The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its ...physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.
•FUS phase transitions between monomer, liquid droplet, and hydrogel states•FUS mutants induce further phase transition into irreversible fibrillar hydrogels•Irreversible hydrogels sequester RNP cargo and impair RNP granule function•Formation of non-amyloid fibrillar hydrogels provides a compelling causative mechanism for neurodegeneration
Murakami et al. show that FUS transitions between monomer, liquid droplet, and hydrogel states during uptake and release of RNP granule cargo. FUS mutations accelerate transition into fibrillar hydrogels that trap RNP cargo, impair RNP granule function, and cause neurodegeneration.
It is unclear whether mutations in fused in sarcoma (FUS) cause familial amyotrophic lateral sclerosis via a loss-of-function effect due to titrating FUS from the nucleus or a gain-of-function effect ...from cytoplasmic overabundance. To investigate this question, we generated a series of independent Caenorhabditis elegans lines expressing mutant or wild-type (WT) human FUS. We show that mutant FUS, but not WT-FUS, causes cytoplasmic mislocalization associated with progressive motor dysfunction and reduced lifespan. The severity of the mutant phenotype in C. elegans was directly correlated with the severity of the illness caused by the same mutation in humans, arguing that this model closely replicates key features of the human illness. Importantly, the mutant phenotype could not be rescued by overexpression of WT-FUS, even though WT-FUS had physiological intracellular localization, and was not recruited to the cytoplasmic mutant FUS aggregates. Our data suggest that FUS mutants cause neuronal dysfunction by a dominant gain-of-function effect related either to neurotoxic aggregates of mutant FUS in the cytoplasm or to dysfunction in its RNA-binding functions.
We report observations of an intrinsic fluorescence in the visible range, which develops during the aggregation of a range of polypeptides, including the disease-related human peptides ...amyloid-β(1-40) and (1-42), lysozyme and tau. Characteristic fluorescence properties such as the emission lifetime and spectra were determined experimentally. This intrinsic fluorescence is independent of the presence of aromatic side-chain residues within the polypeptide structure. Rather, it appears to result from electronic levels that become available when the polypeptide chain folds into a cross-β sheet scaffold similar to what has been reported to take place in crystals. We use these findings to quantify protein aggregation in vitro by fluorescence imaging in a label-free manner.
Although lipid-lowering drugs are not recommended for primary prevention in patients 75+, prevalence of use is high and there is unexplained variation in prescribing between physicians. The objective ...of this study was to determine if physician communication ability and clinical competence are associated with prescribing lipid-lowering drugs for primary and secondary prevention.
We used a cohort of 4,501 international medical graduates, 161,214 U.S. Medicare patients with hyperlipidemia (primary prevention) and 49,780 patients with a history of cardiovascular disease (secondary prevention) not treated with lipid-lowering therapy who were seen by study physicians in ambulatory care. Clinical competence and communication ability were measured by the ECFMG clinical assessment examination. Physician citizenship, age, gender, specialty and patient characteristics were also measured. The outcome was an incident prescription of lipid-lowering drug, evaluated using multivariable GEE logistic regression models for primary and secondary prevention for patients 75+ and 65-74.
Patients 75+ were less likely than those 65-74 to receive lipid-lowering drugs for primary (OR 0.62, 95% CI 0.59-0.66) and secondary (OR 0.70, 95% CI 0.63-0.78) prevention. For every 20% increase in clinical competence score, the odds of prescribing therapy for primary prevention to patients 75+ increased by 24% (95% CI 1.02-1.5). Communication ability had the opposite effect, reducing the odds of prescribing for primary prevention by 11% per 20% score increase (95% CI 0.8-0.99) for both age groups. Physicians who were citizens of countries with higher proportions of Hispanic (South/Central America) or Asian (Asia/Oceania) people were more likely to prescribe treatment for primary prevention, and internal medicine specialists were more likely to treat for secondary prevention than primary care physicians.
Clinical competence, communication ability and physician citizenship are associated with lipid-lowering drug prescribing for primary prevention in patients aged 75+.
Abstract
Background
There is considerable variation among physicians in inappropriate antibiotic prescribing, which is hypothesized to be attributable to diagnostic uncertainty and ineffective ...communication. The objective of this study was to evaluate whether clinical and communication skills are associated with antibiotic prescribing for upper respiratory infections and sinusitis.
Methods
A cohort study of 2,526 international medical graduates and 48,394 U.S. Medicare patients diagnosed by study physicians with an upper respiratory infection or sinusitis between July 2014 and November 2015 was conducted. Clinical and communication skills were measured by scores achieved on the Clinical Skills Assessment examination administered by the Educational Commission for Foreign Medical Graduates (ECFMG) as a requirement for entry into U.S residency programs. Medicare Part D data were used to determine whether patients were dispensed an antibiotic following an outpatient evaluation and management visit with the study physician. Physician age, sex, specialty and practice region were retrieved from the ECFMG databased and American Medical Association (AMA) Masterfile. Multivariate GEE logistic regression was used to evaluate the association between clinical and communication skills and antibiotic prescribing, adjusting for other physician and patient characteristics.
Results
Physicians prescribed an antibiotic in 71.1% of encounters in which a patient was diagnosed with sinusitis, and 50.5% of encounters for upper respiratory infections. Better interpersonal skills scores were associated with a significant reduction in the odds of antibiotic prescribing (OR per score decile 0.93, 95% CI 0.87–0.99), while greater proficiency in clinical skills and English proficiency were not. Female physicians, those practicing internal medicine compared to family medicine, those with citizenship from the US compared to all other countries, and those practicing in southern of the US were also more likely to prescribe potentially unnecessary antibiotics.
Conclusions
Based on this study, physicians with better interpersonal skills are less likely to prescribe antibiotics for acute sinusitis and upper respiratory infections. Future research should examine whether tailored interpersonal skills training to help physicians manage patient expectations for antibiotics could reduce unnecessary antibiotic prescribing.
Brand discount cards have become a popular way for patients to reduce out-of-pocket spending on drugs; however, controversy exists over their potential to increase insurers' costs. We estimated the ...impact of brand discount cards on Canadian drug expenditures.
Using national claims-level pharmacy adjudication data, we performed a retrospective comparison of prescriptions filled using a brand discount card matched to equivalent generic prescriptions between September 2014 and September 2017. We investigated the impact on expenditures for 3 groups of prescriptions: those paid only through private insurance, those paid only through public insurance and those paid only out of pocket.
We studied 2.82 million prescriptions for 89 different medications for which brand discount cards were used. Use of discount cards resulted in 46% higher private insurance expenditures than comparable generic prescriptions (+$23.09 per prescription, 95% confidence interval CI $22.97 to $23.21). Public insurance expenditures were only slightly higher with cards: an increase of 1.3% or $0.37 per prescription (95% CI $0.33 to $0.41). Finally, out-of-pocket transactions using a card resulted in mean patient savings of 7% or $3.49 per prescription (95% CI -$3.55 to -$3.43). The impact varied widely among medicines across all 3 analyses.
The use of brand discount cards increased costs to private insurers, had little impact on public insurers and resulted in mixed impacts for patients. These effects likely resulted from private insurers reimbursing brand drug prices even when generics were available and from discount cards being adjudicated after claims were sent to other insurers in most cases. Patients and their clinicians should recognize that discount cards have mixed impacts on out-of-pocket costs.
Clinical drug trials in patients with heart failure and preserved ejection fraction have failed to demonstrate improvements in mortality.
We systematically searched Medline, Embase and the Cochrane ...Central Register of Controlled Trials for randomised controlled trials (RCT) assessing pharmacological treatments in patients with heart failure with left ventricular (LV) ejection fraction≥40% from January 1996 to May 2016. The primary efficacy outcome was all-cause mortality. Secondary outcomes were cardiovascular mortality, heart failure hospitalisation, exercise capacity (6-min walk distance, exercise duration, VO
max), quality of life and biomarkers (B-type natriuretic peptide, N-terminal pro-B-type natriuretic peptide). Random-effects models were used to estimate pooled relative risks (RR) for the binary outcomes, and weighted mean differences for continuous outcomes, with 95% CI.
We included data from 25 RCTs comprising data for 18101 patients. All-cause mortality was reduced with beta-blocker therapy compared with placebo (RR: 0.78, 95%CI 0.65 to 0.94, p=0.008). There was no effect seen with ACE inhibitors, aldosterone receptor blockers, mineralocorticoid receptor antagonists and other drug classes, compared with placebo. Similar results were observed for cardiovascular mortality. No single drug class reduced heart failure hospitalisation compared with placebo.
The efficacy of treatments in patients with heart failure and an LV ejection fraction≥40% differ depending on the type of therapy, with beta-blockers demonstrating reductions in all-cause and cardiovascular mortality. Further trials are warranted to confirm treatment effects of beta-blockers in this patient group.
Abstract Background Appropriate dissemination of clinical data is crucial for minimising bias. Despite this, high rates of study discontinuation and non-publication have been reported among clinical ...trials. Cardiovascular medicine receives a substantial proportion of academic funding; however, predictors of non-publication among cardiovascular trials are not well-established. Methods The National Clinical Trials database was searched for cardiovascular trials completed between January 2010 and January 2014. Associated publications were identified in Medline or Embase. Relevant variables were extracted and subject to chi-squared and logistic regression to identify predictors of discontinuation and non-publication. Results After reviewing 2035 trials, 431 trials were included, of which 82.1% ( n = 354; 119,233 participants) were completed. Among completed trials, 70.3% ( n = 249; 99,095 participants) were published. Industry funding was associated with increased likelihood of non-publication (odds ratio OR 2.84; 95% confidence interval CI 1.47–5.51; P = 0.002), while small studies non-randomised studies were more likely to remain unpublished than larger randomised counterparts. Industry-funded studies were over three times more likely to be discontinued than those sponsored by academic institutions (OR 3.89; CI 1.54–9.83; P = 0.004). and Trials studying heart failure and atrial fibrillation were more likely to be discontinued compared to trials studying coronary artery disease (OR 2.83; CI 1.23–6.51; and OR 3.10; CI 1.21–7.96, respectively). In total, Of the total 135,714 participants, 25,565 were recruited into trials that did not result in publication. Unpublished studies. Conclusions Discontinuation and non-publication of cardiovascular trials are common, resulting in data from thousands of participants remaining unpublished. Funding source and size randomisation were are strong predictors of non-publication, while sponsor type, phase and blinding status are key predictors of discontinuation.
HIV-associated neurocognitive disorder (HAND) remains prevalent in the era of combination antiretroviral therapy (cART). The prevalence of HAND in Hong Kong is not known.
Between 2013 and 2015, 98 ...treatment-naïve HIV-1-infected individuals were referred to and screened by the AIDS Clinical Service, Queen Elizabeth Hospital with (1) the International HIV Dementia Scale (IHDS), a screening tool that targets moderate to severe HAND, (2) the Montreal Cognitive Assessment (MoCA), a frequently used cognitive screening test and (3) the Patient Health Questionnare-9 (PHQ-9), a 9-item questionnaire that evaluates depression symptoms. Within the study period, 57 of them completed the second set of IHDS and MoCA at 6 months after baseline assessment.
Most participants were male (94%), with a median age of 31 years. At baseline, 38 (39%) and 25 (26%) of them scored below the IHDS (≤10) and MoCA (25/26) cut-offs respectively. Poor IHDS performers also scored lower on MoCA (p = 0.039) but the correlation between IHDS and MoCA performance was weak (r = 0.29, p = 0.004). Up to a third of poor IHDS performers (13/38) showed moderate depression (PHQ-9 > 9). In the multivariable analysis, a lower education level (p = 0.088), a history of prior psychiatric illness (p = 0.091) and the presence of moderate depression (p = 0.079) tended to be significantly associated with poor IHDS performance. At follow-up, 54 out of 57 were on cART, of which 46 (85%) had achieved viral suppression. Their blood CD4+ T-lymphocytes and IHDS scores were higher at follow-up compared to baseline values (both p < 0.001) but their MoCA performance was similar at both assessments. Of note, 17 participants in this subgroup scored below the IHDS cut-off at both assessments.
Poor IHDS performance, and likely cognitive impairment, was frequently observed in treatment-naïve HIV-infected individuals in our locality. A considerable proportion continued to score below the IHDS cut-off at 6 months after cART. Depression was frequently observed in this vulnerable population and was associated with poor IHDS performance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
It is a frequent challenge for physicians to identify pneumonia in patients with acute febrile respiratory symptoms, particularly in stable pediatric patients without respiratory distress. A decision ...rule is required to assist judgement on the need of ordering a chest radiograph.
This was a multicenter prospective study in 3 emergency departments. Children younger than 6 years old with an acute onset of fever and respiratory symptoms were recruited. Split sample method was adopted for derivation and validation of the Pediatric Acute Febrile Respiratory Illness rule (PAFRI Rule). PAFRI was derived from logistic regression with weighting based on adjusted odds ratios.
Out of 967 children evaluated, 530 had taken chest radiograph examination, with 91 demonstrated evidence of pneumonia on radiograph. PAFRI Rule was derived from logistic regression with 5 weighed predictors: duration of fever <3 days (0 points), 3–4 days (2 points), 5–6 days (4 points), ≥7 days (5 points), chills (2 points), nasal symptoms (−2 points), abnormal chest examination (3 points), SpO2 ≤96% or tachypnea (3 points). The Area under ROC curve of the PAFRI Rule, the Bilkis Decision Rule and Bilkis Simpler Rule were 0.733, 0.600 and 0.579 respectively. A PAFRI score of ≥0 gives a sensitivity of 91.7% and negative predictive value of 97.7%.
PAFRI rule can be used as a reference tool for guiding the need for taking Chest radiograph examination for pediatric patients. While promising, the PAFRI rule requires further validation.
It is often a challenge for physicians to identify pneumonia in children acutely febrile with respiratory symptoms, particularly in those who are stable without respiratory distress. The decision to order chest radiograph was based on clinical assessment with heterogenous practice. A valid and verified clinical prediction rule for ordering chest radiograph examination for stable febrile children without signs of respiratory distress would therefore assist in management of this group of patients.
The PAFRI rule, based on parameters from clinical bedside assessment, can be used as a reference tool for guiding the need for referral to emergency department or taking use of chest radiograph for pediatric patients, and triaging for higher priority of clinical care.
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