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Primary amoebic meningoencephalitis (PAM) is a human brain infection caused by Naegleria fowleriwith a 97% mortality rate. Quinazolinones resulting from a Mannich-coupled domino rearrangement were recently identified as inhibitors of the amoeba. Herein, we resolved the effective concentrations for 25 pilot compounds and then, using the Mannich protocol and a key late-stage, N-demethylation/functionalization, we synthesized 53 additional analogs to improve potency, solubility and microsomal stability. We established an antiamoebic quinazolinone pharmacophore, culminating in (±)-trans-57bwhich featured the best combination of potency, selectivity index, solubility, and microsomal stability. Enantiomeric separation afforded (4aS,13bR)-57b(BDGR-20237) with a 41-fold potency advantage over its enantiomer. ADME and mouse pharmacokinetic profiling for BDGR-20237revealed high brain penetrance but a limited half-life which did not statistically enhance the mouse survival in a pilot efficacy study. The pharmacophoric model, supported by 88 quinazolinones, several of which exhibit subnanomolar potency, will guide further scaffold optimization.

Abstract:This annotation explores a newly developed font that allows users to input special characters (ligatures and logograms) found in texts produced by Jesuit missionaries to Japan and their followers. This new font allows users to create transcriptions that are more materially and typographically closer to the original sources, and the syntax used to input these special characters opens up the possibility for digital analysis of these transcriptions. The annotation contextualizes the discussion of the new font, it benefits, and limitations in relation to the current practices used by Japanologists to input these characters.

In this work, we present an iterative learning strategy and experimental validation thereof for optimizing the flight trajectory of an underwater kite. The methodology is adapted to two different power generation configurations. The iterative learning algorithm consists of two main steps, which are executed at each iteration. In the first step, a meta-model is updated using a recursive least squares (RLS) estimate to capture an economic performance index as a function of a set of basis parameters that define the flight trajectory. The second step is an iterative learning update using information from past cycles to update basis parameters at future cycles using a gradient ascent formulation. This algorithm was experimentally validated on a scaled experimental prototype underwater kite system towed behind a test vessel in Lake Norman, North Carolina. Using our experimental system and algorithm, we were able to increase the kite’s mechanical power generation by an average of 24.4% across the tests performed.

The multiple purposes of an electronics “package” include the provision of mechanical support to the silicon chip, for example, and protection from the environment, the delivery of power in and the facilitation of heat out, and the reliable input and output of information signals, whether electrical or optical. In the age of heterogeneous integration, this includes the internal conversion of signal modes between multiple technologies within the package, while maintaining the traditional requirement of reliable information transmission between packages, e.g., on a traditional circuit board. This article presents some selected examples of nanopackaging, i.e., the application of nanotechnologies, (nanoparticles, carbon nanotubes and graphene here,) to electronics packaging.

Purpose Research has focused on cigarette use motives and have not included military personnel. The current study assessed tobacco use motives for different products, and differences within males and females and those with different racial identities given historical disparities in tobacco use.Design A cross-sectional survey about tobacco use was administered from October 2019 to February 2022.Setting Four Technical Training bases in the US.Sample Air Force Airmen who used tobacco (N = 3243).Measures Questions were about sociodemographic characteristics, tobacco use, and the Tobacco Motives Inventory (representing affect regulation, boredom, enhancement, and social motives).Analysis Linear regressions assessed associations between overall tobacco use and motives. Stratified analyses assessed associations between tobacco use and motives among males and females, and individuals from different racial backgrounds. Logistic regressions assessed differences in motives and use of different tobacco products between “some day” and “everyday” users.Results Overall, boredom (B= .09, SE= .01) and affect regulation (B= .05, SE= .00) motives were associated with higher tobacco use. Males and females and individuals from different racial backgrounds endorsed different motives, but all endorsed boredom as a motive for higher tobacco use. Individuals who used cigarettes, e-cigarettes, or smokeless tobacco “some days” endorsed higher social motives than everyday users, but everyday users endorsed different motives across products.Conclusion There are motives differentiating between “some day” and “everyday” users of tobacco products, which may need to be differentially targeted in intervention programs. Additionally, there are some overlapping motives (affect regulation, boredom) that may be beneficial to address with all tobacco users.

Analysis of volatile organic compounds (VOCs) in exhaled breath (EB) has shown great potential for disease detection including lung cancer, infectious respiratory diseases, and chronic obstructive pulmonary disease. Although many breath sample collection and analytical methods have been developed for breath analysis, analysis of metabolic VOCs in exhaled breath is still a challenge for clinical application. Many carbonyl compounds in exhaled breath are related to the metabolic processes of diseases. This work reports a method of ultrahigh-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-MS) for the analysis of a broad range of carbonyl metabolites in exhaled breath. Carbonyl compounds in the exhaled breath were captured by a fabricated silicon microreactor with a micropillar array coated with 2-(aminooxy)ethyl-N,N,N-trimethylammonium (ATM) triflate. A total of six subgroups consisting of saturated aldehydes and ketones, hydroxy-aldehydes, and hydroxy-ketones, unsaturated 2-alkenals, and 4-hydroxy-2-alkenals were identified in the exhaled breath. The combination of a silicon microreactor for the selective capture of carbonyl compounds with UHPLC-MS analysis may provide a quantitative method for the analysis of carbonyls to identify disease markers in exhaled breath.

The use of electronic cigarettes (i.e., e-cigarettes or vapes) has increased substantially among youth and young adults. While research has examined vaping cannabis and tetrahydrocannabinol (THC), little exists related to vaping other drugs, such as opioids, despite the fact that opioids are a leading cause of drug overdoses associated deaths in the U.S. The current study aimed to review the current state of the literature related to vaping opioids given our experience of learning about a youth overdose related to vaping opioids in a public high school in the U.S. while we were engaged in conducting community-based research. Peer-reviewed research publications related to vaping opioids are minimal, although there are several newspaper articles published related to vaping opioids, with most being about youth vaping opioids in school. This is concerning given that media often misconstrue substance use, particularly related to fentanyl, and may provide inaccurate information that perpetuates stigma. Thus, it remains unclear the scope of the issue of vaping opioids. Therefore, we propose a call to action for researchers and public health officials outlining recommendations for increased surveillance, interventions to address vaping-related opioid use, and measures to curb serious adverse consequences of vaping-related opioid use to determine whether this is a rising public health concern and offer mitigation strategies.

Antimitochondrial antibody-positive primary biliary cholangitis (AMA-pos PBC) is an autoimmune disorder in which monoclonal antibodies are produced against epitopes in the mitochondrial membranes of biliary epithelial cells, resulting in progressive nonsuppurative biliary cholangitis. Up to 5% of patients lack these autoantibodies, termed antimitochondrial antibody-negative (AMA-neg) PBC. Although a somewhat new variant of AMA-pos PBC, it is not an overlapping syndrome. Few studies to date have described this phenomenon. An 87-year-old woman was referred to our clinic with elevated serum alkaline phosphatase (714 U/L). She reported fatigue but no other symptoms. A physical examination revealed a benign lesion and bilateral lower extremity swelling secondary to lymphedema. The serological profile was significant for a high antinuclear antibody titer (>1:2,560) with a centromere pattern and negative for antimitochondrial antibody (AMA). The hepatitis panel was negative for viruses A, B, and C. Her serum immunoglobulin G level was 871 mg/dL (normal, <1,600 mg/dL). The rest of the serological tests, including anti-smooth muscle antibodies (ASMA) and anti-liver/kidney microsomal antibodies, were negative. Computed tomography of the abdomen and pelvis without contrast showed normal liver parenchyma and no acute intra-abdominal pathology. Histopathology indicated florid duct lesions. The background parenchyma showed no significant steatosis, and inflammatory changes were limited to the portal areas. Periodic acid-Schiff staining revealed intact hepatic parenchyma and architecture. The patient was diagnosed with AMA-neg PBC and responded well to ursodeoxycholic acid therapy. This case highlights the importance of recognizing AMA-neg PBC as a variant of AMA-pos PBC and differentiating between them. Autoimmune cholangitis is a vague and imprecise condition. All patients with AMA-negative PBC should be tested for other PBC-specific autoantibodies. Although the prognosis and bile duct damage and loss are worse in AMA-neg PBC for unknown reasons, treatment remains the same for both.

Conceptual designs for a European demonstration (EU-DEMO) power plant are based on extrapolations of physics scaling laws and current understanding of engineering limits based on available technologies. It is imperative to quantify the impact of uncertainties in physics and engineering parameters on the ability to produce an economically attractive future fusion power plant that meets key design outcomes. In this work, the sensitivity of the expected capital cost of an EU-DEMO power plant has been studied using the systems code PROCESS. A systems code aims to model interactions between subsystems of a fusion power plant and provide consistent solution across a large parameter space. The PROCESS system code allows for user-defined initial conditions and constraints and then optimizes using a given figure of merit to find optimal design parameters. We present a sensitivity analysis on optimizations around the 2018 pulsed EU-DEMO baseline, and this allows for the identification of the most consequential model parameters and the magnitude of the nonlinear interactions between them. We consider the pulsed EU-DEMO baseline, and while fixing the major radius and optimizing for fusion gain $Q$ , we present a sensitivity analysis of the role of the physics and engineering parameters and constraints in determining the capital cost of such a device. We identify the dominant physics parameter as the power threshold necessary to enter H-mode, which accounts for 45% of the sensitivity and find high interactions between plasma shaping parameters and other power plant subsystems. This analysis allows for the identification of areas of additional technical focus and uncertainty propagation.

To make informed decisions during the concept selection activities of a nuclear fusion power plant, it is necessary to evaluate the impact of uncertainties on the feasibility and performance of each concept. A framework for uncertainty quantification and sensitivity analysis has been developed for the PROCESS systems code to allow the direct comparison of different DEMOnstration power plant (DEMO) power plant concepts. To account for epistemic uncertainty, the uncertainty quantification was based on interval analysis, where only the bounds of the interval have to be assumed for each uncertain parameter, and the uncertainty was propagated with Monte Carlo and Latin hypercube sampling. The sensitivity analysis was based on the pinching method, consisting of reducing the interval uncertainty of each input parameter to a baseline point one by one and measuring the uncertainty reduction in the output interval. Its application is shown using the European H-mode DEMO baseline as a use case. Results suggest that the thermal He-4 fraction in plasma, plasma elongation, and H-factor should be examined further to reduce risks on its feasibility.

Combinations of anti-cancer drugs can overcome resistance and provide new treatments1,2. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or KRAS-mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or KRAS–TP53double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments.

Individuals with autism spectrum disorder (ASD) can experience difficulties functioning in society due to social communication deficits and restrictive and repetitive behaviors. Music therapy has been suggested as a potential intervention used to improve these deficits in ASD. The current systematic literature review focuses on two methods of music therapy: improvisational music therapy (IMT) and singing/listening to songs. We review the extant literature and the associated methodological limitations, and we propose a framework to assess the effectiveness of music therapy as an intervention in ASD. We suggest the creation of a standardized framework that should utilize neuroimaging tools as an objective marker of changes induced by music therapy as well as a combination of functional and behaviourial outputs, rather than assessment methods addressing a broad range of functional and behavioural outputs, rather than only the main symptoms. The methodological limitations found in the current literature prevent us from making a strong statement about the effects of music therapy in autism. We consider treatment fidelity assessments as the key to successful future attempts to truly understand music therapy effects in ASD.

Supplemental digital content is available in the text.

Current evidence suggests that plasma cell-free DNA (cfDNA) is fragmented around a mode of 166 bp. Data supporting this view has been mainly acquired through the analysis of double-stranded cfDNA. The characteristics and diagnostic potential of single-stranded and damaged double-stranded cfDNA in healthy individuals and cancer patients remain unclear. Here, through a combination of high-affinity magnetic bead–based DNA extraction and single-stranded DNA sequencing library preparation (MB-ssDNA), we report the discovery of a large proportion of cfDNA fragments centered at ∼50 bp. We show that these “ultrashort” cfDNA fragments have a greater relative abundance in plasma of healthy individuals (median = 19.1% of all sequenced cfDNA fragments, n= 28) than in plasma of patients with cancer (median = 14.2%, n= 21, P< 0.0001). The ultrashort cfDNA fragments map to accessible chromatin regions of blood cells, particularly in promoter regions with the potential to adopt G-quadruplex (G4) DNA secondary structures. G4-positive promoter chromatin accessibility is significantly enriched in ultrashort plasma cfDNA fragments from healthy individuals relative to patients with cancers (P< 0.0001), in whom G4-cfDNA enrichment is inversely associated with copy number aberration-inferred tumor fractions. Our findings redraw the landscape of cfDNA fragmentation by identifying and characterizing a novel population of ultrashort plasma cfDNA fragments. Sequencing of MB-ssDNA libraries could facilitate the characterization of gene regulatory regions and DNA secondary structures via liquid biopsy. Our data underline the diagnostic potential of ultrashort cfDNA through classification for cancer patients.

Introduction: Healthcare expenditure is on the rise placing greater emphasis on operational excellence, cost containment, and high quality of care. Significant variation is seen in operating room (OR) costs with common surgical procedures such as laparoscopic appendectomy. Surgeons can influence cost through the selection of instrumentation for common surgical procedures such as laparoscopic appendectomy. We aimed to quantify the cost of laparoscopic appendectomy in our healthcare system and compare cost variations to operative times and outcomes. Methods and procedures: We performed a retrospective review of laparoscopic appendectomies in a large regional healthcare system during one-year period (2018). Operating room supply costs and procedure durations were obtained for each hospital. The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) outcomes and demographics were compared to the costs for each hospital. Results: A total of 4757 laparoscopic appendectomies were performed at 20 hospitals (27 to 522 per hospital) by 233 surgeons. The average supply cost per case ranged from $650 to $1067. Individual surgeon cost ranged from $197 to $1181. The average operative time was 41 min (range 33 to 60 min). There was no association between lower cost and longer operative time. The patient demographics and comorbidities were similar between sites. There were no significant differences in postoperative complications between high- and low-cost centers. The items with the greatest increase in cost were single-use energy devices (SUD) and endoscopic stapler. We estimate that a saving of over $417 per case is possible by avoiding the use of energy devices and may be as high as $ 984 by adding selective use of staplers. These modifications would result in an annual savings of $1 million for our health system and more than $ 125 million nationwide. Conclusion: Performing laparoscopic appendectomy with reusable instruments and finding alternatives to expensive energy devices and staplers can significantly decrease costs and does not increase operative time or postoperative complications.

AimsThe results of surgery for Dupuytren’s disease can be compromised by the potential for disease recurrence and loss of function. Selecting which patients will benefit from repeat surgery, when to operate, and what procedure to undertake requires judgement and an understanding of patient expectations and functional needs. We undertook this study to investigate patient outcomes and satisfaction following repeat limited fasciectomy for recurrent Dupuytren’s disease.MethodsWe prospectively identified all patients presenting with recurrence of Dupuytren’s disease who were selected for surgical treatment with repeat limited fasciectomy surgery between January 2013 and February 2015. Patients were assessed preoperatively, and again at a minimum of five years postoperatively. We identified 43 patients who were carefully selected for repeat fasciectomy involving 54 fingers. Patients with severe or aggressive disease with extensive skin involvement were not included; in our practice, these patients are instead counselled and preferentially treated with dermofasciectomy. The primary outcome measured was change in the Michigan Hand Outcomes Questionnaire (MHQ) score. Secondary outcomes were change in finger range of motion, flexion contracture, Semmes-Weinstein monofilament (SWM) values, and overall satisfaction.ResultsThere was a significant improvement in MHQ scores, across all domains, with a mean overall score increase of 24 points (p < 0.001). The summed flexion contracture across the metacarpophalangeal joint (MCPJ) and the proximal interphalangeal joint (PIPJ) reduced from means of 72.0° (SD 15.9°) to 5.6° (SD 6.8°) (p < 0.001). A significant increase in maximal flexion was seen at the MCPJ (p < 0.001) but not the PIPJ (p = 0.550). The mean overall satisfaction score from the visual analogue scale was 8.9 (7.9 to 10.0). Complications were uncommon although five fingers showed reduced sensibility at final follow-up.ConclusionOur study shows that repeat limited fasciectomy for selected patients presenting with recurrence of Dupuytren’s disease can be an effective and safe treatment resulting in excellent patient-reported outcomes and levels of satisfaction.Cite this article: Bone Joint J2021;103-B(5):946–950.

Consolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) remains controversial, with routine practice continuing to include RT in patients with initial bulky disease or residual masses. Positron emission tomography (PET)-computed tomography is a sensitive modality for detecting the presence of residual disease at the end of treatment (EOT). A PET-guided approach to selectively administering RT has been the policy in British Columbia since 2005. Patients with advanced-stage DLBCL diagnosed from 1 January 2005 to 1 March 2017 and treated with at least 6 cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab), who underwent EOT PET, were included in this analysis. Those with complete metabolic response (PET-negative [PET-NEG]) were observed; those with PET-positive (PET-POS) scans were offered consolidative RT, when feasible. Of the patient records reviewed, 723 were identified, with median follow-up of 4.3 years: 517 (72%) were PET-NEG; 206 (28%) were PET-POS. Time to progression (TTP) and overall survival (OS) at 3 years were 83% vs 56% and 87% vs 64%, in patients with PET-NEG and PET-POS scans, respectively. PET-POS patients with nonprogressing disease treated with consolidative RT (109 and 206; 53%) had outcomes approaching those of PET-NEG patients, with 3-year estimates of 76% and 80% for TTP and OS. PET-NEG patients who had bulky disease (≥10 cm) at diagnosis had outcomes indistinguishable from those without bulk, despite the omission of RT. These data suggest that patients with advanced-stage DLBCL who are PET-NEG at EOT and receive no RT have excellent outcomes. 18F-fluorodeoxyglucose-PET can reliably guide selective administration of consolidative RT, even in patients with initially bulky disease.

Consolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) remains controversial, with routine practice continuing to include RT in patients with initial bulky disease or residual masses. Positron emission tomography (PET)-computed tomography is a sensitive modality for detecting the presence of residual disease at the end of treatment (EOT). A PET-guided approach to selectively administering RT has been the policy in British Columbia since 2005. Patients with advanced-stage DLBCL diagnosed from 1 January 2005 to 1 March 2017 and treated with at least 6 cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab), who underwent EOT PET, were included in this analysis. Those with complete metabolic response (PET-negative [PET-NEG]) were observed; those with PET-positive (PET-POS) scans were offered consolidative RT, when feasible. Of the patient records reviewed, 723 were identified, with median follow-up of 4.3 years: 517 (72%) were PET-NEG; 206 (28%) were PET-POS. Time to progression (TTP) and overall survival (OS) at 3 years were 83% vs 56% and 87% vs 64%, in patients with PET-NEG and PET-POS scans, respectively. PET-POS patients with nonprogressing disease treated with consolidative RT (109 and 206; 53%) had outcomes approaching those of PET-NEG patients, with 3-year estimates of 76% and 80% for TTP and OS. PET-NEG patients who had bulky disease (≥10 cm) at diagnosis had outcomes indistinguishable from those without bulk, despite the omission of RT. These data suggest that patients with advanced-stage DLBCL who are PET-NEG at EOT and receive no RT have excellent outcomes. 18F-fluorodeoxyglucose-PET can reliably guide selective administration of consolidative RT, even in patients with initially bulky disease.

It’s been an extraordinary two years, for everyone, and let’s hope it is never to be repeated.

Using first-principles calculations, we investigate the adsorption behavior of hydrogen on the planar hexagonal ZnO sheet. Our calculations find that the planar ZnO monolayer preferably adsorbs hydrogen molecules, where a hydrogen molecule attaches to one oxygen atom with binding energy of ∼0.13 eV. This implies that the interaction between a hydrogen molecule and the ZnO sheet is stronger than that between a hydrogen molecule and graphene. We predict that each oxygen atom in a ZnO sheet can adsorb two hydrogen molecules on opposite sides of the sheet, and thus the gravimetric density for hydrogen storage on ZnO sheet is evaluated to be about 4.7 wt % at zero temperature. Furthermore, our calculations show that the gravimetric density for hydrogen storage on ZnO sheet reaches 1.5–2.1 wt % at 298 K and 5 MPa. This suggests that, despite their weight, ZnO sheets may have potential applications in hydrogen storage.

•N addition enhances iron reduction, nitrate reduction and sulfate reduction.•N addition increases C mineralization rates but decreases methanogenesis rates.•Increased inundation decreases methanogenesis rates.•Inundation counteracts promoting effect of N addition on C mineralization rates.

Metabolic resistance to the maize-selective, HPPD-inhibiting herbicide, mesotrione, occurs via Phase I ring hydroxylation in resistant waterhemp and Palmer amaranth; however, mesotrione detoxification pathways post-Phase I are unknown. This research aims to (1) evaluate Palmer amaranth populations for mesotrione resistance via survivorship, foliar injury, and aboveground biomass, (2) determine mesotrione metabolism rates in Palmer amaranth populations during a time course, and (3) identify mesotrione metabolites including and beyond Phase I oxidation. The Palmer amaranth populations, SYNR1 and SYNR2, exhibited higher survival rates (100%), aboveground biomass (c.a. 50%), and lower injury (25–30%) following mesotrione treatment than other populations studied. These two populations also metabolized mesotrione 2-fold faster than sensitive populations, PPI1 and PPI2, and rapidly formed 4-OH-mesotrione. Additionally, SYNR1 and SYNR2 formed 5-OH-mesotrione, which is not produced in high abundance in waterhemp or naturally tolerant maize. Metabolite features derived from 4/5-OH-mesotrione and potential Phase II mesotrione-conjugates were detected and characterized by liquid chromatography–mass spectrometry (LCMS).

Laparoscopic cholecystectomy is the most common procedure performed by general surgeons in the United States, with approximately 600,000 procedures performed annually. As the cost of care rises, there is increasing emphasis on utilization and quality. Our objective was to evaluate the cost of laparoscopic cholecystectomy in our health system and to compare the operative times and outcomes at high- and low-cost centers. We evaluated all laparoscopic cholecystectomies performed in our system over a 1-year period. The operating room supply costs and procedure durations were obtained for each of the hospitals. The American College of Surgeons National Surgical Quality Improvement Program outcomes and demographics were compared to the costs for each hospital. During the study period, 7601 laparoscopic cholecystectomies were performed at 20 hospitals (170–759/hospital) by 227 surgeons. The average cost per case ranged from $296 at the lowest cost center to $658 at the highest cost center. The average operative time varied between sites from 46 to 95 min. There was no association between cost and operative time or case volume. There was a slight trend toward increased cost with higher number of emergency procedures, but this was not well correlated (R2= 0.03). The patient demographics and comorbidities were similar between sites. There were no significant differences in postoperative complications between high- and low-cost centers. The items with the greatest increase in cost were disposable trocars, disposable hook cautery, disposable endoscissors, and disposable clip appliers. We estimate that a savings of over $300/case is possible by using reusable instruments, which would result in an annual savings of $1.3 million for our health system, and $285 million nationwide. Performing laparoscopic cholecystectomy with reusable instruments can significantly decrease costs and does not increase operative time or postoperative complications.