Unravelling the role of the mandatory use of face covering masks for the control of SARS-CoV-2 in schools: a quasi-experimental study nested in a population-based cohort in Catalonia (Spain).

OBJECTIVE: To assess the effectiveness of mandatory use of face covering masks (FCMs) in schools during the first term of the 2021-2022 academic year. DESIGN: A retrospective population-based study. SETTING: Schools in Catalonia (Spain). POPULATION: 599 314 children aged 3-11 years attending preschool (3-5 years, without FCM mandate) and primary education (6-11 years, with FCM mandate). STUDY PERIOD: From 13 September to 22 December 2021 (before Omicron variant). INTERVENTIONS: A quasi-experimental comparison between children in the last grade of preschool (5 years old), as a control group, and children in year 1 of primary education (6 years old), as an interventional group. MAIN OUTCOME MEASURES: Incidence of SARS-CoV-2, secondary attack rates (SARs) and effective reproductive number (R*). RESULTS: SARS-CoV-2 incidence was significantly lower in preschool than in primary education, and an increasing trend with age was observed. Six-year-old children showed higher incidence than 5 year olds (3.54% vs 3.1%; OR 1.15 (95% CI 1.08 to 1.22)) and slightly lower but not statistically significant SAR (4.36% vs 4.59%; incidence risk ratio 0.96 (95% CI 0.82 to 1.11)) and R* (0.9 vs 0.93; OR 0.96 (95% CI 0.87 to 1.09)). Results remained consistent using a regression discontinuity design and linear regression extrapolation approaches. CONCLUSIONS: We found no significant differences in SARS-CoV-2 transmission due to FCM mandates in Catalonian schools. Instead, age was the most important factor in explaining the transmission risk for children attending school.

Low transmission of SARS-CoV-2 derived from children in family clusters: An observational study of family households in the Barcelona Metropolitan Area, Spain.

BACKGROUND: Family clusters offer a good opportunity to study viral transmission in a stable setting. We aimed to analyze the specific role of children in transmission of SARS-CoV-2 within households. METHODS: A prospective, longitudinal, observational study, including children with documented acute SARS-CoV-2 infection attending 22 summer-schools in Barcelona, Spain, was performed. Moreover, other patients and families coming from other school-like environments that voluntarily accessed the study were also studied. A longitudinal follow-up (5 weeks) of the family clusters was conducted to determine whether the children considered to be primary cases were able to transmit the virus to other family members. The household reproduction number (Re*) and the secondary attack rate (SAR) were calculated. RESULTS: 1905 children from the summer schools were screened for SARS-CoV-2 infection and 22 (1.15%) tested positive. Moreover, 32 additional children accessed the study voluntarily. Of these, 37 children and their 26 households were studied completely. In half of the cases (13/26), the primary case was considered to be a child and secondary transmission to other members of the household was observed in 3/13, with a SAR of 14.2% and a Re* of 0.46. Conversely, the SAR of adult primary cases was 72.2% including the kids that gave rise to the contact tracing study, and 61.5% without them, and the estimated Re* was 2.6. In 4/13 of the paediatric primary cases (30.0%), nasopharyngeal PCR was persistently positive > 1 week after diagnosis, and 3/4 of these children infected another family member (p<0.01). CONCLUSIONS: Children may not be the main drivers of the infection in household transmission clusters in the study population. A prolonged positive PCR could be associated with higher transmissibility.

Assessing wastewater-based epidemiology for the prediction of SARS-CoV-2 incidence in Catalonia.

While wastewater-based epidemiology has proven a useful tool for epidemiological surveillance during the COVID-19 pandemic, few quantitative models comparing virus concentrations in wastewater samples and cumulative incidence have been established. In this work, a simple mathematical model relating virus concentration and cumulative incidence for full contagion waves was developed. The model was then used for short-term forecasting and compared to a local linear model. Both scenarios were tested using a dataset composed of samples from 32 wastewater treatment plants and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) incidence data covering the corresponding geographical areas during a 7-month period, including two contagion waves. A population-averaged dataset was also developed to model and predict the incidence over the full geography. Overall, the mathematical model based on wastewater data showed a good correlation with cumulative cases and allowed us to anticipate SARS-CoV-2 incidence in one week, which is of special relevance in situations where the epidemiological monitoring system cannot be fully implemented.

Individual prevention and containment measures in schools in Catalonia, Spain, and community transmission of SARS-CoV-2 after school re-opening.

BACKGROUND: Despite their clear lesser vulnerability to COVID-19, the extent by which children are susceptible to getting infected by SARS-CoV-2 and their capacity to transmit the infection to other people remains inadequately characterized. We aimed to evaluate the role of school reopening and the preventive strategies in place at schools in terms of overall risk for children and community transmission, by comparing transmission rates in children as detected by a COVID-19 surveillance platform in place in Catalonian Schools to the incidence at the community level. METHODS AND FINDINGS: Infections detected in Catalan schools during the entire first trimester of classes (September-December 2020) were analysed and compared with the ongoing community transmission and with the modelled predicted number of infections. There were 30.486 infections (2.12%) documented among the circa 1.5M pupils, with cases detected in 54.0% and 97.5% of the primary and secondary centres, respectively. During the entire first term, the proportion of "bubble groups" (stable groups of children doing activities together) that were forced to undergo confinement ranged between 1 and 5%, with scarce evidence of substantial intraschool transmission in the form of chains of infections, and with ~75% of all detected infections not leading to secondary cases. Mathematical models were also used to evaluate the effect of different parameters related to the defined preventive strategies (size of the bubble group, number of days of confinement required by contacts of an index case). The effective reproduction number inside the bubble groups in schools (R*), defined as the average number of schoolmates infected by each primary case within the bubble, was calculated, yielding a value of 0.35 for primary schools and 0.55 for secondary schools, and compared with the outcomes of the mathematical model, implying decreased transmissibility for children in the context of the applied measures. Relative homogenized monthly cumulative incidence ([Formula: see text]) was assessed to compare the epidemiological dynamics among different age groups and this analysis suggested the limited impact of infections in school-aged children in the context of the overall community incidence. CONCLUSIONS: During the fall of 2020, SARS-CoV-2 infections and COVID-19 cases detected in Catalan schools closely mirrored the underlying community transmission from the neighbourhoods where they were set and maintaining schools open appeared to be safe irrespective of underlying community transmission. Preventive measures in place in those schools appeared to be working for the early detection and rapid containment of transmission and should be maintained for the adequate and safe functioning of normal academic and face-to-face school activities.

Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Children in Summer Schools Applying Stringent Control Measures in Barcelona, Spain.

BACKGROUND: Understanding the role of children in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission is critical to guide decision-making for schools in the pandemic. We aimed to describe the transmission of SARS-CoV-2 among children and adult staff in summer schools. METHODS: During July 2020, we prospectively recruited children and adult staff attending summer schools in Barcelona who had SARS-CoV-2 infection. Primary SARS-CoV-2 infections were identified through (1) a surveillance program in 22 summer schools of 1905 participants, involving weekly saliva sampling for SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) during 2-5 weeks; and (2) cases identified through the Catalonian Health Surveillance System of children diagnosed with SARS-CoV-2 infection by nasopharyngeal RT-PCR. All centers followed prevention protocols: bubble groups, handwashing, face masks, and conducting activities mostly outdoors. Contacts of a primary case within the same bubble were evaluated by nasopharyngeal RT-PCR. Secondary attack rates and the effective reproduction number in summer schools (Re*) were calculated. RESULTS: Among the >2000 repeatedly screened participants, 30 children and 9 adults were identified as primary cases. A total of 253 close contacts of these primary cases were studied (median, 9 [interquartile range, 5-10] for each primary case), among which 12 new cases (4.7%) were positive for SARS-CoV-2. The Re* was 0.3, whereas the contemporary rate in the general population from the same areas in Barcelona was 1.9. CONCLUSIONS: The transmission rate of SARS-CoV-2 infection among children attending school-like facilities under strict prevention measures was lower than that reported for the general population. This suggests that under preventive measures schools are unlikely amplifiers of SARS-CoV-2 transmission, supporting current recommendations for school opening.

Age-dependency of the Propagation Rate of Coronavirus Disease 2019 Inside School Bubble Groups in Catalonia, Spain.

BACKGROUND: We analyzed contagions of coronavirus disease 2019 inside school bubble groups in Catalonia, Spain, in the presence of strong nonpharmaceutical interventions from September to December 2020. More than 1 million students were organized in bubble groups and monitored and analyzed by the Health and the Educational departments. METHODS: We had access to 2 data sources, and both were employed for the analysis, one is the Catalan school surveillance system and the other of the educational department. As soon as a positive index case is detected by the health system, isolation is required for all members of the bubble group, in addition to a mandatory proactive systematic screening of each individual. All infected cases are reported. It permits the calculation of the average reproductive number (R*), corresponding to the average number of infected individuals per index case. RESULTS: We found that propagation inside of the bubble group was small. Among 75% index cases, there was no transmission to other members in the classroom, with an average R* across all ages inside the bubble of R* = 0.4. We found a significant age trend in the secondary attack rates, with the R* going from 0.2 in preschool to 0.6 in high school youth. CONCLUSIONS: The secondary attack rate depends on the school level and therefore on the age. Super-spreading events (outbreaks of 5 cases or more) in childhood were rare, only occurring in 2.5% of all infections triggered from a pediatric index case.

Stochastic coupled map model of subcellular calcium cycling in cardiac cells.

In this study, we analyze a nonlinear map model of intracellular calcium (Ca) and voltage in cardiac cells. In this model, Ca release from the sarcoplasmic reticulum (SR) occurs at spatially distributed dyadic junctions that are diffusively coupled. At these junctions, release occurs with a probability that depends on key variables such as the SR load and the diastolic interval. Using this model, we explore how nonlinearity and stochasticity determine the spatial distribution of Ca release events within a cardiac cell. In particular, we identify a novel synchronization transition, which occurs at rapid pacing rates, in which the global Ca transient transitions from a period 2 response to a period 1 response. In the global period 2 response dyadic junctions fire in unison, on average, on alternate beats, while in the period 1 regime, Ca release at individual dyads is highly irregular. A close examination of the spatial distribution of Ca reveals that in the period 1 regime, the system coarsens into spatially out-of-phase regions with a length scale much smaller than the system size, but larger than the spacing between dyads. We have also explored in detail the coupling to membrane voltage. We study first the case of positive coupling, where a large Ca transient promotes a long action potential duration (APD). Here, the coupling to voltage synchronizes Ca release so that the system exhibits a robust period 2 response that is independent of initial conditions. On the other hand, in the case of negative coupling, where a large Ca transient tends to shorten the APD, we find a multitude of metastable states which consist of complex spatially discordant alternans patterns. Using an analogy to equilibrium statistical mechanics, we show that the spatial patterns observed can be explained by a mapping to the Potts model, with an additional term that accounts for a global coupling of spin states. Using this analogy, we argue that Ca cycling in cardiac cells exhibits complex spatiotemporal patterns that emerge via first or second order phase transitions. These results show that voltage and Ca can interact in order to induce complex subcellular responses, which can potentially lead to heart rhythm disorders.

Role of connectivity and fluctuations in the nucleation of calcium waves in cardiac cells.

Spontaneous calcium release (SCR) occurs when ion channel fluctuations lead to the nucleation of calcium waves in cardiac cells. This phenomenon is important since it has been implicated as a cause of various cardiac arrhythmias. However, to date, it is not understood what determines the timing and location of spontaneous calcium waves within cells. Here, we analyze a simplified model of SCR in which calcium release is modeled as a stochastic processes on a two-dimensional network of randomly distributed sites. Using this model we identify the essential parameters describing the system and compute the phase diagram. In particular, we identify a critical line which separates pinned and propagating fronts, and show that above this line wave nucleation is governed by fluctuations and the spatial connectivity of calcium release units. Using a mean-field analysis we show that the sites of wave nucleation are predicted by localized eigenvectors of a matrix representing the network connectivity of release sites. This result provides insight on the interplay between connectivity and fluctuations in the genesis of SCR in cardiac myocytes.

Publisher's Note: Role of connectivity and fluctuations in the nucleation of calcium waves in cardiac cells [Phys. Rev. E 92, 052715 (2015)].

This corrects the article DOI: 10.1103/PhysRevE.92.052715.

The timing statistics of spontaneous calcium release in cardiac myocytes.

A variety of cardiac arrhythmias are initiated by a focal excitation that disrupts the regular beating of the heart. In some cases it is known that these excitations are due to calcium (Ca) release from the sarcoplasmic reticulum (SR) via propagating subcellular Ca waves. However, it is not understood what are the physiological factors that determine the timing of these excitations at both the subcellular and tissue level. In this paper we apply analytic and numerical approaches to determine the timing statistics of spontaneous Ca release (SCR) in a simplified model of a cardiac myocyte. In particular, we compute the mean first passage time (MFPT) to SCR, in the case where SCR is initiated by spontaneous Ca sparks, and demonstrate that this quantity exhibits either an algebraic or exponential dependence on system parameters. Based on this analysis we identify the necessary requirements so that SCR occurs on a time scale comparable to the cardiac cycle. Finally, we study how SCR is synchronized across many cells in cardiac tissue, and identify a quantitative measure that determines the relative timing of SCR in an ensemble of cells. Using this approach we identify the physiological conditions so that cell-to-cell variations in the timing of SCR is small compared to the typical duration of an SCR event. We argue further that under these conditions inward currents due to SCR can summate and generate arrhythmogenic triggered excitations in cardiac tissue.

Dependency of calcium alternans on ryanodine receptor refractoriness.

BACKGROUND: Rapid pacing rates induce alternations in the cytosolic calcium concentration caused by fluctuations in calcium released from the sarcoplasmic reticulum (SR). However, the relationship between calcium alternans and refractoriness of the SR calcium release channel (RyR2) remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: To investigate how ryanodine receptor (RyR2) refractoriness modulates calcium handling on a beat-to-beat basis using a numerical rabbit cardiomyocyte model. We used a mathematical rabbit cardiomyocyte model to study the beat-to-beat calcium response as a function of RyR2 activation and inactivation. Bi-dimensional maps were constructed depicting the beat-to-beat response. When alternans was observed, a novel numerical clamping protocol was used to determine whether alternans was caused by oscillations in SR calcium loading or by RyR2 refractoriness. Using this protocol, we identified regions of RyR2 gating parameters where SR calcium loading or RyR2 refractoriness underlie the induction of calcium alternans, and we found that at the onset of alternans both mechanisms contribute. At low inactivation rates of the RyR2, calcium alternans was caused by alternation in SR calcium loading, while at low activation rates it was caused by alternation in the level of available RyR2s. CONCLUSIONS/SIGNIFICANCE: We have mapped cardiomyocyte beat-to-beat responses as a function of RyR2 activation and inactivation, identifying domains where SR calcium load or RyR2 refractoriness underlie the induction of calcium alternans. A corollary of this work is that RyR2 refractoriness due to slow recovery from inactivation can be the cause of calcium alternans even when alternation in SR calcium load is present.