Coronary periarteritis and pericarditis are rare but distinct manifestations of heart involvement in IgG4-related disease: a retrospective cohort study.

BACKGROUND: The heart can be involved in immunoglobulin (Ig)-G4-related disease (IgG4-RD). This study aimed to summarize the clinical features and efficacy of treatment for IgG4-RD patients with heart involvement. METHODS: We conducted a retrospective study enrolling 42 IgG4-RD patients with heart involvement from the IgG4-RD cohorts of the Peking Union Medical College Hospital and Beijing An Zhen Hospital, from 2010 to 2022. Clinical, laboratory, radiological data were collected, and treatment responses to glucocorticoids and immunosuppressants were analyzed. RESULTS: IgG4-related cardiac involvement is a rare part of the IgG4-RD spectrum. The incidences of coronary periarteritis and pericarditis were 1.2%(13/1075) and 3.1%(33/1075), respectively in our cohort. Valvular disease possibly related to IgG4-RD was detected in two patients. None of the patients with myocardial involvement were identified. The average age was 58.2 ± 12.8 years, with a male predominance (76.7%). Coronary artery CT revealed that mass-like and diffuse wall-thickening lesions were the most frequently observed type of coronary periarteritis. Pericarditis presented as pericardial effusion, localized thickening, calcification and mass. After treatment with glucocorticoid and immunosuppressants, all patients achieved a reduced IgG4-RD responder index score and achieved radiological remission. Two patients with coronary peri-arteritis experienced clinical relapses during the maintenance period. CONCLUSIONS: Cardiac involvement in IgG4-RD is rare and easily overlooked since many patients are asymptomatic, and the diagnosis relies on imaging. Patients showed a satisfactory response to glucocorticoid based treatment.

Systemic Corticosteroid as an Adjunct for Acute Respiratory Distress Syndrome in Non-Fatal Fresh Water Drowning: An Evidence-based Case Report.

BACKGROUND: Acute lung injury or acute respiratory distress syndrome (ARDS) is one of the most common complications of non-fatal drowning. Although respiratory societies' guidelines endorse the role of systemic corticosteroids in ARDS, the evidence for systemic corticosteroid use in ARDS due to non-fatal drowning is limited. METHODS: A search was conducted on Pubmed, OVID, and EuropePMC, assessing the clinical question using inclusion and exclusion criteria. The selected studies were critically appraised, and the results were summarized. RESULTS: A total of six retrospective studies were selected and assessed, all studies showed poor validity and a high risk of bias. Out of six studies, only four informed us of steroid administration's effect on outcomes. In two studies, mortality associated with corticosteroid administration seemed to be higher. On the contrary, one study found no mortality in the corticosteroid group, but 100% mortality was observed in the control group. In another study, steroid therapy seemed to not affect hospital length of stay or mechanical ventilation rates. CONCLUSION: Corticosteroid administration for non-fatal drowning and its impact on clinical outcomes remains equivocal. Routine administration of corticosteroids is not indicated and should be done on a case-by-case basis.

Dual-wavelength dye laser combined with betamethasone injection for treatment of keloids: protocol of a randomised controlled trial.

INTRODUCTION: Keloids, benign fibroproliferative tumours characterised by excessive fibroblast proliferation and over-deposition of extracellular matrix, pose a therapeutic challenge with high recurrence rates. Betamethasone (diprospan) injection (BI) is one of the most common non-invasive therapies for keloids. Pulsed dye laser (PDL) has the function of closing microvessels, which may become one of the auxiliary treatment methods of BI and may enhance its curative effect. Some studies suggest that the combination of a dual-wavelength dye laser (DWL) and BI may offer superior efficacy. This randomised controlled trial aims to evaluate whether the combined therapy of DWL+BI outperforms BI alone in treating keloids. METHODS AND ANALYSIS: This single-centre, parallel positive control, randomised trial evaluates the efficacy and safety of DWL (585 nm PDL+1064 nm neodymium-doped yttrium aluminium garnet) combined with BI for keloid treatment. Enrolling 66 adult patients, participants are randomised into DWL+BI or BI groups in a 1:1 ratio. Over 12 weeks, each group undergoes four treatment sessions, ensuring blinding for outcome assessors. Data collection occurs at multiple time points (4, 12, 24 and 52 weeks), with primary outcomes assessing the Vancouver Scar Scale (VSS) improvement rate 24 weeks after the last intervention. Secondary outcomes include VSS improvement rates, changes in keloid volume, changes in relative perfusion index measured by laser speckle contrast imaging, Patient and Observer Scar Assessment Scale results and patient satisfaction. Safety assessments include vital signs, laboratory tests, pregnancy tests and self-reports of adverse reactions. ETHICS AND DISSEMINATION: The results will be presented in peer-reviewed journals and at international conferences. This study is approved by the Ethics Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Register (ChiCTR2400080148).

[Cushing syndrome because of herbal supplement]. / Syndroom van Cushing door kruidenpreparaat.

The use of exogenous glucocorticoids is a common cause of Cushing syndrome. We present a case of exogenous Cushing syndrome caused by Binahong: an over-the-counter 'herbal' supplement. A 54-year-old woman presented with weight gain, joint pain, hypertension and poorly regulated type 2 diabetes mellitus despite the start of semaglutide one year before presentation. Physical examination revealed signs of steroid excess with a moon face and abdominal obesity. Her serum cortisol level and ACTH level were suppressed. Synthetic glucocorticoid screening revealed a positive dexamethason level in the herbal supplement. After stopping the supplement her serum cortisol and dexamethason increased to normal levels. This case emphasizes the importance of awareness for the use of supplements containing hidden glucocorticoids causing Cushing syndrome.

Are adverse events higher among patients with acute optic neuritis prescribed glucocorticoids? A retrospective, longitudinal cohort study.

OBJECTIVE: Optic neuritis (ON) is an acute focal inflammation of the optic nerve routinely treated with glucocorticoids. We aimed to compare adverse events (AE) among glucocorticoid-treated and untreated patients in the real world to guide clinical decision making about treatment tradeoffs. DESIGN: Retrospective, longitudinal cohort study. SETTING: Claims study from a large, private insurer in the USA (2005-2019). PARTICIPANTS: Adults≥18 years old with ≥1 ICD9/10 ON diagnosis with an evaluation/management visit code, and ≥6 months continuous enrolment prior to and following ON diagnosis. INTERVENTION: Glucocorticoid prescription exposure. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was any AE within 90 days of glucocorticoid prescription. Secondary outcome was AE assessment by severity. Generalised estimating equations with logit link assessed relationships between glucocorticoid prescription and AEs. High-dimensional propensity score analyses accounted for potential confounding (eg, sociodemographics and comorbidities). Sensitivity analyses restricted the cohort to high-dose prescriptions (≥100 mg prednisone equivalent, injection/infusion), AEs within 30 days, highly specific ON definition and traditional propensity score match. RESULTS: Of the 14 311 people with 17 404 ON claims, 66.3% were women (n=9481), predominantly White (78.2%; n=9940), with median age (IQR)=48 (37,60) years. Within 90 days of the claim, 15.7% (n=2733/17 404) were prescribed glucocorticoids. The median (IQR) prescription duration=10 (6,20) days. Any and severe AEs were higher among patients prescribed glucocorticoids versus none (any AEs: n=437/2733 (16.0%) vs n=1784/14 671 (12.2%), adjusted OR 1.33 (95% CI: 1.18 to 1.50); severe AEs: n=72/2733 (2.6%) vs n=273/14 671 (1.9%), adjusted OR 1.82 (95% CI: 1.37 to 2.35)). Sensitivity analyses were similar. CONCLUSIONS: Real-world glucocorticoid prescriptions among ON patients were short-term, associated with a 30% relative increase in potentially serious AEs captured within healthcare encounters, including those not previously observed, such as VTE. These results can inform treatment decisions, particularly for ON patients likely to experience only marginal benefits.

Difficulties in the Diagnostics and Treatment of Hashimoto's Encephalopathy-A Systematic and Critical Review.

Hashimoto's encephalopathy (HE) has been a poorly understood disease. It has been described in all age group, yet, there is no specific HE marker. Additionally, the treatment data in the available studies are frequently divergent and contradictory. Therefore, the aim of our systematic and critical review is to evaluate the diagnosis and treatment of HE in view of the latest findings. The databases browsed comprised PubMed, Scopus, and Google Scholar as well as Cochrane Library, and the search strategy included controlled vocabulary and keywords. A total of 2443 manuscripts were found, published since the beginning of HE research until February 2024. In order to determine validity of the data collected from studies, bias assessment was performed using RoB 2 tool. Ultimately, six studies were included in our study. HE should be considered in the differential diagnosis in patients with psychiatric and neurological symptoms. According to our findings, negative thyroid peroxidase antibodies (anti-TPOs) may represent a valuable parameter in ruling out HE. Nonetheless, this result cannot be used to confirm HE. Furthermore, the proposed anti NH2-terminal-α-enolase (anti-NAE) is non-specific for HE. The effectiveness of glucocorticoid therapy is 60.94%, although relapse occurs in 31.67% of patients following the treatment. Our review emphasizes the significance of conducting further large-scale research and the need to take into account the potential genetic factor.

Efficacy and safety of glucocorticoids in the treatment of COVID-19: a systematic review and meta-analysis of RCTs.

In the realm of acute respiratory infections, coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a global public health challenge. The application of corticosteroids (CSs) in COVID-19 remains a contentious topic among researchers. Accordingly, our team performed a comprehensive meta-analysis of randomized controlled trials (RCTs) to meticulously evaluate the safety and efficacy of CSs in hospitalized COVID-19 patients. To explore efficacy of CSs in the treatment of COVID-19 patients, we meticulously screened RCTs across key databases, including PubMed, Web of Science, Embase, Cochrane Library, ClinicalTrials.gov, as well as China's CNKI and Wanfang Data. We focused on assessing the 28 days mortality rates. We evaluated the data heterogeneity using the Chi-square test and I2 values, setting significance at 0.1 and 50%. Data from 21 RCTs involving 5721 participants were analyzed. The analysis did not demonstrate a significant association between CSs intervention and the 28 days mortality risk in hospitalized COVID-19 patients (relative risk [RR] = 0.93; 95% confidence interval [95% CI]: 0.84-1.03; P = 0.15). However, subgroup analysis revealed a significant reduction in 28 days mortality among patients with moderate-to-severe COVID-19 (RR at 0.85; 95% CI: 0.76-0.95; P = 0.004). Specifically, short-term CS administration (≤ 3 days) was associated with a substantial improvement in clinical outcomes (RR = 0.24; 95% CI: 0.09-0.63; P = 0.004), as was longer-term use (≥ 8 days) (RR = 0.88; 95% CI: 0.77-0.99; P = 0.04). Additionally, in patients with moderate-to-severe COVID-19, the administration of dexamethasone increased the number of 28 days ventilator-free days (Mean Difference = 1.92; 95% CI: 0.44-3.40; P = 0.01). Methylprednisolone also demonstrated significant benefits in improving clinical outcomes (RR = 0.24; 95% CI: 0.09-0.63; P = 0.004). Our meta-analysis demonstrated that although there is no significant difference in 28 days mortality rates among hospitalized COVID-19 patients, the use of CSs may be beneficial in improving clinical outcomes in moderate or severe COVID-19 patients. There was no significant increase in the occurrence of adverse events associated with the use of CSs. Our meta-analysis provides evidence that while CSs may not be suitable for all COVID-19 patients, they could be effective and safe in severely ill COVID-19 patients. Consequently, it is recommended to administer CSs for personalized treatments in COVID-19 cases to improve the clinical outcomes while minimizing adverse events.

Toxoplasmosis in the outer retina.

Objective: To present a case of ocular toxoplasmosis. Materials and methods: A sixteen-year-old female patient presented to our clinic with complaints regarding decreased vision in her right eye (BCVA 0.5), starting five days before the exam. Her anamnestic data revealed a previous history of ocular toxoplasmosis in her left eye. OCT scans of the inner retina identified a huge cystic space, located posterior to the inner line, off the outer plexiform layer, with a small amount of hyperreflective foci. Other features of OCT included membranous-like structures on inner borders and elongation and splitting of the inner segment/outer segment junction. In later stages, beginning signs of retinitis and scaring could be observed. Results: The patient was treated with sulfamethoxazole/trimethoprim and prednisolone. After two weeks, total regression occurred and visual acuity and OCT remained stable for 6 months (BCVA 1.0). Discussion: Ocular toxoplasmosis can cause significant vision loss due to retinitis and scarring. Following treatment with sulfamethoxazole/trimethoprim and prednisolone, the patient's condition improved significantly and her visual acuity remained stable. Conclusion: On clinical examination and using OCT, rare morphological cystoid spaces (CS) can be identified as huge outer retina cysts (HORC), which are pathognomonic for posterior uveitis. Abbreviations: HORC = huge outer retinal cyst, OCT = optical coherence tomography, BCVA = best corrected visual acuity, CS = cyst space, OPL = outer plexiform layer, HRF = hyper reflective foci, RPE = retinal pigment epithelium, IS = inner segment, OS = outer segment, ERM = epiretinal membrane, PORT = punctate outer retinal toxoplasmosis, ELM = external limiting membrane.

Unusual clinical features and histopathological findings in a case of Pseudo-endophthalmitis in neovascular glaucoma.

Objective: This case report aimed to describe the unusual clinical presentation and histopathological features of post-injection endophthalmitis. Methods: A 56-year-old male phakic patient with diabetic retinopathy received an intravitreal injection (Bevacizumab as per the patient) for neovascular glaucoma elsewhere and presented to our center one day after the dose with hypopyon. The eye was relatively white without pain or lid oedema. The patient was treated as a case of post-injection endophthalmitis with two doses of intravitreal antibiotics 48 hours apart. During the follow-up, he developed a Covid infection. After one week, when the media cleared, white exudates were seen in the vitreous cavity with a relatively healthy retina. He was taken up for pars plana vitrectomy and vitreous biopsy for histopathological study. Results: The microscopic examination of vitreous aspirate revealed crystalline deposits without any microorganisms. Two control slides, one with a mixture of intravitreal antibiotics, which were previously injected, and the other with fresh Triamcinolone were also examined. Although the findings of the drug mixture did not match the vitreous aspirate, they matched with triamcinolone, which established it as a case of pseudo endophthalmitis due to triamcinolone injected elsewhere. Discussion: Initially, it seemed like a straightforward case of post-injection endophthalmitis, but a further examination of the vitreous aspirate showed that it was pseudoendophthalmitis due to an intravitreal triamcinolone injection. Despite the patient being phakic, neovascularization or elevated intraocular pressure may have led to the disruption of the blood-ocular barrier and the migration of Triamcinolone into the anterior chamber. Conclusion: The case's uniqueness lies in being the first reported case of pseudo endophthalmitis in a phakic patient with an intact lens iris diaphragm. The case also highlighted the judicious use of available resources and out-of-the-box thinking to reach a diagnosis that may not always be obvious. Abbreviations: TA = Triamcinolone acetonide, AC = Anterior chamber, IVB = Intravitreal Bevacizumab, PL = Perception of light.

Dacryoadenitis: do not forget ANCA vasculitis.

Objective: This paper aimed to describe another form of aggressive limited Granulomatosis with polyangiitis (GPA) revealed by dacryoadenitis. Methods and results: We report an unusually limited GPA in a 48-year-old man presenting with bilateral proptosis. She had never presented kidney or pulmonary manifestations, but her disease was persistently active including oto-rhino-laryngological manifestations, dacryoadenitis, and neurological manifestations unresponsive to corticosteroids and immunosuppressors. Discussion: Granulomatosis with polyangiitis (GPA) is an auto-immune inflammatory vasculitis. Involvement of lacrimal glands as the first presentation is uncommon. It is characterized by the development of granulomas. Patients with orbital mass without lacrimal gland involvement have a higher rate of systemic disease, a severe clinical course, and a higher rate of recurrences. A patient with dacryoadenitis seems to be with a good prognosis. Eye manifestations were significantly more common in patients with pachymeningitis. MPO-ANCA-positive pachymeningitis was more frequent in older female patients. PR3-ANCA-positive pachymeningitis had more severe neurological damage. Induction treatment consists of intravenous methylprednisolone (IV) associated with cyclophosphamide. Conclusion: Faced with dacryoadenitis, it is important to screen for ANCA-associated vasculitis. Abbreviations: GPA = Granulomatosis with polyangiitis, ANCA = Antineutrophil Cytoplasmic Antibodies.

Localized pemphigus vulgaris on scalp: an atypical presentation.

We present two middle-aged patients with pruritic, crusted scalp erosions. Skin biopsy showed epidermal acantholysis with IgG and C3 intercellular deposits on direct immunofluorescence, leading to the diagnosis of localized pemphigus vulgaris. Resolution of the lesions without relapse occurred after low doses of oral prednisone and intralesional triamcinolone acetonide.

[Effect of glucocorticoids on the efficacy of non-small cell lung cancer patients treated with immune-checkpoint inhibitors].

Lung cancer is a highly lethal malignant tumor worldwide and in China, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases globally. In recent years, immune checkpoint inhibitor (ICI) had changed the paradigm of lung cancer treatment, either alone or in combination with chemotherapy and recomended as the first-line treatment for NSCLC. NSCLC patients often required glucocorticoid(GC) due to the cancer itself, tumor complications, or immune-related adverse event (irAE). GC had sparked debates on their impact on the therapeutic effectiveness of ICI in NSCLC patients as a substance with immunomodulatory effects. While some studies suggested that GC use did not influence patients survival, others argued the opposite. Understanding the effects of GC on immunotherapy is crucial for managing complaications in cancer patients and addressing irAE. This review explores the impact of GC on the efficacy of ICI in NSCLC patients, aiming to provide insights for clinical treatment.

A Rare Case of Autoimmune Hemolytic Anemia Caused by Autoantibody with Mimicking Anti-D and Anti-C Specificity.

BACKGROUND: Most of the autoantibodies that cause autoimmune hemolytic anemia (AIHA) are non-specific. Autoantibodies expressing alloantibody specificity are rare. METHODS: We present the case of a 4-year-old boy with no history of blood transfusion or underlying medical conditions who developed AIHA caused by autoantibody with mimicking anti-D and anti-C specificity. RESULTS: Following treatment with methylprednisolone sodium succinate and transfusion of red blood cells with negative antigens for D and C, along with administration of human immunoglobulin, the patient's condition gradually improved. He was ultimately discharged with a good prognosis. CONCLUSIONS: This report highlights a rare case of AIHA characterized by autoantibody with mimicking anti-D and anti-C specificity. Treatments of these patients could be antigen-negative red blood cells, glucocorticoid and immunoglobulin.

[Effect of prenatal glucocorticoid therapy on hearing screening in premature infants].

Objective:To explore the effect of prenatal glucocorticoids therapy on hearing screening in premature infants Methods:Data of 693 preterm infants with gestational age of 24-34+6weeks admitted to theJiangxi Maternal and Child Health Hospital within 24 h after birth from June 2022 to June 2023 were retrospectively analyzed. The infants were divided into the DXM group （544 cases） and the non-DXM group （149 cases） based on whether dexamethasone （DXM） was administered prenatally. General data of preterm infants and parturients in two groups were compared, and the effects of different doses and timing of DXM on hearing screening were analyzed. Results:In the terms of preliminary hearing screening. the pass rate of initial hearing screening in DXM group was significantly higher than that in non-DXM group（53.9% vs 35.6%）, with statistical significance（P<0.05）. Further subgroup analysis showed that the passing rate of preliminary hearing screening in adequate prenatal dose（=4 doses） DXM group（58.1%） was significantly higher than that in insufficient group（48.0%） and excessive group（42.4%）, with statistical significance（P<0.05）. Administering DXM 48 hours to 7 days before birth resulted in a higher pass rate for initial hearing screening compared to administration <48 hours or >7 days before birth （56.4% vs. 48.6%）, with a statistically significant difference （P < 0.05）. In terms of re-hearing screening, the pass rate of secondary hearing screening was not significantly correlated with DXM treatment（P>0.05）, but was significantly correlated with gestational age, birth weight, hospital stays, invasive mechanical ventilation, and common neonatal diseases（bronchopulmonary dysplasia, respiratory distress syndrome）（P<0.05）. Among them, bronchopulmonary dysplasia was an independent risk factor forsecondary hearing screening referral（P<0.05）. Conclusion:A single course of adequate dexamethasone use within 48 h-7 d of prenatal has a positive effect on the preliminary hearing screening of preterm infants.

[Advances in glucocorticoid resistance in otorhinolaryngological diseases].

Glucocorticoids（GC） are widely used in the clinical treatment of autoimmune inner ear diseases, sudden sensorineural hearing loss, Meniere's disease, sinusitis and other otolaryngology diseases. However, GC resistance remains a major factor contributing to the poor efficacy of clinical treatments. The mechanism of GC resistance is still unclear. This paper reviews the related mechanisms of GC resistance from the perspectives of GC receptor factors and non-GC receptor factors. Additionally, it summarizes the latest research progress on GC resistance in otolaryngological diseases, with the aim of identifying effective clinical alternative treatment options for reversing GC resistance in the future.

Determinants of clinical outcome in patients with moderate/severe Graves' orbitopathy undergoing treatment with parenteral glucocorticoids: a retrospective study.

Background: Graves' orbitopathy (GO) occurs in approximately 25-40% of patients with Graves' disease (GD). High levels of anti-thyrotropin receptor antibodies (TRAbs), smoking habit, sex, older age, longer duration and amount of hyperthyroidism or hypothyroidism are well-recognized risk factors for the occurrence, severity and clinical course of GO. Oxidative stress (OX) has recently been shown to play a role in the pathogenesis of GO, and several clinical conditions related to OX have been investigated regarding the presentation and severity of GO. Aim: We aimed to evaluate the impact of clinical conditions related to oxidative stress on the outcome of intravenous glucocorticoid (ivGCs) therapy in a cohort of patients with active moderate to severe GO (AMS-GOs) treated at a single institution. Methods: We retrospectively studied a series of patients with AMS-GOs who were treated with ivGCs from January 2013 to May 2022. GO clinical evaluation was performed at baseline and at 6 (W6), 12 (W12) and 24 (W24) weeks after starting ivGCs by the seven-point clinical activity score (CAS) alone and by overall clinical criteria (CI) according to the European Group of Graves' Ophthalmopathy (EUGOGO). Total cholesterol and calculated LDL cholesterol (LDLc), triglyceride, body mass index (BMI), diabetes status, history of hypertension (HoH), smoking status, age and sex were used as covariates for the clinical outcome of GO to ivGCs. Results and conclusions: LDLc and HoH negatively and independently modulated the response of AMS-GOs to ivGCs. Notably, slightly elevated LDLc levels (> 130 mg/dl) reduced the response of orbital soft tissue to ivGCs, whereas more elevated LDLc levels (from 175 mg/dl to 190 mg/dl) and HoH were associated with poorer clinical response of eye motility and proptosis.

Impact of diabetes on COVID-19 and glucocorticoids on patients with COVID-19 and diabetes during the Omicron variant epidemic: a multicenter retrospective cohort study in South China.

BACKGROUND: To explore the impact of diabetes on the clinical features and prognosis of COVID-19 and assess the influence of glucocorticoid use on the prognosis of patients with COVID-19 and diabetes. METHODS: This retrospective multicenter cohort study included patients admitted between December 2022 and January 2023. The patients were grouped according to diabetes and glucocorticoid use. The primary outcome was in-hospital mortality. RESULTS: Among 400 patients with glucocorticoid data, 109 (27.3%) had diabetes. The inflammatory cytokines were higher in patients with diabetes, manifested by higher IL-6 (25.33 vs. 11.29 ng/L, p = 0.011), CRP (26.55 vs. 8.62 mg/L, p = 0.003), and PCT (0.07 vs. 0.04 ng/ml, p = 0.010), while CD4+ (319 vs. 506 /mL, p = 0.004) and CD8+ (141 vs. 261 /mL, p < 0.001) T lymphocytes were lower. The overall mortality rate of hospitalized COVID-19 patients with diabetes was 13.46%. The diabetic patients who received glucocorticoids vs. those who did not receive glucocorticoids had a similar mortality (15.00% vs. 11.39%, p = 0.591). CONCLUSIONS: Patients with COVID-19 and diabetes are more likely to experience hyperinflammatory response and T cell reduction, especially those with severe/critical disease. Glucocorticoid use was not associated with the prognosis of COVID-19 in patients with diabetes. Still, glucocorticoids should be used cautiously in diabetic patients with severe/critical COVID-19.