Pregnancy in women with Hereditary Angioedema due to C1-inhibitor deficiency: Results from the ITACA cohort study on outcome of mothers and children with in utero exposure to plasma-derived C1-inhibitor.

Background: In women with Hereditary Angioedema (HAE) due to C1-inhibitor (C1INH) deficiency (C1INH-HAE), pregnancy counseling and treatment can be challenging. Despite the evidence of the immediate favorable outcome and safety of plasma-derived (pd)C1INH concentrate, there are no data regarding any difference among women who underwent or not pdC1INH during pregnancy or on children with in utero exposure to pdC1INH. The present interview study aimed at analyzing outcome of C1INH-HAE mothers and children according to pdC1INH-exposure during pregnancies. Methods: C1INH-HAE women who experienced at least 1 pregnancy were included from seven centers of the Italian Network for Hereditary and Acquired Angioedema (ITACA). The interview study retrospectively analyzed pregnancies who underwent (group 1) or not (group 2) pdC1INH. The overall goals of the study included immediate and long-term outcomes, in terms of outcomes in the time interval between pregnancy and survey. Results: A total of 168 pregnancies from 87 included women were analyzed. At term delivery (>37 gestation-week, GW) has been registered in 73.8% of cases, while spontaneous abortion (SA) occurred in 14.2% of cases with a mean GW 7 ± 2. The group 1 including pdC1INH-treated pregnancies comprised a third of the cohort (51/168, time interval 1.5 ± 10.4 yrs), while the group 2 represented 69.6% (117/168, time interval 32.8 ± 14 yrs). The same prevalence of SA occurred when comparing group 1 (11.7%) with group 2 (15.4%) with a similar GW at SA. The group 1 was older at the pregnancy time and younger at the interview than the group 2 (P < 0.01 for both); moreover, the group 1 showed a higher prevalence of cesarean delivery (P < 0.0001). The overall prevalence of obstetrical syndromes was similar between two groups: however, gestational diabetes was described only in pdC1INH-untreated pregnancies. In utero pdC1INH-exposed children (n = 45) did not show differences compared with unexposed ones (n = 99) in neonatal short-term outcomes. Conclusion: Through appropriate management and counseling, most of C1INH-HAE women undergo successful pregnancy and delivery. For pregnant C1INH-HAE women being treated with pdC1INH, our findings are reassuring and might lead to an improvement of both the knowledge about treatments and the experience of HAE itself.

Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: The OPuS-2 study.

BACKGROUND: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1-INH-HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS-2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo. METHODS: OPuS-2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator-confirmed attacks. RESULTS: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack-free during the 84-day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE-QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated. CONCLUSIONS: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.

Impact of intensity and timing of integrated home palliative cancer care on end-of-life hospitalization in Northern Italy.

PURPOSE: The Veneto Region implemented a novel integrated home-based palliative cancer care (HPCC) program embedded in primary care. We examined the impact of timing and intensity of this program on the quality of end-of-life (EOL) care. METHODS: We selected adult cancer patients died in the Veneto Region between March and December 2013, excluding those died from haematological malignancies as well as the very elderly (85+ years). We retrieved the claim-based data on hospitalization and homecare visits, and defined two observation windows: 90 to 16 days before death to examine intensity of HPCC exposure, and the last 15 days of life to examine EOL outcomes, including hospital death, any hospital stay for medical reasons and hospital stay ≥7 days for medical reasons. Multivariate analysis was conducted using a Poisson model. RESULTS: Among the 2211 adults who died of solid tumours and received 1+ homecare visits during the exposure period, 1077 (48.7%), 552 (25.0%) and 582 (26.3%) had 0.1-1.9, 2-3.9 and 4+ homecare visits/week, respectively. The median duration between an HPCC home visit and death was 92 days (IQR 42-257 days). Hospital death occurred in 856 (38.7%) patients, while 1087 (49.2%) and 556 (25.1%) had a hospital stay and a hospital stay ≥7 days during the exposure period, respectively. In the multivariate analysis, a greater intensity of integrated HPCC (4+ visits/week) was significantly associated with a lower risk of hospital death (relative risk [RR] = 0.67, 0.59-0.76), any hospital stay (RR = 0.69, 0.62-0.77) and hospital stay ≥7 days for medical reasons (RR = 0.59, 0.49-0.71). A late activation (≤30 days before death) of HPCC was also associated with increased both hospital stay (RR = 1.26, 0.11-1.42) and hospital stay ≥7 days (RR = 1.25, 1.01-1.54). CONCLUSIONS: A greater HPCC program intensity reduces the risk of hospital death and hospital stay in the end-of-life. An early activation of this program can contribute to improve these EOL outcomes.

Risk of prostate cancer in low-dose aspirin users: A retrospective cohort study.

A growing body of evidence indicates that use of low-dose aspirin (LDA) reduces the risk of certain adenocarcinomas. While there are several and consistent findings on the protective effect of LDA on colorectal and other cancers, few and conflicting evidence is available on prostate cancer (PCa). The aim of this study was to assess whether LDA reduces the incidence rate of PCa. We conducted a nationwide, population-based, retrospective cohort study by using Health Search IMS Health Longitudinal Patient Database (HSD). Patients with ischemic cardio- or cerebrovascular disease (index date) were identified. Time-dependent multivariable Cox proportional hazard models were adopted to estimate Hazard Ratios (HRs) and related 95% confidence intervals (95% CI) of PCa associated with use of LDA. The exposure was lagged by one year to consider the latency of drug effect on the outcome onset. Within a cohort 13,453 patients, the overall incidence rate of PCa was 2.5 per 1,000 person-years. Use of LDA was associated with a decreased incidence rate of PCa (HR = 0.64; 95% CI: 0.48-0.86), which was primarily driven by a frequency of LDA use equal to or higher than twice per week (HR = 0.60; 95% CI: 0.43-0.83). Such an association was more pronounced (HR = 0.43; 95% CI: 0.21-0.91) when LDA was used for five or more years. Our findings indicate that LDA use might be associated with a reduction of risk of PCa in patients with cardio- or cerebrovascular diseases.

Current status of implementation of self-administration training in various regions of Europe, Canada and the USA in the management of hereditary angioedema.

Results from a 16-question survey about self-administration of hereditary angioedema (HAE) therapy, administered in Europe, Canada and the USA, were used to guide discussion at an international HAE expert meeting. The aim was to capture information about current practice in self-administered HAE therapy in these countries, including self-administration training, the key benefits of switching to self-administration, the barriers to self-administration and trends in self-administration. Overall, switching to self-administration therapy is looked upon favourably from both patient and clinician perspectives by virtue of the potential improvement in quality of life arising from optimisation of therapy and early intervention. The recent changes to product licences allowing self-administration provide additional options for the management of HAE.

Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study.

BACKGROUND: Hereditary angioedema (HAE) owing to C1 inhibitor deficiency is an autosomal dominant disorder, characterized by recurrent, potentially life-threatening, localized attacks of tissue swelling. Current treatment involves the infusion of C1 inhibitor protein (C1-INH) isolated from human plasma. OBJECTIVES: This open-label extension to a European, Israeli and Argentinean randomized study (NCT00262301) aimed to investigate the efficacy and safety of recombinant human C1 inhibitor (rhC1-INH) as a first-line treatment following an HAE attack, together with its effect on subsequent attacks. METHODS: An HAE-specific visual analogue scale (VAS) 0-100 mm was used by patients to assess the severity of attack at four anatomical locations. Patients were treated with one, single-vial, fixed-dose of rhC1-INH (2100 U), followed by up to two further vials at the investigators discretion. The primary end-point was the time from first rhC1-INH injection to first onset of relief of symptoms (≥ 20 mm decrease on VAS). Response to treatment was defined as the onset of relief within 4 h. RESULTS: A total of 57 patients were treated for 194 HAE attacks. Overall, sustained relief of symptoms was achieved in 87% of rhC1-INH-treated patients within 4 h of treatment, with 57% of attacks requiring only one vial of rhC1-INH. When categorized by successive attacks experienced by individual patients, the response rate to rhC1-INH treatment was 96%, 83%, 87%, 80% and 80% for attacks 1-5 respectively. Treatment with rhC1-INH was well tolerated, with no discontinuations owing to treatment-emergent adverse events and no adverse events relating to immunogenicity. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with rhC1-INH provides fast-onset relief for an HAE attack, with a high rate of therapeutic response maintained throughout subsequent attacks.

Isolated atrial fibrillation (IAF) after local anaesthesia with epinephrine in an anxious dental patient.

Cardiac arrhythmias are not uncommon in dental practice, depending on many factors, including patient features, dental treatment and drugs administered. We describe a case of isolated atrial fibrillation (IAF) developed, in a young patient, soon after a supraperiosteal injection. The patient was admitted to hospital and recovered spontaneously. Since stress is a possible cause of IAF, this may has been triggered by endogenous and/or exogenous epinephrine. We highlight the need for careful preoperative evaluation, including anxiety assessment and treatment in all dental patients.

Practice of opportunistic prostate-specific antigen screening in Italy: data from the Health Search database.

The effectiveness of prostate-specific antigen (PSA) testing for opportunistic screening of prostate cancer is not yet well established, although this practice seems to be widely accepted. To estimate the opportunistic use of PSA by general practitioners (GPs) in Italy, we conducted a survey by querying the Health Search (HS) database, which collects clinical records from a representative sample of the Italian population. Clinical computerized data from 320 GPs and 221,557 male patients were analysed. Among total requests for PSA, 3% were linked to prostate cancer, 18% to a urological disease or symptom and 79% were not linked to any urological condition (opportunistic screening). Opportunistic screening was used for 31.4% of subjects over 50 with a significant (P<0.0001) difference between geographical areas (36.4% north, 33.5% central regions, 22.9% south and isles). This distribution was very similar to prostate cancer prevalence as it resulted from the HS data. PSA testing practice showed an increase over the years (12.7% of men over 50 in 2000, 14.3% in 2001 and 15.9% in 2002). In conclusion, the practice of opportunistic screening of prostate cancer seems to be extensively adopted by Italian GPs and is becoming more and more popular, although to date it is not supported by strong scientific evidence.

Rhetoric and reality of work-based welfare reform.

The argument presented in this article is that although work is one path toward improved well-being for poor families, a successful and humane social welfare policy must recognize and respond to its limitations. The prowork rhetoric surrounding current efforts to move women from welfare to work rests on at least three propositions: Work is the norm, work is good for families, and work leads to self-sufficiency. The article reviews empirical evidence on each of these propositions and concludes that many former welfare participants will earn low wages in unstable employment and will require a broad range of supports to move from welfare to self-sufficiency and improved family well-being.

Effects of complement inactivation and IgG depletion on skin reactivity to autologous serum in chronic idiopathic urticaria.

BACKGROUND: Intradermal injection of autologous serum elicits a wheal-and-flare response in about 60% of patients with chronic idiopathic urticaria (CIU). This reactivity has been attributed to the presence of IgG autoantibodies directed against IgE or the alpha-chain of the high-affinity IgE receptor (FcepsilonRIalpha) expressed on basophils and mast cells, leading to the hypothesis that at least some forms of CIU could be sustained by an autoimmune process. OBJECTIVES: The aim of this study was to investigate the relationship between the presence of anti-IgE or anti-FcepsilonRI antibodies and the ability to induce wheal-and-flare responses in CIU sera selected for the capacity to give a positive skin test response. METHODS: Fifteen patients with CIU and a positive skin test response to autologous serum were injected intradermally with native serum and with serum heated at 56 degrees C for 30 minutes and then adsorbed on Sepharose-protein G to obtain IgG depletion. Serum levels of anti-IgE and anti-FcepsilonRIalpha antibodies were measured by ELISA by using purified IgE and recombinant RIalpha-soluble double-fusion protein RIalpha-human serum albumin-RIalpha, respectively. The histamine-releasing activity of sera was tested by using ELISA with whole human blood from a healthy donor. RESULTS: All patients had positive cutaneous responses to native serum injection. Anti-FcepsilonRIalpha antibodies were present in 14 of 15 native sera, only two of which were able to induce in vitro basophil degranulation. On the contrary, detectable amounts of anti-IgE antibodies were not found in any serum. IgG depletion by protein G resulted in complete (10/14 samples) or considerable (4/14 samples) removal of anti-FcepsilonRIalpha antibodies. The two sera endowed with functional activity lost their capacity to trigger histamine release from basophils after heating and protein G adsorption. Nonetheless, heat-decomplemented/IgG-depleted sera elicited wheal-and-flare reactions comparable with those observed with untreated sera. CONCLUSIONS: These results strongly suggest that skin reactivity to autologous serum could be due to as yet unidentified non-Ig reactants present in the sera of patients with CIU.

General practitioners and mammographic screening uptake: influence of different modalities of general practitioner participation. Working Group.

AIMS AND BACKGROUND: To compare the impact of different modalities of general practitioner (GP) involvement, including the introduction of target payments, on the attendance rate of organized population-based screening programs for breast cancer in Italy. STUDY DESIGN: The study was conducted between 1994 and 1996 in four Italian cities where mammographic screening programs are active: Caltanissetta (CL), Firenze (FI), Modena (MO) and Torino (TO). The impact on attendance rate of different invitation strategies based on active GP involvement was tested in each center. The additional effect of economic incentives was also assessed. The incentives were proportional to the level of compliance attained by each GP and weighted by the size of his eligible patients' list. RESULTS: In the Firenze project, an invitation signed by the GP and the project co-ordinator attained a statistically significant higher participation (difference: 4.2%, chi2 = 7.42, P = 0.006). In Caltanissetta and Torino there was a significant increase of about 7% in the response rate to the postal reminder in the groups contacted by the GPs. No difference was observed in the Modena project between the two groups. CONCLUSIONS: The main contributions of GP involvement can be: "cleaning up" the invitation lists, especially when computerized archives with the mammographic history of the target population are not available; increasing the women's participation by signing the invitation letter, by counseling and active participation in the invitation phase; co-operating in the reminder phase by recalling women non responders at first invitation. The offer of target payment had a certain impact on the screening uptake, but not easily distinguishable from GP signature of the invitation letter; further studies of appropriate design should be planned. Organizational factors, such as availability of a list of non-responders, might be crucial in order to enhance the effect of the GPs' action.

Inhibitory effect of heparin on skin reactivity to autologous serum in chronic idiopathic urticaria.

BACKGROUND: Most patients with chronic idiopathic urticaria (CIU) show cutaneous reactivity to intradermal injection of autologous serum. In some cases this reactivity is associated with the presence of autoantibodies directed against IgE or IgE receptors expressed on mast cells, whereas in others no autoimmune mechanisms can be documented. OBJECTIVES: The aims of this study were to compare the cutaneous reactivity to serum and plasma samples in a series of patients with active CIU and to address the mechanisms of the inhibitory effect exerted by heparin on the cutaneous responsiveness to the histamine-releasing factors (HRFs) present in CIU serum. METHODS: Fourteen patients with CIU were injected intradermally with autologous serum, plasma (anticoagulated by either heparin or EDTA), or serum samples to which heparin had been added. The effects of heparin injection on cutaneous responsiveness to allergens was tested in 5 atopic patients. Moreover, in a set of experiments sera were also adsorbed with Sepharose-conjugated heparin. RESULTS: All the patients had positive cutaneous reactions to autologous serum injection. When heparinized plasma was injected, negative reactions were observed in 12 of 14 patients, and a sizable reduction in the wheal-and-flare reactions was recorded in the remaining 2. Compared with results obtained with serum, no substantial change was observed in 6 of 8 patients injected with EDTA-anticoagulated plasma. When heparin was added to serum, abrogation of skin reactivity was seen; nonetheless, no change in the cutaneous response to allergens was associated with locally administered heparin in 5 atopic patients with no history of CIU. Finally, adsorption of CIU sera with solid-phase heparin abrogated the ability to induce cutaneous reactions in 5 of 7 patients, whereas in the remaining 2 a sizable reduction was observed. CONCLUSIONS: These data indicate that heparin is able to profoundly inhibit the cutaneous response to HRFs present in the sera of patients with CIU. Although the precise level of action of this heparin-mediated effect is unclear from present data, preliminary evidence seems to indicate that heparin could directly interfere with HRFs present in CIU sera.

The impact of wives' earnings on income inequality: issues and estimates.

We estimate the extent to which rising family income inequality can be explained by changes in the earnings of married women. We develop a decomposition equation that separates single persons from married couples (decomposition by population group) and, for married couples, distinguishes the impact of wives' earnings from other sources of income (decomposition by income source). Despite the rising correlation between husbands' and wives' earnings, changes in wives' earnings do not explain a substantial portion of the increase in family income inequality. Our results contradict those of some previous analyses. The inconsistency of recent estimates can be traced to the use of a variety of conceptually different approaches in the previous literature. We clarify these approaches by explicitly distinguishing the conceptual issues, analyzing the empirical components, and providing comprehensive estimates.

Who gets custody?

Changes in the living arrangements of children have implications for social policy and children's well-being. Understanding who gets custody on divorce--mother, father, or both sharing custody--can also inform our understanding of family organization and the merits of alternative theories of marriage and divorce. We examine physical-custody outcomes among recent Wisconsin divorces in an effort to understand the factors associated with shared custody as well as mother-sole custody and father-sole custody. Although mother-sole custody remains the dominant arrangement, shared custody has increased over a nine-year period. We find that the probability of shared custody increases with parent's income. Prior marital history, parents' ages, the age and gender of children, and the legal process also have an impact on the probability of shared custody. In contrast to shared custody, the probability of father-sole custody decreases with parent's income, while the relationship with other significant factors is generally similar. The notable exception is that, unlike shared custody, we find no evidence for an increase over time in the probability of father-sole custody. We also find that when the father has a higher proportion of the couple's total income, both shared custody and father-sole custody are more likely.

Intestinal permeability in patients with chronic urticaria-angioedema with and without arthralgia.

We evaluated the clinical response to oligoallergenic dietary treatment and the intestinal absorption of a protein antigen, cow milk beta-lactoglobulin (BLG) in 24 patients with chronic urticaria/angioedema syndrome 13 of whom also suffered from joint symptoms. Sixteen patients (77% of those with arthralgia) responded to diet (RD) with marked reduction of symptoms; the others did not respond (NR). Ten (all but one RD with arthralgia) had increased permeability to BLG after oral administration of cow milk. Four with high titers of IgG to BLG showed the highest absorption of BLG and the groups with arthralgia showed higher BLG levels than those without arthralgia. In all cases, specific IgE to cow milk was absent. These data suggest that the symptoms of a subgroup of patients with chronic urticaria, and especially patients with joint complaints that subside with diet, are related to excess intestinal permeability. The measurement of gut permeability to food proteins may be useful to define those who may benefit from dietary restriction.

Intestinal permeability in irritable bowel syndrome. Effect of diet and sodium cromoglycate administration.

We studied 14 patients with irritable bowel syndrome for the presence of increased intestinal permeability to food antigens and their responses to diet with and without disodium cromoglycate. After a standardized oral challenge with cow milk, serum beta-lactoglobulin was increased above control values in three patients. This finding did not correlate with response to hypoallergenic diet or treatment with disodium cromoglycate for 3 weeks. However over 50% of patients improved after diet with and without DSCG (2/5 on diet only and 5/7 with disodium cromoglycate of 12 evaluable cases). Since only two patients had elevated serum IgE levels, our results suggest that intolerance rather than hypersensitivity to foods may play a role in the disease. The tests we used to identify immunologic mechanisms could not predict which patients would do better on the diet and/or the drug.

Intestinal permeability and antigen absorption in rheumatoid arthritis. Effects of acetylsalicylic acid and sodium chromoglycate.

Intestinal permeability was measured using cow's milk beta-lactoglobulin absorption (BLG) as a permeability marker in 14 patients with active and inactive rheumatoid arthritis (RA) under three different conditions: after a washout period, after treatment with acetylsalicylic acid (ASA) associated with disodium chromoglycate (DSCG), and with ASA only. No intolerance to cow's milk was present and serum IgE levels were in the normal range in 12 of 14 patients. IgG anti-IgE were present in 7 of 13 patients tested. When off treatment the intestinal permeability to BLG in RA patients was not increased as compared to controls, but we found a significative difference between active and inactive RA. ASA administration strongly increased BLG absorption, not prevented by DSCG pretreatment. In normal controls treated with a single dose of ASA we obtained similar results. Our results suggest that prolonged treatment with nonsteroidal anti-inflammatory drugs induces an increase of food antigen absorption, apparently not related to anaphylaxis mediator release, with possible clinical effects.