Purpose To compare in a randomized, controlled trial topical 1.5% dexamethasone gamma-cyclodextrin nanoparticle eye drops (DexNP) with posterior subtenon injection of triamcinolone acetonide in ...diabetic macular oedema (DME). Methods In this prospective, randomized, controlled trial, 22 eyes of 22 consecutive patients with DME were randomized to (i) topical treatment with DexNP ×3/day (4 weeks), ×2/day (4 weeks) and ×1/day (4 weeks) or (ii) one posterior subtenon injection of 20 mg triamcinolone acetonide. Study visits were at baseline and 4, 8, 12 and 16 weeks. Results The logMAR (Snellen) visual acuity (mean ± SD) improved significantly with DexNP from 0.41 ± 0.3 (Snellen 0.39) to 0.32 ± 0.25 (0.48) and 0.30 ± 0.26 (0.50) at 4 and 8 weeks, respectively. One-third of the DexNP group improved more than 0.3 logMAR units. For triamcinolone, logMAR changed significantly from 0.42 ± 0.28 (0.38) at baseline to 0.32 ± 0.29 (0.48) at 4w and 0.33 ± 0.37 (0.47) at 12w. The central macular thickness (CMT) decreased significantly with DexNP from 483 ± 141 µm to 384 ± 142 µm at 4w and 342 ± 114 µm at 8w. For triamcinolone, CMT decreased significantly at all time-points: 494 ± 94 µm, 388 ± 120, 388 ± 145, 390 ± 136 and 411 ± 104 µm at 0, 4, 8, 12 and 16 weeks, respectively. There was a modest increase in intraocular pressure (IOP) at all time-points with DexNP while no increase was seen with triamcinolone. Serum cortisol was affected by both treatments. Conclusion Topical DexNP significantly improve visual acuity and decrease macular thickness in patients with DME. The effect is similar to that from subtenon triamcinolone. A modest increase in IOP was seen with the nanoparticle eye drops, but IOP normalized after the discontinuation of treatment.
IMPORTANCE: Whether protein risk scores derived from a single plasma sample could be useful for risk assessment for atherosclerotic cardiovascular disease (ASCVD), in conjunction with clinical risk ...factors and polygenic risk scores, is uncertain. OBJECTIVE: To develop protein risk scores for ASCVD risk prediction and compare them to clinical risk factors and polygenic risk scores in primary and secondary event populations. DESIGN, SETTING, AND PARTICIPANTS: The primary analysis was a retrospective study of primary events among 13 540 individuals in Iceland (aged 40-75 years) with proteomics data and no history of major ASCVD events at recruitment (study duration, August 23, 2000 until October 26, 2006; follow-up through 2018). We also analyzed a secondary event population from a randomized, double-blind lipid-lowering clinical trial (2013-2016), consisting of individuals with stable ASCVD receiving statin therapy and for whom proteomic data were available for 6791 individuals. EXPOSURES: Protein risk scores (based on 4963 plasma protein levels and developed in a training set in the primary event population); polygenic risk scores for coronary artery disease and stroke; and clinical risk factors that included age, sex, statin use, hypertension treatment, type 2 diabetes, body mass index, and smoking status at the time of plasma sampling. MAIN OUTCOMES AND MEASURES: Outcomes were composites of myocardial infarction, stroke, and coronary heart disease death or cardiovascular death. Performance was evaluated using Cox survival models and measures of discrimination and reclassification that accounted for the competing risk of non-ASCVD death. RESULTS: In the primary event population test set (4018 individuals 59.0% women; 465 events; median follow-up, 15.8 years), the protein risk score had a hazard ratio (HR) of 1.93 per SD (95% CI, 1.75 to 2.13). Addition of protein risk score and polygenic risk scores significantly increased the C index when added to a clinical risk factor model (C index change, 0.022 95% CI, 0.007 to 0.038). Addition of the protein risk score alone to a clinical risk factor model also led to a significantly increased C index (difference, 0.014 95% CI, 0.002 to 0.028). Among White individuals in the secondary event population (6307 participants; 432 events; median follow-up, 2.2 years), the protein risk score had an HR of 1.62 per SD (95% CI, 1.48 to 1.79) and significantly increased C index when added to a clinical risk factor model (C index change, 0.026 95% CI, 0.011 to 0.042). The protein risk score was significantly associated with major adverse cardiovascular events among individuals of African and Asian ancestries in the secondary event population. CONCLUSIONS AND RELEVANCE: A protein risk score was significantly associated with ASCVD events in primary and secondary event populations. When added to clinical risk factors, the protein risk score and polygenic risk score both provided statistically significant but modest improvement in discrimination.
Objective: To assess the proportion of PBC patients with a biochemical response to ursodeoxycholic acid (UDCA) in a population-based cohort and the association of biochemical response with outcomes.
...Methods: All patients diagnosed with PBC in Iceland from 1991-2015 were identified. Patients taking UDCA for an adequate period of time were analyzed for treatment response according to the Barcelona, Paris I, Paris II and Toronto criteria and outcomes.
Results: Overall 182 females and 40 males were diagnosed with PBC and 135 patients were treated with UDCA. Overall 99 (73%) patients had adequate data on UDCA treatment and results of liver tests to assess biochemical response according to the Barcelona criteria, 95 (70%) according to the Toronto criterion and 85 (63%) according to the Paris I and II criteria. In all 74% (n = 63), 67% (n = 64), 54% (n = 53) and 46% (n = 39) responded to treatment according to the Paris I, Toronto, Barcelona and Paris II criteria. Among nonresponders according to the Paris I, Toronto, Paris II and Barcelona criteria, 50%, 39%, 33% and 30% developed cirrhosis versus 10%, 6%, 5% and 11% of responders, HR 5.36 (p = .002), 6.61 (p = .002), 10.94 (p = .003) and 2.21(p = .11), respectively. Age-adjusted mortality was significantly lower among responders according to the Paris I and Paris II criteria, HR 0.33 (p = .02) and 0.31 (p = .02), respectively.
Conclusion: Development of cirrhosis and higher mortality was significantly associated with a lack of biochemical response to UDCA. Frequent development of cirrhosis and increased mortality in nonresponders underlines the need for a more effective therapy than UDCA for this sizeable subgroup of patients.
Few studies have compared the prognosis and liver-related mortality in patients with NAFLD (nonalcoholic fatty liver disease) and AFLD (alcoholic fatty liver disease). We aimed to investigate the ...etiology and liver-related mortality of patients with liver biopsy verified fatty liver disease in a population based setting.
In this retrospective study, all patients who underwent a liver biopsy 1984-2009 at the National University Hospital of Iceland were identified through a computerized pathological database with the code for fatty liver. Only patients with NAFLD and AFLD were included and medical records reviewed. The patients were linked to the Hospital Discharge Register, the Causes of Death Registry and Centre for Addiction Medicine.
A total of 151 had NAFLD and 94 AFLD with median survival of 24 years and 20 years, respectively (p = NS). A total of 10/151 (7%) patients developed cirrhosis in the NAFLD group and 19/94 (20%) in AFLD group (p = 0.03). The most common cause of death in the NAFLD group was cardiovascular disease (48%). Liver disease was the most common cause of death in the AFLD group (36%), whereas liver-related death occurred in 7% of the NAFLD group. The mean liver-related death rate among the general population during the study period was 0.1% of all deaths. There was a significantly worse survival for patients in the AFLD group compared to the NAFLD group after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.16, p = 0.009). The survival for patients with moderate to severe fibrosis was significantly worse than for patients with mild fibrosis after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.09, p = 0.01).
Patients with fatty liver disease showed a markedly higher risk of developing liver-related death compared to the general population. The AFLD group had higher liver-related mortality and had a worse survival than the NAFLD group. Patients with more severe fibrosis at baseline showed a worse survival than patients with none or mild fibrosis at baseline.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Although epistaxis is one of the most common side effects of oral anticoagulation, it is unclear whether epistaxis rates vary between different oral anticoagulants (OAC).
Objective
To ...compare rates of clinically relevant epistaxis between OAC.
Methods
Epistaxis event rates were compared between new users of apixaban, dabigatran, rivaroxaban, and warfarin in a nationwide population‐based cohort study over a 5‐year study period, 2014–2019. Data was collected from the Icelandic Medicine Registry and the five major hospitals in Iceland. Inverse probability weighting (IPW) was used to yield balanced baseline characteristics, and epistaxis rates were compared using Kaplan–Meier survival estimates and Cox regression.
Results
During the study period, 2098 patients received apixaban, 474 dabigatran, 3106 rivaroxaban, and 1403 warfarin. In total, 93 patients presented with clinically relevant epistaxis, including 11 (12%) major epistaxis events and one fatal epistaxis episode. Furthermore, seven patients (9%) with non‐major epistaxis later presented with major bleeding during the follow‐up period. Warfarin use was associated with higher rates of epistaxis compared to apixaban (2.2 events per 100‐person years (events/100‐py) vs. 0.6 events/100‐py, hazard ratio HR 4.22, 95% confidence interval CI 2.08–8.59, p < 0.001), rivaroxaban (2.2 events/100‐py vs. 1.0 events/100‐py, HR 2.26, 95% CI 1.28–4.01, p = 0.005), and dabigatran (2.2 events/100‐py vs. no events, HR n/a, p < 0.001).
Conclusion
Warfarin treatment was associated with higher rates of clinically relevant epistaxis compared to direct oral anticoagulants.
Lower gastrointestinal bleeding (LGIB) risk scores have mainly focused on identifying high-risk patients. A risk score aimed at predicting which patients will not require hospital-based intervention ...may reduce unnecessary hospital admissions. The aim of the current study was to develop such a risk score.
A retrospective, population-based study that included patients presenting to the emergency room (ER) with LGIB from 2010 to 2013. Hospital-based intervention was defined as blood transfusion, endoscopic hemostasis, arterial embolization or surgery. The study cohort was split into train (70%) and test (30%) data. Train data were used to produce a multiple logistic regression model and a risk score that was validated on the test data.
Overall, 581 patients presented 625 times to the ER, mean age 61 (±22), males 49%. Of train data patients, 72% did not require hospital-based intervention. Independent predictors of low-risk patients (did not require hospital-based intervention) were systolic pressure ≥100mmHg (Odds ratio OR 4.9), hemoglobin >12g/dL (OR 103), hemoglobin 10.5-12.0g/dL (OR 19), no antiplatelets (OR 3.7), no anticoagulants (OR 2.2), pulse ≤100 (OR 2.9), and visible bleeding in the ER (OR 3.8). When validating the score on the test data, only 2% were wrongly predicted to be low-risk, the negative predictive value was 96% and the area under curve was 0.83.
A new risk score has been developed for LGIB that may help identify low-risk patients in the ER that can be managed in an outpatient setting, thereby lowering unnecessary hospital admissions.
Abstract
Background
The TNM system is used to assess prognosis after colorectal cancer (CRC) diagnosis. Other prognostic factors reported include histopathological assessments of the tumour, tumour ...mutations and proteins in the blood. As some of these factors are strongly correlated, it is important to evaluate the independent effects they may have on survival.
Methods
Tumour samples from 2162 CRC patients were visually assessed for amount of tumour stroma, severity of lymphocytic infiltrate at the tumour margins and the presence of lymphoid follicles. Somatic mutations in the tumour were assessed for 2134 individuals. Pre-surgical levels of 4963 plasma proteins were measured in 128 individuals. The associations between these features and prognosis were inspected by a Cox Proportional Hazards Model (CPH).
Results
Levels of stroma, lymphocytic infiltration and presence of lymphoid follicles all associate with prognosis, along with high tumour mutation burden, high microsatellite instability and
TP53
and
BRAF
mutations. The somatic mutations are correlated with the histopathology and none of the somatic mutations associate with survival in a multivariate analysis. Amount of stroma and lymphocytic infiltration associate with local invasion of tumours. Elevated levels of two plasma proteins, CA-125 and PPP1R1A, associate with a worse prognosis.
Conclusions
Tumour stroma and lymphocytic infiltration variables are strongly associated with prognosis of CRC and capture the prognostic effects of tumour mutation status. CA-125 and PPP1R1A may be useful prognostic biomarkers in CRC.
Objectives: Lower gastrointestinal bleeding (LGIB) risk scores have mainly focused on identifying high-risk patients. A risk score aimed at predicting which patients will not require hospital-based ...intervention may reduce unnecessary hospital admissions. The aim of the current study was to develop such a risk score.
Material and Methods: A retrospective, population-based study that included patients presenting to the emergency room (ER) with LGIB from 2010 to 2013. Hospital-based intervention was defined as blood transfusion, endoscopic hemostasis, arterial embolization or surgery. The study cohort was split into train (70%) and test (30%) data. Train data were used to produce a multiple logistic regression model and a risk score that was validated on the test data.
Results: Overall, 581 patients presented 625 times to the ER, mean age 61 (±22), males 49%. Of train data patients, 72% did not require hospital-based intervention. Independent predictors of low-risk patients (did not require hospital-based intervention) were systolic pressure ≥100mmHg (Odds ratio OR 4.9), hemoglobin >12g/dL (OR 103), hemoglobin 10.5-12.0g/dL (OR 19), no antiplatelets (OR 3.7), no anticoagulants (OR 2.2), pulse ≤100 (OR 2.9), and visible bleeding in the ER (OR 3.8). When validating the score on the test data, only 2% were wrongly predicted to be low-risk, the negative predictive value was 96% and the area under curve was 0.83.
Conclusions: A new risk score has been developed for LGIB that may help identify low-risk patients in the ER that can be managed in an outpatient setting, thereby lowering unnecessary hospital admissions.
The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional ...high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in
conferred substantial risks of BCC (OR, 8.0;
= 1.9 × 10
), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the
locus were associated with BCC, suggesting
as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that
loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7,
= 1.6 × 10
) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis. SIGNIFICANCE: This study identifies the tumor-suppressor gene
as a high-impact BCC predisposition gene and indicates that inactivation of
by germline sequence variants may also lead to increased risk of cervical cancer.
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