Long-term prophylaxis in hereditary angioedema management: Current practices in France and unmet needs.

Background: Hereditary angioedema (HAE) is characterized by unpredictable and potentially life-threatening attacks of cutaneous and submucosal swelling. Over the past decade, new agents, based on a better understanding of the underlying biologic mechanisms of HAE, have changed the face of long-term prophylaxis (LTP). Objective: The objective was to describe current practices and unmet needs with regard to LTP for HAE in expert centers in France. Methods: The study was conducted in France in 2020. Based on their experience with patients with HAE who had visited their center at least once in the past 3 years, physicians from 25 centers who are expert in the management of HAE were requested to fill in a questionnaire that encapsulated their active patient list, criteria for prescribing LTP, and medications used. They were asked about potential unmet needs with currently available therapies. They were asked to express their expectations with regard to the future of HAE management. Results: Analysis was restricted to 20 centers that had an active patient file and agreed to participate. There were 714 patients with C1 inhibitor (C1-INH) deficiency, of whom 423 (59.2%) were treated with LTP. Altered quality of life triggered the decision to start LTP, as did the frequency and severity of attacks. Ongoing LTP included androgens (28.4%), progestins (25.8%), lanadelumab (25.3%), tranexamic acid (14.2%), intravenous C1-INHs (5.6%), and recombinant C1-INH (0.7%). Twenty-nine percent of the patents with LTP were considered to still have unmet needs. Physicians' concerns varied among therapies: poor tolerability for androgens and progestins, a lack of efficacy for tranexamic acid and progestins, dosage form, and high costs for C1-INHs and lanadelumab. Physicians' expectations encompassed more-efficacious and better-tolerated medications, easier treatment administration for the sake of improved quality of life of patients, and less-expensive therapies. Conclusion: Despite the recent enrichment of the therapeutic armamentarium for LTP, physicians still expressed unmet needs with currently available therapies.

Hereditary angioedema with normal C1 inhibitor associated with carboxypeptidase N deficiency.

Background: Hereditary angioedema (HAE) is a potentially life-threatening disorder characterized by recurrent episodes of subcutaneous or submucosal swelling. HAE with normal C1 inhibitor (HAE-nC1-INH) is an underdiagnosed condition. Although the association with genetic variants has been identified for some families, the genetic causes in many patients with HAE-nC1-INH remain unknown. The role of genes associated with bradykinin catabolism is not fully understood. Objective: We sought to investigate the biological parameters and the genes related to kallikrein-kinin system in families with a clinical phenotype of HAE-nC1-INH and presenting with a carboxypeptidase N (CPN) deficiency. Methods: This study includes 4 families presenting with HAE-nC1-INH and CPN deficiency. Patients' clinical records were examined, biological parameters of kallikrein-kinin system were measured, and genetics was analyzed by next-generation sequencing and Sanger sequencing. Predictive algorithms (Human Splicing Finder, Sorting Intolerant From Tolerant, Polymorphism Phenotyping v2, MutationTaster, and ClinPred) were used to classify variants as affecting splicing, as benign to deleterious, or as disease-causing. Results: Patients presented with angioedema and urticaria, mainly on face/lips, but also with abdominal pain or laryngeal symptoms. Affected patients displayed low CPN activity-30% to 50% of median value in plasma. We identified 3 variants of the CPN1 gene encoding the catalytic 55-kDa subunit of CPN: c.533G>A, c.582A>G, and c.734C>T. CPN deficiency associated with genetic variants segregated with HAE-nC1-INH symptoms in affected family members. Conclusions: CPN1 gene variants are associated with CPN deficiency and HAE-nC1-INH symptoms in 4 unrelated families. Genetic CPN deficiency may contribute to bradykinin and anaphylatoxin accumulation, with synergistic effects in angioedema and urticarial symptoms.

Mid-infrared supercontinuum generation in fluoroindate fiber.

We report the generation of mid-infrared supercontinua in a step-index fluoroindate-based fiber. The large core of the fluoroindate fiber allows the guiding of multiwatt laser power over a broad spectral range. These fibers exhibit zero dispersion at 1.83 µm, minimal loss of 0.1 dB/m at 3.2 µm up to only 0.8 dB/m at 5 µm. These specifications enable mid-infrared supercontinuum generation and propagation with low loss. By using mid-infrared ultrashort laser pulses from an optical parametric amplifier, we demonstrate generation of a 20 dB spectral flatness supercontinua from 2.7 to 4.7 µm in the fluoroindate fiber, which is twice the spectral broadening compared to a ZBLAN fiber under similar conditions.

Effective Anti-SARS-CoV-2 Immune Response in Patients With Clonal Mast Cell Disorders.

BACKGROUND: Mast cells are key players in innate immunity and the TH2 adaptive immune response. The latter counterbalances the TH1 response, which is critical for antiviral immunity. Clonal mast cell activation disorders (cMCADs, such as mastocytosis and clonal mast cell activation syndrome) are characterized by abnormal mast cell accumulation and/or activation. No data on the antiviral immune response in patients with MCADs have been published. OBJECTIVE: To study a comprehensive range of outcomes in patients with cMCAD with PCR- or serologically confirmed coronavirus disease 2019 and to characterize the specific anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune response in this setting. METHODS: Clinical follow-up and outcome data were collected prospectively over a 12-month period by members of the French Centre de Référence des Mastocytoses rare disease network. Anti-SARS-CoV-2-specific T-cell activity was measured with an ELISA, and humoral responses were evaluated by assaying circulating levels of specific IgG, IgA, and neutralizing antibodies. RESULTS: Overall, 32 patients with cMCAD were evaluated. None required noninvasive or mechanical ventilation. Two patients were admitted to hospital for oxygen and steroid therapy. The SARS-CoV-2-specific immune response was characterized in 21 of the 32 patients. Most had high counts of circulating SARS-CoV-2-specific, IFN-γ-producing T cells and high titers of neutralizing antispike IgGs. The patients frequently showed spontaneous T-cell IFN-γ production in the absence of stimulation; this production was correlated with basal circulating tryptase levels (a marker of the mast cell burden). CONCLUSIONS: Patients with cMCADs might not be at risk of severe coronavirus disease 2019, perhaps due to their spontaneous production of IFN-γ.

Use of the International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form (ICIQ-UI-SF) for an objective assessment of disability determination according to the Modified Katz Scale: a prospective longitudinal study.

BACKGROUND: The aim of this study was to demonstrate that the International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form (ICIQ-UI-SF) tool can be applied for a factual score determining urinary incontinence in the Katz-6 Scale, and it is effective to identify score 2 from score 3. METHODS: Functional capacity of 63 patients (14 M, 49 F aged from 70 to 99 years old) was evaluated with a Mini Mental State Examination (MMSE), Katz Index for Activities of Daily Living, and ICIQ-UI-SF questionnaire. Mean comparative analysis was performed. ICIQ-UI-SF scores were then entered as variables. These data observed in Katz continence item scored 2 and Katz continence item scored 3 were compared in a combined box-and-whisker and dot plot. Sensitivity and specificity of each variable were tested and results were evaluated using a receiver operating characteristic (ROC) curve. The best variable (ICIQ-UI-SF Score) was retained as a breach permitting to distinguish patients to be scored 2 or 3 over continence Katz item. RESULTS: Statistical analysis demonstrated significant difference between the sample of Katz continence item scored 2 and the sample of Katz continence item scored 3 over the ICIQ-UI-SF Score and the Katz global Score, but the difference was not significant concerning the MMSE Score. Using ROC analysis, we compared the discriminant power of the ICIQ-UI-SF Score for continence Katz item Score. Criterion values and coordinates of the ROC curve were studied and the ICIQ-UI-SF score of 13 was considered the best one. CONCLUSIONS: We demonstrated that the best variable (ICIQ-UI-SF Score) to retain as a breach permitting to distinguish patients to be scored 2 or 3 over continence Katz item is 13.

Acute clinical hepatitis by immune restoration in a human immunodeficiency virus/hepatitis B virus co-infected patient receiving antiretroviral therapy.

We describe a human immunodeficiency virus (HIV)-infected patient with chronic active hepatitis B. The patient presented with acute clinical hepatitis during highly active antiretroviral therapy concomitant with immunovirological improvement of HIV infection. The hepatitis resolved within a few weeks despite the pursuit of antiretroviral drugs. Hepatitis B tests, which remained unchanged after two cycles of interferon alfa therapy and continuous administration of lamivudine, were improved with the clearance of hepatitis B virus (HBV) early antigen (HBeAg), the detection of antibody to HBV early antigen (HBeAb) and the undetectability of serum HBV DNA. Several months after this episode, HBV and HIV tests are still controlled.

Optical limiting studies in a carbon-black suspension for subnanosecond and subpicosecond laser pulses.

This paper presents results of measurements of short (0.3 ps, 0.2 ns, and 10 ns) laser pulse transmissions through a liquid suspension of fine carbon particles (named CBS for "carbon-black suspension") at input-pulse energies up to 10 mJ. The 10-ns pulses came from a Nd:YAG laser at 1064 nm, and the shorter pulses came from a Ti:sapphire laser at 800 nm. Limiting was observed with the 10-ns and the 0.2-ns laser pulses, but the 0.3-ps pulses produced white light and underwent the same level of attenuation in the solvent and in the CBS.

Acute respiratory failure secondary to dilatation of herniated stomach.

We report the case of a patient who presented acute respiratory failure (ARF) due to gastric distension secondary to hiatus hernia. This clinical condition may have been induced by an interaction between fluphenazine and ipratropium bromide. This exceptional diagnosis needs to be considered when discussing compressive pneumothorax.

Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases.

We describe 7 cases of renal tubular injury in HIV-infected patients receiving an antiretroviral regimen containing tenofovir. Our patients (5 women and 2 men) developed renal tubular dysfunction, with hypophosphatemia, normoglycemic glycosuria, proteinuria, and decrease of creatinine clearance. The first biologic signs of renal toxicity were observed after duration of tenofovir treatment from 5 weeks to 16 months, and they resolved less than 4 months after discontinuation of tenofovir. Six patients had a low body weight (<60 kg). Five patients received low doses of ritonavir, and 1 received didanosine. In 5 patients, the signs resolved with the discontinuation of only the tenofovir. A renal biopsy performed in 1 patient was consistent with tubulointerstitial injury. Proximal tubulopathy appears to be a rare adverse effect of long-term tenofovir therapy. In patients with low weight or mild preexisting renal impairment, regular monitoring of tubulopathy markers could lead to early detection of this dysfunction.