Optimizing Percutaneous Mitral Valvuloplasty for Rheumatic Mitral Stenosis　- Clinical Significance of Changes in Mitral Valve Area.

BACKGROUND: Percutaneous mitral valvuloplasty (PMV) is a standard treatment for severe rheumatic mitral stenosis (RMS). However, the prognostic significance of the change in mitral valve area (∆MVA) during PMV is not fully understood.Methods and Results: This study analyzed data from the Multicenter mitrAl STEnosis with Rheumatic etiology (MASTER) registry, which included 3,140 patients with severe RMS. We focused on patients with severe RMS undergoing their first PMV. Changes in echocardiographic parameters, including MVA quantified before and after PMV, and composite outcomes, including mitral valve reintervention, heart failure admission, stroke, and all-cause death, were evaluated. An optimal result was defined as a postprocedural MVA ≥1.5 cm2without mitral regurgitation greater than Grade II. Of the 308 patients included in the study, those with optimal results and ∆MVA >0.5 cm² had a better prognosis (log-rank P<0.001). Patients who achieved optimal results but with ∆MVA ≤0.5 cm² had a greater risk of composite outcomes than those with optimal outcomes and ∆MVA >0.5 cm² (nested Cox regression analysis, hazard ratio 2.27; 95% confidence interval 1.09-4.73; P=0.028). CONCLUSIONS: Achieving an increase in ∆MVA of >0.5 cm2was found to be correlated with improved outcomes. This suggests that, in addition to achieving traditional optimal results, targeting an increase in ∆MVA of >0.5 cm2could be a beneficial objective in PMV treatment for RMS.

A novel hydrogel-based moisturizing cream composed of hyaluronic acid for patients with xerosis: An intraindividual comparative analysis.

BACKGROUND: Hyaluronic acid (HA) is mainly used to treat xerosis. It also exerts wound-healing, moisturizing, and antiaging effects. Although HA is considered an effective and safe ingredient in cosmetics, there is a constant demand for a more money-saving and effective formulation. This study aimed to evaluate the safety and efficacy of a novel hydrogel-based moisturizer containing HA cross-linked with silicone polymers, produced solely through irradiation without the use of cross-linking agents. MATERIALS AND METHODS: A safety study enrolled 30 participants with healthy skin to perform patch and photopatch tests while recording adverse events. For the efficacy study, 30 participants with xerosis were compared before and after using the novel hydrogel, evaluating the cutaneous barrier function, xerosis severity scale (XSS) score, participant's satisfaction, and Investigator's Global Assessment (IGA). Furthermore, the efficacy of the novel hydrogel-based moisturizer was evaluated by comparing it with a conventional moisturizer, Physiogel, in another 30 participants with xerosis. RESULTS: In the safety study, no serious adverse events were observed. In the efficacy study before and after use, skin hydration and skin surface lipid increased (p < 0.05) whereas the XSS scores decreased (p < 0.05) with time. In the comparative efficacy study with Physiogel, skin hydration increased whereas the XSS scores decreased (p < 0.05) over time in both groups. Furthermore, IGA improved in 100% of participants in both groups. Also, 100% and 93% of participants were satisfied with the novel hydrogel-based moisturizer and Physiogel, respectively. CONCLUSIONS: The novel hydrogel-based moisturizer proved to be safe and effective for xerosis, showing comparable results to the conventional moisturizer.

Risk Factors and Prognosis of Stroke in Gynecologic Cancer Patients.

Increased life expectancy and cancer prevalence rates expose patients to a higher risk of developing other comorbidities such as stroke. This study aimed to evaluate the risk factors for and prognosis of stroke in patients with gynecological cancers. A single-center retrospective cohort study was conducted on patients with cervical, endometrial, and epithelial ovarian cancers. Patients were classified into three groups based on the period of stroke onset: at least one year before cancer diagnosis, within one year before cancer diagnosis to six months after the last treatment date, and six months after the last treatment date. Among the 644 patients, stroke occurred in 54 (8.4%). In univariate analysis, stroke was significantly associated with overall survival. In contrast, in multivariate analysis, stroke was significantly associated with age and hypertension, but not with overall survival. Age, pulmonary thromboembolism/deep vein thrombosis, histological grade, and tumor stage were significantly associated with overall survival. Therefore, it is important to establish an appropriate examination and treatment plan for patients with gynecologic cancers using a multidisciplinary approach that incorporates the patient's age, medical condition, and tumor characteristics rather than excessively considering the adverse effects of stroke on cancer prognosis.

Lipid peroxidation-derived modification and its effect on the activity of glutathione peroxidase 1.

Oxidative stress and the resulting lipid peroxidation are associated with various pathological states, including neurodegenerative diseases and cancer. The end products of lipid peroxidation, such as 4-oxo-2(E)-nonenal (ONE), 4-hydroxy-2(E)-nonenal (HNE), and methylglyoxal (MG), exert several biological effects through modification of various cellular components, including DNA and proteins. Glutathione peroxidase 1 (GPx1) is an intracellular antioxidant enzyme that uses glutathione (GSH) to reduce a variety of peroxides, thereby modulating cellular oxidative stress and redox-mediated responses. GPx1 contains nucleophilic amino acids at its active (one Sec) and GSH-binding (four Arg and one Lys) sites. We found that lipid peroxidation-derived reactive aldehydes (ONE, HNE, and MG) modified the GSH-binding site, resulting in the inhibition of GPx1 activity. Mass spectrometry-based proteomic analysis identified the sites modified by each aldehyde (ONE, 14 sites; HNE, 7 sites; MG, 9 sites). The GSH-binding sites modified were as follows: ONE, Arg57, 103, 184, and 185; HNE, Lys91; MG, Arg103. Upon incubation of GPx1 with each aldehyde, ONE reduced GPx1 activity more significantly than did HNE or MG in a dose- and time-dependent manner. The addition of GSH to GPx1 3 h after incubation with ONE prevented further inhibition by trapping ONE as a ONE-GSH adduct. However, the activity of GPx1 was not restored to the initial level, indicating that ONE modified GPx1 irreversibly. This study suggests that oxidative damage to lipids, resulting in the formation of reactive aldehydes, can amplify cellular oxidative stress via direct inactivation of GPx1, which increases the production of intracellular peroxides.

Lipid hydroperoxide-derived insulin resistance and its inhibition by pyridoxamine in skeletal muscle cells.

Oxidative stress is strongly associated with the onset and/or progression of diabetes. Under conditions of oxidative stress, lipid hydroperoxides are decomposed to reactive aldehydes that have been reported to induce insulin resistance by modifying proteins involved in insulin signaling. Pyridoxamine (PM) can inhibit the formation of advanced glycation/lipoxidation end products by scavenging reactive carbonyl species. Thus, PM has emerged as a promising drug candidate for various chronic conditions, including diabetic complications. In this study, L6 skeletal muscle cells were treated with 4-oxo-2(E)-nonenal (ONE), one of the most abundant and reactive lipid-derived aldehydes. Cellular insulin resistance was assessed by measuring insulin-stimulated glucose uptake using 2-deoxyglucose. ONE induced a time- and dose-dependent decrease in glucose uptake. Liquid chromatography/electrospray ionization-mass spectrometry analysis of the reaction between ONE and insulin receptor substrate 1 (IRS1) lysate identified multiple modifications that could disturb the interaction between IRS1 and activated IR, leading to insulin resistance. Pretreatment of the cells with PM restored the ONE-induced decrease in glucose uptake. Concomitantly, the formation of PM-ONE adducts in cell culture medium was increased in a PM-dose dependent manner. PM can therefore prevent lipid hydroperoxide-derived insulin resistance by quenching ONE. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-022-00155-z.

Clinical significance of right ventricular-pulmonary arterial coupling in patients with tricuspid regurgitation before closure of atrial septal defect.

Background: Functional tricuspid regurgitation (TR) usually decreases after atrial septal defect (ASD) closure; however, it may persist and cause heart failure that requires treatment. We aimed to investigate clinical and echocardiographic factors predicting persistent TR after ASD closure. Methods: Among 348 adults who underwent isolated ASD closure between January 2010 and September 2020, 91 (26.1%) patients with significant TR (at least moderate degree) before ASD closure were included. Persistent TR was defined as significant TR on echocardiography at 6 months to 1 year after ASD correction. We comprehensively analyzed the echocardiogram before ASD closure, including speckle-tracking imaging. Right ventricular (RV)-pulmonary arterial (PA) (RV-PA) coupling was assessed by the ratio of RV global longitudinal strain (RV GLS) and tricuspid annular S' velocity to PA systolic pressure (PASP). Results: Persistent TR was observed in 22 (24.2%) patients. Patients with persistent TR were significantly older and had larger TR jet areas and lower RV-PA coupling parameters than those without persistent TR. On multivariable regression, persistent TR was independently associated with age [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01-1.14, p = 0.030) and |RV GLS|/PASP (OR 0.001, 95% CI 0.00-0.017, p = 0.012). ROC curves analysis showed that |RV GLS|/PASP's best cut-off for persistent TR was 0.46 (cut-off 0.46, the area under the curve 0.789, p < 0.001). Conclusion: Persistent TR after ASD closure is not rare. Old age and RV-PA uncoupling could be associated with persistent TR after ASD closure. In older patients with abnormal RV-PA coupling, careful evaluation and concomitant or subsequent TR intervention may be considered.

Validation of Relationship between Patients' Descriptions of Pruritus and Patient-burden of Chronic Pruritus using Structural Equation Modelling.

Patients with chronic itch describe their pruritus in a wide variety of ways. However, these subjective descriptions are often not taken into consideration by physicians. This study aimed to validate patients' descriptions of pruritus, and to investigate the relationship between various descriptions of pruritus and the patient burden of chronic pruritus by examining the mediating effects of sleep disturbance and sexual dysfunction on patient's quality of life, as predicted by various descriptions of pruritus. Exploratory and confirmatory factor analyses were performed to identify the factor structure measured by 11 descriptions of pruritus. The study then analysed differences in the degree of sleep disturbance, sexual dysfunction, and quality of life deterioration factors using a structural equation modelling method. Using data from 419 patients with chronic pruritus, 11 descriptions of pruritus were classified into 2 groups: (i) sensory pruritus (i.e. stinging, stabbing, burning, painful, formication, throbbing, and cold) that are linked with descriptions of pruritus patterns; and (ii) affective pruritus (i.e. annoying, unbearable, worrisome, and warm) from patient reports of psychological or emotional distress. The study found that affective pruritus decreases patient's quality of life either directly or indirectly through sleep disturbance. In conclusion, clues about a patients' sleep disturbance or poor quality of life can be obtained through their descriptions of pruritus.

Safety and efficacy of a new hydrogel based on hyaluronic acid as cosmeceutical for xerosis.

BACKGROUND: Hyaluronic acid (HA) is among the most effective and safe ingredients frequently used in cosmetics. However, a more economical and efficient formulation is still required. OBJECTIVE: We sought to assess the safety and efficacy of a novel hydrogel manufactured only by irradiation containing cross-linked HA and polyethylene glycol polymers with addition of polysiloxane. METHODS: The study included 30 people with normal skin and 30 patients with xerosis. In the normal skin group, to evaluate the safety, a patch test and a photopatch test were performed, and patients' discomfort was investigated. In those with xerosis, to assess the efficacy, a skin barrier function test was performed at baseline and at 2, 4, and 8 weeks after the application of the novel hydrogel. Additionally, the xerosis severity scale (XSS), patient satisfaction, Investigator's Global Assessment (IGA), and adverse responses were evaluated. RESULTS: In the safety study, there was no significant discomfort in the experimental group compared with the control group. In the efficacy study, at 2, 4, and 8 weeks after the application of the novel hydrogel, the mean value of skin hydration and sebum content increased and the mean value of XSS decreased with time in the experimental group, and a difference was observed when compared with the control group. IGA showed improvement in 97%, 77%, and 80% at each visit and the proportions of satisfied patients were 90%, 87%, and 90%, respectively. CONCLUSIONS: The novel HA-based hydrogel tested herein could be a safe and effective therapeutic remedy for xerosis.

Cancer Therapy-Related Cardiac Dysfunction in Patients Treated with a Combination of an Immune Checkpoint Inhibitor and Doxorubicin.

Backgrounds: There are scarce data on whether immune checkpoint inhibitors (ICIs) increase the risk of cardiac dysfunction when used with cardiotoxic agents. Thus, we evaluated cardiac dysfunction in patients with sarcoma receiving doxorubicin with or without ICI using echocardiography and left ventricular global longitudinal strain (LVGLS). Methods: A total of 95 patients were included in this study. Echocardiography and LVGLS were evaluated at baseline and follow-up (at 3 and 6 months of chemotherapy) and compared with the doxorubicin (Dox; n = 73) and concomitant ICI with doxorubicin (Dox-ICI; n = 22) groups. Cancer therapy-related cardiac dysfunction (CTRCD) was defined as a left ventricular ejection fraction (LVEF) drop of >10% and LVEF of <50% (definite CTRCD), LVEF drop of >10%, LVEF of ≥50%, and LVGLS relative reduction of >15% (probable CTRCD) at six months. Results: There were no significant differences in age, cumulative dose of doxorubicin, and cardiovascular risk factors between the two groups. At baseline, the LVEF was similar in the Dox and Dox-ICI groups (p = 0.493). In the Dox group, LVEF decreased to 59 ± 6% (Δ −7 ± 1.3%, p < 0.001) and LVGLS decreased from −17.3 ± 3.2% to −15.4 ± 3.2% (Δ −10.1 ± −1.9%, p < 0.001) at six months. In the Dox-ICI group, LVEF decreased to 55 ± 9% (Δ −9 ± 2.1%, p < 0.001), along with a significant decrease in LVGLS (from −18.6 ± 1.9% to −15.3 ± 3.6%, Δ −12.4 ± −2.4%, p < 0.001). Over a median follow-up of 192 days, there were no cases with clinical manifestations of fulminant myocarditis. In the Dox group, definite and probable CTRCD were observed in seven (10.1%) and five (7.4%) patients, respectively. In the Dox-ICI group, definite and probable CTRCD were observed in four (19%) and four (19%) patients, respectively. The total number of patients who developed CTRCD was significantly higher in the Dox-ICI group than in the Dox group (38.1% vs. 17.4%, p = 0.042). Serum troponin-T level was significantly higher in the Dox-ICI group than in the Dox group (53.3 vs. 27.5 pg/mL, p = 0.023). Conclusions: ICIs may increase the risk of CTRCD when used with cardiotoxic agents. CTRCD should be monitored in patients treated with ICIs by cardiac biomarkers and echocardiography, including LV-GLS.

Comparative studies for amyloid beta degradation: "Neprilysin vs insulysin", "monomeric vs aggregate", and "whole Aß40 vs its peptide fragments".

Amyloid beta (Aß) proteins are produced from amyloid precursor protein cleaved by ß- and γ-secretases, and are the main components of senile plaques pathologically found in Alzheimer's disease (AD) patient brains. Therefore, the relationship between AD and Aßs has been well studied for both therapeutic and diagnostic purposes. Several enzymes have been reported to degrade Aßs in vivo, with neprilysin (NEP) and insulysin (insulin-degrading enzyme, IDE) being the most prominent. In this article, we describe the mass spectrometric characterization of peptide fragments generated using NEP and IDE, and clarify the differences in digestion specificities between these two enzymes for non-aggregated Aß40, aggregated Aß40, and Aß40 peptide fragments, including Aß16. Our results allowed identification of all the peptide fragments from non-aggregated Aß40: NEP, 23 peptide fragments consisting of 2-11 amino-acid residues, 17 cleavage sites; IDE, 23 peptide fragments consisting of 6-33 amino-acid residues, 15 cleavage sites. Also, we confirmed that IDE can digest only whole Aß40, whereas NEP can digest both Aß40 and partial structures such as Aß16 and peptide fragments generated by the digestion of Aß40 by IDE. Furthermore, we confirmed that IDE and NEP are unable to digest aggregated Aß40.

Development of aldolase-based catalysts for the synthesis of organic chemicals.

Aldol chemicals are synthesized by condensation reactions between the carbon units of ketones and aldehydes using aldolases. The efficient synthesis of diverse organic chemicals requires intrinsic modification of aldolases via engineering and design, as well as extrinsic modification through immobilization or combination with other catalysts. This review describes the development of aldolases, including their engineering and design, and the selection of desired aldolases using high-throughput screening, to enhance their catalytic properties and perform novel reactions. Aldolase-containing catalysts, which catalyze the aldol reaction combined with other enzymatic and/or chemical reactions, can efficiently synthesize diverse complex organic chemicals using inexpensive and simple materials as substrates. We also discuss the current challenges and emerging solutions for aldolase-based catalysts.

Robust analysis of angiotensin peptides in human plasma: Column switching-parallel LC/ESI-SRM/MS without adsorption or enzymatic decomposition.

Angiotensin (Ang) peptides are the main effectors of the renin-angiotensin system (RAS) regulating diverse physiological conditions and are involved in renal and vascular diseases. Currently, quantitative analyses of Ang peptides in human plasma mainly rely on radioimmunoassay-based methods whose reported levels are quite divergent. Analyses are further complicated by the potential of Ang peptides to bind to solid surfaces, to be enzymatically decomposed during sample preparation, and to undergo post-translational modifications. A column switching-parallel LC/ESI-SRM/MS method has been developed for seven Ang peptides (Ang I, Ang II, Ang III, Ang IV, Ang 1-9, Ang 1-7, and Ang A) in human plasma. Aqueous acetonitrile (5%) containing 50 mM arginine (Arg) as a dissolving solution and a combination of protease inhibitors with formic acid were used to prevent adsorption and enzymatic degradation, respectively. Plasma samples were simply deproteinized with acetonitrile followed by clean-up with an on-line trap column via column-switching. Stable isotope dilution with [13C5,15N1-Val]-Ang peptides as internal standards was employed for quantitative analysis. The current methodology has been successfully applied to determine the plasma levels of Ang peptides in healthy participants, suggesting future applicability to studies of various diseases related to RAS.

Extensive Nevus Comedonicus with Inflammatory Nodules and Cysts Controlled with Adalimumab.

Nevus comedonicus is a very rare skin disorder characterized by the presence of comedo-like dilated pores with keratinous plugs, rarely resulting in painful recurrent inflammatory nodules or cysts. It presents as localized or extensive form. It displays unilaterally or bilaterally segmental distribution. Histopathologically, it is characterized by keratin-filled epidermal invagination with bulbous proliferation of keratinocytes. The condition may be caused by fibroblast growth factor receptor 2 mutation. Although it may be controlled by a variety of therapeutic modalities, it is difficult to achieve complete resolution. We report a case of extensive nevus comedonicus with inflammatory nodules and cysts controlled with adalimumab.

Participants' Satisfaction with the Atopic Dermatitis Education Program: Assessing the Impact of Each Content Using Structural Equation Modeling.

BACKGROUND: Only a few studies have tried to assess factors relevant to the satisfaction of the participants in atopic dermatitis (AD) educational programs. More systematic modeling of this issue is needed. OBJECTIVE: To examine the benefit of a conjoint educational program for AD on patients and caregivers in a clinical setting. METHODS: In a half-day educational program called "AD school", 831 people (493 patients and 338 family members) participated for 8 years. Various educational and entertaining programs were provided. The on-site survey was administered to measure participants' satisfaction and perception of the benefit. We applied structural equation modeling to identify the relations among satisfaction and perception. RESULTS: A total of 209 family survey data was obtained and analyzed. The survey items were grouped into four categories. The categories were classified as individual education, group education, fun activity, and overall satisfaction (fun, benefit, intention to re-join and recommend to others). According to the model that we built, comprehensive group education was demonstrated to be the most relevant factor affecting overall satisfaction. CONCLUSION: Our holistic approach would allow dermatologists to improve the efficacy of the conjoint educational program for AD.

Effect of Red Ginseng Oil on Cultured Sebocytes and Outer Root Sheath Cells after Treatment with Lipopolysaccharide.

BACKGROUND: Ginseng has been known in Korea as a health-supportive herbal medicine from time immemorial. Essential oil isolated from fresh ginseng has been shown to display antibacterial and anti-inflammatory activities. OBJECTIVE: The effects of red ginseng oil (RGO) on the lipopolysaccharide (LPS)-treated sebocytes and outer root sheath (ORS) cells were studied. METHODS: The cultured cells were treated with either 0.1% dimethyl sulfoxide, 5 µg/ml LPS, 50 µg/ml RGO, or 5 µg/ml LPS plus 50 µg/ml RGO for 6 and 24 hours. RT-PCR, real-time PCR, enzyme-linked immunosorbent assay, western blot, and immunofluorescence staining were performed for the analysis of inflammatory cytokine. RESULTS: RGO showed the increased gene and protein expression of inflammatory cytokines, including interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor-α in the LPS-treated sebocytes and ORS cells. RGO also showed the increased protein expression of p-c-jun and p-JNK in the LPS-treated sebocytes and ORS cells. Gene expression of TLR2 was increased in LPS-treated sebocytes following treatment with RGO. Additionally, RGO resulted in an increased expression of LL-37 in the LPS-treated sebocytes and ORS cells. Moreover, it remarkably increased the production of sebum in LPS-treated sebocytes. CONCLUSION: RGO might be among the aggravating factors of acne vulgaris. It would be better to stop taking red ginseng in patients with inflammatory acne.

Prognostic Implications of Left Ventricular Global Longitudinal Strain in Patients With Surgically Treated Mitral Valve Disease and Preserved Ejection Fraction.

BACKGROUND: This study investigated whether left ventricular (LV) global longitudinal strain (LV-GLS), as an LV function parameter less affected by mitral valve (MV) repair or prosthesis, is associated with clinical outcomes in patients with surgically treated MV disease. METHODS: Among 750 patients who underwent MV surgery, we assessed LV-GLS by speckle tracking echocardiography in 344 patients (148 men, mean age 58 ± 13 years) who showed preserved LV ejection fraction on echocardiography between 6 months and 2 years after MV surgery and who did not undergo aortic valve surgery. The assessed clinical events included admission for worsening of heart failure and cardiac death. RESULTS: During a period of 42.4 ± 26.0 months, 32 (9.3%) patients were hospitalized for worsening heart failure, and 3 (0.8%) died due to cardiac causes. The absolute value of LV-GLS (|LV-GLS|) was significantly lower in patients with clinical events than in those without (12.1 ± 3.1 vs. 15.0 ± 3.2%, p < 0.001) despite comparable LV ejection fraction between groups. |LV-GLS| showed predictive value for clinical events (cut-off 13.9%, area under the curve 0.744, p < 0.001). Patients with |LV-GLS| ≤14.0% had poorer outcomes than those with |LV-GLS| >14.0% (log-rank p < 0.001). Prognosis was worse in patients with |LV-GLS| ≤14.0% and pulmonary hypertension than among those who with |LV-GLS| ≤14.0% without pulmonary hypertension (log rank p < 0.001). In nested Cox proportional hazard regression models, reduced |LV-GLS| was independently associated with the occurrence of clinical events. CONCLUSIONS: In patients with surgically treated MV and preserved LV ejection fraction, assessment of LV-GLS provides functional information associated with cardiovascular outcomes.

Discriminatory performance of insulin-like growth factor 1 and insulin-like growth factor binding protein-3 by correlating values to chronological age, bone age, and pubertal status for diagnosis of isolated growth hormone deficiency.

PURPOSE: The discriminatory performance of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) was investigated by correlating their values with chronological age (CA), bone age (BA), and pubertal status (PS) for diagnosis of isolated growth hormone deficiency (IGHD). METHODS: We evaluated IGF-1 and IGFBP-3 levels in 310 short-stature subjects subdivided into 2 groups: IGHD (n=31) and non-IGHD (n=279). IGF-1 and IGFBP-3 were assayed using immune-radiometric assay and transformed into standard deviation score (SDS) according to CA, BA, and PS. RESULTS: The highest sensitivity was found in IGF-1-SDS for CA and IGFBP-3-SDS for CA (22.6% and 30.0%, respectively). The highest specificity was found in IGF-1-SDS for PS and IGFBP-3-SDS for PS (98.2% and 94.4%, respectively). Groups with the highest positive predictive values were IGF-1-SDS for BA and IGFBP-3-SDS for BA (10.9% and 5.1%, respectively). Highest negative predictive values were seen in IGF-1-SDS for CA and IGFBP-3-SDS for CA (98.4% and 98.4%, respectively). CONCLUSION: IGF-1-SDS for CA, instead of IGF-1-SDS for BA or PS, could be used as a standard variable for IGHD screening. The sufficiently high specificity of IGF-1-SDS for PS suggests that this value is a useful tool for identification of IGHD.