Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma.

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.

Quenching measurements of Kr 5p[3/2]2 ← ← 4p6 1S0 electronic transition using absorption spectra.

Quenching rate is an important parameter to include in fluorescence measurements that are aimed at quantifying the thermochemical field of a reacting flow. Traditionally, the quenching measurements were obtained at low pressures using the direct measurements of quenching times followed by a linear scaling to the desired pressure. This approach, however, cannot account for the possible deviation from the linear pressure scaling at elevated pressures due to three and multi-body collisions. Furthermore, the best accuracy on the quenching rate is obtained with ultra-short pulse lasers that are typically not readily available. This study offsets these limitations by demonstrating a new approach for making direct quenching measurements at atmospheric conditions and using nanosecond lasers. The quenching measurements are demonstrated in a krypton-perturber system, and the 5p[32]2←←4p 6 1 S 0 two-photon electronic transition is accessed. A theoretical construct is presented that relates the absorption spectral parameters and the integrated fluorescence signal to the quenching rate, referenced to a given species and conditions. Using this formulation, the relative quenching rates for different perturber species, namely, air, C H 4, C 2 H 4, and C O 2, are reported as measured at 1 atm and 300 K. As such, the present technique is limited to the measurement of the relative quenching rate, unlike the previous studies where absolute quenching rates are measured. Nonetheless, when the reference quenching rate is independently measured, the relative quenching rates can be converted to absolute values.

Monitoring groundwater quality with real-time data, stable water isotopes, and microbial community analysis: A comparison with conventional methods.

Groundwater provides much of the world's potable water. Nevertheless, groundwater quality monitoring programmes often rely on a sporadic, slow, and narrowly focused combination of periodic manual sampling and laboratory analyses, such that some water quality deficiencies go undetected, or are detected too late to prevent adverse consequences. In an effort to address this shortcoming, we conducted enhanced monitoring of untreated groundwater quality over 12 months (February 2019-February 2020) in four shallow wells supplying potable water in Finland. We supplemented periodic manual sampling and laboratory analyses with (i) real-time online monitoring of physicochemical and hydrological parameters, (ii) analysis of stable water isotopes from groundwater and nearby surface waters, and (iii) microbial community analysis of groundwater via amplicon sequencing of the 16S rRNA gene and 16S rRNA. We also developed an early warning system (EWS) for detecting water quality anomalies by automating real-time online monitoring data collection, transfer, and analysis - using electrical conductivity (EC) and turbidity as indirect water quality indicators. Real-time online monitoring measurements were largely in fair agreement with periodic manual measurements, demonstrating their usefulness for monitoring water quality; and the findings of conventional monitoring, stable water isotopes, and microbial community analysis revealed indications of surface water intrusion and faecal contamination at some of the studied sites. With further advances in technology and affordability expected into the future, the supplementary methods used here could be more widely implemented to enhance groundwater quality monitoring - by contributing new insights and/or corroborating the findings of conventional analyses.

Mixture fraction measurement in turbulent non-premixed MILD jet flame using Rayleigh scattering.

Turbulent combustion of jet flames in a hot diluted coflow of combustion products is conducive to the transition from conventional flamelet combustion to a regime of moderate or intense low oxygen dilution (MILD) combustion, which is commonly characterized by a very low emission and noise. MILD combustion is also characterized by distributed combustion where the net heat release is positive across the entire combustion domain. The turbulence/chemistry interactions in this regime that determine the flame structure, local temperature, and species distribution critically depend on the mixture fraction and scalar dissipation fields. However, there are no experimental tools to measure the mixture fraction field in a distributed (MILD) combustion regime. The present work offsets this limitation by demonstrating a Rayleigh scattering-based approach to measure mixture fraction in a turbulent ethylene MILD combustion zone. 1D counterflow flame simulations enabled mapping the locally calibrated Rayleigh scattering fields to mixture fractions in the fuel-rich regions. This approach also shows very low sensitivity to the local temperature and composition. Overall, the results provide compelling evidence that the distributed heat release does not significantly impact the turbulent processes of the flow-field for the conditions examined. The measurement uncertainty from this approach and its extension to more complex fuels are also discussed. The present technique is limited to mildly turbulent, fully MILD/distributed flame with representative scalar dissipation rates.

Enhanced on-chip frequency measurement using weak value amplification.

We present an integrated design to sensitively measure changes in optical frequency using weak value amplification with a multi-mode interferometer. The technique involves introducing a weak perturbation to the system and then post-selecting the data in such a way that the signal is amplified without amplifying the technical noise, as has previously been demonstrated in a free-space setup. We demonstrate the advantages of a Bragg grating with two band gaps for obtaining simultaneous, stable high transmission and high dispersion. The device is more robust and easily scalable than the free-space implementation, and provides amplified sensitivity compared to other methods of measuring changes in optical frequency on a chip, such as an integrated Mach-Zehnder interferometer.

Surface Water Intrusion, Land Use Impacts, and Bacterial Community Composition in Shallow Groundwater Wells Supplying Potable Water in Sparsely Populated Areas of a Boreal Region.

Rural communities often rely on groundwater for potable water supply. In this study, untreated groundwater samples from 28 shallow groundwater wells in Finland (<10 m deep and mostly supplying untreated groundwater to <200 users in rural areas) were assessed for physicochemical water quality, stable water isotopes, microbial water quality indicators, host-specific microbial source tracking (MST) markers, and bacterial community composition, activity, and diversity (using amplicon sequencing of the 16S rRNA gene and 16S rRNA). Indications of surface water intrusion were identified in five wells, and these indications were found to be negatively correlated, overall, with bacterial alpha diversity (based on amplicon sequencing of the 16S rRNA gene). High levels of turbidity, heterotrophs, and iron compromised water quality in two wells, with values up to 2.98 nephelometric turbidity units (NTU), 16,000 CFU/ml, and 2,300 µg/liter, respectively. Coliform bacteria and general fecal indicator Bacteroidales bacteria (GenBac3) were detected in 14 and 10 wells, respectively (albeit mostly at low levels), and correlations were identified between microbial, physicochemical, and environmental parameters, which may indicate impacts from nearby land use (e.g., agriculture, surface water, road salt used for deicing). Our results show that although water quality was generally adequate in most of the studied wells, the continued safe use of these wells should not be taken for granted. IMPORTANCE Standard physicochemical water quality analyses and microbial indicator analyses leave much of the (largely uncultured) complexity of groundwater microbial communities unexplored. This study combined these standard methods with additional analyses of stable water isotopes, bacterial community data, and environmental data about the surrounding areas to investigate the associations between physicochemical and microbial properties of 28 shallow groundwater wells in Finland. We detected impaired groundwater quality in some wells, identified potential land use impacts, and revealed indications of surface water intrusion which were negatively correlated with bacterial alpha diversity. The potential influence of surface water intrusion on groundwater wells and their bacterial communities is of particular interest and warrants further investigation because surface water intrusion has previously been linked to groundwater contamination, which is the primary cause of waterborne outbreaks in the Nordic region and one of the major causes in the United States and Canada.

Enhanced on-chip phase measurement by inverse weak value amplification.

Optical interferometry plays an essential role in precision metrology such as in gravitational wave detection, gyroscopes, and environmental sensing. Weak value amplification enables reaching the shot-noise-limit of sensitivity, which is difficult for most optical sensors, by amplifying the interferometric signal without amplifying certain technical noises. We implement a generalized form of weak value amplification on an integrated photonic platform with a multi-mode interferometer. Our results pave the way for a more sensitive, robust, and compact platform for measuring phase, which can be adapted to fields such as coherent communications and the quantum domain. In this work, we show a 7 dB signal enhancement in our weak value device over a standard Mach-Zehnder interferometer with equal detected optical power, as well as frequency measurements with 2 kHz sensitivity by adding a ring resonator.

The Escherichia coli MarA protein regulates the ycgZ-ymgABC operon to inhibit biofilm formation.

The Escherichia coli marRAB operon is a paradigm for chromosomally encoded antibiotic resistance. The operon exerts its effect via an encoded transcription factor called MarA that modulates efflux pump and porin expression. In this work, we show that MarA is also a regulator of biofilm formation. Control is mediated by binding of MarA to the intergenic region upstream of the ycgZ-ymgABC operon. The operon, known to influence the formation of curli fibres and colanic acid, is usually expressed during periods of starvation. Hence, the ycgZ-ymgABC promoter is recognised by σ38 (RpoS)-associated RNA polymerase (RNAP). Surprisingly, MarA does not influence σ38 -dependent transcription. Instead, MarA drives transcription by the housekeeping σ70 -associated RNAP. The effects of MarA on ycgZ-ymgABC expression are coupled with biofilm formation by the rcsCDB phosphorelay system, with YcgZ, YmgA and YmgB forming a complex that directly interacts with the histidine kinase domain of RcsC.

Interprofessional Attitudes and Interdisciplinary Practices for Older Adults With Back Pain Among Doctors of Chiropractic: A Descriptive Survey.

OBJECTIVE: The purpose of this study is to report on attitudes of doctors of chiropractic (DCs) toward integrative medicine and their self-reported interdisciplinary practices for older adults with back pain. METHODS: This descriptive survey was conducted with licensed DCs in a Midwestern community in the United States. Respondents completed a 53-item postal survey of demographics, practice characteristics, referral and co-management patterns, attitudes toward interdisciplinary practice, and the Integrative Medicine-30 Questionnaire (IM-30). Descriptive statistical analysis was performed. RESULTS: Fifty-seven DCs completed the survey (29% response). Geriatric-focused chiropractic practices were uncommon (<15%), although 56% reported that 25% to 49% of the patients treated each week were older adults. Respondents had a moderate orientation toward collaboration with other health care providers (IM-30 mean [standard deviation] 61.3 [11.5]). The IM-30 subscales placed DCs high on measures of integrative medicine safety; moderate on patient-centeredness, openness to working with other providers, and referral readiness; and low on learning from alternative paradigms. Doctors of chiropractic most referred older patients to neurologists, family physicians, massage therapists, orthopedists, and other chiropractors. Doctors of chiropractic reported the highest levels of co-management with family physicians, physical therapists, and massage therapists. Most DCs (92%) were confident in their own ability to manage back pain in older adults, with modest confidence expressed for treatments from professionals using manual therapies. Most (77%) responded that older patients would experience the most improvement if DCs collaborated with another chiropractor, rather than with medical professionals. CONCLUSION: Doctors of chiropractic in one geographic community are moderately oriented toward interprofessional practice with other health care providers for older adults with back pain. Follow-up studies in representative national and international samples are recommended.

Interdisciplinary Practice Models for Older Adults With Back Pain: A Qualitative Evaluation.

Purpose: Older adults seek health care for low back pain from multiple providers who may not coordinate their treatments. This study evaluated the perceived feasibility of a patient-centered practice model for back pain, including facilitators for interprofessional collaboration between family medicine physicians and doctors of chiropractic. Design and Methods: This qualitative evaluation was a component of a randomized controlled trial of 3 interdisciplinary models for back pain management: usual medical care; concurrent medical and chiropractic care; and collaborative medical and chiropractic care with interprofessional education, clinical record exchange, and team-based case management. Data collection included clinician interviews, chart abstractions, and fieldnotes analyzed with qualitative content analysis. An organizational-level framework for dissemination of health care interventions identified norms/attitudes, organizational structures and processes, resources, networks-linkages, and change agents that supported model implementation. Results: Clinicians interviewed included 13 family medicine residents and 6 chiropractors. Clinicians were receptive to interprofessional education, noting the experience introduced them to new colleagues and the treatment approaches of the cooperating profession. Clinicians exchanged high volumes of clinical records, but found the logistics cumbersome. Team-based case management enhanced information flow, social support, and interaction between individual patients and the collaborating providers. Older patients were viewed positively as change agents for interprofessional collaboration between these provider groups. Implications: Family medicine residents and doctors of chiropractic viewed collaborative care as a useful practice model for older adults with back pain. Health care organizations adopting medical and chiropractic collaboration can tailor this general model to their specific setting to support implementation.

Patient-centered professional practice models for managing low back pain in older adults: a pilot randomized controlled trial.

BACKGROUND: Low back pain is a debilitating condition for older adults, who may seek healthcare from multiple providers. Few studies have evaluated impacts of different healthcare delivery models on back pain outcomes in this population. The purpose of this study was to compare clinical outcomes of older adults receiving back pain treatment under 3 professional practice models that included primary medical care with or without chiropractic care. METHODS: We conducted a pilot randomized controlled trial with 131 community-dwelling, ambulatory older adults with subacute or chronic low back pain. Participants were randomly allocated to 12 weeks of individualized primary medical care (Medical Care), concurrent medical and chiropractic care (Dual Care), or medical and chiropractic care with enhanced interprofessional collaboration (Shared Care). Primary outcomes were low back pain intensity rated on the numerical rating scale and back-related disability measured with the Roland-Morris Disability Questionnaire. Secondary outcomes included clinical measures, adverse events, and patient satisfaction. Statistical analyses included mixed-effects regression models and general estimating equations. RESULTS: At 12 weeks, participants in all three treatment groups reported improvements in mean average low back pain intensity [Shared Care: 1.8; 95% confidence interval (CI) 1.0 to 2.6; Dual Care: 3.0; 95% CI 2.3 to 3.8; Medical Care: 2.3; 95% CI 1.5 to 3.2)] and back-related disability (Shared Care: 2.8; 95% CI 1.6 to 4.0; Dual Care: 2.5; 95% CI 1.3 to 3.7; Medical Care: 1.5; 95% CI 0.2 to 2.8). No statistically significant differences were noted between the three groups on the primary measures. Participants in both models that included chiropractic reported significantly better perceived low back pain improvement, overall health and quality of life, and greater satisfaction with healthcare services than patients who received medical care alone. CONCLUSIONS: Professional practice models that included primary care and chiropractic care led to modest improvements in low back pain intensity and disability for older adults, with chiropractic-inclusive models resulting in better perceived improvement and patient satisfaction over the primary care model alone. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01312233 , 4 March 2011.

Jefferson Teamwork Observation Guide (JTOG): An Instrument to Observe Teamwork Behaviors.

Interprofessional education (IPE) is becoming an integral part of the education of health professions students. However, teaching students to become successful members of interprofessional teams is complex, and it is important for students to learn the combinations of skills necessary for teams to function effectively. There are many instruments available to measure many features related to IPE. However, these instruments are often too cumbersome to use in an observational situation since they tend to be lengthy and contain many abstract characteristics that are difficult to identify. The Jefferson Teamwork Observation Guide (JTOG) is a short tool that was created for students early in their educational program to observe teams in action with a set of guidelines to help them focus their observation on behaviors indicative of good teamwork. The JTOG was developed over a 2-year period based on student and clinician feedback and the input of experts in IPE. While initially developed as a purely educational tool for prelicensure students, it is becoming clear that it is an easy-to-use instrument that assesses the behavior of clinicians in practice.

ENABLING SMART MANUFACTURING TECHNOLOGIES FOR DECISION-MAKING SUPPORT.

Smart manufacturing combines advanced manufacturing capabilities and digital technologies throughout the product lifecycle. These technologies can provide decision-making support to manufacturers through improved monitoring, analysis, modeling, and simulation that generate more and better intelligence about manufacturing systems. However, challenges and barriers have impeded the adoption of smart manufacturing technologies. To begin to address this need, this paper defines requirements for data-driven decision making in manufacturing based on a generalized description of decision making. Using these requirements, we then focus on identifying key barriers that prevent the development and use of data-driven decision making in industry as well as examples of technologies and standards that have the potential to overcome these barriers. The goal of this research is to promote a common understanding among the manufacturing community that can enable standardization efforts and innovation needed to continue adoption and use of smart manufacturing technologies.

Prevention in dangerous industries: does safety certification prevent tree-faller injuries?

OBJECTIVES: The aim of this study was to evaluate if safety certification reduces the risk of work injury among experienced manual tree-fallers. METHODS: This study used a retrospective cohort study design. Experienced manual tree-fallers employed in the Canadian province of British Columbia (N=3251) between 2003-2008 were enumerated from a mandatory faller registry. Registry records with demographic and certification data were linked to workers' compensation claims for injury outcomes. Data were analyzed using discrete time survival analysis over a two-year period, centered on certification date with pre- and post-certification demarcated into four three-month periods. Models were adjusted for demographic, occupation/industry, previous injury, and seasonal/temporal effects. RESULTS: The relative risk (RR) of work injury during the post certification periods were elevated in comparison to the pre-certification reference period, but the 95% confidence intervals included "1" for all estimates by the end of follow-up, suggesting no statistically significant increased risk of injury. Results were consistent across different outcome measures of acute injury (ie, fracture or amputations) (N=186), musculoskeletal injury (ie, back strain) (N=137), and serious injury claims (ie, long duration, high cost and/or fatal) (N=155). CONCLUSION: Certification did not reduce the risk of work injury among experienced tree-fallers in the province of British Columbia. Non-statistically significant increases in the observed risk of work injury in the months immediately following certification may be attributable to an intervention effect or a methodological limitation related to a lack of individual-level, time-at-risk exposure data.

Power-recycled weak-value-based metrology.

We improve the precision of the interferometric weak-value-based beam deflection measurement by introducing a power recycling mirror, creating a resonant cavity. This results in all the light exiting to the detector with a large deflection, thus eliminating the inefficiency of the rare postselection. The signal-to-noise ratio of the deflection is itself magnified by the weak value. We discuss ways to realize this proposal, using a transverse beam filter and different cavity designs.

Using formal methods to scope performance challenges for Smart Manufacturing Systems: focus on agility.

Smart Manufacturing Systems (SMS) need to be agile to adapt to new situations by using detailed, precise, and appropriate data for intelligent decision-making. The intricacy of the relationship of strategic goals to operational performance across the many levels of a manufacturing system inhibits the realization of SMS. This paper proposes a method for identifying what aspects of a manufacturing system should be addressed to respond to changing strategic goals. The method uses standard modeling techniques in specifying a manufacturing system and the relationship between strategic goals and operational performance metrics. Two existing reference models related to manufacturing operations are represented formally and harmonized to support the proposed method. The method is illustrated for a single scenario using agility as a strategic goal. By replicating the proposed method for other strategic goals and with multiple scenarios, a comprehensive set of performance challenges can be identified.

Randomized trial to evaluate azithromycin's effects on serum and upper airway IL-8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis.

BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis in infancy is a major risk factor for recurrent wheezing and asthma. Because azithromycin attenuated neutrophilic airway inflammation in a murine viral bronchiolitis model, demonstration of similar effects in human subjects might provide a strategy for the prevention of postbronchiolitis recurrent wheezing. OBJECTIVES: We sought to investigate whether azithromycin treatment during RSV bronchiolitis reduces serum and nasal lavage IL-8 levels and the occurrence of postbronchiolitis recurrent wheezing. METHOD: We performed a randomized, double-masked, placebo-controlled proof-of-concept trial in 40 otherwise healthy infants hospitalized with RSV bronchiolitis who were treated with azithromycin or placebo for 14 days. IL-8 levels were measured in nasal lavage fluid and serum on randomization, day 8, and day 15 (nasal lavage only). The occurrence of wheezing episodes was assessed monthly over the ensuing 50 weeks. RESULTS: Compared with placebo, azithromycin treatment did not reduce serum IL-8 levels at day 8 (P = .6) but resulted in a greater decrease in nasal lavage fluid IL-8 levels by day 15 (P = .03). Twenty-two percent of azithromycin-treated participants experienced at least 3 wheezing episodes compared with 50% of participants in the placebo group (P = .07). Azithromycin treatment resulted in prolonged time to the third wheezing episode (P = .048) and in fewer days with respiratory symptoms over the subsequent year in comparison with placebo (36.7 vs 70.1 days, P = .01). CONCLUSION: In this proof-of-concept study azithromycin treatment during RSV bronchiolitis reduced upper airway IL-8 levels, prolonged the time to the third wheezing episode, and reduced overall respiratory morbidity over the subsequent year.

IDENTIFYING PERFORMANCE ASSURANCE CHALLENGES FOR SMART MANUFACTURING.

Smart manufacturing has the potential to address many of the challenges faced by industry. However, the manufacturing community often needs assistance to leverage available technologies to improve their systems. To assure the performance of these technologies, this paper proposes a shared knowledge base that collects problem areas, solutions, and best practices for manufacturing technology. An Implementation Risk Assessment Framework (IRAF) is also described to identify the primary weaknesses of technologies in specific manufacturing contexts. Such approaches have the potential to stimulate new ideas and drive standardization activities critical to scale up and deploy smart manufacturing technologies successfully and quickly.

The health mentors program: three years experience with longitudinal, patient-centered interprofessional education.

Increased emphasis on team care has accelerated interprofessional education (IPE) of health professionals. The health mentors program (HMP) is a required, longitudinal, interprofessional curriculum for all matriculating students from medicine, nursing, occupational therapy, physical therapy, pharmacy, and couple and family therapy. Volunteer lay health mentors serve as educators. Student teams complete four modules over 2 years. A mixed-methods approach has been employed since program inception, evaluating 2911 students enrolled in HMP from 2007 to 2013. Program impact on 577 students enrolled from 2009-2011 is reported. Two interprofessional scales were employed to measure attitudes toward IPE and attitudes toward interprofessional practice. Focus groups and reflection papers provide qualitative data. Students enter professional training with very positive attitudes toward IPE, which are maintained over 2 years. Students demonstrated significantly improved attitudes toward team care, which were not different across programs. Qualitative data suggested limited tolerance for logistic challenges posed by IPE, but strongly support that students achieved the major program goals of understanding the roles of colleagues and understanding the perspective of patients. Ongoing longitudinal evaluation will further elucidate the impact on future practice and patient outcomes.

Sustainability Characterization for Additive Manufacturing.

Additive manufacturing (AM) has the potential to create geometrically complex parts that require a high degree of customization, using less material and producing less waste. Recent studies have shown that AM can be an economically viable option for use by the industry, yet there are some inherent challenges associated with AM for wider acceptance. The lack of standards in AM impedes its use for parts production since industries primarily depend on established standards in processes and material selection to ensure the consistency and quality. Inability to compare AM performance against traditional manufacturing methods can be a barrier for implementing AM processes. AM process sustainability has become a driver due to growing environmental concerns for manufacturing. This has reinforced the importance to understand and characterize AM processes for sustainability. Process characterization for sustainability will help close the gaps for comparing AM performance to traditional manufacturing methods. Based on a literature review, this paper first examines the potential environmental impacts of AM. A methodology for sustainability characterization of AM is then proposed to serve as a resource for the community to benchmark AM processes for sustainability. Next, research perspectives are discussed along with relevant standardization efforts.