neuromaps: structural and functional interpretation of brain maps.

Imaging technologies are increasingly used to generate high-resolution reference maps of brain structure and function. Comparing experimentally generated maps to these reference maps facilitates cross-disciplinary scientific discovery. Although recent data sharing initiatives increase the accessibility of brain maps, data are often shared in disparate coordinate systems, precluding systematic and accurate comparisons. Here we introduce neuromaps, a toolbox for accessing, transforming and analyzing structural and functional brain annotations. We implement functionalities for generating high-quality transformations between four standard coordinate systems. The toolbox includes curated reference maps and biological ontologies of the human brain, such as molecular, microstructural, electrophysiological, developmental and functional ontologies. Robust quantitative assessment of map-to-map similarity is enabled via a suite of spatial autocorrelation-preserving null models. neuromaps combines open-access data with transparent functionality for standardizing and comparing brain maps, providing a systematic workflow for comprehensive structural and functional annotation enrichment analysis of the human brain.

Association of Bipolar Disorder With Major Adverse Cardiovascular Events: A Population-Based Historical Cohort Study.

OBJECTIVE: This study aimed to assess the association of bipolar disorder (BD) with risk of major adverse cardiac events (MACEs) after adjusting for established cardiovascular disease (CVD) risk factors. METHODS: We conducted a population-based historical cohort study using the Rochester Epidemiology Project. Patients older than 30 years with a clinical encounter from 1998 to 2000 with no prior MACE, atrial fibrillation, or heart failure were followed up through March 1, 2016. BD diagnosis was validated by chart review. Cox proportional hazards regression models were adjusted for established CVD risk factors, alcohol use disorder, other substance use disorders (SUDs), and major depressive disorder (MDD). RESULTS: The cohort included 288 individuals with BD (0.81%) and 35,326 individuals without BD as the reference group (Ref). Median (interquartile range) follow-up was 16.5 (14.6-17.5) years. A total of 5636 MACE events occurred (BD, 59; Ref, 5577). Survival analysis showed an association between BD and MACE (median event-free-survival rates: BD, 0.80; Ref, 0.86; log-rank p = .018). Multivariate regression adjusting for age and sex also yielded an association between BD and MACE (hazard ratio [HR] = 1.93; 95% confidence interval [CI] = 1.43-2.52; p < .001). The association remained significant after further adjusting for smoking, diabetes mellitus, hypertension, high-density lipoprotein cholesterol, and body mass index (HR = 1.66; 95% CI = 1.17-2.28; p = .006), and for alcohol use disorder, SUD, and MDD (HR = 1.56; 95% CI = 1.09-2.14; p = .010). CONCLUSIONS: In this study, BD was associated with an increased risk of MACE, which persisted after adjusting for established CVD risk factors, SUDs, and MDD. These results suggest that BD is an independent risk factor for major clinical cardiac disease outcomes.

Gradients of structure-function tethering across neocortex.

The white matter architecture of the brain imparts a distinct signature on neuronal coactivation patterns. Interregional projections promote synchrony among distant neuronal populations, giving rise to richly patterned functional networks. A variety of statistical, communication, and biophysical models have been proposed to study the relationship between brain structure and function, but the link is not yet known. In the present report we seek to relate the structural and functional connection profiles of individual brain areas. We apply a simple multilinear model that incorporates information about spatial proximity, routing, and diffusion between brain regions to predict their functional connectivity. We find that structure-function relationships vary markedly across the neocortex. Structure and function correspond closely in unimodal, primary sensory, and motor regions, but diverge in transmodal cortex, particularly the default mode and salience networks. The divergence between structure and function systematically follows functional and cytoarchitectonic hierarchies. Altogether, the present results demonstrate that structural and functional networks do not align uniformly across the brain, but gradually uncouple in higher-order polysensory areas.

The two-component system RstAB regulates production of a polysaccharide capsule with a role in virulence in the marine pathogen Photobacterium damselae subsp. damselae.

The marine bacterium Photobacterium damselae subsp. damselae (Pdd) causes disease in marine animals and humans. Previous studies demonstrated that mutation of the two-component system RstAB strongly impacts virulence of this pathogen, but the RstAB regulon has not been thoroughly elucidated. We here compared the transcriptomes of Pdd RM-71 and ΔrstA and ΔrstB derivatives using RNA-seq. In accordance with previous studies, RstAB positively regulated cytotoxins Dly, PhlyP and PhlyC. This analysis also demonstrated a positive regulation of outer membrane proteins, resistance against antimicrobials and potential virulence factors by this system. Remarkably, RstAB positively regulated two hitherto uncharacterised gene clusters involved in the synthesis of a polysaccharide capsule. Presence of a capsular layer in wild-type cells was confirmed by transmission electron microscopy, whereas rstA and rstB mutants were non-capsulated. Mutants for capsule synthesis genes, wza and wzc exhibited acapsular phenotypes, were impaired in resistance against the bactericidal action of fish serum and mucus, and were strongly impaired in virulence for fish, indicating a major role of capsule in virulence. Collectively, this study demonstrates that RstAB is a major positive regulator of key virulence factors including a polysaccharide capsule essential for full virulence in a pathogenic Photobacterium.

Suicidality and self-injurious behavior among adolescent social media users at psychiatric hospitalization.

BACKGROUND: The current study sought to examine the relationship between documented social media use and suicidality and self-injurious behaviors in adolescents at the time of psychiatric hospitalization. METHODS: We retrospectively identified adolescents (aged 12-17 years) hospitalized on an inpatient psychiatric unit during 1 year. Abstracted information included documented social media use, demographic variables, documented self-injurious behaviors, the Patient Health Questionnaire-9, and the Suicide Status Form-II. Logistic regression was implemented to examine the effect of social media use on the risk of self-injurious behaviors and suicidality. RESULTS: Fifty-six adolescents who used social media were identified and matched with 56 non-social media users. Those with reported social media use had significantly greater odds of self-injurious behaviors at admission (odds ratio, 2.55; 95% confidence intervals, 1.17-5.71; P = .02) vs youth without reported social media use. Adolescents with reported social media use also had greater odds of increased suicidal ideation and suicide risk than those with no reported use, but these relationships were not statistically significant. CONCLUSIONS: Social media use in adolescents with a psychiatric admission may be associated with the risk of self-injurious behaviors and could be a marker of impulsivity. Further work should guide the assessment of social media use as part of a routine adolescent psychiatric history.

Optimism and social support as contributing factors to spirituality in Cancer patients.

BACKGROUND/OBJECTIVE: The impact a cancer diagnosis and its treatment are affected by psychosocial factors and how these factors interrelate among themselves. The objective of this study was to analyze the relationship between optimism and social support in spiritual wellbeing in cancer patients initiating chemotherapy. METHODS: A cross-sectional, multi-center (15 sites), prospective study was conducted with 912 cancer patients who had undergone curative surgery for a stage I-III cancer and were to receive adjuvant chemotherapy. They completed the Functional Assessment of Chronic Illness-Spiritual Well-being Scale (FACIT-Sp), Life Orientation Test-Revised (LOT-R), and the Multidimensional Scale of Perceived Social Support (MSPSS). RESULTS: Significant differences on spirituality scales (meaning/peace and faith) were detected depending on age (≤ 65 vs > 65), sex, marital status, employment, and cancer treatment. Married or partnered participants had significantly higher meaning/peace scores compared to their non-partnered counterparts (p = 0.001). Women, > 65 years, unemployed, and patients treated with chemotherapy and radiotherapy had significantly higher faith scores versus men, ≤ 65 years, employed, and subjects only receiving adjuvant chemotherapy (all p < 0.030). Multivariate analyses indicated that meaning/peace and faith correlated positively with optimism and social support. CONCLUSION: During oncological treatment, the positive effects of optimism and social support exhibit a positive correlation with spiritual coping. A brief assessment evaluation of these factors can aid in identifying at risk for a worse adaptation to the disease.

Malignant otitis externa: An updated review.

Malignant otitis externa is a progressive infection of the external auditory canal and skull base. Pseudomonas aeruginosa is the most isolated microorganism and it affects mostly to diabetic, elderly, and immunocompromised individuals. Non-resolving otalgia and chronic otorrhea are the clinical manifestations presented. Facial nerve palsy is a common and well recognized complication. (Computed tomography) CT scan is useful for initial assessment, Technetium-99m is highly sensitive and is part of the protocol for diagnosis. Treatment should be individualized, with multidisciplinary cooperation among specialties. Management involves systemic antipseudomonal antibiotics and monitoring with radiologic techniques, it also involves the strict control of diabetes. It is essential to follow up the patients for at least a year post-treatment. In refractory malignant otitis externa and affection of facial nerve, surgical management is recommended. We reviewed the most recent studies on epidemiology, clinical manifestations, diagnosis, and treatment to provide an update on Malignant Otitis Externa that can offer an overview for clinical practice and future research.

Electrochemical Oxidation as a Tool for Generating Vitamin D Metabolites.

The electrochemical behavior of the vitamers cholecalciferol and ergocalciferol was investigated in order to determine whether it is possible to evaluate phase-I and phase-II metabolism of these steroids and yield metabolites that can serve as reference material. The vitamers were electrochemically-oxidized using an electrochemical system (ROXY™ EC system). The influence of pH value, solvent, and potential was evaluated. When using methanol or ethanol, the formation of artificial methoxy or ethoxy groups, respectively, was observed, while the use of acetonitrile did not show any formation of further functional groups. A neutral pH value and use of a constant potential led to the highest number of oxidation products with intensive signals. Additionally, a binding study between vitamin D and glucuronic acid as an example for phase-II conjugation was carried out. It was possible to detect adduct formation. Coupling mass spectrometry directly to electrochemistry (EC-MS) is a promising approach for generating vitamin D metabolites and/or yielding a number of metabolites without in vivo or in vitro test systems. It can support or even replace animal studies in the long-term and might be promising for yielding reference compounds.

Dementia Care at End of Life: Current Approaches.

PURPOSE OF REVIEW: Dementia is a progressive and life-limiting condition that can be described in three stages: early, middle, and late. This article reviews current literature on late-stage dementia. RECENT FINDINGS: Survival times may vary across dementia subtypes. Yet, the overall trajectory is characterized by progressive decline until death. Ideally, as people with dementia approach the end of life, care should focus on comfort, dignity, and quality of life. However, barriers prevent optimal end-of-life care in the final stages of dementia. Improved and earlier advanced care planning for persons with dementia and their caregivers can help delineate goals of care and prepare for the inevitable complications of end-stage dementia. This allows for timely access to palliative and hospice care, which ultimately improves dementia end-of-life care.

Electrochemical Oxidation of Primary Bile Acids: A Tool for Simulating Their Oxidative Metabolism?

Bile acids are a subgroup of sterols and important products of cholesterol catabolism in mammalian organisms. Modifications (e.g., oxidation and 7-dehydroxylation) are predominantly exerted by the intestinal microbiota. Bile acids can be found in almost all living organisms, and their concentration and metabolism can be used for the assessment of the pathological and nutritional status of an organism. Electrochemical oxidation is a rapid, relatively inexpensive approach to simulate natural metabolic redox processes in vitro. This technique further allows the identification of oxidative degradation pathways of individual substances, as well as the demonstration of binding studies of generated oxidation products with biologically relevant molecules. When coupling an electrochemical and a high-resolution mass spectrometric system, oxidation products can be generated and identified directly by non-targeted ESI-MS. Here, a method for the generation of oxidation products of the primary bile acids cholic acid and chenodeoxycholic acid was exemplarily developed. Most products and the highest intensities were observed at a pH value of 6. For cholic acid, a high potential of 3 V was necessary, while for chenodeoxycholic acid, a potential of 2.4 V led to a higher number of oxidation products. In a second approach, a binding study with glutathione was performed to simulate phase II metabolism. It was possible to detect signals of free glutathione, free bile acids, and adducts of both reactants. As the resulting mass spectra also showed some new signals of the oxidized bile acid, which could not be observed without glutathione, it can be assumed that glutathione is able to bind reactive oxidation species before reacting with other products.

Ocular Ultrasonography and Biometry in the Cinereous Vulture (Aegypius monachus).

To establish reference standards for ocular ultrasound and biometry, 24 cinereous vultures (Aegypius monachus) (45 eyes) underwent B-mode and A-mode ultrasonographic examination using a 12.5-MHz probe. The vultures were manually restrained without sedation, and the eyes were topically anesthetized. Biometry was performed in the sagittal plane for axial length of the globe (AGL), anterior chamber depth (ACD), lens thickness (LT), and vitreous chamber depth (VCD). Biometry of the pecten oculi (LP) was measured on images of transversal scan at 9 hours. Biometric findings were as follows: AGL=27.74 ± 0.77 mm, ACD=3.73 ± 0.62 mm, LT=5.41 ± 0.18 mm, VCD=18.60 ± 0.58 mm, and LP=10.21 ± 1.19 mm. No correlation was found between body weight and AGL. Right and left globe sizes were not significantly different, but AGL and VCD were significantly longer (P < .05) in male than in female vultures. Including diagnostic protocols such as ocular ultrasound may improve the ophthalmologic care of endangered raptors injured by blunt trauma, when opacities of the ocular media prevent examination of the internal ocular structures.

Overexpression of Dyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex.

The dual-specificity tyrosine phosphorylation-regulated kinase DYRK1A is a serine/threonine kinase involved in neuronal differentiation and synaptic plasticity and a major candidate of Down syndrome brain alterations and cognitive deficits. DYRK1A is strongly expressed in the cerebral cortex, and its overexpression leads to defective cortical pyramidal cell morphology, synaptic plasticity deficits, and altered excitation/inhibition balance. These previous observations, however, do not allow predicting how the behavior of the prefrontal cortex (PFC) network and the resulting properties of its emergent activity are affected. Here, we integrate functional, anatomical, and computational data describing the prefrontal network alterations in transgenic mice overexpressingDyrk1A(TgDyrk1A). Usingin vivoextracellular recordings, we show decreased firing rate and gamma frequency power in the prefrontal network of anesthetized and awakeTgDyrk1Amice. Immunohistochemical analysis identified a selective reduction of vesicular GABA transporter punctae on parvalbumin positive neurons, without changes in the number of cortical GABAergic neurons in the PFC ofTgDyrk1Amice, which suggests that selective disinhibition of parvalbumin interneurons would result in an overinhibited functional network. Using a conductance-based computational model, we quantitatively demonstrate that this alteration could explain the observed functional deficits including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome. SIGNIFICANCE STATEMENT: DYRK1Ais a major candidate gene in Down syndrome. Its overexpression results into altered cognitive abilities, explained by defective cortical microarchitecture and excitation/inhibition imbalance. An open question is how these deficits impact the functionality of the prefrontal cortex network. Combining functional, anatomical, and computational approaches, we identified decreased neuronal firing rate and deficits in gamma frequency in the prefrontal cortices of transgenic mice overexpressingDyrk1A We also identified a reduction of vesicular GABA transporter punctae specifically on parvalbumin positive interneurons. Using a conductance-based computational model, we demonstrate that this decreased inhibition on interneurons recapitulates the observed functional deficits, including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome.

Enantioselective Synthesis of Cyclobutenes by Intermolecular [2+2] Cycloaddition with Non-C2 Symmetric Digold Catalysts.

The enantioselective intermolecular gold(I)-catalyzed [2+2] cycloaddition of terminal alkynes and alkenes has been achieved using non-C2-chiral Josiphos digold(I) complexes as catalysts, by the formation of the monocationic complex. This new approach has been applied to the enantioselective total synthesis of rumphellaone A.

Associations Between Psychological Constructs and Cardiac Biomarkers After Acute Coronary Syndrome.

OBJECTIVE: Psychological constructs are associated with cardiovascular health, but the biological mechanisms mediating these relationships are unknown. We examined relationships between psychological constructs and markers of inflammation, endothelial function, and myocardial strain in a cohort of post-acute coronary syndrome (ACS) patients. METHODS: Participants (N = 164) attended study visits 2 weeks and 6 months after ACS. During these visits, they completed self-report measures of depressive symptoms, anxiety, optimism, and gratitude; and blood samples were collected for measurement of biomarkers reflecting inflammation, endothelial function, and myocardial strain. Generalized estimating equations and linear regression analyses were performed to examine concurrent and prospective relationships between psychological constructs and biomarkers. RESULTS: In concurrent analyses, depressive symptoms were associated with elevated markers of inflammation (interleukin-17: ß = .047; 95% confidence interval [CI] = .010-.083]), endothelial dysfunction (endothelin-1: ß = .020; 95% [CI] = .004-.037]), and myocardial strain (N-terminal pro-B-type natriuretic peptide: ß = .045; 95% [CI] = .008-.083]), independent of age, sex, medical variables, and anxiety, whereas anxiety was not associated with these markers in multivariable adjusted models. Optimism and gratitude were associated with lower levels of markers of endothelial dysfunction (endothelin-1: gratitude: ß = -.009; 95% [CI] = -.017 to - .001]; optimism: ß = -.009; 95% [CI] = -.016 to - .001]; soluble intercellular adhesion molecule-1: gratitude: ß = -.007; 95% [CI] = -.014 to - .000]), independent of depressive and anxiety symptoms. Psychological constructs at 2 weeks were not prospectively associated with biomarkers at 6 months. CONCLUSIONS: Depressive symptoms were associated with more inflammation, myocardial strain, and endothelial dysfunction in the 6 months after ACS, whereas positive psychological constructs were linked to better endothelial function. Larger prospective studies may clarify the directionality of these relationships. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01709669.

Levels of blood lead in Griffon vultures from a Wildlife Rehabilitation Center in Spain.

Lead is considered a highly toxic contaminant with important impacts to bird wildlife. Griffon vultures (Gyps fulvus) are a sensitive indicator of the level of environmental contamination due to their position at the top of the food chain and their dependence on human activities. The aim of this study was to assess susceptibility to lead intoxication in Griffon vultures admitted to Wildlife Rehabilitation Centers (WRC), measuring blood lead levels and determining if blood lead concentrations are related to clinical signs, hematological, biochemical or radiographic findings. Also, the influence of age, gender, body condition, season and primary cause of admission were evaluated. This study was realized in all Griffon vultures admitted during a period of one year in the Rehabilitation Center GREFA. Blood lead levels are measured by using anodic stripping voltammetry. In Griffon vultures, we observed that 26% of the analyzed birds presented lead levels above 20µg/dL with 74% below 20µg/dL ([Pb]<20 =9.34±5.60µg/dL). In our study, statistically significant differences were found for lead according to sex, season of admission to the center and body condition. A negative correlation was found between levels of metal and hematocrit. No association was found between clinical signs and blood lead levels in Griffon vultures, except for digestive signs as stasis and weight loss. On numerous occasions, the intoxication in this specie is related to ingestion of lead ammunition; however, we have not detected radiographic lead in our vultures. Compared with other studies, we generally found low levels of lead in blood of Griffon vultures but the blood of all birds admitted to WRC presented detectable lead concentrations. This species apparently presents a higher sensibility to the toxic effects of this metal than that described by other authors. It have been observed that there is some evidence that suggests that subclinical levels of lead could be related with a predisposition to injury or diseases, even though these birds might be admitted for other causes. The detection of levels of blood lead in animals that are admitted to a recovery center will give valuable information which could be used to monitor spatial and temporal variations and provide a clearer picture of temporal levels of this contaminant in this emblematic avian specie.

Cost-Effectiveness of a Collaborative Care Depression and Anxiety Treatment Program in Patients with Acute Cardiac Illness.

OBJECTIVE: To use data from a randomized trial to determine the cost-effectiveness of a collaborative care (CC) depression and anxiety treatment program and to assess effects of the CC program on health care utilization. METHODS: The CC intervention's impact on health-related quality of life, depression-free days (DFDs), and anxiety-free days (AFDs) over the 24-week postdischarge period was calculated and compared with the enhanced usual care (EUC) condition using independent samples t tests and random-effects regression models. Costs for both the CC and EUC conditions were calculated on the basis of staff time, overhead expenses, and treatment materials. Using this information, incremental cost-effectiveness ratios were calculated. A cost-effectiveness acceptability plot was created using nonparametric bootstrapping with 10,000 replications, and the likelihood of the CC intervention's cost-effectiveness was assessed using standard cutoffs. As a secondary analysis, we determined whether the CC intervention led to reductions in postdischarge health care utilization and costs. RESULTS: The CC intervention was more costly than the EUC intervention ($209.86 vs. $34.59; z = -11.71; P < 0.001), but was associated with significantly greater increases in quality-adjusted life-years (t = -2.49; P = 0.01) and DFDs (t = -2.13; P = 0.03), but not AFDs (t = -1.92; P = 0.057). This translated into an incremental cost-effectiveness ratio of $3337.06 per quality-adjusted life-year saved, $13.36 per DFD, and $13.74 per AFD. Compared with the EUC intervention, the CC intervention was also associated with fewer emergency department visits but no differences in overall costs. CONCLUSIONS: This CC intervention was associated with clinically relevant improvements, was cost-effective, and was associated with fewer emergency department visits in the 24 weeks after discharge.

Positive Psychology Interventions for Patients With Heart Disease: A Preliminary Randomized Trial.

BACKGROUND: Positive psychologic characteristics have been linked to superior cardiac outcomes. OBJECTIVE: Accordingly, in this exploratory study, we assessed positive psychology interventions in patients who had recently undergone a procedure to treat cardiovascular disease. METHOD: Participants were randomly assigned to receive 1 of 3 different 6-week face-to-face interventions or a wait-list control condition. We assessed intervention feasibility and compared changes in psychologic outcome measures postintervention (7wk) and at follow-up (15wk) between intervention and control participants. Across the interventions, 74% of assigned sessions were completed. RESULTS: When comparing outcomes between interventions and control participants (N = 55 total), there were no between-group differences post-intervention, but at follow-up intervention participants had greater improvements in happiness (ß = 14.43, 95% CI: 8.66-20.2, p < 0.001), depression (ß = -3.87, 95% CI: -7.72 to 0.02, p = 0.049), and hope (ß = 7.12, 95% CI: 1.25-13.00, p =0.017), with moderate-large effect sizes. Efficacy of the 3 interventions was similar. CONCLUSIONS: Future studies are needed to identify an optimal positive psychology intervention for cardiac patients.

Effects of Positive Psychology Interventions on Risk Biomarkers in Coronary Patients: A Randomized, Wait-List Controlled Pilot Trial.

BACKGROUND: Among cardiac patients, positive psychologic factors are consistently linked with superior clinical outcomes and improvement in key markers of inflammation and hypothalamic-pituitary-adrenal axis functioning. Further, positive psychology interventions (PPI) have effectively increased psychologic well-being in a wide variety of populations. However, there has been minimal study of PPIs in cardiac patients, and no prior study has evaluated their effect on key prognostic biomarkers of cardiac outcome. Accordingly, we investigated the effect of 3 distinct PPIs on risk biomarkers in cardiac patients. METHODS: In an exploratory trial, 69 patients with recent coronary artery bypass graft surgery or percutaneous intervention were randomized to (1) one of three 6-week in-person PPIs (based on the work of Seligman, Lyubomirsky, or Fordyce) or (2) a wait-list control group. Risk biomarkers were assessed at baseline, postintervention (7 weeks), and at 15-week follow-up. Between-group differences in change from baseline biomarker levels were examined via random effects models. RESULTS: Compared with the control group, participants randomized to the Seligman (B = -2.06; p = 0.02) and Fordyce PPI (B = -1.54; p = 0.04) had significantly lower high-sensitivity C-reactive protein levels at 7 weeks. Further, the Lyubomirsky PPI (B = -245.86; p = 0.04) was associated with a significantly lower cortisol awakening response at 7 weeks when compared with control participants. There were no other significant between-group differences. CONCLUSION: Despite being an exploratory pilot study with multiple between-group comparisons, this initial trial offers the first suggestion that PPIs might be effective in reducing risk biomarkers in high-risk cardiac patients.

Understanding motivations to participate in an observational research study: Why do patients enroll?

By understanding common motivations for participating in observational research studies, clinicians may better understand the perceived benefits of research participation from their clients' perspective. We enrolled 164 cardiac patients in a study about the effects of gratitude and optimism. Two weeks post-enrollment, participants completed a four-item questionnaire regarding motivations for study enrollment. Altruistic motivation ranked highest, while intellectual, health-related, and financial motivations rated lower. Four subgroups of participants emerged, each with distinct characteristics and different priorities for participating. These findings may help front-line clinicians to understand which motivations for participation apply to their clients who enroll in non-treatment-based research projects.