Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy

BACKGROUND: Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). METHODS: Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE. RESULTS: Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44-0.79]; P<0.001). Mortality was also reduced in the continuous tafamidis (versus placebo to tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33-0.99]; P=0.05) and wild-type transthyretin amyloidosis (0.61 [0.43-0.87]; P=0.006); and baseline New York Heart Association class I and II (0.56 [0.38-0.82]; P=0.003) and class III (0.65 [0.41-1.01]; P=0.06). CONCLUSIONS: In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01994889 and NCT02791230

Family connections versus optimised treatment-as-usual for family members of individuals with borderline personality disorder: non-randomised controlled study

Background: Borderline personality disorder (BPD) is challenging for family members who are often required to fulfil multiple roles such as those of advocate, caregiver, coach and guardian. To date, two uncontrolled studies by the treatment developers suggest that Family Connections (FC) is an effective programme to support, educate and teach skills to family members of individuals with BPD. However, such studies have been limited by lack of comparison to other treatment approaches. This study aimed to compare the effectiveness of FC with an optimised treatment-as-usual (OTAU) programme for family members of individuals with BPD. A secondary aim was to introduce a long term follow-up to investigate if positive gains from the intervention would be maintained following programme completion. Methods: This study was a non-randomised controlled study, with assessment of outcomes at baseline (pre-intervention) and end of programme (post-intervention) for both FC and OTAU groups, and at follow-up (3 months post-intervention; 12 or 19 months post-intervention) for the FC group. Eighty family members participated in the FC (n = 51) and the OTAU (n = 29) programmes. Outcome measures included burden, grief, depression and mastery. Linear mixed-effects models were used to assess baseline differences in the outcome measures by gender, age group and type of relationship to the individual with BPD. Linear mixed-effects models were also used to estimate the treatment effect (FC versus OTAU) utilising all available data from baseline and end of programme. Results: The FC group showed changes indicating significant improvement with respect to all four outcome measures (p < 0.001). The OTAU group showed changes in the same direction as the intervention group but none of the changes were statistically significant. The intervention effect was statistically significant for total burden (including both subscales; p = .02 for subjective burden and p = .048 for objective burden) and grief (p = 0.013). Improvements were maintained at follow-up for FC participants. Conclusions: The findings of the current study indicate that FC results in statistically significant improvements on key measures while OTAU does not yield comparable changes. Lack of significant change on all measures for OTAU suggests that a three session psycho-education programme is of limited benefit. Further research is warranted on programme components and long-term supports for family members

Standards for UNiversal reporting of patient Decision Aid Evaluation studies: the development of SUNDAE Checklist

Background: Patient decision aids (PDAs) are evidence-based tools designed to help patients make specific and deliberated choices among healthcare options. The International Patient Decision Aid Standards (IPDAS) Collaboration review papers and Cochrane systematic review of PDAs have found significant gaps in the reporting of evaluations of PDAs, including poor or limited reporting of PDA content, development methods, and delivery. This study sought to develop and reach consensus on reporting guidelines to improve the quality of publications evaluating PDAs. Methods: An international workgroup, consisting of members from IPDAS Collaboration, followed established methods to develop reporting guidelines for PDA evaluation studies. This paper describes the results from three completed phases (1) Planning, (2) Drafting, and (3) Consensus, which included a modified, two stage, online international Delphi process. The work was conducted over two years with bi-monthly conference calls and three in-person meetings. The workgroup used input from these phases to produce a final set of recommended items in the form of a checklist. Results: The SUNDAE Checklist (Standards for UNiversal reporting of patient Decision Aid Evaluations) includes 26 items recommended for studies reporting evaluations of PDAs. In the two-stage Delphi process, 117/143 (82%) experts from 14 countries completed round 1 and 96/117 (82%) completed round 2. Respondents reached a high level of consensus on the importance of the items and indicated strong willingness to use the items when reporting PDA studies. Conclusion: The SUNDAE Checklist will help ensure that reports of PDA evaluation studies are understandable, transparent, and of high quality. A separate Explanation and Elaboration publication provides additional details to support use of the Checklist

Protective CD8+ T lymphocytes in Primates Immunized with Malaria Sporozoites

Live attenuated malaria vaccines are more potent than the recombinant protein, bacterial or viral platform vaccines that have been tested, and an attenuated sporozoite vaccine against falciparum malaria is being developed for humans. In mice, attenuated malaria sporozoite vaccines induce CD8+ T cells that kill parasites developing in the liver. We were curious to know if CD8+ T cells were also important in protecting primates against malaria. We immunized 9 rhesus monkeys with radiation attenuated Plasmodium knowlesi sporozoites, and found that 5 did not develop blood stage infections after challenge with live sporozoites. We then injected 4 of these protected monkeys with cM-T807, a monoclonal antibody to the CD8 molecule which depletes T cells. The fifth monkey received equivalent doses of normal IgG. In 3 of the 4 monkeys receiving cM-T807 circulating CD8+ T cells were profoundly depleted. When re-challenged with live sporozoites all 3 of these depleted animals developed blood stage malaria. The fourth monkey receiving cM-T807 retained many circulating CD8+ T cells. This monkey, and the vaccinated monkey receiving normal IgG, did not develop blood stage malaria at re-challenge with live sporozoites. Animals were treated with antimalarial drugs and rested for 4 months. During this interval CD8+ T cells re-appeared in the circulation of the depleted monkeys. When all vaccinated animals received a third challenge with live sporozoites, all 5 monkeys were once again protected and did not develop blood stage malaria infections. These data indicate that CD8+ T cells are important effector cells protecting monkeys against malaria sporozoite infection. We believe that malaria vaccines which induce effector CD8+ T cells in humans will have the best chance of protecting against malaria

Successful Internalization of a Chronic Biliary Cutaneous Fistula After Liver Transplantation: Deepithelializing the Fistula Tract

Biliary cutaneous fistulas are uncommon sequelae after biliary surgery and can be a source of significant morbidity. We describe a liver recipient who developed a biliary cutaneous fistula secondary to hepatic artery thrombosis; this subsequently drained for over 7 years. Through a novel approach, using the transabdominal fistula tract as a conduit, the fistula skin opening was deepithelialized and anastomosed to a jejunal loop, internally draining the tract. For over 7 years postoperatively, this internal drainage procedure has continued to function effectively. This approach may have value in internalizing longstanding biliary cutaneous fistulas in well-selected patients in whom there is no existing biliary ductal system or the existing system anatomically does not lend itself to restoration of functional internal drainage through conventional approaches

A preliminary study of genetic factors that influence susceptibility to bovine tuberculosis in the British cattle herd

Associations between specific host genes and susceptibility to Mycobacterial infections such as tuberculosis have been reported in several species. Bovine tuberculosis (bTB) impacts greatly the UK cattle industry, yet genetic predispositions have yet to be identified. We therefore used a candidate gene approach to study 384 cattle of which 160 had reacted positively to an antigenic skin test (‘reactors’). Our approach was unusual in that it used microsatellite markers, embraced high breed diversity and focused particularly on detecting genes showing heterozygote advantage, a mode of action often overlooked in SNP-based studies. A panel of neutral markers was used to control for population substructure and using a general linear model-based approach we were also able to control for age. We found that substructure was surprisingly weak and identified two genomic regions that were strongly associated with reactor status, identified by markers INRA111 and BMS2753. In general the strength of association detected tended to vary depending on whether age was included in the model. At INRA111 a single genotype appears strongly protective with an overall odds ratio of 2.2, the effect being consistent across nine diverse breeds. Our results suggest that breeding strategies could be devised that would appreciably increase genetic resistance of cattle to bTB (strictly, reduce the frequency of incidence of reactors) with implications for the current debate concerning badger-culling

Sampling constrained probability distributions using Spherical Augmentation

Statistical models with constrained probability distributions are abundant in machine learning. Some examples include regression models with norm constraints (e.g., Lasso), probit, many copula models, and latent Dirichlet allocation (LDA). Bayesian inference involving probability distributions confined to constrained domains could be quite challenging for commonly used sampling algorithms. In this paper, we propose a novel augmentation technique that handles a wide range of constraints by mapping the constrained domain to a sphere in the augmented space. By moving freely on the surface of this sphere, sampling algorithms handle constraints implicitly and generate proposals that remain within boundaries when mapped back to the original space. Our proposed method, called {Spherical Augmentation}, provides a mathematically natural and computationally efficient framework for sampling from constrained probability distributions. We show the advantages of our method over state-of-the-art sampling algorithms, such as exact Hamiltonian Monte Carlo, using several examples including truncated Gaussian distributions, Bayesian Lasso, Bayesian bridge regression, reconstruction of quantized stationary Gaussian process, and LDA for topic modeling.Comment: 41 pages, 13 figure

Cross-protection between attenuated Plasmodium berghei and P. yoelii sporozoites

An attenuatedPlasmodium falciparum sporozoite (PfSPZ) vaccine is under development, in part, based on studies in mice withP. berghei. We usedP. berghei andP. yoelii to study vaccine-induced protection against challenge with a species of parasite different from the immunizing parasite in BALB/c mice. One-hundred percent of mice were protected against homologous challenge. Seventy-nine percent immunized with attenuatedP. berghei sporozoite (PbSPZ)(six experiments) were protected against challenge withP. yoelii sporozoite (PySPZ), and 63% immunized with attenuatedPySPZ(three experiments) were protected against challenge withPbSPZ. Antibodies in sera of immunized mice only recognized homologous sporozoites and could not have mediated protection against heterologous challenge. Immunization with attenuatedPySPZ orPbSPZ induced CD8+ T cell-dependent protection against heterologous challenge. Immunization with attenuatedPySPZ induced CD8+ T cell-dependent protection against homologous challenge. However, homologous protection induced by attenuatedPbSPZ was not dependent on CD8+ or CD4+ T cells, and depletion of both populations only reduced protection by 36%. Immunization of C57BL/10 mice withPbSPZ induced CD8+ T cell-dependent protection againstP. berghei, but no protection againstP. yoelii. The cross-protection data in BALB/c mice support testing a human vaccine based on attenuatedPfSPZ for its efficacy againstP. vivax

Biosensor immunoassay for traces of hazelnut protein in olive oil

The fraudulent addition of hazelnut oil to more expensive olive oil not only causes economical loss but may also result in problems for allergic individuals as they may inadvertently be exposed to potentially allergenic hazelnut proteins. To improve consumer safety, a rapid and sensitive direct biosensor immunoassay, based on a highly specific monoclonal antibody, was developed to detect the presence of hazelnut proteins in olive oils. The sample preparation was easy (extraction with buffer); the assay time was fast (4.5 min only) and the limit of detection was low (0.08 μg/g of hazelnut proteins in olive oil). Recoveries obtained with an olive oil mixed with different amounts of a hazelnut protein containing hazelnut oil varied between 93% and 109%