A Comprehensive Diagnostic Algorithm for Direct Antiglobulin Test-Negative Autoimmune Hemolytic Anemia Reveals the Relative Ratio of Three Mechanisms in a Single Laboratory.

BACKGROUND: Direct antiglobulin test (DAT)-negative warm autoimmune hemolytic anemia (AIHA) is mainly caused by three mechanisms: red blood cell (RBC)-bound immunoglobulin (Ig)G below the detection limit of routine DAT; RBC-bound IgA or IgM; or low-affinity autoantibodies. Although most cases of DAT-negative AIHA are thought to be caused by RBC-bound IgG, and combinatory serological analyses are recommended, the relative ratios of each mechanism have not been clarified. METHODS: Two groups of patients with undiagnosed hemolytic anemia and negative conventional tube method-DAT (TM-DAT) were investigated using anti-IgA and anti-IgM sera, or column agglutination method-DAT (CM-DAT), respectively, in addition to radioimmunological quantitation of RBC-bound IgG. RESULTS: Three of 73 patients with DAT-negative AIHA showed positive RBC-bound IgA and normal amounts of RBC-bound IgG. Another group of 3 patients were RBC-bound IgM-positive, but only one of these showed normal amounts of RBC-bound IgG. In another group of patients with DAT-negative AIHA, 4 of the 20 showed positive CM-DAT and negative CM-DAT after washing RBCs. Three of these patients had normal amounts of RBC-bound IgG. Five patients with positive CM-DAT both before and after washing RBCs had high amounts of RBC-bound IgG. CONCLUSION: Relative ratios of patients with DAT-negative AIHA resulting from RBC-bound IgG, RBC-bound IgA, RBC-bound IgM, and low-affinity IgG were estimated as 80, 4, 1 and 15%, respectively. A new classification and diagnostic algorithm for DAT-negative AIHA were proposed.

Non-diabetic Glucose levels and Cancer Mortality: A Literature Review.

BACKGROUND: Although diabetes mellitus is a risk factor for cancer, the relationship of an increased glucose concentration at a non-diabetic glucose level with cancer mortality is yet to be determined. OBJECTIVE: The aim was to observe whether an increased glucose concentration and/or glucose intolerance at the non-diabetic glucose level can predict cancer mortality. METHODS: Population-based prospective cohort studies evaluating cancer mortality at the non-diabetic level (defined as fasting plasma glucose <7.0 mmol/L and two-hour plasma glucose <11.1mmol/L following an oral glucose tolerance test) were collected via a PubMed search with an additional Google scholar search between 1 January 1966 and 31 July 2016. RESULTS: We identified seven studies, which met the defined criteria. Studies examining fasting/casual states indicated an increase in cancer mortality with a slight increase in fasting/casual glucose levels in men in particular. Not all, but some studies using a glucose tolerance test indicated an increase in cancer mortality with impaired glucose tolerance/prediabetes. Concerning cause-cancer mortality, glucose intolerance states appeared to have an increase in mortality, particularly due to the stomach, liver and pancreatic cancers. CONCLUSION: In these studies reviewed, cancer mortality increased in individuals with an increased glucose concentration and an increased potential was seen in those patients with glucose intolerance even at non-diabetic glucose levels. The outcome of these findings is promising and forms the basis for further studies to directly address the relevance of increased (non-diabetic) glucose and glucose intolerance as a prognostic indicator of cancer mortality.

Association between smoking and the peripheral vestibular disorder: a retrospective cohort study.

Common inner ear diseases include peripheral vestibular disorder (PVD) and hearing impairment. The association between smoking and peripheral vestibular disorder (PVD) is unclear. We examined associations between smoking and new PVD events. In this retrospective study, we consecutively enrolled 393 participants aged ≥20 years [mean age 65.3 years; males 133 (33.8%)] treated for hypertension, dyslipidaemia, or diabetes mellitus at a primary care clinic between November 2011 and March 2013. Participants were categorized as ever-smokers (including current and past -smokers; divided per <30 and ≥30 pack-years), and never-smokers. New PVD events were reported over a 1-year follow-up period. Hazard ratios (HR) for new onset PVD were estimated using the Cox proportional hazard regression model. Compared to never-smokers, the adjusted HR was 2.22 for ever-smokers and 2.70 for all ever-smokers with ≥30 pack-years among all 393 participants. Among male participants, compared to never-smokers, the adjusted HR was 4.41 for ever-smokers with ≥30 pack-years. A smoking history of ≥30 pack-years was strongly associated with the risk of new onset PVD in males but not, females. This study may assist patients with smoking cessation for the prevention of new PVD events among males.

Influence of family history on the willingness of outpatients to undergo genetic testing for salt-sensitive hypertension: a cross-sectional study.

OBJECTIVES: It is unclear whether family medical history influences the willingness to undergo genetic testing. This study aimed to determine how family history affected the willingness to undergo genetic testing for salt-sensitive hypertension in patients with and without hypertension. DESIGN: Cross-sectional study using a self-administered questionnaire. SETTING: Six primary care clinics and hospitals in Japan. PARTICIPANTS: Consecutive 1705 outpatients aged >20 years, 578 of whom had hypertension. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome variable was the willingness to undergo genetic testing to determine the risk of salt-sensitive hypertension, and the secondary variables were age, sex, education level, family history and concerns about hypertension. Factors associated with a willingness to undergo genetic testing were evaluated in patients with and without hypertension using a logistic regression model. RESULTS: In the hypertension and non-hypertension groups, 323 (55.9%) and 509 patients (45.2%), respectively, were willing to undergo genetic testing. This willingness was related with a high level of education (adjusted OR (ad-OR): 1.81, 95% CI 1.12 to 2.93), family history of stroke (1.55, 1.04 to 2.31) and concerns about hypertension (2.04, 1.27 to 3.28) in the hypertension group, whereas in the non-hypertension group, it was influenced by education level (ad-OR: 1.45, 95% CI 1.13 to 1.86), family history of hypertension (1.52, 1.17 to 1.98) and concerns about hypertension (2.03, 1.53 to 2.68). CONCLUSIONS: The influence of family history on the willingness to undergo genetic testing for risk of salt-sensitivity hypertension differed between participants with and without hypertension. In particular, participants without hypertension wished to know their likelihood of developing hypertension, whereas those with hypertension were interested to know the risk of stroke (a complication of hypertension). Family history could help better counsel patients about genetic testing on the basis of their medical history.

Factor VII and incidence of myocardial infarction in a Japanese population: The Jichi Medical School Cohort Study.

BACKGROUND: The role of factor VII (FVII) as a risk factor in myocardial infarction (MI) has been the subject of numerous studies. However, it remains uncertain whether the FVII levels are associated with development of MI. METHODS: The subjects were 4142 men and women whose activated FVII (FVIIa) and FVII coagulant (FVIIc) levels were measured in the Jichi Medical School Cohort Study. Subjects were divided into tertiles by FVIIa and FVIIc levels, and Cox's proportional hazard model was used to calculate hazard ratios (HRs) for MI. RESULTS: The multivariate-adjusted HRs (95% confidential interval [CI]) for FVIIa in men were 0.67 (0.67-1.78) in tertile 2 (T2), and 0.52 (0.17-1.60) in T3. In women, the multivariate-adjusted HRs (95% CI) were 0.18 (0.02-1.60) in T2, and 0.39 (0.07-2.20) in T3. The multivariate-adjusted HRs (95% CI) for FVIIc in men were 0.54 (0.21-1.36) in T2, and 0.20 (0.04-0.91) in T3. In women, the multivariate-adjusted HRs (95% CI) were 0.44 (0.07-2.85) in T2, and 0.35 (0.06-2.22) in T3. We used T1 as a reference for all measures. CONCLUSION: Our findings revealed a significant association between low FVIIc level and incidence of MI in men. The FVIIa and FVIIc levels were inversely related to increased MI risk, but did not reach statistical significance. Future studies are needed to confirm this association.

The serum concentration of soluble interleukin-2 receptor in patients with Kawasaki disease.

Kawasaki disease is a febrile disease of childhood that is associated with increased inflammatory cytokines and immunoregulatory abnormalities. While the serum concentrations of soluble IL-2 receptor can change under such pathologies, the relevance of the soluble IL-2 receptor concentration in patients with Kawasaki disease has not been specified. We aimed to summarize the existing studies that reported the soluble IL-2 receptor concentrations in patients with Kawasaki disease. Original articles that were published up to July 2016 were collected using a PubMed/Medline-based search engine. A total of nine articles that reported the serum soluble IL-2 receptor concentrations in acute-phase Kawasaki disease were eligible. All of the articles described a high soluble IL-2 receptor concentration in patients with Kawasaki disease relative to the level of controls or the reference range. Two of five articles on patients with coronary artery aneurysms described a significantly higher soluble IL-2 receptor concentration in patients with coronary artery aneurysms than patients without. Two articles on patients with intravenous immunoglobulin therapy described a significant decrease of the soluble IL-2 receptor concentration after the therapy. Accordingly, the serum soluble IL-2 receptor can be a potent marker of disease activity and therapeutic effects in patients with Kawasaki disease; further studies are thus warranted for its use in the clinical setting.

Progression from prehypertension to hypertension and risk of cardiovascular disease.

BACKGROUND: Subjects with prehypertension (pre-HT; 120/80 to 139/89 mm Hg) have an increased risk of cardiovascular disease (CVD); however, whether the risk of pre-HT can be seen at the pre-HT status or only after progression to a hypertensive (HT; ≥140/90 mm Hg) state during the follow-up period is unknown. METHODS: The Jichi Medical Cohort study enrolled 12,490 subjects recruited from a Japanese general population. Of those, 2227 subjects whose BP data at baseline and at the middle of follow-up and tracking of CVD events were available (median follow-up period: 11.8 years). We evaluated the risk of HT in those with normal BP or pre-HT at baseline whose BP progressed to HT at the middle of follow-up compared with those whose BP remained at normal or pre-HT levels. RESULTS: Among the 707 normotensive patients at baseline, 34.1% and 6.6% of subjects progressed to pre-HT and HT, respectively, by the middle of follow-up. Among 702 subjects with pre-HT at baseline, 26.1% progressed to HT. During the follow-up period, there were 11 CVD events in normotensive patients and 16 CVD events in pre-HT patients at baseline. The subjects who progressed from pre-HT to HT had 2.95 times higher risk of CVD than those who remained at normal BP or pre-HT in a multivariable-adjusted Cox hazard model. CONCLUSION: This relatively long-term prospective cohort study indicated that the CVD risk with pre-HT might increase after progression to HT; however, the number of CVD events was small. Therefore, the results need to be confirmed in a larger cohort.

Does a medical history of hypertension influence disclosing genetic testing results of the risk for salt-sensitive hypertension, in primary care?

OBJECTIVE: Disclosing genetic testing results may contribute to the prevention and management of many common diseases. However, whether the presence of a disease influences these effects is unclear. This study aimed to clarify the difference in the effects of disclosing genetic testing results of the risk for developing salt-sensitive hypertension on the behavioral modifications with respect to salt intake in hypertensive and nonhypertensive patients. METHODS: A cross-sectional study using a self-administered questionnaire was conducted for outpatients aged >20 years (N=2,237) at six primary care clinics and hospitals in Japan. The main factors assessed were medical histories of hypertension, salt preferences, reduced salt intakes, and behavior modifications for reducing salt intake. Behavioral modifications of participants were assessed using their behavior stages before and after disclosure of the hypothetical genetic testing results. RESULTS: Of the 2,237 participants, 1,644 (73.5%) responded to the survey. Of these respondents, 558 (33.9%) patients were hypertensive and 1,086 (66.1%) were nonhypertensive. After being notified of the result "If with genetic risk", the nonhypertensive participants were more likely to make positive behavioral modifications compared to the hypertensive patients among all participants and in those aged <65 years (adjusted relative ratio [ad-RR], 1.76; 95% confidence interval, 1.12-2.76 and ad-RR, 1.99; 1.11-3.57, respectively). In contrast, no difference in negative behavioral modifications between hypertensive and nonhypertensive patients was detected after being notified of the result "If without genetic risk" (ad-RR, 1.05; 95% confidence interval, 0.70-1.57). CONCLUSION: The behavior of modifying salt intake after disclosure of the genetic testing results differed between hypertensive and nonhypertensive patients. Disclosing a genetic risk for salt-sensitive hypertension was likely to cause nonhypertensive patients, especially those aged <65 years, to improve their behavior regarding salt intake. We conclude that disclosing genetic testing results could help prevent hypertension, and that the doctor should communicate the genetic testing results to those patients with a medical history of hypertension, or those who are at risk of developing hypertension.

Carotid plaque is a new risk factor for peripheral vestibular disorder: a retrospective cohort study.

Many chronic diseases are associated with dizziness or vertigo, as is peripheral vestibular disorder (PVD). Although carotid plaque development is linked to atherosclerosis, it is unclear whether such plaques can lead to the development of PVD. We therefore conducted this study to investigate the presence of an association between carotid plaque and new PVD events.In this retrospective study, we consecutively enrolled 393 patients ≥20 years old who had been treated for chronic diseases such as hypertension, dyslipidemia, and diabetes mellitus for ≥6 months at a primary care clinic (Oki Clinic, Japan) between November 2011 and March 2013. Carotid plaque presence was measured with high-resolution ultrasonography for all patients. During a 1-year follow-up period, an otorhinolaryngologist diagnosed and reported any new PVD events (the main end point). Hazard ratios (HRs) and 95% confidence intervals (CIs) for new PVD occurrence were estimated using the Cox proportional hazard regression model.The mean age of the participants was 65.5 years; 33.8% were men, and 12.7%, 82.4%, and 93.1% had diabetes mellitus, hypertension, and dyslipidemia, respectively. There were 76 new PVD events; patients with carotid plaque had a greater risk of such events (crude HR: 3.25; 95% CI: 1.62-6.52) compared to those without carotid plaque. This risk was even higher after adjusting for traditional risk factors for atherosclerosis (adjusted HR: 4.41; 95% CI: 1.75-11.14).Carotid plaques are associated with an increased risk of new PVD events.

Relationship Between Serum High-Sensitivity C-Reactive Protein and Myocardial Infarction in a General Japanese Population.

BACKGROUND: Due to ethic differences in its serum levels, clinical applicability of high-sensitivity C-reactive protein (hsCRP) to the primary prevention of atherosclerotic events has not completely been established in Japanese people whose hsCRP levels are lower than in Western people. This study investigated the relationship between hsCRP and myocardial infarction (MI) in general Japanese people. METHODS: In relation to hsCRP, the incidence of MI was determined in a multiregional population-based prospective cohort study (n = 6,637; mean age 54.9 years; 2,513 men/4,124 women). RESULTS: Fifty-six cases of MI were confirmed during a follow-up period of 10.7 years. The cut-off levels of hsCRP between the highest quartile (fourth quartile) and the other quartiles combined were 0.368 mg/l in men and 0.279 mg/l in women. The hazard ratio (HR) of the highest quartile for MI was significantly greater than that of the other quartiles combined (multivariate-adjusted HR: 2.07, 95% confidence interval: 1.03-4.15) in men, but not in women (1.03, 0.35-2.21). CONCLUSIONS: In this population, serum hsCRP measurement predicted MI in men, but not in women. Under the low hsCRP level, a method of applicability of hsCRP to a risk assessment for preventing MI among Japanese people should be further explored.

Differences in genotype frequencies of salt-sensitive genes between fishing and nonfishing communities in Japan.

PURPOSE: To identify the differences in genotype frequencies of salt-sensitive genes between residents of fishing communities (FCs) and nonfishing communities (NFCs). METHODS: The subjects included 18,156 individuals (8,043 males [44%] and 10,113 females [56%]; average age: 57.2±16.1 years) from the general population who were registered with large-scale genome banks and resided in 30 prefectures and 78 different regions in Japan. The measurement items were age, sex, blood pressure, presence or absence of hypertension, body mass index, alcohol consumption, and smoking habit. Furthermore, to analyze the genotype frequencies of salt-sensitive genes, α-adducin 1 (ADD1), angiotensinogen (AGT), angiotensin II receptor type 1 (AT1), and guanine nucleotide-binding protein ß peptide 3 (GNB3) were measured. According to the 2004 government classification of municipalities (cities, towns, and villages), communities existing in areas bordering an ocean and with an ocean port were defined as FCs (28 areas). The others were defined as NFCs (50 areas). A logistic regression model was used for comparison of genotype frequencies between subjects residing in FCs and NFCs. RESULTS: Of the included subjects, 4,916 (27.0%) and 13,240 (73.0%) resided in FCs and NFCs, respectively. In FCs, the mean age was 59.4±16.7 years and men accounted for 41.0% of the cohort (n=2,015). In NFCs, the mean age was 56.4±15.8 years and men accounted for 45.5% of the cohort (n=6,028). The adjusted odds ratios of the AA and AG genotypes compared with the GG genotype for AGT were 0.80 (95% confidence interval [CI]: 0.68-0.95) and 0.76 (95% CI: 0.64-0.91), respectively. The adjusted odds ratio of the CC genotype compared with AA for AT1 was 0.63 (95% CI: 0.40-0.93). CONCLUSION: The incidence of the salt-sensitive genotypes AGT and AT1 in residents of FCs were significantly lower than in NFCs.

Identifying Patients with Bacteremia in Community-Hospital Emergency Rooms: A Retrospective Cohort Study.

OBJECTIVES: (1) To develop a clinical prediction rule to identify patients with bacteremia, using only information that is readily available in the emergency room (ER) of community hospitals, and (2) to test the validity of that rule with a separate, independent set of data. DESIGN: Multicenter retrospective cohort study. SETTING: To derive the clinical prediction rule we used data from 3 community hospitals in Japan (derivation). We tested the rule using data from one other community hospital (validation), which was not among the three "derivation" hospitals. PARTICIPANTS: Adults (age ≥ 16 years old) who had undergone blood-culture testing while in the ER between April 2011 and March 2012. For the derivation data, n = 1515 (randomly sampled from 7026 patients), and for the validation data n = 467 (from 823 patients). ANALYSIS: We analyzed 28 candidate predictors of bacteremia, including demographic data, signs and symptoms, comorbid conditions, and basic laboratory data. Chi-square tests and multiple logistic regression were used to derive an integer risk score (the "ID-BactER" score). Sensitivity, specificity, likelihood ratios, and the area under the receiver operating characteristic curve (i.e., the AUC) were computed. RESULTS: There were 241 cases of bacteremia in the derivation data. Eleven candidate predictors were used in the ID-BactER score: age, chills, vomiting, mental status, temperature, systolic blood pressure, abdominal sign, white blood-cell count, platelets, blood urea nitrogen, and C-reactive protein. The AUCs was 0.80 (derivation) and 0.74 (validation). For ID-BactER scores ≥ 2, the sensitivities for derivation and validation data were 98% and 97%, and specificities were 20% and 14%, respectively. CONCLUSIONS: The ID-BactER score can be computed from information that is readily available in the ERs of community hospitals. Future studies should focus on developing a score with a higher specificity while maintaining the desired sensitivity.

Incidence of dizziness and vertigo in Japanese primary care clinic patients with lifestyle-related diseases: an observational study.

OBJECTIVE: Dizziness and vertigo are highly prevalent symptoms among patients presenting at primary care clinics, and peripheral vestibular disorder (PVD) is their most frequent cause. However, the incidence of PVD has not been well documented. This study aimed to investigate the incidence of dizziness, vertigo, and PVD among patients presenting at a primary care clinic. DESIGN: This was an observational study. SETTING AND PARTICIPANTS: Between November 2011 and March 2013, we observed 393 patients, all at least 20 years old, who had been treated for chronic diseases such as hypertension, dyslipidemia, and diabetes mellitus for at least 6 months at a primary clinic (Oki Clinic) in Japan. OUTCOME: The main outcome of interest was new incidence of dizziness, vertigo, and PVD events. During the 1-year follow-up period, the otorhinolaryngologist diagnosed and reported new PVD events. RESULTS: The mean age of the 393 participants at entry was 65.5 years. Of the study participants, 12.7%, 82.4%, and 92.6% had diabetes mellitus, hypertension, and dyslipidemia, respectively. We followed up all the participants (100%). During the 662.5 person-years of follow-up, 121 cases of dizziness or vertigo (dizziness/vertigo) and 76 cases of PVD were observed. The incidence of dizziness/vertigo and PVD was 194.7 (95% confidence interval: 161.6-232.6) per 1,000 person-years and 115.7 (95% confidence interval: 92.2-142.6) per 1,000 person-years, respectively. There were 61 cases of acute peripheral vestibulopathy, 12 of benign paroxysmal positional vertigo, and three of Meniere's disease among the 76 PVD patients. CONCLUSION: We reported the incidence of dizziness/vertigo among Japanese primary care clinic patients, which was higher than that usually observed in the general population. Furthermore, we described the incidence of PVD and found that it was a major cause of dizziness/vertigo.

Serum non-high-density lipoprotein cholesterol levels and the incidence of ischemic stroke in a Japanese population: the Jichi Medical School cohort study.

The predictive value of serum non-high-density lipoprotein cholesterol (non-HDL-C) levels for the incidence of ischemic stroke and its subtypes has not yet been established. The present cohort study investigated their relationships in a Japanese population. The first incidence of ischemic stroke and its subtypes was documented as the primary outcome. A total of 249 ischemic stroke patients (men/women = 145/104) were identified during a follow-up period of 10.7 years among 10 760 community-dwelling subjects (men/women = 4212/6548). Cox proportional hazard model analyses revealed that when compared with the lowest tertile of non-HDL-C, multivariate-adjusted hazard ratios for the highest tertile were 0.55 (95% confidence interval = 0.32-0.95, P = .03) on ischemic stroke and 0.29 (95% confidence interval = 0.08-1.05, P = .06) on cardioembolic infarction in women. Men did not show such significant relationships. Low serum non-HDL-C levels may be a predictive marker associated with an increase in the incidence of ischemic stroke and possibly of cardioembolic infarction in Japanese women.

Insulin resistance and risk of cerebral infarction in a Japanese general population: the Jichi Medical School Cohort Study.

The aim of the study was to investigate the relation between insulin resistance and risk of cerebral infarction in a Japanese general population. The subjects were 2610 men and women without past history of stroke or myocardial infarction and who were under treatment for diabetes. Subjects were divided into quartiles by the homeostasis model assessment of insulin resistance (HOMA-IR), and Cox's proportional hazard model was used to calculate hazard ratios (HRs) for cerebral infarction. In men, the multivariate-adjusted HRs were 2.51 (95% confidence interval [CI] = 0.98-6.42) in quartile 1 (Q1), 1.43 (95% CI = 0.54-3.82) in Q2, and 2.13 (95% CI = 0.82-5.51) in Q4, using Q3 as the reference. In women, the multivariate-adjusted HRs were 2.12 (95% CI = 0.72-6.31) in Q1, 2.96 (95% CI = 1.06-8.26) in Q3, and 2.31 (95% CI = 0.80-6.69) in Q4, using Q2 as the reference. The association between risk of cerebral infarction and HOMA-IR was not dose dependent.

Reasons for encounter and diagnoses of new outpatients at a small community hospital in Japan: an observational study.

PURPOSE: Although many new patients are seen at small hospitals, there are few reports of new health problems from such hospitals in Japan. Therefore, we investigated the reasons for encounter (RFE) and diagnoses of new outpatients in a small hospital to provide educational resources for teaching general practice methods. METHODS: This observational study was conducted at the Department of General Internal Medicine in a small community hospital between May 6, 2010 and March 11, 2011. We classified RFEs and diagnoses according to component 1, "Symptoms/Complaints", and component 7, "Diagnosis/Diseases", of the International Classification of Primary Care, 2nd edition (ICPC-2). We also evaluated the differences between RFEs observed and common symptoms from the guidelines Model Core Curriculum for Medical Students and Goals of Clinical Clerkship. RESULTS: We analyzed the data of 1,515 outpatients. There were 2,252 RFEs (1.49 per encounter) and 170 ICPC-2 codes. The top 30 RFE codes accounted for 80% of all RFEs and the top 55 codes accounted for 90%. There were 1,727 diagnoses and 196 ICPC-2 codes. The top 50 diagnosis codes accounted for 80% of all diagnoses, and the top 90 codes accounted for 90%. Of the 2,252 RFEs, 1,408 (62.5%) included at least one of the 36 symptoms listed in the Model Core Curriculum and 1,443 (64.1%) included at least one of the 35 symptoms in the Goals of Clinical Clerkship. On the other hand, "A91 Abnormal result investigation", "R21 Throat symptom/complaint", and "R07 Sneezing/nasal congestion", which were among the top 10 RFEs, were not included in these two guidelines. CONCLUSION: We identified the common RFEs and diagnoses at a small hospital in Japan and revealed the inconsistencies between the RFEs observed and common symptoms listed in the guidelines. Our findings can be useful in improving the general practice medical education curricula.