Distribution of the intraosseous branch of the posterior superior alveolar artery relative to the posterior maxillary teeth.

Purpose: Preoperative identification of the intraosseous posterior superior alveolar artery (PSAA) is critical when planning sinus surgery. This study was conducted to determine the distance between the cementoenamel junction and the PSAA, as well as to identify factors influencing the detection of the PSAA on cone-beam computed tomography (CBCT). Materials and Methods: In total, 254 CBCT scans of maxillary sinuses, acquired with 2 different scanners, were examined to identify the PSAA. The distance from the cementoenamel junction (CEJ) to the PSAA was recorded at each maxillary posterior tooth position. Binomial logistic regression and multiple linear regression were employed to evaluate the effects of scanner type, CBCT parameters, sex, and age on PSAA detection and CEJ-PSAA distance, respectively. P-values less than 0.05 were considered to indicate statistical significance. Results: The mean CEJ-PSAA distances at the second molar, first molar, second premolar, and first premolar positions were 17.0±4.0 mm, 21.8±4.1 mm, 19.5±4.7 mm, and 19.9±4.9 mm for scanner 1, respectively, and 17.3±3.5 mm, 16.9±4.3 mm, 18.5±4.1 mm, and 18.4±4.3 mm for scanner 2. No independent variable significantly influenced PSAA detection. However, tooth position (b=-0.67, P<0.05) and scanner type (b=-1.3, P<0.05) were significant predictors of CEJ-PSAA distance. Conclusion: CBCT-based estimates of CEJ-PSAA distance were comparable to those obtained in previous studies involving cadavers, CT, and CBCT. The type of CBCT scanner may slightly influence this measurement. No independent variable significantly impacted PSAA detection.

A tandem activity-based sensing and labeling strategy reveals antioxidant response element regulation of labile iron pools.

Iron is an essential element for life owing to its ability to participate in a diverse array of oxidation-reduction reactions. However, misregulation of iron-dependent redox cycling can also produce oxidative stress, contributing to cell growth, proliferation, and death pathways underlying aging, cancer, neurodegeneration, and metabolic diseases. Fluorescent probes that selectively monitor loosely bound Fe(II) ions, termed the labile iron pool, are potentially powerful tools for studies of this metal nutrient; however, the dynamic spatiotemporal nature and potent fluorescence quenching capacity of these bioavailable metal stores pose challenges for their detection. Here, we report a tandem activity-based sensing and labeling strategy that enables imaging of labile iron pools in live cells through enhancement in cellular retention. Iron green-1 fluoromethyl (IG1-FM) reacts selectively with Fe(II) using an endoperoxide trigger to release a quinone methide dye for subsequent attachment to proximal biological nucleophiles, providing a permanent fluorescent stain at sites of elevated labile iron. IG1-FM imaging reveals that degradation of the major iron storage protein ferritin through ferritinophagy expands the labile iron pool, while activation of nuclear factor-erythroid 2-related factor 2 (NRF2) antioxidant response elements (AREs) depletes it. We further show that lung cancer cells with heightened NRF2 activation, and thus lower basal labile iron, have reduced viability when treated with an iron chelator. By connecting labile iron pools and NRF2-ARE activity to a druggable metal-dependent vulnerability in cancer, this work provides a starting point for broader investigations into the roles of transition metal and antioxidant signaling pathways in health and disease.

Bioengineering a plant NLR immune receptor with a robust binding interface toward a conserved fungal pathogen effector.

Bioengineering of plant immune receptors has emerged as a key strategy for generating novel disease resistance traits to counteract the expanding threat of plant pathogens to global food security. However, current approaches are limited by rapid evolution of plant pathogens in the field and may lack durability when deployed. Here, we show that the rice nucleotide-binding, leucine-rich repeat (NLR) immune receptor Pik-1 can be engineered to respond to a conserved family of effectors from the multihost blast fungus pathogen Magnaporthe oryzae. We switched the effector binding and response profile of the Pik NLR from its cognate rice blast effector AVR-Pik to the host-determining factor pathogenicity toward weeping lovegrass 2 (Pwl2) by installing a putative host target, OsHIPP43, in place of the native integrated heavy metal-associated domain (generating Pikm-1OsHIPP43). This chimeric receptor also responded to other PWL alleles from diverse blast isolates. The crystal structure of the Pwl2/OsHIPP43 complex revealed a multifaceted, robust interface that cannot be easily disrupted by mutagenesis, and may therefore provide durable, broad resistance to blast isolates carrying PWL effectors in the field. Our findings highlight how the host targets of pathogen effectors can be used to bioengineer recognition specificities that have more robust properties compared to naturally evolved disease resistance genes.

Relevance of learning health systems to physiatrists and its synergy with implementation science: A commentary.

As health care attempts to bridge the gap between evidence and practice, the concept of the learning health system (LHS) is becoming increasingly relevant. LHS integrates evidence with health systems data, driving health care quality and outcomes through updates in policy, practice, and care delivery. In addition, LHS research is becoming critically important as there are several initiatives underway to increase research capacity, expertise, and implementation, including attempts to stimulate increasing numbers of LHS researchers. Physical Medicine & Rehabilitation (PM&R) physicians (physiatrists), nurses, therapists (physical therapists, occupational therapists, speech therapists, clinical psychologists), and scientists are affiliated with LHSs. As LHS research expands in health care systems, better awareness and understanding of LHSs and LHS research competencies are key for rehabilitation professionals including physiatrists. To address this need, the Agency of Healthcare Research and Quality (AHRQ) identified 33 core competencies, grouped into eight domains, for training LHS researchers. The domains are: (1) Systems Science; (2) Research Questions and Standards of Scientific Evidence; (3) Research Methods; (4) Informatics; (5) Ethics of Research and Implementation in Health Systems; (6) Improvement and Implementation Science; (7) Engagement, Leadership, and Research Management; and the recently added (8) Health and Healthcare Equity and Justice. The purpose of this commentary is to define LHS and its relevance to physiatrists, present the role of implementation science (IS) in LHSs and application of IS principles to design LHSs, illustrate current LHS research in rehabilitation, and discuss potential solutions to improve awareness and to stimulate interest in LHS research and IS among physiatrists in LHSs.

Evaluating and Updating the IMPACT model to predict outcomes in two contemporary North American TBI cohorts.

The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) model is a widely recognized prognostic model applied after traumatic brain injury (TBI). However, it was developed with patient cohorts that may not reflect modern practice patterns in North America. We analyzed data from two sources: the placebo arm of the phase II double-blind, multicenter randomized controlled trial Prehospital Tranexamic Acid for TBI (TXA) cohort and data from an observational cohort with similar inclusion/exclusion criteria (Predictors of Low-risk Phenotypes after Traumatic Brain Injury Incorporating Proteomic Biomarker Signatures (PROTIPS) cohort). All three versions of the IMPACT model - core, extended, and laboratory - were evaluated for 6-month mortality (GOSE=1) and unfavorable outcomes (GOSE=1-4). Calibration (intercept and slope) and discrimination (ROC-AUC) were used to assess model performance. We then compared three model updating methods - recalibration in the large, logistic recalibration, and coefficient update - with the best update method determined by likelihood ratio tests.　 In our calibration analysis, recalibration improved both intercepts and slopes, indicating more accurate predicted probabilities when recalibration was done. Discriminative performance of the IMPACT models, measured by AUC, showed mortality prediction ROCs between 0.61 to 0.82 for the TXA cohort, with the coefficient updated Lab model achieving the highest at 0.84. Unfavorable outcomes had lower AUCs, ranging from 0.60 to 0.79. Similarly, in the PROTIPS cohort, AUCs for mortality ranged from 0.75 to 0.82, with the coefficient updated Lab model also showing superior performance (AUC 0.84). Unfavorable outcomes in this cohort presented AUCs from 0.67 to 0.73, consistently lower than mortality predictions. The closed testing procedure using likelihood ratio tests consistently identified the coefficient update model as superior, outperforming the original and recalibrated models across all cohorts. In our comprehensive evaluation of the IMPACT model, the coefficient updated models were the best-performing across all cohorts through a structured closed testing procedure. Thus, standardization of model updating procedures is needed to reproducibly determine the best performing versions of IMPACT that reflect the specific characteristics of a dataset.

Strict compliance to a thoracic enhanced recovery after surgery protocol is associated with improved outcomes compared with partial compliance: A prospective cohort study.

BACKGROUND: Benefits of thoracic enhanced recovery after surgery programs have been described. However, there is ongoing discussion on the importance of full protocol compliance. The objective of this study was to determine whether strict adherence to an enhanced recovery after surgery protocol leads to further improvement in outcomes compared with less strict compliance. METHODS: This was a multihospital prospective cohort study of all consecutive anatomic lung resection patients on the thoracic enhanced recovery after surgery pathway from May 2021 to March 2023, with comparison with a historical control from January 2019 to April 2021. Compliance to 5 key protocol elements was tracked. Patients were grouped into high- and low-compliance cohorts, defined as adherence to 4-5/5 or 0-3/5 elements, respectively. The primary outcome was overall morbidity; secondary outcomes included cardiac, respiratory, and infectious morbidity and length of stay. RESULTS: Of the 960 patients, 429 (44.7%) were enhanced recovery after surgery patients and 531 (55.3%) were in the historical control group. Across all patients, 250 (26.0%) were considered high compliance and 710 (74.0%) were considered low compliance. After adjustment for enhanced recovery after surgery status and confounders, the association between high compliance and improved outcomes persisted for all but infectious morbidity. Compared with low compliance, high compliance was associated with decreased odds of any morbidity (0.41 [95% CI, 0.22-0.77]), cardiac morbidity (0.31 [0.11-0.91]), respiratory morbidity (0.46 [0.23-0.90]) and decreased length of stay (0.38 [0.18-0.87]). CONCLUSION: Enhanced recovery after surgery protocols improve outcomes after anatomic lung resection. Increasing compliance to individual elements (>80%) further improves patient outcomes. Continued efforts should be directed at increasing compliance to individual protocol elements.

Role of Supplemental Breast MRI in Screening Women with Mammographically Dense Breasts: A Systematic Review and Meta-analysis.

BACKGROUND: High mammographic density increases breast cancer risk and reduces mammographic sensitivity. We reviewed evidence on accuracy of supplemental MRI for women with dense breasts at average or increased risk. METHODS: PubMed and Embase were searched 1995-2022. Articles were included if women received breast MRI following 2D or tomosynthesis mammography. Risk of bias was assessed using QUADAS-2. Analysis used independent studies from the articles. Fixed-effect meta-analytic summaries were estimated for predefined groups (PROSPERO: 230277). RESULTS: Eighteen primary research articles (24 studies) were identified in women aged 19-87 years. Breast density was heterogeneously or extremely dense (BI-RADS C/D) in 15/18 articles and extremely dense (BI-RADS D) in 3/18 articles. Twelve of 18 articles reported on increased-risk populations. Following 21 440 negative mammographic examinations, 288/320 cancers were detected by MRI. Substantial variation was observed between studies in MRI cancer detection rate, partly associated with prevalent vs incident MRI exams (prevalent: 16.6/1000 exams, 12 studies; incident: 6.8/1000 exams, 7 studies). MRI had high sensitivity for mammographically occult cancer (20 studies with at least 1-year follow-up). In 5/18 articles with sufficient data to estimate relative MRI detection rate, approximately 2 in 3 cancers were detected by MRI (66.3%, 95% CI, 56.3%-75.5%) but not mammography. Positive predictive value was higher for more recent studies. Risk of bias was low in most studies. CONCLUSION: Supplemental breast MRI following negative mammography in women with dense breasts has breast cancer detection rates of ~16.6/1000 at prevalent and ~6.8/1000 at incident MRI exams, considering both high and average risk settings.

Persistent changes in calcium-regulating hormones and bone turnover markers in living kidney donors more than 20 years after donation.

In a previous study, we observed decreased 1,25-dihydroxyvitamin D levels, secondary hyperparathyroidism, and increased bone turnover markers in living kidney donors (LKDs) at 3 months and 36 months after kidney donation. In our recent survey-based study, we found no increased risk of fractures of all types but observed significantly more vertebral fractures in LKDs compared with matched controls. To elucidate the long-term effects of kidney donation on bone health, we recruited 139 LKDs and 139 age and sex matched controls from the survey-based participants for further mechanistic analyses. Specifically, we assessed whether LKDs had persistent abnormalities in calcium- and phosphorus-regulating hormones and related factors, in bone formation and resorption markers, and in density and microstructure of bone compared with controls. We measured serum markers, bone mineral density (BMD), bone microstructure and strength (via high-resolution peripheral quantitative computed tomography and micro-finite element analysis [HRpQCT]), and advanced glycation end-products in donors and controls. LKDs had decreased 1,25-dihydroxyvitamin D concentrations (donors mean 33.89 pg/mL vs. controls 38.79 pg/mL, percent difference = -12.6%; P < .001), increases in both parathyroid hormone (when corrected for ionized calcium; donors mean 52.98 pg/mL vs. controls 46.89 pg/mL,% difference 13%; P = .03) and ionized calcium levels (donors mean 5.13 mg/dL vs. controls 5.04 mg/dL; P < .001), and increases in several bone resorption and formation markers versus controls. LKDs and controls had similar measures of BMD; however, HRpQCT suggested that LKDs have a statistically insignificant tendency toward thinner cortical bone and lower failure loads as measured by micro-finite element analysis. Our findings suggest that changes in the hormonal mileu after kidney donation and the long-term cumulative effects of these changes on bone health persist for decades after kidney donation and may explain later-life increased rates of vertebral fractures.

Facility-Level and Racial Disparities in Access to Inpatient Psychiatric Occupational Therapy Services in the Veterans Health Administration.

IMPORTANCE: Veterans receiving inpatient psychiatric services with limitations in activities of daily living (ADLs) benefit from occupational therapy, yet disparities in access are unknown. OBJECTIVE: To investigate whether ADL limitations, an indicator of occupational therapy need, was associated with inpatient psychiatric occupational therapy utilization in the Veterans Health Administration (VHA) and whether this relationship differs by facility characteristics. DESIGN: Secondary analysis of VHA data. Modified Poisson regression modeled occupational therapy utilization as a function of ADL limitations, facility characteristics, and covariates. Interactions estimated whether the relationship between ADL limitations and occupational therapy utilization differed across facility characteristics. SETTING: VHA inpatient psychiatric setting. PARTICIPANTS: Veterans receiving VHA inpatient psychiatric care from 2015 to 2020 (N = 133,844). OUTCOMES AND MEASURES: Occupational therapy utilization. RESULTS: Veterans with ADL limitations were more likely to receive occupational therapy. Veterans receiving care in facilities with higher complexity and greater inpatient psychiatric care quality were more likely to receive occupational therapy. Additionally, Black veterans were less likely to receive occupational therapy relative to their White, non-Hispanic counterparts. Interactions indicated that the extent to which ADL limitations drove access to occupational therapy utilization was weaker within facilities with higher complexity and care quality. CONCLUSIONS AND RELEVANCE: Veterans with ADL limitations were more likely to access inpatient psychiatric occupational therapy, suggesting that such services are generally allocated to veterans in need. However, findings indicate disparities in access across patient-level (e.g., Black race) and facility-level (e.g., facility complexity) factors, informing efforts to eliminate barriers to accessing these valuable services. Plain-Language Summary: This is the first study, to our knowledge, to examine disparities in access to inpatient psychiatric occupational therapy in the Veterans Health Administration (VHA). The study findings show that access to inpatient psychiatric occupational therapy is partly driven by the needs of the patient. However, nonclinical factors, such as a patient's race and the characteristics of the facility at which they receive care (complexity, number of psychiatric beds available, and the quality of psychiatric care), are also important drivers of access. Identifying factors influencing access to these valuable services is the first step in developing strategies that reduce barriers to access for veterans in need.

Multinational, Multicenter Evaluation of Prostate Cancer Tissue in Sub-Saharan Africa: Challenges and Opportunities.

PURPOSE: Prostate cancer disproportionately affects men of African descent, yet their representation in tissue-based studies is limited. This multinational, multicenter pilot study aims to establish the groundwork for collaborative research on prostate cancer in sub-Saharan Africa. METHODS: The Men of African Descent and Carcinoma of the Prostate network formed a pathologist working group representing eight institutions in five African countries. Formalin-fixed paraffin-embedded prostate tissue specimens were collected from Senegal, Nigeria, and Ghana. Histology slides were produced and digitally scanned. A central genitourinary pathologist (P.L.) and eight African general pathologists reviewed anonymized digital whole-slide images for International Society of Urological Pathology grade groups and other pathologic parameters. Discrepancies were re-evaluated, and consensus grading was assigned. A virtual training seminar on prostate cancer grading was followed by a second assessment on a subcohort of the same tissue set. RESULTS: Of 134 tissue blocks, 133 had evaluable tissue; 13 lacked cancer evidence, and four were of insufficient quality. Post-training, interobserver agreement for grade groups improved to 56%, with a median Cohen's quadratic weighted kappa of 0.83 (mean, 0.74), compared with an initial 46% agreement and a quadratic weighted kappa of 0.77. Interobserver agreement between African pathologist groups was 40%, with a quadratic weighted kappa of 0.66 (95% CI, 0.51 to 0.76). African pathologists tended to overgrade (36%) more frequently than undergrade (18%) compared with the reference genitourinary pathologist. Interobserver variability tended to worsen with a decrease in tissue quality. CONCLUSION: Tissue-based studies on prostate cancer in men of African descent are essential for a better understanding of this common disease. Standardized tissue handling protocols are crucial to ensure good tissue quality and data. The use of digital slide imaging can enhance collaboration among pathologists in multinational, multicenter studies.

Unlocking the genomic potential of Red Sea coral probiotics.

The application of beneficial microorganisms for corals (BMC) decreases the bleaching susceptibility and mortality rate of corals. BMC selection is typically performed via molecular and biochemical assays, followed by genomic screening for BMC traits. Herein, we present a comprehensive in silico framework to explore a set of six putative BMC strains. We extracted high-quality DNA from coral samples collected from the Red Sea and performed PacBio sequencing. We identified BMC traits and mechanisms associated with each strain as well as proposed new traits and mechanisms, such as chemotaxis and the presence of phages and bioactive secondary metabolites. The presence of prophages in two of the six studied BMC strains suggests their possible distribution within beneficial bacteria. We also detected various secondary metabolites, such as terpenes, ectoines, lanthipeptides, and lasso peptides. These metabolites possess antimicrobial, antifungal, antiviral, anti-inflammatory, and antioxidant activities and play key roles in coral health by reducing the effects of heat stress, high salinity, reactive oxygen species, and radiation. Corals are currently facing unprecedented challenges, and our revised framework can help select more efficient BMC for use in studies on coral microbiome rehabilitation, coral resilience, and coral restoration.

Visual Function Measurements in Eyes With Diabetic Retinopathy: An Expert Opinion on Available Measures.

Clinical Relevance: Visual function impairment from diabetic retinopathy can have a considerable impact on patient's quality of life. Best-corrected visual acuity (BCVA) is most commonly used to assess visual function and guide clinical trials. However, BCVA is affected late in the disease process, is not affected in early disease, and does not capture some of the visual disturbances described by patients with diabetes. The goal of this report is to evaluate the relationship between diabetic retinal disease (DRD) and visual function parameters to determine which if any of them may be used in a future DRD staging system. Methods: The visual functions working group was 1 of 6 areas of DRD studied as part of the DRD staging system update, a project of the Mary Tyler Moore Vision Initiative. The working group identified 12 variables of possible interest, 7 of which were judged to have sufficient preliminary data to suggest an association with DR to warrant further review: microperimetry, static automated perimetry, electroretinogram (ERG) oscillatory potentials, flicker ERG, low luminance visual acuity (LLVA), contrast sensitivity (CS), and BCVA. The objective field analyzer (OFA) was added after subsequent in-person workshops. Results: Currently, the only visual function test available for immediate use is BCVA; the remaining tests are either promising (within 5 years) or have potential (>5 years) use. Besides BCVA, most visual function tests had a limited role in current clinical care; however, LLVA, CS, flicker ERG, and OFA demonstrated potential for screening and research purposes. Conclusions: Although current visual function tests are promising, future prospective studies involving patients with early and more advanced retinopathy are necessary to determine if these tests can be used clinically or as endpoints for clinical studies. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Cumulative Impact of Serial Partial Nephrectomy for the Treatment of Recurrent Renal Masses.

PURPOSE: Reoperative partial nephrectomy (RePN) offers several advantages for the treatment of recurrent, multifocal renal masses. RePN has been previously demonstrated to be technically feasible and delay the need for renal replacement therapy. However, there is still inherent complexity and known risks to reoperative nephrectomy. We studied the largest population of RePNs to characterize renal functional outcomes and the likelihood of intra- and postoperative complications. MATERIALS AND METHODS: Query of an institutional surgical registry was conducted. Demographic data, serum creatinine for estimated glomerular filtration rate (eGFR), and protein dipstick results were assessed within 1 week prior to surgery, and postoperative function assessments were studied within a year of surgery. RePN was defined as serial surgical resection of the ipsilateral renal unit. RESULTS: A total of 1131 partial nephrectomies performed on 663 patients at a single center were retrospectively evaluated. In reoperative cases, median number of operations per renal unit was 2 (range: 2-6). There was a stepwise decline in eGFR with an average decline of 6.1 with each RePN. With each subsequent nephrectomy, surgical duration, estimated blood loss, and incidence of preoperative anemia increased. Postoperative eGFR showed a significant positive association with preoperative eGFR, while negative associations were found with age, number of previous ipsilateral partial nephrectomies, number of tumors, and largest tumor size. High-grade complications were associated with the number of ipsilateral partial nephrectomies, tumor count, and tumor size. Robotic or laparoscopic procedures exhibited a likelihood of grade 3 or greater complications compared to open surgery. CONCLUSION: RePN contributes to renal dysfunction and an increased risk of surgical complications. Intraoperative blood loss and surgical duration increase with subsequent nephrectomy. Such risks are dependent on the number of prior operative interventions on the kidney, suggesting a stepwise progression of surgical morbidity.

Pulsed reduced-dose rate re-irradiation for patients with recurrent grade 2 gliomas.

Background: Patients with grade 2 glioma exhibit highly variable survival. Re-irradiation for recurrent disease has limited mature clinical data. We report treatment results of pulsed reduced-dose rate (PRDR) radiation for patients with recurrent grade 2 glioma. Methods: A retrospective analysis of 58 patients treated with PRDR from 2000 to 2021 was performed. Radiation was delivered in 0.2 Gy pulses every 3 minutes encompassing tumor plus margin. Survival outcomes and prognostic factors on outcome were Kaplan-Meier and Cox regression analyses. Results: The median survival from the date of initial surgery was 8.6 years (95% CI: 5.5-11.8 years). 69% of patients showed malignant transformation to grade 3 (38%) or grade 4 (31%) glioma. Overall survival following PRDR was 12.6 months (95% CI: 8.3-17.0 months) and progression-free survival was 6.2 months (95% CI: 3.8-8.6 months). Overall response rate based on post-PRDR MRI was 36%. In patients who maintained grade 2 histology at recurrence, overall survival from PRDR was 22.0 months with 5 patients remaining disease-free, the longest at 8.2 and 11.4 years. PRDR was generally well tolerated. Conclusions: To the best of our knowledge, this is the largest reported series of patients with recurrent grade 2 gliomas treated with PRDR radiation for disease recurrence. We demonstrate promising survival and acceptable toxicity profiles following re-irradiation. In the cohort of patients who maintain grade 2 disease, prolonged survival (>5 years) is observed in selected patients. For the entire cohort, 1p19q codeletion, KPS, and longer time from initial diagnosis to PRDR were associated with improved survival.

PGC-1α integrates insulin signaling with mitochondrial physiology and behavior in a Drosophila model of Fragile X Syndrome.

Fragile X Syndrome (FXS) is the most prevalent monogenetic form of intellectual disability and autism. Recently, dysregulation of insulin signaling (IS) and aberrations in mitochondrial function have emerged as robust, evolutionarily conserved components of FXS pathophysiology. However, the mechanisms by which altered IS and mitochondrial dysfunction impact behavior in the context of FXS remain elusive. Here, we show that normalization of IS improves mitochondrial volume and function in flies that lack expression of dfmr1, the Drosophila homolog of the causal gene of FXS in humans. Further, we demonstrate that dysregulation of IS underlies diminished expression of the mitochondrial master regulator PGC-1α/Spargel in dfmr1 mutant flies. These results are behaviorally relevant, as we show that pan-neuronal augmentation of PGC-1α/Spargel improves circadian behavior in dfmr1 mutants. Notably, we also show that modulation of PGC-1α/Spargel expression in wild-type flies phenocopies the dfmr1 mutant circadian defect. Taken together, the results presented herein provide a mechanistic link between mitochondrial function and circadian behavior both in FXS pathogenesis as well as more broadly at the interface between metabolism and behavioral output.

Impact of long-term rapamycin treatment on age-related osteoarthritis in common marmoset.

Objective: Pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) can attenuate experimental osteoarthritis (OA) in young, male preclinical models. However, the potential of mTOR inhibition as a therapeutic mechanism for OA remains unknown. The goal of this study was to determine if mTOR-inhibition by oral rapamycin can modify OA pathology in the common marmoset, a translational model of age-associated OA. Methods: microCT and histopathologic assessments of the knee were performed on formalin-fixed hindlimbs obtained from common marmosets treated with oral rapamycin (n=24; 1mg/kg/day) or parallel control group (n=41). Rapamycin started at 9.2±3.0 years old and lasted until death (2.1±1.5 years). In a subset of marmosets, contralateral hind limbs were collected to determine mTOR signaling in several joint tissues. Results: Rapamycin decreased P-RPS6Ser235/36 and increased P-Akt2Ser473 in cartilage, meniscus, and infrapatellar fat pad, suggesting inhibition of mTORC1 but not mTORC2 signaling. Rapamycin-treated marmosets had lower lateral synovium score versus control but there was no difference in the age-related increase in microCT or cartilage OA scores. Subchondral bone thickness and thickness variability were not different with age but were lower in rapamycin-treated geriatric marmosets, which was largely driven by females. Rapamycin also tended to worsen age-related meniscus calcification in female marmosets. Conclusion: Oral rapamycin attenuated mTORC1 signaling and may have caused feedback activation of mTORC2 signaling in joint tissues. Despite modifying site-specific aspects of synovitis, rapamycin did not modify the age-associated increase in OA in geriatric marmosets. Conversely, rapamycin may have had deleterious effects on meniscus calcification and lateral tibia subchondral bone, primarily in geriatric female marmosets.

Study protocol: optical coherence tomography angiography for the detection of neovascular age-related macular degeneration: a comprehensive multicentre diagnostic accuracy study in the UK-the ATHENA study.

INTRODUCTION: The diagnosis of neovascular age-related macular degeneration (nAMD), the leading cause of visual impairment in the developed world, relies on the interpretation of various imaging tests of the retina. These include invasive angiographic methods, such as Fundus Fluorescein Angiography (FFA) and, on occasion, Indocyanine-Green Angiography (ICGA). Newer, non-invasive imaging modalities, predominately Optical Coherence Tomography (OCT) and Optical Coherence Tomography Angiography (OCTA), have drastically transformed the diagnostic approach to nAMD. The aim of this study is to undertake a comprehensive diagnostic accuracy assessment of the various imaging modalities used in clinical practice for the diagnosis of nAMD (OCT, OCTA, FFA and, when a variant of nAMD called Polypoidal Choroidal Vasculopathy is suspected, ICGA) both alone and in various combinations. METHODS AND ANALYSIS: This is a non-inferiority, prospective, randomised diagnostic accuracy study of 1067 participants. Participants are patients with clinical features consistent with nAMD who present to a National Health Service secondary care ophthalmology unit in the UK. Patients will undergo OCT as per standard practice and those with suspicious features of nAMD on OCT will be approached for participation in the study. Patients who agree to take part will also undergo both OCTA and FFA (and ICGA if indicated). Interpretation of the imaging tests will be undertaken by clinicians at recruitment sites. A randomised design was selected to avoid bias from consecutive review of all imaging tests by the same clinician. The primary outcome of the study will be the difference in sensitivity and specificity between OCT+OCTA and OCT+FFA (±ICGA) for nAMD detection as interpreted by clinicians at recruitment sites. ETHICS AND DISSEMINATION: The study has been approved by the South Central-Oxford B Research Ethics Committee with reference number 21/SC/0412.Dissemination of study results will involve peer-review publications, presentations at major national and international scientific conferences. TRIAL REGISTRATION NUMBER: ISRCTN18313457.

NB compounds are potent and efficacious FOXM1 inhibitors in high-grade serous ovarian cancer cells.

BACKGROUND: Genetic studies implicate the oncogenic transcription factor Forkhead Box M1 (FOXM1) as a potential therapeutic target in high-grade serous ovarian cancer (HGSOC). We evaluated the activity of different FOXM1 inhibitors in HGSOC cell models. RESULTS: We treated HGSOC and fallopian tube epithelial (FTE) cells with a panel of previously reported FOXM1 inhibitors. Based on drug potency, efficacy, and selectivity, determined through cell viability assays, we focused on two compounds, NB-73 and NB-115 (NB compounds), for further investigation. NB compounds potently and selectively inhibited FOXM1 with lesser effects on other FOX family members. NB compounds decreased FOXM1 expression via targeting the FOXM1 protein by promoting its proteasome-mediated degradation, and effectively suppressed FOXM1 gene targets at both the protein and mRNA level. At the cellular level, NB compounds promoted apoptotic cell death. Importantly, while inhibition of apoptosis using a pan-caspase inhibitor rescued HGSOC cells from NB compound-induced cell death, it did not rescue FOXM1 protein degradation, supporting that FOXM1 protein loss from NB compound treatment is specific and not a general consequence of cytotoxicity. Drug washout studies indicated that FOXM1 reduction was retained for at least 72 h post-treatment, suggesting that NB compounds exhibit long-lasting effects in HGSOC cells. NB compounds effectively suppressed both two-dimensional and three-dimensional HGSOC cell colony formation at sub-micromolar concentrations. Finally, NB compounds exhibited synergistic activity with carboplatin in HGSOC cells. CONCLUSIONS: NB compounds are potent, selective, and efficacious inhibitors of FOXM1 in HGSOC cells and are worthy of further investigation as HGSOC therapeutics.

Composition-dependent morphologies of CeO2 nanoparticles in the presence of Co-adsorbed H2O and CO2: a density functional theory study.

Catalytic activity is affected by surface morphology, and specific surfaces display greater activity than others. A key challenge is to define synthetic strategies to enhance the expression of more active surfaces and to maintain their stability during the lifespan of the catalyst. In this work, we outline an ab initio approach, based on density functional theory, to predict surface composition and particle morphology as a function of environmental conditions, and we apply this to CeO2 nanoparticles in the presence of co-adsorbed H2O and CO2 as an industrially relevant test case. We find that dissociative adsorption of both molecules is generally the most favourable, and that the presence of H2O can stabilise co-adsorbed CO2. We show that changes in adsorption strength with temperature and adsorbate partial pressure lead to significant changes in surface stability, and in particular that co-adsorption of H2O and CO2 stabilizes the {100} and {110} surfaces over the {111} surface. Based on the changes in surface free energy induced by the adsorbed species, we predict that cuboidal nanoparticles are favoured in the presence of co-adsorbed H2O and CO2, suggesting that cuboidal particles should experience a lower thermodynamic driving force to reconstruct and thus be more stable as catalysts for processes involving these species.

Epigenetic Priming by Hypomethylation Enhances the Immunogenic Potential of Tolinapant in T-cell Lymphoma.

Programmed cell death mechanisms are important for the regulation of tumor development and progression. Evasion of and resistance to apoptosis are significant factors in tumorigenesis and drug resistance. Bypassing apoptotic pathways and eliciting another form of regulated cell death, namely necroptosis, an immunogenic cell death (ICD), may override apoptotic resistance. Here, we present the mechanistic rationale for combining tolinapant, an antagonist of the inhibitor of apoptosis proteins (IAP), with decitabine, a hypomethylating agent (HMA), in T-cell lymphoma (TCL). Tolinapant treatment alone of TCL cells in vitro and in syngeneic in vivo models demonstrated that ICD markers can be upregulated, and we have shown that epigenetic priming with decitabine further enhances this effect. The clinical relevance of ICD markers was confirmed by the direct measurement of plasma proteins from patients with peripheral TCL treated with tolinapant. We showed increased levels of necroptosis in TCL lines, along with the expression of cancer-specific antigens (such as cancer testis antigens) and increases in genes involved in IFN signaling induced by HMA treatment, together deliver a strong adaptive immune response to the tumor. These results highlight the potential of a decitabine and tolinapant combination for TCL and could lead to clinical evaluation. SIGNIFICANCE: The IAP antagonist tolinapant can induce necroptosis, a key immune-activating event, in TCL. Combination with DNA hypomethylation enhances tolinapant sensitivity and primes resistant cells by re-expressing necrosome proteins. In addition, this combination leads to increases in genes involved in IFN signaling and neoantigen expression, providing further molecular rationale for this novel therapeutic option.