A two-center pilot study on the effects of clinical ethics support on coercive measures in psychiatry.

BACKGROUND: The use of formal coercion such as seclusion, mechanical restraint, and forced medication is one of the most challenging and complex issues in mental health care, on the clinical, the legal, and the ethical level. Clinical ethics support aims at assisting healthcare practitioners in determining the morally most justifiable course of action in these situations. However, the effectiveness of clinical ethics support has hardly been studied so far. METHODS: Monthly moral case deliberation (MCD) was implemented in two acute wards of two different psychiatric hospitals in Switzerland. Frequency and intensity of coercion was measured on ward level (npatients = 405), and the Moral Attentiveness Scale, Knowledge on Coercion Scale, and Staff Attitudes towards Coercion Scale were applied on healthcare practitioner level (nHP = 46). Pre-post-comparisons were conducted using multi-level modeling where appropriate. RESULTS: After implementation of MCD, formal coercion was less frequent (particularly seclusion, small effect size; 9.6 vs. 16.7%, p = .034, Cramér's V = .105) and less intense (particularly mechanical restraint, large effect size; 86.8 ± 45.3 vs. 14.5 ± 12.1 h, exact p = .019, r = -.74), and approval for coercive measures among healthcare practitioners was lower when controlling for the number of MCD sessions attended. CONCLUSIONS: Clinical ethics support such as MCD may be a hitherto underutilized service for the reduction of coercion, complementing existing strategies and programs. Implementing clinical ethics support may help improve quality of care for persons suffering from severe mental illness.

Characteristics of Suicides and Toxicology in a Cohort of Individuals With Opioid Use Disorder.

Suicide in patients with opioid use disorder (OUD) is a complex issue. In addition to accidental intoxications, a higher prevalence of fatal suicides in patients with OUD can be found compared to the general population. In this study, suicides with a diagnosis of OUD documented in the project "Suicides, A National Survey" were extracted from our data bank. Individuals with a diagnosis of OUD in their medical history were compared to other suicides. The analyses included clinical and demographic factors as well as an investigation of suicide methods and toxicology of psychotropic drugs. For the statistical analyses, we applied chi-square tests and calculated odds ratios. Out of 6,495 suicide cases in Switzerland between 2000 and 2010, 215 individuals with a medical history of OUD could be identified. Persons in OUD cases were significantly younger than in other suicide cases (p < .001) and had more frequently a positive history for suicide attempts (p = .02). In addition, persons in OUD cases were more often female (p = .076). Intentional self-poisoning with medication was applied more often in individuals with OUD compared to other suicide methods (p < .001). When self-poisoning with drugs was compared to violent suicide methods, a combination of benzodiazepines with antidepressants was predominantly found. Our study yielded significant characteristics and risk factors for suicides in individuals with OUD. The predominant method of suicide in individuals with OUD was intended self-poisoning by medication. This knowledge is of clinical importance for the monitoring of at-risk individuals with OUD as well as for suicide prevention in this patient group.

Suicide by hanging: Results from a national survey in Switzerland and its implications for suicide prevention.

BACKGROUND: Hanging is a frequent suicide method, but developing measures to prevent suicide by this method is particularly challenging. The aim of this study is to gain new knowledge that would enable the design of effective of measures that would help prevent suicide by hanging. METHODS: A total of 6,497 suicides registered across the eight Swiss Forensic Institutes (IRM) were analysed. Of these, 1,282 (19.7%) persons hung themselves. T-test and chi-square tests. and chi-square tests were used to analyse …(or determine, or investigate) …group differences regarding sociodemographic variables and triggers. FINDINGS: Men and women who hung themselves showed no significant differences in sociodemographic variables. However, women were significantly more likely to have a psychiatric illness history, whereas men were more likely to have somatic diagnoses. In controlled environments, people used shelves, plumbing and windows more often than beams, pipes, bars and hooks to hang themselves. Compared with other suicide methods, hanging was more likely to have been triggered by partner and financial problems. CONCLUSIONS: Suicide by hanging can be best prevented in institutions (e.g. psychiatric hospitals, somatic hospitals, prisons). These institutions should be structurally evaluated and modified with a primary focus on sanitary areas, windows and shelves. Otherwise, it is important to use general suicide prevention measures, such as awareness raising and staff training in medical settings, low-threshold treatment options and regular suicide risk assessment for people at risk.

Assisted Suicide in Switzerland: An Analysis of Death Records From Swiss Institutes of Forensic Medicine.

BACKGROUND: The aim of this research project, part of a program initiated by the Swiss Federal Council, was to trace the development of organized assisted suicide in Switzerland, starting from the very first case in 1985. METHODS: Retrospective data on 3666 death records from Swiss institutes of foren- sic medicine for the years 1985 to 2014 were systematically compiled, read into a database, and for the most part quantitatively evaluated. RESULTS: Alongside a marked increase in the overall number of assisted suicides since the turn of the century, the number of people traveling to Switzerland from other countries-predominantly Germany-for this purpose has risen steadily. The proportion of women was 60%, and the age at death ranged from 18 to 105 years (median 73). The largest diagnostic category was malignancy overall, neurological disease for those from other countries. The next largest category was age-related functional limitation, e.g., sensory impairment (loss of sight and hearing), the conse- quences of which were stated in writing as the reason for the wish to die. Following the Swiss Federal Court's promulgation of binding requirements in 2006, the docu- mentation contained in the death records for the subsequent period up to 2014 is much more detailed, but still not uniform or even necessarily complete. CONCLUSION: The number of candidates for organized assisted suicide increased steadily during the study period, but no standard procedures were followed. The question therefore arises of whether further regulation or the introduction of a cen- tral registration office to maximize standardization and promote transparency would lead to improved quality assurance.

Attitudinal variance among patients, next of kin and health care professionals towards the use of containment measures in three psychiatric hospitals in Switzerland.

BACKGROUND: In psychiatric treatment containment measures are used to de-escalate high-risk situations. These measures can be characterized by their immanent amount of coercion. Previous research could show that the attitudes towards different containment measures vary throughout countries. The aim of this study was to compare the attitudes towards containment measures between three study sites in Switzerland which differ in their clinic traditions and policies and their actual usage of these measures. METHODS: We used the Attitude to Containment Measures Questionnaire (ACMQ) in three psychiatric hospitals in Switzerland (Zurich, Muensingen and Monthey) in patients, their next of kin (NOK) and health care professionals (HCP). Furthermore, we assessed the cultural specifics and rates of coercive measures for these three hospitals. RESULTS: We found substantial differences in the usage of and the attitudes towards some containment measures between the three study sites. The study site accounted for a variance of nearly zero in as needed medication to 15% in seclusion. The differences between study sites were bigger in the HCPs' attitudes (up to 50% of the variance), compared to NOK and patients. In the latter the study site accounted for up to 6% of the variance. The usage/personal experience of containment measures in general was associated with higher agreement. CONCLUSIONS: Although being situated in the same country, there are substantial differences in the rates of containment measures between the three study sites. We showed that the HCP's attitudes are more associated with the clinic traditions and policies compared to patients' and their NOKs' attitudes. One can conclude that patients' preferences depend less on clinic traditions and policies. Therefore, it is important to adapt treatment to the individual patients' attitudes. TRIAL REGISTRATION: The study was reviewed and approved by the Cantonal Ethics Commission of Zurich, Switzerland (Ref.-No. EK: 2016-01526, decision on 28.09.2016) and the Cantonal Ethics Commission of Bern, Switzerland (Ref.-Nr. KEK-BE: 2015-00074). This study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The permission for conduction of the study was granted by the medical directors at the three study sites. The authors informed the respondents (patients, NOK, HCP) of their rights in the study in an oral presentation and/or a cover letter. They assured the participants of the confidentiality and anonymity of the data, and the voluntariness of participation. Patients were given an information sheet with the possibility to consent in the conduction of the study. Return of the completed questionnaires from HCP and NOK was constituted as confirmation of their consent. No identifying factors were collected to ensure privacy. This article does not contain any studies with animals performed by any of the authors.

Suicide by firearm in Switzerland: who uses the army weapon? Results from the national survey between 2000 and 2010.

AIMS: In comparison with other central European countries, Switzerland has a high prevalence of gun ownership and a high rate of suicide by shooting. After the Army XXI reform in 2003, which reduced personnel from about 400,000 to approximately 200,000, a decline in suicides by firearms and a decline in the total number of suicides was observed in national data spanning the period from 2000 to 2010. It is, however, unclear whether this decline can be linked to the reduced availability of military guns. This study explored whether the decline in suicide by firearms is related to the decline of suicides by army weapons. METHODS: In 83.1% (n = 1112) of the 1338 suicides by firearm between 2000 and 2010 in Switzerland, the firearm could be categorised as an army weapon or a non-army weapon. The army weapon was used in 39.1% of these suicides. In comparison with other firearms, those who used army weapons tended to be younger and more likely to have a university degree. A prior suicide attempt was found less often in cases using a military weapon than other firearms. After the Army XXI reform, there was a significant drop in suicides by males aged 18 to 43 years using an army weapon, but no change in male suicide rates in the same age group who used a non-army weapon. The drop was statistically linked to a reduction of suicide by the army gun. RESULTS: The army weapon was used in 39.1% of suicides by firearm between 2000 and 2010 in Switzerland. In comparison with other methods, those who used army weapons tended to be younger and more likely to have a university degree. A prior suicide attempt was found less often in cases using a military weapon than other methods. After the Army XXI reform, there was a significant drop in suicides by males aged 18 to 43 years using an army weapon, but no change in males' suicide rates in the same age group who used a non-army weapon. The drop was statistically linked to a reduction of suicide by the army gun. CONCLUSIONS: Males who use army weapons differ from those who use other types of weapons. The significant drop in suicides was found in males aged 18 to 43 but there was no change in males of the same age group who used a non-army weapon. These results support the hypotheses that the observed drop in suicides is linked to the Army XXI reform and that restriction of access to guns is essential for reducing suicides by firearm.

Comparing Attitudes to Containment Measures of Patients, Health Care Professionals and Next of Kin.

Background: In clinical psychiatric practice, health care professionals (HCP) must decide in exceptional circumstances after the weighing of interests, which, if any, containment measures including coercion are to be used. Here, the risk for patients, staff, and third parties, in addition to therapeutic considerations, factor into the decision. Patients' preference and the inclusion of relatives in these decisions are important; therefore, an understanding of how patients and next of kin (NOK) experience different coercive measures is crucial for clinical decision making. The aim of this study is to compare how patients, HCP, and NOK assess commonly used coercive measures. Methods: A sample of 435 patients, 372 HCP, and 230 NOK completed the Attitudes to Containment Measures Questionnaire (ACMQ). This standardized self-rating questionnaire assessed the degree of acceptance or rejection of 11 coercive measures. Results: In general, HCPs rated the coercive measures as more acceptable than did NOK and patients. The largest discrepancy in the ratings was found in regard to the application of coercive intramuscular injection of medication (effect size: 1.0 HCP vs. patients). However, the ratings by NOK were significantly closer to the patients' ratings compared to patients and HCP. The only exception was the acceptance of treatment in a closed acute psychiatric ward, which was deemed significantly more acceptable by NOK than by patients. Also, patients who had experienced coercive measures themselves more strongly refused other measures. Conclusion: Patients most firmly rejected intramuscular injections, and the authors agree that these should only be used with reservation considering a high threshold. This knowledge about the discrepancy of the ratings should therefore be incorporated into professional training of HCP.

Hepatitis C virus genetic diversity by geographic region within genotype 1-6 subtypes among patients treated with glecaprevir and pibrentasvir.

Hepatitis C virus (HCV) is genetically diverse and includes 7 genotypes and 67 confirmed subtypes, and the global distribution of each HCV genotype (GT) varies by geographic region. In this report, we utilized a large dataset of NS3/4A and NS5A sequences isolated from 2348 HCV GT1-6-infected patients treated with the regimen containing glecaprevir/pibrentasvir (GLE/PIB) to assess genetic diversity within HCV subtypes by geographic region using phylogenetic analyses, and evaluated the prevalence of baseline amino acid polymorphisms in NS3 and NS5A by region/country and phylogenetic cluster. Among 2348 NS3/4A and NS5A sequences, phylogenetic analysis identified 6 genotypes and 44 subtypes, including 3 GT1, 8 GT2, 3 GT3, 13 GT4, 1 GT5, and 16 GT6 subtypes. Phylogenetic analysis of HCV subtype 1a confirmed the presence of two clades, which differed by geographic region distribution and NS3 Q80K prevalence. We detected phylogenetic clustering by country in HCV subtypes 1a, 1b, 2a, 2b, and 5a, suggesting that genetically distinct virus lineages are circulating in different countries. In addition, two clades were detected in HCV GT4a and GT6e, and NS5A amino acid polymorphisms were differentially distributed between the 2 clades in each subtype. The prevalence of NS3 and NS5A baseline polymorphisms varied substantially by genotype and subtype; therefore, we also determined the activity of GLE or PIB against replicons containing NS3/4A or NS5A from HCV GT1-6 clinical samples representing 6 genotypes and 21 subtypes overall. GLE and PIB retained activity against the majority of HCV replicons containing NS3/4A or NS5A from HCV GT1-6 clinical samples, with a median EC50 of 0.29 nM for GLE and 1.1 pM for PIB in a transient replicon assay. The data presented in this report expands the available data on HCV epidemiology, subtype diversity by geographic region, and NS3 and NS5A baseline polymorphism prevalence.

Pooled Resistance Analysis in Patients with Hepatitis C Virus Genotype 1 to 6 Infection Treated with Glecaprevir-Pibrentasvir in Phase 2 and 3 Clinical Trials.

Over 2,200 patients infected with hepatitis C virus (HCV) genotypes (GT) 1 to 6, with or without cirrhosis, who were treatment naive or experienced to interferon, ribavirin, and/or sofosbuvir were treated with glecaprevir/pibrentasvir for 8, 12, or 16 weeks in eight registrational phase 2 and 3 clinical studies. High rates of sustained virologic response at 12 weeks postdosing (SVR12) were achieved with a <1% virologic failure (VF) rate. The prevalence of baseline polymorphisms (BPs) in NS3 at amino acid position 155 or 168 was low (<3%) in patients infected with GT1, GT2, GT3, GT4, and GT6, while 41.9% of the GT5-infected patients had NS3-D168E; BPs were not detected at position 156 in NS3. The prevalence of NS5A-BPs was high across genotypes, driven by common polymorphisms at amino acid position 30 or 31 in GT2, 58 in GT4, and 28 in GT6. The prevalence of NS5A T/Y93 polymorphisms was 5.5% in GT1, 4.9% in GT3, and 12.5% in GT6. Consistent with the activity of glecaprevir and pibrentasvir against most amino acid polymorphisms in vitro, BPs in NS3 and/or NS5A did not have an impact on treatment outcome for patients infected with GT1 to GT6, with the exception of treatment-experienced GT3-infected patients treated for 12 weeks, for whom a 16-week regimen of glecaprevir/pibrentasvir was required to achieve SVR12 rates of ≥95%. Among the 22 patients experiencing VF, treatment-emergent substitutions were detected in NS3 in 50% of patients and in NS5A in 82% of patients, frequently as a combination of substitutions that conferred resistance to glecaprevir and/or pibrentasvir. The glecaprevir/pibrentasvir regimen, when the recommended durations are used, allows for a pan-genotypic treatment option without the need for baseline resistance testing.

Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection.

Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) are potent and pangenotypic hepatitis C virus (HCV) direct-acting antivirals. This report describes the baseline polymorphisms and treatment-emergent substitutions in NS3 or NS5A detected in samples from HCV genotype 1-infected patients receiving 3-day monotherapy of glecaprevir or pibrentasvir, respectively. None of the NS3 polymorphisms detected in the 47 baseline samples collected prior to glecaprevir monotherapy conferred reduced susceptibility to glecaprevir. The NS3 A156T substitution, which conferred resistance to glecaprevir but had low replication efficiency, emerged in one genotype 1a-infected patient among the 35 patients with available post-baseline sequence data. Baseline NS5A polymorphisms were detected in 12 of 40 patients prior to pibrentasvir monotherapy; most polymorphisms were single-position NS5A amino acid substitutions that did not confer resistance to pibrentasvir. Among the 19 patients with available post-baseline NS5A sequence data, 3 had treatment-emergent NS5A substitutions during pibrentasvir monotherapy. All treatment-emergent NS5A substitutions were linked multiple-position, almost exclusively double-position, substitutions that conferred resistance to pibrentasvir. Replicons engineered with these double-position substitutions had low replication efficiency. In conclusion, resistance-conferring substitutions emerged in a small number of genotype 1-infected patients during glecaprevir or pibrentasvir monotherapy; unlike other NS5A inhibitors, pibrentasvir did not select single-position NS5A substitutions during monotherapy.

Reasons for living and dying in suicide attempters: a two-year prospective study.

BACKGROUND: The internal suicide debate hypothesis assumes that in a suicidal crisis, individuals are involved in an internal struggle over whether to live or die. Reasons for living (RFL) and Reasons for dying (RFD) are important individual reasons for staying alive (e.g. family) or wanting to die (e.g. hopelessness) and reflect this internal motivational conflict of the suicidal mind. The aim of this study was to explore the association between RFL and RFD of suicide attempters and current and future suicide ideation and behavior. METHOD: The sample consisted of 60 patients who were admitted at a psychiatric emergency unit in Switzerland following an attempted suicide. They received treatment as usual, participated in an assessment interview and completed self-report questionnaires. Additionally, they were instructed to write down up to five individual RFL and RFD. The number of RFL and RFD responses, depressive symptoms, and suicide ideation were assessed at baseline and 6, 12, and 24 months follow-up. Outcome measures were suicide ideation and repeated suicide attempts. Multiple imputations were used in order to address missing data. RESULTS: The number of RFD responses was the strongest predictor for increased suicide ideation at baseline. The number of RFL responses was not associated with suicide ideation and reattempts. RFD, depressive symptoms, and baseline suicide ideation predicted subsequent suicide reattempt up to 12 months later in simple regression analyses. Mediation analyses suggested that RFD mediated the effect of depressive symptoms at baseline on suicide ideation at 12-months follow-up. CONCLUSION: RFL were unrelated to the mental health of study participants and did not function as protective factor against suicide risk. RFD may be an important motivational driver in the suicidal process. Clinical interventions should focus more on the reduction of RFD than on RFL in suicidal individuals.

Highlights of the Structure-Activity Relationships of Benzimidazole Linked Pyrrolidines Leading to the Discovery of the Hepatitis C Virus NS5A Inhibitor Pibrentasvir (ABT-530).

Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component of these treatments is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the component NS5A inhibitors, do not exhibit equivalent efficacy against HCV virus genotypes 1-6. In particular, these first generation NS5A inhibitors tend to select for viral drug resistance. Ombitasvir is a first generation HCV NS5A inhibitor included as a key component of Viekira Pak for the treatment of patients with HCV genotype 1 infection. Since the launch of next generation HCV treatments, functional cure for genotype 1-6 HCV infections has been achieved, as well as shortened treatment duration across a wider spectrum of genotypes. In this paper, we show how we have modified the anchor, linker, and end-cap architecture of our NS5A inhibitor design template to discover a next generation NS5A inhibitor pibrentasvir (ABT-530), which exhibits potent inhibition of the replication of wild-type genotype 1-6 HCV replicons, as well as improved activity against replicon variants demonstrating resistance against first generation NS5A inhibitors.

[Suicides of Psychiatric Inpatients - A Systematic Recording in Switzerland of the Years 2000 to 2010]. / Suizide während psychiatrischen Hospitalisationen.

OBJECTIVE: To analyze characteristics of suicide methods of psychiatric inpatients that were carried out within and outside of psychiatric hospitals in order to identify adequate suicide prevention measures. METHODS: Data of 436 inpatient suicides were included in the data base of all institutes of forensic medicine in Switzerland for the years 2000 - 2010. We compared details of suicide methods that were applied within and outside psychiatric hospitals. RESULTS: About two thirds of all suicides were carried out outside psychiatric hospitals. Inpatients most often used jumping in front of a train, jumps from heights and drowning outside of the hospital. Within psychiatric care units patients most often died by hanging, jumps from height and self-poisoning. Heights of fall were significantly lower in suicides carried out within the hospital (Median 9 versus 22 m). In psychiatric hospitals incomplete hanging was found in 75.6 %. Waist belts were the tools most often employed. CONCLUSIONS: Windows and other spots in inpatient units should be secured if higher than first storey respectively 4 meters. Suspension points have to be secured at a low level especially in non-public rooms.

Resistance characterization of hepatitis C virus genotype 2 from Japanese patients treated with ombitasvir and paritaprevir/ritonavir.

Treatment of HCV genotype (GT) 2-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) without ribavirin for 12 weeks in the phase 2 study M12-536, and with ribavirin for 16 weeks in phase 3 study GIFT II resulted in SVR rates of 72.2% to 91.5%. Overall, 11 out of 125 patients with GT2a and 37 out of 79 patients with GT2b infection experienced virologic failure. The prevalence of baseline polymorphisms in NS3 and NS5A and their the impact on treatment outcome, as well as the development of viral resistance in GT2-infected patients experiencing virologic failure were evaluated by HCV NS3 and NS5A population and clonal sequence analyses. Baseline polymorphisms in NS3 that confer resistance to paritaprevir were rare in both GT2a- and GT2b-infected patients, while baseline polymorphisms in NS5A that confer resistance to ombitasvir were detected in 11.2% and 14.1% of the GT2a- and GT2b-infected patients, respectively. There was no significant impact of baseline polymorphisms on treatment outcome in Japanese patients. The most common treatment-emergent substitutions at the time of virologic failure occurred at amino acid positions 168 in NS3 and 28 in NS5A in both GT2a- and GT2b-infected patients. Although there was a higher rate of virologic failure in patients with GT2b infection, the resistance analyses presented in this report support the conclusion that testing for baseline resistance-associated polymorphisms is not warranted for HCV GT2-infected patients treated with a regimen of ombitasvir/paritaprevir/ritonavir + ribavirin for 16 weeks.

Integrated Resistance Analysis of CERTAIN-1 and CERTAIN-2 Studies in Hepatitis C Virus-Infected Patients Receiving Glecaprevir and Pibrentasvir in Japan.

Glecaprevir and pibrentasvir are hepatitis C virus (HCV) pangenotypic inhibitors targeting NS3/4A protease and NS5A, respectively. This once-daily, fixed-dose combination regimen demonstrated high sustained virologic response 12 weeks postdosing (SVR12) rates in CERTAIN-1 and CERTAIN-2 studies in Japanese HCV-infected patients, with a low virologic failure rate (1.2%). There were no virologic failures among direct-acting antiviral (DAA)-treatment-naive genotype 1a (GT1a) (n = 4)-, GT1b (n = 128)-, and GT2 (n = 97)-infected noncirrhotic patients treated for 8 weeks or among GT1b (n = 38)- or GT2 (n = 20)-infected patients with compensated cirrhosis treated for 12 weeks. Two of 33 DAA-experienced and 2 of 12 GT3-infected patients treated for 12 weeks experienced virologic failure. Pooled resistance analysis, grouped by HCV subtype, treatment duration, prior treatment experience, and cirrhosis status, was conducted. Among DAA-naive GT1b-infected patients, the baseline prevalence of NS3-D168E was 1.2%, that of NS5A-L31M was 3.6%, and that of NS5A-Y93H was 17.6%. Baseline polymorphisms in NS3 or NS5A were less prevalent in GT2, with the exception of the common L/M31 polymorphism in NS5A. Among DAA-experienced GT1b-infected patients (30/32 daclatasvir plus asunaprevir-experienced patients), the baseline prevalence of NS3-D168E/T/V was 48.4%, that of NS5A-L31F/I/M/V was 81.3%, that of the NS5A P32deletion was 6.3%, and that of NS5A-Y93H was 59.4%. Common baseline polymorphisms in NS3 and/or NS5A had no impact on treatment outcomes in GT1- and GT2-infected patients; the impact on GT3-infected patients could not be assessed due to the enrollment of patients infected with diverse subtypes and the limited number of patients. The glecaprevir-pibrentasvir combination regimen allows a simplified treatment option without the need for HCV subtyping or baseline resistance testing for DAA-naive GT1- or GT2-infected patients. (The CERTAIN-1 and CERTAIN-2 studies have been registered at ClinicalTrials.gov under identifiers NCT02707952 and NCT02723084, respectively.).

In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS3/4A Protease Inhibitor Glecaprevir.

Glecaprevir (formerly ABT-493) is a novel hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) with pangenotypic activity. It inhibited the enzymatic activity of purified NS3/4A proteases from HCV genotypes 1 to 6 in vitro (half-maximal [50%] inhibitory concentration = 3.5 to 11.3 nM) and the replication of stable HCV subgenomic replicons containing proteases from genotypes 1 to 6 (50% effective concentration [EC50] = 0.21 to 4.6 nM). Glecaprevir had a median EC50 of 0.30 nM (range, 0.05 to 3.8 nM) for HCV replicons containing proteases from 40 samples from patients infected with HCV genotypes 1 to 5. Importantly, glecaprevir was active against the protease from genotype 3, the most-difficult-to-treat HCV genotype, in both enzymatic and replicon assays demonstrating comparable activity against the other HCV genotypes. In drug-resistant colony selection studies, glecaprevir generally selected substitutions at NS3 amino acid position A156 in replicons containing proteases from genotypes 1a, 1b, 2a, 2b, 3a, and 4a and substitutions at position D/Q168 in replicons containing proteases from genotypes 3a, 5a, and 6a. Although the substitutions A156T and A156V in NS3 of genotype 1 reduced susceptibility to glecaprevir, replicons with these substitutions demonstrated a low replication efficiency in vitro Glecaprevir is active against HCV with most of the common NS3 amino acid substitutions that are associated with reduced susceptibility to other currently approved HCV PIs, including those at positions 155 and 168. Combination of glecaprevir with HCV inhibitors with other mechanisms of action resulted in additive or synergistic antiviral activity. In summary, glecaprevir is a next-generation HCV PI with potent pangenotypic activity and a high barrier to the development of resistance.

In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir.

Pibrentasvir (ABT-530) is a novel and pan-genotypic hepatitis C virus (HCV) NS5A inhibitor with 50% effective concentration (EC50) values ranging from 1.4 to 5.0 pM against HCV replicons containing NS5A from genotypes 1 to 6. Pibrentasvir demonstrated similar activity against a panel of chimeric replicons containing HCV NS5A of genotypes 1 to 6 from clinical samples. Resistance selection studies were conducted using HCV replicon cells with NS5A from genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a, or 6a at a concentration of pibrentasvir that was 10- or 100-fold over its EC50 for the respective replicon. With pibrentasvir at 10-fold over the respective EC50, only a small number of colonies (0.00015 to 0.0065% of input cells) with resistance-associated amino acid substitutions were selected in replicons containing genotype 1a, 2a, or 3a NS5A, and no viable colonies were selected in replicons containing NS5A from other genotypes. With pibrentasvir at 100-fold over the respective EC50, very few colonies (0.0002% of input cells) were selected by pibrentasvir in genotype 1a replicon cells while no colonies were selected in other replicons. Pibrentasvir is active against common resistance-conferring substitutions in HCV genotypes 1 to 6 that were identified for other NS5A inhibitors, including those at key amino acid positions 28, 30, 31, or 93. The combination of pibrentasvir with HCV inhibitors of other classes produced synergistic inhibition of HCV replication. In summary, pibrentasvir is a next-generation HCV NS5A inhibitor with potent and pan-genotypic activity, and it maintains activity against common amino acid substitutions of HCV genotypes 1 to 6 that are known to confer resistance to currently approved NS5A inhibitors.

Comparing Different Suicide Prevention Measures at Bridges and Buildings: Lessons We Have Learned from a National Survey in Switzerland.

The goal of the study was to compare the effectiveness of different suicide prevention measures implemented on bridges and other high structures in Switzerland. A national survey identified all jumping hotspots that have been secured in Switzerland; of the 15 that could be included in this study, 11 were secured by vertical barriers and 4 were secured by low-hanging horizontal safety nets. The study made an overall and individual pre-post analysis by using Mantel-Haenszel Tests, regression methods and calculating rate ratios. Barriers and safety nets were both effective, with mean suicide reduction of 68.7% (barriers) and 77.1% (safety nets), respectively. Measures that do not secure the whole hotspot and still allow jumps of 15 meters or more were less effective. Further, the analyses revealed that barriers of at least 2.3 m in height and safety-nets fixed significantly below pedestrian level deterred suicidal jumps. Secured bridgeheads and inbound angle barriers seemed to enhance the effectiveness of the measure. Findings can help to plan and improve the effectiveness of future suicide prevention measures on high structures.

Discovery of fluorobenzimidazole HCV NS5A inhibitors.

Research toward a next-generation HCV NS5A inhibitor has identified fluorobenzimidazole analogs that demonstrate potent, broad-genotype in vitro activity against HCV genotypes 1-6 replicons as well as HCV NS5A variants that are orders of magnitude less susceptible to inhibition by first-generation NS5A inhibitors in comparison to wild-type replicons. The fluorobenzimidazole inhibitors have improved pharmacokinetic properties in comparison to non-fluorinated benzimidazole analogs. Discovery of these inhibitors was facilitated by exploring SAR in a structurally simplified inhibitor series.