Management of adult patients with podocytopathies: an update from the ERA Immunonephrology Working Group.

The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are entities without immune complex deposits which can cause podocyte injury, thus are frequently grouped under the umbrella of podocytopathies. Whether MCD and FSGS may represent a spectrum of the same disease remains a matter of conjecture. Both frequently require repeated high-dose glucocorticoid therapy with alternative immunosuppressive treatments reserved for relapsing or resistant cases and response rates are variable. There is an unmet need to identify patients who should receive immunosuppressive therapies as opposed to those who would benefit from supportive strategies. Therapeutic trials focusing on MCD are scarce, and the evidence used for the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the management of glomerular diseases largely stems from observational and pediatric trials. In FSGS, the differentiation between primary forms and those with underlying genetic variants or secondary forms further complicates trial design. This article provides a perspective of the Immunonephrology Working Group (IWG) of the European Renal Association (ERA) and discusses the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases focusing on the management of MCD and primary forms of FSGS in the context of recently published evidence, with a special emphasis on the role of rituximab, cyclophosphamide, supportive treatment options and ongoing clinical trials in the field.

CONNECTing Concussion Care with Research Across Ontario.

Common data elements (CDEs) for concussion, as established by international bodies, are not being widely used in Ontario, resulting in significant variability in the data being assessed and collected across clinics. CDEs support standardization of care as well as large-scale data sharing for high impact research. A collaborative network - Concussion Ontario Network: Neuroinformatics to Enhance Clinical care and Translation (CONNECT) - comprised of health care professionals, researchers, members from advocacy groups, and patients was formed to establish and implement CDEs for concussion care and research. While the seeds have been planted and initial effectiveness demonstrated, future challenges exist.

An inosine triphosphate pyrophosphatase safeguards plant nucleic acids from aberrant purine nucleotides.

In plants, inosine is enzymatically introduced in some tRNAs, but not in other RNAs or DNA. Nonetheless, our data show that RNA and DNA from Arabidopsis thaliana contain (deoxy)inosine, probably derived from nonenzymatic adenosine deamination in nucleic acids and usage of (deoxy)inosine triphosphate (dITP and ITP) during nucleic acid synthesis. We combined biochemical approaches, LC-MS, as well as RNA-Seq to characterize a plant INOSINE TRIPHOSPHATE PYROPHOSPHATASE (ITPA) from A. thaliana, which is conserved in many organisms, and investigated the sources of deaminated purine nucleotides in plants. Inosine triphosphate pyrophosphatase dephosphorylates deaminated nucleoside di- and triphosphates to the respective monophosphates. ITPA loss-of-function causes inosine di- and triphosphate accumulation in vivo and an elevated inosine and deoxyinosine content in RNA and DNA, respectively, as well as salicylic acid (SA) accumulation, early senescence, and upregulation of transcripts associated with immunity and senescence. Cadmium-induced oxidative stress and biochemical inhibition of the INOSINE MONOPHOSPHATE DEHYDROGENASE leads to more IDP and ITP in the wild-type (WT), and this effect is enhanced in itpa mutants, suggesting that ITP originates from ATP deamination and IMP phosphorylation. Inosine triphosphate pyrophosphatase is part of a molecular protection system in plants, preventing the accumulation of (d)ITP and its usage for nucleic acid synthesis.

Crystal structure analysis of N-acetylated proline and ring size analogs.

Crystal structures of N-acetylated proline and homologs with four- and six-membered rings (azetidine carboxylic acid and piperidine carboxylic acid) were obtained and compared. The distinctly different conformations of the four-, five-, and six-membered rings reflect Bayer strain, n → π* interaction, and allylic strain, and result in crystal lattices with a zigzag structure.

Peptide-PAINT Enables Investigation of Endogenous Talin with Molecular Scale Resolution in Cells and Tissues.

Talin is a cell adhesion molecule that is indispensable for the development and function of multicellular organisms. Despite its central role for many cell biological processes, suitable methods to investigate the nanoscale organization of talin in its native environment are missing. Here, we overcome this limitation by combining single-molecule resolved PAINT (points accumulation in nanoscale topography) imaging with the IRIS (image reconstruction by integrating exchangeable single-molecule localization) approach, enabling the quantitative analysis of genetically unmodified talin molecules in cells. We demonstrate that a previously reported peptide can be utilized to specifically label the two major talin isoforms expressed in mammalian tissues with a localization precision of <10 nm. Our experiments show that the methodology performs equally well as state-of-the-art single-molecule localization techniques, and the first applications reveal a thus far undescribed cell adhesion structure in differentiating stem cells. Furthermore, we demonstrate the applicability of this peptide-PAINT technique to mouse tissues paving the way to single-protein imaging of endogenous talin proteins under physiologically relevant conditions.

Complement in Renal Disease as a Potential Contributor to Arterial Hypertension.

OBJECTIVE: Complement deposition is prevalent in kidney biopsies of patients with arterial hypertension and hypertensive nephropathy, but an association of hypertension and complement deposition or involvement of complement in the pathogenesis of hypertensive nephropathy has not been shown to date. METHODS: In this study, we analyzed complement C1q and C3c deposition in a rat model of overload and hypertension by subtotal nephrectomy (SNX) and in archival human renal biopsies from 217 patients with known hypertension and 91 control patients with no history of hypertension using semiquantitative scoring of C1q and C3c immunohistochemistry and correlation with parameters of renal function. To address whether complement was only passively deposited or actively expressed by renal cells, C1q and C3 mRNA expression were additionally analyzed. RESULTS: Glomerular C1q and C3c complement deposition were significantly higher in kidneys of hypertensive SNX rats and hypertensive compared to nonhypertensive patients. Mean arterial blood pressure (BP) in SNX rats correlated well with the amount of glomerular C1q and C3c deposition and with left ventricular weight, as an indirect parameter of high BP. Quantitative mRNA analysis showed that C3 was not only deposited but also actively produced by glomerular cells of hypertensive SNX rats and in human renal biopsies. Of note, in patients CKD-stage correlated significantly with the intensity of glomerular C3c staining, but not with that of C1q. CONCLUSION: Renal complement deposition correlated with experimental hypertension as well as the presence of hypertension in a variety of renal diseases. To answer the question, if and how exactly renal complement is causative for the pathogenesis of arterial hypertension in men, further studies are needed.

Does the public feel prepared to be substitute decision-makers? Gaps in preparedness and support for a high school curriculum: a national survey.

BACKGROUND: Substitute decision-makers (SDMs) make decisions on behalf of patients who do not have capacity, in line with previously expressed wishes, values and beliefs. However, miscommunications and poor awareness of previous wishes often lead to inappropriate care. Increasing public preparedness to communicate on behalf of loved ones may improve care in patients requiring an SDM. METHODS: We conducted an online survey in January 2019 with a representative sample of the Canadian population. The primary outcome was self-reported preparedness to be an SDM. The secondary outcome was support for a high school curriculum on the role of SDMs. The effect of socio-demographics, known enablers and barriers to acting as an SDM, and attitudes towards a high school curriculum were assessed using multivariate analysis. RESULTS: Of 1,000 participants, 53.1% felt prepared to be an SDM, and 75.4% stated they understood their loved one's values. However, only 55.6% reported having had a meaningful conversation with their loved one about values and wishes, and only 61.7% reported understanding the SDM role. Engagement in advance care planning for oneself was low (23.1%). Age, experience, training and comfort with communication were associated with preparedness in our multivariate analysis. A high school curriculum was supported by 61.1% of respondents, with 28.3% neutral and 10.6% against it. INTERPRETATION: There is a gap between perceived and actual preparedness to be an SDM. Many report understanding their loved one's values yet have not asked them about wishes in illness or end of life. The majority of respondents support high school education to improve preparedness.

Autonomic Dysregulation in Adolescent Concussion Is Sex- and Posture-Dependent.

OBJECTIVE: To study autonomic responses to postural changes in concussed adolescents. The influence of sex was also studied. DESIGN: Longitudinal cohort observational study. PARTICIPANTS: Concussed adolescents (CONC; n = 65; 26 male adolescents; age 15 ± 1 years, range = 12-18 years) and a control (CTRL) group of nonconcussed adolescents of similar age and sport (CTRL; n = 54; 29 male adolescents; age 14 ± 1 years, range = 12-18 years). INTERVENTIONS: Concussed participants were monitored through 6 weekly visits throughout usual physician care. Control participants underwent 2 visits separated by at least 1 week to account for intrapersonal variation in testing measures. MAIN OUTCOME MEASURES: Heart rate variability as the root mean square of successive differences in R-R intervals (RMSSD), heart rate (HR), and blood pressure [mean arterial pressure (MAP) and diastolic blood pressure (DBP)] were measured in supine, sitting, and standing postures. RESULTS: A mixed analysis of variance revealed a group × sex × posture interaction (P = 0.04) where seated values of RMSSD were less in concussed female participants versus control female participants (42 ± 4 vs 61 ± 7 ms; P = 0.01; Mann-Whitney rank test). Compared with CTRL, CONC exhibited increased pretesting seated DBP (69 ± 1 vs 74 ± 1 mm Hg; P < 0.01), MAP (83 ± 1 vs 86 ± 1 mm Hg; P = 0.02), and baseline seated HR (72 ± 1 vs 77 ± 2 bpm; P = 0.03). Values of DBP (P = 0.03) and MAP (P < 0.01) improved at clinical discharge, whereas the RMSSD in female participants did not (P > 0.5). Data are mean ± SEM. CONCLUSIONS: A modest reduction in female cardiac autonomic regulation was observed during seated postures. Alterations in seated concussed DBP and MAP, but not RMSSD, resolved at clinical discharge (median = 37 days). The results indicate that, in adolescents, concussion may impair cardiovagal function in a sex- and posture-dependent manner. The findings also suggest that BP metrics, but not RMSSD, are associated with clinical concussion recovery.

Determination of Background Concentrations of Ag, Pd, Pt and Au in Highly Mineralized Ground Waters at Sub-ng L-1 Concentrations by Online Matrix Separation/Pre-Concentration Coupled to ICP-SFMS.

Though not regulated in directives such as the Water Framework Directive of the European Union, the investigation of geogenic background concentrations of certain elements such as precious metals is of increasing interest, in particular for the early detection of a potential environmental pollution due to the increased use in various industrial and technological applications and in medicine. However, the precise and accurate quantification of precious metals in natural waters is challenging due to the complex matrices and the ultra-low concentrations in the (sub-) ng L-1 range. A methodological approach, based on matrix separation and pre-concentration on the strong anion exchange resin TEVA® Resin in an online mode directly coupled to ICP-SFMS, has been developed for the determination of Ag, Pt, Pd and Au in ground water. Membrane desolvation sample introduction was used to reduce oxide-based spectral interferences, which complicate the quantification of these metals with high accuracy. To overcome errors arising from matrix effects-in particular, the highly varying major ion composition of the investigated ground water samples-an isotope dilution analysis and quantification based on standard additions, respectively, were performed. The method allowed to process four samples per hour in a fully automated mode. With a sample volume of only 8 mL, enrichment factors of 6-9 could be achieved, yielding detection limits <1 ng L-1. Validation of the trueness was performed based on the reference samples. This method has been used for the analysis of the total concentrations of Ag, Pt, Pd and Au in highly mineralized ground waters collected from springs located in important geological fault zones of Austria's territory. Concentrations ranges of 0.21-64.2 ng L-1 for Ag, 0.65-6.26 ng L-1 for Pd, 0.07-1.55 ng L-1 for Pt and 0.26-1.95 ng L-1 for Au were found.

End-of-life care in patients with a highly transmissible respiratory virus: implications for COVID-19.

Symptom management and end-of-life care are core skills for all physicians, although in ordinary times many anesthesiologists have fewer occasions to use these skills. The current coronavirus disease (COVID-19) pandemic has caused significant mortality over a short time and has necessitated an increase in provision of both critical care and palliative care. For anesthesiologists deployed to units caring for patients with COVID-19, this narrative review provides guidance on conducting goals of care discussions, withdrawing life-sustaining measures, and managing distressing symptoms.

RéSUMé: La prise en charge des symptômes et les soins de fin de vie sont des compétences de base pour tous les médecins, bien qu'en temps ordinaire, de nombreux anesthésiologistes n'ont que peu d'occasions de mettre en pratique ces compétences. La pandémie actuelle de coronavirus 2019 (COVID-19) a provoqué un taux de mortalité significatif dans un court intervalle et a nécessité une augmentation des besoins en soins intensifs et en soins palliatifs. Destiné aux anesthésiologistes déployés dans les unités prenant soin de patients atteints de la COVID-19, ce compte rendu narratif offre des recommandations quant à la façon de mener les discussions à propos des objectifs de soins, du retrait des thérapies de soutien vital, et de la prise en charge de symptômes de détresse.

Concussion Symptoms Predictive of Adolescent Sport-Related Concussion Injury.

OBJECTIVE: To assess the predictive capability of the postconcussion symptom scale (PCSS) of the sport concussion assessment tool (SCAT) III to differentiate concussed and nonconcussed adolescents. DESIGN: Retrospective. SETTING: Tertiary. PARTICIPANTS: Sixty-nine concussed (15.2 ± 1.6 years old) and 55 control (14.4 ± 1.7 years old) adolescents. INDEPENDENT VARIABLES: Postconcussion symptom scale. MAIN OUTCOME MEASURE: Two-proportion z-test determined differences in symptom endorsement between groups. To assess the predictive power of the PCSS, we trained an ensemble classifier composed of a forest of 1000 decision trees to classify subjects as concussed, or not concussed, based on PCSS responses. The initial classifier was trained on all 22-concussion symptoms addressed in the PCSS, whereas the second classifier removed concussion symptoms that were not statistically significant between groups. RESULTS: Concussion symptoms common between groups were trouble falling asleep, more emotional, irritability, sadness, and anxious. After removal, analysis of the second classifier indicated that the 5 leading feature rankings of symptoms were headache, head pressure, light sensitivity, noise sensitivity, and "don't feel right," which accounted for 52% of the variance between groups. CONCLUSIONS: Collectively, self-reported symptoms through the PCSS can differentiate concussed and nonconcussed adolescents. However, predictability for adolescent patients may be improved by removing emotional and sleep domain symptoms.

Concussion in Adolescents Impairs Heart Rate Response to Brief Handgrip Exercise.

OBJECTIVE: Test the hypotheses that (1) concussion in adolescents impairs autonomic neural control of heart rate (HR), and (2) HR reactivity improves with symptom resolution. DESIGN: Observational, case-control. PARTICIPANTS: Nineteen concussed adolescents (8 female adolescents; age 15 ± 2 years) and 16 healthy controls (6 female adolescents, age 15 ± 2 years). INTERVENTION: All participants performed an isometric handgrip (IHG) at 30% maximum voluntary contraction lasting 30 seconds. Heart rate (electrocardiogram) and hemodynamic responses (photoplethysmographic Finometer) were recorded from 30 seconds of baseline and the last 10 seconds of handgrip. MAIN OUTCOME MEASURES: The HR response (ΔHR) at the onset of moderate-intensity IHG using a mixed 1-way analysis of variance. RESULTS: A group × time interaction (P < 0.005) indicated that handgrip evoked a greater ΔHR among control participants (13 ± 10 beats/min) compared with concussed (6.4 ± 6.3 beats/min; group P = 0.63; time P < 0.001; d = 0.77). CONCLUSION: These preliminary results suggest that a concussion impairs the ability to elevate HR at the exercise onset and, given the nature of the task, this could be interpreted to reflect reduced ability to withdraw cardiovagal control. Therefore, the data support the hypothesis of neural cardiac dysregulation in adolescents diagnosed with concussion. CLINICAL RELEVANCE: The IHG test could aid concussion diagnosis and support return-to-play decisions.

Evaluating the Effects of a Novel Neuromuscular Neck Training Device on Multiplanar Static and Dynamic Neck Strength: A Pilot Study.

Versteegh, TH, Dickey, JP, Emery, CA, Fischer, LK, MacDermid, JC, and Walton, DM. Evaluating the effects of a novel neuromuscular neck training device on multiplanar static and dynamic neck strength: A pilot study. J Strength Cond Res 34(3): 708-716, 2020-The neck serves an important function in damping the transference of acceleration forces between the head and the trunk, such as that occurring during contact sports or motor vehicle collisions. An inability to adequately dissipate forces has been proposed as a potential mechanism for clinical conditions such as whiplash or concussion, but current approaches to neck training may not be targeting the correct mechanisms. The purpose of this study was to explore the training effect of a novel neuromuscular strengthening protocol on dynamic and static neck strength. This was a quasiexperimental pilot study design with intervention (n = 8) and control (n = 10) groups. The intervention group was trained (twice/week, ∼10 minutes, for 7 weeks) on a training device that uses self-generated centripetal force to create a dynamic rotational resistance. This protocol is intended to target the ability of the neck muscles to perform coordinated multiplanar plyometric contractions. Both groups also continued with traditional neck strengthening that included training on a straight-plane, isotonic, 4-way neck machine. Performance on the training device showed improvement after routine practice within 1 week, as evidenced by a trend toward increased peak speed in revolutions per minute (RPM). After 7 weeks, peak RPM increased from 122.8 (95% confidence interval [CI], 91.3-154.4) to 252.3 (95% CI, 241.5-263.1). There was also a large positive effect size (Hedge's d, 0.68) in isometric composite (multiplane) neck strength favoring the intervention group over the control group (difference, 20 N; 95% CI, -8 to 48). The largest magnitude strength improvement in a single plane was in axial rotation and also favored the intervention group over the control group (Hedge's d, 1.24; difference, 46 N; 95% CI, 9-83). Future studies should explore whether the dynamic training presented here could help reduce the risk of sports concussion, whiplash, or other head-neck trauma.

Psychosoziale Arbeitsbedingungen und Burnout-Symptome in der stationären somatischen und psychiatrischen Gesundheits- und Krankenpflege.

Psychosocial working conditions and symptoms of burnout in somatic and psychiatric nursing Abstract. Background: While mental workload and stress among nurses are generally well-documented, differences within the nursing profession have hardly been investigated so far. Aim: This study aims to examine the differences and associations between psychosocial working conditions and symptoms of burnout of nurses working in somatic and psychiatric settings. Methods: A cross-sectional study has been conducted with employees in one somatic and one psychiatric hospital (n = 576). The Copenhagen Psychosocial Questionnaire and the Copenhagen Burnout Inventory were used to assess psychosocial workloads and burnout symptoms. The data analysis was carried out by univariate, bivariate and multivariate (regression) analyses. Results: About 50 % of respondents report at least a moderate level of symptoms of burnout with somatic nurses more frequently affected. While quantitative and physical demands are higher in somatic nursing, psychiatric nurses have a higher degree of emotional demands, socialß = 0.33) in somatic nursing and emotional demands (ß = 0.29) in psychiatric nursing serve as strongest predictors of burnout symptoms. Conclusions: Findings suggest specific profiles of psychosocial workload in somatic and psychiatric nursing as well as a high need for differentiated approaches for occupational health promotion.

Unforgettable force - crosstalk and memory of mechanosensitive structures.

The ability of cells to sense and respond to mechanical stimuli is crucial for many developmental and homeostatic processes, while mechanical dysfunction of cells has been associated with numerous pathologies including muscular dystrophies, cardiovascular defects and epithelial disorders. Yet, how cells detect and process mechanical information is still largely unclear. In this review, we outline major mechanisms underlying cellular mechanotransduction and we summarize the current understanding of how cells integrate information from distinct mechanosensitive structures to mediate complex mechanoresponses. We also discuss the concept of mechanical memory and describe how cells store information on previous mechanical events for different periods of time.

FI-ICP-TOFMS for quantification of biologically essential trace elements in cerebrospinal fluid - high-throughput at low sample volume.

In this work, we introduce a high-throughput quantitative multi-element method for biological fluids enabled by omitting sample preparation and an analysis time of a few seconds per sample. For the first time, flow injection of an undiluted cerebrospinal fluid (CSF) was combined to state-of-the-art ICP-TOFMS detection for multi-element analysis. Owing to the low sample volume and trace element concentrations of the CSF, flow injection methods with only 5 µL sample intake were used in combination with an icpTOF 2R TOF-based ICP-MS instrument. Due to the lack of certified reference materials for CSF analysis, a validated method employing open vessel digestion of the CSF material in combination with ICP-sectorfield-MS analysis was carried out and used as a reference. Additionally, the performance of the flow injection ICP-TOFMS was cross-validated by flow injection quadrupole-based ICP-MS/MS analysis using both external calibration and isotope dilution strategies. In the latter case, the sample had to be injected several times because of the need for tailored gas conditions for different elements. Overall, flow injection of biological fluids delivered quantitative values, which were in excellent agreement with the gold standard established by ICP-SFMS demonstrating the capability of ICP-TOFMS analysis in terms of resolution and sensitivity for the accurate quantification of trace elements in biological samples.

Reduced brain glutamine in female varsity rugby athletes after concussion and in non-concussed athletes after a season of play.

The purpose of this study was to use non-invasive proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) to monitor changes in prefrontal white matter metabolite levels and tissue microstructure in female rugby players with and without concussion (ages 18-23, n = 64). Evaluations including clinical tests and 3 T MRI were performed at the beginning of a season (in-season) and followed up at the end of the season (off-season). Concussed athletes were additionally evaluated 24-72 hr (n = 14), three months (n = 11), and six months (n = 8) post-concussion. Reduced glutamine at 24-72 hr and three months post-concussion, and reduced glutamine/creatine at three months post-concussion were observed. In non-concussed athletes (n = 46) both glutamine and glutamine/creatine were lower in the off-season compared to in-season. Within the MRS voxel, an increase in fractional anisotropy (FA) and decrease in radial diffusivity (RD) were also observed in the non-concussed athletes, and correlated with changes in glutamine and glutamine/creatine. Decreases in glutamine and glutamine/creatine suggest reduced oxidative metabolism. Changes in FA and RD may indicate neuroinflammation or re-myelination. The observed changes did not correlate with clinical test scores suggesting these imaging metrics may be more sensitive to brain injury and could aid in assessing recovery of brain injury from concussion.

Heart failure and palliative care in the emergency department.

OBJECTIVES: Heart failure is a common ED presentation that is underserved by palliative care services and is associated with significant morbidity and mortality. We sought to evaluate use of palliative care services in patients with heart failure presenting to the ED. The primary outcome studied was palliative care involvement. Secondary outcomes of the study were: (1) 1-year mortality, (2) ED visits, (3) hospital admissions and (4) heart failure clinic involvement. METHODS: We conducted a health records review of 500 patients with heart failure who presented to two Canadian academic hospital EDs from January to August 2013. RESULTS: Patients were of mean age 80.7 years, women (53.2%) and had significant comorbidities. Only 41% of all deceased patients at 1 year had any palliative care involvement. Of those with palliative care, 44 (76%) patients had less than 2 weeks of palliative care involvement prior to death. Compared with those with no palliative care, the 79 (15.8%) patients with palliative care involvement had a higher 1-year mortality rate (70.9% vs 18.8%) and more hospital admissions/year (1.4 vs 0.85) for heart failure. CONCLUSIONS: We found that few patients with heart failure had palliative care services. Additionally, the majority of those who have palliative care involvement do not meet current recommendations for early palliative care involvement in heart failure. This study suggests that the ED may be an appropriate setting to identify and refer high-risk patients with heart failure who could benefit from earlier palliative care involvement.

Common Data Elements for Concussion in Tertiary Care: Phase One in Ontario.

BACKGROUND: Standardized data collection for traumatic brain injury (TBI) (including concussion) using common data elements (CDEs) has strengthened clinical care and research capacity in the United States and Europe. Currently, Ontario healthcare providers do not collect uniform data on adult patients diagnosed with concussion. OBJECTIVE: The Ontario Concussion Care Strategy (OCCS) is a collaborative network of multidisciplinary healthcare providers, brain injury advocacy groups, patient representatives, and researchers with a shared vision to improve concussion care across the province, starting with the collection of standardized data. METHODS: The International Framework of Functioning Disability and Health was selected as the conceptual framework to inform the selection of CDEs. The CDEs recommended by the OCCS were identified using key literature, including the National Institute of Neurological Disorders and Stroke-Zurich Consensus Statements for concussion in sport and the Ontario Neurotrauma Foundation Concussion/mTBI clinical guidelines. RESULTS: The OCCS has recommended and piloted CDEs for Ontario that are readily available at no cost, clinically relevant, patient friendly, easy to interpret, and recognized by the international scientific community. CONCLUSIONS: The implementation of CDEs can help to shift Ontario toward internationally recognized standard data collection, and in so doing yield a more comprehensive evidence-based approach to care while also supporting rigorous research.