The influence of the COVID-19 pandemic on physical activity in Stockholm County - Evidence from time series models of smartphone measured daily steps data spanning over 3 years.

BACKGROUND: It has been reported that physical activity levels decreased during the COVID-19 pandemic. Previous studies often relied on self-reported physical activity, which has low accuracy. Studies based on objectively measured physical activity have had short data collection periods, thereby not allowing the consideration of pre-pandemic levels of physical activity or the influence over the different waves of the pandemic. METHODS: In this study, we utilize smartphone-measured step data from a nonprobability sample in Stockholm County, Sweden, where measures to limit the spread of COVID-19 differed from those in many other countries. The results are based on 522 individuals and 532,739 person-days with step data spanning from 2019 to 2021. Generalized additive models were fitted for each individual, and meta-regression was used to combine the results from individual models. RESULTS: Daily steps decreased during the first wave but increased during the third wave compared to individual pre-pandemic levels. The decrease in daily steps occurred primarily in young individuals and those with occupations allowing remote work. Individuals of retirement age on the contrary increased their daily steps during the same period. CONCLUSIONS: This study reveal that the influence of the COVID-19 pandemic was temporary and that younger age and the possibility of working from home were associated with a decreasing trend in physical activity.

Health impact of the Tajogaite volcano eruption in La Palma population (ISVOLCAN study): rationale, design, and preliminary results from the first 1002 participants.

BACKGROUND: The eruption of the Tajogaite volcano began on the island of La Palma on September 19, 2021, lasting for 85 days. This study aims to present the design and methodology of the ISVOLCAN (Health Impact on the Population of La Palma due to the Volcanic Eruption) cohort, as well as the preliminary findings from the first 1002 enrolled participants. METHODS: A prospective cohort study was conducted with random selection of adult participants from the general population, with an estimated sample size of 2600 individuals. The results of the first 857 participants are presented, along with a group of 145 voluntary participants who served as interveners during the eruption. Data on epidemiology and volcano exposure were collected, and participants underwent physical examinations, including anthropometry, blood pressure measurement, spirometry, and venous blood extraction for toxicological assessment. RESULTS: In the general population (n = 857), descriptive analysis revealed that the participants were mostly middle-aged individuals (50.8 ± 16.4), with a predominance of females. Before the eruption, the participants resided at a median distance of 6.7 km from the volcano in the Western region and 10.9 km in the Eastern region. Approximately 15.4% of the sample required evacuation, whose 34.8% returning to their homes on average after 3 months. A significant number of participants reported engaging in daily tasks involving cleaning of volcanic ash both indoors and outdoors. The most reported acute symptoms included ocular irritation, insomnia, mood disorders (anxiety-depression), and respiratory symptoms. Multivariate analysis results show that participants in the western region had a higher likelihood of lower respiratory tract symptoms (OR 1.99; 95% CI:1.33-2.99), depression and anxiety (OR 1.95; 95% CI:1.30-2.93), and insomnia (OR 2.03; 95% CI:1.33-3.09), compared to those in the eastern region. CONCLUSION: The ongoing follow-up of the ISVOLCAN cohort will provide valuable insights into the short, medium, and long-term health impact related to the material emitted during the Tajogaite eruption, based on the level of exposure suffered by the affected population.

Differences in Covid-19 mortality among persons 70 years and older in an integrated care setting in region Stockholm: a multi-level analysis between March 2020-February 2021.

BACKGROUND: In Norrtälje municipality, within Region Stockholm, there is a joint integrated care organisation providing health and social care, which may have facilitated a more coordinated response to the covid-19 pandemic compared to the otherwise decentralised Swedish system. This study compares the risk of covid-19 mortality among persons 70 years and older, in the municipalities of Stockholm, Södertälje, and Norrtälje, while considering area and individual risk factors. METHODS: A population-based study using linked register data to examine covid-19 mortality among those 70 + years (N = 127,575) within the municipalities of interest between the periods March-August 2020 and September 2020-February 2021. The effect of individual and area level variables on covid-19 mortality among inhabitants in 68 catchment areas were examined using multi-level logistic models. RESULTS: Individual factors associated with covid-19 mortality were sex, older age, primary education, country of birth and poorer health as indicated by the Charlson Co-morbidity Index. The area-level variables associated were high deprivation (OR: 1.56, CI: 1.18-2.08), population density (OR: 1.14, CI: 1.08-1.21), and usual care. Together, this explained 85.7% of the variation between catchment areas in period 1 and most variation was due to individual risk factors in period 2. Little of the residual variation was attributed to differences between catchment areas. CONCLUSION: Integrated care in Norrtälje may have facilitated a more coordinated response during period 1, compared to municipalities with usual care. In the future, integrated care should be considered as an approach to better protect and meet the care needs of older people during emergency situations.

[Diabetes control and visits to the family doctor during the COVID-19 pandemic: a multicenter study in primary care]. / Control de diabetes y consultas al médico de familia durante la pandemia de COVID-19: estudio multicéntrico en atención primaria.

OBJECTIVES: To determine whether in patients with type 2 diabetes (DM2) the changes in their relationship with family doctors during the COVID-19 pandemic, in-person (iPC) and telematic (TC) consultations, were associated with control of their disease. DESIGN: Multicentric study of retrospective follow-up. SETTING: Seven health centers in Tenerife, Spain. PARTICIPANTS: 3543 patients with DM2. MAIN MEASUREMENTS: Sex, age, iPC, TC and DM2 control using glycosylated hemoglobin (A1c) during the period 2019-2021. Logistic regression models were fitted with DM2 control as an effect, and with the other measurements as independent variables. RESULTS: 50% were women. 38% were less than 65 years old. A1c was measured in 84% of patients in 2019, 68% in 2020, and 77% in 2021. 58.4% had good control in 2019, 46.1% in 2020, and 50.3% in 2021. Median iPC were 7 in 2019, 4 in 2020 and 5 in 2021 (p<0.001). The OR(95%CI) of good control in 2019 were 1.04(1.04-1.05) per year of age and 1.03(1.01-1.04) for each iPC; In 2020 they were 1.04 (1.03-1.05) per year of age, 1.05 (1.04-1.07) for each iPC and 1.04 (1.02-1.07) for each TC; in 2021 they were 1.04 (1.04-1.05) per year of age, 1.05 (1.03-1.06) for each iPC and 1.02 (1.00-1.04) for each TC. CONCLUSIONS: The control of patients with DM2 during the period 2019-2021 had a direct relationship with the change in the frequency of consultations at the health center, with differences depending on the type of consultation and the age of the patient.

Individual and neighborhood risk factors of hospital admission and death during the COVID-19 pandemic: a population-based cohort study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) disproportionately affects minority populations in the USA. Sweden - like other Nordic countries - have less income and wealth inequality but lacks data on the socioeconomic impact on the risk of adverse outcomes due to COVID-19. METHODS: This population-wide study from March 2020 to March 2022 included all adults in Stockholm, except those in nursing homes or receiving in-home care. Data sources include hospitals, primary care (individual diagnoses), the Swedish National Tax Agency (death dates), the Total Population Register "RTB" (sex, age, birth country), the Household Register (size of household), the Integrated Database For Labor Market Research "LISA" (educational level, income, and occupation), and SmiNet (COVID data). Individual exposures include education, income, type of work and ability to work from home, living area and living conditions as well as the individual country of origin and co-morbidities. Additionally, we have data on the risks associated with living areas. We used a Cox proportional hazards model and logistic regression to estimate associations. Area-level covariates were used in a principal component analysis to generate a measurement of neighborhood deprivation. As outcomes, we used hospitalization and death due to COVID-19. RESULTS: Among the 1,782,125 persons, male sex, comorbidities, higher age, and not being born in Sweden increase the risk of hospitalization and death. So does lower education and lower income, the lowest incomes doubled the risk of death from COVID-19. Area estimates, where the model includes individual risks, show that high population density and a high percentage of foreign-born inhabitants increased the risk of hospitalization. CONCLUSIONS: Segregation and deprivation are public health issues elucidated by COVID-19. Neighborhood deprivation, prevalent in Stockholm, adds to individual risks and is associated with hospitalization and death. This finding is paramount for governments, agencies, and healthcare institutions interested in targeted interventions.

Are the estimated needs for mental health care among adolescents from different socioeconomic backgrounds met equally in Sweden? A longitudinal survey-registry linkage study.

Evidence of inequality in the utilisation of mental health care (MHC) by adolescents in Nordic countries is mixed. This study aims to investigate if there are socioeconomic differences in the utilisation of MHC, while accounting for adolescents' mental health status. We analysed a cohort of 3517 adolescents, followed from 7 to 9th grade (ages 13-16), to examine the association between parental socioeconomic position (SEP: education and disposable income), adolescents' estimated needs, and the utilisation of MHC (defined as visits to secondary psychiatric care or receipt of psychotropic medication). Logistic and negative binomial regression models, with mental health status as moderator, were used to predict utilisation during each grade. Lower SEP predicted higher odds of utilising MHC in adolescents with no/mild symptoms (e.g., odds ratio, OR = 1.33, 95% CI 1.04-1.72, lower vs highest education), but not in those with moderate-to-severe symptoms (estimates close to one and non-significant). This pattern was largely explained by treatment of attention deficit hyperactivity disorder/autism spectrum disorders (ADHD/ASD) in boys. For girls with severe symptoms, lower SEP predicted reduced odds of utilising MHC for other mental disorders (OR = 0.48, 95% CI 0.25-0.92, lower education), and fewer outpatient visits when in contact with such care, although non-significant (incidence rate ratio, IRR = 0.51, 95% CI 0.25-1.05, lowest vs highest income). Our findings suggest a more equitable use of MHC for treating ADHD/ASD, but not other mental disorders such as depression and anxiety, particularly among girls.

Characterization of data-driven clusters in diabetes-free adults and their utility for risk stratification of type 2 diabetes.

BACKGROUND: The prevention of type 2 diabetes is challenging due to the variable effects of risk factors at an individual level. Data-driven methods could be useful to detect more homogeneous groups based on risk factor variability. The aim of this study was to derive characteristic phenotypes using cluster analysis of common risk factors and to assess their utility to stratify the risk of type 2 diabetes. METHODS: Data on 7317 diabetes-free adults from Sweden were used in the main analysis and on 2332 diabetes-free adults from Mexico for external validation. Clusters were based on sex, family history of diabetes, educational attainment, fasting blood glucose and insulin levels, estimated insulin resistance and ß-cell function, systolic and diastolic blood pressure, and BMI. The risk of type 2 diabetes was assessed using Cox proportional hazards models. The predictive accuracy and long-term stability of the clusters were then compared to different definitions of prediabetes. RESULTS: Six risk phenotypes were identified independently in both cohorts: very low-risk (VLR), low-risk low ß-cell function (LRLB), low-risk high ß-cell function (LRHB), high-risk high blood pressure (HRHBP), high-risk ß-cell failure (HRBF), and high-risk insulin-resistant (HRIR). Compared to the LRHB cluster, the VLR and LRLB clusters showed a lower risk, while the HRHBP, HRBF, and HRIR clusters showed a higher risk of developing type 2 diabetes. The high-risk clusters, as a group, had a better predictive accuracy than prediabetes and adequate stability after 20 years. CONCLUSIONS: Phenotypes derived using cluster analysis were useful in stratifying the risk of type 2 diabetes among diabetes-free adults in two independent cohorts. These results could be used to develop more precise public health interventions.

Detection and follow-up of chronic health conditions in Rio de Janeiro - the impact of residency training in family medicine.

BACKGROUND: There is a need for evidence that residency training in family medicine can benefit the care of patients in primary care in low- and middle-income countries. We tested the hypothesis that two years of residency training in family medicine enables doctors to better detect chronic health conditions while requesting fewer laboratory tests and providing more follow-up visits. METHODS: We performed a retrospective longitudinal observational analysis of medical consultations from 2013 to 2018 in primary care in Rio de Janeiro, comparing doctors without residency training in family medicine (Generalists) versus family physicians (FPs). Multivariate multilevel binomial regression models estimated the risks of patients being diagnosed for a list of 31 chronic health conditions, having a follow-up visit for these conditions, and having laboratory tests ordered from a list of 30 exams. RESULTS: 569.289 patients had 2.908.864 medical consultations performed by 734 generalists and 231 FPs. Patients seen by FPs were at a higher risk of being detected for most of the chronic health conditions, at a lower risk of having any of the 30 laboratory tests requested, and at a higher risk of having a follow-up visit in primary care. CONCLUSIONS: Residency training in family medicine can make physicians more skilled to work in primary care. Policymakers must prioritize investments in capacity building of healthcare workforce to make primary care truly comprehensive.

[Uncontrolled type 2 diabetes in primary care health center: Modifiable factors and target population]. / Mal control de la diabetes tipo 2 en un centro de salud de atención primaria: factores modificables y población diana.

AIMS: To detect modifiable factors and target populations associated with uncontrolled type 2 diabetes in primary care. DESIGN: Retrospective cross-sectional descriptive study. LOCATION: Health center of Barranco Grande, Tenerife. PARTICIPANTS: Random selection of patients with DM2 attended by 12 family doctors and 12 nurses. MAIN MEASUREMENTS: In addition to the control of DM2, sociodemographic, clinical data, lifestyle and follow-up of preventive and therapeutic measures were obtained. After bivariate analysis, a multilevel multivariate model was adjusted by taking the quota of patients assisted by each physician as a second-level mixed-effect variable and the rest as first-level variables. RESULTS: 587 patients were recruited (46.5% female), treated with 1.9-1.1 antidiabetic drugs, with 4.1% therapeutic non-compliance, and suffering 13.8% therapeutic inertia. 23.7% showed poor DM2 control, being significantly worse (p<0.05) in male sex, age <65 years, evolution DM2 -5 years, work-active, upper-middle studies, inadequate diet, metabolic syndrome, ratio TG/HDL-3, complications of DM2, Charlson index<5, nursing visits <3/year, without ECG in the last year, and more drugs prescribed for DM2. The doctor-nurse quota was associated with poor control with an intraclass coefficient of 0.01. CONCLUSIONS: Men under 65 years of age with DM2 evolution longer than 5 years are a target population to intensify interventions. Therapeutic non-compliance, inadequate diet, lack of adherence protocols and ratio TG/HDL>3 are the main modifiable factors on which to intervene. The association of the doctor-nurse quota with the control of DM2 is weak, probably due to adequate follow-up of preventive programs.

Major amputations in type 2 diabetes between 2001 and 2015 in Spain: regional differences.

BACKGROUND: To analyze the trend of lower extremity major amputations (MA) among patients with type 2 diabetes mellitus (T2DM) in the Regions of Spain from year 2001 until 2015. METHODS: Descriptive study of 40,392 MA. Data were obtained from the national hospital discharge database in patients with T2DM. The incidence rate was calculated in each Region, in addition to the incidence ratios (IR) between annual incidence and incidence of the year 2001. The length of hospital stay and mortality risks were analyzed using regression models adjusted for sex, age and smoking. RESULTS: The major amputations incidence rate per 100,000 person-years was 0.48 in Spain; Canary Islands showed the highest incidence (0.81). The trend was a slight decrease or stability of the incidence in all Regions except in the Canary Islands (IR2015 = 2.0 [CI95% = 1.5, 2.6]) and in Madrid (IR2015 = 0.1 [CI95% = 0.1, 0.2]). Mortality after major amputations was 10% in Spain; Cantabria suffered the highest risk of death [1.7 (CI95% = 1.4; 2.1), p < 0.001] and La Rioja the lowest risk (0.5 [CI95% = 0.2; 0.9]; p = 0.026). The longest hospital stay was registered in the Canary Islands [(CI95% = 11.4;13.3], p < 0.001)], and the shortest in the Valencian Community [(CI95% = - 7.3; - 5.8), p < 0.001)]. CONCLUSION: MA in T2DM followed a growing trend in the Canary Islands, which diverged from the downward trend in Spain. The variability of mortality and hospital stay, suggest to review the clinical management in some Regions. Sudden incidence decrease in Madrid suggests checking the record procedures of hospital discharges.

[Evolution of Smoking According to Social Class in the Adult Population of the Canary Islands During 2000-2015: Follow-up of the CDC-Canary Cohort]. / Evolución del tabaquismo según clase social en la población adulta de las Islas Canarias durante el periodo 2000-2015: seguimiento de la cohorte CDC-Canarias.

OBJECTIVE: To determine the status of tobacco consumption in the Canary Islands during 2000-2015, according to social class. LOCATION: Canary Islands. PARTICIPANTS: General population cohort, with contacts in 2000 (n=6,729), 2008 (n=6,171) and 2015 (n=4,705). MAIN MEASUREMENTS: Smoking, gender, age, and social class. RESULTS: Consumption decreased by 6% (5-7%, P<.001) in general, being more accentuated in the period 2000-2008 (5%). The decrease was greater in men, although they continued to smoke more than women, with a prevalence of 25% (24-26%) compared to 18% (17-19%, P<.001). A decrease in consumption was only observed in the younger groups (6% [3-5%], P=.011) and intermediate ages (7% [6-8%], P<.001). A similar decrease was observed in all the social classes, but there was a higher prevalence of smoking in the upper class: 24% (23-25%) in 2015 (P<.001). By jointly assessing gender, age, and social class, younger and middle age men had the greatest decreases in consumption: 8% (7-9%) low and upper classes, 10% (9-11%) middle class. In the lower social class, younger women continue to smoke more (27%) although more of them quit smoking (14%), a phenomenon that occurred in the middle class at intermediate ages. CONCLUSIONS: The evolution of tobacco consumption in the Canary Islands follows a pattern similar to that of mainland Spain. The abandonment of tobacco consumption has slowed down in the period 2008-2015, especially in men, and middle and upper social classes.

Genomic Analyses of Human European Diversity at the Southwestern Edge: Isolation, African Influence and Disease Associations in the Canary Islands.

Despite the genetic resemblance of Canary Islanders to other southern European populations, their geographical isolation and the historical admixture of aborigines (from North Africa) with sub-Saharan Africans and Europeans have shaped a distinctive genetic makeup that likely affects disease susceptibility and health disparities. Based on single nucleotide polymorphism array data and whole genome sequencing (30×), we inferred that the last African admixture took place ∼14 generations ago and estimated that up to 34% of the Canary Islander genome is of recent African descent. The length of regions in homozygosis and the ancestry-related mosaic organization of the Canary Islander genome support the view that isolation has been strongest on the two smallest islands. Furthermore, several genomic regions showed significant and large deviations in African or European ancestry and were significantly enriched in genes involved in prevalent diseases in this community, such as diabetes, asthma, and allergy. The most prominent of these regions were located near LCT and the HLA, two well-known targets of selection, at which 40‒50% of the Canarian genome is of recent African descent according to our estimates. Putative selective signals were also identified in these regions near the SLC6A11-SLC6A1, KCNMB2, and PCDH20-PCDH9 genes. Taken together, our findings provide solid evidence of a significant recent African admixture, population isolation, and adaptation in this part of Europe, with the favoring of African alleles in some chromosome regions. These findings may have medical implications for populations of recent African ancestry.

Detection of colistin resistance mcr-1 gene in Salmonella enterica serovar Rissen isolated from mussels, Spain, 2012- to 2016.

Nineteen Salmonella strains were isolated from 5,907 randomly selected mussel samples during a monitoring programme for the presence of Salmonella in shellfish in Galicia, north-west Spain (2012-16). Serovars, sequence type and antimicrobial resistance genes were determined through genome sequencing. Presence of the mcr-1 gene in one strain belonging to serovar Rissen and ST-469 was identified. The mcr-1 gene had not been isolated previously in environmental Salmonella isolated from mussels in Spain.

Epidemic Dynamics of Vibrio parahaemolyticus Illness in a Hotspot of Disease Emergence, Galicia, Spain.

Galicia in northwestern Spain has been considered a hotspot for Vibrio parahaemolyticus infections. Infections abruptly emerged in 1998 and, over the next 15 years, were associated with large outbreaks caused by strains belonging to a single clone. We report a recent transition in the epidemiologic pattern in which cases throughout the region have been linked to different and unrelated strains. Global genome-wide phylogenetic analysis revealed that most of the pathogenic strains isolated from infections were associated with globally diverse isolates, indicating frequent episodic introductions from disparate and remote sources. Moreover, we identified that the 2 major switches in the epidemic dynamics of V. parahaemolyticus in the regions, the emergence of cases and an epidemiologic shift in 2015-2016, were associated with the rise of sea surface temperature in coastal areas of Galicia. This association may represent a fundamental contributing factor in the emergence of illness linked to these introduced pathogenic strains.

Austerity Policies and Mortality in Spain After the Financial Crisis of 2008.

OBJECTIVES: To analyze mortality in Spain and the United States before and after these countries implemented divergent policies in response to the financial crisis of 2008. METHODS: We examined mortality statistics in both countries in the years 2000 to 2015. Spain started austerity policies in 2010. We compared differences in mortality ratios, on the basis of trends and effect size analysis. RESULTS: During 2000 to 2010, overall mortality rates (r = 0.98; P < .001; Cohen's d = -0.228) decreased in both countries. In 2011, this trend changed abruptly in Spain, where observed mortality surpassed expected mortality by 29% in 2011 and by 41% in 2015. By contrast, observed mortality surpassed expected mortality in the United States by only 8% in 2015. As the mortality statistics diverged, the effect size greatly increased (d = 7.531). During this 5-year period, there were 505 559 more deaths in Spain than the expected number, while in the United States the difference was 431 501 more deaths despite the 7-fold larger population in the United States compared with Spain. CONCLUSIONS: The marked excess mortality in 2011 to 2015 in Spain is attributable to austerity policies.

Robotic surgery in public hospitals of Latin-America: a castle of sand?

INTRODUCTION: There is no information about the evolution of robotic programs in public hospitals of Latin-America. OBJECTIVE: To describe the current status and functioning of robotic programs in Latin-American public hospitals since their beginning to date. METHODS: We conducted a survey among leading urologists working at public hospitals of Latin-America who had acquired the Da Vinci laparoscopic-assisted robotic system. Questions included: date the program started, its utilization by other services, number and kind of surgeries, surgery paying system, surgery related deaths, occurrence and reasons of robotic program interruptions and its use for training purposes. Medians and 25-75 centiles (IQR) were estimated. RESULTS: Since 2009, there are ten public hospitals of four Latin-American countries that acquired the Da Vinci robotic system. The median number of months robotic programs has been functioning without considering transitory interruption: 43 (IQR 35, 55). Median number of urologic and total surgeries performed: 140 (IQR 94, 168) and 336 (IQR 292, 621), respectively. The corresponding median number of urologic and total surgeries performed per month: 3 (IQR 2, 5) and 8 (IQR 5, 11). Median number of total surgeries performed per year per institution was 94 (IQR 68,123). The median proportion of urologic cases was 40% (IQR 31, 48), ranging from 24 to 66%. Five of ten institutions had their urology programs transitory or definitively closed due to the high burden costs. CONCLUSION: Adoption and development of robotic surgery in some public hospitals of Latin-America have been hindered by high costs.

Preliminary Results on the Evaluation of the Occurrence of Tetrodotoxin Associated to Marine Vibrio spp. in Bivalves from the Galician Rias (Northwest of Spain).

Tetrodotoxins (TTX) are a potent group of natural neurotoxins putatively produced by symbiotic microorganisms and affecting the aquatic environment. These neurotoxins have been recently found in some species of bivalves and gastropods along the European Coasts (Greece, UK, and The Netherlands) linked to the presence of high concentrations of Vibrio, in particular Vibrio parahaemolyticus. This study is focused on the evaluation of the presence of Vibrio species and TTX in bivalves (mussels, oysters, cockles, clams, scallops, and razor clams) from Galician Rias (northwest of Spain). The detection and isolation of the major Vibrio spp. and other enterobacterial populations have been carried out with the aim of screening for the presence of the pathways genes, poliketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) possibly involved in the biosynthesis of these toxins. Samples containing Vibrio spp. were analyzed by biochemical (API20E-galery) and genetic tests (PCR-RT). These samples were then screened for TTX toxicity by a neuroblastoma cell-based assay (N2a) and the presence of TTX was further confirmed by LC-MS/MS. TTX was detected in two infaunal samples. This is the first confirmation of the presence of TTX in bivalve molluscs from the Galician Rias.

Effects of NO2 exposure on daily mortality in São Paulo, Brazil.

BACKGROUND: Recent reports have suggested that air pollution mixtures represented by nitrogen dioxide (NO2) may have effects on human health, which are independent from those of particulate matter mass. We evaluate the association between NO2 and daily mortality among elderly using one- and multipollutant models. METHODS: This study was a daily time series of non-accidental and cause-specific mortality among the elderly living in São Paulo, Brazil, between 2000 and 2011. Effects of NO2, particulate matter smaller than 10µm (PM10), carbon monoxide (CO) and ozone (O3) were estimated in Poisson generalized additive models. The single lag effect at lags 0 and 1 days and the cumulative effect from 0 to lag 10 days were evaluated in one-, two-, three- and four-pollutant models. The cumulative risk index (CRI) recently proposed to analyze associations with health of multiple correlated pollutants was additionally estimated for each multipollutant model. RESULTS: An association between NO2, PM10, CO and O3 exposures and non-accidental and cause-specific deaths was found in one-pollutant models. NO2 effects remained significant in multipollutant models for non-accidental and circulatory deaths. The estimated CRIs suggested that circulatory deaths were mainly associated with NO2, and respiratory deaths mainly with CO and O3, regardless the lag. For non-accidental deaths, multipollutant models were associated with the highest CRI, with the main pollutants depending on the chosen lag. CONCLUSIONS: The results suggest that air pollution mixtures represented by NO2 have an effect on non-accidental and circulatory mortality, which is independent from PM10, CO and O3. The CRI was always larger than the risks associated with single pollutants.

Prediction of Activity Cliffs Using Condensed Graphs of Reaction Representations, Descriptor Recombination, Support Vector Machine Classification, and Support Vector Regression.

Activity cliffs (ACs) are formed by structurally similar compounds with large differences in activity. Accordingly, ACs are of high interest for the exploration of structure-activity relationships (SARs). ACs reveal small chemical modifications that result in profound biological effects. The ability to foresee such small chemical changes with significant biological consequences would represent a major advance for drug design. Nevertheless, only few attempts have been made so far to predict whether a pair of analogues is likely to represent an AC-and even fewer went further to quantitatively predict how "deep" a cliff might be. This might be due to the fact that such predictions must focus on compound pairs. Matched molecular pairs (MMPs), defined as pairs of structural analogs that are only distinguished by a chemical modification at a single site, are a preferred representation of ACs. Herein, we report new strategies for AC prediction that are based upon two different approaches: (i) condensed graphs of reactions, which were originally introduced for modeling of chemical reactions and were here adapted to encode MMPs, and, (ii) plain descriptor recombination-a strategy used for quantitative structure-property relationship (QSPR) modeling of nonadditive mixtures (MQSPR). By applying these concepts, ACs were encoded as single descriptor vectors used as input for support vector machine (SVM) classification and support vector regression (SVR), yielding accurate predictions of AC status (i.e., cliff vs noncliff) and potency differences, respectively. The latter were predicted in a compound order-sensitive manner returning the signed value of expected potency differences between AC compounds.

Predicting bioactive conformations and binding modes of macrocycles.

Macrocyclic compounds experience increasing interest in drug discovery. It is often thought that these large and chemically complex molecules provide promising candidates to address difficult targets and interfere with protein-protein interactions. From a computational viewpoint, these molecules are difficult to treat. For example, flexible docking of macrocyclic compounds is hindered by the limited ability of current docking approaches to optimize conformations of extended ring systems for pose prediction. Herein, we report predictions of bioactive conformations of macrocycles using conformational search and binding modes using docking. Conformational ensembles generated using specialized search technique of about 70 % of the tested macrocycles contained accurate bioactive conformations. However, these conformations were difficult to identify on the basis of conformational energies. Moreover, docking calculations with limited ligand flexibility starting from individual low energy conformations rarely yielded highly accurate binding modes. In about 40 % of the test cases, binding modes were approximated with reasonable accuracy. However, when conformational ensembles were subjected to rigid body docking, an increase in meaningful binding mode predictions to more than 50 % of the test cases was observed. Electrostatic effects did not contribute to these predictions in a positive or negative manner. Rather, achieving shape complementarity at macrocycle-target interfaces was a decisive factor. In summary, a combined computational protocol using pre-computed conformational ensembles of macrocycles as a starting point for docking shows promise in modeling binding modes of macrocyclic compounds.