Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL.

The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.

Healthy Air, Healthy Brains: Advancing Air Pollution Policy to Protect Children's Health.

Evidence is growing on the adverse neurodevelopmental effects of exposure to combustion-related air pollution. Project TENDR (Targeting Environmental Neurodevelopmental Risks), a unique collaboration of leading scientists, health professionals, and children's and environmental health advocates, has identified combustion-related air pollutants as critical targets for action to protect healthy brain development. We present policy recommendations for maintaining and strengthening federal environmental health protections, advancing state and local actions, and supporting scientific research to inform effective strategies for reducing children's exposures to combustion-related air pollution. Such actions not only would improve children's neurological development but also would have the important co-benefit of climate change mitigation and further improvements in other health conditions.

Improved Calcium Scoring at Dual-Energy Computed Tomography Angiography Using a High-Z Contrast Element and Novel Material Separation Technique.

OBJECTIVES: The aim of this study was to compare the accuracy of existing dual-energy computed tomography (CT) angiography coronary artery calcium scoring methods to those obtained using an experimental tungsten-based contrast material and a recently described contrast material extraction process (CMEP). METHODS: Phantom coronary arteries of varied diameters, with different densities and arcs of simulated calcified plaque, were sequentially filled with water, iodine, and tungsten contrast materials and scanned within a thorax phantom at rapid-kVp-switching dual-energy CT. Calcium and contrast density images were obtained by material decomposition (MD) and CMEP. Relative calcium scoring errors among the 4 reconstructed datasets were compared with a ground truth, 120-kVp dataset. RESULTS: Compared with the 120-kVp dataset, tungsten CMEP showed a significantly lower mean absolute error in calcium score (6.2%, P < 0.001) than iodine CMEP, tungsten MD, and iodine MD (9.9%, 15.7%, and 40.8%, respectively). CONCLUSIONS: Novel contrast elements and material separation techniques offer improved coronary artery calcium scoring accuracy and show potential to improve the use of dual-energy CT angiography in a clinical setting.

Selective inhibition of M5 muscarinic acetylcholine receptors attenuates cocaine self-administration in rats.

Cocaine use disorder (CUD) remains a debilitating health problem in the United States for which there are no Food and Drug Administration-approved treatment options. Accumulating anatomical and electrophysiological evidence indicates that the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5 ) plays a critical role in the regulation of the mesolimbic dopaminergic reward circuitry, a major site of action for cocaine and other psychostimulants. In addition, M5 knockout mice exhibit reduced cocaine self-administration behaviors with no differences in sugar pellet-maintained responding relative to wild-type mice. These findings suggest that selective inhibition of M5 mAChR may provide a novel pharmacological approach for targeting CUD. Recently, we reported the synthesis and characterization of ML375, a selective negative allosteric modulator (NAM) for the rat and human M5 mAChR with optimized pharmacokinetic properties for systemic dosing in rodents. In the present study, male Sprague-Dawley rats were trained to self-administer intravenous cocaine (0.1-0.75 mg/kg/infusion) under a 10-response fixed ratio or a progressive ratio schedule of reinforcement. Under both schedules of reinforcement, ML375 produced dose-related reductions in cocaine self-administration. ML375 also modestly reduced sugar pellet-maintained responding on the 10-response, fixed ratio schedule but had no effect under a progressive ratio schedule of reinforcement. Further, ML375 did not affect general motor output as assessed by a rotarod test. Collectively, these results provide the first demonstration that selective inhibition of M5 using the M5 NAM ML375 can attenuate both the reinforcing effects and the relative strength of cocaine and suggest that M5 NAMs may represent a promising, novel treatment approach for CUD.

Predictors of CT Radiation Dose and Their Effect on Patient Care: A Comprehensive Analysis Using Automated Data.

Purpose To determine patient, vendor, and institutional factors that influence computed tomography (CT) radiation dose. Materials and Methods The relevant institutional review boards approved this HIPAA-compliant study, with waiver of informed consent. Volume CT dose index (CTDIvol) and effective dose in 274 124 head, chest, and abdominal CT examinations performed in adult patients at 12 facilities in 2013 were collected prospectively. Patient, vendor, and institutional characteristics that could be used to predict (a) median dose by using linear regression after log transformation of doses and (b) high-dose examinations (top 25% of dose within anatomic strata) by using modified Poisson regression were assessed. Results There was wide variation in dose within and across medical centers. For chest CTDIvol, overall median dose across all institutions was 11 mGy, and institutional median dose was 7-16 mGy. Models including patient, vendor, and institutional factors were good for prediction of median doses (R2 = 0.31-0.61). The specific institution where the examination was performed (reflecting the specific protocols used) accounted for a moderate to large proportion of dose variation. For chest CTDIvol, unadjusted median CTDIvol was 16.5 mGy at one institution and 6.7 mGy at another (adjusted relative median dose, 2.6 mGy [95% confidence interval: 2.5, 2.7]). Several variables were important predictors that a patient would undergo high-dose CT. These included patient size, the specific institution where CT was performed, and the use of multiphase scanning. For example, while 49% of patients (21 411 of 43 696) who underwent multiphase abdominal CT had a high-dose examination, 8% of patients (4977 of 62 212) who underwent single-phase CT had a high-dose examination (adjusted relative risk, 6.20 [95% CI: 6.17, 6.23]). If all patients had been examined with single-phase CT, 69% (18 208 of 26 388) of high-dose examinations would have been eliminated. Patient size, institutional-specific protocols, and multiphase scanning were the most important predictors of dose (change in R2 = 8%-32%), followed by manufacturer and iterative reconstruction (change in R2, 0.2%-15.0%). Conclusion CT doses vary considerably within and across facilities. The primary factors that influenced dose variation were multiphase scanning and institutional protocol choices. It is unknown if the variation in these factors influenced diagnostic accuracy. © RSNA, 2016.

Radiation Dose Reduction during Uterine Fibroid Embolization Using an Optimized Imaging Platform.

PURPOSE: To assess radiation dose reduction during uterine fibroid embolization (UFE) using an optimized angiographic processing and acquisition platform. MATERIALS AND METHODS: Radiation dose data for 70 women (mean age, 46 y; range, 34-67 y) who underwent UFE were retrospectively analyzed. Twenty-one patients underwent UFE using the baseline fluoroscopic and angiographic image acquisition platform, and 49 underwent UFE after implementing an optimized imaging platform in otherwise identical angiography suites. Cumulative kerma-area product (CKAP), cumulative air kerma (CAK), total fluoroscopy time, and image exposure number were collected for each procedure. Image quality was assessed by 3 interventional radiologists blinded to the platform used for image acquisition and processing. RESULTS: Patients undergoing UFE using the new x-ray fluoroscopy platform had significantly lower CKAP and CAK indicators than patients for whom baseline settings were used. Mean CKAP decreased by 60% from 438.5 Gy · cm2 (range, 180.3-1,081.1 Gy · cm2) to 175.2 Gy · cm2 (range, 47.1-757.0 Gy · cm2; P < .0001). Mean CAK decreased by 45% from 2,034.2 mGy (range, 699.3-5,056.0 mGy) to 1,109.8 mGy (range, 256.6-4,513.6 mGy; P = .001). No degradation of image quality was identified through qualitative evaluation. CONCLUSIONS: Significant reduction in patient radiation dose indicators can be achieved with use of an optimized image acquisition and processing platform.

Pulmonary tumor embolism secondary to soft tissue and bone sarcomas: a case report and literature review.

BACKGROUND: Tumor embolisms (TE) are an underappreciated source of pulmonary embolisms in sarcoma. Most evidence in the literature is limited to case reports and none have described the presence of TE secondary to myxofibrosarcoma. We report the first case of myxofibrosarcoma TE and perform a review of the literature for TE secondary to bone and soft tissue sarcomas (STS). CASE PRESENTATION: A 36-year-old female presented with debilitating pain of the right upper extremity secondary to a recurrent soft tissue sarcoma. She had distant metastasis to the lung. An MRI revealed a 25-cm shoulder mass involving the proximal arm muscles with encasement of the axillary artery, vein, and brachial plexus. A palliative forequarter amputation was performed and tumor thrombus was evident within the axillary artery and vein. Postoperatively, she developed an acute onset of dyspnea and hypoxia. A computed tomography scan revealed a pulmonary saddle embolism. A bilateral lower extremity venous duplex was negative. She became hemodynamically unstable despite resuscitation and was placed on vasopressor support. A transthoracic echocardiogram revealed elevated pulmonary artery pressure, tricuspid regurgitation, right heart dilation, and reduced right heart systolic function consistent with acute cor pulmonale. The patient did not want to pursue a median sternotomy with pulmonary artery embolectomy and expired from cardiopulmonary arrest within 24 h of the operation. The final pathology revealed a 25 × 16 × 13 cm high-grade myxofibrosarcoma with invasion into the bone, skin, and neurovascular bundle as well as evidence of tumor thrombus. CONCLUSION: TE is a rare but deadly cause of pulmonary embolism in sarcoma. A high index of suspicion is necessary in individuals who present with respiratory-related symptoms, especially dyspnea. Diagnostic confirmation with a computed tomography scan of the chest and echocardiogram should be rapid. Unlike venous thromboembolism, pulmonary embolectomy remains the preferred therapeutic approach.

Image quality and dose optimisation for infant CT using a paediatric phantom.

OBJECTIVE: To optimise image quality and reduce radiation exposure for infant body CT imaging. METHODS: An image quality CT phantom was created to model the infant body habitus. Image noise, spatial resolution, low contrast detectability and tube current modulation (TCM) were measured after adjusting CT protocol parameters. Reconstruction method (FBP, hybrid iterative and model-based iterative), image quality reference parameter, helical pitch and beam collimation were systematically investigated for their influence on image quality and radiation output. RESULTS: Both spatial and low contrast resolution were significantly improved with model-based iterative reconstruction (p < 0.05). A change in the helical pitch from 0.969 to 1.375 resulted in a 23% reduction in total TCM, while a change in collimation from 20 to 40 mm resulted in a 46% TCM reduction. Image noise and radiation output were both unaffected by changes in collimation, while an increase in pitch enabled a dose length product reduction of ~6% at equivalent noise. An optimised protocol with ~30% dose reduction was identified using model-based iterative reconstruction. CONCLUSIONS: CT technology continues to evolve and require protocol redesign. This work provides an example of how an infant-specific phantom is essential for leveraging this technology to maintain image quality while reducing radiation exposure. KEY POINTS: • A size-specific phantom is critical in protocol development for infant CT. • New reconstruction technology enables ~30% dose reduction at equivalent image quality. • A consistent performance is observed for this scanner system across protocol changes. • A tradeoff exists between reducing exposure time and enabling tube current modulation.

Evaluation of a Net Dose-Reducing Organ-Based Tube Current Modulation Technique: Comparison With Standard Dose and Bismuth-Shielded Acquisitions.

OBJECTIVE: The purpose of this study was to compare the dose and image noise associated with two methods of radiation dose reduction to the superficial anterior organs: bismuth shielding and a net dose-reducing organ-based tube current modulation TCM technique. MATERIALS AND METHODS: Three scanning modes-the reference dose, bismuth-shielded, and organ dose-modulated modes-were evaluated. With the use of an anthropomorphic phantom, surface doses to the eye, thyroid, and female breast were measured using optically stimulated luminescence detectors. A CT dose index (CTDI) phantom was used to compare doses with the overall phantom volume in the different modes. RESULTS: The dose to the anterior surface was reduced by 35%, 42%, and 37% in the head, neck, and chest regions, respectively, when the bismuth-shielded scanning mode was used, whereas surface dose reductions of 20%, 34%, and 38%, respectively, were noted for the organ-based TCM scanning mode. The CTDI-type dose was reduced by 13%, 14%, and 17% in the head, neck, and chest regions, respectively, when the bismuth-shielded mode was used, whereas dose reductions of 9%, 18%, and 20%, respectively, were observed for the organ-based TCM mode. Anterior image noise increased by 0.1, 9.5, and 0.7 HU in the head, neck, and chest regions, respectively, when the bismuth-shielded mode was used. These findings compared with increases in image noise of 0.1, 0.5, and 0.6 HU, respectively, for the organ-based TCM mode. CONCLUSION: The implementation of organ-based TCM reduces the net tube current per rotation, so no body region receives increased radiation exposure. The use of this method allows the dose to the anterior surface to be reduced to an extent similar to that observed with the use of the bismuth shield, yet it does not produce the image quality degradation associated with bismuth shielding.

Radiation Doses in Consecutive CT Examinations from Five University of California Medical Centers.

PURPOSE: To summarize data on computed tomographic (CT) radiation doses collected from consecutive CT examinations performed at 12 facilities that can contribute to the creation of reference levels. MATERIALS AND METHODS: The study was approved by the institutional review boards of the collaborating institutions and was compliant with HIPAA. Radiation dose metrics were prospectively and electronically collected from 199 656 consecutive CT examinations in 83 181 adults and 3871 consecutive CT examinations in 2609 children at the five University of California medical centers during 2013. The median volume CT dose index (CTDIvol), dose-length product (DLP), and effective dose, along with the interquartile range (IQR), were calculated separately for adults and children and stratified according to anatomic region. Distributions for DLP and effective dose are reported for single-phase examinations, multiphase examinations, and all examinations. RESULTS: For adults, the median CTDIvol was 50 mGy (IQR, 37-62 mGy) for the head, 12 mGy (IQR, 7-17 mGy) for the chest, and 12 mGy (IQR, 8-17 mGy) for the abdomen. The median DLPs for single-phase, multiphase, and all examinations, respectively, were as follows: head, 880 mGy · cm (IQR, 640-1120 mGy · cm), 1550 mGy · cm (IQR, 1150-2130 mGy · cm), and 960 mGy · cm (IQR, 690-1300 mGy · cm); chest, 420 mGy · cm (IQR, 260-610 mGy · cm), 880 mGy · cm (IQR, 570-1430 mGy · cm), and 550 mGy · cm (IQR 320-830 mGy · cm); and abdomen, 580 mGy · cm (IQR, 360-860 mGy · cm), 1220 mGy · cm (IQR, 850-1790 mGy · cm), and 960 mGy · cm (IQR, 600-1460 mGy · cm). Median effective doses for single-phase, multiphase, and all examinations, respectively, were as follows: head, 2 mSv (IQR, 1-3 mSv), 4 mSv (IQR, 3-8 mSv), and 2 mSv (IQR, 2-3 mSv); chest, 9 mSv (IQR, 5-13 mSv), 18 mSv (IQR, 12-29 mSv), and 11 mSv (IQR, 6-18 mSv); and abdomen, 10 mSv (IQR, 6-16 mSv), 22 mSv (IQR, 15-32 mSv), and 17 mSv (IQR, 11-26 mSv). In general, values for children were approximately 50% those for adults in the head and 25% those for adults in the chest and abdomen. CONCLUSION: These summary dose data provide a starting point for institutional evaluation of CT radiation doses.

Patient Radiation Dose Reduction during Transarterial Chemoembolization Using a Novel X-Ray Imaging Platform.

PURPOSE: To evaluate radiation dose reduction in patients undergoing transarterial chemoembolization with the use of a new image acquisition and processing platform. MATERIALS AND METHODS: Radiation-dose data were obtained from 176 consecutive chemoembolization procedures in 135 patients performed in a single angiography suite. From January 2013 through October 2013, 85 procedures were performed by using our institution's standard fluoroscopic settings. After upgrading the x-ray fluoroscopy system with an image acquisition and processing platform designed to reduce image noise and reduce skin entrance dose, 91 chemoembolization procedures were performed from November 2013 through December 2014. Cumulative dose-area product (CDAP), cumulative air kerma (CAK), and total fluoroscopy time were recorded for each procedure. Image quality was assessed by three interventional radiologists blinded to the x-ray acquisition platform used. RESULTS: Patient radiation dose indicators were significantly lower for chemoembolization procedures performed with the novel imaging platform. Mean CDAP decreased from 3,033.2 dGy·cm(2) (range, 600.3-9,404.1 dGy·cm(2)) to 1,640.1 dGy·cm(2) (range, 278.6-6,779.9 dGy·cm(2); 45.9% reduction; P < .00001). Mean CAK decreased from 1,445.4 mGy (range, 303.6-5,233.7 mGy) to 971.7 mGy (range, 144.2-3,512.0 mGy; 32.8% reduction; P < .0001). A 20.3% increase in mean total fluoroscopy time was noted after upgrading the imaging platform, but blinded analysis of the image quality revealed no significant degradation. CONCLUSIONS: Although a small increase in fluoroscopy time was observed, a significant reduction in patient radiation dose was achieved by using the optimized imaging platform, without image quality degradation.

COVID-19 and the Americans with Disabilities Act: Implications for employment and higher education.

BACKGROUND: The Americans with Disabilities Act (ADA) is a federal law that protects individuals with disabilities from discrimination in all areas of public life. The ADA contributes to equal opportunity across policy areas, including the interconnected domains of higher education and employment. Since the onset of the COVID-19 pandemic in 2020, emerging research has begun to document the disparities in impact on people with disabilities, among other marginalized groups. However, no research to date has reviewed and synthesized literature that addresses disability discrimination related to COVID-19 that has implications for application of the ADA. OBJECTIVE: This rapid evidence review aims to increase understanding about how COVID-19 has resulted in challenges for people with disabilities in the domains of employment and higher education that may be resolved through application of the ADA. METHODS: Keyword searches were conducted in five electronic databases. Title, abstract, and full text screening was conducted followed by a thematic analysis of key ADA themes. RESULTS: Twelve final articles were included in this review, eight categorized within higher education and four within employment. In relation to the ADA and COVID-19, five studies revealed findings related to web accessibility, eight related to effective communication, and four related to reasonable accommodations. CONCLUSION: The findings provide a broad overview of the current research on how COVID-19 has affected accessibility, communications and accommodations in employment and higher education and identify gaps in the literature within these policy domains.

Reflection on the application of the Consolidated Framework for Implementation Research to a national policy to improve inclusion of people with disabilities.

People with disabilities face many barriers in the built environment impacting their mobility, health, and social participation. In the US, under the Americans with Disabilities Act (ADA), municipalities were required to develop and implement barrier-removal plans for pedestrian infrastructure, called ADA transition plans, but very few have done so. Many communities know they need a plan but do not know how to get it done because of a lack of understanding of the many different implementation considerations. Implementation science offers a useful approach for understanding complex policy implementation such as ADA plans. This paper provides a reflection on the adaptation of the Consolidated Framework for Implementation Research (CFIR) to evaluate the implementation of ADA transition planning. To apply the CFIR, we tailored the construct definitions and modified them to fit the specific context of the ADA transition planning process. We documented the constructs that were more challenging to apply, those that were not relevant, and those that were particularly useful. This paper can serve as a valuable example that other researchers can use when considering adapting the CFIR or other implementation frameworks for the evaluation of complex social policy beyond the ADA.

Use of Quantitative Electroencephalography to Inform Age- and Sex-Related Differences in NMDA Receptor Function Following MK-801 Administration.

Sex- and age-related differences in symptom prevalence and severity have been widely reported in patients with schizophrenia, yet the underlying mechanisms contributing to these differences are not well understood. N-methyl-D-aspartate (NMDA) receptor hypofunction contributes to schizophrenia pathology, and preclinical models often use NMDA receptor antagonists, including MK-801, to model all symptom clusters. Quantitative electroencephalography (qEEG) represents a translational approach to measure neuronal activity, identify targetable biomarkers in neuropsychiatric disorders and evaluate possible treatments. Abnormalities in gamma power have been reported in patients with schizophrenia and correspond to psychosis and cognitive impairment. Further, as gamma power reflects cortical glutamate and GABA signaling, it is highly sensitive to changes in NMDA receptor function, and NMDA receptor antagonists aberrantly increase gamma power in rodents and humans. To evaluate the role of sex and age on NMDA receptor function, MK-801 (0.03-0.3 mg/kg, SC) was administered to 3- and 9-month-old male and female Sprague-Dawley rats that were implanted with wireless EEG transmitters to measure cortical brain function. MK-801-induced elevations in gamma power were observed in 3-month-old male and female and 9-month-old male rats. In contrast, 9-month-old female rats demonstrated blunted maximal elevations across a wide dose range. Importantly, MK-801-induced hyperlocomotor effects, a common behavioral screen used to examine antipsychotic-like activity, were similar across all groups. Overall, sex-by-age-related differences in gamma power support using qEEG as a translational tool to evaluate pathological progression and predict treatment response across a heterogeneous population.

Cognitive performance as a behavioral phenotype associated with cocaine self-administration in female and male socially housed monkeys.

Considerable research has suggested that certain cognitive domains may contribute to cocaine misuse. However, there are gaps in the literature regarding whether cognitive performance before drug exposure predicts susceptibility to cocaine self-administration and how cognitive performance relates to future cocaine intake. Thus, the present study aimed to examine cognitive performance, as measured using automated CANTAB cognitive battery, prior to and following acquisition of cocaine self-administration under a concurrent drug vs. food choice procedure in female and male socially housed cynomolgus macaques. The cognitive battery consisted of measures of associative learning (stimulus and compound discrimination tasks), behavioral flexibility (intradimensional and extradimensional tasks), and behavioral inhibition (stimulus discrimination reversal, SDR, and extra-dimensional reversal tasks). After assessing cognitive performance, monkeys were trained to self-administer cocaine (saline, 0.01-0.1 mg/kg/injection) under a concurrent cocaine vs. food schedule of reinforcement. After a history of cocaine self-administration across 3-4 years, the cognitive battery was re-assessed and compared with sensitivity to cocaine reinforcement. Results showed drug-naïve monkeys that were less accurate on the SDR task, measuring behavioral inhibition, were more sensitive to cocaine reinforcement under the concurrent cocaine vs. food choice procedure. Furthermore, following chronic cocaine self-administration, cocaine intake was a negative predictor of accuracy on the SDR behavioral inhibition task. After cocaine maintenance, monkeys with higher cocaine intakes required more trials to complete the SDR behavioral inhibition task and made more incorrect responses during these trials. No sex or social rank differences were noted. Overall, these findings suggest that cognitive performance may influence vulnerability to cocaine misuse. Also, chronic cocaine may decrease levels of behavioral inhibition as measured via the SDR task in both females and males.

Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38ß MAPK) for the treatment of facioscapulohumeral muscular dystrophy. METHODS: We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. FINDINGS: Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. INTERPRETATION: Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. FUNDING: Fulcrum Therapeutics.

Adverse outcomes and an immunosuppressed endotype in septic patients with reduced IFN-γ ELISpot.

BACKGROUNDSepsis remains a major clinical challenge for which successful treatment requires greater precision in identifying patients at increased risk of adverse outcomes requiring different therapeutic approaches. Predicting clinical outcomes and immunological endotyping of septic patients generally relies on using blood protein or mRNA biomarkers, or static cell phenotyping. Here, we sought to determine whether functional immune responsiveness would yield improved precision.METHODSAn ex vivo whole-blood enzyme-linked immunosorbent spot (ELISpot) assay for cellular production of interferon γ (IFN-γ) was evaluated in 107 septic and 68 nonseptic patients from 5 academic health centers using blood samples collected on days 1, 4, and 7 following ICU admission.RESULTSCompared with 46 healthy participants, unstimulated and stimulated whole-blood IFN-γ expression was either increased or unchanged, respectively, in septic and nonseptic ICU patients. However, in septic patients who did not survive 180 days, stimulated whole-blood IFN-γ expression was significantly reduced on ICU days 1, 4, and 7 (all P < 0.05), due to both significant reductions in total number of IFN-γ-producing cells and amount of IFN-γ produced per cell (all P < 0.05). Importantly, IFN-γ total expression on days 1 and 4 after admission could discriminate 180-day mortality better than absolute lymphocyte count (ALC), IL-6, and procalcitonin. Septic patients with low IFN-γ expression were older and had lower ALCs and higher soluble PD-L1 and IL-10 concentrations, consistent with an immunosuppressed endotype.CONCLUSIONSA whole-blood IFN-γ ELISpot assay can both identify septic patients at increased risk of late mortality and identify immunosuppressed septic patients.TRIAL REGISTRYN/A.FUNDINGThis prospective, observational, multicenter clinical study was directly supported by National Institute of General Medical Sciences grant R01 GM-139046, including a supplement (R01 GM-139046-03S1) from 2022 to 2024.

Effects of chronic methylphenidate on cocaine self-administration under a progressive-ratio schedule of reinforcement in rhesus monkeys.

It has been hypothesized that drugs that serve as substrates for dopamine (DA) and norepinephrine (NE) transporters may be more suitable medications for cocaine dependence than drugs that inhibit DA and NE uptake by binding to transporters. Previous studies have shown that the DA/NE releaser d-amphetamine can decrease cocaine self-administration in preclinical and clinical studies. The present study examined the effects of methylphenidate (MPD), a DA uptake inhibitor, for its ability to decrease cocaine self-administration under conditions designed to reflect clinically relevant regimens of cocaine exposure and pharmacotherapy. Each morning, rhesus monkeys pressed a lever to receive food pellets under a fixed-ratio 50 schedule of reinforcement; cocaine was self-administered under a progressive-ratio schedule of reinforcement in the evening. After cocaine (0.003-0.56 mg/kg per injection, i.v.) dose-response curves were determined, self-administration sessions were suspended and MPD (0.003-0.0056 mg/kg per hour, i.v.; or 1.0-9.0 mg/kg p.o., b.i.d.) was administered for several weeks. A cocaine self-administration session was conducted every 7 days. When a MPD dose was reached that either persistently decreased cocaine self-administration or produced disruptive effects, the cocaine dose-effect curve was re-determined. In most cases, MPD treatment either produced behaviorally disruptive effects or increased cocaine self-administration; it took several weeks for these effects to dissipate. These data are consistent with the largely negative results of clinical trials with MPD. In contrast to the positive effects with the monoamine releaser d-amphetamine under identical conditions, these results do not support use of monoamine uptake inhibitors like MPD as a medication for cocaine dependence.

Identifying mRNAs Residing in Myelinating Oligodendrocyte Processes as a Basis for Understanding Internode Autonomy.

In elaborating and maintaining myelin sheaths on multiple axons/segments, oligodendrocytes distribute translation of some proteins, including myelin basic protein (MBP), to sites of myelin sheath assembly, or MSAS. As mRNAs located at these sites are selectively trapped in myelin vesicles during tissue homogenization, we performed a screen to identify some of these mRNAs. To confirm locations, we used real-time quantitative polymerase chain reaction (RT-qPCR), to measure mRNA levels in myelin (M) and 'non-myelin' pellet (P) fractions, and found that five (LPAR1, TRP53INP2, TRAK2, TPPP, and SH3GL3) of thirteen mRNAs were highly enriched in myelin (M/P), suggesting residences in MSAS. Because expression by other cell-types will increase p-values, some MSAS mRNAs might be missed. To identify non-oligodendrocyte expression, we turned to several on-line resources. Although neurons express TRP53INP2, TRAK2 and TPPP mRNAs, these expressions did not invalidate recognitions as MSAS mRNAs. However, neuronal expression likely prevented recognition of KIF1A and MAPK8IP1 mRNAs as MSAS residents and ependymal cell expression likely prevented APOD mRNA assignment to MSAS. Complementary in situ hybridization (ISH) is recommended to confirm residences of mRNAs in MSAS. As both proteins and lipids are synthesized in MSAS, understanding myelination should not only include efforts to identify proteins synthesized in MSAS, but also the lipids.

Metabotropic glutamate receptor function and regulation of sleep-wake cycles.

Metabotropic glutamate (mGlu) receptors are the most abundant family of G-protein coupled receptors and are widely expressed throughout the central nervous system (CNS). Alterations in glutamate homeostasis, including dysregulations in mGlu receptor function, have been indicated as key contributors to multiple CNS disorders. Fluctuations in mGlu receptor expression and function also occur across diurnal sleep-wake cycles. Sleep disturbances including insomnia are frequently comorbid with neuropsychiatric, neurodevelopmental, and neurodegenerative conditions. These often precede behavioral symptoms and/or correlate with symptom severity and relapse. Chronic sleep disturbances may also be a consequence of primary symptom progression and can exacerbate neurodegeneration in disorders including Alzheimer's disease (AD). Thus, there is a bidirectional relationship between sleep disturbances and CNS disorders; disrupted sleep may serve as both a cause and a consequence of the disorder. Importantly, comorbid sleep disturbances are rarely a direct target of primary pharmacological treatments for neuropsychiatric disorders even though improving sleep can positively impact other symptom clusters. This chapter details known roles of mGlu receptor subtypes in both sleep-wake regulation and CNS disorders focusing on schizophrenia, major depressive disorder, post-traumatic stress disorder, AD, and substance use disorder (cocaine and opioid). In this chapter, preclinical electrophysiological, genetic, and pharmacological studies are described, and, when possible, human genetic, imaging, and post-mortem studies are also discussed. In addition to reviewing the important relationships between sleep, mGlu receptors, and CNS disorders, this chapter highlights the development of selective mGlu receptor ligands that hold promise for improving both primary symptoms and sleep disturbances.