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.

Virtual reality in the assessment and treatment of psychosis: a systematic review of its utility, acceptability and effectiveness.

Over the last two decades, there has been a rapid increase of studies testing the efficacy and acceptability of virtual reality in the assessment and treatment of mental health problems. This systematic review was carried out to investigate the use of virtual reality in the assessment and the treatment of psychosis. Web of Science, PsychInfo, EMBASE, Scopus, ProQuest and PubMed databases were searched, resulting in the identification of 638 articles potentially eligible for inclusion; of these, 50 studies were included in the review. The main fields of research in virtual reality and psychosis are: safety and acceptability of the technology; neurocognitive evaluation; functional capacity and performance evaluation; assessment of paranoid ideation and auditory hallucinations; and interventions. The studies reviewed indicate that virtual reality offers a valuable method of assessing the presence of symptoms in ecologically valid environments, with the potential to facilitate learning new emotional and behavioural responses. Virtual reality is a promising method to be used in the assessment of neurocognitive deficits and the study of relevant clinical symptoms. Furthermore, preliminary findings suggest that it can be applied to the delivery of cognitive rehabilitation, social skills training interventions and virtual reality-assisted therapies for psychosis. The potential benefits for enhancing treatment are highlighted. Recommendations for future research include demonstrating generalisability to real-life settings, examining potential negative effects, larger sample sizes and long-term follow-up studies. The present review has been registered in the PROSPERO register: CDR 4201507776.

Update on treatment of hereditary angioedema.

Hereditary angioedema (HAE) is a rare disease characterized by recurrent, self-limiting episodes of swelling. New research and therapies have recently emerged and are now available; however, many physicians are not aware of the new developments in HAE. To update immunologists and other health care providers on new advances in HAE therapies, a PubMed, OVID and Google literature search were used to develop this manuscript. English language peer-reviewed angioedema articles were selected. High quality clinical trials were reviewed and summarized. Acute therapy in the past often consisted of symptom relief with narcotics, hydration and fresh frozen plasma (FFP). Androgens and FFP are frequently used despite multiple, significant side-effects. Newer therapies include C1-inhibitor - both human plasma derived and recombinant - as well as contact system modulators such as ecallantide and icatibant. These newer products can be used for treatment of acute attacks of HAE, and C1-inhibitors can also be used for prophylaxis. These disease-specific therapies have proven to work by placebo-controlled studies, have minimal adverse effects and can be utilized for the treatment of HAE.

Review of recent guidelines and consensus statements on hereditary angioedema therapy with focus on self-administration.

Consensus meetings and the resulting recommendations shape treatment choices in rare diseases such as hereditary angioedema (HAE) because they combine the experience of prescribing physicians and the patients who are receiving therapy. Self-administration of HAE therapy was recognised as a potential treatment option in the first consensus publication in 2003. Recent studies have confirmed that self-administration of therapy resolves attacks quickly, safely and minimises burden of disease; however, the discovery of inconsistent treatment approaches is a concern and warrants investigation into the barriers that prevent adherence with current recommendations.

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.

C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks--final results of the I.M.P.A.C.T.2 study.

BACKGROUND: The placebo-controlled study International Multicentre Prospective Angioedema C1-INH Trial 1 (I.M.P.A.C.T.1) demonstrated that 20 U/kg C1 esterase inhibitor (C1-INH) concentrate (Berinert®; CSL Behring, Marburg, Germany) is effective in treating acute abdominal and facial Hereditary Angioedema (HAE) attacks. METHODS: I.M.P.A.C.T.2 was an open-label extension study of I.M.P.A.C.T.1 to evaluate the safety and efficacy of long-term treatment with 20 U/kg C1-INH for successive HAE attacks at any body location. Efficacy outcomes included patient-reported time to onset of symptom relief (primary) and time to complete resolution of all symptoms (secondary), analysed on a per-patient and per-attack basis. Safety assessments included adverse events, vital signs, viral safety and anti-C1-INH antibodies. RESULTS: During a median study duration of 24 months, 1085 attacks were treated in 57 patients (10-53 years of age). In the per-patient analysis, the median time to onset of symptom relief was 0.46 h and was similar for all types of attacks (0.39-0.48 h); the median time to complete resolution of symptoms was 15.5 h (shortest for laryngeal attacks: 5.8 h; 12.8-26.6 h for abdominal, peripheral and facial attacks). Demographic factors, type of HAE, intensity of attacks, time to treatment, use of androgens and presence of anti-C1-INH antibodies had no clinically relevant effect on the efficacy outcomes. There were no treatment-related safety concerns. No inhibitory anti-C1-INH antibodies were detected in any patient. CONCLUSIONS: A single dose of 20 U/kg C1-INH concentrate is safe and provides reliable efficacy in the long-term treatment of successive HAE attacks at any body location.

Correlations between exhaled nitric oxide, rs28364072 polymorphism of FCER2 gene, asthma control, and inhaled corticosteroid responsiveness in children with asthma.

In children with asthma, the responsiveness of inhaled corticosteroids (ICS) is depended on asthma endotype and phenotype. This study aimed to describe the clinical and biological characteristics, and its correlation with polymorphism of rs28364072 in FCER2 of asthmatic children. This work aimed to study the correlation between fractional concentration of exhaled nitric oxide (FENO) level and rs28364072 polymorphism of FCER2 gene with ICS responsiveness and disease control in children with asthma. This study was a prospective and descriptive study. All clinical characteristics, FENO, blood eosinophil counts (BEC), skin prick test (SPT), total IgE, asthma control test, and FCER2 gene polymorphism were performed for each patient. One hundred and seven asthmatic children who were over 5 years old (9.2 ± 2.6), were included. Patients with FENO > 20 ppb had higher percentage of positive SPT, total IgE level, and BEC (89.2 vs 80.0%, 851.1 vs 656.9 UI ml-1, and 785 ± 576 G L-1 vs 425 ± 364 G L-1; respectively). Among them, there were 54.2% of homozygous TT, 36.4% of heterozygous TC, and 9.4% of homozygous CC of rs28364072 polymorphism in FCER2. The percentage of patients with controlled asthma was increasing after 1 month and 3 months (47.1% and 58.8%; respectively). During the study, the ICS was decreasing as indicated by asthma control (348 ± 118 mcg at 1st month vs 329 ± 119 mcg at 3rd month; p < 0.05). CC genotype had the lowest level of increasing FEV1 compared to that in genotype TC and TT (8.4% vs 8.7% and 27.1%; p > 0.05 and p < 0.05; respectively). The percentage of polymorphism in rs28364072 of FCER2 was significant higher in patients with controlled asthma compared to uncontrolled asthma. Asthmatic children with high FENO and rs28364072 polymorphism in FCER2 gene are good responders to ICS; however, asthmatic children with homozygous variant CC of rs28364072 are poorly responsive to ICS.

Social care: an essential aspect of mental health rehabilitation services.

This study is aimed at the importance of social care in rehabilitation. A brief overview of the social care theme is used as the methodology. There is a tension in mental health care between biological and psychological treatments that focus on deficits at the individual level (symptoms, disabilities) and social interventions that try to address local inequalities and barriers in order to improve access for service users to ordinary housing, employment and leisure opportunities. The history of mental health care tells us that social care is often underfunded and too easily dismissed as not the business of health care. But too much emphasis on a health model of individual deficits is a slippery slope to institutionalisation by way of therapeutic nihilism. Rehabilitation services follow the biopsychosocial model but with a shift in emphasis, recognising the vital role played by social interventions in improving the functional outcomes that matter to service users including access to housing, occupation, leisure facilities and the support of family and friends. In conclusion, rehabilitation is framed within a model of personal recovery in which the target of intervention is to boost hope and help the individual find a meaning to life, living well regardless of enduring symptoms.

Predicting worsening asthma control following the common cold.

The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean+/-SD increase in mini-ACQ score of 0.69+/-0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.

Variable phenotypic spectrum of diabetes mellitus in a family carrying a novel KCNJ11 gene mutation.

AIMS: Heterozygous activating mutations in KCNJ11, which encodes the Kir6.2 subunit of the pancreatic ATP-sensitive potassium (K(ATP)) channel, cause both permanent and transient neonatal diabetes. Identification of KCNJ11 mutations has important therapeutic implications, as many patients can replace insulin injections with sulphonylurea tablets. The aim was to determine if a KCNJ11 mutation was responsible for a dominantly inherited form of diabetes mellitus, showing variability in age at diagnosis, in an Italian family. METHODS: We sequenced KCNJ11 in members of a three-generation family with variable phenotypes of dominantly inherited diabetes mellitus. One had transient early-onset diabetes, one had impaired glucose tolerance during the second pregnancy, and two had young-onset diabetes. None of the subjects showed permanent neonatal diabetes or neurological symptoms. RESULTS: A novel heterozygous mutation (c. 679C-->G and c. 680A-->T) was identified, resulting in a GAG-->CTG (E227L) substitution in KCNJ11. Functional studies of recombinant heterozygous K(ATP) channels revealed a small reduction in channel inhibition by ATP (IC(50) of 15 micromol/l and 38 micromol/l for wild-type and heterozygous channels, respectively) and an increase in the resting K(ATP) current. This would be expected to impair insulin secretion. The results are in agreement with the mild phenotype of the patients. CONCLUSIONS: Our results broaden the spectrum of diabetes phenotypes resulting from KCNJ11 mutations. They indicate testing for KCNJ11 mutations should be considered not only for neonatal diabetes but also for other forms of dominantly inherited diabetes with later onset, especially where these are associated with a low body mass index and low birth weight.

Ten-year outcomes in first episode psychotic major depression patients compared with schizophrenia and bipolar patients.

We aimed to investigate long-term outcomes in psychotic major depression patients compared to schizophrenia and bipolar/manic psychosis patients, in an incidence sample, while accounting for diagnostic change. Based on Aetiology and Ethnicity in Schizophrenia and Other Psychoses (ÆSOP and ÆSOP-10), a first episode psychosis cohort was followed-up 10years after first presentation. The Schedules for Clinical Assessment in Neuropsychiatry, WHO Life Chart and Global Assessment of Functioning were used to assess clinical, social and service use outcomes. Seventy-two PMD patients, 218 schizophrenia patients and 70 psychotic bipolar disorder/mania patients were identified at baseline. Differences in outcome between PMD and bipolar patients based on baseline and lifetime diagnosis were minimal. Differences in clinical, social and service use outcomes between PMD and schizophrenia were more substantial with PMD patients showing better outcomes on most variables. However, there was some weak evidence (albeit not quite statistically significant at p<0.05) based on lifetime diagnoses that PMD patients were more likely to attempt suicide (OR 2.31, CI 0.98-5.42, p0.055) and self-harm (OR 2.34, CI 0.97-5.68, p0.060). PMD patients have better social and service use outcomes compared to people with schizophrenia, but may be more likely to attempt suicide or self-harm. This unique profile is important for clinicians to consider in any risk assessment.

Mortality among psychiatric inpatients. Age-adjusted comparison of populations before and after psychotropic drug era.

Comparison of age-adjusted death rates for inpatient and general populations from three pre-drug era and one post-drug era samples revealed a progressive decline in mortality that was most marked among elderly men. When length of stay was considered, the post-drug era sample showed a 30% reduction in mortality among patients hospitalized less than one year and a 50% reduction among longer-stay patients. The findings fail to support an increased mortality risk associated with the use of psychotropic drugs but dramatize the increased need for psychiatric services resulting from the increased survival of patients, especially those with long-term hospital stays.

Influence of demographic characteristics on two measures of depressive symptoms: the relation of prevalence and persistence of symptoms with sex, age, education, and marital status.

Respondents from community and inpatient populations were asked to recall for the preceding week the prevalence (presence of symptom at any time) and persistence (presence of symptom for five to seven days) of 16 symptoms associated with depression. The rates were adjusted for four-variable combinations of sex, age, education, marital status, and clinical status. For the majority of symptoms, statistically significant associations were found between prevalence and sex, age, and marital status and between persistence and education. These results suggest that white women, young adults, and those not currently married have a higher prevalence of transient depressed affect than those in the other categories of each variable, while the less well-educated are at greater risk than those in other education categories of having the depressive syndrome requiring therapeutic intervention.

An epidemiologic study of problems associated with violence among psychiatric inpatients.

Approximately 11% of a 1-year sample of psychiatric inpatients from a single catchment area engaged in assaultive behavior before admission to the hospital. Among schizophrenic, alcoholic, and organic brain syndrome patients, assaultiveness was linked to emotional turmoil, as manifested by agitation and anger. In contrast, male patients with other diagnoses showed assaultiveness in the absence of substantial emotional distress, and patients with affective disorders were unlikely to exhibit assaultiveness even when high levels of agitation and anger were reported. The findings suggest that assessment and treatment of violent behavior in psychiatric patients are primarily linked to the nature of the underlying psychopathology.

Medication use and deaths attributed to asphyxia among psychiatric patients.

In a review of the charts of inpatients who died in 1969-1977 the author found 49 whose death could be attributed to asphyxia. Compared with a matched control group, 48 of the asphyxia patients represented three distinct pathologic categories: 1) older patients with a history of serious physical illness whose deaths appeared unrelated to psychotropic medication use (40%), 2) a group whose deaths were associated with seizures (31%), raising questions about subtherapeutic anticonvulsant levels in association with the use of psychotropic drugs, and 3) a group of patients who choked to death (29%). Choking has been theoretically linked to a combination of dopamine blockade plus strong anticholinergic effects leading to impairment of swallowing. The third category appears to have been virtually eliminated by the use of a drug monitoring system and the Heimlich maneuver.

Cocaine precipitation of panic disorder.

The authors describe three patients whose panic disorder began during recreational use of cocaine and continued autonomously even after the drug was stopped. Theoretical and practical implications are discussed.

Clinician-computer interaction: automated review of psychotropic drugs.

Five years after its introduction at a state mental hospital, an automated drug exception review system continues to show a long-term impact on the prescribing practices of hospital physicians. Although the overall rate of exceptions has remained low, approximately 25% of all new exceptions pointed out by the computer result in a change in the order by the physician. The fact that 60% of new exceptions are justified suggests that some forms of polypharmacy may be appropriate. The integration of the exception-reporting system into the clinical review process has avoided the danger of the computer's being seen as an adversary to the clinician or as exerting undue control over psychopharmacologic prescription practices.

The coexistence of parkinsonism-like symptoms and tardive dyskinesia.

The authors used the Simpson-Angus Neurological Rating Scale and the Simpson Abbreviated Dyskinesia Rating Scale to evaluate 132 psychiatric inpatients for the presence of parkinsonism-like symptoms and tardive dyskinesia, respectively. Ninety-four percent of these patients had been on a stable drug regimen for a minimum of 2 weeks before assessment; 91% were being treated with neuroleptics, 42% with antiparkinson agents, and 7% with tricyclic antidepressants. Tardive dyskinesia and parkinsonism-like symptoms coexisted in 17.4% of the 132 patients. Such coexistence poses a therapeutic dilemma for the clinician because drug treatment of improve one neurological condition may exacerbate the other.

Death and deinstitutionalization.

Death rates during a period of rapid deinstitutionalization of a state mental hospital population showed consistent reductions that were statistically significant in the elderly patient population 65 years and older. These reductions were most marked for deaths due to pneumonia; there was a moderate decrease in cardiac deaths, and essentially no change in cancer death rates. The findings suggest that through a variety of mechanisms deinstitutionalization may have had a beneficial effect on the mortality of elderly patients who remained hospitalized. Moreover, the resultant increased need for beds for these patients dramatizes the importance for program planners to base their projections for hospital use on a continuing analysis of trends rather than on static data.