Transition from electromagnetically-induced transparency to absorption in a single microresonator.

Electromagnetically induced transparency (EIT) and absorption (EIA) are two phenomena that can be observed in whispering-gallery-mode (WGM) optical microresonators. Transition from EIT to EIA has potential applications in optical switching, filtering and sensing. In this paper an observation of the transition from EIT to EIA in a single WGM microresonator is presented. A fiber taper is used to couple light into and out of a sausage-like microresonator (SLM) that contains two coupled optical modes with significantly different quality factors. By stretching the SLM axially the resonance frequencies of the two coupled modes are tuned to the same, a transition from EIT to EIA is then observed in the transmission spectra when the fiber taper is moved closer to the SLM. It is the special spatial distribution of the optical modes of the SLM that provide a theoretical basis for the observation.

Burnout and resilience among pharmacy technicians: A Singapore study.

BACKGROUND: Burnout describes emotional exhaustion (EE), depersonalization (DP), and low personal achievement caused by work and is known to bring about negative consequences to practitioners, patients, and health systems. Various organizational and personal factors, such as organizational strategies and resilience, have been associated with this phenomenon. However, there is a paucity of data describing the prevalence of burnout among pharmacy staff within Singapore and Asia, especially in the pharmacy technician (PT) population. OBJECTIVES: This study aimed to (1) quantify burnout in PTs in patient-care sectors in Singapore and (2) explore factors that may be associated with burnout. METHODS: A cross-sectional survey among PTs in patient-care areas in Singapore, which includes hospitals, primary and secondary care institutions, and retail pharmacies, across both public and private sectors was conducted from February to April 2020. The Maslach Burnout Inventory - Human Services Survey and Brief Resilience Scale were used to assess burnout and resilience among participants. Demographic, employment, and well-being information were also collected and summarized. Univariate analysis and multivariate logistic regression were used to assess associations between burnout and potential risk and impact factors. RESULTS: Slightly more than half (52.0%) of PTs reported burnout (EE score ≥27 or DP ≥10 or both). Statistically significant factors associated with burnout include resilience, age, years of experience, ethnicity, marital status, nationality, highest qualifications, pharmacy-related certification, full-time employment status, and work hours. Impact associated with burnout includes intent for job change, job satisfaction, sleep, and presence of mental conditions. Statistically significant reported reasons for burnout and ways to build resilience were also elucidated. CONCLUSION: Burnout affects most PTs in Singapore and is primarily driven by workload and nature of their work, low resilience, and poor social support structures. National and organizational efforts are needed to arrest the vicious cycle that propagates burnout in PTs.

Characteristics of non-culprit plaques in acute coronary syndrome patients with calcified plaque at the culprit lesion.

OBJECTIVES: To investigate the non-culprit plaques (NCPs) characteristics in acute coronary syndrome (ACS) patients with calcified plaques (CP). BACKGROUND: Recently, a new in vivo classification of calcified culprit plaques in patients with ACS was proposed. Characteristics of NCPs in this group of patients are unknown. METHODS: A total of 692 NCPs from 492 ACS patients were retrospectively compared based on the culprit plaque phenotype: 71 from CP patients, 383 from plaque rupture (PR) patients, 238 from plaque erosion (PE) patients. RESULTS: NCPs of CP patients had greater maximal calcium thickness, wider calcium arc, longer calcium length, and greater calcium index, compared to PR or PE patients (CP vs. PR: all p < .001, CP vs. PE: all p < .001). Thin-cap fibroatheroma was less prevalent (p = .023), fibrous cap was thicker (p = .035), and mean lipid arc was narrower in CP than in PR (p < .001). CONCLUSIONS: In conclusion, NCPs of CP patients had greater calcium burden and less vulnerability. This information may help to better understand the underlying mechanisms of ACS and to develop strategy for tailored management.

Circadian variations in pathogenesis of ST-segment elevation myocardial infarction: an optical coherence tomography study.

Previous studies have reported a circadian variation in the onset of ST-segment elevation myocardial infarction (STEMI). However, underlying mechanisms for the circadian variation have not been fully elucidated. We investigated the relationship between onset of STEMI and the underlying pathology using optical coherence tomography (OCT). Patients with a diagnosis of STEMI were selected from a multicenter OCT registry. Patients were divided into 4 groups based on the estimated time of onset (00:00-05:59, 06:00-11:59, 12:00-17:59, or 18:00-23:59). Underlying pathologies of MI (plaque rupture, plaque erosion, and calcified plaque) were compared among the 4 groups. Among 648 patients, plaque rupture was diagnosed in 386 patients (59.6%), plaque erosion in 197 patients (30.4%), and calcified plaque in 65 patients (10.0%). A marked circadian variation was detected in the incidence of plaque rupture with a peak at 09:00, whereas it was not evident in plaque erosion or calcified plaque. The probability of plaque rupture significantly increased in the periods of 06:00-11:59 [odds ratio (OR) 2.13, 95% confidence interval (CI) 1.30-3.49, p = 0.002] and 12:00-17:59 (OR 2.10, 95% CI 1.23-3.58, p = 0.005), compared to the period of 00:00-05:59. This circadian pattern was observed only during weekdays (p = 0.010) and it was not evident during the weekend (p = 0.742). Plaque rupture occurred most frequently in the morning and this circadian variation was evident only during weekdays. Acute MI caused by plaque rupture may be related to catecholamine surge.

Effects of Asian dust-derived particulate matter on ST-elevation myocardial infarction: retrospective, time series study.

BACKGROUND: Dust storms affect human health by impairing visibility and promoting interactions with microscopic organisms, such as bacteria and fungi. Although ST-elevation MI (STEMI) and non-ST-elevation MI (NSTEMI) differ mechanistically, few studies have investigated the incidence of cardiovascular diseases according to infarction type; these studies have yielded inconsistent findings. This study aimed to examine whether PM size (< 2.5 µm (PM2.5) and < 10 µm (PM10)) modifies the effect of Asian dust on acute myocardial infarction (AMI), with separate analyses for STEMI and NSTEMI. METHODS: MI-related data from 9934 emergency visits were collected from the Korea AMI Registry from 2005 to 2017. Asian dust events were defined as days with visibility of ≤10 km. Generalized linear models were used to analyze data with natural cubic splines. To examine potential modifiers, analyses were stratified by age, smoking status, and body mass index (BMI). RESULTS: No significant associations were observed between Asian dust and AMI. By adjusting for different lag structures, a significant effect was exclusively observed in STEMI. For moving average lags, the largest value at lag 5 (relative risk [RR] 1.083; 95% confidence interval [CI], 1.007-1.166) for single and lags 0-7 (RR 1.067; 95% CI: 1.002-1.136) was observed for PM2.5; for PM10, the largest significant effect was observed at lag 4 (RR 1.075; 95% CI: 1.010-1.144) for single and lags 0-7 (RR 1.067; 95% CI: 1.002-1.136). RRs were significantly higher in < 65-year-olds than in ≥65-year-olds. Additionally, RRs between the BMI < 25 and BMI ≥ 25 groups were not different; statistically significant effects were observed for concentration at lags 0-5 (RR: 1.073; 95% CI: 1.002-1.150) and lags 0-6 (RR: 1.071; 95% CI: 1.001-1.146) in the BMI < 25 group. A negative exposure-response association was observed between daily average visibility-adjusted PM and STEMI and daily average visibility-adjusted PM in < 65-year-olds. CONCLUSIONS: Reducing PM2.5 and PM10 emissions, particularly during the days of Asian dust, may be crucial and reduce STEMI and AMI incidence among < 65-year-olds. These results indicate that the Asian dust alarm system needs revision to protect vulnerable populations.

Intravascular modality-guided versus angiography-guided percutaneous coronary intervention in acute myocardial infarction.

BACKGROUND: Few data are available for current usage patterns of intravascular modalities such as intravascular ultrasound (IVUS), optical coherence tomography (OCT), and fractional flow reserve (FFR) in acute myocardial infarction (AMI). Moreover, patient and procedural-based outcomes related to intravascular modality guidance compared to angiography guidance have not been fully investigated yet. METHODS: We examined 11,731 patients who underwent percutaneous coronary intervention (PCI) from the Korea AMI Registry-National Institute of Health database. Patient-oriented composite endpoint (POCE) was defined as all-cause death, any infarction, and any revascularization. Device-oriented composite endpoint (DOCE) was defined as cardiac death, target-vessel reinfarction, and target-lesion revascularization. RESULTS: Overall, intravascular modalities were utilized in 2,659 (22.7%) patients including 2,333 (19.9%) IVUS, 277 (2.4%) OCT, and 157 (1.3%) FFR. In the unmatched cohort, POCE (5.4 vs. 8.5%; adjusted hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.61-0.93; p = .008) and DOCE (4.6 vs. 7.4%; adjusted HR 0.77; 95% CI 0.61-0.97; p = .028) were significantly lower in intravascular modality-guided PCI compared with angiography-guided PCI. In the propensity-score-matched cohorts, POCE (5.9 vs. 7.7%; HR 0.74; 95% CI 0.60-0.92; p = .006) and DOCE (5.0 vs. 6.8%; HR 0.72; 95% CI 0.57-0.90; p = .004) were significantly lower in intravascular modality guidance compared with angiography guidance. The difference was mainly driven by reduced all-cause mortality (4.4 vs. 7.0%; p < .001) and cardiac mortality (3.3 vs. 5.2%; p < .001). CONCLUSION: In this large-scale AMI registry, intravascular modality guidance was associated with an improving clinical outcome in selected high-risk patients.

Relative risk of plaque erosion among different age and sex groups in patients with acute coronary syndrome.

Postmortem studies reported plaque erosion is frequent in young women. Recent in vivo studies failed to show age and sex differences in the plaque erosion prevalence. The aim of this study was to investigate the prevalence of plaque erosion by age and sex among acute coronary syndromes (ACS) patients. From 1699 ACS patients, 1083 with plaque erosion or rupture were analyzed. Patients were categorized as 5 age groups (≤ 50, 51-60, 61-70, 71-80, ≥ 81 years). Overall prevalence of plaque erosion was similar between males and females (p = 0.831). Males age ≤ 50 had higher (p = 0.018) and age 71-80 had lower (p = 0.006) prevalence of plaque erosion. Females age 61-70 had higher (p = 0.021) and age 71-80 had lower (p = 0.045) prevalence of plaque erosion. In advanced age groups (≥ 71 years), rupture was the dominant etiology in both sexes. In multivariate analysis of males, age ≤ 50 demonstrated a trend to increase (OR 1.418, 95% CI 0.961-2.093, p = 0.078) the erosion risk. Females age ≤ 70 independently increased (OR 2.138, 95% CI 1.249-3.661, p = 0.006) the risk for erosion. The prevalence of plaque erosion was similar between males and females. Plaque erosion risk was increased in the males age ≤ 50 and in the females age ≤ 70 among ACS patients.

AEG-1 promotes angiogenesis and may be a novel treatment target for tongue squamous cell carcinoma.

BACKGROUND: The study explored the potential function of astrocyte elevated gene-1 (AEG-1) on angiogenesis in tongue squamous cell carcinoma (TSCC) in TSCC cell lines. METHODS: The different degrees of angiogenesis were detected in TSCC cell lines expressing different levels of AEG-1 by chick chorioallantoic membrane (CAM) experimental model. Next, we established xenografts of different TSCC cell lines with different expression levels of AEG-1 in nude mice and conducted immunohistochemistry to evaluate the expression of the angiogenesis-associated factor, that is, vascular endothelial growth receptor factor 2 (VEGFR-2) and microvessel density (MVD). Vascular endothelial growth factor (VEGF) was detected by ELISA. RESULTS: CAM assay showed that the number of vessels was significantly reduced in AEG-1-down um1 cell line (p < .05), whereas the number was significantly increased in AEG-1-over um2 cell line (p < .05). Moreover, up-regulated AEG-1 expression level was associated with higher tumor angiogenesis, which was reflected by augmented expression levels of VEGF (p < .01), VEGFR-2 (p < .05), and MVD counting (p < .01). CONCLUSIONS: This study demonstrated that AEG-1 can promote tumor angiogenesis in TSCC and inhibition of tumor angiogenesis by repressing the expression of AEG-1 may be a novel potential treatment approach for TSCC.

Rumpel-Leede Phenomenon-An alarming rash with benign etiology in 4 healthy infants.

The Rumpel-Leede phenomenon (RLP) is a rare clinical presentation and in some cases shown to be related to serious systemic conditions. In children, it has been described in association with idiopathic thrombocytopenic purpura and Henoch-Schönlein purpura. We present a series of pediatric cases of RLP with mechanical etiologies that had a benign course. We propose minimal investigations for pediatric RLP cases who are systemically well and have a clear suggestive history of a mechanical cause.

Prognostic Impact of ß-Blocker Dose After Acute Myocardial Infarction.

BACKGROUND: The differential prognostic impact of ß-blocker dose after acute myocardial infarction (AMI) has been under debate. The current study sought to compare clinical outcome after AMI according to ß-blocker dose using the Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH). Methods and Results: Of the total population of 13,104 consecutive AMI patients enrolled in the KAMIR-NIH, the current study analyzed 11,909 patients. These patients were classified into 3 groups (no ß-blocker; low-dose [<25% of target dose]; and high-dose [≥25% of target dose]). The primary outcome was cardiac death at 1 year. Compared with the no ß-blocker group, both the low-dose and high-dose groups had significantly lower risk of cardiac death (HR, 0.435; 95% CI: 0.363-0.521, P<0.001; HR, 0.519; 95% CI: 0.350-0.772, P=0.001, respectively). The risk of cardiac death, however, was similar between the high- and low-dose groups (HR, 1.194; 95% CI: 0.789-1.808, P=0.402). On multivariable adjustment and inverse probability weighted analysis, the result was the same. CONCLUSIONS: The use of ß-blockers in post-AMI patients had significant survival benefit compared with no use of ß-blockers. There was no significant additional benefit of high-dose ß-blockers compared with low-dose ß-blockers, however, in terms of 1-year risk of cardiac death.

Isolated complete unilateral ptosis with intact extraocular eye movements.

An 88-year-old woman presented with a 2-day history of inability to open her left eye with no ocular discomfort or blurred vision. She had a long-standing history of diabetes mellitus, hypertension and stroke disease. Examination revealed an isolated complete left eye ptosis with no pupillary involvement and intact extraocular movements. There were no other neurological deficits and fatigability was not elicited. Magnetic resonance imaging of the brain showed an acute infarct of the left red nucleus. Oculomotor nerve fascicles are widely separated in the midbrain before they exit at the interpeduncular fossa. A discrete lesion involving the most caudal fibres of the levator palpebrae is the most likely explanation. Although uncommon, this should be considered in patients with underlying cardiovascular risk factors.

Effects of Statin Intensity on Clinical Outcome in Acute Myocardial Infarction Patients.

BACKGROUND: There has been debate regarding the added benefit of high-intensity statins compared with low-moderate-intensity statins, especially in patients with acute myocardial infarction (AMI).Methods and Results:The Korea Acute Myocardial Infarction Registry-National Institutes of Health consecutively enrolled 13,104 AMI patients. Of these, a total of 12,182 patients, who completed 1-year follow-up, were included in this study, and all patients were classified into 3 groups (no statin; low-moderate-intensity statin; and high-intensity statin). The primary outcome was major adverse cardiac event (MACE) including cardiac death, non-fatal MI, and repeat revascularization at 1 year. Both low-moderate-intensity and high-intensity statin significantly reduced low-density lipoprotein cholesterol (LDL-C; all P<0.001). Compared with the no statin group, both statin groups had significantly lower risk of MACE (low-moderate intensity: HR, 0.506; 95% CI: 0.413-0.619, P<0.001; high intensity: HR, 0.464; 95% CI: 0.352-0.611, P<0.001). The risk of MACE, however, was similar between the low-moderate- and high-intensity statin groups (HR, 0.917; 95% CI: 0.760-1.107, P=0.368). Multivariable adjustment, propensity score matching, and inverse probability weighted analysis also produced the same results. CONCLUSIONS: When adequate LDL-C level is achieved, patients on a low-moderate-intensity statin dose have similar cardiovascular outcomes to those on high-intensity statins.

Prevalence and Predictors of Multiple Coronary Plaque Ruptures: In Vivo 3-Vessel Optical Coherence Tomography Imaging Study.

OBJECTIVE: Plaque rupture may be the local expression of a widespread coronary instability. This study aimed to investigate: (1) the prevalence and characteristics of nonculprit plaque rupture; (2) the pancoronary atherosclerotic phenotype in patients with and without nonculprit plaque rupture; and (3) the prevalence and predictors of multiple plaque ruptures. APPROACH AND RESULTS: Six hundred and seventy-five nonculprit plaques from 261 patients (34 acute myocardial infarction, 73 unstable angina pectoris, and 154 stable angina pectoris) were analyzed by 3-vessel optical coherence tomography. Nonculprit plaque ruptures were identified in 51 patients (20%). Patients with nonculprit plaque ruptures had higher prevalence of thin-cap fibroatheroma (51% versus 13%; P<0.001) in the 3 major epicardial coronary vessels. Multiple plaque ruptures were observed in 20% of patients (38% acute myocardial infarction versus 10% unstable angina pectoris versus 19% stable angina pectoris; P=0.042). Thin-cap fibroatheroma, intimal vasculature, and macrophages were independent morphological predictors of multiple plaque ruptures, whereas acute myocardial infarction and chronic kidney disease were independent clinical predictors. Patients with nonculprit plaque ruptures showed higher 1-year rates of nontarget lesion revascularization (11.8% versus 4.4%; P=0.039). CONCLUSIONS: Nonculprit plaque ruptures were observed in 20% of patients with coronary artery disease and were associated with pancoronary vulnerability and higher 1-year revascularization rate.

Unmarried patients with early cognitive impairment are more likely than their married counterparts to complete advance care plans.

BACKGROUND: Patients with early cognitive impairment (ECI) face the prospect of progressive cognitive decline that impairs their ability to make decisions on financial and personal matters. Advance care planning (ACP) is a process that facilitates decision making on future care and often includes identifying a proxy decision maker. This prospective study explores factors related to completion or non-completion of ACP in patients with ECI. METHODS: Patients with ECI (n = 158, M age = 76.2 ± 7.25 years) at a memory clinic received psycho-education and counseling on the importance of ACP and followed-up longitudinally for up to 12 months to ascertain if ACP had been completed. Univariate and logistic regression were used to analyze factors related to completion and non-completion of ACP. RESULTS: Seventy-seven patients (48.7%) were initially willing to consider ACP after the counseling and psycho-educational session but only 17 (11.0%) eventually completed ACP. On logistic regression, patients who were single were 8.9 times more likely to complete ACP than those who were married (p = 0.007). Among those initially willing to consider ACP, factors impeding completion of ACP included patient (48.0%), process (31.0%), and family factors (21.0%). CONCLUSIONS: As unmarried patients may not have immediate family members to depend on to make decisions, they may perceive ACP to be more important and relevant. Understanding the barriers to ACP completion can facilitate targeted interventions to improve the uptake of ACP.

Multicenter Cohort Study of Acute Myocardial Infarction in Korea　- Interim Analysis of the Korea Acute Myocardial Infarction Registry-National Institutes of Health Registry.

BACKGROUND: The Korea Acute Myocardial Infarction Registry (KAMIR)-National Institutes of Health (NIH) registry has the aim of evaluating the clinical characteristics, management, and long-term outcomes of patients with acute myocardial infarction (AMI) in Korea. METHODS AND RESULTS: Patients hospitalized for AMI in 20 tertiary university hospitals in Korea have been enrolled since November 2011. The study is expected to complete the scheduled enrollment of approximately 13,000 patients in October 2015, and follow-up duration is up to 5 years for each patient. As of October 2015, an interim analysis of 13,623 subjects was performed to understand the baseline clinical profiles of the study population. The mean age was 64.1 years; 73.5% were male; and 48.2% were diagnosed with ST-segment elevation AMI. Hypertension is a leading cause of AMI in Korea (51.2%), followed by smoking (38.5%) and diabetes mellitus (28.6%). Percutaneous coronary intervention was performed in 87.4% and its success rate was very high (99.4%). In-hospital, 1-year, and 2-year mortality rates were 3.9%, 4.3%, and 8.6%, respectively. The rates of major adverse cardiac events at 1 and 2 years were 9.6% and 18.8%, respectively. CONCLUSIONS: This analysis demonstrated the clinical characteristics of Korean AMI patients in comparison with those of other countries. It is necessary to develop guidelines for Asian populations to further improve their prognosis. (Circ J 2016; 80: 1427-1436).

A Case of Eczematoid Graft-Versus-Host Disease.

A 13-year-old boy underwent allogeneic hematopoietic stem cell transplantation (HSCT) for underlying acute lymphoblastic leukemia and achieved neutrophil engraftment 28 days after HSCT. He developed ichthyosis 6 weeks after HSCT and then keratotic follicular papules, palmoplantar keratoderma, and a seborrheic dermatitis-like eruption 18 weeks after HSCT. From skin biopsies he was diagnosed with eczematoid graft-versus host disease (GVHD), which showed spongiosis with scattered necrotic keratinocytes. He responded to oral and topical steroids and an increase in cyclosporine dose. Although uncommon, eczematoid GVHD must be considered in children who have undergone HSCT and then develop an atypical eczematous eruption, especially in the absence of a history of atopy.

Tricho-hepato-enteric syndrome (THE-S): two cases and review of the literature.

UNLABELLED: Tricho-hepato-enteric syndrome (THE-S) is characterized by severe infantile diarrhea, failure to thrive, dysmorphism, woolly hair, and immune or hepatic dysfunction. We report two cases of East Asian descent with THE-S who had remained undiagnosed despite extensive investigations but were diagnosed on whole exome sequencing (WES). Both cases presented with chronic diarrhea, failure to thrive, and recurrent infections. Case 1 had posteriorly rotated low set ears, mild retrognathia, and fine curly hypopigmented hair. She was managed with prolonged total parenteral nutrition and intravenous immunoglobulin infusions. Case 2 had sparse coarse brown hair as well as multiple lentigines and café-au-lait macules. She was managed with amino acid-based formula. For both cases, routine investigations were inconclusive. WES in both cases showed biallelic truncating mutations in TTC37 (c.3507T>G;p.Y1169X and c.3601C>T;p.R1201X in case 1 and c.3507T>G;p.Y1169X and c.154G>T;p.E52X in case 2), suggesting a diagnosis of THE-S. CONCLUSION: We present novel mutations in the TTC37 gene in two individuals of East Asian descent with the rare THE-S, detected by WES. Future identification of patients with THE-S and establishing genotype-phenotype correlations will aid in counseling the patients and their families. WHAT IS KNOWN: • Tricho-Hepato-Enteric syndrome (THE-S) is characterized by severe infantile diarrhea, failure to thrive, dysmorphism, woolly hair, and immune or hepatic dysfunction. • Complex patients with diagnostic dilemmas undergo extensive investigations. What is New: • This is a report of novel mutations in TTC37 in individuals of East Asian descent. • Whole exome sequencing (WES) can be useful in certain complex cases with diagnostic dilemmas.

The Prognostic Value of the Left Ventricular Ejection Fraction Is Dependent upon the Severity of Mitral Regurgitation in Patients with Acute Myocardial Infarction.

The prognostic value of the left ventricle ejection fraction (LVEF) after acute myocardial infarction (AMI) has been questioned even though it is an accurate marker of left ventricle (LV) systolic dysfunction. This study aimed to examine the prognostic impact of LVEF in patients with AMI with or without high-grade mitral regurgitation (MR). A total of 15,097 patients with AMI who received echocardiography were registered in the Korean Acute Myocardial Infarction Registry (KAMIR) between January 2005 and July 2011. Patients with low-grade MR (grades 0-2) and high-grade MR (grades 3-4) were divided into the following two sub-groups according to LVEF: LVEF ≤ 40% (n = 2,422 and 197, respectively) and LVEF > 40% (n = 12,252 and 226, respectively). The primary endpoints were major adverse cardiac events (MACE), cardiac death, and all-cause death during the first year after registration. Independent predictors of mortality in the multivariate analysis in AMI patients with low-grade MR were age ≥ 75 yr, Killip class ≥ III, N-terminal pro-B-type natriuretic peptide > 4,000 pg/mL, high-sensitivity C-reactive protein ≥ 2.59 mg/L, LVEF ≤ 40%, estimated glomerular filtration rate (eGFR), and percutaneous coronary intervention (PCI). However, PCI was an independent predictor in AMI patients with high-grade MR. No differences in primary endpoints between AMI patients with high-grade MR (grades 3-4) and EF ≤ 40% or EF > 40% were noted. MR is a predictor of a poor outcome regardless of ejection fraction. LVEF is an inadequate method to evaluate contractile function of the ischemic heart in the face of significant MR.