Risk assessment of Cryptosporidium intake in drinking water treatment plant by a combination of predictive models and event-tree and fault-tree techniques.

Risk-informed decision making permits a more effective water safety management. In this framework, this article introduces the rationale and proposes a new approach to carry out a quantitative risk assessment along the water chain, from river source to tap water, by integrating predictive modelling combined with event-tree and fault-tree techniques. The model developed by this approach could not only account for normal but also for abnormal process conditions in the water treatment plant, as well as assess the real impact of the applied safety controls, such as turbidity control. A sensitivity study was conducted to determine the effect of considering a typical drinking water treatment plant (DWTP), i.e. coagulation, sedimentation and filtration with two turbidity controls (on intake and after filtration) on the risk of infection due to exposure to Cryptosporidium in tap water. The results showed that, with the current effectiveness of turbidity reduction in the DWTP, the first control did not minimise the annual risk of Cryptosporidium infection (3.6E-04) and only limiting turbidity after filtration to below 0.01NTU provided a clear reduction in risk (7.7E-05) at the cost of rejecting 60 % of the water after the control. The lowest risk was found when turbidity reduction was set at 4 logs (8.48E-06), although this means that the effectiveness of turbidity reduction should be greatly improved. It was therefore concluded that supplementing the current treatment with alternative barriers such as UV or ozone disinfection and/or implementing direct control of Cryptosporidium concentration should be considered.

Evolution of the «frontal flap advancement¼ in congenital ptosis.

The treatment of congenital ptosis with poor levator activity is often based upon the union of the superior eyelid to the frontalis muscle by using different materials as potential grafts. Nevertheless, theses grafts may lead some complications. In order to avoid them, a new technic has been described using an advancement flap of the frontalis muscle, that is tided to the upper tarsus, eliminating the need of a graft. Although, it is not yet a standard procedure, reason why many variants has been recently described with the objective of improve the aesthetical and functional results. The goal of this systematic review is to conscientiously evaluate these variants with the propose of determine which one gives the best results in terms of safety, functional and aesthetical outcomes. From the review of the published procedures, we conclude that the best technique in terms of functional and aesthetical results is: sub-orbicularis dissection via lid crease incision reaching the orbital margin, followed by blunt dissection of the frontalis muscle and creation of a "U" shaped flap (that might be associated to a levator advancement in severe cases), finally, the frontalis flap is stitched to the upper end of the tarsus taking care to maintain a symmetrical contour when compared to the contralateral eye. The final eyelid margin height should be 1.5 mm above the sclero-corneal limbus.

Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels.

AIM: An increased risk of venous thromboembolism (VTE) in patients with COVID-19 pneumonia admitted to intensive care unit (ICU) has been reported. Whether COVID-19 increases the risk of VTE in non-ICU wards remains unknown. We aimed to evaluate the burden of asymptomatic deep vein thrombosis (DVT) in COVID-19 patients with elevated D-dimer levels. METHOD: In this prospective study consecutive patients hospitalized in non-intensive care units with diagnosis of COVID-19 pneumonia and D-dimer > 1000 ng/ml were screened for asymptomatic DVT with complete compression doppler ultrasound (CCUS). The study was approved by the Institutional Ethics Committee. RESULTS: The study comprised 156 patients (65.4% male). All but three patients received standard doses of thromboprophylaxis. Median days of hospitalization until CCUS was 9 (IQR 5-17). CCUS was positive for DVT in 23 patients (14.7%), of whom only one was proximal DVT. Seven patients (4.5%) had bilateral distal DVT. Patients with DVT had higher median D-dimer levels: 4527 (IQR 1925-9144) ng/ml vs 2050 (IQR 1428-3235) ng/ml; p < 0.001. D-dimer levels > 1570 ng/ml were associated with asymptomatic DVT (OR 9.1; CI 95% 1.1-70.1). D-dimer showed an acceptable discriminative capacity (area under the ROC curve 0.72, 95% CI 0.61-0.84). CONCLUSION: In patients admitted with COVID-19 pneumonia and elevated D-dimer levels, the incidence of asymptomatic DVT is similar to that described in other series. Higher cut-off levels for D-dimer might be necessary for the diagnosis of DVT in COVID-19 patients.

Effect of an oral supplementation with a formula containing R-lipoic acid in glaucoma patients. / Efecto de la suplementación oral con una fórmula que contiene ácido R-lipoico en pacientes con glaucoma.

OBJECTIVE: To analyse the safety and effectiveness of the oral administration of a commercialised supplement containing R-alpha lipoic acid, taurine, vitamins C and E, lutein, zeaxanthin, zinc, copper and docosahexaenoic acid, in patients with primary open angle glaucoma (POAG), and in control subjects. MATERIAL AND METHODS: A prospective study of cases and controls was carried out, including 30 participants of both genders that were divided into: POAG Group (n=15) and a control group (CG; n=15), assigned to the oral intake of NuaDHA preparations Vision® (1 pill/day)+NuaDHA 1000 (2 pills/day) for 6 months. Participants were interviewed, ophthalmologically examined, and peripheral blood was taken for routine analysis and the determination of the pro-oxidant (malondialdehyde) and total antioxidant status. Statistical analysis was performed using the SPSS 22.0 program. RESULTS: After 6 months of supplementation, there was a significant increase in the plasma total antioxidant status (1.073±0.090mM vs 1.276±0.107mM, P=.028), along with a parallel decrease in malondialdehyde (7.066±1.070µM vs 2.771±0.462µM, P=.005) in the POAG group. The malondialdehyde also decreased in the control group (6.17±1.336 vs. 2.51±0.391, P=.028). The Schirmer test improved (20-30%) and the subjective dry eye signs/symptoms noticeably decreased in the POAG group versus the CG. CONCLUSIONS: Formulations containing antioxidant vitamins, R-alpha lipoic acid and docosahexaenoic acid, administered for 6 consecutive months, counteracted the oxidative stress by further stabilising the morphological/functional parameters of both the ocular surface and the glaucoma, without presenting with adverse effects or intolerances.

Monitoring anti-Xa levels in patients with cancer-associated venous thromboembolism treated with bemiparin.

OBJECTIVE: To analyze the relationship between therapeutic (weight-adjusted) dose of bemiparin and anti-Xa activity in patients with venous thromboembolism (VTE) and cancer in comparison with a cohort of patients with VTE without cancer, and its relationship with outcomes. MATERIALS AND METHODS: This is a prospective cohort study that comprised a cohort of patients with cancer-associated VTE and a cohort of non-cancer patients with VTE, all of them treated with bemiparin. The ethics committee approved the study and informed consent was obtained from the patients. RESULTS: One hundred patients were included (52 with cancer and 48 without cancer), with a median follow-up of 9.8 months. Mean anti-Xa activity was 0.89 (± 0.33) UI/mL in oncological patients and 0.83 (± 0.30) UI/mL in non-cancer patients (mean difference - 0.05 95% CI - 0.18; 0.06). A multiple linear regression model showed that anti-Xa peak was associated with the dose/kg independently of possible confounding variables (presence of cancer, age, sex and eGFR-estimated Glomerular Filtration Rate), in a way that for every 1 UI of dose/kg increase, the anti-Xa peak activity increased 0.006 UI/mL (95% CI 0.003; 0.009) (p < 0.001). The predictive capacity of anti-Xa peak in the oncology cohort showed an area under the ROC curve of 0.46 (95% CI 0.24-0.68), 0.70 (95% CI 0.49-0.91) and 0.74 (95% CI 0.44-0.94) for death, first bleeding and recurrence of VTE, respectively, and none was statistically significant. CONCLUSION: In patients with venous thromboembolism treated with bemiparin, anti-Xa levels were not influenced by the presence of cancer.

Next generation sequencing in bleeding disorders: two novel variants in the F5 gene (Valencia-1 and Valencia-2) associated with mild factor V deficiency.

Inherited bleeding coagulation disorders (IBCDs) have a powerful diagnostic tool in next generation sequencing (NGS) that not only offers confirmation of diagnosis but also aids in genetic counselling, prenatal diagnosis and helps to predict the clinical course and follow-up of a disease. In our group, targeted-NGS using a Custom SureSelect QXT Panel (Agilent Technologies, Inc., Santa Clara, CA, USA) was designed to screen for causal variants in 40 genes related with the coagulation cascade. In this work, we used NGS for screening all the coding and intronic boundary regions of F5 gene in two patients affected by factor V (FV) deficiency (parahemophilia). Two new mutations were found: c.4745A>G (p.Tyr1582Cys, NM_000130.4) and c.1999_2002dupAATT (p.Ser668ter; NM_000130.4), both located in exon 13 of the F5 gene. We designated them Valencia-1 and Valencia-2 respectively. Valencia-1 could provoke loss of the fifth cupredoxin domain of the FV, and would be responsible for its defective activity. Valencia-2 prematurely stops the translation of mRNA, resulting in a truncated FV protein which lacks completely the B domain and the light chain. NGS has permitted to describe an increasing number of FV deficiency-causing mutations and a better understanding of FV's structure and function. The description of deficiency-causing mutations will continue to increase our knowledge of the functional residues of FV, as well as those which are involved in the correct folding of the protein. In this sense, NGS is a useful tool for studying IBCDs, as permits studying the whole coagulation cascade at once and gives a global view of the patient's genetic background.

The Mexican consensus on nonalcoholic fatty liver disease. / Consenso mexicano de la enfermedad por hígado graso no alcohólico.

Nonalcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Mexico is one of the countries whose population has several risk factors for the disease and its prevalence could surpass 50%. If immediate action is not taken to counteract what is now considered a national health problem, the medium-term panorama will be very bleak. This serious situation prompted the Asociación Mexicana de Gastroenterología and the Asociación Mexicana de Hepatología to produce the Mexican Consensus on Fatty Liver Disease. It is an up-to-date and detailed review of the epidemiology, pathophysiology, clinical forms, diagnosis, and treatment of the disease, whose aim is to provide the Mexican physician with a useful tool for the prevention and management of nonalcoholic fatty liver disease.

Massive generalized crystal-storing histiocytosis associated with extracellular crystalline nephropathy: clinical, immunohistochemical, and ultrastructural studies of a unique disorder and review of the literature.

Crystal-storing histiocytosis (CSH) is a rare disorder characterized by the accumulation of nonneoplastic histiocytes containing intracytoplasmic crystallized immunoglobulins. In most cases, there is an associated underlying lymphoplasmacytic neoplasm expressing Ig kappa light chain. About 131 cases of CSH have been identified. There is a localized and a generalized form of CSH and it can involve several sites including bone marrow, lungs, lymph nodes, liver, spleen, gastrointestinal tract, and kidney. Generalized CSH is less frequent and involves multiple organs and tends to have a worst prognosis than localized CSH. Around 20 cases of renal involvement in CSH have been reported so far. Paraprotein-induced crystalline nephropathy can be divided into two categories based on whether the crystals in the kidney are intracellular (including light chain proximal tubulopathy with crystals and CSH) or extracellular (including the crystalline variant of myeloma cast nephropathy and crystalglobulin-induced nephropathy). The former tends to present with slowly worsening kidney dysfunction and generally has a good prognosis, whereas the latter usually presents with rapidly progressive renal failure and is associated with poor renal outcome. We present a case of generalized CSH associated with extracellular crystalline nephropathy with a fulminant and fatal clinical course. Kappa light-chain crystals were found exclusively extracellularly within the tubular lumen, not within the tubular epithelial cells nor the histiocytes, and the massive presence of those precipitates led to the acute renal failure. Consequently, we review the renal involvement in CSH in the literature and discuss the unique mechanism of renal injury in this case.

Frequency and clinical impact of CDKN2A/ARF/CDKN2B gene deletions as assessed by in-depth genetic analyses in adult T cell acute lymphoblastic leukemia.

Recurrent deletions of the CDKN2A/ARF/CDKN2B genes encoded at chromosome 9p21 have been described in both pediatric and adult acute lymphoblastic leukemia (ALL), but their prognostic value remains controversial, with limited data on adult T-ALL. Here, we investigated the presence of homozygous and heterozygous deletions of the CDKN2A/ARF and CDKN2B genes in 64 adult T-ALL patients enrolled in two consecutive trials from the Spanish PETHEMA group. Alterations in CDKN2A/ARF/CDKN2B were detected in 35/64 patients (55%). Most of them consisted of 9p21 losses involving homozygous deletions of the CDKNA/ARF gene (26/64), as confirmed by single nucleotide polymorphism (SNP) arrays and interphase fluorescence in situ hybridization (iFISH). Deletions involving the CDKN2A/ARF/CDKN2B locus correlated with a higher frequency of cortical T cell phenotype and a better clearance of minimal residual disease (MRD) after induction therapy. Moreover, the combination of an altered copy-number-value (CNV) involving the CDKN2A/ARF/CDKN2B gene locus and undetectable MRD (≤ 0.01%) values allowed the identification of a subset of T-ALL with better overall survival in the absence of hematopoietic stem cell transplantation.

Identification of new candidate genes for retinopathy in type 2 diabetics. Valencia Study on Diabetic Retinopathy (VSDR). Report number 3. / Identificación de nuevos genes candidatos para la retinopatía en diabéticos tipo 2. Estudio Valencia sobre Retinopatía Diabética (EVRD). Informe n.° 3.

OBJECTIVE: To identify genes involved in the pathogenic mechanisms of non-proliferative diabetic retinopathy (NPDR), among which include oxidative stress, extracellular matrix changes, and/or apoptosis, in order to evaluate the risk of developing this retinal disease in a type2 diabetic (DM2) population. MATERIAL AND METHODS: A case-control study was carried out on 81 participants from the Valencia Study on Diabetic Retinopathy (VSDR) of both genders, with ages 25-85years. They were classified into: (i)DM2 group (n=49), with DR (+DR; n=14) and without DR (-DR; n=35), and (ii)control group (GC; n=32). The protocols included a personal interview, standardised ophthalmological examination, and blood collection (to analyse the DNA for determining the gene expression (TP53, MMP9, and SLC23A2) in the study groups. Statistical analyses were performed using the SPSS v22.0 program. RESULTS: The TP53 and MMP9 genes showed a higher expression in the DM2 group compared to the GC, although the difference was only significant for the MMP9 gene (TP53: 10.40±1.20 vs. 8.23±1.36, P=.084; MMP9: 1.45±0.16 vs. 0.95±0.16, P=.036), and the SLC23A2 gene showed a significant lower expression in the DM2 vs CG (5.58±0.64 vs. 11.66±1.90, P=.026). When sub-dividing the DM2 group according to the presence of retinopathy, the expression of the TP53, MMP9 and SLC23A2 genes showed significant differences between the DM2-RD, DM2+RD and GC groups (TP53: 9.95±1.47 vs. 11.52±2.05 vs. 8.23±1.36, P=.038; MMP9: 1.47±0.20 vs. 1.41±0.27 vs. 0.95±0.16, P=.021; SLC23A2: 5.61±0.77 vs. 5.51±1.21 vs. 11.66±1.90, P=.018). CONCLUSIONS: Genes involved in extracellular matrix integrity (MMP9) and/or apoptosis (TP53), could be considered potential markers of susceptibility to the development/progression of NPDR. Interestingly, the SLC232A2 gene (ascorbic acid transporter) can be considered a protector of the risk of the development/progression of the retinopathy.

Impact of NADPH oxidase functional polymorphisms in acute myeloid leukemia induction chemotherapy.

Efficacy and toxicity of anthracycline treatment in acute myeloid leukemia (AML) is mediated by reactive oxygen species (ROS). NADPH oxidase is the major endogenous source of ROS and a key mediator of oxidative cardiac damage. The impact of NADPH oxidase polymorphisms (CYBA:rs4673, NCF4:rs1883112, RAC2:rs13058338) was evaluated in 225 adult de novo AML patients. Variant alleles of NCF4 and RAC2 were related to higher complete remission (P=0.035, P=0.016), and CYBA homozygous variant showed lower overall survival with recessive model (P=0.045). Anthracycline-induced cardiotoxicity was associated to NCF4 homozygous variant (P=0.012) and CYBA heterozygous genotype (P=0.027). Novel associations were found between variant allele of CYBA and lower lung and gastrointestinal toxicities, and a protective effect in nephrotoxicity and RAC2 homozygous variant. Moreover, RAC2 homozygous variant was related to delayed thrombocytopenia recovery. This study supports the interest of NADPH oxidase polymorphisms regarding efficacy and toxicity of AML induction therapy, in a coherent integrated manner.

Energy transduction and signal averaging of fluctuating electric fields by a single protein ion channel.

We demonstrate the electrical rectification and signal averaging of fluctuating signals using a biological nanostructure in aqueous solution: a single protein ion channel inserted in the lipid bilayer characteristic of cell membranes. The conversion of oscillating, zero time-average potentials into directional currents permits charging of a load capacitor to significant steady-state voltages within a few minutes in the case of the outer membrane porin F (OmpF) protein, a bacterial channel of Escherichia coli. The experiments and simulations show signal averaging effects at a more fundamental level than the traditional cell and tissue scales, which are characterized by ensembles of many ion channels operating simultaneously. The results also suggest signal transduction schemes with bio-electronic interfaces and ionic circuits where soft matter nanodiodes can be coupled to conventional electronic elements.

Eosinophilic Esophagitis: An Evidence-Based Approach to Therapy.

In recent years, several randomized controlled trials and meta-analyses have evaluated the efficacy of the various therapeutic options available for treating patients with eosinophilic esophagitis, including dietary modifications, proton pump inhibitors, topical corticosteroids, and endoscopic esophageal dilation. Proton pump inhibitors are currently considered the first-line treatment for eosinophilic esophagitis, achieving histological remission and improvement of symptoms in 50.5% and 60.8% of patients, respectively. The efficacy of topical corticosteroids in eosinophilic esophagitis has been assessed in several trials. Meta-analyses summarizing results indicate that budesonide and fluticasone propionate are significantly superior to placebo, both in decreasing eosinophil densities in the esophageal mucosa and in relieving symptoms. However, owing to differences in drug delivery, viscous budesonide seems to be the best pharmacological therapy for eosinophilic esophagitis. Results for dietary modifications have been mixed depending on the type of diet prescribed. Thus, while exclusive amino acid-based elemental diets are the most effective in inducing histological remission of eosinophilic esophagitis (90.8%), their severe drawbacks limit their implementation in clinical practice. Allergy testing-based food elimination provides a suboptimal remission rate of 45.5%, although this is lower in adults than in children (32.2% vs 47.9%, respectively). In addition, the various available studies are highly heterogeneous. Empirical 6-food elimination diets were shown to be the best diet-based therapy, with a homogeneous remission rate of 72%. Simpler, more convenient empirical schemes have also been evaluated. The aim of this review is to provide an evidence-based overview on the efficacy of the options available for treatment of eosinophilic esophagitis along with a practical management algorithm.