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.

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.

Two-dimensional plasma density evolution local to the inversion layer during sawtooth crash events using beam emission spectroscopy.

We present methods for analyzing Beam Emission Spectroscopy (BES) data to obtain the plasma density evolution associated with rapid sawtooth crash events at the DIII-D tokamak. BES allows coverage over a 2D spatial plane, inherently local measurements, with fast time responses, and, therefore, provides a valuable new channel for data during sawtooth events. A method is developed to remove sawtooth-induced edge-light pulses contained in the BES data. The edge light pulses appear to be from the Dα emission produced by edge recycling during sawtooth events, and are large enough that traditional spectroscopic filtering and data analysis techniques are insufficient to deduce physically meaningful quantities. A cross-calibration of 64 BES channels is performed by using a novel method to ensure accurate measurements. For the large-amplitude density oscillations observed, we discuss and use the non-linear relationship between the BES signal δI/I0 and the plasma density variation δne/ne0. The 2D BES images cover an 8 × 20 cm2 region around the sawtooth inversion layer and show large-amplitude density oscillations, with additional significant spatial variations across the inversion layer that grows and peaks near the time of the temperature crash. The edge light removal technique and method of converting large-amplitude δI/I0 to δne/ne0 presented here may help analyze other impulsive MHD phenomena in tokamaks.

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].

The Skinner Burial of Ontario, Canada, and the Question of Paget's Disease in the Americas.

PURPOSE: To examine a possible case of Paget's disease of bone (PDB) in an Indigenous pre-contact male from Canada, individual D of the Skinner site in Ontario. METHODS: Radiographs, CT scan and histological analysis. RESULTS: The histological analysis revealed the mosaic pattern that characterizes PDB. CT scans show advanced sclerosis of the cranium and a diminished diplÓ§e with osteolytic lesions. CONCLUSIONS: The pathological features that have been identified are collectively characteristic of PDB. SIGNIFICANCE: The Skinner case advances our understanding of the global history and distribution of PDB. LIMITATIONS OF STUDY: Only two New World cases have been identified and neither has been studied in sufficient detail. SUGGESTIONS FOR FUTURE RESEARCH: The older individuals in precolonial New World skeletal series should be given CT scans, which are non-intrusive, to be followed by histological and genetic analyses when indicated.

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.

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 multi-approach assessment of land use effects on groundwater quality in a karstic aquifer.

Groundwater represents almost half of the drinking water worldwide and more than one third of water used for irrigation. Agro-industrial activities affect water resources in several manners; one of the most important is leaching of agrochemical residues. This research identifies the major contributors of changes in groundwater quality comparing two contrasting land uses in a karstic area of the Yucatan peninsula as case study. Using a multiple approach, we assess the impact of land use with physicochemical data, multivariate analyses, hydrogeochemistry and nitrate isotopic composition. We confirmed that agricultural land use has a greater impact on groundwater quality, observed in higher concentration of nitrates, ammonium, potassium and electrical conductivity. Seasonality has an influence on phosphates and the chemical composition of the groundwater, increasing the concentration of dissolved substances in the rainy season. There was a clear effect of manure application in the agricultural zone and the nitrate isotopic composition of groundwater points toward recharge in certain areas. We consider that seasonality and land use effects are intertwined and sometimes difficult to separate, likely because of land use intensity and hydrogeochemical process at a local scale. Finally, we observed poor groundwater quality in the agricultural area during the wet season; thus, it is desirable to maintain non-agricultural areas that provide groundwater of appropriate quality.

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.

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/.

Imaging Assessment of Partial Liquid Ventilation in Bronchopulmonary Dysplasia.

Partial liquid ventilation is proposed as an alternative ventilation strategy to reduce surface tension, increase alveolar recruitment, and decrease inflammation. Studied in acute respiratory distress and other indications, liquid ventilation is being revisited for infants with bronchopulmonary dysplasia. Perfluorooctyl bromide used for liquid ventilation is radiopaque, allowing radiographic visualization of lung liquid ventilation patterns that may provide additional insight into pulmonary pathophysiology. Current protocols utilize reduced liquid dosing, resulting in unique imaging features. We discuss optimal radiographic technique and report initial ultrasound evaluation results. With renewed interest in partial liquid ventilation, it may be helpful for pediatric radiologists to familiarize themselves with the clinical use and radiographic appearance of liquid ventilation material.

Blue Vision (Cyanopsia) Associated With TURP Syndrome: A Case Report.

There have been many complications associated with transurethral resection of the prostate (TURP), known as TURP syndrome. Of the various irrigation fluids used for TURP, glycine irrigant has been historically popular given its relatively low cost. It is also a nonconductive solution and only slightly hypoosmolar, reducing the risk of burn injury or significant hemolysis. However, there have been many case reports of central nervous system toxicity such as transient blindness and encephalopathy related to glycine toxicity. Here, we report blue vision (cyanopsia), which has never been reported as a symptom of TURP syndrome.