Targeted proteomics in urinary extracellular vesicles identifies biomarkers for diagnosis and prognosis of prostate cancer

Rapid and reliable diagnosis of prostate cancer (PCa) is highly desirable as current used methods lack specificity. In addition, identification of PCa biomarkers that can classify patients into high- and low-risk groups for disease progression at early stage will improve treatment decision-making. Here, we describe a set of protein-combination panels in urinary extracellular vesicles (EVs), defined by targeted proteomics and immunoblotting techniques that improve early non-invasive detection and stratification of PCa patients.We report a two-protein combination in urinary EVs that classifies benign and PCa patients (ADSV-TGM4), and a combination of five proteins able to significantly distinguish between high- and low-grade PCa patients (CD63-GLPK5-SPHM-PSA-PAPP). Proteins composing the panels were validated by immunohistochemistry assays in tissue microarrays (TMAs) confirming a strong link between the urinary EVs proteome and alterations in PCa tissues. Moreover, ADSV and TGM4 abundance yielded a high diagnostic potential in tissue and promising TGM4 prognostic power. These results suggest that the proteins identified in urinary EVs distinguishing high- and low grade PCa are a reflection of histological changes that may be a consequence of their functional involvement in PCa development. In conclusion, our study resulted in the identification of protein-combination panels present in urinary EVs that exhibit high sensitivity and specificity for PCa detection and patient stratification. Moreover, our study highlights the potential of targeted proteomic approaches-such as selected reaction monitoring (SRM)-as diagnostic assay for liquid biopsies via urinary EVs to improve diagnosis and prognosis of suspected PCa patients

Morbidity, outcomes and cost-benefit analysis of wildlife rehabilitation in Catalonia (Spain)

Background There are few studies of careful examination of wildlife casualties in Wildlife Rehabilitation Centers. These studies are essential for detecting menaces to wild species and providing objective criteria about cost-benefit of treatments in those centers. The release rate is considered the main outcome indicator, but other parameters such as length of stay at the center and a cost-benefit index expressed as number of released animals per euro and day, could be used as reliable estimators of the rehabilitation costs. Methodology A retrospective study based on 54772 admissions recorded from 1995-2013 in the database of the Wildlife Rehabilitation Center of Torreferrussa (Catalonia, NW Spain) assessed the morbidity, outcomes and cost-benefits of the rehabilitation practices. Results Three hundred and two species were included: 232 birds (n = 48633), 37 mammals (n = 3293), 20 reptiles (n = 2705) and 13 amphibians (n = 141). The most frequent causes of admission were: 39.8% confiscation of protected species (89.4% passerines), 31.8% orphaned young animals (35.3% swifts, 21.7% diurnal raptors and owls) and 17.4% trauma casualties (46.7% raptors and owls). The highest proportion of releases was found in the captivity confiscation category [87.4% passerines (median time of stay: 12 days)], followed by the orphaned category [78% owls (66 days), 76.5% diurnal birds of prey (43 days), 75.6% hedgehogs (49 days), 52.7% swifts (19 days) and 52% bats (55 days)]. For the trauma group, 46.8% of releases were hedgehogs (44 days) and 25.6% owls (103 days). As regards the cost-benefit index, the trauma casualties and infectious diseases had the worse values with 1.3 and 1.4 released animals/euro/day respectively, and were particularly low in raptors, waders, marine birds and chiroptera. On the contrary, captivity (4.6) and misplacement (4.1) had the best index, particulary in amphibian, reptiles and passerines. Conclusions/significance Cost-benefit studies including the release rate, the time of stay at the center and the costbenefit index should be implemented for improving management efficiency of the Wildlife Rehabilitation Centers

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Morbidity, outcomes and cost-benefit analysis of wildlife rehabilitation in Catalonia (Spain)

Background There are few studies of careful examination of wildlife casualties in Wildlife Rehabilitation Centers. These studies are essential for detecting menaces to wild species and providing objective criteria about cost-benefit of treatments in those centers. The release rate is considered the main outcome indicator, but other parameters such as length of stay at the center and a cost-benefit index expressed as number of released animals per euro and day, could be used as reliable estimators of the rehabilitation costs. Methodology A retrospective study based on 54772 admissions recorded from 1995-2013 in the database of the Wildlife Rehabilitation Center of Torreferrussa (Catalonia, NW Spain) assessed the morbidity, outcomes and cost-benefits of the rehabilitation practices. Results Three hundred and two species were included: 232 birds (n = 48633), 37 mammals (n = 3293), 20 reptiles (n = 2705) and 13 amphibians (n = 141). The most frequent causes of admission were: 39.8% confiscation of protected species (89.4% passerines), 31.8% orphaned young animals (35.3% swifts, 21.7% diurnal raptors and owls) and 17.4% trauma casualties (46.7% raptors and owls). The highest proportion of releases was found in the captivity confiscation category [87.4% passerines (median time of stay: 12 days)], followed by the orphaned category [78% owls (66 days), 76.5% diurnal birds of prey (43 days), 75.6% hedgehogs (49 days), 52.7% swifts (19 days) and 52% bats (55 days)]. For the trauma group, 46.8% of releases were hedgehogs (44 days) and 25.6% owls (103 days). As regards the cost-benefit index, the trauma casualties and infectious diseases had the worse values with 1.3 and 1.4 released animals/euro/day respectively, and were particularly low in raptors, waders, marine birds and chiroptera. On the contrary, captivity (4.6) and misplacement (4.1) had the best index, particu-lary in amphibian, reptiles and passerines. Conclusions/significance Cost-benefit studies including the release rate, the time of stay at the center and the cost-benefit index should be implemented for improving management efficiency of the Wildlife Rehabilitation Centers

Morbidity, outcomes and cost-benefit analysis of wildlife rehabilitation in Catalonia (Spain)

Background There are few studies of careful examination of wildlife casualties in Wildlife Rehabilitation Centers. These studies are essential for detecting menaces to wild species and providing objective criteria about cost-benefit of treatments in those centers. The release rate is considered the main outcome indicator, but other parameters such as length of stay at the center and a cost-benefit index expressed as number of released animals per euro and day, could be used as reliable estimators of the rehabilitation costs. Methodology A retrospective study based on 54772 admissions recorded from 1995-2013 in the database of the Wildlife Rehabilitation Center of Torreferrussa (Catalonia, NW Spain) assessed the morbidity, outcomes and cost-benefits of the rehabilitation practices. Results Three hundred and two species were included: 232 birds (n = 48633), 37 mammals (n = 3293), 20 reptiles (n = 2705) and 13 amphibians (n = 141). The most frequent causes of admission were: 39.8% confiscation of protected species (89.4% passerines), 31.8% orphaned young animals (35.3% swifts, 21.7% diurnal raptors and owls) and 17.4% trauma casualties (46.7% raptors and owls). The highest proportion of releases was found in the captivity confiscation category [87.4% passerines (median time of stay: 12 days)], followed by the orphaned category [78% owls (66 days), 76.5% diurnal birds of prey (43 days), 75.6% hedgehogs (49 days), 52.7% swifts (19 days) and 52% bats (55 days)]. For the trauma group, 46.8% of releases were hedgehogs (44 days) and 25.6% owls (103 days). As regards the cost-benefit index, the trauma casualties and infectious diseases had the worse values with 1.3 and 1.4 released animals/euro/day respectively, and were particularly low in raptors, waders, marine birds and chiroptera. On the contrary, captivity (4.6) and misplacement (4.1) had the best index, particulary in amphibian, reptiles and passerines. Conclusions/significance Cost-benefit studies including the release rate, the time of stay at the center and the costbenefit index should be implemented for improving management efficiency of the Wildlife Rehabilitation Centers

Outcome rates in the different zoological groups.

<p>Outcome rates in the different zoological groups.</p

Outcome rates according to the zoological group in the different prognostic categories.

<p>Category description: 1, apparently healthy; 2, mild weakness or thinning, uncomplicated fractures; 3, severe (including dehydration, open fractures, deep wounds) and 4, very severe (major injuries, emaciation, paralysis, blindness, respiratory distress).</p