Selection bias due to conditioning on a collider

Effect estimates may be biased when the study design or the data analysis is conditional on a collider—a variable that is caused by two other variables. Causal directed acyclic graphs are a helpful tool to identify colliders that may introduce selection bias in observational research.S

Effectiveness of mRNA vaccine boosters against infection with the SARS-CoV-2 omicron (B.1.1.529) variant in Spain: a nationwide cohort study

Factor de impacto: 25,71 Q1Background: The omicron (B.1.1.529) variant of SARS-CoV-2 has increased capacity to elude immunity and cause breakthrough infections. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters (third dose) against infection with the omicron variant by age, sex, time since complete vaccination, type of primary vaccine, and type of booster. Methods: In this nationwide cohort study, we linked data from three nationwide population registries in Spain (Vaccination Registry, Laboratory Results Registry, and National Health System registry) to select community-dwelling individuals aged 40 years or older, who completed their primary vaccine schedule at least 3 months before the start of follow-up, and had not tested positive for SARS-CoV-2 since the start of the pandemic. On each day between Jan 3, and Feb 6, 2022, we matched individuals who received a booster mRNA vaccine and controls of the same sex, age group, postal code, type of vaccine, time since primary vaccination, and number of previous tests. We estimated risk of laboratory-confirmed SARS-CoV-2 infection using the Kaplan-Meier method and compared groups using risk ratios (RR) and risk differences. Vaccine effectiveness was calculated as one minus RR. Findings: Between Jan 3, and Feb 6, 2022, 3 111 159 matched pairs were included in our study. Overall, the estimated effectiveness from day 7 to 34 after a booster was 51·3% (95% CI 50·2-52·4). Estimated effectiveness was 52·5% (51·3-53·7) for an mRNA-1273 booster and 46·2% (43·5-48·7) for a BNT162b2 booster. Effectiveness was 58·6% (55·5-61·6) if primary vaccination had been with ChAdOx1 nCoV-19 (Oxford-AstraZeneca), 55·3% (52·3-58·2) with mRNA-1273 (Moderna), 49·7% (48·3-51·1) with BNT162b2 (Pfizer-BioNTech), and 48·0% (42·5-53·7) with Ad26.COV2.S (Janssen). Estimated effectiveness was 43·6% (40·0-47·1) when the booster was administered between 151 days and 180 days after complete vaccination and 52·2% (51·0-53·3) if administered more than 180 days after primary scheduled completion. Interpretation: Booster mRNA vaccine-doses were moderately effective in preventing infection with the omicron variant of SARS-CoV-2 for over a month after administration, which indicates their suitability as a strategy to limit the health effects of COVID-19 in periods of omicron variant domination. Estimated effectiveness was higher for mRNA-1273 compared with BNT162b2 and increased with time between completed primary vaccination and booster.S

Effectiveness of non-pharmaceutical interventions in nine fields of activity to decrease SARS-CoV-2 transmission (Spain, September 2020–May 2021)

Background: We estimated the association between the level of restriction in nine different fields of activity and SARS-CoV-2 transmissibility in Spain, from 15 September 2020 to 9 May 2021. Methods: A stringency index (0–1) was created for each Spanish province (n = 50) daily. A hierarchical multiplicative model was fitted. The median of coefficients across provinces (95% bootstrap confidence intervals) quantified the effect of increasing one standard deviation in the stringency index over the logarithmic return of the weekly percentage variation of the 7-days SARS-CoV-2 cumulative incidence, lagged 12 days. Results: Overall, increasing restrictions reduced SARS-CoV-2 transmission by 22% (RR = 0.78; one-sided 95%CI: 0, 0.82) in 1 week, with highest effects for culture and leisure 14% (0.86; 0, 0.98), social distancing 13% (0.87; 0, 0.95), indoor restaurants 10% (0.90; 0, 0.95) and indoor sports 6% (0.94; 0, 0.98). In a reduced model with seven fields, culture and leisure no longer had a significant effect while ceremonies decreased transmission by 5% (0.95; 0, 0.96). Models R2 was around 70%. Conclusion: Increased restrictions decreased COVID-19 transmission. Limitations include remaining collinearity between fields, and somewhat artificial quantification of qualitative restrictions, so the exact attribution of the effect to specific areas must be done with caution.This work has been partially supported by GAIN (Galician Innovation Agency) and the Regional Ministry of Economy, Employment and Industry, Xunta de Galicia IN845D 2020/26 (Grant COV20/00604) through the ERDF (2014-2020). The research of DGU has been financed in part by the Spanish Agencia Estatal de Investigación under grants PID2021-122154NB-I00 and TED2021-129455B-I00, and by a 2021 BBVA Foundation project for research in Mathematics. He also acknowledges support from the EU under the 2014-2020 ERDF Operational Programme and the Department of Economy, Knowledge, Business and University of the Regional Government of Andalusia (FEDER-UCA18-108393).S

Comparison of oxidative stress markers in HIV-infected patients on efavirenz or atazanavir/ritonavir-based therapy

INTRODUCTION: Chronic low-grade inflammation and immune activation may persist in HIV patients despite effective antiretroviral therapy (ART). These abnormalities are associated with increased oxidative stress (OS). Bilirubin (BR) may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UGT1A1, thus increasing unconjugated BR levels, a distinctive feature of this drug. We compared changes in OS markers in HIV patients on ATV/r versus efavirenz (EFV)-based first-line therapies. MATERIALS AND METHODS: Cohort of the Spanish Research Network (CoRIS) is a multicentre, open, prospective cohort of HIV-infected patients naïve to ART at entry and linked to a biobank. We identified hepatitis C virus/hepatitis B virus (HCV/HBV) negative patients who started first-line ART with either ATV/r or EFV, had a baseline biobank sample and a follow-up sample after at least nine months of ART while maintaining initial regimen and being virologically suppressed. Lipoprotein-associated Phospholipase A2 (Lp-PLA2), Myeloperoxidase (MPO) and Oxidized LDL (OxLDL) were measured in paired samples. Marker values at one year were interpolated from available data. Multiple imputations using chained equations were used to deal with missing values. Change in the OS markers was modelled using multiple linear regressions adjusting for baseline marker values and baseline confounders. Correlations between continuous variables were explored using Pearson's correlation tests. RESULTS: 145 patients (97 EFV; 48 ATV/r) were studied. Mean (SD) baseline values for OS markers in EFV and ATV/r groups were: Lp-PLA2 [142.2 (72.8) and 150.1 (92.8) ng/mL], MPO [74.3 (48.2) and 93.9 (64.3) µg/L] and OxLDL [76.3 (52.3) and 82.2 (54.4) µg/L]. After adjustment for baseline variables patients on ATV/r had a significant decrease in Lp-PLA2 (estimated difference -16.3 [CI 95%: -31.4, -1.25; p=0.03]) and a significantly lower increase in OxLDL (estimated difference -21.8 [-38.0, -5.6; p<0.01] relative to those on EFV, whereas no differences in MPO were found. Adjusted changes in BR were significantly higher for the ATV/r group (estimated difference 1.33 [1.03, 1.52; p<0.01]). Changes in BR and changes in OS markers were significantly correlated. CONCLUSIONS: In virologically suppressed patients on stable ART, OS was lower in ATV/r-based regimens compared to EFV. We hypothesize these changes could be in part attributable to increased BR plasma levels.S

Comparison of oxidative stress markers in HIV-infected patients on efavirenz or atazanavir/ritonavir-based therapy

Introduction Chronic low‐grade inflammation and immune activation may persist in HIV patients despite effective antiretroviral therapy (ART). These abnormalities are associated with increased oxidative stress (OS). Bilirubin (BR) may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UGT1A1, thus increasing unconjugated BR levels, a distinctive feature of this drug. We compared changes in OS markers in HIV patients on ATV/r versus efavirenz (EFV)‐based first‐line therapies. Materials and Methods Cohort of the Spanish Research Network (CoRIS) is a multicentre, open, prospective cohort of HIV‐infected patients naïve to ART at entry and linked to a biobank. We identified hepatitis C virus/hepatitis B virus (HCV/HBV) negative patients who started first‐line ART with either ATV/r or EFV, had a baseline biobank sample and a follow‐up sample after at least nine months of ART while maintaining initial regimen and being virologically suppressed. Lipoprotein‐associated Phospholipase A2 (Lp‐PLA2), Myeloperoxidase (MPO) and Oxidized LDL (OxLDL) were measured in paired samples. Marker values at one year were interpolated from available data. Multiple imputations using chained equations were used to deal with missing values. Change in the OS markers was modelled using multiple linear regressions adjusting for baseline marker values and baseline confounders. Correlations between continuous variables were explored using Pearson's correlation tests. Results 145 patients (97 EFV; 48 ATV/r) were studied. Mean (SD) baseline values for OS markers in EFV and ATV/r groups were: Lp‐PLA2 [142.2 (72.8) and 150.1 (92.8) ng/mL], MPO [74.3 (48.2) and 93.9 (64.3) µg/L] and OxLDL [76.3 (52.3) and 82.2 (54.4) µg/L]. After adjustment for baseline variables patients on ATV/r had a significant decrease in Lp‐PLA2 (estimated difference −16.3 [CI 95%: −31.4, −1.25; p=0.03]) and a significantly lower increase in OxLDL (estimated difference −21.8 [−38.0, −5.6; p<0.01] relative to those on EFV, whereas no differences in MPO were found. Adjusted changes in BR were significantly higher for the ATV/r group (estimated difference 1.33 [1.03, 1.52; p<0.01]). Changes in BR and changes in OS markers were significantly correlated. Conclusions In virologically suppressed patients on stable ART, OS was lower in ATV/r‐based regimens compared to EFV. We hypothesize these changes could be in part attributable to increased BR plasma levels

HIV testing policies for migrants and ethnic minorities in EU/EFTA Member States.

In the context of an European Centre for Disease Prevention and Control (ECDC) research project, our objective was to describe current recommendations regarding HIV testing and counselling targeting migrants and ethnic minorities in the European Union/European Economic Area/European Free Trade Association (EU/EEA/EFTA) Member States. An on-line survey was conducted among 31 EU/EEA/EFTA Member States. The survey inquired on the existence of specific HIV testing and counselling recommendations or policies for migrants and/or ethnic minorities and the year of their publication. Additionally, we performed a review of national recommendations, guidelines or any other policy documents retrieved from an Internet search through the different countries' competent bodies. Twenty-nine (94%) country representatives responded the survey, and 28 documents from 27 countries were identified. National guidelines on HIV testing are heterogeneous and tailored, according to the epidemiological situation. Twenty-two countries identify migrants and four countries identify ethnic minorities as particularly vulnerable to HIV. Sixteen countries explicitly recommend offering an HIV test to migrants/ethnic minorities. Guidelines especially target people originating from HIV endemic countries, and benefits of HIV early detection are highlighted. HIV testing is not mandatory in any country, but some countries overtly facilitate this practice. Benefits of HIV testing in migrants and ethnic minorities, at both individual and community levels are recognized by many countries. In spite of this, not all countries identify the need to test these groups.European Centre for Disease Prevention and Control, Spanish Network of HIV/AIDS Research [RIS- RD06/0006] and the Biomedical Research Centre Network for Epidemiology and Public Health [CIBER de Epidemiología y Salud Pública].S

Clinically relevant transmitted drug resistance to first line antiretroviral drugs and implications for recommendations

Background The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. Methods We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007-2011. Using the Stanford algorithm "Low-level resistance", "Intermediate resistance" and "High-level resistance" categories were considered as "Resistant". Results 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8-7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9-9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8-2.9) vs. 3.6% (2.9-4.3) by the WHO list] and PIs [0.8% (0.4-1.1) vs. 1.7% (1.2-2.2)], while it was higher for NNRTIs [4.6% (3.8-5.3) vs. 3.7% (3.0-4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02). Conclusions Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations

The impact of COVID-19 on sick leave of the persons working in nursing homes in Spain. Usefulness of sick leave for the surveillance of the pandemic evolution.

[ES] Fundamentos: Los centros sociosanitarios representaron entornos de alto riesgo de contagio por SARS-CoV-2, tanto para los residentes como para las personas trabajadoras. Se evaluó el impacto en términos de incapacidad temporal (IT) por COVID-19 en las personas que trabajan en centros sociosanitarios y se comparó con la evolución de la pandemia en la población general de 16 a 65 años, para valorar la utilidad de la IT como indicador complementario de la epidemia por SARS-CoV-2. Métodos: Se realizó un estudio descriptivo de todos los procesos de incapacidad temporal por COVID-19 registrados entre el 15 de febrero de 2020 y el 1 de mayo de 2021 en establecimientos residenciales. Se obtuvieron las ratios de incapacidad temporal por contacto estrecho/incapacidad temporal por infección, las tasas de incapacidad temporal por 100.000 afiliados/ocupados y se compararon con la incidencia acumulada de casos COVID-19 notificados a la Red Nacional de Vigilancia Epidemiológica (RENAVE). Resultados: Se registraron 261.892 procesos de incapacidad temporal. La mediana de la ratio de incapacidad temporal por contacto estrecho/incapacidad temporal por infección en residencias fue de 1,8 (Rango intercuartílico, RIC: 1,1- 3,3), con valores menores a 1 en periodos. Las IT por infección fueron superiores en número, tasa y anteriores en el tiempo a los casos registrados en RENAVE. Por tipo de residencia, la tasa de incapacidad temporal osciló entre 81.679/100.000 ocupados en asistencia en establecimientos residenciales con cuidados sanitaros y 4.895/100.000 en otros establecimientos residenciales. Conclusiones: Los resultados confirmaron el enorme impacto que tuvo la COVID-19 en los centros sociosanitarios y la desigualdad que ha caracterizado este impacto. Apoyan también la posible utilización de la incapacidad temporal como fuente de información alternativa para la vigilancia epidemiológica y de salud pública, lo cual resulta de especial interés en este momento en el que se está planteando una transición en la vigilancia del COVID-19 hacia un sistema que ya no incluya una vigilancia individualizada universal. [EN] Background: The nursing homes represented high-risksettings for SARS-CoV-2 infection, both for residents and forthe employees. The COVID-19 impact on long-term care facilities (LTCFs) is evaluated, measured through the employees sick leave (SL). The pandemic evolution in the general population aged between 16 and 65 years was analyzed together with the sick leave to assess the latter as a complementary indicator of the SARS-CoV-2 surveillance. Methods: A descriptive study of all sick leave processes due to COVID-19 recorded between February 15th 2020and May 1st 2021 in nursing homes was carried out. The close contact sick leave/infection sick leave ratios, the 100,000 affiliated/occupied sick leave rates were computed and compared with the COVID-19 cases cumulative incidence notified to the National Network of epidemiological Surveillance (RENAVE). Results: 261.892 SL processes were recorded. The close contact sick leave/infection sick leave median ratio in nursing homes was 1.8 (Interquartile range, ICR: 1.1-3.3), with values lower than 1 at certain periods. The infection sick leaves were higher in number and ratio and prior to the cases recorded in RENAVE. The sick leave ratio ranged between 81.679/100.000 occupied in nursing homes with medical careand 4.895/100.000 in other residential facilities. Conclusions: The results confirmed the dramatic impact of COVID-19 in nursing homes and the inequalities characterizing this impact. They also confirmed the potential use of sick leave as an alternative source for epidemiological and public health surveillance, especially now, when the transitionof the COVID-19 surveillance to a system not including universal individual surveillance is being discussed.S

Comparative severity of COVID-19 cases caused by Alpha, Delta or Omicron SARS-CoV-2 variants and its association with vaccination

[EN] Background: This study compares the severity of SARS-CoV-2 infections caused by Alpha, Delta or Omicron variants in periods of co-circulation in Spain, and estimates the variant-specific association of vaccination with severe disease. Methods: SARS-CoV-2 infections notified to the national epidemiological surveillance network with information on genetic variant and vaccination status were considered cases if they required hospitalisation or controls otherwise. Alpha and Delta were compared during June-July 2021; and Delta and Omicron during December 2021-January 2022. Adjusted odds ratios (aOR) were estimated using logistic regression, comparing variant and vaccination status between cases and controls. Results: We included 5,345 Alpha and 11,974 Delta infections in June-July and 5,272 Delta and 10,578 Omicron in December-January. Unvaccinated cases of Alpha (aOR: 0.57; 95% CI: 0.46-0.69) or Omicron (0.28; 0.21-0.36) had lower probability of hospitalisation vs. Delta. Complete vaccination reduced hospitalisation, similarly for Alpha (0.16; 0.13-0.21) and Delta (June-July: 0.16; 0.14-0.19; December-January: 0.36; 0.30-0.44) but lower from Omicron (0.63; 0.53-0.75) and individuals aged 65+ years. Conclusion: Results indicate higher intrinsic severity of the Delta variant, compared with Alpha or Omicron, with smaller differences among vaccinated individuals. Nevertheless, vaccination was associated to reduced hospitalisation in all groups. [ES]Introducción: El objetivo es comprar la gravedad de las infecciones por las variantes Alfa, Delta y Ómicron del SARS-CoV-2 en periodos de co-circulación en España, y estimar la asociación entre vacunación y gravedad en cada variante. Métodos: Las infecciones por SARS-CoV-2 notificadas a la red nacional de vigilancia epidemiológica con información sobre la variante viral y el estado de vacunación se clasificaron como casos si habían requerido hospitalización, o como controles en caso contrario. Alfa y Delta se compararon durante junio-julio de 2021, y Delta y Ómicron durante diciembre de 2021-enero de 2022. Se estimaron odds ratios ajustadas (ORa) mediante regresión logística, comparando la variante y el estado de vacunación entre casos y controles. Resultados: Se incluyeron 5.345 infecciones por variante Alfa y 11.974 por Delta en junio-julio y 5.272 infecciones por Delta y 10.578 por Ómicron en diciembre-enero. Los casos no vacunados por Alfa (aOR: 0,57; IC 95%: 0,46-0,69) u Ómicron (0,28; IC 95%: 0,21-0,36) tuvieron menor probabilidad de hospitalización comparados con Delta. La vacunación completa se asoció a menor hospitalización de forma similar para Alfa (0,16; IC 95%: 0,13-0,21) y Delta (junio-julio: 0,16; IC 95%: 0,14-0,19; diciembre-enero: 0,36; IC 95%: 0,30-0,44) pero menor para Ómicron (0,63; IC 95%: 0,53-0,75) y para individuos con 65+ años. Conclusión: Los resultados indican una mayor gravedad intrínseca de la variante Delta comparada con Alfa u Ómicron, con menor diferencia entre personas vacunadas. La vacunación se asoció a menor hospitalización en todos los grupos.In this study the identification of variants by genomic sequencing has been partially supported by HERA-Incubator ECDC/GRANT/2021/024-Enhancing Whole Genome Sequencing (WGS) and/or Reverse Transcription Polymerase Chain Reaction (RT-PCR) national infrastructures and capacities to respond to the Covid-19 pandemic in Spain.S