A propensity score matched comparison of blood pressure lowering in essential hypertension patients treated with antihypertensive Chinese herbal Medicine: comparing the real-world registry data vs. randomized controlled trial.

BACKGROUND: Randomized controlled trials have demonstrated that Songling Xuemaikang capsule (SXC) is effective in blood pressure (BP) lowering for essential hypertension. However, the effectiveness of SXC in real-world clinical practice remains unknown. We aimed to investigate whether the BP-lowering effectiveness of SXC in the real-world practice setting is comparable to the efficacy of the intervention in a randomized controlled trial. METHODS: We included 1325 patients treated with SXC monotherapy from a real-world registry and 300 from the SXC-BP trial. A propensity score matching (PSM) approach was used to select participants from the two cohorts. The primary outcome was a change in the office of BP from baseline to 8 weeks. RESULTS: After PSM, there were 552 patients for the comparative analysis. Clinically meaningful BP reductions were observed both in the real world and in the RCT cohorts after 8-week SXC treatment. The 8-week systolic/diastolic BP was 129.50/81.33 mm Hg vs. 134.97/84.14 mm Hg in the real-world population and the RCT population, respectively. The changes in systolic BP (15.82 ± 10.71 vs. 10.48 ± 10.24; P < .001), and diastolic BP (10.01 ± 7.73 vs. 7.75 ± 8.14; P = .001) from baseline to 8 weeks were significantly greater in the real-world population. CONCLUSION: The current comparison demonstrated that SXC monotherapy is at least as effective in real-world settings as within the randomized controlled trial for BP lowering in patients with grade 1 hypertension.

[Effects of 12-week Tai Chi exercise on the microvascular reactivity of the middle-aged and elderly patients with mild hypertension and its mechanism].

Objective: To study the effects of 12-week Taijiquan exercise on the microvascular reactivity of middle-aged and elderly patients with mild hypertension and to explore the mechanisms of microvascular reactivity. Methods: Thirty patients with mild hypertension were divided into exercise group (53.8±6.3 years old) and control group (52.6±7.5 years old). The number and gender ratio of the two groups were the same. The exercise group performed Tai Chi exercise for 12 weeks, and the control group maintained the original lifestyle and did not do other regular sports. The two groups of subjects were tested for microvascular reactivity, blood pressure, serum nitric oxide content, and nitric oxide synthase activity before exercise intervention, 6th week and 12th week, respectively. Results: There was no significant difference in the basic values of each index between the two groups of subjects before the test (P＞ 0.05). In the 6th week, the microvascular reactivity (blood flow increase rate), systolic blood pressure, diastolic blood pressure, nitric oxide content, nitric oxide synthase activity of the exercise group did not significantly change from the basic value (P＞0.05). At the 12th week, the microvascular reactivity, nitric oxide content, c nitric oxide synthase activity were significantly higher than those of the base values and the control group (P＜0.05), but the systolic blood pressure and diastolic blood pressure were significantly lower than those of the base values and control group (P＜0.05). In the control group, there were no significant changes in the 6th and 12th week values of each index from the basic value (P＞0.05). Conclusion: Twelve weeks of Taijiquan exercise can improve the microvascular reactivity of middle-aged hypertensive patients, reduce blood pressure, and increase the nitric oxide content and c nitric oxide synthase of patients. The increase of endogenous nitric oxide production is one of the biological mechanisms of Tai Chi exercise to improve the microvascular responsiveness of hypertension patients.

Association between Advanced Glycation End Products, Soluble RAGE Receptor, and Endothelium Dysfunction, Evaluated by Circulating Endothelial Cells and Endothelial Progenitor Cells in Patients with Mild and Resistant Hypertension.

The aim of the present study was to evaluate advanced glycation end products (AGEs) and soluble form of receptor RAGE (sRAGE) concentrations as well as the AGEs/sRAGE ratio in mild (MH) and resistant (RH) hypertensive patients in comparison with normotensive individuals. We also evaluated the association between AGEs, sRAGE as well as AGEs/sRAGE ratio and circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPCs). The MH group consisted of 30 patients, whereas 30 patients were classified for the RH group. The control group (C) included 25 normotensive volunteers. AGEs and sRAGE were measured using enzyme-linked-immunosorbent assay (ELISA). The multicolor flow cytometry was used for analysis of CECs and CEPCs. Significantly higher levels of AGEs in RH cohort were observed as compared to C cohort. Furthermore, significantly lower sRAGE levels as well as a higher AGEs/sRAGE ratio were observed between MH and RH cohorts. Significant correlations were found in the MH cohort for sRAGE and CECs, and CEPCs. The elevation of AGEs levels suggests that oxidative modification of proteins occurs in hypertension pathogenesis. The decrease in sRAGE levels and elevation of the AGEs/sRAGE ratio in MH and RH groups may suggest that hypertensive patients are less protected against the side effects of AGEs as a consequence of an insufficient competitive role of sRAGE against the AGEs-RAGE axis. Finally, it may be concluded that the level of AGEs may be an independent predictor of the condition and function of the endothelium. Furthermore, sRAGE may be classified as a potential biomarker of inflammation and endothelium dysfunction.

Blood pressure trajectory and category and risk of hypertensive disorders of pregnancy in nulliparous women.

BACKGROUND: Recently updated American College of Cardiology/ American Heart Association (ACC/AHA) guidelines redefine blood pressure categories as stage 1 hypertension (systolic, 130-139 mm Hg or diastolic, 80-89 mm Hg), elevated (systolic, 120-129 mm Hg and diastolic, <80 mm Hg), and normal (<120/<80 mm Hg), but their relevance to an obstetric population is uncertain. OBJECTIVE: We sought to evaluate the risk of gestational hypertension or preeclampsia based on early pregnancy blood pressure category and trajectory. STUDY DESIGN: We utilized data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort, a prospective observational study of nulliparous women with singleton pregnancies conducted at 8 clinical sites between 2010 and 2014. Women included in this analysis had no known history of prepregnancy hypertension (blood pressure, ≥140/90 mm Hg) or diabetes. We compared the frequency of hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, among women based on ACC/AHA blood pressure category at a first-trimester study visit and blood pressure trajectory between study visits in the first and second trimesters. Blood pressure trajectories were categorized based on blood pressure difference between visits 1 and 2 as stable (<5 mm Hg difference), upward (≥5 mm Hg), or downward (≤-5 mm Hg). Associations of blood pressure category and trajectory with preeclampsia and gestational hypertension were assessed via univariate analysis and multinomial logistic regression analysis with covariates identified a priori. RESULTS: A total of 8899 women were included in the analysis. Study visit 1 occurred at a mean gestational age of 11.6 ± 1.5 weeks and study visit 2 at a mean gestational age of 19.0 ± 1.6 weeks. First-trimester blood pressure category was significantly associated with both preeclampsia and gestational hypertension, with increasing blood pressure category associated with a higher risk of all hypertensive disorders of pregnancy. Elevated blood pressure was associated with an adjusted relative risk of 1.54 (95% confidence interval, 1.18-2.02) and stage 1 hypertension was associated with adjusted relative risk of 2.16 (95% confidence interval, 1.31-3.57) of any hypertensive disorder of pregnancy. Stage 1 hypertension was associated with the highest risk of preeclampsia with severe features, with an adjusted relative risk of 2.48 (95% confidence interval, 1.38-8.74). Both systolic and diastolic blood pressure trajectories were also significantly associated with the risk of hypertensive disorders of pregnancy independent of blood pressure category (P < .001). Women with a blood pressure categorized as normal and with an upward systolic trajectory had a 41% increased risk of any hypertensive disorder of pregnancy (adjusted relative risk, 1.41; 95% confidence interval, 1.20-1.65) compared to women with a downward systolic trajectory. CONCLUSION: In nulliparous women, blood pressure category and trajectory in early pregnancy are independently associated with risk of preeclampsia and gestational hypertension. Our study demonstrates that blood pressure categories with lower thresholds than those traditionally used to identify individuals as hypertensive may identify more women at risk for preeclampsia and gestational hypertension.

sRAGE and early signs of cardiac target organ damage in mild hypertensives.

BACKGROUND: Soluble Receptor for Advanced Glycation End Products (sRAGE) may be considered a marker inversely related to inflammation and its participation has been established in patients with advanced atherosclerotic vascular diseases. However, it is still unknown whether sRAGE reduction could be early metabolic change in the first stage of hypertension and initial hypertension-associated cardiac damage. We sought to determine the sRAGE values in otherwise healthy, untreated and recently diagnosed mild hypertensives and evaluate their association with blood pressure (BP) values, metabolic parameters, and with subclinical initial signs of cardiac target organ damage (TOD). METHODS: sRAGE were measured in 100 hypertensive and 100 normotensive subjects matched for age, gender and body mass index (BMI), submitted to a clinic visit and both ambulatory BP monitoring and echocardiography to determine the presence of initial cardiac TOD (presence of signs of left ventricular hypertrophy: left ventricular mass indexed for height2.7 (LVMi) > 48 g/m2.7 for men and > 44 g/m2.7 for women and/or increased left atrial volume 4-chamber indexed for body surface area (LAVi) > 34 ml/m2). RESULTS: sRAGE levels were similar between hypertensive and normotensive subjects and were not significantly correlated with office and 24-h BPs values. However, when subgrouping the hypertensive patients in Hyp-TOD and Hyp-withoutTOD, sRAGE was found to be different among the three groups (p = 0.030), being lower in the Hyp-TOD group than the values of both Hyp-withoutTOD (p = 0.038) and normotensives (p = 0.038). In hypertensive patients sRAGE was negatively related with both LVMi (r = - 0.239, p = 0.034) and LAVi (r = - 0.315, p = 0.005) and was independently related to cardiac TOD also in multivariable analysis. CONCLUSIONS: In this population of mild hypertensives, low circulating sRAGE may be a very early marker of initial TOD, suggesting the possible participation of oxidative stress in initial cardiac changes in human hypertension.

Acupuncture for patients with mild hypertension: A randomized controlled trial.

Acupuncture may be beneficial for patients with mild hypertension, but the evidence is not convincing. We aimed to examine the effect of acupuncture on blood pressure (BP) reduction in patients with mild hypertension. We conducted a multicenter, single-blind, sham-controlled, randomized trial in eleven hospitals in China. The trial included 428 patients with systolic blood pressure (SBP) from 140 to 159 mm Hg and/or with diastolic blood pressure (DBP) from 90 to 99 mm Hg. The patients were randomly assigned to receive 18 sessions of affected meridian acupuncture (n = 107) or non-affected meridian acupuncture (n = 107) or sham acupuncture (n = 107) during 6 weeks, or to stay in a waiting-list control (n = 107). All patients received 24-hour ambulatory blood pressure monitoring at weeks 6, 9, and 12. We included 415 participants in the intention-to-treat analysis. The two acupuncture groups were pooled in the analysis, since they had no difference in all outcomes. SBP decreased at week 6 in acupuncture group vs sham acupuncture vs waiting-list group (7.2 ± 11.0 mm Hg vs 4.1 ± 11.5 mm Hg vs 4.1 ± 13.2 mm Hg); acupuncture was not superior to sham acupuncture (mean difference 2.7 mm Hg, 95% CI 0.4 to 5.9, adjusted P = 0.103) or waiting-list control (2.9 mm Hg, 95% CI -0.2 to 6.0, adjusted P = 0.078). However, acupuncture was superior to sham acupuncture (3.3 mm Hg, 95% CI 0.2 to 6.3, adjusted P = 0.035) and waiting-list control (4.8 mm Hg, 95% CI 1.8 to 7.8, P < 0.001) at week 9. Acupuncture had a small effect size on the reduction of BP in patients with mild hypertension.

The endothelial status reflected by circulating endothelial cells, circulating endothelial progenitor cells and soluble thrombomodulin in patients with mild and resistant hypertension.

BACKGROUND: The aim of the present study was to evaluate endothelial status by measuring the concentration of novel markers of endothelial dysfunction (ED): a number of circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPCs) and their ratio (CEPCs/CECs) as well as a traditional parameter - soluble thrombomodulin (sTM) in patients with resistant (RH) and mild hypertension (MH). MATERIALS AND METHODS: Thirty patients with MH and thirty subjects with RH were involved in the study. The control group included thirty-three age and sex-matched normotensive volunteers. We used multicolor flow cytometry for CECs and CEPCs analysis and the commercial human sTM ELISA kit to measure plasma sTM concentration. RESULTS: An elevated CECs number and a decreased CEPCs/CECs ratio was found in MH as well as in RH patients in comparison with normotensive volunteers. CECs correlated positively with an increased triglycerides in MH patients and an elevated LDL-cholesterol and hsCRP in RH group. Positive correlation between CEPCs and LDL-cholesterol level was observed in both types of hypertension. CONCLUSIONS: The results of the present study suggest that an endothelial alteration accompanies hypertension. The number of CECs reflecting the extent of endothelial damage does not appear to be related to the severity of disease. The drastically decreased ratio between CEPCs and CECs observed in both groups of patients suggests an inadequate process of endothelial regeneration. Among analyzed factors inflammation and lipid abnormalities may have significant contribution in endothelial pathology in hypertension.

Renal Denervation for Treatment of Hypertension: a Second Start and New Challenges.

Following the publication of the randomized controlled but open-label trial Symplicity HTN-2, catheter-based renal sympathetic denervation was proposed as a novel treatment for drug-resistant hypertension. Thousands of procedures were routinely performed in Europe, Australia and Asia, and many observational studies were published. A sudden shift from overoptimistic views to radical scepticism occurred later, when the large US randomized sham-controlled trial Symplicity HTN-3 failed to meet its primary blood pressure lowering efficacy endpoint. Experts are divided on the reasons accounting for the large discrepancy between the results of initial studies and those of Symplicity HTN-3. Indeed, the blood pressure lowering effect associated with renal denervation was overestimated in initial trials due to various patient and physician-related biases, whereas it could have been underestimated in Symplicity HTN-3, which was well designed but not rigorously executed. Still, there is a large consensus on the need to further study catheter-based renal denervation in more controlled conditions, with particular emphasis on identification of predictors of blood pressure response. US and European experts have recently issued very similar recommendations on design of upcoming trials, procedural aspects, drug treatment, patient population and inclusion-exclusion criteria. Application of these new standards may represent a second chance for renal denervation to demonstrate--or not--its efficacy and safety in various patient populations. With its highly standardized treatment regimen, the French trial DENERHTN paved the way for this new approach and may inspire upcoming studies testing novel renal denervation systems in different populations.

Association between dietary salt intake and reservation of renal function in patients with mild hypertension.

BACKGROUND: It is now hypothesized whether restricted salt intake can be a potential precursor to renal dysfunction in mild hypertension state. We aimed to study the association between salt intake and renal function in patients with mild hypertension. METHODS: One hundred consecutive hypertensive Iranian patients (with systolic blood pressure 140-160 mmHg and/or diastolic 90-100 mmHg) who were referred to the hypertension research center, Isfahan, Iran, between 2011 and 2014 for screening of hypertension were assessed. Renal function was assessed by measuring serum creatinine (Cr) and creatinine clearance (CrCl). Daily salt intake was assessed on the basis of 24 h urinary sodium excretion. RESULTS: There was no association between the amounts of sodium intake and serum Cr concentration (r = 0.138, P = 0.174), however, an association was revealed between sodium intake and value of CrCl (r = 0.303, P = 0.003). Multivariable linear regression model showed that sodium intake could effectively predict renal function assessed by CrCl (Beta = 0.070, P = 0.016). CONCLUSION: There is an association between sodium intake and reservation of renal function in mild hypertension state and thus by restriction of dietary salt intake, reserving renal function, and preventing appearance and progression of renal insufficiency in higher degrees of hypertension can be facilitated.

Efectividad del tratamiento acupuntural en pacientes con hipertensión arterial leve / Effectiveness of the acupunctural treatment in patients with mild hypertension

Se realizó un estudio de intervención terapéutica en 66 pacientes de 20 a 59 años edad con hipertensión arterial leve, que acudieron a la Sala de Rehabilitación del municipio de Segundo Frente en la provincia de Santiago de Cuba, desde agosto del 2013 hasta igual mes del 2014, con vistas a determinar la efectividad del tratamiento acupuntural en ellos, para lo cual se conformaron 2 grupos: uno de estudio, al que se le aplicó la acupuntura, y otro de control, que recibió tratamiento convencional; ambos grupos fueron evaluados a los 5, 10 y 15 días de iniciada la terapia. Como principales resultados se obtuvo que todos los pacientes tratados con acupuntura disminuyeran las cifras de tensión arterial elevadas en un corto periodo de tiempo y sin necesidad de recurrir a otro tipo de terapia, lo cual demostró que esta alternativa terapéutica es efectiva para tratar la hipertensión arterial leve, por lo cual se recomendó su uso a tal efecto.

A study of therapeutic intervention in 66 patients from 20 to 59 years with mild hypertension who went to the Rehabilitation Room in Segundo Frente municipality in Santiago de Cuba province was carried out from August, 2013 to the same month of 2014, aimed at determining the effectiveness of the acupunctural treatment in them, for which 2 groups were formed: a study group, to which the acupuncture was applied, and a control group who received conventional treatment; both groups were evaluated at 5, 10 and 15 days of initiating the therapy. As main results it was obtained that all the patients treated with acupuncture decreased the values of high blood pressure in a short period of time and without necessity of appealing to another therapy type, which demonstrated that this therapeutic alternative is effective to treat the mild hypertension, reason why its use was recommended to this disorder.

Do we over treat mild hypertension?

The important question whether 'mild' hypertension should or should not be treated by drugs is difficult to answer, because the only randomized controlled trials (RCTs) investigating this question were conducted when the definition of 'mild' hypertension was based on diastolic blood pressure only, whereas the present definition of grade 1 hypertension includes both systolic and diastolic values (SBP/DBP), and the concept of 'mild' hypertension also includes that of low-moderate cardiovascular risk (< 5% cardiovascular death rate in 5 years). Due to the lack of evidence from specific RCTs, guidelines recommend drug treatment of mild hypertension only on the basis of expert opinion. However, recent meta-analyses have provided some support to drug treatment intervention in low-moderate risk grade 1 hypertensives and have shown that, when treatment is deferred until organ damage or cardiovascular disease occur, absolute residual risk (events occurring despite treatment) markedly increases. Although evidence favoring therapeutic intervention in mild hypertension is nowadays stronger than expert opinion, meta-analyses are not substitutes for specific RCTs, and the wide BP spans defining grade 1 hypertension as well as the span defining low-moderate risk leave a wide space for individualized or personalized decisions.

Long-term survival in the randomized trial of drug treatment in mild to moderate hypertension of the Oslo study 1972-3.

BACKGROUND: In the Oslo cardiovascular study of 1972-3 a 5-year randomized trial in mild to moderate hypertension was performed. Several changes in treatment practices have been recommended since that time. We followed the mortality patterns up to 40 years. METHODS: Invited to the Oslo study screening were 25,915 middle-aged men and 16,203 (63%) participated. Reexaminations were done to select suitable participants into the trial. Men had blood pressure 150-179/95-109 mm Hg and the active group (n=406) was treated with thiazides, alpha-methyldopa and propranolol versus untreated controls (n=379). Cox regression analysis was used for statistical analyses. RESULTS: There was no trend towards reduction in total mortality by treatment. A nominally significant increase in risk of death at first myocardial infarction was observed in the trial treatment group across the follow-up period, HR=1.51 (1.01-2.25); (P=0.042). The excess risk developed rapidly during the first 15 years, but the gap between the groups diminished to a large extent during the next 15 years, but the curves stayed at a certain distance for the last 10 years. Cerebrovascular death tended to be non-significantly reduced, HR=0.85 (0.52-1.41). CONCLUSIONS: Drug treatment of mild hypertensive men initiated in the 1970s did not reduce mortality at first MI or total mortality. However, during the period (late 1980s and whole 1990s), when large changes in hypertension treatment practices occurred into regimes with more use of combination therapies including metabolically neutral drugs at lower doses, beneficial effects on MI mortality could be observed.

Blood pressure measurement under standardized indoor condition may mask seasonal blood pressure variation in men with mildly elevated blood pressure.

BACKGROUND: Blood pressure (BP) is generally higher in cold than in warm seasons. This seasonal BP change is largely attributable to outdoor temperature changes. However, if such a typical seasonal change is observed in BP measured under a standardized indoor condition remains unclear. METHODS: Resting supine BPs and heart rate (HR) were measured under a standardized room temperature during summer and the next winter in 104 untreated men (38.1 ± 4.4 years). Subjects were classified as having normotension (NT group: n = 79) or mildly elevated BP (ME group: n = 25) according to the summer measurements. Seasonal variation was defined as the difference from winter to summer measurements. We also examined body composition, endocrine parameters, and renal function. RESULTS: Age did not differ in the two groups (37.6 ± 4.2 versus 39.1 ± 4.9 years). The mean seasonal change in systolic BP was 2.7 ± 1.1 mmHg for the NT group and -4.6 ± 1.9 mmHg for the ME group (p = 0.001). Laboratory and outdoor temperatures did not differ between the two groups in either season. HR, noradrenaline, and estimated glomerular filtration rate were significantly higher during winter in the NT group but not in ME group. CONCLUSIONS: Typical seasonal change in BP may be masked in mildly elevated BP measured under a standardized indoor condition. The mechanisms are multifactorial. Our data suggest that out-of-office BP measurements are necessary for correctly understanding seasonal BP change especially in individuals with mildly elevated BP.

Effect of a traditional Japanese garlic preparation on blood pressure in prehypertensive and mildly hypertensive adults.

Numerous clinical studies have used differing garlic preparations leading to controversial results with regard to the hypotensive effect of garlic. This randomized, double-blind, placebo-controlled study was designed to determine the effect of a traditional Japanese garlic homogenate-based supplementary diet (GH diet) product on blood pressure (BP) in subjects with prehypertension and in those with mild hypertension. In total, 34 eligible subjects with prehypertension and 47 with mild hypertension were treated with a daily dose of GH diet (300 mg as dried garlic homogenate; n=16 and 23, respectively) or placebo (n=18 and 24, respectively) for 12 weeks. Of these, 32 prehypertensive subjects (15 on the GH diet and 17 on the placebo) and 40 mildly hypertensive subjects (19 on the GH diet and 21 on the placebo) completed the study and were subjected to efficacy analyses. Systolic and diastolic BPs were monitored at weeks 4, 8 and 12 during the treatment and at post-week 4 following the termination of the treatment. The GH diet induced significant reductions of systolic BP (of between 6.6 and 7.5 mmHg) and diastolic BP (of between 4.6 and 5.2 mmHg) compared with the placebo subsequent to 8 and 12 weeks of treatment. A 12-week intake of the GH diet did not cause any clinically problematic side-effects. We conclude that the GH diet was well tolerated, and had a clinically relevant hypotensive effect in adults with mild hypertension, but not in those with prehypertension.

Effects of changing daily exercise habit on body composition and maximal exercise test. One-year follow-up study of healthy males and males with mild hypertension / 体力科学

The effects of changing daily exercise habit on body fat, serum lipids and symptom-limited maximal exercise test (treadmill by Balke protocol) were evaluated in healthy males and males with mild hypertension (MHT) aged 30 to 59 yr during a period of one year. The subjects were selected from males who underwent physical examination. The results were as follows :<BR>A. HEALTHY MALES<BR>Study 1 : Subjects who exercised regularly (3 times or more/week) showed higher exercise tolerance and HDL cholesterol (HDLC) and less body fat. Compared to inactive subjects (sports 0-2 times/week), exercise tolerance was higher in the group who tried to walk as much as possible in their every day life.<BR>Study 2 : Inactive subjects without a family history of HT were classified by percentage body fat into three groups (H, M and L) . The obese group showed lower exercise tolerance, higher total cholesterol (TC) and lower HDLC. Heart rate (HR) and systolic blood pressure (BPs) at the same load during the exercise test were higher in the obese group.<BR>Study 3 : Revisited subjects who did not change their dietary habit for one year were selected from the average group of study 2. The subjects who increased their daily physical activity showed reduced body weight and body fat, increased exercise tolerance and HDLC, and lower HR and BPs under the same work load.<BR>B. MALES WITH MILD HYPERTENSION<BR>Study 4 : A similar study was conducted in inactive men with MHT (diastolic BP 90-104 mmHg), non-drug therapy at the first visit and no change in dietary habit for one year. Subjects who increased their daily activity for one year showed reduced body weight and body fat, and both resting BPs and BPd fell by 7 mmHg. HR and BPs decreased under the same work load.<BR>These results suggest that an increase in daily physical activity improves physical fitness, reduces blood pressure and decreases body fat in previously healthy males and in males with MHT.