Search PubMed⌕ Search

Biomedical subjects

A Rosen

Publications and source records attributed to A Rosen.

At least 55 records · Page 3Linked to original sources

Practice-related functional activation changes in a working memory task.

The effects of practice on the functional anatomy of a visuospatial working memory (VSWM) task were studied using functional Magnetic Resonance Imaging (fMRI). Functional imaging was conducted as subjects completed a moderate (Experiment 1) or extensive (Experiment 2) amount of practice on a delayed-match-to-sample task. While improvement in task performance was seen with practice, the task's dependence upon VSWM did not change. Activations in frontal (inferior, middle, and precentral gyri and superior frontal sulcus), parietal (intra-parietal sulcus, inferior parietal lobule, and precuneus) and cingulate (anterior and posterior) regions were observed as were bilateral insular and occipital activations. With the exception of the posterior cingulate, practice produced activation decreases in these regions, thus providing little evidence for a re-organization of the functional neuroanatomy. Fewer regions passing statistical criteria were observed at the end of practice relative to early in practice. Regions that were lost were mostly posterior (occipital and precuneus) but also included the left middle frontal gyrus, left precentral gyrus, and right insula suggesting that a more precise VSWM functional map can be observed once processes specific to encountering a novel task are removed. Little further activation changes were observed after extensive practice. These results suggest, minimally, that practice effects should be considered so as to avoid incorrectly attributing functional activation to a cognitive process of interest. Further, these data show that the dynamics of functional change can be tracked while a task is being learned and as an important cognitive process becomes more skilled.

Adult↗

Non-Invasive detection of respiratory effort-related arousals (REras) by a nasal cannula/pressure transducer system.

STUDY OBJECTIVES: The published AASM guidelines approve use of a nasal cannula/pressure transducer to detect apneas/hypopneas, but require esophageal manometry for Respiratory Effort-Related Arousals (RERAs). However, esophageal manometry may be poorly tolerated by many subjects. We have shown that the shape of the inspiratory flow signal from a nasal cannula identifies flow limitation and elevated upper-airway resistance. This study tests the hypothesis that detection of flow limitation events using the nasal cannula provides a non-invasive means to identify RERAs. DESIGN: N/A. SETTING: N/A. PATIENTS: 10 UARS/OSAS and 5 normal subjects INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: All subjects underwent full NPSG. Two scorers identified events from the nasal cannula signal as apneas, hypopneas, and flow limitation events. Two additional scorers identified events from esophageal manometry. Arousals were scored in a separate pass. Interscorer reliability and intersignal agreement were assessed both without and with regard to arousal. The total number of respiratory events identified by the two scorers of the nasal cannula was similar with an Intraclass Correlation (ICC) =0.96, and was essentially identical to the agreement for the two scorers of esophageal manometry (ICC=0.96). There was good agreement between the number of events detected by the two techniques with a slight bias towards the nasal cannula (4.5 events/hr). There was no statistically significant difference (bias 0.9/hr, 95%CI -0.3-2.0) between the number of nasal cannula flow limitation events terminated by arousal and manometry events terminated by arousal (RERAs). CONCLUSION: The nasal cannula/pressure transducer provides a non-invasive reproducible detector of all events in sleep disordered breathing; in particular, it detects the same events as esophageal manometry (RERAs).

Adult↗

Long-term clinical outcome in the Bypass Angioplasty Revascularization Investigation Registry: comparison with the randomized trial. BARI Investigators.

BACKGROUND: The Bypass Angioplasty Revascularization Investigation (BARI) included 4039 patients with multivessel coronary artery disease; 1829 consented to randomization, and 2010 did not but were followed up in a registry. Thus, we can evaluate the outcome of physician-guided versus random assignment of percutaneous transluminal coronary angioplasty (PTCA) versus coronary artery bypass graft surgery (CABG). METHODS AND RESULTS: We compared the baseline features and outcomes for PTCA and CABG in the overall registry and its predesignated subgroups. We assessed the impact of treatment by choice versus random assignment by comparing the results in the registry with those of the randomized trial. Statistical adjustments for differences in baseline characteristics were made. Within the registry, nearly twice as many patients were selected for PTCA (1189) as CABG (625); mortality at 7 years was similar for PTCA (13.9%) and CABG (14.2%) (P=0.66) before and after adjustment for baseline differences between patients selected for PTCA versus CABG (adjusted RR, 1.02; P=0.86). In contrast to the randomized trial, the 7-year mortality rate of treated diabetics in the registry was equally high (26%) with PTCA or CABG. Seven-year mortality was higher for patients undergoing PTCA in the randomized trial than in the registry (19.1% versus 13.9%, P<0.01) but not for those undergoing CABG (15.6% versus 14.2%, P=0.57). The adjusted relative mortality risk for PTCA in the randomized versus registry population was 1.17 (P=0.16). CONCLUSIONS: BARI physicians were able to select PTCA rather than CABG for 65% of registry patients who underwent revascularization without compromising long-term survival either in the overall population or in treated diabetics.

Angina Pectoris↗

The inhibition of apoptosis in myositis and in normal muscle cells.

The mechanism of injury and death of muscle cells in the inflammatory myopathies (dermatomyositis, polymyositis, and inclusion body myositis) remains obscure. We and others have not detected apoptosis in the muscle biopsies from patients with myositis despite clear evidence of cell damage and loss. We provide evidence in this study that Fas ligand (FasL) as well as Fas is present on muscle cells and inflammatory cells in myositis biopsies: Fas is present on most muscle cells and lymphocytes, and FasL is present on degenerating muscle cells and many infiltrating mononuclear cells. The expression of both Fas and FasL in the inflamed tissue makes the absence of apoptosis more striking. To address the mechanisms of this resistance to classical apoptosis in muscle cells, we have investigated the expression of the antiapoptotic molecule FLICE (Fas-associated death domain-like IL-1-converting enzyme)-inhibitory protein (FLIP) in muscle biopsies of myositis patients and in cultured human skeletal muscle cells. Using laser capture microscopy, we have shown that FLIP is expressed in the muscle fibers and on infiltrating lymphocytes of myositis biopsies. Furthermore, we have shown that FLIP, but not Bcl-2, is expressed in cultured human skeletal muscle cells stimulated with proinflammatory cytokines, and inhibition of FLIP with antisense oligonucleotides promotes significant cleavage of poly(ADP-ribose) polymerase autoantigen, a sensitive indicator of apoptosis. These studies strongly suggest that the resistance of muscle to Fas-mediated apoptosis is due to the expression of FLIP in muscle cells in the inflammatory environment in myositis.

Apoptosis↗

Caspase-2 is localized at the Golgi complex and cleaves golgin-160 during apoptosis.

Caspases are an extended family of cysteine proteases that play critical roles in apoptosis. Animals deficient in caspases-2 or -3, which share very similar tetrapeptide cleavage specificities, exhibit very different phenotypes, suggesting that the unique features of individual caspases may account for distinct regulation and specialized functions. Recent studies demonstrate that unique apoptotic stimuli are transduced by distinct proteolytic pathways, with multiple components of the proteolytic machinery clustering at distinct subcellular sites. We demonstrate here that, in addition to its nuclear distribution, caspase-2 is localized to the Golgi complex, where it cleaves golgin-160 at a unique site not susceptible to cleavage by other caspases with very similar tetrapeptide specificities. Early cleavage at this site precedes cleavage at distal sites by other caspases. Prevention of cleavage at the unique caspase-2 site delays disintegration of the Golgi complex after delivery of a pro-apoptotic signal. We propose that the Golgi complex, like mitochondria, senses and integrates unique local conditions, and transduces pro-apoptotic signals through local caspases, which regulate local effectors.

Apoptosis↗

[Laparoscopic surgery in treating hepatic cysts].

Solitary and multiple hepatic cysts are now more commonly found because of advances in imaging techniques. Most hepatic cysts are asymptomatic, but when they do cause symptoms they require surgical intervention. The advent of laparoscopy and of laparoscopic ultrasonography allow comprehensive evaluation and treatment of the cysts. 12 patients with hepatic cysts were treated laparoscopically. 8 with single cysts underwent successful subtotal cyst resection without signs of recurrence (up to 20 years of follow-up). 4 with polycystic liver disease underwent sub-total resection of superficial cysts. Deep cysts were unroofed and drained under laparoscopic ultrasound guidance. In this group, 1 experienced recurrence of symptoms and required partial hepatectomy of the involved segment. In another, a connection between a deep cyst and bile ducts was demonstrated and cystojejunostomy was performed. The laparoscopic approach in the management of patients with liver cysts is effective and safe, and we recommend it as the procedure of choice for single hepatic cysts. In polycystic liver disease the procedure is much less successful.

Adult↗

Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset.

STATEMENT OF FINDINGS: An inception cohort of 238 patients having peripheral joint synovitis of less than 12 months duration was evaluated clinically and followed prospectively for 1 year to determine the clinical significance of a number of rheumatoid arthritis (RA) associated autoantibodies. Serum samples collected at the time of the initial evaluation were tested for rheumatoid factor (RF) and antibodies to Sa (anti-Sa), RA-33, (pro)filaggrin [antifilaggrin antibody (AFA)], cyclic citrullinated peptide (anti-CCP), calpastatin, and keratin [antikeratin antibody (AKA)]. RF had a sensitivity of 66% and a specificity of 87% for RA. Anti-Sa, AFA, and anti-CCP all had a specificity of more than 90%, but a sensitivity of less than 50% for this diagnosis. Overall, there was a high degree of correlation between AFA, AKA, anti-Sa or anti-CCP, this being highest between anti-Sa and anti-CCP (odds ratio, 13.3; P < 0.001). Of the 101 patients who were positive for at least one of these four autoantibodies, 57% were positive for only one. Finally, anti-SA identified a subset of predominantly male RA patients with severe, erosive disease. Anti-SA, AFA and anti-CCP are all specific for early RA but, overall, have little additional diagnostic value over RF alone. Although these antibodies may preferentially recognize citrullinated antigens, the modest degree of concordance between them in individual patient sera suggests that it is unlikely a single antigen is involved in generating these responses.

Acute Disease↗

Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial.

CONTEXT: Despite evidence that methadone maintenance treatment (MMT) is effective for opioid dependence, it remains a controversial therapy because of its indefinite provision of a dependence-producing medication. OBJECTIVE: To compare outcomes of patients with opioid dependence treated with MMT vs an alternative treatment, psychosocially enriched 180-day methadone-assisted detoxification. DESIGN: Randomized controlled trial conducted from May 1995 to April 1999. SETTING: Research clinic in an established drug treatment service. PATIENTS: Of 858 volunteers screened, 179 adults with diagnosed opioid dependence were randomized into the study; 154 completed 12 weeks of follow-up. INTERVENTIONS: Patients were randomized to MMT (n = 91), which required 2 hours of psychosocial therapy per week during the first 6 months; or detoxification (n = 88), which required 3 hours of psychosocial therapy per week, 14 education sessions, and 1 hour of cocaine group therapy, if appropriate, for 6 months, and 6 months of (nonmethadone) aftercare services. MAIN OUTCOME MEASURES: Treatment retention, heroin and cocaine abstinence (by self-report and monthly urinalysis), human immunodeficiency virus (HIV) risk behaviors (Risk of AIDS Behavior scale score), and function in 5 problem areas: employment, family, psychiatric, legal, and alcohol use (Addiction Severity Index), compared by intervention group. RESULTS: Methadone maintenance therapy resulted in greater treatment retention (median, 438.5 vs 174.0 days) and lower heroin use rates than did detoxification. Cocaine use was more closely related to study dropout in detoxification than in MMT. Methadone maintenance therapy resulted in a lower rate of drug-related (mean [SD] at 12 months, 2.17 [3.88] vs 3.73 [6.86]) but not sex-related HIV risk behaviors and in a lower severity score for legal status (mean [SD] at 12 months, 0.05 [0.13] vs 0.13 [0.19]). There were no differences between groups in employment or family functioning or alcohol use. In both groups, monthly heroin use rates were 50% or greater, but days of use per month dropped markedly from baseline. CONCLUSIONS: Our results confirm the usefulness of MMT in reducing heroin use and HIV risk behaviors. Illicit opioid use continued in both groups, but frequency was reduced. Results do not provide support for diverting resources from MMT into long-term detoxification.

Adult↗

Annexin V binds to viable B cells and colocalizes with a marker of lipid rafts upon B cell receptor activation.

Recombinant annexin V (rAnV) has been used to identify apoptotic cells based on its ability to bind phosphatidylserine (PS), a lipid normally restricted to the cytoplasmic face of the plasma membrane, but externalized early during apoptosis. However, this association of rAnV binding and apoptosis is not an obligatory one. We demonstrate that rAnV binds to a large fraction of murine B cells bearing selectable Ag receptors despite the fact that these cells are not apoptotic. Phosphatidylserine, which is uniformly distributed on resting B cells, is mobilized to co-cap with IgM on anti-IgM-treated B cells and to colocalize with GM1, a marker of lipid rafts. Cross-linking PS before anti-IgM treatment sequesters this lipid and alters signaling through IgM. Thus, PS exposed on the majority of B cells in vivo does not reflect early apoptosis, but, instead, plays a role in receptor-mediated signaling events.

Animals↗

The impact of laparoscopy and laparoscopic ultrasonography on the management of pancreatic cancer.

HYPOTHESIS: Laparoscopy and laparoscopic ultrasonographic (LAPUS) examinations combined with a biopsy of the pancreatic lesion contribute significantly in the determination of resectability of pancreatic cancer. DESIGN: A prospective evaluation of the impact of laparoscopy and LAPUS on surgical decision making in patients with pancreatic cancer. SETTING: A general community hospital; the department of surgery serves as referral for pancreatic surgery. PATIENTS: During a 36-month period, 94 patients with pancreatic lesions were prospectively examined. Twenty-seven patients were found to have advanced disease. The remaining 67 patients were examined by laparoscopy and LAPUS to determine the resectability of the pancreatic tumor. RESULTS: Laparoscopy and LAPUS contributed new, additional data in 40 patients (60%). Advanced disease was found in 30 patients, precluding curative resection. The study indicated potentially resectable tumors in 37 patients (55%), including 3 defined by conventional imaging studies as probably unresectable, and these patients were operated on with the intention of curative resection. Thirty-three patients underwent resection, and 4 (6%) were found to have nonresectable disease and form the false-positive group of the study. A summary of the results shows that the study resulted in a change of the decision regarding surgical intervention in 24 patients (36%) and avoided unnecessary laparotomies in 21 (31%). The study had a sensitivity of 100%, a specificity of 88%, and a false-positive rate of 6%. The positive predictive value of the study is 89%, and the negative predictive value is 100%. CONCLUSIONS: Although rather invasive procedures that require general anesthesia and hospitalization, laparoscopy and LAPUS significantly contribute to the staging of patients with potentially resectable pancreatic cancer, avoiding unnecessary explorative laparotomies. These procedures should be performed in all patients with potentially resectable pancreatic cancer before explorative laparotomy.

Female↗

The impact of laparoscopy and laparoscopic ultrasound on the management of pancreatic cystic lesions.

HYPOTHESIS: Laparoscopic ultrasound examination combined with biopsy of the cystic wall and aspiration of cystic fluid improves differential diagnosis of pancreatic cystic lesions contributing to surgical decision making. STUDY DESIGN: A prospective evaluation of the impact of laparoscopic ultrasound on surgical decision making in patients with pancreatic cysts. SETTING: A general community hospital; the department of surgery serves as referral for pancreatic surgery. PATIENTS: During a 36-month period, 15 patients with pancreatic cystic lesions were prospectively evaluated by laparoscopy and laparoscopic ultrasound with ultrasound-guided biopsy of the cystic wall and aspiration of cystic fluid for cytologic study, viscosity, and determination of levels of amylase and tumor markers (carcinoembryonic antigen, cancer antigen 19.9). RESULTS: Laparoscopic ultrasound contributed new, additional data in 8 patients (53%) when compared with compiled imaging data obtained by conventional ultrasound, computed tomography, magnetic resonance imaging, and endoscopic ultrasound. A solid cystic component was detected in 6 patients and additional small (<1 cm) cysts in 3 patients. Amylase and tumor marker levels, biopsy of the cystic wall, and cytologic examination had significant impact on surgical decision making in 6 patients. Nine patients underwent resection of the cystic lesion. Three patients diagnosed as having benign cysts had laparoscopy with laparoscopic ultrasound only. Three patients with suspicious lesions refused surgery. Laparoscopic ultrasound predicted correctly the nature of the cyst in 7 of 9 surgically treated patients (sensitivity, 78%). Two patients with serous cystadenoma had high levels of tumor markers (false-positive). CONCLUSION: Although a rather invasive procedure that requires general anesthesia and hospitalization, laparoscopy with laparoscopic ultrasonography was found to significantly contribute to the differential diagnosis of pancreatic cystic lesions.

Adult↗

Quantitative FISH analysis and in vitro suspension cultures of erythroid cells from maternal peripheral blood for the isolation of fetal cells.

Several techniques for the enrichment of nucleated fetal red blood cells present in maternal blood have been reported. Here we describe the use of a quantitative fluorescence in situ hybridization (FISH) method and in vitro suspension cultures of erythroid cells from newborn cord blood and maternal peripheral blood. Together with a rapid high performance liquid chromatography (HPLC) method, that allows us to determine as few as 100 cells containing haemoglobin F (HbF), we have scrutinized the reported enrichment methods for fetal nucleated cells in peripheral maternal blood. One hundred FISH analyses on maternal peripheral blood were performed. The method comprises a cell lysis method for depletion of red cells with minimal losses of nucleated cells, uniform numbers of cells (750 000 cells each) on microscopic slides, and inclusion of internal controls to monitor the efficacy of hybridization. Twenty-six cultures of pure erythroid progenitor cells from maternal peripheral blood were analysed for the expansion of fetal cells. To generate these in vitro cultures, nucleated cells from 10-20 ml of peripheral blood from 26 pregnant women were grown in media containing growth factors and hormones to yield over 10(7) of immature erythroid cells within two weeks. Of those, 13 cultures were from pregnancies with confirmed male fetuses. A total of approximately 8x10(8) maternal cells were added into tissue culture medium for these 13 cultures, resulting in about 2x10(8) nearly pure erythroid cells after two weeks. Whereas fetal cells, alone or added into cultures of peripheral blood, grow rapidly and can be detected quantitatively, we could not find any fetal cells in cultures from maternal blood. Likewise, in 7.5x10(7) peripheral blood cells probed by FISH analysis (half of which were from pregnancies with male fetuses) no single Y chromosome was detected. In summary, suspension cultures of erythroid cells can be established routinely and easily. With the quantitative FISH technique used, 750 000 cells per slide can be screened reliably for cells with Y chromosomes. However, the stringent quality-criteria and most elaborate methods indicate that fetal cells in maternal peripheral blood can not be found using the current technology.

Cell Culture Techniques↗

Autoantibody recognition of distinctly modified forms of the U1-70-kd antigen is associated with different clinical disease manifestations.

OBJECTIVE: To examine whether autoantibody recognition of modified forms of the U1-70-kd RNP antigen correlates with manifestations of rheumatic disease. METHODS: Blinded to clinical disease manifestations, sera from 27 rheumatic disease patients with U1-70-kd antibodies were used to immunoblot control, apoptotic, and oxidatively modified HeLa cell lysates. Using densitometry, recognition of antigen fragments was quantitated. The presence or absence of 1) lupus skin disease and 2) Raynaud's phenomenon (RP) was determined for each patient by chart review. The ability of patient sera to recognize the different fragments was compared for patients with and without skin disease and with and without RP. RESULTS: Patients with lupus skin disease had higher recognition of apoptotic U1-70 kd than did patients without skin disease (mean +/- SD fragment recognition index [FRI] 1.35 +/- 0.57 versus 0.95 +/- 0.25; P < 0.024, by Student's t-test). Patients with RP had higher recognition of oxidatively modified U1-70 kd than did patients without RP (mean +/- SD FRI 0.95 +/- 0.80 versus 0.24 +/- 0.22; P < 0.048). CONCLUSION: Recognition of apoptotically and oxidatively modified forms of the U1-70-kd autoantigen are associated with distinct clinical rheumatic disease manifestations. This finding provides in vivo evidence for the hypothesis that immune recognition of modified forms of self antigens may be relevant to the pathogenesis of systemic rheumatic diseases. Understanding the antigenic modifications to which patients react may help predict the expression of rheumatic syndromes.

Antigens↗

Threshold Assessment Grid (TAG): the development of a valid and brief scale to assess the severity of mental illness.

BACKGROUND: Lack of consensus about the meaning of severe mental illness makes it difficult to prioritise the severely mentally ill for specialist mental health care. The goal of this study was to develop a valid and brief assessment of severity of mental illness. METHOD: Six search workshops (n = 57) using consensus techniques developed a draft assessment acceptable to users, carers, practitioners and policy makers. A two-round Delphi consultation (n = 58) was held to identify consensus on this instrument. RESULTS: Search workshops agreed seven domains relevant to identifying the severely mentally ill: intentional and unintentional self-harm, risk from and to others, and survival, psychological, and social needs and disabilities. The Delphi consultation indicated at least agreement with all aspects in both rounds. CONCLUSIONS: The Threshold Assessment Grid (TAG) is a brief method of identifying the severely mentally ill, which has adequate face, concurrent, construct and content validity.

Delphi Technique↗

Bone marrow cells inhibit the generation of autologous EBV-specific CTL.

Recently, we reported that human bone marrow cells (BMC) inhibited the proliferative (recall) response of lymphocytes to Epstein-Barr virus (EBV) and cytomegalovirus (CMV) protein antigens [12]. To clarify further the effect of BMC on the immune response to viral antigens, we obtained PBL from EBV IgG antibody positive kidney transplant recipients (R) and their living-related donors (LRD) 1 year after renal transplantation and generated EBV-specific CTL in vitro in the presence or absence of autologous BMC. The addition of freshly aspirated autologous iliac crest BMC from either R or LRD caused a significant inhibitory effect on the generation of EBV-specific CTL from CTL precursors, in contrast to the addition of autologous PBL used as controls (62.29 +/- 10.85% inhibition using BMC from the kidney transplant recipients; 74.47 +/- 15.21% inhibition using BMC from the living-related donors). This inhibitory effect was only exerted during the CTL generation phase; but not in the effector CTL killing phase. The expression of CD94, a component of the killer inhibitory receptor (KIR) on CD3(+) cells was elevated in the cultures with BMC, in contrast to the cultures without BMC. The BMC inhibitory effect was partially abrogated by pre-incubation of the CTL effectors with anti-CD94 monoclonal antibody, in contrast with its isotype control. In addition, supernatants obtained from the CTL generating cultures with BMC contained high levels of prostaglandin E(2) (PGE(2)), and EBV-specific CTL activity was inhibited by the addition of exogenous PGE(2) in the absence of BMC. The induction of CD40L cell surface expression by anti-CD3 was also decreased on the effector T cell population when BMC were added. There was a concomitant reduction in protein kinase C (PKC) activity. These studies demonstrate that BMC exert an inhibitory effect on T cell-mediated immunity to viral antigens in humans by regulating autologous effector T cell generation and early T cell activation signaling pathways.

Antigens, CD↗

Apoptosis in systemic lupus erythematosus. Clinical implications.

SLE is a heterogeneous and complex group of disorders of uncertain cause. Recent studies have suggested that abnormalities in the apoptotic cell death process may play an important role in the initiation and propagation of this spectrum of disease by altering the generation and cleavage of antigens, and through abnormalities in immunoregulation. The clustering and concentration of autoantigens in and on the surface blebs of apoptotic cells, modifications of antigen structure during certain forms of apoptotic death, and abnormalities in apoptotic cell clearance in humans with SLE and in certain animal models are reviewed and synthesized into a comprehensive model of systemic autoimmunity.

Animals↗

Ethics of early prevention in schizophrenia.

OBJECTIVE: To represent a cross-section of current thinking on the ethics of early (primary) prevention in schizophrenia. METHOD: Ethical considerations presented at the First Australian Schizophrenia Prevention Conference, Sydney, March 1999, particularly from the final session on 'Ethics', are recorded here together with complementary referenced material. RESULTS: Ethical concerns arise in the arenas of research over clinical priorities; screening ethics, including stigma, confidentiality, informed consent and support required through waiting periods; and the ethics of prolonged assessments in the absence of disorder, the right not to know and the possible ethical prematurity or otherwise of screening for schizophrenia. CONCLUSIONS: There are several legitimate ethical concerns that must be understood and addressed by those undertaking the developing of primary preventive measures in schizophrenia. Such measures must still be regarded as more experimental the further ahead the measures are undertaken from the onset of the disorder. Anticipatory ethical guidelines should be developed to inform such research.

Ethics, Medical↗