Conversion of Magnetic Energy to Plasma Kinetic Energy During Guide Field Magnetic Reconnection in the Laboratory.

We present laboratory measurements showing the two-dimensional (2D) structure of energy conversion during magnetic reconnection with a guide field over the electron and ion diffusion regions, resolving the separate energy deposition on electrons and ions. We find that the electrons are energized by the parallel electric field at two locations, at the X line and around the separatrices. On the other hand, the ions are energized ballistically by the perpendicular electric field in the vicinity of the high-density separatrices. An energy balance calculation by evaluating the terms of the Poynting theorem shows that 40% of the magnetic energy is converted to particle energy, 2/3 of which is transferred to ions and 1/3 to electrons. Further analysis suggests that the energy deposited on particles manifests mostly in the form of thermal kinetic energy in the diffusion regions.

Examining nonadherence in the treatment of tuberculosis: The patterns that lead to failure.

AIMS: Adherence has been shown to be a major predictor of tuberculosis treatment failure and relapse. The current adherence metrics can be improved to provide higher resolution of adherence patterns and identify patients in need of alternative treatment interventions. We investigated how adherence patterns affect treatment outcomes, when adherence is likely to decrease during treatment and which patients are at risk of being nonadherent. METHODS: Individual-level data were pooled from 3 clinical trials (n = 3724) for treatment of drug susceptible tuberculosis where monthly or weekly adherence patterns were collected and adherence patterns were quantified to assess the impact of clustered missed doses vs. randomly missed doses on tuberculosis treatment outcomes. Significance was determined through univariate and multivariate cox regression models. RESULTS: Patients who miss doses in clusters have an increased hazard risk for unfavourable outcomes and missing as little as 4 treatment days in 1 month resulted in 61% higher risk of unfavourable outcomes compared to patients who missed no treatment days (P < .01). Patients older than 50 years, and patients who experienced an adverse event were associated with lower adherence. CONCLUSION: Our results show that the pattern in which patients miss their drugs is important to their overall outcomes and missing treatment days in clusters rather than randomly increases the risk of poor outcomes. In the future more intensive and longitudinal adherence measurements will be valuable for clinical trials and regimen design and interpretation.

Outcomes of extensive stage extrapulmonary small cell cancer.

BACKGROUND: Extrapulmonary small cell cancer (EPSCC) is a rare malignancy with an incidence of approximately 0.1%-0.4% of all cancers. Treatment of this disease is often based on small cell lung cancer. AIMS: We aimed to investigate real-world clinical outcomes of patients with extensive-stage (ES) ESPCC. METHODS: Patients diagnosed with ES EPSCC between 2010 and 2020 from multiple centres in New South Wales were identified. Patient, disease and treatment characteristics were collected and presented using descriptive statistics. Survival was analysed using the Kaplan-Meier method. Univariate and multivariate Cox regression hazard models were used to identify potential prognostic factors. RESULTS: Sixty eligible ES EPSCC patients were identified, including 65% male and 35% female. The mean age was 69 years (range 37-88). Forty-five per cent were never smokers, 42% ex-smokers and 13% current smokers, and 17% of patients had limited-stage disease prior to development of ES disease. The most common primary sites were genitourinary (42%; mainly prostate (n = 14) and bladder (n = 10)), gastrointestinal (28%; mainly oesophagus (n = 5) and colon (n = 4)) and unknown primary (22%). Treatments received included palliative chemotherapy (67%), palliative radiotherapy (53%), palliative surgery (13%) and best supportive care alone (13%). The median overall survival (OS) was 8.0 months. The median progression-free survival was 5.4 months, and response rate to first-line chemotherapy was 65%. Platinum-based chemotherapy was prognostic of longer OS (HR 0.27, CI 0.12-0.60, P = 0.001). CONCLUSIONS: Patients with ES EPSCC had good response to palliative chemotherapy, but OS remained poor. Further research is required to improve the prognosis in this population.

Reforming Physician Payments to Achieve Greater Equity and Value in Health Care: A Position Paper of the American College of Physicians.

Socioeconomic factors remain one of the most clinically significant contributors to health outcomes in this country, yet the current fee-for-service payment structure incentivizes volume and does not address such factors. The American College of Physicians proposes specific policy recommendations on reforming payment programs, including those designed to treat underserved patient populations, to better address value in health care and achieve greater equity. The proposal advocates that population-based prospective payment models, including hybrid models that combine fee-for-service with prospective payments, not only have the potential to achieve high-value care but can also be designed in such a way as to adjust for the social drivers that impact health outcomes. The need to recognize health care disparities and inequities in the implementation of the Quality Payment Program in particular and risk scoring in general and the need for social policies to improve access to health information technology are further examples of policy prescriptions that can advance equity. Evidence-based services and programs in Medicare Part B that are shown to preserve the Medicare trust fund through savings in Part A should be able to be scored as offsets for the cost of those new programs. The approach of building a health care system that is smarter about how dollars are spent to make people healthier must shift to one with a clear intention of decreasing health inequities and addressing social drivers of health.

Design of proton deflectometry with in situ x-ray fiducial for magnetized high-energy-density systems.

We report a design and implementation of proton deflectometry with an in situ reference x-ray image of a mesh to precisely measure non-uniform magnetic fields in expanding plasmas at the OMEGA and OMEGA EP laser facilities. The technique has been developed with proton and x-ray sources generated from both directly driven capsule implosions and short pulse laser-solid interactions. The accuracy of the measurement depends on the contrast of both the proton and x-ray images. We present numerical and analytic studies to optimize the image contrast using a variety of mesh materials and grid spacings. Our results show clear enhancement of the image contrast by factors of four to six using a high Z mesh with large grid spacing. This leads to further improvement in the accuracy of the magnetic field measurement using this technique in comparison with its first demonstration at the OMEGA laser facility [Rev. Sci. Instrum.93, 023502 (2022)RSINAK0034-674810.1063/5.0064263].

Mathematical model and tool to explore shorter multi-drug therapy options for active pulmonary tuberculosis.

Standard treatment for active tuberculosis (TB) requires drug treatment with at least four drugs over six months. Shorter-duration therapy would mean less need for strict adherence, and reduced risk of bacterial resistance. A system pharmacology model of TB infection, and drug therapy was developed and used to simulate the outcome of different drug therapy scenarios. The model incorporated human immune response, granuloma lesions, multi-drug antimicrobial chemotherapy, and bacterial resistance. A dynamic population pharmacokinetic/pharmacodynamic (PK/PD) simulation model including rifampin, isoniazid, pyrazinamide, and ethambutol was developed and parameters aligned with previous experimental data. Population therapy outcomes for simulations were found to be generally consistent with summary results from previous clinical trials, for a range of drug dose and duration scenarios. An online tool developed from this model is released as open source software. The TB simulation tool could support analysis of new therapy options, novel drug types, and combinations, incorporating factors such as patient adherence behavior.

A dynamic magnetic tension force as the cause of failed solar eruptions.

Coronal mass ejections are solar eruptions driven by a sudden release of magnetic energy stored in the Sun's corona. In many cases, this magnetic energy is stored in long-lived, arched structures called magnetic flux ropes. When a flux rope destabilizes, it can either erupt and produce a coronal mass ejection or fail and collapse back towards the Sun. The prevailing belief is that the outcome of a given event is determined by a magnetohydrodynamic force imbalance called the torus instability. This belief is challenged, however, by observations indicating that torus-unstable flux ropes sometimes fail to erupt. This contradiction has not yet been resolved because of a lack of coronal magnetic field measurements and the limitations of idealized numerical modelling. Here we report the results of a laboratory experiment that reveal a previously unknown eruption criterion below which torus-unstable flux ropes fail to erupt. We find that such 'failed torus' events occur when the guide magnetic field (that is, the ambient field that runs toroidally along the flux rope) is strong enough to prevent the flux rope from kinking. Under these conditions, the guide field interacts with electric currents in the flux rope to produce a dynamic toroidal field tension force that halts the eruption. This magnetic tension force is missing from existing eruption models, which is why such models cannot explain or predict failed torus events.

Pneumonia: Hiding in Plain (Film) Sight.

Herein, a case describing how point-of-care lung ultrasound was used to identify the source of progressive multiorgan failure when a chest x-ray and other routine tests failed to provide a conclusive answer is presented. The discussion after the case focuses on the following: (1) the relative strengths and weaknesses of chest x-ray versus lung ultrasound in screening for lung disease and (2) suggestions of how lung ultrasound practice can be standardized within the field of anesthesiology.

Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization.

BACKGROUND: The sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization. METHODS AND FINDINGS: A total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26-22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21-2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03-0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed treatment and underwent lung resection surgery. These results still need further exploration and validation in larger and more diverse cohorts. CONCLUSIONS: Our results suggest that the ability to reach and maintain therapeutic concentrations is both lesion and drug specific, indicating that stratifying patients based on disease extent, lesion types, and individual drug-susceptibility profiles may eventually be useful for guiding the selection of patient-tailored drug regimens and may lead to improved TB treatment outcomes. We provide a web-based tool to further explore this model and results at http://saviclab.org/tb-lesion/.

Non-Invasive Buccal Swab Gene Testing for Skin Cancer Risk

Background: Studies have identified numerous genetic polymorphisms associated with increased risk of melanoma and non-melanoma skin cancer (NMSC). In this pilot study, we aimed to examine whether previously identified melanoma and non-melanoma associated single nucleotide polymorphisms (SNPs) which were found to be associated with cutaneous malignancy were also present in a relatively heterogeneous population with a history of skin cancer versus an age and environmental matched controls. The undertaking of this project serves to further the current understanding of the genetic profile for those at higher risk for developing skin cancer. Methods: Nineteen NMSC patients and their age-matched and environmental controls underwent genotyping of 7 previously discovered SNPs associated with melanoma and NMSC. Results: In a random, heterogeneous population in Southern California, SNP's Chr1, PAD16, PIGU, TDG had a similar association with NMSC previously reported in prior studies. Due to small trial size, no conclusions or observable associations could be drawn from the SNPs MC1R, TP53, and XRCC1. Conclusion: This data supports that 4 of the 7 SNP's studied had similar associations and could potentially be predictive tool of NMSC risk in this patient population. The remaining three SNP's did not have a definitive association with malignancy. Larger studies are needed to further elucidate the specific roles of these SNPs collectively and ultimately to develop a genetic profile for those patients at increased risk of developing skin cancer. J Drugs Dermatol. 2019;18(5):448-453.

Emergent Dialysis and its Impact on Quality of Life in Undocumented Patients with End-Stage Renal Disease.

OBJECTIVE: This study aimed to define the ethnographic composition and assess the health-related quality of life (HRQoL) of a large population of undocumented patients with end-stage renal disease (ESRD) seeking emergent dialysis in the emergency department (ED) of a large public hospital in the United States. DESIGN: All ESRD patients presenting to the hospital's main ED were identified during a 4-week consecutive enrollment period. Consenting patients completed two surveys-an ethnographic questionnaire and the validated kidney disease quality of life-36 (KDQOL-36) instrument. SETTING: The study was conducted at a large county hospital in Dallas, Texas. In 2013, the hospital recorded >50,000 ED visits and administered approximately 6,000 dialysis treatments to ED patients. PARTICIPANTS: 88 of 101 unfunded patients presenting to the ED during the study period consented to participate, resulting in an 87.1% response rate. 65 of these patients were undocumented immigrants. MAIN OUTCOME MEASURES: Quantitative scores for the 5 subscales of the KDQOL-36 were calculated for the study population. RESULTS: Measures of physical and mental health in our study population were lower than those published for scheduled dialysis patients. 79.5% of our patients lost employment due to their dialysis requirements. At least 71.4% of the study patients were unaware that they required dialysis before immigrating to the United States. CONCLUSIONS: Quality of life scores were found to be low among our population of undocumented emergent dialysis patients. Our data also provide some evidence that availability of dialysis at no cost is not a primary driver of illegal immigration of ESRD patients to the United States.

Non-dysbaric arterial gas embolism associated with chronic necrotizing pneumonia, bullae and coughing: a case report.

Arterial gas embolism (AGE) can be clinically devastating, and is most often associated with exposure to changes in ambient pressure, medical procedure or congenital malformation. Here we report a case of AGE in a 78-year-old male without these traditional risk factors. Rather, the patient's history included chronic obstructive pulmonary disease, necrotizing pneumonia, bullous disease and coughing. He was safely treated with hyperbaric oxygen (HBO2) therapy for AGE, with initial clinical improvement, but ultimately died from his underlying condition. Pathophysiology is discussed. This case illustrates the possibility that AGE can occur due to rupture of lung tissue in the absence of traditional risk factors. HBO2 therapy should be considered in the management of such patients.

Laboratory Observation of Resistive Electron Tearing in a Two-Fluid Reconnecting Current Sheet.

The spontaneous formation of plasmoids via the resistive electron tearing of a reconnecting current sheet is observed in the laboratory. These experiments are performed during driven, antiparallel reconnection in the two-fluid regime within the Magnetic Reconnection Experiment. It is found that plasmoids are present even at a very low Lundquist number, and the number of plasmoids scales with both the current sheet aspect ratio and the Lundquist number. The reconnection electric field increases when plasmoids are formed, leading to an enhanced reconnection rate.

Changing landowners, changing ecosystem? Land-ownership motivations as drivers of land management practices.

Motivations for owning rural land are shifting from an agricultural-production orientation to a preference for natural and cultural amenities. Resultant changes in land management have significant implications for the type and distribution of landscape-level disturbances that affect the delivery of ecosystem services. We examined the relationship between motivations for owning land and the implementation of conservation land management practices by landowners in the Southern Great Plains of the United States. Using a mail survey, we classified landowners into three groups: agricultural production, multiple-objective, and lifestyle-oriented. Cross tabulations of landowner group with past, current, and future use of 12 different land management practices (related to prescribed grazing, vegetation management, restoration, and water management) found that lifestyle-oriented landowners were overall less likely to adopt these practices. To the degree that the cultural landscape of rural lands transitions from production-oriented to lifestyle-oriented landowners, the ecological landscape and the associated flow of ecosystem services will likely change. This poses new challenges to natural resource managers regarding education, outreach, and policy; however, a better understanding about the net ecological consequences of lower rates of adoption of conservation management practices requires consideration of the ecological tradeoffs associated with the changing resource dependency of rural landowners.

Treatment algorithm for the comprehensive management of severe lichen sclerosus in boys based on the pathophysiology of the disease.

INTRODUCTION: It is estimated that approximately one out of 200 boys has the diagnosis of lichen sclerosus (LS), previously referred to as BXO (balanitis xerotica obliterans). Severe progressive disease is rare however, mismanagement of urethral tissues may contribute to progression of LS. STUDY DESIGN: The current literature regarding the management of severe lichen sclerosus was reviewed alongside our management of seven patients with ages ranging from six to ten years of age with severe lichen sclerosus who required surgical intervention. These patients were identified out of a busy pediatric practice that saw 5507 patients during the four-year span. Based on the pathophysiology of lichen sclerosus, urethral anatomy, and our management an algorithm was developed for medical and surgical management. RESULTS: All patients received initial medical treatment with topical steroids. Three patients underwent urethral mobilization and serial biopsy. One of these patients with severe disease required a second distal urethral mobilization. Three patients were treated with circumcision, and one is responding well to topical steroids after complex reconstruction. None developed postoperative urethral disease. DISCUSSION: Lichen sclerosus affects squamous epithelium but can extend to unaffected tissue if traumatized via the Koebner phenomenon. There are no randomized control trials for the management of the disease. Thus, appropriate early management with avoidance of urethral dilation or incision may prevent extension down the urethra that can lead to severe stricture disease. Several authors identified this as one of the worst forms of stricture diseases to manage. Based on the pathophysiology of the disease and our 4-year experience treating patients, we propose an algorithm for management of severe lichen sclerosus in boys. The diagnosis of lichen sclerosus in boys requires a high level of suspicion, and early biopsies should be obtained if suspected. If identified before circumcision or meatotomy, initial treatment should be medical. If the patient fails topical steroid therapy, circumcision and biopsy are the initial recommended surgical approach. Optimally, a biopsy with the first meatotomy establishes the diagnosis. If the disease persists, urethral mobilization may represent a curative treatment as it advances healthy urethra and allows complete removal of distal squamous epithelium instead of traumatic repeated dilations or incisions. CONCLUSION: This paper summarizes the available literature on the management of severe LS and provides a flow diagram based on the pathophysiology of the disease and our experience sever cases.

Federally Funded Randomized Controlled Trials Increase Analysis and Reporting of Study Outcomes by Sex, Race, and Ethnicity.

Background: We previously examined National Institutes of Health (NIH)-funded randomized controlled trials (RCTs) published in 2004, 2009, and 2015 and found low compliance with NIH policies on inclusion, analysis, and reporting results for female and minoritized subgroups, with no improvement over time. We conducted a fourth wave of data collection using RCTs published in 2021, comparing current results with previous years. Materials and Methods: The authors used PubMed to find 657 RCTs published in print in 14 leading US medical journals in 2021. Of those, 93 (14.2%) were eligible for analysis. We reviewed all parts of eligible studies and any published commentary. Fisher's exact statistics compared proportions of studies analyzing or reporting results for subgroups in 2021 compared with RCTs studied in previous waves. Posthoc analysis compared eligible RCTs about the Covid-19 pandemic to eligible RCTs on other topics. Results: Twenty-five of 93 studies (26.9%) analyzed or reported outcomes by race or ethnicity, an increase over previous years (p < 0.01). Among 79 RCTs with participants of both sexes, the median proportion of female participants was 43%. Moreover, 34 (43.0%) reported an outcome by sex, included sex as a covariate in statistical analysis, or reported results by sex, also an increase over previous waves (p < 0.01). Eleven eligible studies (11.8%) were on a SARS-CoV-2 topic; there was no difference between SARS-CoV-2 RCTs and RCTs on other topics. Conclusions: Analysis and reporting by sex, race, and ethnicity for NIH-funded RCTs published in 2021 significantly increased from previous waves, despite no corresponding increase in enrollment.

Treatment and survival of osseous renal cell carcinoma metastases.

BACKGROUND: Renal cell carcinoma is the seventh leading cause of cancer deaths. Studies have shown patients with solitary osseous metastases have a better prognosis; however, methods of resection are not well defined. The purpose of this study was to review factors associated with survival and assess the impact of wide versus intralesional management on function and disease-specific outcomes in patients with renal cell carcinoma metastases. METHODS: Sixty-nine patients with 86 osseous renal cell metastases were reviewed. Potential factors associated with survival were evaluated with Kaplan-Meier curves. ANOVA was performed to compare means between groups. RESULTS: One year survival for the group was 77% and 32.5% at 5 years. The absence of metastatic disease at presentation, nephrectomy, and pre-operative status were associated with improved survival. There was a lower rate of local recurrence with wide resection (5%) versus intralesional procedures (27%). CONCLUSIONS: Improved pre-operative status, nephrectomy, and metachronous lesions had better overall survival. Wide resection results in decreased local recurrence and revision surgeries. However, it did not reliably predict improved survival. Our recommendation is for individual evaluation of each patient with osseous renal cell carcinoma metastases. Wide excision may be used for resectable lesions to prevent local progression and subsequent surgeries.

Inhibition of HER-kinase activation prevents ERK-mediated degradation of PPARgamma.

R-etodolac, a nonsteroidal anti-inflammatory drug, inhibits the progression of CWRSA6 androgen-independent and LuCaP-35 androgen-dependent prostate cancer xenograft growth through downregulation of cyclin D1 expression via the PPARgamma pathway. PPARgamma protein degradation, observed post-R-etodolac treatment, resulted from phospho-MAP kinase (p44/42) induction by R-etodolac negatively regulating PPARgamma function. Negative regulation of PPARgamma was overcome by a combination regimen of R-etodolac with the HER-kinase axis inhibitor, rhuMab 2C4, which demonstrated an additive antitumor effect. We further show that the inhibition of HER-kinase activity by rhuMab 2C4 is sufficient to inhibit PPARgamma protein degradation. This study introduces a novel concept of an in vivo crosstalk between the HER-kinase axis and PPARgamma pathways, ultimately leading to negative regulation of PPARgamma activity and tumor growth inhibition.