A Single-blinded, Randomized Clinical Trial of How to Implement an Evidence-based Treatment for Generalized Anxiety Disorder [IMPLEMENT] — Effects of Three Different Strategies of Implementation

BACKGROUND: Despite long-standing calls to disseminate evidence-based treatments for generalized anxiety (GAD), modest progress has been made in the study of how such treatments should be implemented. The primary objective of this study was to test three competing strategies on how to implement a cognitive behavioral treatment (CBT) for out-patients with GAD (i.e., comparison of one compensation vs. two capitalization models). METHODS: For our three-arm, single-blinded, randomized controlled trial (implementation of CBT for GAD [IMPLEMENT]), we recruited adults with GAD using advertisements in high-circulation newspapers to participate in a 14-session cognitive behavioral treatment (Mastery of your Anxiety and Worry, MAW-packet). We randomly assigned eligible patients using a full randomization procedure (1:1:1) to three different conditions of implementation: adherence priming (compensation model), which had a systematized focus on patients' individual GAD symptoms and how to compensate for these symptoms within the MAW-packet, and resource priming and supportive resource priming (capitalization model), which had systematized focuses on patients' strengths and abilities and how these strengths can be capitalized within the same packet. In the intention-to-treat population an outcome composite of primary and secondary symptoms-related self-report questionnaires was analyzed based on a hierarchical linear growth model from intake to 6-month follow-up assessment. This trial is registered at ClinicalTrials.gov (identifier: NCT02039193) and is closed to new participants. FINDINGS: From June 2012 to Nov. 2014, from 411 participants that were screened, 57 eligible participants were recruited and randomly assigned to three conditions. Forty-nine patients (86%) provided outcome data at post-assessment (14% dropout rate). All three conditions showed a highly significant reduction of symptoms over time. However, compared with the adherence priming condition, both resource priming conditions indicated faster symptom reduction. The observer ratings of a sub-sample of recorded videos (n = 100) showed that the therapists in the resource priming conditions conducted more strength-oriented interventions in comparison with the adherence priming condition. No patients died or attempted suicide. INTERPRETATION: To our knowledge, this is the first trial that focuses on capitalization and compensation models during the implementation of one prescriptive treatment packet for GAD. We have shown that GAD related symptoms were significantly faster reduced by the resource priming conditions, although the limitations of our study included a well-educated population. If replicated, our results suggest that therapists who implement a mental health treatment for GAD might profit from a systematized focus on capitalization models. FUNDING: Swiss Science National Foundation (SNSF-Nr. PZ00P1_136937/1) awarded to CF. KEYWORDS: Cognitive behavioral therapy; Evidence-based treatment; Implementation strategies; Randomized controlled trial

Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials

BACKGROUND: Neovascular age-related macular degeneration (AMD) has a poor prognosis if left untreated, frequently resulting in legal blindness. Ranibizumab is approved for treating neovascular AMD. However, further guidance is needed to assist ophthalmologists in clinical practice to optimise treatment outcomes. METHODS: An international retina expert panel assessed evidence available from prospective, multicentre studies evaluating different ranibizumab treatment schedules (ANCHOR, MARINA, PIER, SAILOR, SUSTAIN and EXCITE) and a literature search to generate evidence-based and consensus recommendations for treatment indication and assessment, retreatment and monitoring. RESULTS: Ranibizumab is indicated for choroidal neovascular lesions with active disease, the clinical parameters of which are outlined. Treatment initiation with three consecutive monthly injections, followed by continued monthly injections, has provided the best visual-acuity outcomes in pivotal clinical trials. If continued monthly injections are not feasible after initiation, a flexible strategy appears viable, with monthly monitoring of lesion activity recommended. Initiation regimens of fewer than three injections have not been assessed. Continuous careful monitoring with flexible retreatment may help avoid vision loss recurring. Standardised biomarkers need to be determined. CONCLUSION: Evidence-based guidelines will help to optimise treatment outcomes with ranibizumab in neovascular AMD.

Population based screening - the difficulty of how to do more good than harm and how to achieve it

Screening people without symptoms of disease is an attractive idea. Screening allows early detection of disease or elevated risk of disease, and has the potential for improved treatment and reduction of mortality. The list of future screening opportunities is set to grow because of the refinement of screening techniques, the increasing frequency of degenerative and chronic diseases, and the steadily growing body of evidence on genetic predispositions for various diseases. But how should we decide on the diseases for which screening should be done and on recommendations for how it should be implemented? We use the examples of prostate cancer and genetic screening to show the importance of considering screening as an ongoing population-based intervention with beneficial and harmful effects, and not simply the use of a test. Assessing whether screening should be recommended and implemented for any named disease is therefore a multi-dimensional task in health technology assessment. There are several countries that already use established processes and criteria to assess the appropriateness of screening. We argue that the Swiss healthcare system needs a nationwide screening commission mandated to conduct appropriate evidence-based evaluation of the impact of proposed screening interventions, to issue evidence-based recommendations, and to monitor the performance of screening programmes introduced. Without explicit processes there is a danger that beneficial screening programmes could be neglected and that ineffective, and potentially harmful, screening procedures could be introduced.

Two ways to common knowledge

It is not clear what a system for evidence-based common knowledge should look like if common knowledge is treated as a greatest fixed point. This paper is a preliminary step towards such a system. We argue that the standard induction rule is not well suited to axiomatize evidence-based common knowledge. As an alternative, we study two different deductive systems for the logic of common knowledge. The first system makes use of an induction axiom whereas the second one is based on co-inductive proof theory. We show the soundness and completeness for both systems.

Disorders of paravertebral lumbar muscles: from pathology to cross-sectional imaging

Paravertebral lumbar muscles are important for spine stabilization and mobility. They may be abnormal in several disorders that may be associated with pain or functional impairment. Special attention should be paid to the paravertebral muscles during imaging, so that a possible muscular disease is not overlooked, especially in patients with low back pain. This article reviews such imaging abnormalities.

Second-Personal Reasons and Special Obligations

The paper discusses the second-personal account of moral obligation as put forward by Stephen Darwall. It argues that on such an account, an important part of our moral practice cannot be explained, namely special obligations that are grounded in special relationships between persons. After highlighting the problem, the paper discusses several strategies to accommodate such special obligations that are implicit in some of Darwall’s texts, most importantly a disentanglement strategy and a reductionist strategy. It argues that neither one of these strategies is entirely convincing. The last part of the papers sketches a novel account of how to accommodate special obligations in a second-personal framework: According to this suggestion, special obligations might be due to the fact that relationships change the normative authority that persons have over each other.

Long-term results of therapeutic local anesthesia (neural therapy) in 280 referred refractory chronic pain patients

BACKGROUND: Can the application of local anesthetics (Neural Therapy, NT) alone durably improve pain symptoms in referred patients with chronic and refractory pain? If the application of local anesthetics does lead to an improvement that far exceeds the duration of action of local anesthetics, we will postulate that a vicious circle of pain in the reflex arcs has been disrupted (hypothesis). METHODS: Case series design. We exclusively used procaine or lidocaine. The inclusion criteria were severe pain and chronic duration of more than three months, pain unresponsive to conventional medical measures, written referral from physicians or doctors of chiropractic explicitly to NT. Patients with improvement of pain who started on additional therapy during the study period for a reason other than pain were excluded in order to avoid a potential bias. Treatment success was measured after one year follow-up using the outcome measures of pain and analgesics intake. RESULTS: 280 chronic pain patients were included; the most common reason for referral was back pain. The average number of consultations per patient was 9.2 in the first year (median 8.0). After one year, in 60 patients pain was unchanged, 52 patients reported a slight improvement, 126 were considerably better, and 41 pain-free. At the same time, 74.1 % of the patients who took analgesics before starting NT needed less or no more analgesics at all. No adverse effects or complications were observed. CONCLUSIONS: The good long-term results of the targeted therapeutic local anesthesia (NT) in the most problematic group of chronic pain patients (unresponsive to all evidence based conventional treatment options) indicate that a vicious circle has been broken. The specific contribution of the intervention to these results cannot be determined. The low costs of local anesthetics, the small number of consultations needed, the reduced intake of analgesics, and the lack of adverse effects also suggest the practicality and cost-effectiveness of this kind of treatment. Controlled trials to evaluate the true effect of NT are needed.

A proposed framework to operationalize ESS for the mitigation of soil threats

Despite various research activities in the last decades across the world, many challenges remain to integrate the concept of ecosystem services (ESS) in decision-making, and a coherent approach to assess and value ESS is still lacking. There are a lot of different – often context-specific – ESS frameworks with their own definitions and understanding of terms. Based on a thorough review, the EU FP7 project RECARE (www.recare-project.eu) suggests an adapted framework for ecosystem services related to soils that can be used for practical application in preventing and remediating degradation of soils in Europe. This lays the foundation for the development and selection of appropriate methods to measure, evaluate, communicate and negotiate the services we obtain from soils with stakeholders in order to improve land management. Similar to many ESS frameworks, the RECARE framework distinguishes between an ecosystem and human well-being part. As the RECARE project is focused on soil threats, this is the starting point on the ecosystem part of the framework. Soil threats affect natural capital, such as soil, water, vegetation, air and animals, and are in turn influenced by those. Within the natural capital, the RECARE framework focuses especially on soil and its properties, classified in inherent and manageable properties. The natural capital then enables and underpins soil processes, while at the same time being affected by those. Soil processes, finally, are the ecosystem’s capacity to provide services, thus they support the provision of soil functions and ESS. ESS may be utilized to produce benefits for individuals and human society. Those benefits are explicitly or implicitly valued by individuals and human society. The values placed on those benefits influence policy and decision-making and thus lead to a societal response. Individual (e.g. farmers’) and societal decision making and policy determine land management and other (human) driving forces, which in turn affect soil threats and natural capital. In order to improve ESS with Sustainable Land Management (SLM) – i.e. measures aimed to prevent or remediate soil threats, the services identified in the framework need to be “manageable” (modifiable) for the stakeholders. To this end, effects of soil threats and prevention / remediation measures are captured by key soil properties as well as through bio-physical (e.g. reduced soil loss), socio-economic (e.g. reduced workload) and socio-cultural (e.g. aesthetics) impact indicators. In order to use such indicators in RECARE, it should be possible to associate the changes in soil processes to impacts of prevention / remediation measures (SLM). This requires the indicators to be sensitive enough to small changes, but still sufficiently robust to provide evidence of the change and attribute it to SLM.

A Metalloproteinase Mirolysin of Tannerella forsythia Inhibits All Pathways of the Complement System

Recent reports focusing on virulence factors of periodontal pathogens implicated proteinases as major determinants of remarkable pathogenicity of these species, with special emphasis on their capacity to modulate complement activity. In particular, bacteria-mediated cleavage of C5 and subsequent release of C5a seems to be an important phenomenon in the manipulation of the local inflammatory response in periodontitis. In this study, we present mirolysin, a novel metalloproteinase secreted by Tannerella forsythia, a well-recognized pathogen strongly associated with periodontitis. Mirolysin exhibited a strong effect on all complement pathways. It inhibited the classical and lectin complement pathways due to efficient degradation of mannose-binding lectin, ficolin-2, ficolin-3, and C4, whereas inhibition of the alternative pathway was caused by degradation of C5. This specificity toward complement largely resembled the activity of a previously characterized metalloproteinase of T. forsythia, karilysin. Interestingly, mirolysin released the biologically active C5a peptide in human plasma and induced migration of neutrophils. Importantly, we demonstrated that combination of mirolysin with karilysin, as well as a cysteine proteinase of another periodontal pathogen, Prevotella intermedia, resulted in a strong synergistic effect on complement. Furthermore, mutant strains of T. forsythia, devoid of either mirolysin or karilysin, showed diminished survival in human serum, providing further evidence for the synergistic inactivation of complement by these metalloproteinases. Taken together, our findings on interactions of mirolysin with complement significantly add to the understanding of immune evasion strategies of T. forsythia and expand the knowledge on molecular mechanisms driving pathogenic events in the infected periodontium.

A fungal endophyte helps plants to tolerate root herbivory through changes in gibberellin and jasmonate signaling

Plant–microbe mutualisms can improve plant defense, but the impact of root endophytes on below-ground herbivore interactions remains unknown. We investigated the effects of the root endophyte Piriformospora indica on interactions between rice (Oryza sativa) plants and its root herbivore rice water weevil (RWW; Lissorhoptrus oryzophilus), and how plant jasmonic acid (JA) and GA regulate this tripartite interaction. Glasshouse experiments with wild-type rice and coi1-18 and Eui1-OX mutants combined with nutrient, jasmonate and gene expression analyses were used to test: whether RWW adult herbivory above ground influences subsequent damage caused by larval herbivory below ground; whether P. indica protects plants against RWW; and whether GA and JA signaling mediate these interactions. The endophyte induced plant tolerance to root herbivory. RWW adults and larvae acted synergistically via JA signaling to reduce root growth, while endophyte-elicited GA biosynthesis suppressed the herbivore-induced JA in roots and recovered plant growth. Our study shows for the first time the impact of a root endophyte on plant defense against below-ground herbivores, adds to growing evidence that induced tolerance may be an important root defense, and implicates GA as a signal component of inducible plant tolerance against biotic stress.