Dynamic and Seasonal Distribution of Enteric Viruses in Surface and Well Water in Riyadh (Saudi Arabia).

Enteric viruses are the major cause of gastroenteritis and enteric hepatitis worldwide, but in some areas like Saudi Arabia, little is known about their presence in water sources. The available information from clinical samples is not enough to figure out their actual prevalence. The aim of this study was to gather information for the first time in Saudi Arabia on the presence of the Norovirus (NoV) genogroup GI and GII, hepatitis A virus (HAV), and hepatitis E virus (HEV) in water. For this purpose, thirteen monthly samples were collected from Lake Wadi Hanifa and surrounding wells from December 2014 to November 2015. Viruses were detected and quantified using real-time RT-qPCR. Despite HEV findings being anecdotic, our results highlight interesting behaviors of the other viruses. There was a higher prevalence of noroviruses in Wadi Hanifa samples than in well water samples (46.43% vs. 12.5% of NoV GI; 66.67% vs. 8.33% of NoV GII). On the contrary, similar levels of HAV positivity were observed (40.48% in surface water vs. 43.06% in well water). Also, a strong influence of flooding events on HAV and NoV GI occurrence was observed in both surface and well water samples, with NoV GII apparently not affected.

Reference ranges of thyroid hormones during the first trimester in Catalan women using the Atellica® IM Solution Immunoassay Analyzer.

BACKGROUND: Gestational hypothyroidism has been shown to be associated with adverse pregnancy outcomes as well as adverse outcomes for the child. Thyroid hormones concentrations change in gestation, especially within the first trimester, so the results of thyroid function test often are outside non-pregnant reference ranges. The objective of this study was to establish the first trimester reference ranges for thyroid stimulating hormone (TSH) and free thyroxine (FT4) for pregnant women in Barcelona (Spain). METHODS: It was a prospective study in which 673 women were recruited during their first trimester of gestation (8-13 weeks). Serum TSH, FT4 and antithyroid peroxidase antibodies (TPOAb) were measured with Atellica® IM 1600 (Siemens Healthineers). After excluding 418 women, the reference ranges for TSH and FT4 were calculated by the 2.5th and 97.5th percentiles. Potential variables examined in this study were age, body mass index (BMI), ethnicity, iodine supplementation and smoking habit. RESULTS: The reference ranges established on the Atellica® IM 1600 for the first trimester pregnancy in our population were 0.111 to 4.291 mIU/L for TSH and 11.45 to 17.76 pmol/L for FT4. No significant differences were found in thyroid hormones concentrations regarding maternal age (≤30 years vs >30 years) (p = .117), iodine supplementation (p = .683) and smoking habit (p = .363). The prevalence of TPOAb was estimated at 10.0%. CONCLUSIONS: We found that in our local population, the optimal TSH upper reference limit in the first trimester of gestation was 4.3 mIU/L, similar to that proposed by de ATA-2017 guideline (4.0 mIU/L).

Drassanes Exprés: a public and confidential testing service for asymptomatic STIs with same-day result notification.

BACKGROUND: STIs are a major public health concern. Screening programmes for asymptomatic users are key components of STI control. Traditional limitations of screening programmes include low population coverage and delays in treatments, thus reducing the expected impact on STI control. In our centre, the normal time from test to results was 4 days, and 7 days until treatment was established.To reduce time to treatment and to increase population coverage, we developed 'Drassanes Exprés', a testing service for asymptomatic STIs. The objectives of this study were to provide a guide for the implementation of a service with these characteristics and to evaluate the results of this intervention. METHODS: The Drassanes Exprés programme was launched in Spain on 07 November 2016 as a public, confidential and free-of-charge testing service for asymptomatic STIs, with same-day result notification. For this walk-in service, confidentiality was obtained by registering all information into the Laboratory Internal Software instead of the Electronic Patient Records. Samples were processed in a point-of-care laboratory and result notification was provided via mail or short message service.Information about workflow, screening protocols and result interpretation is detailed. Additionally, demographic characteristics, STI prevalence, and time from patients' sample collection to notification and treatment are analysed. RESULTS: Between 07 November 2016 and 07 November 2019, 13 993 users attended the Drassanes Exprés screening programme. Of these, 0.5% were transgender people, 29.3% women, 45.2% men who have sex with men and 25.1% men who have sex with women. The median age was 31 years (range: 26-39 years). Overall, 14.6% of users tested positive for at least one STI. The most prevalent infection was Chlamydia trachomatis (8.3%), followed by Neisseria gonorrhoeae (5.7%), syphilis (1.8%), HIV (0.4%) and hepatitis C virus (0.2%). The median time from test to results was 2.4 hours (range: 2-3.1 hours). Of 2049 users diagnosed with an STI, treatment was achieved in 97.0% of cases; the average time to treatment was 2.0 days. CONCLUSIONS: Drassanes Exprés is the first public programme for rapid, asymptomatic, STI screening and treatment in Spain. Assessing high-risk practices and providing confidentiality, easy access and rapid results/treatments are key elements in the development of STI screening programmes.

Evolving patterns of care and outcomes in relapsed/refractory FLT3 mutated acute myeloid leukemia adult patients.

We have analyzed treatment patterns and outcomes of relapsed/refractory(R/R) FLT3mut AML adult patients registered in our institutional data base between 1998 and 2018. Overall, 147 patients were evaluable: 34 from 1998 to 2009, 113 from 2010 to 2018. Salvage treatments were intensive chemotherapy (n = 25, 74%), and supportive care (n = 9, 26%) in the 1998-2009 period, and intensive chemotherapy (n = 63, 56%), hypomethylating agent (n = 7, 6%), low-dose cytarabine-based (n = 8, 7%), clinical trial (n = 16, 14%) and supportive care (n = 19, 17%) in the 2010-2018 period. Complete remission (CR) or with incomplete recovery (CRi) rate was 44%, 49% among patients treated intensively (vs 30% with non-intensive p = 0.005). Median overall survival since first R/R was 5.8 months, and 16.3 months in subjects receiving an allo-HSCT in CR/CRi after first salvage (vs 3.8 in the remaining patients p < 0.0001). Clinical outcomes of R/R FLT3mut AML remain unsatisfactory. Inclusion in clinical trials and expanding options could lead to improved outcomes.

Extracorporeal photopheresis vs standard therapies for steroid-refractory chronic graft-vs-host disease: Pharmacoeconomic assessment of hospital resource use in Spain.

BACKGROUND: This study assessed pharmacoeconomic costs associated with extracorporeal photopheresis (ECP) compared with other available second-line therapies for chronic graft-vs-host disease (cGvHD) in a tertiary Spanish institution. METHODS: Patients (≥18 years) diagnosed with steroid-refractory cGvHD were eligible. Data were collected retrospectively from index date until 1 year or relapse. Patients were distributed in two cohorts (ECP vs non-ECP), matched by age (≤ or > 40), hematopoietic stem cell transplant (HLA-identical sibling donor or other) and number of previous immunosuppressive lines (1, 2, or ≥ 3). Costs were assigned using the 2016 diagnosis-related group (DRG) system: DRG 579 (€22 383) overnight stay due to major complication (ie, sepsis, pneumonia, parenteral nutrition, or respiratory failure), and DRG 875 (€5154) if no major complication. The primary endpoint was healthcare resource utilization per patient. RESULTS: Forty patients (n = 20 per cohort) were included. Median age was 49, and 37.5% were female. Mean total cost per patient was €25 319 (95% CI: €17 049-€33 590) across the two cohorts, with a slightly lower mean cost per ECP-treated patient (€23 120) compared with the non-ECP cohort (€27 519; P = .597). Twenty-seven inpatient hospitalizations occurred among ECP-treated patients, vs 33 in the non-ECP cohort. Day hospital and external consultations were more frequent in the ECP cohort. However, fewer inpatient admissions included DRG 579 compared with the non-ECP cohort (44% vs 58%). Inpatient length of stay was slightly shorter in the ECP cohort (30 vs 49 days; P = .298). CONCLUSIONS: ECP treatment may yield economic savings in Spain through resource savings and moving costs toward outpatient care.

Healthcare resource utilization in adult patients with relapsed/refractory FLT3 mutated acute myeloid leukemia: A retrospective chart review from Spain.

BACKGROUND: Information regarding impact on healthcare systems of relapsed or refractory (R/R) FLT3 mutated (FLT3mut) acute myeloid leukemia (AML) is scarce. OBJECTIVE: To assess the time and reimbursement associated with hospitalizations of patients with R/R FLT3mut AML in a tertiary Spanish hospital. METHODS: Retrospective review of medical charts identified patients aged ≥ 18 years with R/R FLT3mut AML between 1998 and 2018. Data were collected from the date of first diagnosis of R/R FLT3mut AML (index) until death or loss to follow-up. The primary end point was duration and frequency of hospitalization, use of outpatient resources and transfusion burden. Reimbursement associated with hospitalizations (including associated chemotherapy) was also assessed. RESULTS: Thirty-eight patients were eligible for inclusion. Their median age was 52 years, and 30 (79%) received intensive salvage chemotherapy; FLAG-IDA-based regimens were the most frequent (24 patients, 63%). Overall, there were 150 hospitalizations (mean 3.9/patient; mean duration 21 days). Patients spent a mean of 24% of the study period in hospital. Total mean reimbursement was €108 293 per patient; the majority (€89 834) attributable to inpatient stays (€22 576 /hospitalization). During chemotherapy period (prior to first alloHSCT), there were 73 hospitalizations (mean duration 22 days); mean reimbursement was €19 776 per hospitalization and €49 819 per patient. AlloHSCT (n = 16) involved 77 hospitalizations (mean duration 21 days), mean reimbursement €25 231/hospitalization and €131 515 per patient. CONCLUSION: Data from this study suggest that there is a substantial healthcare resource utilization and cost burden on R/R FLT3mut AML patients in Spain receiving active treatments.

Big data and reference intervals: rationale, current practices, harmonization and standardization prerequisites and future perspectives of indirect determination of reference intervals using routine data.

Reference intervals are commonly used as a decision-making tool. In this review, we provide an overview on "big data" and reference intervals, describing the rationale, current practices including statistical methods, essential prerequisites concerning data quality, including harmonization and standardization, and future perspectives of the indirect determination of reference intervals using routine laboratory data.

Infectivity of Norovirus GI and GII from Bottled Mineral Water during a Waterborne Outbreak, Spain.

During a waterborne outbreak of norovirus in Spain, we estimated 50% illness doses for a group of exposed (secretor) persons to be 556 (95% CI 319-957) genome copies/day for norovirus GI and 2,934 (95% CI 1,683-5,044) genome copies/day for norovirus GII. Use of a propidium monoazide viability assay reduced these values.

Glass Wool Concentration Optimization for the Detection of Enveloped and Non-enveloped Waterborne Viruses.

An extremely affordable virus concentration method based on adsorption-elution to glass wool and subsequent reconcentration through polyethylene glycol 6000 (PEG) precipitation was optimized to recover not only non-enveloped viruses but also enveloped viruses. Hepatitis A virus (HAV) and transmissible gastroenteritis virus (TGEV) were employed as surrogates for naked and enveloped viruses, respectively, to set up the methodology. Initial experimentation in small-volume samples showed that both types of particles readily adsorbed to the positively charged glass wool but were poorly detached from it through standard elution with 0.05 M glycine with 3% of beef extract buffer, pH 9.5, with elution efficiencies of 7.2% and 2.6%, for HAV and TGEV, respectively. To improve the recovery of enveloped viruses, several modifications in the elution were assayed: increasing the elution pH, extending glass wool and eluent contact time, adding a detergent, or performing the elution by recirculation or under agitation. Considering practicability and performance, recircularization of the eluent at pH 11.0 for 20 min was the elution procedure of choice, with efficiencies of 25.7% and 18.8% for HAV and TGEV in 50 L of water. Additionally, employing 20% PEG instead of 10% for virus reconcentration improved recoveries up to 47% and 51%, respectively. The optimized procedure was applied to detect naturally occurring HAV and coronaviruses in surface water of Wadi Hanifa, Riyadh. HAV was detected in 38% of the samples, while one sample was positive for an alphacoronavirus. This cheap virus detection system enables the comprehensive surveillance of viruses present in water samples.

Norovirus in Bottled Water Associated with Gastroenteritis Outbreak, Spain, 2016.

In April 2016, an outbreak of gastrointestinal illness (4,136 cases) occurred in Catalonia, Spain. We detected high levels of norovirus genotypes I and II in office water coolers associated with the outbreak. Infectious viral titer estimates were 33-49 genome copies/L for genotype I and 327-660 genome copies/L for genotype II.

Evaluación multicéntrica de materiales para el control de calidad de los índices séricos / Multicenter evaluation of materials for the quality control of the serum indexes

Introducción. La hemólisis, la turbidez y la presencia de concentraciones elevadas de bilirrubina son las fuentes de interferencia más frecuentes en el laboratorio clínico. Muchos analizadores incorporan sistemas de detección de estos interferentes denominados «índices séricos» de hemólisis, ictericia y lipidemia. El grado de veracidad de los índices no suele ser verificado por la dificultad en conseguir materiales de referencia adecuados. En este trabajo se presentan los resultados de un estudio interlaboratorios de los índices hemólisis, ictericia y lipidemia empleando materiales de referencia con concentraciones conocidas de los interferentes. Material y métodos. En el estudio han participado los laboratorios clínicos de 10 centros con 7 analizadores distintos. Los materiales de referencia de índices séricos contenían concentraciones conocidas de bilirrubina, hemoglobina (hemolisado) y triglicéridos (Intralipid). Resultados. Todos los instrumentos proporcionaron resultados aceptables para el índice de ictericia y de hemólisis. Entre los analizadores que dan valores cuantitativos se encontraron resultados bajos en uno de los analizadores para los materiales que contenían Intralipid. Los analizadores que expresan el resultado en forma de un intervalo proporcionaron resultados correctos para los materiales con turbidez menor y bajos para el material con turbidez mayor. Conclusiones. Los materiales de referencia utilizados han demostrado su utilidad para verificar los índices séricos de ictericia, hemólisis y lipidemia en los analizadores. Generalmente los índices proporcionados por los instrumentos concuerdan entre sí y con los valores asignados. Las diferencias más importantes entre analizadores se encuentran en el índice de lipidemia (AU)

Introduction. Hemolysis, turbidity and the presence of high concentrations of bilirubin are the most frequent sources of interference in the clinical laboratory. Many analyzers incorporate detection systems for these interferents called “serum indexes” of hemolysis, icterus and lipidemia. The accuracy of such indexes is usually not verified by the difficulty in obtaining appropriate reference materials. In this work we show the results of an interlaboratory study of hemolysis, icterus and lipidemia indexes using reference materials containing known concentrations of these interfering substances. Material and methods. Ten clinical laboratories from different centres have participated in the study using 7 different analyzers. The reference materials for the serum indexes contained known concentrations of bilirubin, hemoglobin (hemolysate) and triglycerides (Intralipid). Results. All instruments provided acceptable results for the icterus and hemolysis index. Among the analyzers providing quantitative values, low results were found in one of the analyzers for materials containing Intralipid. The analyzers expressing the result as an interval provided correct results for materials with low turbidity but a low result for the material with the highest turbidity. Conclusions. The reference materials used have proved to be useful to verify the serum indexes for hemolysis, icterus and lipidemia in analyzers. The results obtained in different instruments generally agree among them and with the assigned values. The most important differences between analyzers were found in the lipidemia index (AU)

Pharmacokinetic study of conversion from tacrolimus twice-daily to tacrolimus once-daily in stable lung transplantation.

BACKGROUND: Tacrolimus twice-daily (TAC BID) is widely used in lung transplantation (LT), but there are little data on the use of tacrolimus once-daily (TAC QD) in this population. The objective of this study was to compare the pharmacokinetics (PK) of TAC BID and TAC QD in stable, adult LT patients. METHODS: Phase II, open-label, single-center, single-arm, prospective pilot PK study. Nineteen LT recipients with more than 6 months of postoperative follow-up and on TAC BID-based therapy were converted to TAC QD on a 1:1 (mg/mg) basis. Patients had been stable during the previous 3 months, and cystic fibrosis patients were excluded. One 24-hr PK profile was obtained on day -14 while patients were under TAC BID. A second PK profile was obtained 14 to 28 days after switching (day 0) to the same dose of TAC QD. Pre- and post-switch 24-hr PK profiles were compared. RESULTS: Mean AUC0-24 hr was 279.8 ng mL/hr for TAC BID and 278.7 ng mL/hr for TAC QD (P=0.92). AUC0-12 hr of TAC BID was higher than the AUC12-24 hr. There was a good correlation between AUC0-24 hr and C24 for both QD (r=0.96) and BID (r=0.94) formulations. There were no differences in the adverse events occurring with the two formulations. CONCLUSIONS: Tacrolimus bioavailability in steady state is similar in BID and QD formulations after conversion in stable LT recipients, excluding those with cystic fibrosis. Thus, our results indicate TAC BID can be safely switched to the more convenient QD formulation in this population.

Safety of ornithine phenylacetate in cirrhotic decompensated patients: an open-label, dose-escalating, single-cohort study.

AIMS: Confirm in patients with cirrhosis and gastrointestinal bleeding the safety of ornithine phenylacetate (OP) and assess the pharmacokinetic profile of OP and its effects on plasma ammonia. BACKGROUND: OP is a drug that has shown experimentally to decrease hyperammonemia and improve hepatic encephalopathy. OP is safe in healthy subjects and in stable patients with cirrhosis, but there are no data in decompensated cirrhosis. METHODS: We performed a study to assess safety and tolerance of OP in cirrhotic patients after an episode of upper gastrointestinal bleeding.Ten patients were included within 24 hours of an upper gastrointestinal bleeding. OP was administered as a continuous infusion up to a maximum of 10 g/24 h (0.42 g/h) for 5 days. The infusion was started at 33% of the target dose and increased at 12-hour intervals achieving target dose at 24 hours. Ammonia was also assessed in control group of 10 patients. RESULTS: No severe adverse events were observed. Mild adverse events were reported in 4 patients. Plasma ammonia (baseline: 80±43 µmol/L) showed a progressive drop between baseline and 36 hours (42±15 µmol/L), 72 hours (44±15 µmol/L), 96 hours (40±24 µmol/L), and 120 hours (33±14 µmol/L). Plasma ammonia at 24 hours was significantly higher in the control group. Plasma glutamine showed a significant decrease (-37% at day 5) and its excretion in urine as phenylacetylglutamine, a progressive rise (52±35 mmol at day 5). CONCLUSIONS: OP is a safe and well-tolerated drug in decompensated cirrhotics that may decrease plasma ammonia by inducing its appearance as phenylacetylglutamine in urine.

Hepatitis A virus cellular receptor 1/kidney injury molecule-1 is a susceptibility gene for clear cell renal cell carcinoma and hepatitis A virus cellular receptor/kidney injury molecule-1 ectodomain shedding a predictive biomarker of tumour progression.

AIM OF THE STUDY: To correlate hepatitis A virus cellular receptor (HAVCR)/kidney injury molecule-1 (KIM-1) expression in clear cell renal cell carcinoma (ccRCC) tumours with patient outcome and study the consequences of HAVCR/KIM-1 ectodomain shedding. METHODS: HAVCR/KIM-1 expression in ccRCC, oncocytomes, papillary carcinomas and unaffected tissue counterparts was evaluated. Minimal change disease and pre-clamping normal and ccRCC tissue biopsies were included. Tissue microarrays from 98 ccRCC tumours were analysed. Tumour registry data and patient outcome were retrospectivelly collected. Deletions in HAVCR/KIM-1 ectodomain and lentiviral infection of 786-O cells with HAVCR/KIM-1 mutated constructs to determine their subcellular distribution and invasive capacity were performed. RESULTS: HAVCR/KIM-1 was expressed in ccRCC, papillary tumours and in tubule cells of adjacent and distal unaffected counterparts of ccRCC tumours. The latest was not related to ischemic or tumour-related paracrine effects since pre-clamping normal biopsies were positive for HAVCR/KIM-1 and unaffected counterparts of papillary tumours were negative. HAVCR/KIM-1 analyses in patients and the invasive capacity of HAVCR/KIM-1 shedding mutants in cell lines demonstrated that: (i) relative low HAVCR/KIM-1 membrane levels correlate with activated shedding in ccRCC patients and mutant cell lines; (ii) augmented shedding directly correlates with higher invasiveness and tumour malignancy. CONCLUDING STATEMENTS: Constitutive expression of HAVCR/KIM-1 in kidney might constitute a susceptibility trait for ccRCC tumour development. Enhanced HAVCR/KIM-1 ectodomain shedding promotes invasive phenotype in vitro and more aggressive tumours in vivo.