), only Aboriginality was significantly associated with reinfection (AOR: 2.73, 95% CI: 1.33-5.60, p = 0.006). High rates of HCV reinfection in populations with multiple vulnerabilities and continued drug use, especially among Aboriginal and Torres Strait Islander people, highlight the need for ongoing regular HCV testing and retreatment in order to achieve HCV elimination. A priority is resourcing testing and treatment for Aboriginal and/or Torres Strait Islander people. Our findings support the need for novel and holistic healthcare strategies for PWID and the upscaling of Indigenous cultural approaches and interventions.

Trends in HIV testing and HIV stage at diagnosis among people newly diagnosed with HIV.

OBJECTIVE: To identify groups more likely to be referred for HIV testing because of symptomatic presentation rather than as part of asymptomatic screening. DESIGN: A retrospective analysis of Australian National HIV Registry (NHR) surveillance data including sociodemographic and clinical data, as well as reasons for HIV test. METHODS: Using notification records from 2017 to 2022, we summarised reasons for testing leading to an HIV diagnosis. Reasons for testing were combined with clinical status at diagnosis to derive HIV testing categories: testing while symptomatic; asymptomatic HIV screening; seroconversion; and other test reason. We stratified these categories by stage of HIV at diagnosis with late-stage HIV defined as a CD4 count <350 cells/µL at time of diagnosis. RESULTS: Among 4,134 HIV notifications with at least one reason for testing recorded, STI screening was the predominant reason for test referral (38%), followed by HIV indicative symptoms (31%), and risk behaviour (13%). By testing category, people aged 50 years or older (24%), people with HIV attributed to heterosexual sex (21%), people born in Sub-Saharan Africa (19%), and women (17%) had lower levels of asymptomatic screening. More late-stage HIV diagnoses resulted from testing while symptomatic (58%) compared with asymptomatic screening (25%). CONCLUSIONS: Older people and heterosexuals may not access HIV focused healthcare where HIV screening is routinely offered. Instead, HIV testing opportunities may arise in other settings. By normalising HIV testing and offering low-cost HIV screening in a range of settings, it may be possible to facilitate earlier HIV diagnoses, better health outcomes, and reduced onward transmission.

The Clinical Utility of a 7-Gene Biosignature on Radiation Therapy Decision Making in Patients with Ductal Carcinoma In Situ Following Breast-Conserving Surgery: An Updated Analysis of the DCISionRT® PREDICT Study.

BACKGROUND: Breast-conserving surgery (BCS) followed by adjuvant radiotherapy (RT) is a standard treatment for ductal carcinoma in situ (DCIS). A low-risk patient subset that does not benefit from RT has not yet been clearly identified. The DCISionRT test provides a clinically validated decision score (DS), which is prognostic of 10-year in-breast recurrence rates (invasive and non-invasive) and is also predictive of RT benefit. This analysis presents final outcomes from the PREDICT prospective registry trial aiming to determine how often the DCISionRT test changes radiation treatment recommendations. METHODS: Overall, 2496 patients were enrolled from February 2018 to January 2022 at 63 academic and community practice sites and received DCISionRT as part of their care plan. Treating physicians reported their treatment recommendations pre- and post-test as well as the patient's preference. The primary endpoint was to identify the percentage of patients where testing led to a change in RT recommendation. The impact of the test on RT treatment recommendation was physician specialty, treatment settings, individual clinical/pathological features and RTOG 9804 like criteria. Multivariate logisitc regression analysis was used to estimate the odds ratio (ORs) for factors associated with the post-test RT recommendations. RESULTS: RT recommendation changed 38% of women, resulting in a 20% decrease in the overall recommendation of RT (p < 0.001). Of those women initially recommended no RT (n = 583), 31% were recommended RT post-test. The recommendation for RT post-test increased with increasing DS, from 29% to 66% to 91% for DS <2, DS 2-4, and DS >4, respectively. On multivariable analysis, DS had the strongest influence on final RT recommendation (odds ratio 22.2, 95% confidence interval 16.3-30.7), which was eightfold greater than clinicopathologic features. Furthermore, there was an overall change in the recommendation to receive RT in 42% of those patients meeting RTOG 9804-like low-risk criteria. CONCLUSIONS: The test results provided information that changes treatment recommendations both for and against RT use in large population of women with DCIS treated in a variety of clinical settings. Overall, clinicians changed their recommendations to include or omit RT for 38% of women based on the test results. Based on published clinical validations and the results from current study, DCISionRT may aid in preventing the over- and undertreatment of clinicopathological 'low-risk' and 'high-risk' DCIS patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03448926 ( https://clinicaltrials.gov/study/NCT03448926 ).

Assigning the CH stretch overtone spectrum of benzene and naphthalene with extension to anthracene and tetracene using 2- and 3-quanta anharmonic quantum chemical computations.

The CH stretch overtone region (5750-6300 cm-1) of benzene and naphthalene is assigned herein using anharmonic quantum chemical computations, and the trend of how this extends to larger polycyclic aromatic hydrocarbons (PAHs) is established. The assignment of all experimental bands to specific vibrational states is performed for the first time. Resonance polyads and the inclusion of 3-quanta vibrational states are both needed to compute accurate vibrational frequencies with the proper density-of-states to match the experimental band shape. Hundreds of 3-quanta states produce the observed band structure in naphthalene, anthracene, and tetracene, and this number is expected to increase drastically for larger PAHs. The width and shape of the main peak are consistent from naphthalene to anthracene, necessitating further exploration of this trend to confirm whether it is representative of all PAHs in the CH stretch overtone region. Understanding observations of PAH sources in the 1-3 µm region from the NIRSpec instrument aboard JWST requires new computational data, and this study provides a benchmark and foundation for their computation.

Accretion of "young" Phanerozoic subcontinental lithospheric mantle triggered by back-arc extension-the case of the Ivrea-Verbano Zone.

The subcontinental lithospheric mantle (SCLM) beneath Phanerozoic regions is mostly constituted by fertile lherzolites, which sharply contrast with cratonic mantle made of highly-depleted peridotites. The question of whether this chemical difference results from lower degrees of melting associated with the formation of Phanerozoic SCLM or from the refertilization of ancient depleted SCLM remains a subject of debate. Additionally, the timing and geodynamic environment of accretion of the fertile SCLM in many Phanerozoic regions are poorly constrained. We here document new geochemical and Nd-Hf isotopic data for orogenic lherzolite massifs from the Ivrea-Verbano Zone (IVZ), Southern Alps. Even though a few Proterozoic Re depletion ages are locally preserved in these mantle bodies, our data reveal that the IVZ lherzolitic massifs were "recently" accreted to the SCLM in the Upper Devonian (ca. 370 Ma) during Pangea amalgamation, with a petrochemical evolution characterized by low-degree (~ 5-12%) depletion and nearly contemporaneous pervasive to focused melt migration. The lithospheric accretion putatively took place through asthenospheric upwelling triggered by Variscan intra-continental extension in a back-arc setting related to the subduction of the Rheic Ocean. We thus conclude that the fertile sections of Phanerozoic SCLM can be accreted during "recent" events of back-arc continental extension, even where Os isotopes preserve memories of melting events in much older times.

Informed, but uncertain: managing transmission risk and isolation in the 2022 mpox outbreak among gay and bisexual men in Australia.

In 2022, a global outbreak of mpox (formerly 'monkeypox') emerged in non-endemic countries, including Australia, predominantly affecting gay, bisexual and other men who have sex with men. Public health advice on transmission and isolation emerged rapidly from different sources, sometimes conflicting and producing uncertainty. Using the concept of 'counterpublic health', which acknowledges the incorporation of official science and experiences of affected communities into embodied practice, this paper investigates how people affected by mpox in Australia managed risk of transmission and navigated self-isolation. In-depth interviews were conducted with 16 people: 13 people diagnosed with mpox and three close contacts. All participants were cisgender gay and bisexual men living in Australia. Participants thought critically about public health advice, often finding it restrictive and unresponsive to the needs of people with mpox. Participants' decisions about reducing mpox risk and isolating often drew on experiences with other infections (i.e. HIV; COVID-19) and were made collaboratively with the people closest to them (e.g. partners, friends, family) to sustain relationships. Future public health responses to infectious disease outbreaks would benefit from identifying more opportunities to formalise and embed mechanisms to obtain feedback from affected communities so as to inform responses.

Influence of emulsifier on lipid oxidation in spray-dried microencapsulated O/W emulsions.

Lipid oxidation limits the shelf-life of dried microencapsulated oils (DMOs), such as infant formula. However, it is poorly understood how lipid oxidation is affected by different types of emulsifiers. To improve our understanding, we prepared DMOs with different emulsifiers (whey protein isolate (WPI), pea protein isolate (PPI), and non-proteinaceous CITREM) and studied lipid oxidation in both the free and encapsulated fat. Only a small difference in oxidation rate was observed between these fat fractions for all formulations. We ascribed this to a non-discrete distribution of the fractions and the subsequent low fractionation selectivity as shown by Raman microscopy. The DMO with PPI showed hardly any oxidation during a 7-week incubation at 40 °C, whereas the DMOs with WPI and CITREM both reached significantly higher contents of oxidation products (lipid hydroperoxides, aldehydes, and epoxides). The enhanced stability of DMO-PPI could not be ascribed to the presence of phytic acid. In conclusion, we demonstrate the potential of using PPI to produce oxidatively stable DMOs.

Mitochondria regulate proliferation in adult cardiac myocytes.

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske iron-sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, the hearts underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA sequencing revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in α-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes, resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.

EZH2-driven immune evasion defines high-risk pediatric AML with t(16;21) FUS::ERG gene fusion.

Despite decades of research, acute myeloid leukemia (AML) remains a remarkably lethal malignancy. While pediatric AML (pAML) carries a more favorable prognosis than adult AML, the past 25 years of large clinical trials have produced few improvements in pAML survival. Nowhere is this more evident than in patients carrying a t(16;21)(p11;q22) translocation, which yields the FUS::ERG fusion transcript. Patients with FUS::ERG -positive AML are often primary refractory, and most responders quickly relapse. In COG clinical trials, allogeneic stem cell transplantation was of no benefit to FUS::ERG pAML patients; 100% of transplanted patients succumbed to their disease. Expression of major histocompatibility complex (MHC) class I & II and costimulatory molecules is absent at diagnosis in FUS::ERG AML, mirroring the epigenetic mechanism of post-transplant relapse seen in adult AML and its associated dismal outcomes. Here we show that this class-defining immune-repressive phenotype is driven by overexpression of the EZH2 histone lysine methyltransferase in vitro and in multiple clinical cohorts. We show that treatment with the FDA-approved EZH2 inhibitor tazemetostat along with IFN-γ reverses this phenotype, re-establishes MHC presentation, and severely impairs the viability of FUS::ERG AML cells. EZH2 inhibitors may thus provide the first targeted therapeutic option for patients with this high-risk subtype of pAML, with particular benefit as a bridge to successful allogeneic stem cell transplantation. STATEMENT OF SIGNIFICANCE: FUS::ERG pAML patients have dismal outcomes. Here we show a ubiquitous immune-evasive phenotype, defined by elevated EZH2 levels and loss of MHC class I and II receptors, present in these patients at diagnosis. Treatment with the EZH2 inhibitor tazemetostat and IFN-γ reverses this phenotype in patient-derived cell lines.

Chronic Obstructive Pulmonary Disease Exacerbations Increase the Risk of Subsequent Cardiovascular Events: A Longitudinal Analysis of the COPDGene Study.

BACKGROUND: Cardiovascular disease (CVD) is the most important comorbidity in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations not only contribute to COPD progression but may also elevate the risk of CVD. This study aimed to determine whether COPD exacerbations increase the risk of subsequent CVD events using up to 15 years of prospective longitudinal follow-up data from the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. METHODS AND RESULTS: The COPDGene study is a large, multicenter, longitudinal investigation of COPD, including subjects at enrollment aged 45 to 80 years with a minimum of 10 pack-years of smoking history. Cox proportional hazards models and Kaplan-Meier survival curves were used to assess the risk of a composite end point of CVD based on the COPD exacerbation rate. Frequent exacerbators exhibited a higher cumulative incidence of composite CVD end points than infrequent exacerbators, irrespective of the presence of CVD at baseline. After adjusting for covariates, frequent exacerbators still maintained higher hazard ratios (HRs) than the infrequent exacerbator group (without CVD: HR, 1.81 [95% CI, 1.47-2.22]; with CVD: HR, 1.92 [95% CI, 1.51-2.44]). This observation remained consistently significant in moderate to severe COPD subjects and the preserved ratio impaired spirometry population. In the mild COPD population, frequent exacerbators showed a trend toward more CVD events. CONCLUSIONS: COPD exacerbations are associated with an increased risk of subsequent cardiovascular events in subjects with and without preexisting CVD. Patients with COPD experiencing frequent exacerbations may necessitate careful monitoring and additional management for subsequent potential CVD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00608764.