The COVID-19 pandemic has a large impact worldwide and is known to particularly affect the older population. This paper outlines the protocol for external validation of prognostic models predicting mortality risk after presentation with COVID-19 in the older population. These prognostic models were originally developed in an adult population and will be validated in an older population (≥ 70 years of age) in three healthcare settings: the hospital setting, the primary care setting, and the nursing home setting.Based on a living systematic review of COVID-19 prediction models, we identified eight prognostic models predicting the risk of mortality in adults with a COVID-19 infection . These eight models will be validated in six different cohorts of the Dutch older population . All prognostic models will be validated in a hospital setting while the GAL-COVID-19 mortality model will be validated in hospital, primary care, and nursing home settings. The study will include individuals ≥ 70 years of age with a highly suspected or PCR-confirmed COVID-19 infection from March 2020 to December 2020 . The predictive performance will be evaluated in terms of discrimination, calibration, and decision curves for each of the prognostic models in each cohort individually. For prognostic models with indications of miscalibration, an intercept update will be performed after which predictive performance will be re-evaluated.Insight into the performance of existing prognostic models in one of the most vulnerable populations clarifies the extent to which tailoring of COVID-19 prognostic models is needed when models are applied to the older population. Such insight will be important for possible future waves of the COVID-19 pandemic or future pandemics.The online version contains supplementary material available at 10.1186/s41512-023-00144-2. COVID-19 has a large impact worldwide, causing over 6 million deaths . In the Hundreds of prognostic models have been developed to quantify (differences in) mortality risk or other outcomes in COVID-19 patients and to identify individuals at greater risk of developing various future health outcomes . COVID-1In this protocol, we describe a comprehensive external validation study to evaluate the predictive performance of eight prognostic models in the older population, defined as individuals aged 70 and older, in hospital, primary care, and nursing home settings. The predictive performance of the prognostic models will be evaluated in a different population than they were derived on, being the older population of individuals aged 70 and older compared to the general adult population. One model will be evaluated in all healthcare settings  to assess predictive performance across settings.We have adhered to the TRIPOD guidelines checklist for external validation studies  in reporwww.covid-precise.org) [www.probast.org) [In the living systematic review of diagnostic and prognostic prediction models for COVID-19 (ise.org) , all pubast.org) , 12, a qast.org) , CUCAF-Sast.org) , CUCA-SFast.org) , and QCOast.org)  for maleast.org)  and NEWSast.org) ) were exast.org) , 4C Mortast.org) , Xie modast.org) , and Wanast.org) ) and werast.org) , CURB65 ast.org) , and SOFast.org) ) , primary care setting 2 cohorts), and nursing home setting (1 cohort)  presenting with highly suspected or reverse transcription polymerase chain reaction (RT-PCR) confirmed COVID-19 from March 2020 to December 2020 in hospital, primary care, and nursing home settings.Before the widespread use of the RT-PCR test for COVID-19 diagnosis, participants were included using proxy criteria. In the hospital cohorts , the reported respiratory diseases that had COVID-like symptomology are used as an inclusion criterion until 31 March 2020. From April 2020 onwards, a confirmed RT-PCR test for COVID-19 is used as an inclusion criterion. In the primary care cohorts (PHARMO and JHN/ANH/AHA), the participants are included based on free text information and reports of respiratory infections. From June 2020 onwards, ICPC R83.03 for COVID-19 infection is used as an inclusion criterion. The nursing home cohort (Ysis) used RT-PCR as an inclusion criterion. Only participant data on the first presentation or admission of COVID-19 will be included. In the three hospital cohorts, admissions with a duration fewer than 7 days between discharge and readmission will be considered a single hospital admission.All prediction models have mortality as the predicted outcome Table . In all Definitions and timing of the predictor variables for the eight models were extracted from original publications Table . RecordeWe will externally validate the eight COVID-19 prognostic models in the six cohorts of older patients with COVID-19, aiming to assess their predictive performance when transported from a general adult population to a specific older population. The performance of the GAL-COVID-19 model is assessed across the three healthcare settings. The GAL-COVID-19 mortality model was developed in a primary care setting  and will be validated across different settings  . The 4C Participant characteristics and predictor information will be described in all study cohorts  to identify differences in case-mix between the development and validation study populations . These cThe missing data will be described to determine possible reasons for and patterns in missingness . Based oFor each prognostic model, we will apply the model according to the authors’ original descriptions and evaluate its predictive performance. We will evaluate discrimination  and calibration  in each cohort . DiscrimCalibration will be assessed by visualizing the calibration of expected versus observed risk using LOESS-smoothed plots on stacked imputed data sets . The GALDecision curve analyses will be performed to quantify the net benefit achieved by each model for predicting the originally intended endpoint across a range of risk thresholds ranging from zero to one .Prediction models showing miscalibration will be adjusted using an intercept update, and predictive performance will be re-assessed for the recalibrated model.Two sensitivity analyses will be performed to assess the variation in the predictive performance of the eight COVID-19 prognostic models when implemented in different time periods: January 2021 to December 2021 and March 2020 to December 2021. Additionally, predictive performance in estimating the 90-day mortality risk will be evaluated in cohorts that have data available on this outcome .Using national statistics from July 2020 to December 2021, the COVID-related mortality fraction for the older population (≥ 70 years) living at home in the Netherlands (including self-reported COVID-19-positive patients) was around 3% . Since wThis external validation study will assess the predictive performance of pre-existing clinical and COVID-19-specific prognostic models in the older population. Our study will reveal the validity of these COVID-19 prognostic models in one of the most vulnerable populations, the older population, as well as give insight into the requirements for tailored prediction models for the older population in future COVID-19 waves or pandemics.While previous studies have largely focused on external validation of COVID-19 prediction models in the general adult population , 40, 41,External validation in multiple cohorts across different healthcare settings allows for the assessment of between-setting heterogeneity in predictive performance and applicability at different points of care in older COVID-19 patients. This is one of the first studies to evaluate prognostic models for COVID-19 disease in individuals living in nursing homes.There are certain challenges that we anticipate encountering while conducting this research. Definitions of participant inclusion and predictor measurement procedures are expected to differ across cohorts. Although we have carefully planned to collect information on the definition of a COVID-19 infection and predictor measurements for each cohort, we cannot rule out the possibility of heterogeneity occurring across different settings and its effects on model performance . HoweverA limitation of this study is that not all low risk of bias COVID-19 prognostic models identified by the living systematic review could be included in this external validation. This was due to the lack of predictor information available in the cohorts. Similarly, predictor measurements and incidence of mortality due to COVID-19 can vary over time due to newer variants, better medical management, and improved vaccination coverage . These tExternal validation of newer and existing COVID-19 prognostic models can provide evidence about their predictive performance when implemented in the older population as tools of effective risk stratification and in aiding decision-making for targeted and timely clinical interventions.Additional file 1: Supplementary file 1. Description of excluded prognostic models.Additional file 2: Supplementary file 2. Prediction models and risk scores.Additional file 3: Supplementary file 3. Predictor measurements in derivation and validation cohorts.Additional file 4: Supplementary file 4. TRIPOD checklist for validation of prediction model


Moreover, data collection time was a significant factor explaining parental willingness in the multivariable meta-regression, with a 13% decrease in parental willingness by each month increase in time, explaining 11.44% of variance. Qualitative synthesis results showed that parents’ COVID-19 vaccine knowledge, trust in theCOVID-19 vaccine, and facilitators in vaccination  were significant factors for higher willingness, while mental health problems  were significant factors for lower willingness. Given that the acceptance rate was relatively low (57%) and does not achieve the requirement of herd immunity , governments and healthcare authorities should try to elevate parents’ knowledge and trust in the COVID-19 vaccine, facilitate in vaccination, and reduce their mental difficulties to improve the overall vaccination rate among children.Currently, the best method to well control the spread of COVID-19 without severe mental health problems is to reach herd immunity. Therefore, the vaccination rate of the COVID-19 vaccine is critical. Among the populations, children are the vulnerable ones to get vaccinated; therefore, it is important to assess parents’ and guardians’ willingness to have their children vaccinated. The present systematic review and meta-analysis synthesized evidence to estimate the parents’ acceptance rate of COVID-19 vaccination toward their children. Additionally, factors explaining the acceptance rate were investigated. Four academic databases  together with Google Scholar were searched, and the references of the included publications were searched as well. Using the PECO-S framework , observational studies of cross-sectional, cohort, or case-control studies were included. The outcome was parents’ or guardians’ willingness to let their children be vaccinated. The studies included in the present review were restricted to English and peer-reviewed papers published between December 2019 and July 2022. A total of 98 papers across 69 different countries with 413,590 participants were included. The mean age of the parents was 39.10 (range: 18–70) years and that of their children was 8.45 (range: 0–18) years. The pooled estimated prevalence of parental acceptance to vaccinate their children with the COVID-19 vaccine was 57% (98 studies, 95% CI: 52–62%, I On 11 March 2020, WHO declared COVID-19 as a global pandemic, which has led to serious disruptions in the economy and society ,4,5,6. BIn order to overcome the limitations of school time reduction during the pandemic, immunization seems to be the safest and most cost-effective health intervention implemented throughout history, saving millions of lives annually ,14. To dVaccination in children often requires the consent of their parents or guardians . To faciThe purpose of this study is to investigate the prevalence and factors affecting the acceptance of the COVID-19 vaccine for children under legal age among their parents. Specifically, the present study investigated children’s vaccination attitudes, whether their parents have been vaccinated against COVID-19, parents’ age, etc. According to our literature review, prior systematic review and meta-analysis studies did not consider the diverse subgroups when synthesizing data to examine the variables related to the acceptance of the COVID-19 vaccine, especially for children. Moreover, the latest studies recommend new vaccines against COVID-19 for children and adolescents ,41, whicAssessment of heterogeneity and its possible sources for estimated pooled prevalence of parental acceptance/willingness to vaccinate their children with the COVID-19 vaccine;Moderator analyses to determine influential variables sources for estimated pooled prevalence of parental acceptance/willingness to vaccinate their children with the COVID-19 vaccine;Determining influential factors for parents to accept COVID-19 vaccination for their children.This study aimed primarily to estimate the prevalence of parental acceptance/willingness to vaccinate their children with the COVID-19 vaccine. The secondary aims were:The study protocol was registered in the PROSPERO, International prospective register of systematic reviews under decree code of CRD42022333337 .The systematic review question was formulated using PECO-S framework. The PECO-S is a framework to formulate search questions assessing associations between exposures and outcomes in various fields of health . The PECWhat is the worldwide estimated prevalence of parental acceptance to vaccinate their children with the COVID-19 vaccine?The eligibility criteria based on PECO components were set as follows: (1) Population: parents or children’s guardian with no limitation regarding their demographic characteristics; (2) Exposure: COVID-19 pandemic; (3) Comparison: other populations other than children; (4) Outcome: Frequency or prevalence of COVID-19 vaccination acceptance (and/or no hesitance) or willingness to receive COVID-19 vaccines for children; and (5) Study design: observational studies including cross sectional, cohort, or case-control design.Other eligibility criteria include being published between December 2019 and July 2022, using English language, published as a peer-reviewed paper, reporting data on frequency or prevalence of parents or children’s guardian acceptance for their children’s COVID-19 vaccination.Academic databases including PubMed, Scopus, Web of Science (WoS), and ProQuest were systematically searched from the beginning of December 2019 to the end of July 2022. To have a more comprehensive search, reference lists of the included publications and medRxiv were independently searched.The main search terms included COVID-19, vaccine, parents, and children. The search strategy was developed using Boolean operators . The advanced search attributes of each database were considered and customizing the search syntax was adapted.In the first step, the title and abstract of all retrieved papers during the electronic and manual search processes were evaluated based on the inclusion criteria. This was followed by examination of the full texts of the potentially relevant articles based on the above-mentioned criteria. These processes were performed independently by two reviewers. Initial disagreements about the selection of studies were resolved through discussions.Data were extracted and recorded in pre-designed Excel datasheets by two reviewers independently. The following data were abstracted from each study: first-author name; country in which the study had been conducted as well as its income level and development status based on World Bank data; sample size; data collection date; parents and children ages; country location based on WHO regions; type of study; quality of study; and raw data to calculate prevalence of parents’ willingness of their children to be vaccinated against COVID-19.The Newcastle–Ottawa Scale (NOS) was used to assess risk of bias within included studies. This checklist evaluates the methodological quality of observational studies in the following three sections: selection, comparability, and outcome ,46. The 2 index [The selected summary measure of the present study for meta-analysis was the frequency or prevalence of the acceptance of the COVID-19 vaccine and their 95% confidence intervals (CIs). Numerical evidence regarding the prevalence of the COVID-19 vaccine acceptance was quantitatively synthesized using STATA software version 14. Meta-analysis using a random-effects model was conducted to consider both within-study and between-study variances . Severit2 index .Contributing factors influencing acceptance of COVID-19 vaccines were pooled using a meta-synthesis approach due to methodological heterogeneity of variables and measures.Funnel plot and Begg’s test were used to assess publication bias . Meta-trTo investigate moderators for COVID-19 vaccine acceptance, subgroup analysis and meta-regression were conducted.The initial search in four academic databases as well as Google Scholar resulted in retrieval of 8816 records: PubMed (n = 2553); Scopus (n = 1538); WoS (n = 1664); and ProQuest (n = 3061). After removing duplicates (n = 2986), the remaining manuscripts were screened based on their titles and abstracts. Finally, 145 papers appeared to be potentially eligible and their full texts were reviewed. In this process, 98 studies were pooled in the meta-analysis. The search process based on the PRISMA flowchart is illustrated in Ninety-eight studies comprised 413,590 participants from 69 different countries  were included. The highest number of studies were, respectively, conducted in AMR region , EUR region , WPR region , EMR region  and SEAR . Three studies were conducted as multi-country studies. Half of the studies (49 out of 98) were conducted in developed countries with high income (61 out of 98). The smallest sample size was 50 (from the U.S.), and the largest sample size was 227,740 (from Latin America and the Caribbean). Most study respondents (68.1%) were mothers. The mean age of parents was 39.10 (range between 18 and 70 years) and that of their children was 8.45 years (range between 0 and 18 years). Almost all studies used a cross-sectional design, with only two studies adopting a longitudinal design. The first study was conducted during February 2020 in China and the last one was conducted during January 2022 in Saudi Arabia. Most studies (58 out of 98) were categorized as being low-quality (or high risk of bias) studies. The total score of methodological quality is provided in , with de2: 99.92%, τ2: 0.06). The pooled estimated prevalence of parental acceptance to vaccinate their children with COVID-19 vaccine was 57%  and funnel plot. Based on the asymmetric funnel plot  of parents’ willingness to vaccinate their children with the COVID-19 vaccine. High-income countries had the lowest prevalence of parental willingness (52%) compared to low- and upper-intermediate-income countries . The lowest prevalence of parental willingness was observed in countries located in EMR compared to other regions . Data collection method was another significant variable influencing the pooled estimated parental willingness (p = 0.02). Studies collected data using phone interview had the lowest prevalence of willingness (35%). In the uni-variable meta-regression, data collection time was the only significant variable (p = 0.001) in predicting parental willingness. Multivariable meta-regression revealed that both data collection time (13% decrease in willingness by each increase in month) and country income level (7% decrease by increasing level of country income) were only significant predictors of parental willingness, which explained 11.44% of variance. None of the examined variables affect the heterogeneity.Predictors of COVID-19 vaccine willingness were assessed using subgroup analysis  and univTwo main categories of contributing factors  were identified among included studies using a qualitative synthesized approach.Parent self-vaccination ,134,136 History of COVID infection in parents, children, or family members did not have consistent results among included studies, showing positive association ,127,135,Parents’ age showed associations with their willingness to vaccinate their children. In most studies ,135,139,Mothers showed more hesitancy regarding their children’s vaccination compared to fathers in almost all studies ,116,133;Source of information regarding the vaccine influenced parents’ decision for their children’s vaccination. When they received information from healthcare providers, physicians, or pediatrics, they reported more willingness to vaccinate their children ,134,136.Parents reported more willingness to vaccinate children if their children are older ,138,139.Parents with a higher number of children reported inconsistent decisions regarding willingness to accept their children’s vaccination. A higher number of children was associated with less willingness in some studies ,105,108,Parents’ higher levels of stress, anxiety, and psychological distress were associated with less intention for children’s vaccination ,89,113. Parents’ education level showed inconsistent results in association with parental willingness for children’s vaccination. Some studies showed positive association of parents’ higher level of education with vaccination willingness ,126,134,Parents’ higher economic status showed positively higher association with parents’ willingness to vaccinate their children in almost all included studies ,113,125,Parents having chronic conditions reported higher prevalence of vaccination willingness for their children in three studies ,113, whiParents living in rural and sub-urban areas showed less willingness compared to those in urban areas ,113,125,Parents reported more children’s vaccination willingness when they believe that children vaccination is necessary to halt the pandemic and to reach a better national economic situation ,115,120.Worry about vaccine safety and its potential adverse effect ,140,142,Cost of vaccine ,59,73, vTrust in the COVID-19 vaccine ,128,142,Parents who reported more positive attitudes/beliefs toward vaccination ,107,109 Obtaining influenza immunization was a positive contributing factor for parents to accept their children’s COVID-19 vaccination ,121,140.Parents who perceived the risk of COVID-19 transition from children to adults ,106,118 Comparisons between domestic and foreign vaccine preference have been investigated in very few studies, and domestic vaccines were preferred by parents for themselves and their children ,142.2 > 90%) as similar to previous meta-analyses [In order to provide thorough estimation regarding parents’ willingness to have their children vaccinated, the present systematic review and meta-analysis synthesized data from studies published between December 2019 and July 2022 (98 papers). Apart from using meta-analysis to quantitatively synthesize parents’ acceptance rate of having children vaccinated, quantitative  and qualitative approaches have been used to synthesize the factors explaining parents’ willingness on their children’s vaccination. The synthesized results showed that the pooled estimated rate of parents’ willingness was 57% (95% CI = 52–62%). The low willingness to let children get vaccinated concurs with prior results reported by meta-analysis: 60.1% . Althouganalyses ,33, the Although having similar point-estimation in the parents’ willingness to have their children vaccinated, the present systematic review and meta-analysis had a narrower 95% CI than the two previous systematic review and meta-analyses ,37. A poData collection time was a significant factor explaining dropped willingness (13% decreased by each month increased). This can be explained by risk compensation ,144 and Although the parents’ willingness to have their children vaccinated, it is important to maintain the vaccination rate across time to adhere to the herd immunity. That is, a decreased vaccination rate may cause another wave of COVID-19 outbreak as documented in the literature. Therefore, governments and health authorities should have appropriate methods to maintain willingness of having children vaccinated among parents. The present systematic review and meta-analysis used the qualitative synthesis to find the importance of parents’ COVID-19 vaccine knowledge, trust in COVID-19 vaccine, and facilitators in vaccination  to improve their willingness to have children vaccinated. Moreover, mental health problems  might reduce parents’ willingness to have their children vaccinated. Therefore, government and healthcare authorities should consider building campaigns on COVID-19 vaccine knowledge improvement, COVID-19 vaccine support systems, and psychological distress reduction to elevate the parents’ willingness to have their children vaccinated.The strengths of the present systematic review and meta-analysis included (i) a comprehensive search of the literature across WHO-defined regions  to cover different ethnic and country populations; (ii) the use of robust methodology in reviewing papers ; (iii) synthesized findings from both quantitative and qualitative approaches to identify all potential factors explaining parents’ willingness of having children vaccinated.There are some limitations in the present systematic review and meta-analysis. First, the COVID-19 pandemic had different severities and progresses across the studied papers because different countries controlled the COVID-19 pandemic with different situations. Therefore, it is hard to control this important confounder when cumulating the empirical data across countries worldwide. Most of the studies did not report data regarding the time window between vaccines availability at national level or time of vaccine approval for different age groups and collecting the data. Second, almost all papers analyzed in the present systematic review and meta-analysis did not use a standardized instrument assessing willingness to children’s vaccination. Subsequently, there might have been some measurement biases across the analyzed papers. Third, over half of the papers were at high risk of bias and the findings of the present systematic review and meta-analysis could be affected by the high risk of bias. Therefore, additional studies with low risk of bias are needed to further investigate the issue regarding parents’ willingness to have their children vaccinated. Fourth, although the present systematic review and meta-analysis had sought several academic databases  and Google Scholar, the Google’s search engine was not used to search for potential grey literature. Therefore, it is possible that some relevant articles might not be included in the present systematic review and meta-analysis. Lastly, the following important information was not able to retrieve from the analyzed studies in the present systematic review and confounded the present findings: definitions of children ; available vaccine (brands or types); and the vaccination procedure .2 = 99.92%). Moreover, time appeared to be the primarily significant factor explaining high levels of acceptance. Qualitative synthesized results showed that parents’ knowledge on COVID-19 vaccine, trust in COVID-19 vaccine, and facilitators in vaccination  could improve parents’ acceptance of children vaccination. In contrast, parents’ mental difficulties  were barriers to improve their willingness.In conclusion, the present systematic review and meta-analysis updates the current understanding of parents’ willingness and hesitancy of letting their children get vaccinated. The willingness of the parents was generally low , although it was highly heterogeneous (I


Patients treated with radiotherapy to the chest region are at risk of cardiac sequelae, however, identification of those with greatest risk of complications remains difficult. Here, we sought to determine whether short-term changes in circulating miRNA expression are related to measures of cardiac dysfunction in follow-up.Two parallel patient cohorts were enrolled and followed up for 3 years after completion of RT to treat left-sided breast cancer. In the primary group (N=28) we used a a panel of 752 miRNAs to identify miRNAs associated with radiation and cardiac indices at follow up. In the second, independent cohort (N=56) we validated those candidate miRNAs with a targeted qPCR panel. In both cohorts. serum samples were collected before RT, 24h after the last dose and 1 month after RT; cardiac echocardiography was performed 2.5-3 year after RT.Seven miRNAs in the primary group showed marked changes in serum miRNAs immediately after RT compared to baseline and associations with cardiopulmonary dose-volume histogram metrics. Among those miRNAs: miR-15b-5p, miR-22-3p, miR-424-5p and miR-451a were confirmed to show significant decrease of expression 24 hours post-RT in the validation cohort. Moreover, miR-29c, miR-451 and miR-424 were correlated with the end-diastolic diameter of the left ventricle, which was also confirmed in multivariable analysis adjusting for RT-associated factors.We identified a subset of circulating miRNAs predictive for cardiac function impairment in patients treated for left-sided breast cancer, although longer clinical observation could determine if these can be used to predict major clinical endpoints. Breast cancer is the most common malignancy in women, accounting for 30% of all female cancers . RadiothThere is a variety of known risk factors of RACT, including presence or risk factors for coronary artery disease or other cardiovascular disease, the use of cardiotoxic chemotherapy, left-sided breast irradiation and earlier age at treatment , as wellRACT is a serious and complex process, however cellular changes are not specific to RT. Ionizing radiation accelerates and aggravates damage due to oxidative stress, inflammation, and mitochondrial and endoplasmic reticulum injury . This daCardiomyocytes and pacemaker cells are particularly sensitive to oxidative stress as they have limited capacity to cope with free radicals  and high vulnerability to cell membrane oxidation as these cells possess huge amounts of phospholipids , 15. ThiIt is upon development of fibrosis that symptoms and signs of cardiac toxicity are observed. Fibrosis ultimately leads to impaired ventricular filling and valvular function, acceleration of atherosclerosis  and incrRACT is mediated by inflammatory cytokines, including Transforming Growth Factor (TGF)-β . SeveralBesides classical biomarkers, blood levels of microRNAs (miRNAs) have been linked to radiation-induced toxicity of normal tissues , 29. MiRHere, we aimed to evaluate the potential of serum miRNAs as early biomarkers of cardiac toxicity in two prospectively followed cohorts of patients with breast cancer.The study was approved by the Bioethics Committee of the Medical University of Lodz, Poland (RNN/291/17/KE) on 5th September 2017. After obtaining approval we recruited women with left-sided breast cancer, consecutively admitted to the Radiotherapy Department between March 2017 and August 2017. All participants provided written informed consent for participation. Inclusion criteria were: histologically diagnosed breast cancer, planned radical treatment with highly conformal RT (3D or Volumetric Modulated Arc Therapy (VMAT) or Intensity Modulated Radiation Therapy (IMRT)) either alone or in combination with systemic treatment, baseline ejection fraction > 56%, age > 18 years and signed informed consent for the study. Patients treated with breast-conserving surgery or mastectomy were deemed eligible for the study. Exclusion criteria were: any cardiac disease at baseline or any advanced chronic disease . Total dose of radiation was 5000 cGy delivered in 200 cGy daily fractions over 5 days a week, with a boost to surgical bed up to total dose of 6000-6600 cGy in the BCS group. All patients after mastectomy with indications for RT underwent chest wall and axillary irradiation not including internal mammary nodes. No boost was performed for surgical scar. Target volumes were contoured according to RTOG guidelines. RT was planned in Eclipse (version 10) with AriaTM (version 10) software with pencil beam calculation algorithm. Treatment was performed on Varian iX Linacs.All patients underwent adjuvant chemotherapy prior to RT, if indicated. Concomitant treatment with systemic therapies other than chemotherapy was allowed, including treatment with trastuzumab, tamoxifen or aromatase inhibitors. From eligible patients, three serum samples were collected: prior to starting RT, 24 hours after receiving the last fraction of RT, and one month after the last fraction of RT, during a routine visit. All patients were invited for a follow-up visit 2.5-3 years after the end of RT, during which echocardiographic examination was performed. The echocardiographic variables evaluated at follow-up were directed at cardiac function evaluation with a particular focus on incipient dilatory cardiac dysfunction. A detailed list and reference ranges for the quantified parameters is presented in A validation group of patients was recruited between March 2018 and August 2019 in the Department of Radiation Oncology in Holy Cross Cancer Center in Kielce, following the same inclusion and exclusion criteria. This group was followed up for at least 2.5 years after completion of breast cancer treatment. Patients from the validation group had serum samples collected under the same protocol as in the primary group: at baseline, 24 hours after administering the last fraction of RT and 1 month after RT. At follow-up, the patients were evaluated echocardiographically by an experienced cardiologist using Philips iE33 ultrasound machine (manufactured in 2010) and S5-1 cardiac sector probe. The sample size was estimated to be twice that of the primary cohort. MiRNAs associated with radiation exposure (significant differences between the second and other timepoints) and relevant reference miRNAs, described below, were selected for testing in the validation group.Clinical characteristics of the study group and dosimetric data for the lungs and the heart are presented in ® Green master mix (Exiqon/Qiagen). Negative controls excluding template from the reverse transcription reaction was performed and profiled like the samples. In the validation cohort custom pick-and-mix arrays were designed (Exiqon/Qiagen) for miRNAs chosen for this part of the study and all miRNAs were quantified in triplicate. Amplification was performed in a LightCycler® 480 Real-Time PCR System (Roche) in 384 well plates. The amplification curves were analyzed using the Roche LC software, both for determination of Cq (by the 2nd derivative method) and for melting curve analysis. Raw data from qPCR panel profiling were uploaded as At all abovementioned timepoints, 2 ml of venous blood were collected to clotting activator-coated tubes  and processed as in prior studies , 36. BriThe amplification efficiency was calculated using algorithms similar to those of the LinReg software. All assays were inspected for distinct melting curves and the Tm was checked to be within known specifications for the assay. Furthermore, assayed miRNAs must have been detected with ≥ 5 Cqs less than the negative control, and with Cq < 37 to be included in the data analysis. miRNAs that did not pass these criteria were omitted from any further analysis. Cq was calculated as the 2nd derivative. All data were normalized to the average of assayed miRNAs detected in all samples (average – assay Cq). NormiRazor software was used to identify the best combination of normalizer miRNAs for validation group analysis out of all miRNAs expressed in sample in the primary cohort . All tesTo identify candidate biomarker miRNAs, we evaluated, using qPCR profiling, serum miRNA expression in samples collected at baseline, 24 hours and 1 month after radiotherapy, in the primary patient group  parameters. miRNAs that showed significant increases after RT (miR-30d and miR-24) were positively correlated with DVH parameters (Spearman R ranging between 0.27 to 0.73), while miRNAs decreased after RT  showed negative correlations with DVHs . Among diseases, cardiomegaly was the most significant association (adjusted p < 0.001) with miR-15b, miR-22, miR-24, miR-29c, miR-30d and miR-451a being reported as involved in this disease. Moreover, significant (adjusted p = 0.011) association was noted for all 7 miRNAs with the “MicroRNAs in cardiomyocyte hypertrophy” pathway and 5 out of 7 in the “dilated cardiomyopathy” one . Cardiac indices equaled: E/e’=10.03+/-2.70; E/A=0.90+/-0.28 and the Left ventricular end-diastolic diameter = 31.63+/-4.00 mm respectively.In this validation, the effects exerted by RT on the expression of 7 miRNAs were similar to those identified in the primary analysis, as demonstrated by correlation of fold changes between the post-RT and baseline timepoints in both groups , miR-424  and miR-451a  showed moderately strong correlations with left ventricle end-diastolic diameter. A non-significant correlation of the left ventricle end-diastolic diameter was observed with the mean heart dose , and that in turn was associated with DVH parameters and use of chemotherapy. In multivariable regression analysis performed to investigate independent association of miRNA levels with echocardiography indices, miR-29c , miR-424  and miR-451  were significantly associated with left ventricle end-diastolic diameter. Correlations between other cardiovascular or dosimetric parameters with post-RT levels of circulating miRNAs were not significant .Radiation-induced cardiotoxicity is a serious clinical problem in long-term breast cancer survivors that warrants efforts aimed at minimizing risk and identifying predisposed individuals. In this study, we found that several miRNAs measured in patient sera shortly (24 hours) after RT completion showed significantly altered expression, and these changes correlated with dosimetric parameters and echocardiographic findings performed 3 years after RT, pointing to their potential use as biomarkers. The radiation-induced changes in miRNA expression mostly reverted to normal 1 month after RT, reflecting the acute impact of radiation rather than ongoing physiological changes. That said, although the changes were transient, they may reflect acute processes that ultimately culminate in chronic pathophysiology in individuals prone to cardiac issues.Previously, we reported that serum lipopolysaccharide-binding protein (LBP) concentrations changed dynamically over the course of RT in patients with left-sided breast cancer and are correlated with the E/E′ echocardiographic index reflective of diastolic function evaluated 3 years after the completion of RT. We therefore proposed LBP as an early biomarker of cardiac function . Since iHere, we explored the potential of serum miRNAs for early diagnosis of RT cardiotoxicity. We found that several miRNAs, including miR-22-3p, miR-24-3p, miR-29c-3p, miR-30d-5p, miR-424-5p, and miR-451a were significantly altered 24 hours post-RT and that their levels measured 24h post-RT were significantly correlated with dosimetric parameters.in vitro and in mice  and cardiomyocyte hypertrophy. In general, left ventricle end-diastolic dimension is strongly associated with structural remodeling, contrary to the left ventricle end-systolic dimension and left ventricle ejection fraction (LVEF), which better represent systolic function than the structure of the left ventricle. In long term, radiotherapy may result in structural remodeling manifesting as left ventricular dilatation. Radiotherapy-induced long-term cardiotoxicity is associated with fibrosis, a process in which miRNAs may be involved. Therefore, the correlation between microRNA expression and LV end diastole dimension might be explained by the hypothetical role that the microRNAs play in the regulation of molecular mechanisms responsible for remodeling. While testing the tissue expression of these miRNAs in a clinical setting would be infeasible and mechanistic studies are required to identify the exact nature of these associations, these results serve as an additional line of evidence for the involvement of radiation-inducible miRNAs in processes that lead to long-term cardiac sequelae in patients with breast cancer treated with RT. Prior studies on radiation-induced toxicity in animal models identified several miRNAs associated with this process through experimental models. Notably, these include miR-223 , miR-21 Our study has several limitations. First, the correlations between miRNA expression and dosimetry parameters observed in the validation group were somewhat smaller than those in the primary group. A possible reason is the higher radiation dose delivered to the cardiac structures in the validation group, which was recruited at a different oncology centre and drawn from a potentially slightly different population of patients, possibly resulting in diminished differences in radiation-induced miRNA expression between patients (ceiling effect). Furthermore, due to sample size, the validation group was more heterogenous with respect to treatment strategy (mastectomy vs breast conservation therapy), resulting in variations in RT planning approaches. Nevertheless, the effects were generally validated in terms of direction of change and oftentimes significance, showing robustness of the findings. Thirdly, the strength of association of miRNAs with the evaluated effects was moderate (R~0.4) and no clinical endpoints were reached by the studied patients. However, the observed magnitude of effects was similar to that of dosimetric parameters which, given the independence of the identified miRNAs from DVH potentially allows for composite risk scores with better predictive performance. Due to the lack of cardiac outcomes in the observed patients, the analysis relied on association of miRNAs’ levels with echocardiographic parameters predictive for cardiac outcomes. The left ventricle end-diastolic diameter was correlated with radiation-associated miRNAs, but in all but one patient, remained within normal value range. This would suggest that a longer observation period would be needed to accumulate more data about the predictive capabilities of miRNAs towards clinically-evident cardiac sequelae. Finally, a different reason for the miRNAs dysregulation after treatment could be their association with breast cancer and the course of the disease rather than the impact of radiation itself. However, the miRNAs that we identified here as potential early biomarkers of cardiac toxicity were not reported among microRNAs significantly differentially expressed postoperatively in patients treated for breast cancer using surgery, but not radiotherapy . The miRTaken together, the consistency of radiation-induced miRNA expression patterns between the two recruited patient cohorts and with prior studies shows that expression of circulating miRNAs as biomarkers in radiation oncology is a promising area for biomarker discovery for short- and long-term sequelae of RT.Significant RT-induced changes are observed transiently after the completion of treatment and those miRNAs are associated with dosimetric variables including doses to several cardiac structures. Considering also the links between specific miRNAs identified in this study and processes relevant for cardiac remodeling after radiotherapy, further large-scale should explore their potential to guide clinical management of patients with breast cancer at high risk of cardiac toxicity.https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE225243) under the accession number GSE225243.The expression profiling data using miRNA arrays were uploaded to the Gene Expression Omnibus database  on 5th September 2017. The patients/participants provided their written informed consent to participate in this study.JC-F and WF designed and planned the experiments. JC-F, ID, ŁG, GP, BT, MS, JF, AP-U and PK collected data and performed the experiments. WF and ZN performed statistical analyses. JC-F, ZN, WF, BT and DK interpret the results and wrote the manuscript. All authors contributed to the article and approved the submitted version. JC-F and ZN contributed equally.


Despite the negative impact of poor sleep on mental health, evidence-based insomnia management guidelines have not been translated into routine mental healthcare. Here, we evaluate a state-wide knowledge translation effort to disseminate sleep and insomnia education to graduate psychology programs online using the RE-AIM  evaluation framework.Using a non-randomized waitlist control design, graduate psychology students attended a validated 6-hour online sleep education workshop delivered live as part of their graduate psychology program in Victoria, Australia. Sleep knowledge, attitudes, and practice assessments were conducted pre- and post-program, with long-term feedback collected at 12 months.p < .001). Implementation feedback was positive, with 96% of students rating the workshop as very good-to-excellent. Twelve-month maintenance data demonstrated that 83% of students had used the sleep knowledge/skills learned in the workshop in their clinical practice. However, more practical training is required to achieve CBT-I competency.Seven out of ten graduate psychology programs adopted the workshop (adoption rate = 70%). The workshop reached 313 graduate students, with a research participation rate of 81%. The workshop was effective at improving students’ sleep knowledge and self-efficacy to manage sleep disturbances using cognitive behavioral therapy for insomnia (CBT-I), compared to the waitlist control with medium-to-large effect sizes (all Online sleep education workshops can be scaled to deliver cost-effective foundational sleep training to graduate psychology students. This workshop will accelerate the translation of insomnia management guidelines into psychology practice to improve sleep and mental health outcomes nationwide.  Sleep is critical for good mental health, yet psychologists do not routinely use evidence-based insomnia treatments. To help translate insomnia management guidelines into psychology practice, we evaluated the state-wide rollout of an online sleep education workshop to graduate psychology programs using the RE-AIM  evaluation framework. There was strong demand for sleep education, with 70% of graduate programs adopting the workshop, reaching 313 trainee psychologists. The workshop increased trainees’ sleep knowledge and self-efficacy to manage insomnia, with gains maintained at 12 months. Notably, 94% of trainees endorsed that cognitive behavioral therapy for insomnia should be a standard part of the graduate psychology curriculum. This novel RE-AIM study demonstrates that online sleep education programs can improve insomnia management in mental healthcare.Sleep and circadian rhythm disturbances have traditionally been viewed as symptoms or byproducts of mental disorders; however, this view is outdated. Sleep and circadian rhythm disturbances share a bidirectional relationship with mental disorders . For exaDespite these updates to practice guidelines, CBT-I has yet to be translated into routine mental healthcare. Mental healthcare providers, such as psychologists, do not view sleep problems as a treatment priority , nor do A second barrier to CBT-I dissemination is that our mental healthcare providers lack general sleep and insomnia knowledge due to the limited sleep education taught within university-based healthcare training programs , 81, 93.n = 11) and focused on only one university for a short period (one semester), which is unlikely to bring about sustained change in the number of psychologists with sleep and CBT-I knowledge.To address these knowledge gaps, sleep education needs to be integrated into the graduate psychology curriculum. Three small studies have developed a sleep education curriculum for graduate psychology programs with promising results , 111. FoTo make large-scale improvements in the translation of CBT-I into mental healthcare, sleep education must be widely integrated into the graduate psychology curriculum. Ideally, this should be aided by a knowledge translation framework to target the barriers to implementation , 81, 112We used a non-randomized waitlist control design, guided by the RE-AIM Framework, to evaluate the implementation of the Sleep Psychology Workshop into all graduate psychology programs in Victoria, Australia in 2020–2021. A non-randomized design was chosen to provide initial scoping data on the state-wide uptake of the Sleep Psychology Workshop  into theThe RE-AIM framework is widely used in healthcare to evaluate the implementation of evidence-based interventions in the real world and has been used across a variety of settings  , 114. TaThe Sleep Psychology Workshop: Better Sleep for Better Mental Health is 6 hours, live, interactive online workshop designed to provide graduate psychology students with foundational knowledge and skills in sleep, circadian rhythms, and insomnia management for psychology practice. The 6-hour content could be delivered as 3, 2-hour workshops  or 2, 3-hour workshops (compressed delivery mode) depending on the structure of the graduate psychology program. The development and pilot study of the Sleep Psychology Workshop has been described elsewhere ; howevern = 10) were emailed an invitation by the research team to participate in the Sleep Psychology Workshop trial. Program coordinators were advised that the Sleep Psychology Workshop could be run free of charge for their graduate students as part of their coursework requirements or offered as an extracurricular workshop for students to attend in their own time. Program coordinators were also advised that all graduate students could attend the Sleep Psychology Workshop, but their participation in the research project evaluating the workshop was optional. Ethics committee approvals were obtained for this study (RMIT University CHEAN: 05-19/21939 and Monash University MUHREC: 28828).Program coordinators of graduate-level psychology training at Victorian universities in Australia . Therefore, all students eligible for this research trial were in their fifth year of psychology study or higher. In Australia, there are two graduate pathways to psychology registration: (1) fifth and six (plus) year sequence of formal psychology study ; or (2) 5 + 1 Internship, which includes a formal fifth year of psychology study, followed by 1 year of supervised practice, and completion of the national psychology exam .Graduate psychology students  attending the Sleep Psychology Workshop at their university were invited to participate in the evaluation study. The research team emailed the attending students (details obtained from program coordinators) prior to the workshop to provide information about the voluntary research components of the workshop, along with a copy of the participant information and consent form . Students were advised that participating in the research study was voluntary and would not impact their university assessments, grades, or relationships with university staff in any way. Students provided their consent to participate in the evaluation study by ticking a consent box in the online study questionnaire.The Graduate Psychology Knowledge, Attitudes, and Practice in Sleep questionnaire (GradPsyKAPS) was used to collect demographic information and measure graduate students’ knowledge, self-efficacy, preparedness, and confidence in sleep and insomnia management from pre- to post-workshop (RE-AIM domains = reach and effectiveness) , 111. A Graduate students in the intervention groups also completed an additional post-workshop survey to provide feedback about the Sleep Psychology Workshop (RE-AIM domain = implementation). This survey, which took approximately 10 minutes to complete, assessed students’ ratings of the workshop and facilitator, as well as more specific feedback regarding their training experience, learning, and workshop content (see online A long-term online feedback survey was administered to students 12 months post-workshop (RE-AIM domain = Maintenance). This measure collected data regarding students’ use of workshop-related sleep psychology knowledge and skills in their clinical practice and took approximately 10 minutes to complete . Students who did not wish to participate in the research activities were permitted to do other quiet activities while other students completed the online survey. After completing the Sleep Psychology Workshop, students were asked to complete the online post-workshop questionnaire within 2 weeks (T2). Twelve months post-workshop, students were invited via email to complete an online follow-up survey.Students were informed at the beginning of the study that those who completed both the pre- and post-workshop GradPsyKAPS questionnaire and scored at least 50% on the post-Sleep Psychology Knowledge Quiz would receive a certificate of completion for the workshop. In addition, each university group of graduate students who completed the pre- and post-workshop assessments went in the draw to win a $50 e-gift voucher for participating in the study. At 12 months post-workshop, all graduate students who completed the long-term follow-up survey could enter a draw to win one of the five $100 e-gift vouchers.The waitlist control group ran in the first half of 2021. Graduate students in the waitlist control group were provided with information about the research components via email 3 weeks prior to the running of the Sleep Psychology Workshop. They were asked to complete the first GradPsyKAPS questionnaire 2 weeks before the Sleep Psychology Workshop (T1). Students then completed a second administration of the GradPsyKAPS at the beginning of Sleep Psychology Workshop lecture (T2). Students who completed both assessments went in the draw to win a $50 e-gift voucher for participating in the study. If students wished, they could complete the GradPsyKAPS again after the workshop to receive a certificate of completion if they scored more than 50% on the Sleep Psychology Knowledge Quiz.r (r = z/ √N). Statistical significance level was p < .05 (two-tailed). Where specified, a Bonferroni correction was applied to account for multiple post hoc comparisons between the waitlist control, intervention groups 1, and intervention group 2 (p < .017).Study data were analyzed and visualized using Statistical Package for the Social Sciences 28.0 and GraphPad Prism 9.4.1. Descriptive statistics were used to describe the sample. Baseline differences in continuous Sleep Psychology Knowledge Quiz scores were assessed via one-way Analysis of Variance (ANOVA). Changes in pre- to post-workshop sleep psychology knowledge quiz scores were analyzed using mixed between-within ANOVA. For Likert scale ordinal data  change scores from pre-to post-workshop were calculated and used to compare groups with Kruskal–Wallis tests and post hoc Dunn’s tests using effect size Post-workshop evaluation items were reported on a 7-point Likert scale and collapsed into overall agreement, midpoint (neither agree nor disagree), and disagreement to simplify data visualization. Descriptive statistics were also used to analyze long-term follow-up data regarding knowledge and skills used by students since completing the workshop. Lastly, students’ free-text items reporting workshop feedback were coded and grouped according to content and frequency of responses .Seven out of ten graduate psychology programs across Victoria, Australia agreed to participate in the Sleep Psychology Workshop trial (adoption rate = 70%). In total, the workshop was delivered 11 times across the seven different graduate programs. Four graduate programs included the Sleep Psychology Workshop as part of their graduate coursework requirements, while three offered it as an extracurricular workshop for students to attend independently. Four programs chose the compressed delivery mode (i.e. two by 3-hour workshops instead of three by 2-hour workshops). For the three nonparticipating programs, reasons provided for nonparticipation included: (1) being unable to approve the curriculum change in time for the research project, (2) coronavirus disease 2019 pandemic challenges, and (3) no response to the study invitation.In total, 313 graduate psychology students across these seven graduate programs attended the Sleep Psychology Workshop, with 262 consenting to participate in the evaluation study. Eight participants’ data were excluded from the analysis; five due to being enrolled in a Master of Counseling rather that a psychology degree, and three due to missing participant ID codes, leaving 254 for the analysis (participation rate = 81%). Of students who consented to the trial, 177 completed both pre- and post-workshop assessments (70% study completion rate).n = 172) to the Psychology Board of Australia Registrant data from 2020. This allowed us to ascertain the total number of provisional psychologists enrolled in a Higher Degree Program (n = 982) or 5 + 1 internship (n = 427) in Victoria, Australia  [To calculate the reach of the workshop to the target population of all graduate psychology students provisionally registered as psychologists in the state of Victoria, Australia, we compared the number of participants in the intervention group in 2020 ( = 1409) . The rean = 202), with 20% (n = 50) in their sixth year of study. As data collection allowed us to capture graduate psychology students at different stages of their training, students completing the Sleep Psychology Workshop were grouped according to their year of study . Graduate students in the waitlist control group were all in their fifth year of psychology study (waitlist group = fifth years).Group characteristics are displayed in F  = 10.33, p < .001. Post hoc tests indicated that intervention group 2 (sixth+ years) scored significantly higher on baseline sleep knowledge than both intervention group 1 (fifth years) (p < .001) and waitlist control group (fifth years) (p < .001) (see p = .51).Baseline differences in sleep psychology knowledge were assessed via one-way ANOVA and revealed a significant difference between the groups, 001) see . No diffF  = 102.78, p < .001, partial eta squared = 0.54, indicating that sleep psychology knowledge quiz results across time differed between the intervention and waitlist groups. There was a significant main effect of time, Wilks Lambda = 0.37, F  = 294.03, p < .001, with large effect size , as well as a significant main effect of group, F  = 57.02, p < .001), with large effect size . Inspection of descriptive statistics and graphs revealed a large increase in sleep psychology knowledge scores for both intervention group 1 (fifth years) from T1  to T2  and intervention group 2 (sixth years) from T1  to T2 . No change was observed in the waitlist control group from T1  to T2  (see To assess changes in students’ sleep psychology knowledge from pre- (T1) to post-workshop (T2), a mixed-between within-subjects ANOVA was conducted. There was a significant interaction effect between group and time, Wilks’ Lambda = 0.47, .08) see .p < .001; see p < .001). In addition, intervention group 1 and 2 reported an increase in their perceived skills to assess and diagnose common sleep and circadian rhythm disorders, compared to the waitlist control (p < .001). Similarly, both intervention groups reported increased knowledge of common sleep disturbances seen in mental health disorders, knowing where to go to access further training in sleep, sleep disorders, and circadian rhythms, as well as knowing more about sleep than other graduate psychology students, compared to the waitlist group . Both intervention groups reported an increase in how prepared they felt to conduct a sleep evaluation and treat a sleep disturbance using an evidence-based approach (e.g. CBT-I), compared to the waitlist group . However, no differences in students’ post-workshop sleep knowledge quiz scores were identified between the compressed and normal workshop delivery modes (p = .098). Lastly, “break out” group work was not possible at one site due to technical difficulties, so role-play exercises were completed as a whole class rather than in pairs.The Sleep Psychology Workshop was implemented across the different universities using the same study protocol; however, some inconsistencies in delivery were noted. Time allocation within the workshop was the main challenge, with some workshop content, mainly the cognitive therapy components of CBT-I, receiving less attention at some universities. For example, more extensive sleep questions by students led to more detailed discussions with some groups than others and consequently reduced the planned didactic content of cognitive therapy strategies (e.g. constructive worry and cognitive restructuring) at these sites. However, all workshops prioritized and covered the delivery of sleep restriction therapy, stimulus control therapy, and the insufficiency of sleep hygiene for treating chronic insomnia. In addition, technical issues at one university led to a delay in commencing the workshop, which again rushed some final workshop content. Of note, these time allocation difficulties occurred more at sites that chose the compressed workshop delivery mode , with 95% of students reporting they attended all 6 hours of the Sleep Psychology Workshop. Students provided positive feedback about the workshop, with 96% rating it as very good-to-excellent , and 99% of students also rating the workshop facilitator as very good-to-excellent . Additionally, >73% of students endorsed their overall agreement across the different aspects of training experience, learning, and workshop content items .Post-workshop, students recognized the importance of sleep, sleep disorders, and circadian rhythms education for psychologists. Overall, 99% of students believed that training in sleep, sleep disorders, and circadian rhythms was important to their future careers as psychologists, with 100% agreeing that all psychologists should understand the relationship between sleep and mental health see . NotablyTwenty-nine students  provided written feedback on workshop limitations. Nine students commented that the workshops were rushed at the end; seven students commented that they experienced zoom fatigue with the online workshop format; and six reported they would have preferred 3, 2-hour workshops, instead of the 2, 3-hour workshops. Five students also suggested extending the time of the workshop . In regard to workshop content, six students requested more interactive activities , more case examples, and time for discussion with the group, with some reduction in the didactic presentation.Twelve months after completing the Sleep Psychology Workshop trial, four of the seven graduate programs enquired as to whether the workshop could be delivered to the subsequent years graduate cohort. In addition, two of the graduate programs that did not participate in the research trial contacted the research team requesting the inclusion of the workshop at their university the following year. This indicates an ongoing demand from at least six out of ten universities in Victoria, Australia, for sleep, circadian rhythms, and insomnia education within their programs.Additionally, one graduate program integrated a shortened version of the Sleep Psychology Workshop into their program coursework (with the researcher’s permission using a “train the trainer” model). This modified version of the Sleep Psychology Workshop formed the basis of a new placement opportunity for students at that university to undertake sleep assessments for members of the community on the University Open Day, and to provide individualized feedback on sleep–wake patterns, sleep duration, chronotype, insomnia symptoms, risk of obstructive sleep apnea, and refer on to appropriate sleep services if required.At 12 months post-workshop, 87 students from the intervention groups responded to a request to complete a long-term follow-up survey about the Sleep Psychology Workshop (response rate = 51%). Most students were still finishing their graduate degrees; however, 41% of students reported they had completed their studies. Students reported working with a range of mental health presentations since completing the Sleep Psychology Workshop, including anxiety disorders (82%), depressive disorders (68%); relationship difficulties (56%), learning and attention problems (54%), trauma and stressor-related disorders (53%), health and wellbeing (44%), grief and loss (43%), family/domestic violence (40%) developmental disorders (38%), obsessive-compulsive and related disorders (35%), substance use problems (33%), personality disorders (25%), schizophrenia and other psychotic disorders (20%), feeding and eating disorders (18%), neurological disorders (14%), and forensic/correctional psychology (10%). Students advised that they gained exposure to these mental health presentations through clinical placements/work in private practice (39%), community mental health settings (30%), school/educational settings (29%), hospital settings (21%), counseling service (21%), academia/research (5%), and medical clinics (3%).Since completing the Sleep Psychology Workshop, 87% endorsed working with clients experiencing sleep disturbances while on placement/internship or in clinical practice. Insomnia was the most common sleep presentation (71%), followed by hypersomnia (31%), nightmares (30%), circadian rhythms sleep–wake disorders (17%), and obstructive sleep apnea (10%). On average, participants estimated that 46% (SD ± 26%) of their clients reported sleep disturbances, and they addressed these sleep disturbances with 36% (SD ± 24%) of clients.Students reported using foundational behavioral sleep medicine skills at the 12-month follow-up, with 100% routinely asking their clients about sleep and 96% feeling comfortable providing psychoeducation about sleep. However, they were less confident in more advanced skills, such as taking a sleep history, referral processes, and delivering evidence-based interventions see .Graduate students reported strong implementation and maintenance of the knowledge and skills learned in Sleep Psychology Workshop. Overall, 83% of students endorsed using some of the knowledge and/or skills learned in the workshop on placement or in their clinical practice see . HoweverTwelve months on, 91% of students rated the Sleep Psychology Workshop as very good-to-excellent . There was still strong agreement that all graduate psychology students (99%) and registered psychologists (96%) should receive training in sleep, sleep disorders, and circadian rhythms. Notably, 100% of students endorsed that it was important to address sleep disturbances with their clients in clinical practice.Since workshop completion, 53% reported they had referred to the workshop materials; mainly lecture slides, sleep diaries, and sleep restriction therapy information. In the overall workshop feedback, it was noted that students would have preferred a take-away workshop manual for easy reference. Some students reported completing additional sleep education activities to upskill in CBT-I since completing the workshop, including accessing online sleep information , reading journal articles/textbooks (25%), and individual or peer supervision (22%). Few had taken an online course (5%) or an in-person workshop (1%). However, 38% of students endorsed wanting to receive further training in CBT-I.This large, controlled trial examined the state-wide implementation of a foundational sleep education workshop for graduate psychology programs using the RE-AIM framework. The Sleep Psychology Workshop had a strong adoption rate by graduate programs (70%), reaching 313 graduate psychology students across the state. Compared to the control condition, the workshop was highly effective at improving graduate students’ sleep psychology knowledge and their self-efficacy, preparedness, and confidence to manage insomnia in clinical practice. Notably, students maintained their sleep knowledge and skills 12 months post-workshop. Students also strongly endorsed that sleep, circadian rhythms, and CBT-I education should be incorporated into all graduate psychology training programs. Overall, this novel sleep education trial measured key implementation outcomes according to the RE-AIM knowledge translation framework  to improThe strong adoption rate of the Sleep Psychology Workshop demonstrates great interest and demand for sleep education within graduate psychology programs. Not only was the Sleep Psychology Workshop adopted by 70% of programs, but after the research trial concluded, 60% of programs reported ongoing demand for the workshop at their university. While most universities wanted the researchers to facilitate ongoing sleep education workshops, one graduate program used a “train the trainer” model to integrate a shortened version of the workshop into their curriculum. Our research demonstrates that graduate programs are willing to adopt a sleep education workshop into their curriculum if facilitated by external experts. Therefore, sustainable annual training models should be established to enable additional sleep education curriculum to be integrated across graduate psychology programs . Examplen = 313), representing 12% of all graduate psychology students holding a provisional psychology license in Victoria in 2020. However, factors beyond our control limited our ability to capture a higher proportion of graduate students during the study period. Due to time limitations and coronavirus disease 2019 restrictions, we were only able to run the workshop at some universities for 1 year level (e.g. fifth years) and so did not reach other enrolled students (e.g. sixth years). Furthermore, students enrolled in the 5 + 1 internship are off campus working full-time for their internship year and may not have been informed of, or able to attend, the Sleep Psychology Workshop. Lastly, Psychology Board of Australia registrant numbers include graduate students who are no longer enrolled in classes , limiting their ability to attend the workshop, despite being counted in registrant numbers [The Sleep Psychology Workshop reached a meaningful number of future mental healthcare providers  . This diWe assessed the real-world implementation of a sleep education workshop within healthcare professional training programs using the validated RE-AIM evaluation framework. By using RE-AIM, we moved beyond individual-level effectiveness data (e.g. changes in students’ sleep knowledge from pre-to post-workshop) to setting-level adoption, implementation, and maintenance data. Setting-level data provided valuable evidence that sleep education can feasibly be implemented into real-world healthcare provider training programs at a state-level. The RE-AIM framework has highlighted the need to focus on the long-term maintenance of the sleep education within graduate psychology programs and provide more practical sleep training opportunities for students to achieve CBT-I competency.Limitations of this work include that we did not use a randomized-controlled design or include objective clinical competency measures. Also, only one facilitator conducted the workshop, which may have affected workshop efficacy. Future studies would benefit from increasing the number of facilitators conducting the workshop. Also, future studies should allocate graduate programs to the intervention or waitlist group in a randomized fashion, ensuring that all groups have an equal distribution of clinical psychology students and fifth versus sixth-year students. Additionally, including objective competency assessments  would allow for the assessment of students’ practical sleep skills in post-workshop. Lastly, students were advised at the study outset that they would receive a certificate of completion for scoring ≥ 50% on the post-workshop Sleep Psychology Knowledge Quiz, which may have influenced their motivation to retain the sleep information presented in the workshop.The goal of this innovative study was to widely disseminate an online sleep education workshop to graduate psychology students in Australia. The Sleep Psychology Workshop was effective at both the individual- and setting- level for improving students’ sleep knowledge and skills with a strong adoption rate by graduate psychology programs. To improve the long-term maintenance of this program within graduate psychology programs, we are collaborating with the Australasian Sleep Association (ASA)’s Behavioral Management of Sleep Disorders Education Subcommittee to strengthen the workshop and drive this dissemination initiative. We also plan to improve the implementation and maintenance of students’ sleep knowledge and skills by offering ongoing group consultation/supervision through a Behavioral Sleep Medicine Online Community of Practice (BSM Online CoP) established through the ASA. Together, we can drive the increase of sleep knowledge and skills within the mental healthcare workforce and build the number of psychologists with CBT-I expertise. For the field of CBT-I dissemination, these are “exciting times, indeed!” Author 1 is supported by an Australian Government Research Training Program Scholarship administered through Monash University (previously through RMIT University). Monash University’s School of Graduate Research provided funding for participant gift vouchers.zsad169_suppl_Supplementary_MaterialClick here for additional data file.


Diarrheal disease continues to be a significant cause of morbidity and mortality. We investigated how anomalies in monthly average temperature, precipitation, and surface water storage (SWS) impacted bacterial, and viral diarrhea morbidity in Taiwan between 2004 and 2015.A multivariate analysis using negative binomial generalized estimating equations was employed to quantify age-specific and cause-specific cases of diarrhea associated with anomalies in temperature, precipitation, and SWS.Temperature anomalies were associated with an elevated rate of all-cause infectious diarrhea at a lag of 2 months, with the highest risk observed in the under-5 age group . Anomalies in SWS were associated with increased viral diarrhea rates, with the highest risk observed in the under-5 age group at a 2-month lag  and a lesser effect at a 1-month lag . Furthermore, cause-specific diarrheal diseases were significantly affected by extreme weather events in Taiwan. Both extremely cold and hot conditions were associated with an increased risk of all-cause infectious diarrhea regardless of age, with IRRs ranging from 1.03  to 1.18 .The risk of all-cause infectious diarrhea was significantly associated with average temperature anomalies in the population aged under 5 years. Viral diarrhea was significantly associated with anomalies in SWS. Therefore, we recommend strategic planning and early warning systems as major solutions to improve resilience against climate change. Escherichia coli, followed by Shigella, Salmonella, Campylobacter (primarily associated with childhood diarrhea), Yersinia, and Clostridium spp. ), viral cases , and all other infectious diarrheal cases (ICD-9: 001-009 and ICD-10: A00-A09).We obtained the monthly number of emergency room and outpatient visit records (2004-2015) of cause-specific diarrheal disease cases from the National Health Insurance (NHI) database of the Ministry of Health and Welfare for the 6 regions of Taiwan  . The NHIhttp://flood.umd.edu/). The population data for each location stratified by age group were retrieved from National Statistics, Republic of China, which provides open access to the yearly population. Further detailed information about population data is available on its official portal (https://eng.stat.gov.tw/).We obtained weather data from the Taiwan Central Weather Bureau, including average temperature (°C) and precipitation (mm) for 18 weather stations located in the 6 regions of Taiwan for the same period . WeatherTo evaluate the effect of changing climate on infectious diarrheal disease, we adopted anomalies in weather variables as the exposure metric, since they reflect changes in the historical context (climate) rather than direct measurements of weather variables. More specifically, we decided to focus on long-term monthly anomalies instead of weekly or daily variability. We aggregated weather data and health outcomes onto a monthly temporal scale, since we believe that a monthly scale would show distinct patterns of anomalies compared to a daily or weekly scale. To achieve this, we first calculated a 30-year baseline (1980-2010) to obtain a longterm monthly average for each calendar month specific to each of the 6 regions. We then calculated the anomalies for our study period (2004-2015) by subtracting the monthly mean weather data from their respective long-term averages.We used a multivariate generalized estimating equation (GEE) model with negative binomial regression  to examiLog[Y]~+++(season)+(time)+Lunar New Year event+offset(population)mei-yu , typhoon (July-August), and autumn (September-November) [The study also included the effect of seasonality and Lunar New Year events in the model. Population statistics were included in the model as an offset variable. Based on the hydrological cycle, the seasons in Taiwan are classified into 5: winter (December-January), spring (March-April), ovember) . We creaovember) ,32.We also categorized the predictor variables into 5 groups based on their percentile distribution and used the normal category as the reference group for the analysis. For example, average temperature anomalies were categorized as extremely cold (< 5th), cold (≥ 5-< 30th), normal (≥ 30-≤ 70th), hot (> 70-≤ 95th), and extremely hot temperature (> 95th). The categorization for precipitation and SWS followed suit. The detailed classification is presented in The study was approved by Institutional Review Board at the Chung Yuan Christian University and University of Maryland. All methods were carried out in accordance with relevant guidelines and all protocols were approved by Taiwan National Health Research Institutes (code: EC1090703-F-E).A total of over 10 million diarrheal disease cases were reported from 2004 to 2015 in Taiwan . The monThe monthly average temperature during the study period was 23.24°C across the 6 regions of Taiwan. The monthly mean values for precipitation and SWS were 178.24 mm and 1.11 mm, respectively. The temperature ranged from 14.8°C to 20.7°C during the cold months (December to February) and 26.5°C to 29.5°C during the hot months (June to August) . The preThe results from the univariate analysis of the associations between anomalies in temperature, precipitation, and SWS and the risk of diarrheal disease are depicted in This study did not find any significant positive association between extreme anomaly precipitation events and all-cause infectious diarrhea . HoweverWe also observed a strong positive association between viral diarrhea and Lunar New Year events, with risk ranging from 38% for all age groups  to 33% for the under-5 age group . In the seasonal analysis, except for a significant increase in the risk of bacterial diarrhea in the under-5 age group during the typhoon season , the risk of all studied diseases gradually decreased from winter to the typhoon season. Viral diarrhea showed the highest risk of cases during the winter season for both the all-age and under-5 age groups .This is the first population-based study to evaluate the associations between all infectious and cause-specific diarrhea and climatic factors, including anomalies in temperature, precipitation, and SWS along with seasons. Our study identified an association between a +1°C anomaly in temperature and all infectious diarrhea, although some of the associations were no longer significant when the analysis was stratified by viral and bacterial diarrhea. Furthermore, viral diarrhea was significantly associated with a +1 mm SWS anomaly. As we defined the weather variables by percentile, both extreme cold and extreme heat increased the risk of all-cause infectious diarrhea in Taiwan. However, extremely dry and drier conditions were associated with a decreased risk of viral diarrhea. Interestingly, our study also identified the culturally important Lunar New Year event, which happens during the winter in Taiwan, as an important risk factor for infectious diarrhea.This study identified a positive association between average temperature anomalies and all-cause infectious diarrhea in Taiwan at a lag of 2 months . In addiWe found there were no apparent effects of precipitation anomalies on the risk of infectious diarrhea in Taiwan. Our results are in contrast with a study conducted in Bangladesh that found a positive association between precipitation and reported typhoid cases at lags of 0-3 weeks, with 45% of total cases recorded during the monsoon period . Prior sThis study utilized SWS to represent all surface water, including both water constrained in water bodies and water overflowing onto the surrounding plains . GFMS prA prior study from Taiwan reported that the incidence of rotavirus infections had an epidemic peak in cooler months between January and March, supporting our findings . The TaiThere are several strengths of this study, including its long temporal coverage (2004-2015) and comprehensive cause-specific outcome measure. This is the first study to link SWS with an increased diarrhea burden. This study successfully investigated associations between SWS/weather anomalies and cause-specific infectious diarrhea, which is more relevant in the context of climate change, using a negative binomial regression GEE model. Future studies incorporating other statistical modeling techniques, including a distributed lag nonlinear model, will furnish enriched epidemiological evidence linking cause-specific diarrheal disease and these novel climate change exposure metrics. Some limitations are noted as well. First, we did not control for confounding factors, such as socio-demographic details, as this individual-level information was not available. Second, we used a monthly temporal scale. Furthermore, the majority of the outpatient infectious diarrheal disease cases belonged to all-cause infectious diarrhea because clinical laboratory tests of the causative pathogen were not performed in outpatient departments most of the time, as stool testing for pathogens is done only for patients suffering from severe or moderate diarrhea. Despite these limitations, this study provides an in-depth assessment of vulnerability, which varied by age and the cause of diarrhea, including all infectious diarrhea, bacterial diarrhea, and viral diarrhea. The findings of the study can help in the development of appropriate mitigation strategies for infectious disease consequences under climate-change scenarios. Since extreme weather events are projected to increase despite mitigation efforts, we argue that data like ours should be used to develop location-specific early warning systems that can help communities adapt to the threats of climate change .Our findings suggest that anomalies in SWS are significantly associated with the diarrhea burden in Taiwan, particularly for viral diarrhea. Moreover, extreme heat-related infectious diarrhea was most pronounced in the under-5 age group, while extremely cold months also elevated the risk of viral diarrhea in this age group. The winter season and Lunar New Year also increased the risk of all-cause infectious diarrhea and viral diarrhea, regardless of the age group. Since diarrheal disease continues to be a major cause of morbidity and mortality among young children, and climate change is leading to increases in extreme weather events, coordinated efforts are needed to enhance preparedness and management of diarrheal diseases.


Background: We have previously reported that the incidence of postoperative conduction disorders, especially left bundle branch block (LBBB), after implantation of a rapid deployment Intuity™ Elite aortic valve prosthesis , was significantly increased compared with conventional aortic valve replacement. We were now interested in how these disorders behaved at intermediate follow-up. Methods: All 87 patients who had undergone surgical aortic valve replacement (SAVR) using the rapid deployment Intuity™ Elite prosthesis and were shown to have conduction disorders at the time of hospital discharge were followed up after surgery. These patients’ ECGs were recorded at least 1 year after surgery, and the persistence of the new postoperative conduction disorders was assessed. Results: At hospital discharge, 48.1% of the patients had developed new postoperative conduction disorders, with LBBB being the predominant conduction disturbance (36.5%). At medium-term follow-up  = 169.6, standard error (SE) = 19.3 days, respectively), 44% of the new LBBB and 50% of the new right bundle branch block (RBBB) had disappeared. There was no new atrio-ventricular block III (AVB III) that occurred. One new pacemaker (PM) was implanted during follow-up because of AVB II Mobitz type II. Conclusions: At medium-term follow-up after the implantation of a rapid deployment Intuity™ Elite aortic valve prosthesis, the number of new postoperative conduction disorders, especially LBBB, has considerably decreased but remains high. The incidence of postoperative AV block III remained stable. Rapid deployment aortic valve prostheses are associated with an increased incidence of postoperative conduction disorders compared with conventional aortic valve replacement ,6,7,8,9.The population of patients receiving transcatheter aortic valve replacement (TAVR) has already been investigated with regard to not only the incidence of LBBB but also the reduction during follow-up. At 1 year after the implantation, a reduction of 30% to 40% was described . No follThis is a single-center, nonrandomized cohort study following patients who had undergone aortic valve replacement with the rapid-deployment Intuity™ Elite aortic valve prosthesis , between May 2014 and May 2017. In brief, 200 consecutive all-comer patients were retrospectively evaluated concerning the new incidence of conduction disorders  after surgery. Surgeries included minimally invasive and conventional approaches, isolated and combined procedures, not excluding endocarditis [At least one year after surgery, the patients and their general practitioners and/or cardiologists were contacted. ECGs of the 87 affected patients were collected, and the persistence of the conduction disorders was evaluated. The ECGs were written as twelve-channel surface ECGs. ECGs were written in our hospital or on an outpatient basis by the general practitioner/cardiologist. All ECGs written on an outpatient basis were sent to the department of cardiac surgery at Klinikum Passau and evaluated here for the presence of any conduction abnormality. Among the patients who had received a pacing device because of a new postoperative AVB III, the pacing rate of the implanted device was evaluated. Devices included pacemakers, implantable cardioverter defibrillators (ICD), and cardiac resynchronization therapy- defibrillators (CRT-D).Data are descriptively presented as means with standard deviation, standard error of the mean for continuous variables and, if applicable, as percentages for categorical variables.Perioperative data had been reported previously . In brieThe incidence of new postoperative conduction disorders was 48.1%. LBBB was the most frequent conduction disturbance (36.5%). RBBB occurred in 2.3% and AVB III in 9.3%. All patients with AV-Block III had been treated with PM, ICD, or CRT-D .A total of 87 patients with postoperative conduction disorders were followed up for at least one year after surgery. Data were complete for 78 patients , representing a follow-up rate of 90%. Nine patients were lost to follow-up; they could not be contacted either by telephone or by mail. In addition to that, in all these nine cases, neither general practitioners nor cardiologists had any follow-up information. The mean time between surgery and the follow-up ECG was 19 months (12 to 34 months).At the time of follow-up, LBBB had disappeared in twenty-six patients (44%) and RBBB in two patients (50%). Among the patients who had received a pacing device after surgery, the pacing rate of the implanted device  was evaluated. Nine PM patients (60%) showed to have a pacing rate over 99%, three patients (20%) had a pacing rate between 56%, and 99% and one patient (6.7%) had a pacing rate of 0.2%. Two of the patients who had received a pacemaker after surgery were lost to follow-up. Patients with an ICD or CRT-D had a device activity of 100%. No new cases of AVB III occurred during follow-up. One patient with LBBB developed an AV block II Mobitz type and received a new pacemaker during follow-up .Conduction abnormalities after aortic valve implantation are a well-known incident and more often occur after SAVR with a sutureless aortic valve prosthesis than after SAVR with a conventional prosthesis ,9,15,16.Physiologically speaking, LBBB represents a loss of ventricles’ contraction synchrony and is a serious perioperative complication, especially in young patients. In the current literature, LBBB is clearly associated with worsening of left ventricular function and, lately, even with an increase in mortality during follow-up in affected patients ,23,24,25Our present work is the first to focus on these data in a SAVR population. In parallel to the TAVR population, we observed a decrease in LBBB at medium-term follow-up, at least 1 year after surgery. However, LBBB remained persistent in 56% of the patients who had acquired it after surgery and only regressed in 44%. The rate of RBBB decreased by one half, and none of the LBBB and RBBB progressed to AVB III during follow-up. In patients with postoperative AVB III and subsequent device implantation , AV block III completely regressed in only one patient (pace-rate < 1%), changed to intermittent block in three patients  and was persistent in eleven patients (pacing-rate > 99%). The persistence of the AV block III in the patient who had received a CRT-D device could not be assessed by pace-rate alone, because of permanent resynchronization pacing.Immediately postoperatively, the Intuity™ Elite prosthesis, had shown excellent hemodynamic properties and low rates of PVL on the one hand but high rates of postoperative conduction disorders on the other hand. These data had caused a certain reluctance to implant the prosthesis, especially in younger patients, and had motivated us to perform the study presented herein. The decreasing trend at medium-term follow-up is certainly encouraging. However, the remaining 19% of the overall population, who continue to have left bundle brunch block more than one and a half year after surgery deserve further follow-up, including information on functional and clinical data.In addition to age, frailty, patient-prosthesis mismatch, paravalvular leakage and need for pacemaker implantation, the incidence and persistence of left bundle brunch block thus deserves consideration when the heart team tries to find the best prosthesis for any individual patient with aortic stenosis.Our study has limitations. This is a single-center cohort study carrying all the disadvantages of non-randomized studies, but on the other hand, offers the advantages of a real-world registry. Nine patients could, unfortunately, not be contacted, only offering a 90% complete follow-up.We conclude that, after SAVR with the rapid deployment Intuity™ Elite aortic valve prosthesis, the number of postoperative conduction disorders considerably decreases at medium-term follow-up. However, the percentage of left bundle branches, being the most frequently observed conduction abnormality, remained elevated at 19% of the original population.The present results confirm our policy of reluctance to liberally implant this rapid deployment prosthesis because we observed a persistence of left bundle branch block in almost 20% of our patients at medium-term follow-up. Future investigation is warranted to further follow the fate of LBBB and to monitor the hemodynamic and clinical data of the respective patients.In the meantime, the incidence and persistence of left bundle branch block after the implantation of any specific aortic valve prosthesis should be considered when the heart team decides upon the best treatment for a patient with aortic valve stenosis.