Red-flag symptom clusters in transthyretin familial amyloid polyneuropathy

© 2015 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, progressive, life-threatening, hereditary disorder caused by mutations in the transthyretin gene and characterized by extracellular deposition of transthyretin-derived amyloid fibrils in peripheral and autonomic nerves, heart, and other organs. TTR-FAP is frequently diagnosed late because the disease is difficult to recognize due to phenotypic heterogeneity. Based on published literature and expert opinion, symptom clusters suggesting TTR-FAP are reviewed, and practical guidance to facilitate earlier diagnosis is provided. TTR-FAP should be suspected if progressive peripheral sensory-motor neuropathy is observed in combination with one or more of the following: family history of a neuropathy, autonomic dysfunction, cardiac hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel syndrome, renal impairment, or ocular involvement. If TTR-FAP is suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy, large- and small-fiber assessment by nerve conduction studies and autonomic system evaluations, and cardiac testing should be performed.info:eu-repo/semantics/publishedVersio

Changing paradigm in the treatment of amyloidosis: From disease-modifying drugs to anti-fibril therapy.

Cardiac amyloidosis is a rare, debilitating, and usually fatal disease increasingly recognized in clinical practice despite patients presenting with non-specific symptoms of cardiomyopathy. The current standard of care (SoC) focuses on preventing further amyloid formation and deposition, either with anti-plasma cell dyscrasia (anti-PCD) therapies in light-chain (AL) amyloidosis or stabilizers of transthyretin (TTR) in transthyretin amyloidosis (ATTR). The SoC is supplemented by therapies to treat the complications arising from organ dysfunction; for example, heart failure, arrhythmia, and proteinuria. Advancements in treatments have improved patient survival, especially for those whose disease is detected and for whom treatment is initiated at an early stage. However, there still are many unmet medical needs, particularly for patients with severe disease for whom morbidity and mortality remain high. There currently are no approved treatments to reverse amyloid infiltration and deplete the amyloid fibrils already deposited in organs, which can continue to cause progressive dysfunction. Anti-fibril therapies aimed at removing the deposited fibrils are being investigated for safety and efficacy in improving outcomes for patients with severe disease. However, there is no clinical evidence yet that removing deposited amyloid fibrils will improve organ function, thereby improving quality of life or extending life. Nevertheless, anti-fibril therapies are actively being investigated in clinical trials to evaluate their ability to complement and synergize with current SoC.This manuscript was funded by Alexion AstraZeneca Rare Disease. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.S

Efficacy of tigecycline for the treatment of complicated intraabdominal infections in real-life clinical practice from five european observational studies

Objectives: Tigecycline is a broad-spectrum antibiotic approved for the treatment of complicated intra-abdominal infections (cIAIs). The efficacy of tigecycline when administered as monotherapy or in combination with other antibacterials in the treatment of cIAIs in routine clinical practice is described. Patients and methods: Individual patient-level data were pooled from five European observational studies (July 2006 to October 2011). Results: A total of 785 cIAI patients who received tigecycline were included (mean age 63.1+14.0 years). Of these, 56.6% were in intensive care units, 65.6% acquired their infection in hospital, 88.1% had at least one comorbidity and 65.7% had secondary peritonitis. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores at the beginning of treatment were 16.9+7.6 (n=614) and 7.0+4.2 (n=108), respectively, indicating high disease severity. Escherichia coli (41.8%), Enterococcus faecium (40.1%) and Enterococcus faecalis (21.1%) were the most frequently isolated pathogens; 49.1% of infections were polymicrobial and 17.5% were due to resistant pathogens. Overall, 54.8% (n=430) received tigecycline as monotherapy and 45.2% (n=355) as combination therapy for a mean duration of 10.6 days. Clinical response rates at the end of treatment were 77.4% for all patients (567/733), 80.6% for patients who received tigecycline as monotherapy (329/408), 75.2% for patients with a nosocomial infection (354/471), 75.8% for patients with an APACHE II score .15 (250/330) and 54.2% (32/59) for patients with a SOFA score =7. Conclusions: In these real-life studies, tigecycline, alone and in combination, achieved favourable clinical response rates in patients with cIAI with a high severity of illness

Antibiotic treatment patterns across Europe in patients with complicated skin and soft-tissue infections due to meticillin-resistant <em>Staphylococcus aureus</em>:a plea for implementation of early switch and early discharge criteria

AbstractThis retrospective observational medical chart review aimed to describe country-specific variations across Europe in real-world meticillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infection (cSSTI) treatment patterns, antibiotic stewardship activity, and potential opportunities for early switch (ES) from intravenous (i.v.) to oral formulations and early discharge (ED) from hospital using standardised data collection and criteria and economic implications of these opportunities. Patients were randomly sampled from 12 countries (Austria, Czech Republic, France, Germany, Greece, Ireland, Italy, Poland, Portugal, Slovakia, Spain and the UK), aged ≥18 years, with documented MRSA cSSTI, hospitalised between 1 July 2010 and 30 June 2011, discharged alive by 31 July 2011. Of 1502 patients, 1468 received MRSA-targeted therapy. Intravenous-to-oral switch rates ranged from 2.0% to 20.2%, i.v. length of therapy from 10.1 to 18.6 days and hospital length of stay (LoS) from 15.2 to 25.0 days across Europe. Of 341 sites, 82.9% had antibiotic steering committees, 23.7% had i.v.-to-oral switch antibiotic protocols and 12.9% had ED protocols for MRSA cSSTI. ES and ED eligibility ranged from 12.0% (Slovakia) to 56.3% (Greece) and from 10% (Slovakia) to 48.2% (Portugal), respectively. Potential cost savings per ED-eligible patient ranged from €414 (Slovakia) to €2703 (France). MRSA cSSTI treatment patterns varied widely across countries, but further reductions in i.v. therapy, hospital LoS and associated costs could be realised. These data provide insight into clinical practice patterns across diverse European healthcare systems and identify potential opportunities for local clinicians and policy-makers to improve clinical care and cost-effectiveness of this therapeutic area

Influence of real-world characteristics on outcomes for patients with methicillin-resistant Staphylococcal skin and soft tissue infections:a multi-country medical chart review in Europe

BACKGROUND: Patient-related (demographic/disease) and treatment-related (drug/clinician/hospital) characteristics were evaluated as potential predictors of healthcare resource use and opportunities for early switch (ES) from intravenous (IV)-to-oral methicillin-resistant Staphylococcus aureus (MRSA)-active antibiotic therapy and early hospital discharge (ED). METHODS: This retrospective observational medical chart study analyzed patients (across 12 European countries) with microbiologically confirmed MRSA complicated skin and soft tissue infections (cSSTI), ≥3 days of IV anti-MRSA antibiotics during hospitalization (July 1, 2010-June 30, 2011), and discharged alive by July 31, 2011. Logistic/linear regression models evaluated characteristics potentially associated with actual resource use (length of IV therapy, length of hospital stay [LOS], IV-to-oral antibiotic switch), and ES and ED (using literature-based and expert-verified criteria) outcomes. RESULTS: 1542 patients (mean ± SD age 60.8 ± 16.5 years; 61.5% males) were assessed with 81.0% hospitalized for MRSA cSSTI as the primary reason. Several patient demographic, infection, complication, treatment, and hospital characteristics were predictive of length of IV therapy, LOS, IV-to-oral antibiotic switch, or ES and ED opportunities. Outcomes and ES and ED opportunities varied across countries. Length of IV therapy and LOS (r = 0.66, p < 0.0001) and eligibilities for ES and ED (r = 0.44, p < 0.0001) showed relatively strong correlations. IV-to-oral antibiotic switch patients had significantly shorter length of IV therapy (−5.19 days, p < 0.001) and non-significantly shorter LOS (−1.86 days, p > 0.05). Certain patient and treatment characteristics were associated with increased odds of ES (healthcare-associated/ hospital-acquired infection) and ED (patient living arrangements, healthcare-associated/ hospital-acquired infection, initiating MRSA-active treatment 1–2 days post cSSTI index date, existing ED protocol), while other factors decreased the odds of ES (no documented MRSA culture, ≥4 days from admission to cSSTI index date, IV-to-oral switch, IV line infection) and ED (dementia, no documented MRSA culture, initiating MRSA-active treatment ≥3 days post cSSTI index date, existing ES protocol). CONCLUSIONS: Practice patterns and opportunity for further ES and ED were affected by several infection, treatment, hospital, and geographical characteristics, which should be considered in identifying ES and ED opportunities and designing interventions for MRSA cSSTI to reduce IV days and LOS while maintaining the quality of care. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2334-14-476) contains supplementary material, which is available to authorized users

The capacity of short-chain fructo-oligosaccharides to stimulate faecal bifidobacteria: a dose-response relationship study in healthy humans

BACKGROUND: Short-chain fructo-oligosaccharides (scFOS) are well-known for their bifidogenicity. In a large study comprising 200 healthy volunteers, we determined the bifidogenic properties of 7 non-digestible carbohydrates administered at a dose of 10 g/d in the diet; we analysed dose-response relationships of the bifidogenic substrates at doses ranging from 2.5 to 10 g/d in comparison with a placebo. The aim of this presentation is to give more details about the dose-response effects of short-chain fructo-oligosaccharides (scFOS). METHODS: Forty healthy volunteers (18 males, 22 females) eating their usual diets were randomly divided into 5 groups of 8 subjects and received scFOS at a dose of 2.5, 5.0, 7.5 and 10 g/d or a placebo for 7 d. Stools were collected before (day (d) 8) and at the end (day (d) 15) of sugar consumption, and tolerance was evaluated using a daily chart. RESULTS (M ± SEM): Bifidobacteria counts increase was higher in scFOS than in placebo group for all doses tested [2.5 g/d (from 9.15 ± 0.59 to 9.39 ± 0.70; P = 0.02); 5 g/d (from 10.21 ± 0.21 to 10.67 ± 0.22; P = 0.03); 7.5 g/d (from 9.28 ± 0.49 to 9.85 ± 0.35;P = 0.01); 10 g/d (from 9.00 ± 0.81 to 10.18 ± 0.60; P = 0.003)]. A significant correlation between the ingested dose of scFOS and faecal bifidobacteria counts was observed at d15 (r(2 )= 0.307, P < 0.001). Total anaerobes increased at the dose of 10 g/d. No significant differences were found for Bacteroides, Lactobacillus, enterobacteria or pH in any group. The frequency of digestive symptoms was not different between scFOS at any of the doses tested and placebo. Bloating was significantly more intense during scFOS ingestion at doses of 2.5 and 5 g/d, but not at doses of 7.5 and 10 g/d. Excess flatus, borborygmi and abdominal pain did not differ from the placebo at any of the doses tested. CONCLUSION: This study showed that scFOS is bifidogenic and well tolerated at doses ranging from 2.5 to 10 g/d, and that there is a dose-response relationship in healthy volunteers

The capacity of short-chain fructo-oligosaccharides to stimulate faecal bifidobacteria: a dose-response relationship study in healthy humans

Abstract Background Short-chain fructo-oligosaccharides (scFOS) are well-known for their bifidogenicity. In a large study comprising 200 healthy volunteers, we determined the bifidogenic properties of 7 non-digestible carbohydrates administered at a dose of 10 g/d in the diet; we analysed dose-response relationships of the bifidogenic substrates at doses ranging from 2.5 to 10 g/d in comparison with a placebo. The aim of this presentation is to give more details about the dose-response effects of short-chain fructo-oligosaccharides (scFOS). Methods Forty healthy volunteers (18 males, 22 females) eating their usual diets were randomly divided into 5 groups of 8 subjects and received scFOS at a dose of 2.5, 5.0, 7.5 and 10 g/d or a placebo for 7 d. Stools were collected before (day (d) 8) and at the end (day (d) 15) of sugar consumption, and tolerance was evaluated using a daily chart. Results (m ± SEM) Bifidobacteria counts increase was higher in scFOS than in placebo group for all doses tested [2.5 g/d (from 9.15 ± 0.59 to 9.39 ± 0.70; P = 0.02); 5 g/d (from 10.21 ± 0.21 to 10.67 ± 0.22; P = 0.03); 7.5 g/d (from 9.28 ± 0.49 to 9.85 ± 0.35;P = 0.01); 10 g/d (from 9.00 ± 0.81 to 10.18 ± 0.60; P = 0.003)]. A significant correlation between the ingested dose of scFOS and faecal bifidobacteria counts was observed at d15 (r2 = 0.307, P Conclusion This study showed that scFOS is bifidogenic and well tolerated at doses ranging from 2.5 to 10 g/d, and that there is a dose-response relationship in healthy volunteers.</p

Prescription behaviours for tigecycline in real-life clinical practice from five European observational studies

There is limited information on the use of tigecycline in real-life clinical practice. This analysis aims to identify and understand tigecycline prescribing patterns and associated patient outcomes for approved indications