Analysis of viral pneumonia and risk factors associated with severity of influenza virus infection in hospitalized patients from 2012 to 2016.

BACKGROUND: Influenza viruses cause pneumonia in approximately one-third of cases, and pneumonia is an important cause of death. The aim was to identify risk factors associated with severity and those that could predict the development of pneumonia. METHODS: This retrospective, observational study included all adult patients with confirmed influenza virus infection admitted to Son Espases University Hospital during four influenza seasons in Spain (October to May) from to 2012-2016. RESULTS: Overall, 666 patients with laboratory-confirmed influenza were included, 93 (14%) of which were severe; 73 (10.9%) were admitted to Intensive Care Unit (ICU), 39 (5.8%) died, and 185 (27.7%) developed pneumonia. Compared to less severe cases, patients with severe disease: were less vaccinated (40% vs. 28%, p = 0.021); presented with more confusion (26.9% vs. 6.8%), were more hypoxemic (Horowitz index (PaO2/FiO2) 261 vs. 280), had higher C-reactive protein (CRP) (12.3 vs. 4.0), had more coinfections (26.8% vs. 6.3%) and had more pleural effusion (14% vs. 2.6%) (last six all p < 0.001). Risk factors significantly associated with severity were pneumonia [OR (95% CI) = 4.14 (2.4-7.16)], history of heart disease (1.84, 1.03-3.28), and confusion at admission (4.99, 2.55-9.74). Influenza vaccination was protective (0.53, 0.28-0.98). Compared to those without pneumonia, the pneumonia group had higher CRP (11.3 vs. 4.0, p < 0.001), lower oxygen saturation (92% vs. 94%, p < 0.001), were more hypoxic (PaO2/FiO2 266 vs. 281, p < 0.001), and incurred more mechanical ventilation, septic shock, admission to the ICU, and deaths (all four p < 0.001). Higher CRP and lower oxygen saturation were independent variables for predicting the development of pneumonia. CONCLUSIONS: Pneumonia, history of heart disease, confusion and no influenza vaccination were independent variables to present complications in patients admitted with influenza infection.

Spatiotemporal variability in socioeconomic inequalities in COVID-19 vaccination in Catalonia, Spain.

OBJECTIVES: Socioeconomic inequalities have played a significant role in the unequal coverage of the COVID-19 vaccine. The objectives of this study were to (1) assess the socioeconomic inequalities in COVID-19 vaccination coverage in Catalonia, Spain; (2) analyse the spatial variation over time of these inequalities; and (3) assess variations in time and space in the effect of vaccination on inequalities in COVID-19 outcomes. STUDY DESIGN: A mixed longitudinal ecological study design was used. METHODS: Catalonia is divided in to 373 Basic Health Areas. Weekly data from these Basic Health Areas were obtained from the last week of December 2020 until the first week of March of 2022. A joint spatio-temporal model was used with the dependent variables of vaccination and COVID-19 outcomes, which were estimated using a Bayesian approach. The study controlled for observed confounders, unobserved heterogeneity, and spatial and temporal dependencies. The study allowed the effect of the explanatory variables on the dependent variables to vary in space and in time. RESULTS: Areas with lower socioeconomic level were those with the lowest vaccination rates and the highest risk of COVID-19 outcomes. In general, individuals in areas that were located in the upper two quartiles of average net income per person and in the lower two quartiles of unemployment rate (i.e., the least economically disadvantaged) had a higher propensity to be vaccinated than those in the most economically disadvantaged areas. In the same sense, the greater the percentage of the population aged ≥65 years, the higher the propensity to be vaccinated, while areas located in the two upper quartiles of population density and areas with a high percentage of poor housing had a lower propensity to be vaccinated. Higher vaccination rates reduced the risk of COVID-19 outcomes, while COVID-19 outcomes did not influence the propensity to be vaccinated. The effects of the explanatory variables were not the same in all areas or between the different waves of the pandemic, and clusters of excess risk of low vaccination in the most disadvantaged areas were detected. CONCLUSIONS: COVID-19 vaccination inequalities in the most disadvantaged areas could be a result of structural barriers, such as the lack of access to information about the vaccination process, and/or logistical challenges, such as the lack of transportation, limited Internet access or difficulty in scheduling appointments. Public health strategies should be developed to mitigate these barriers and reduce vaccination inequalities.

Short-term effects of air pollution and noise on emergency hospital admissions in Madrid and economic assessment.

INTRODUCTION: The aim of this study was to study the effect of air pollution and noise has on the population in Madrid Community (MAR) in the period 2013-2018, and its economic impact. METHODS: Time series study analysing emergency hospital admissions in the MAR due to all causes (ICD-10: A00-R99), respiratory causes (ICD-10: J00-J99) and circulatory causes (ICD-10: I00-I99) across the period 2013-2018. The main independent variables were mean daily PM2.5, PM10, NO2, 8-h ozone concentrations, and noise. We controlled for meteorological variables, Public Holidays, seasonality, and the trend and autoregressive nature of the series, and fitted generalised linear models with a Poisson regression link to ascertain the relative risks and attributable risks. In addition, we made an economic assessment of these hospitalisations. RESULTS: The following associations were found: NO2 with admissions due to natural (RR: 1.007, 95% CI: 1.004-1.011) and respiratory causes (RR: 1.012, 95% CI: 1.005-1.019); 8-h ozone with admissions due to natural (RR: 1.049, 95% CI: 1.014-1.046) and circulatory causes (RR: 1.088, 95% CI: 1.039-1.140); and diurnal noise (LAeq7-23h) with admissions due to natural (RR: 1.001, 95% CI: 1.001-1.002), respiratory (RR: 1.002, 95% CI: 1.001-1.003) and circulatory causes (RR: 1.003, 95% CI: 1.002-1.005). Every year, a total of 8246 (95% CI: 4580-11,905) natural-cause admissions are attributable to NO2, with an estimated cost of close on €120 million and 5685 (95% CI: 2533-8835) attributed to LAeq7-23h with an estimated cost of close on €82 million. CONCLUSIONS: Nitrogen dioxide, ozone and noise are the main pollutants to which a large number of hospitalisations in the MAR are attributed, and are thus responsible for a marked deterioration in population health and high related economic impact.

Diagnostic delay and outcome in immunocompetent patients with primary central nervous system lymphoma in Spain: a multicentric study.

INTRODUCTION: To assess the management of immunocompetent patients with primary central nervous system lymphomas (PCNSL) in Spain. METHODS: Retrospective analysis of 327 immunocompetent patients with histologically confirmed PCNSL diagnosed between 2005 and 2014 in 27 Spanish hospitals. RESULTS: Median age was 64 years (range: 19-84; 33% ≥ 70 years), 54% were men, and 59% had a performance status (PS) ≥ 2 at diagnosis. Median delay to diagnosis was 47 days (IQR 24-81). Diagnostic delay > 47 days was associated with PS ≥ 2 (OR 1.99; 95% CI 1.13-3.50; p = 0.016) and treatment with corticosteroids (OR 2.47; 95% CI 1.14-5.40; p = 0.023), and it did not improve over the years. Patients treated with corticosteroids (62%) had a higher risk of additional biopsies (11.7% vs 4.0%, p = 0.04) but corticosteroids withdrawal before surgery did not reduce this risk and increased the diagnostic delay (64 vs 40 days, p = 0.04). Median overall survival (OS) was 8.9 months [95% CI 5.9-11.7] for the whole series, including 52 (16%) patients that were not treated, and 14.1 months (95%CI 7.7-20.5) for the 240 (73.4%) patients that received high-dose methotrexate (HD-MTX)-based chemotherapy. Median OS was shorter in patients ≥ 70 years (4.1 vs. 13.4 months; p < 0.0001). Multivariate analysis identified age ≥ 65 years, PS ≥ 2, no treatment, and cognitive/psychiatric symptoms at diagnosis as independent predictors of short survival. CONCLUSIONS: Corticosteroids withdrawal before surgery does not decrease the risk of a negative biopsy but delays diagnosis. In this community-based study, only 73.4% of patients could receive HD-MTX-based chemotherapy and OS remains poor, particularly in elderly patients ≥ 70 years.

Differences in clinical manifestations and increased severity of systemic lupus erythematosus between two groups of Hispanics: European Caucasians versus Latin American mestizos (data from the RELESSER registry).

BACKGROUND: Systemic lupus erythematosus (SLE) is regarded as a prototype autoimmune disease because it can serve as a means for studying differences between ethnic minorities and sex. Traditionally, all Hispanics have been bracketed within the same ethnic group, but there are differences between Hispanics from Spain and those from Latin America, not to mention other Spanish-speaking populations. OBJECTIVES: This study aimed to determine the demographic and clinical characteristics, severity, activity, damage, mortality and co-morbidity of SLE in Hispanics belonging to the two ethnic groups resident in Spain, and to identify any differences. METHODS: This was an observational, multi-centre, retrospective study. The demographic and clinical variables of patients with SLE from 45 rheumatology units were collected. The study was conducted in accordance with Good Clinical Practice guidelines. Hispanic patients from the registry were divided into two groups: Spaniards or European Caucasians (EC) and Latin American mestizos (LAM). Comparative univariate and multivariate statistical analyses were carried out. RESULTS: A total of 3490 SLE patients were included, 90% of whom were female; 3305 (92%) EC and 185 (5%) LAM. LAM patients experienced their first lupus symptoms four years earlier than EC patients and were diagnosed and included in the registry younger, and their SLE was of a shorter duration. The time in months from the first SLE symptoms to diagnosis was longer in EC patients, as were the follow-up periods. LAM patients exhibited higher prevalence rates of myositis, haemolytic anaemia and nephritis, but there were no differences in histological type or serositis. Anti-Sm, anti-Ro and anti-RNP antibodies were more frequently found in LAM patients. LAM patients also had higher levels of disease activity, severity and hospital admissions. However, there were no differences in damage index, mortality or co-morbidity index. In the multivariate analysis, after adjusting for confounders, in several models the odds ratio (95% confidence interval) for a Katz severity index >3 in LAM patients was 1.45 (1.038-2.026; p = 0.02). This difference did not extend to activity levels (i.e. SLEDAI >3; 0.98 (0.30-1.66)). CONCLUSION: SLE in Hispanic EC patients showed clinical differences compared to Hispanic LAM patients. The latter more frequently suffered nephritis and higher severity indices. This study shows that where lupus is concerned, not all Hispanics are equal.

Will there be cold-related mortality in Spain over the 2021-2050 and 2051-2100 time horizons despite the increase in temperatures as a consequence of climate change?

INTRODUCTION: Global warming is resulting in an increase in temperatures which is set to become more marked by the end of the century and depends on the accelerating pace of greenhouse gas emissions into the atmosphere. Yet even in this scenario, so-called "cold waves" will continue to be generated and have an impact on health. OBJECTIVES: This study sought to analyse the impact of cold waves on daily mortality at a provincial level in Spain over the 2021-2050 and 2051-2100 time horizons under RCP4.5 and RCP 8.5 emission scenarios, on the basis of two hypotheses: (1) that the cold-wave definition temperature (T threshold) would not vary over time; and, (2) that there would be a variation in T threshold. MATERIAL AND METHODS: The results of a retrospective study undertaken for Spain as a whole across the period 2000-2009 enabled us to ascertain the cold-wave definition temperature at a provincial level and its impact on health, measured by reference to population attributable risk (PAR). The minimum daily temperatures projected for each provincial capital considering the above time horizons and emission scenarios were provided by the State Meteorological Agency. On the basis of the T threshold definition values and minimum daily temperatures projected for each province, we calculated the expected impact of low temperatures on mortality under the above two hypotheses. Keeping the PAR values constant, it was assumed that the mortality rate would vary in accordance with the available data. RESULTS: If T threshold remained constant over the above time horizons under both emission scenarios, there would be no cold-related mortality. If T threshold were assumed to vary over time, however, then cold-related mortality would not disappear: it would instead remain practically constant over time and give rise to an estimated overall figure of around 250 deaths per year, equivalent to close on a quarter of Spain's current annual cold-related mortality and entailing a cost of approximately €1000 million per year. CONCLUSION: Given that cold waves are not going to disappear and that their impact on mortality is far from negligible and is likely to remain so, public health prevention measures must be implemented to minimise these effects as far as possible.

Mortality attributable to high temperatures over the 2021-2050 and 2051-2100 time horizons in Spain: Adaptation and economic estimate.

BACKGROUND: In recent years, a number of studies have been conducted with the aim of analysing the impact that high temperatures will have on mortality over different time horizons under different climate scenarios. Very few of these studies take into account the fact that the threshold temperature used to define a heat wave will vary over time, and there are practically none which calculate this threshold temperature for each geographical area on the assumption that there will be variations at a country level. OBJECTIVE: To analyse the impact that high temperatures will have on mortality across the periods 2021-2050 and 2051-2100 under a high-emission climate scenario (RCP8.5), in a case: (a) where adaptation processes are not taken into account; and (b) where complete adaptation processes are taken into account. MATERIAL AND METHODS: Based on heat-wave definition temperature (Tthreshold) values previously calculated for the reference period, 2000-2009, for each Spanish provincial capital, and their impact on daily mortality as measured by population attributable risk (PAR), the impact of high temperatures on mortality will be calculated for the above-mentioned future periods. Two hypotheses will be considered, namely: (a) that Tthreshold does not vary over time (scenario without adaptation to heat); and, (b) that Tthreshold does vary over time, with the percentile to which said Tthreshold corresponds being assumed to remain constant (complete adaptation to heat). The temperature data were sourced from projections generated by Coupled Model Intercomparison Project (CMIP5) climate models adapted to each region's local characteristics by the State Meteorological Agency (Agencia Estatal de Meteorología/AEMET). Population-growth projections were obtained from the National Statistics Institute (Instituto Nacional de Estadística/INE). In addition, an economic estimate of the resulting impact will be drawn up. RESULTS: The mean value of maximum daily temperatures will rise, in relation to those of the reference period (2000-2009), by 1.6°C across the period 2021-2050 and by 3.3°C across the period 2051-2100. In a case where there is no heat-adaptation process, overall annual mortality attributable to high temperatures in Spain would amount to 1414 deaths/year (95% CI: 1089-1771) in the period 2021-2050, rising to 12,896 deaths/year (95% CI: 9852-15,976) in the period 2051-2100. In a case where there is a heat-adaptation process, annual mortality would be 651 deaths/year (95% CI: 500-807) in the period 2021-2050, and 931 deaths per year (95% CI: 770-1081) in the period 2051-2100. These results display a high degree of heterogeneity. The savings between a situation that does envisage and one that does not envisage an adaptive process is €49,100 million/year over the 2051-2100 time horizon. CONCLUSION: A non-linear increase in maximum daily temperatures was observed, which varies widely from some regions to others, with an increase in mean values for Spain as a whole that is not linear over time. The high degree of heterogeneity found in heat-related mortality by region and the great differences observed on considering an adaptive versus a non-adaptive process render it necessary for adaptation plans to be implemented at a regional level.

Syndrome and outcome of antibody-negative limbic encephalitis.

BACKGROUND AND PURPOSE: The aim was to report the clinical characteristics of 12 patients with limbic encephalitis (LE) who were antibody-negative after a comprehensive immunological study. METHODS: The clinical records of 163 patients with LE were reviewed. Immunohistochemistry on rat brain, cultured neurons and cell-based assays were used to identify neuronal autoantibodies. Patients were included if (i) there was adequate clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging information to classify the syndrome as LE, (ii) magnetic resonance images were accessible for central review and (iii) serum and CSF were available and were confirmed negative for neuronal antibodies. RESULTS: Twelve (7%) of 163 LE patients [median age 62 years; range 40-79; 9 (75%) male] without neuronal autoantibodies were identified. The most frequent initial complaints were deficits in short-term memory leading to hospital admission in a few weeks (median time 2 weeks; range 0.5-12). In four patients the short-term memory dysfunction remained as an isolated symptom during the entire course of the disease. Seizures, drowsiness and psychiatric problems were unusual. Four patients had solid tumors (one lung, one esophagus, two metastatic cervical adenopathies of unknown primary tumor) and one chronic lymphocytic leukemia. CSF showed pleocytosis in seven (58%) with a median of 13 white blood cells/mm3 (range 9-25). Immunotherapy included corticosteroids, intravenous immunoglobulins and combinations of both drugs or with rituximab. Clinical improvement occurred in six (54%) of 11 assessable patients. CONCLUSIONS: Despite the discovery of new antibodies, 7% of LE patients remain seronegative. Antibody-negative LE is more frequent in older males and usually develops with predominant or isolated short-term memory loss. Despite the absence of antibodies, patients may have an underlying cancer and respond to immunotherapy.

Dysregulation of Wnt inhibitory factor 1 (Wif1) expression resulted in aberrant Wnt-ß-catenin signaling and cell death of the cloaca endoderm, and anorectal malformations.

In mammalian urorectal development, the urorectal septum (urs) descends from the ventral body wall to the cloaca membrane (cm) to partition the cloaca into urogenital sinus and rectum. Defective urs growth results in human congenital anorectal malformations (ARMs), and their pathogenic mechanisms are unclear. Recent studies only focused on the importance of urs mesenchyme proliferation, which is induced by endoderm-derived Sonic Hedgehog (Shh). Here, we showed that the programmed cell death of the apical urs and proximal cm endoderm is particularly crucial for the growth of urs during septation. The apoptotic endoderm was closely associated with the tempo-spatial expression of Wnt inhibitory factor 1 (Wif1), which is an inhibitor of Wnt-ß-catenin signaling. In Wif1(lacZ/lacZ) mutant mice and cultured urorectum with exogenous Wif1, cloaca septation was defective with undescended urs and hypospadias-like phenotypes, and such septation defects were also observed in Shh(-/-) mutants and in endodermal ß-catenin gain-of-function (GOF) mutants. In addition, Wif1 and Shh were expressed in a complementary manner in the cloaca endoderm, and Wif1 was ectopically expressed in the urs and cm associated with excessive endodermal apoptosis and septation defects in Shh(-/-) mutants. Furthermore, apoptotic cells were markedly reduced in the endodermal ß-catenin GOF mutant embryos, which counteracted the inhibitory effects of Wif1. Taken altogether, these data suggest that regulated expression of Wif1 is critical for the growth of the urs during cloaca septation. Hence, Wif1 governs cell apoptosis of urs endoderm by repressing ß-catenin signal, which may facilitate the protrusion of the underlying proliferating mesenchymal cells towards the cm for cloaca septation. Dysregulation of this endodermal Shh-Wif1-ß-catenin signaling axis contributes to ARM pathogenesis.

Improving detection and genetic counseling in carriers of spinal muscular atrophy with two copies of the SMN1 gene.

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by mutations in the survival motor neuron1 gene (SMN1). Global carrier frequency is around 1 in 50 and carrier detection is crucial to define couples at risk to have SMA offspring. Most SMA carriers have one SMN1 copy and are currently detected using quantitative methods. A few, however, have two SMN1 genes in cis (2/0 carriers), complicating carrier diagnosis in SMA. We analyzed our experience in detecting 2/0 carriers from a cohort of 1562 individuals, including SMA parents, SMA relatives, and unrelated individuals of the general population. Interestingly, in three couples who had an SMA child, both the parents had two SMN1 copies. Families of this type have not been previously reported. Our results emphasize the importance of performing a detailed carrier study in SMA parents with two SMN1 copies. Expanding the analysis to other key family members might confirm potential 2/0 carriers. Finally, when a partner of a known carrier presents two SMN1 copies, the study of both parents will provide a more accurate diagnosis, thus optimizing genetic counseling.

[Neurocognitive and behavioral disturbances after adenotonsillectomy in obstructive sleep apnea syndrome]. / Alteraciones cognitivas y conductuales tras adenoamigdalectomía en el síndrome de apnea del sueño.

INTRODUCTION: Adenotonsillectomy is an effective treatment for sleep-disordered breathing in children, but its ability to resolve neurocognitive issues, is not clear. OBJECTIVE: To analyze the outcomes of cognitive and behavioral disorders after one year of adenotonsillectomy. METHOD: We studied the behavioral and cognitive abnormalities in 45 children with obstructive sleep apnea and 30 healthy controls, aged 3 to 13 years. Psychological tests were performed in both groups at baseline and at 12 months. RESULTS: Preoperatively, all cognitive and behavioral disturbances were higher in the study group than in the control group: attention in 46.7% of cases in the study group versus 20% in the control group (P=.016), anxiety 60.9% versus 40.9% (not significant); memory 55.6% versus 36.7% (P=.019), spatial structuring 64.4% versus 36.7% (P=.017), hyperactivity 42.9% versus 12.5% (P=.016), and attention deficit 46.4% versus 8.3% (P=.003). After one year we observed more disturbances in all variables in the study group. However, significant differences remained only in spatial structure (31.3% versus 3.3%, P=.017), and attention deficit (40.5% versus 16.7%, P=.031). The percentages of patients that improved in one year were not significantly different between both groups. CONCLUSION: Behavioral and cognitive disturbances in children with sleep apnea were partially resolved following adenotonsillectomy. Improvements in the cognitive and behavioral variables did not differ significantly from those the normal evolution of the individual, and were independent of the resolution of respiratory disorders.

Quantification of relative proportions of intact cells in microbiological samples using the example of Cryptosporidium parvum oocysts.

UNLABELLED: The fast analysis of relative proportions of live and dead cells can be of great value whether for comparing inactivation efficiencies of different biocidal treatments or for monitoring organisms of interest in environmental samples. We introduce here a straightforward method to determine the percentage of intact cells based on treatment of samples with the viability dye propidium monoazide (PMA). PMA selectively enters membrane-damaged cells and suppresses their PCR detection through modification of their DNA. The study was performed using Cryptosporidium parvum oocysts as a model although the principle should be applicable to other organisms. Validation was performed with defined mixtures of live and heat-killed oocysts and by exposing oocysts to a heat stress gradient. The method correctly indicated increasingly lower proportions of intact cells with increasing temperatures. When comparing the loss of membrane integrity of UV-killed (40 mJ cm(-2) ) oocysts during storage in nonsterile tap water, results suggested that integrity declines slowly (over weeks) and at a rate comparable to non-UV-exposed oocysts. For all experiments, the amplification of longer DNA sequences was found beneficial. In the UV experiment, longer amplicons revealed not only higher sensitivity in excluding membrane-damaged oocysts, but also in excluding DNA with UV-induced damage. SIGNIFICANCE AND IMPACT OF THE STUDY: Whether in the context of microbial ecology or in an industrial context, many questions in microbiology are linked to microbial viability. As cultivation of micro-organisms can be long or may not be possible, fast methods to assess the numbers of live cells are in great demand. We present here a straightforward strategy to determine the relative proportions of intact cells. The PCR-based rapid method is expected to be useful where relative information is sufficient (e.g. for comparing the effect of different antimicrobial treatments on known numbers of micro-organisms) or when the presence of PCR inhibitors does not allow absolute quantification.

Alternative indicators for monitoring Cryptosporidium oocysts in reclaimed water.

With the widespread use of reclaimed water all over the world, there is a clear need to optimise its management in order to guarantee water safety. Model microorganisms (with either indicator or index function) are commonly used to assess risks related to the presence of enteric pathogens in water. Samples from five water reclamation plants located in Northeastern Spain were analysed to validate the use of three model microorganisms (Escherichia coli, somatic coliphages and spores of sulphite-reducing clostridia) as surrogates of Cryptosporidium total or infectious oocysts (TOO and IOO, respectively) in reclaimed water. Probability plots, simple and multiple linear regression and discriminant analyses were performed to assess their relationships. Results show that the detection of E. coli alone is not useful to model either the behaviour or concentrations of Cryptosporidium. However, discriminant analyses showed a high rate of correctly classified samples (91.9%) when E. coli and somatic coliphages data were used together to predict the presence/absence of IOO. Spores of sulphite-reducing clostridia (SRC) showed parallel reduction patterns and high correlation values (r = 0.76) with reductions in TOO. Furthermore, simple regression analyses of SRC and TOO in reclaimed water showed high correlation values (r = 0.85). Therefore, at the treatment plants studied, SRC can be considered to have good indicator and index functions for TOO. From the point of view of health protection, the use of SRC together with E. coli (which is mandatory in the current Spanish regulations) would satisfy the need for improved reclaimed water management.

Direct and indirect QMRA of infectious Cryptosporidium oocysts in reclaimed water.

Water scarcity leads to an increased use of reclaimed water, which in turn calls for an improvement in water reclamation procedures to ensure adequate quality of the final effluent. The presence of infectious Cryptosporidium oocysts (IOO) in reclaimed water is a health hazard for users of this resource. Here, we gathered information on Cryptosporidium (concentrations, infectivity and genotype) in order to perform quantitative microbial risk assessment (QMRA). Moreover, data concerning the spores of sulphite-reducing clostridia (SRC) were used to undertake QMRA at a screening level. Our results show that the probability of infection (PI) by Cryptosporidium depends on the tertiary treatment type. The mean PI using the exponential dose-response model was 3.69 × 10(-6) in tertiary effluents (TE) treated with UV light, whereas it was 3 log(10) units higher, 1.89 × 10(-3), in TE not treated with this disinfection method. With the ß-Poisson model, the mean PI was 1.56 × 10(-4) in UV-treated TE and 2 log(10) units higher, 4.37 × 10(-2), in TE not treated with UV. The use of SRC to perform QMRA of Cryptosporidium showed higher PI than when using directly IOO data. This observation suggests the former technique is a conservative method of QMRA.

Association of CD247 with systemic lupus erythematosus in Asian populations.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. METHODS: In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. RESULTS: The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10(-7); rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production. CONCLUSION: A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.

Two missense variants in UHRF1BP1 are independently associated with systemic lupus erythematosus in Hong Kong Chinese.

UHRF1BP1 encodes a highly conserved protein with unknown function. Previously, a coding variant in this gene was found to be associated with systemic lupus erythematosus (SLE) in populations of European ancestry (rs11755393, R454Q, P=2.22 x 10⁻8, odds ratio=1.17). In this study, by a combination of genome-wide study and replication involving a total of 1230 patients and 3144 controls, we confirmed the association of this coding variant to SLE in Hong Kong Chinese. We also identified another coding variant in this gene that independently contributes to SLE susceptibility (rs13205210, M1098T, P=4.44 x 10⁻9, odds ratio=1.49). Cross-population confirmation establishes the involvement of this locus in SLE and indicates that distinct alleles are contributing to disease susceptibility.

Replication study of SNP associations for colorectal cancer in Hong Kong Chinese.

BACKGROUND: Recent genome-wide association studies of colorectal cancer (CRC) have identified common single-nucleotide polymorphisms (SNPs) mapping to 10 independent loci that confer modest increased risk. These studies have been conducted in European populations and it is unclear whether these observations generalise to populations with different ethnicities and rates of CRC. METHODS: An association study was performed on 892 CRC cases and 890 controls recruited from the Hong Kong Chinese population, genotyping 32 SNPs, which were either associated with CRC in previous studies or are in close proximity to previously reported risk SNPs. RESULTS: Twelve of the SNPs showed evidence of an association. The strongest associations were provided by rs10795668 on 10p14, rs4779584 on 15q14 and rs12953717 on 18q21.2. There was significant linear association between CRC risk and the number of independent risk variants possessed by an individual (P=2.29 × 10(-5)). CONCLUSION: These results indicate that some previously reported SNP associations also impact on CRC risk in the Chinese population. Possible reasons for failure of replication for some loci include inadequate study power, differences in allele frequency, linkage disequilibrium structure or effect size between populations. Our results suggest that many associations for CRC are likely to generalise across populations.

The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor.

Homozygous mutations of the telomeric SMN1 gene lead to degeneration of motor neurons causing spinal muscular atrophy (SMA). A highly similar centromeric gene (SMN2) can only partially compensate for SMN1 deficiency. The c.859G>C variant in SMN2 has been recently reported as a positive disease modifier. We identified the variant in 10 unrelated chronic SMA patients with a wide spectrum of phenotypes ranging from type II patients who can only sit to adult walkers. Haplotype analysis strongly suggests that the variant originated from a common ancestor. Our results confirm that the c.859G>C variant is a milder SMN2 allele and predict a direct correlation between SMN activity and phenotypic severity.

Fine mapping of the 9q31 Hirschsprung's disease locus.

Hirschsprung's disease (HSCR) is a congenital disorder characterised by the absence of ganglia along variable lengths of the intestine. The RET gene is the major HSCR gene. Reduced penetrance of RET mutations and phenotypic variability suggest the involvement of additional modifying genes in the disease. A RET-dependent modifier locus was mapped to 9q31 in families bearing no coding sequence (CDS) RET mutations. Yet, the 9q31 causative locus is to be identified. To fine-map the 9q31 region, we genotyped 301 tag-SNPs spanning 7 Mb on 137 HSCR Dutch trios. This revealed two HSCR-associated regions that were further investigated in 173 Chinese HSCR patients and 436 controls using the genotype data obtained from a genome-wide association study recently conducted. Within one of the two identified regions SVEP1 SNPs were found associated with Dutch HSCR patients in the absence of RET mutations. This ratifies the reported linkage to the 9q31 region in HSCR families with no RET CDS mutations. However, this finding could not be replicated. In Chinese, HSCR was found associated with IKBKAP. In contrast, this association was stronger in patients carrying RET CDS mutations with p = 5.10 x 10(-6) [OR = 3.32 (1.99, 5.59)] after replication. The HSCR-association found for IKBKAP in Chinese suggests population specificity and implies that RET mutation carriers may have an additional risk. Our finding is supported by the role of IKBKAP in the development of the nervous system.