Self-compassion is negatively associated with aggressive behaviors. However, the association between self-compassion and cyber aggression toward stigmatized people  has not been investigated in the COVID-19 context and the mechanism underlying this association remains underexplored. On the basis of emotion regulation theory and attribution theory, this study examined the indirect effects of self-compassion on cyber aggression toward people infected with COVID-19 through attribution and public stigma of COVID-19. Data were collected from 1162 Chinese college students . Participants completed an online questionnaire including measurement of the key variables and basic demographic information. Results indicated that self-compassion was negatively associated with cyber aggression through the lower attribution of COVID-19 and lower public stigma of COVID-19. A sequential pathway from the attribution of COVID-19 to public stigma of COVID-19 was identified in the relationship between self-compassion and cyber aggression. Our findings are consistent with emotion regulation theory and attribution theory, which posit that emotion regulation strategies are associated with interpersonal mistreatment through cognitive pathways. These findings suggest that emotional self-regulation strategies can be used to reduce cyber aggression toward stigmatized people by reducing attribution and public stigma in the COVID-19 context. Self-compassion improvement could be target for the interventions aiming at alleviating public stigma and interpersonal mistreatment toward stigmatized people. The outbreak of coronavirus disease 2019 (COVID-19) in 2019 caused great threat to the general public , especiaBecause of the negative effects of the COVID-19 pandemic , individuals feel stressed and are more likely to exhibit hostile attitudes and treat others aggressively , 9, 10, According to emotion regulation theory , self-coThe beneficial role of self-compassion in dealing with emotional distress and maintaining positive emotional function has been highly emphasized in studies examining the relationship between self-compassion and aggressive behaviors. A negative association between self-compassion and aggressive behaviors  and inclinations has been identified in different populations  , 17, 18.Attribution theory provides a perspective for investigating the mechanism underlying the relationship between self-compassion and cyber aggression. Weiner and colleagues (1988) developed a conceptual framework demonstrating that individuals’ attribution of a disease affects their affective responses and behavioral judgment toward groups with the disease. The model posits that people who consider the cause of the disease to be associated with the responsibility and control of those with the disease tend to blame them and endorse increased stigmatization . AccordiAttribution of COVID-19 refers to the cognitive process in which the cause of COVID-19 infection is assigned , 23. IntPublic stigma of COVID-19 refers to the devaluation of and discriminatory attitudes and beliefs regarding individuals infected with COVID-19 as endorsed by the general population . Social Studies have provided empirical evidence related to the attribution model in stigma attached to mental illness and infectious disease , 37, demAlthough several studies have addressed aggression during the COVID-19 pandemic, research on the prevention and reduction of aggression has been largely neglected. Identifying psychological factors and intrapersonal resources that may alleviate aggressive behaviors, especially aggression toward individuals infected with COVID-19, is crucial. In addition, delivering interventions on the basis of these factors may help to prevent future mistreatment and stigmatization. According to emotion regulation theory, self-compassion is an effective emotional self-regulation strategy and self-related resource for reducing aggressive behaviors. Moreover, the attribution model of stigma provides a perspective for further examination of the underlying mechanism and potential indirect roles of attribution and public stigma of COVID-19 in the association between self-compassion and cyber aggression. During the COVID-19 pandemic, college students became more reliant on online learning because of lockdown and social distancing policies, which might increase the likelihood of cyberbullying , 44. ThuData were sourced from a project conducted to investigate the effect of the pandemic fatigue and public stigma of COVID-19 on psychosocial adjustment. Chinese undergraduates and postgraduates aged ≥ 18 years at Beijing Normal University were recruited to participate in the survey. Participants were informed of the research objectives, procedures, and confidentiality policy. Participation was voluntary, and participants were informed that they had the right to withdraw from the survey without any penalty. Participants provided informed consent before responding the online questionnaire. Ethical approval was provided by the research ethics committee of the School of Social Development and Public Policy at Beijing Normal University. Participants who provided a valid response received a small monetary reward .n = 37) and those that failed attention checking (n = 118), we obtained 1162 valid surveys . The average age of the participants was 21.61 (SD = 2.81) years. The percentages of undergraduate and postgraduate participants were 65.2% and 34.8%, respectively. The participants’ household monthly income was 19,811.49 RMB . Participant characteristics are listed in Table In total, 1317 students provided valid survey responses. After removing surveys with duplicate responses  , 46. Accα for this scale in the present study was 0.76.Attribution of COVID-19 was assessed using a three-item scale developed by our research team. Three scale items measuring blame, controllability, and responsibility were extracted from the Chinese version of the scale of public stigma toward various infectious diseases . Each itα for this scale in the present study was 0.88.Public stigma of COVID-19 was measured using an 11-item scale modified from the Chinese version of an existing scale assessing public stigma of mental illness . The oriα for this scale in the present study was 0.74.Cyber aggression toward individuals infected with COVID-19 was measured using three items, which were modified from three original items in Chinese used to measure aggressive online behaviors toward Chinese people because of COVID-19 . ResponsCovariates in the present study included demographic variables  and variables related to health  and COVID-19 infection experience of participants or people they knew. Physical health was assessed using one item  that participants rated on a 5-point scale ranging from 1 (very poor) to 5 (excellent). COVID-19 infection experience was assessed using one item that asked participants whether they or people they knew had been infected with COVID-19.Initial analyses  were conducted using SPSS version 24. The SPSS macro PROCESS (Model 6)  was usedThe descriptive statistics and bivariate correlations of key variables are displayed in Table b =  − 0.121, SE = 0.029, 95% CI =  − 0.180 to − 0.066), public stigma of COVID-19 , and attribution and public stigma of COVID-19 in sequence . Details of the specific paths and unstandardized path coefficients are presented in Fig. The specific direct and indirect effects of self-compassion on cyber aggression are displayed in Table Our findings are in agreement with those of previous studies indicating that self-compassion is beneficial for individuals’ well-being and that of others , 53. ComIndirect effects of self-compassion on cyber aggression are through attribution and public stigma of COVID-19. This finding supports that self-compassion is associated with individuals’ cognitive processes, especially how they view and interpret their negative experiences and their attitudes , 27. SelConsistently with prior studies, the results of the current study demonstrated that self-compassion was negatively associated with stigma –57. SelfSelf-compassion is associated with cyber aggression through a sequential pathway from the attribution and public stigma of COVID-19, which supports attribution theory , 23. ThiThis study has some limitations. First, because the present study has a cross-sectional design, it could not examine causal relationships among self-compassion, attribution, public stigma, and cyber aggression. Future studies could employ a longitudinal design to examine the mediating roles of attribution and public stigma of COVID-19 in the relationship between self-compassion and aggression. Second, the sample of Chinese college students in the present study limits the generalizability of the findings to other populations. To improve research diversity, the framework of the present study could be applied in other populations  in different developmental stages and cultures. Third, the present study examined only cognition-based mechanisms (attribution and public stigma) between self-compassion and cyber aggression. Self-compassion affects cyber aggression through other cognitive, emotional, or moral pathways  , 19. FutOur findings have theoretical and practical implications. They contribute to the understanding of how self-compassion is associated with interpersonal mistreatment toward stigmatized people in the COVID-19 context. On the basis of emotion regulation theory and the attribution model of public stigma, our study demonstrated the importance of cognitive pathways (attribution and public stigma) when applying emotion regulation strategies for dealing with cyber aggression. These pathways shed light on the cognitive-based mechanism underlying the emotional regulation/dysregulation–interpersonal mistreatment in the aggression (prevention) studies , 66. Thi


A 53-day-old girl with absent right atrioventricular (AV) connection, malposed great vessels, and pulmonary atresia underwent placement of a central shunt on the sixth day of her life. Her postoperative course was complicated by progressive desaturation, and computed tomographic angiography (CTA) demonstrated near-complete occlusion of her left pulmonary artery (LPA). Angiography demonstrated a nonocclusive thrombus in the distal central shunt and a thrombus with complete occlusion of the LPA. The Indigo aspiration system (Penumbra) was used to remove the thrombus from the central shunt and LPA, allowing placement of a stent in the narrowed LPA. Subsequent angiography showed a wide patient central shunt and LPA. The Indigo aspiration system (Penumbra) provides a viable option for removing thrombus in a patients refractory to other methods. In patients with cyanotic congenital heart disease who are unable to undergo complete primary repair, staged palliation by initially placing a systemic-to-pulmonary arterial shunt is a standard method of providing a temporizing source of pulmonary blood flow . UnfortuThe options for managing shunt thrombosis include thrombolytic therapy and systemic anticoagulation, which carry a high risk of bleeding complications, especially in young infants . CatheteWe describe the case of a 53-day-old girl with central shunt thrombosis in the setting of pulmonary atresia where novel use of the Indigo aspiration system (Penumbra) allowed safe and effective removal of a thrombus from her central shunt and left pulmonary artery facilitating stent placement in her narrowed left pulmonary artery.A 53-day-old, term 3-kg girl with a history of absent right AV connection, malposed great vessels, and pulmonary atresia underwent stage I palliation with a 3.5-mm aortopulmonary polytetrafluoroethylene (PTFE) graft shunt from the proximal aortic arch to the main pulmonary artery, atrial septectomy, and bilateral branch pulmonary artery patch augmentation on the sixth day of her life. Her postoperative course was complicated by ectopic atrial tachycardia, for which she was commenced on digoxin, and desaturation secondary to multilevel airway obstruction with mild supraglottic edema, laryngomalacia, and left vocal cord paralysis. As part of her assessment for low oxygen saturation, a CT scan was performed and demonstrated near-complete occlusion of her LPA and narrowing of her left main stem bronchus . FollowiPercutaneous right carotid access was obtained, and a 4-Fr sheath was inserted. A 4-Fr Glide catheter (Terumo) with a 0.035 in. Glidewire (Terumo) was used to access the central shunt. The wire was removed, and an 0.014 in. PT Graphix wire (Boston Scientific) was inserted into the 4-Fr Glide catheter (Terumo) and positioned across the RPA. An angiogram was performed, which demonstrated a thrombus extending from the left pulmonary artery into the distal central shunt. Multiple wires and catheters were used to attempt to access the left pulmonary artery but were unsuccessful in passing through the thrombus. A second wire was placed into the distal right pulmonary artery. A 4-Fr, 50-cm-long Penumbra CAT3 catheter was advanced through the right carotid artery over both wires attached to the Indigo aspiration system, and a thrombectomy was performed. Although no thrombus was detected in the filter, there was a decrease in the size of the thrombus in the central shunt and LPA on serial angiography, with new evidence of flow seen to the distal LPA .A 3.3-Fr JR 1.0 catheter (Pediavascular) was placed next to the wire in the right pulmonary artery and positioned at the mouth of the left pulmonary artery. An 0.014 in. PT Graphix wire (Boston Scientific) was then placed through this catheter and positioned in the distal LPA. An angiogram was performed to confirm positioning. An 0.014 in. Grand Slam wire  was then used as the working wire over which to advance a 4 mm × 8 mm Resolute Onyx drug-eluting stent (DES) (Medtronic) and was positioned across the area of LPA stenosis. The balloon was inflated to 14 atm, and the stent was deployed in the LPA. Angiography demonstrated antegrade flow to the distal LPA with significant diameter improvement of the central shunt and the LPA.Following the procedure, she was commenced on a continuous unfractionated heparin infusion on the night following the procedure and then transitioned to therapeutic-dose subcutaneous low-molecular-weight heparin in conjunction with aspirin until her second-stage palliation procedure. Follow-up echocardiography demonstrated a patent central shunt with improved flow through the LPA stent and no evidence of a residual thrombus or distal thrombus. Follow-up CT was not performed due to the clinical improvement of the patient following the procedure. She was discharged 6 days postprocedure with no neurological sequelae and successfully underwent second-stage palliation at 4 months of age. At the time of her second-stage palliation, the LPA was hypoplastic, and the LPA stent had evidence of previous thrombosis and profound intimal irregularities. The stent was therefore removed, and the LPA was augmented using a circular Matracell patch.Shunt thrombosis remains a potential life-threatening complication of palliative arterial shunt procedures, particularly in the immediate postoperative period, with a reported prevalence of 12% and a mortality rate of 4% . The patSystemic thrombolysis with tissue plasminogen activator has the disadvantage of increasing the risk of bleeding complications in these already vulnerable patients. Local thrombolytic therapy has been used successfully in some infants, but the experience is limited, and extreme caution is still necessary , 7. AddiAlthough, historically, surgery was undertaken to manage shunt occlusion, catheter-based interventions have now been used successfully for many years , 9. CathWhen pharmacologic thrombolysis is not feasible or ineffective, thrombus removal using mechanical thrombectomy may be indicated. Catheter-directed percutaneous mechanical thrombectomy does not carry the same risks associated with systemic thrombolytic therapy. Mechanical thrombectomy catheters as primary or adjuvant therapy for the removal of thrombus are well described in adults and older children , 12. DatThe Indigo aspiration system (Penumbra) is an endovascular mechanical thrombectomy device comprised of a continuous aspiration source attached to Indigo aspiration catheters (CAT), which have been engineered to be robust, trackable, and atraumatic. The built-in microprocessor features a proprietary thrombus removal algorithm that automatically controls a valve in the tubing to provide continuous or intermittent aspiration and provides procedural feedback via audio–visual cues. Catheters are available in a selection of sizes that provide access to different-sized distal peripheral vessels of the upper and lower extremities. Catheter choice depends on the size of the lumen of the vessel and the desired location of its use. A 4-Fr catheter was used in this case to minimize access sheath size in the carotid artery in a small infant. It has been safely and effectively used in the management of pulmonary embolism and peripheral vessel thrombus in adults and older children . Its benWe report the novel use of the Indigo aspiration system in the removal of a thrombus from a systemic-to-pulmonary shunt and left pulmonary artery in an infant with tricuspid atresia. The Indigo aspiration system is a safe and effective alternative for catheter-based mechanical thrombectomy that can be used in combination with current catheter-based techniques in the event of acute shunt thrombosis in patients with system-to-pulmonary shunts.


Self-stigma is widespread in patients with bipolar disorder, with many consequences for family, social and occupational functioning, as well as treatment adherence.The aim of this study was to evaluate self-stigma in remitted patients with bipolar disorder and to investigate its impact upon functioning.We conducted a cross-sectional, descriptive, and analytical study of 61 patients with bipolar disorder. Euthymia was verified using the Hamilton scale for depression and the Young scale for mania. We used the Internalized Stigma of Mental Illness (ISMI) to evaluate self-stigma, the Functioning Assessment Short Test (FAST) to assess functioning.-3). To decompose the relationship between stigma and functioning into more specific spheres, we found that all scores on the different domains of functioning were associated with a significantly higher mean self-stigma score.The mean age of patients was 43.4 years. The sex ratio was 2.4. The mean score on the ISMI was 2.36. More than half of our patients (59%) were self-stigmatized. Regarding functioning, a global impairment was noted in more than two thirds of the patients (71%). Occupational functioning was the most affected area (82%). Patients with higher self-stigma scores had significantly more impaired functioning (p<10The relationship between self-stigma and functioning seems to be bidirectional. Therefore, improved social functioning could reduce self-stigma and improve self-esteem.No significant relationships.


Many people who are treated with 5-FU experience severe toxicity to the drug, and in severe cases, patients can die. This review discusses current methods for identifying people who are at high risk for severe side effects to 5-FU therapy.DPYD) has been recognized for the past 3 decades as a pharmacogenetic syndrome associated with high risk of 5-FU toxicity. An appreciable fraction of patients with DPD deficiency that receive 5-FU-based chemotherapy die as a result of toxicity. In this manuscript, we review recent progress in identifying actionable markers of DPD deficiency and the current status of integrating those markers into the clinical decision-making process. The limitations of currently available tests, as well as the regulatory status of pre-therapeutic DPYD testing, are also discussed.Severe adverse events (toxicity) related to the use of the commonly used chemotherapeutic drug 5-fluorouracil (5-FU) affect one in three patients and are the primary reason cited for premature discontinuation of therapy. Deficiency of the 5-FU catabolic enzyme dihydropyrimidine dehydrogenase (DPD, encoded by  The fluoropyrimidine analog 5-fluorouracil (5-FU) was introduced as an anti-cancer agent in the late 1950s and remains one of the most widely prescribed chemotherapeutics, with an estimated 2 million people worldwide receiving 5-FU or one of its prodrug forms  each year ,4, amongDPYD) that segregated independently and demonstrated an autosomal codominant pattern of inheritance . In. In10]. eritance . The ceneritance ,15,16. Teritance ,17,18.DPYD variants have been studied in clinical studies of 5-FU toxicity and in pre-clinical models of DPD function or 5-FU metabolism. Four variants have reproducibly shown significant association with elevated risk of severe toxicity to 5-FU  was identified in individuals with self-declared African American race/ancestry [DPYD [While these four variants have been studied in depth, they are unlikely to be the only variants associated with risk. By measuring DPD activity ex vivo using PBMCs collected from a population of volunteer subjects, ancestry ,40,41. Iancestry , and thery [DPYD . Additiory [DPYD , suggestMost clinical studies and, by extension, meta-analyses have been conducted exclusively in Europe or in individuals of European ancestry  ,21,43,44DPYD. Neonatal screening programs based in the Netherlands have identified numerous cases of pyrimidine imbalance that were linked to DPYD variants in both the domestic Netherlands and international populations [DPYD. The analysis of carriers and the use of patient-agnostic approaches to characterize these variants have greatly improved our understanding of the repertoire of DPD-deficiency-associated alleles [Case reports and population-agnostic functional studies that utilize cellular or in vitro models of DPD deficiency have been instrumental in identifying additional candidate 5-FU risk variants within ulations ,47,48,49 alleles ,50,51,52The clinical data linking DPD deficiency to 5-FU toxicity, as well as the well-studied metabolism pathway DPD as the major 5-FU catabolic enzyme, have made identifying patients with DPD deficiency a clinical priority for potential therapeutic dose adjustment. Varied methods of assessing DPD deficiency have been developed, each with potential advantages and disadvantages. These tests include genetic tests of varying coverage, the measurement of blood metabolites as an indicator of DPD function, measurement of DPD function directly in PBMCs as a proxy for liver function, and others. The following sections will outline these varied approaches and review the literature relevant to their use. Because of the rapid evolution occurring in the field of DPD testing, specific companies and products will not be named.Genotype-based approaches to identify DPD deficiency are becoming more common and offer potential advantages over phenotypic tests, including high diagnostic accuracy with results that are not influenced by environmental factors or methodological differences in sample handling and processing . As suchDPYD variant, most commonly c.1905+1G>A, and do not genotype for any other risk variants. Therefore, it is important for users to understand the limitations of incomplete genotyping, especially since the more common causal alleles in Europeans  might not be genotyped by a targeted test.Most genotypic tests for DPD deficiency use targeted assays to identify the allele status for individual preselected single nucleotide variations (SNVs). Some commercially offered tests only provide the genotype for a single Within most European populations, targeted tests for the four well-studied variants discussed above will likely identify most carriers for variants associated with DPD deficiency. While individual risk variants outside of the four commonly studied variants are individually rare, when considered collectively, these variants are likely carried by a measurable fraction of the European population . FurtherDPYD variants are now included on some targeted genotyping panels offered by a small number of testing laboratories. Given the discrepancies between test offerings from various laboratories, it is critical that those ordering genetics tests be aware of the variants that are included in a given test.Unfortunately, targeted genetic tests likely have extremely limited utility in individuals with non-European ancestry, where the four well-studied risk variants are exceedingly uncommon and other variants predominate. As new information has been gained in the field, some testing laboratories are introducing expanded tests to keep pace with developments. For example, the c.557A>G variant and additional rare deleterious Targeted genotyping can be advantageous for cost and turnaround considerations; however, the tests do not provide information outside of the specific SNVs being tested. As an alternative approach, sequence-based genotype assessment is starting to be offered by some testing laboratories. Sequencing has the potential to identify deleterious variants that would be missed by variant-specific genotype methods , making While sequence-based genotyping has the potential to overcome some of the limitations with SNV-specific assays, the contributions to 5-FU toxicity risk for the variants that are detected may not always be interpretable. Treatment guidance may be available for carriers of some alleles ; howeverDPYD variants, we developed a gene-specific variant classifier that was developed using features intrinsic to DPYD and 5-FU metabolism and trained using a robust in vitro measure of SNV impacts on DPD enzyme activity [DPYD variants were deleterious. A comparison of this new tool with existing general classifiers demonstrated that the gene-specific tool was more accurate than conventional general tools and correctly classified all well-studied variants and most novel ones [DPYD and TPMT variants using an ensemble learning approach and confirmed that gene-specific variant classifiers have the potential to dramatically improve prediction accuracy for DPYD variants of unknown significance [DPYD variants identified through sequencing.A new generation of prediction tools seeks to fill that gap. With respect to activity . Using evel ones . Additioificance . Companiificance  and RegSificance  have thePhenotypic approaches for measuring DPD activity were developed as research tools to identify DPD deficiency and subsequently characterize the genetics of the condition in pedigrees linked to individuals with severe 5-FU toxicity  express functional DPD, and modest correlation has been noted between DPD activity measured in PBMCs and liver biopsies from the same patients ,69, makis e.g., ,71). To . To DPYDs  can be measured in blood plasma [2 is reduced, resulting in elevated U and a reduced ratio of UH2:U. Exceptionally high levels of plasma U have been shown to indicate complete DPD deficiency and be predictive of elevated risk for severe 5-FU toxicity [As an alternative approach to estimating systemic DPD function, the levels of uracil (U) and the DPD-metabolism product dihydrouracil  is another approach for identifying DPD deficiency. Early TDM research utilized subtherapeutic test doses of 5-FU that were administered to patients, and the circulating levels of 5-FU and metabolites were directly measured in blood thereafter using a variety of analytical approaches . In 2020, the EMA published a direct healthcare professional communication (DHPC) that recommends testing for DPD deficiency prior to 5-FU treatment . Additioagement” , and the testing .DPYD variants was modestly cost-saving, with the degree of cost-effectiveness most sensitive to hospitalization risk in variant carriers, the number and frequency of genotypes tested, and the cost of the test itself [DPYD would be cost-effective if at least 2.1 cases of neutropenia were avoided out of 1000 patients tested [DPYD testing could be cost-saving, using data from [DPYD variants incurred higher costs associated with managing toxicity than non-carriers and were at elevated risk for hospitalization related to toxicity [DPYD variants had higher healthcare-associated costs, poorer survival, and lower quality of life metrics [Studies into the cost-effectiveness of pre-treatment testing for DPD deficiency have, to date, been limited to those that have used genotyping; the cost-effectiveness of phenotypic tests is unknown at present. Two studies in the Netherlands that used prospective genotyping prior to 5-FU treatment demonstrated that upfront genotyping for t itself ,101. In s tested . A studyata from . A studytoxicity . Another metrics . OverallDeficiency of DPD is strongly linked to an increased risk of severe and potentially fatal toxicity to the commonly used chemotherapeutic 5-FU. Many methods have been used to identify patients with DPD deficiency. While phenotype-based tests have been instrumental in the research setting, genetic tests currently show the greatest promise for 5-FU dose individualization due to well-defined risk and dose-adjustment metrics for variant carriers. Recommendations for testing have been gaining momentum, with the EMA publication of guidelines for universal DPD testing prior to 5-FU use likely serving as what will be viewed in hindsight as a pivotal policy implementation in the field.


Retinopathy screening via digital imaging is promising for early detection and timely treatment, and tracking retinopathic abnormality over time can help to reveal the risk of disease progression. We developed an innovative physician-oriented artificial intelligence-facilitating diagnosis aid system for retinal diseases for screening multiple retinopathies and monitoring the regions of potential abnormality over time.Our dataset contains 4908 fundus images from 304 eyes with image-level annotations, including diabetic retinopathy, age-related macular degeneration, cellophane maculopathy, pathological myopia, and healthy control (HC). The screening model utilized a VGG-based feature extractor and multiple-binary convolutional neural network-based classifiers. Images in time series were aligned via affine transforms estimated through speeded-up robust features. Heatmaps of retinopathy were generated from the feature extractor using gradient-weighted class activation mapping++, and individual candidate retinopathy sites were identified from the heatmaps using clustering algorithm. Nested cross-validation with a train-to-test split of 80% to 20% was used to evaluate the performance of the screening model.F1-score, and Cohen’s kappa coefficient of 0.70. Moreover, visualization results were also shown to provide reasonable candidate sites of retinopathy.Our screening model achieved 99% accuracy, 93% sensitivity, and 97% specificity in discriminating between patients with retinopathy and HCs. For discriminating between types of retinopathy, our model achieved an averaged performance of 80% accuracy, 78% sensitivity, 94% specificity, 79% Our results demonstrated the capability of the proposed model for extracting diagnostic information of the abnormality and lesion locations, which allows clinicians to focus on patient-centered treatment and untangles the pathological plausibility hidden in deep learning models. The resulting presentation of drusen, cellophane, exudate, hemorrhage, or chorioretinal scarring can have a profound effect on the vision of its victims, in which the most common causes may be diabetic retinopathy (DR),–Color fundus imaging is a non-invasive cost-effective tool for ophthalmological examinations.–In the current study, we developed an artificial intelligent (AI) diagnostics platform for screening multiple retinopathies and monitoring regions of potential abnormality over time. A schematic illustration of the proposed system, referred to as the physician-oriented AI-facilitating diagnosis aid system for retinal diseases (PADAr), is shown in 22.1This study was approved by the Ethics Committee of the Institutional Review Board of Taipei Veterans General Hospital, Taiwan . Participants provided written informed consent allowing the retrospective collection of their retinal images. Participants were included if they were diagnosed with a major retinopathy in either eye, such as AMD, DR, CM, and PM. A total of 200 participants were selected for inclusion by a retina specialist from the Department of Ophthalmology of Taipei Veterans General Hospital in Taiwan. Sampling covered the period from 2002 to 2019.Color fundus images of multiple fields were captured using multiple cameras equipped with lenses covering a field-of-view of 35 deg to 55 deg. The multiple fields were indicated using the seven fields designated in the general early treatment of diabetic retinopathy study (ETDRS) protocol: optic disc centered field (F1); macular centered field (F2); and all peripheral fields . Images lacking anatomical landmarks  were removed. The images were cropped to 2.2The present study proposed two models. The screening model  based onThe main-classifier is used to discriminate between cases of retinopathy and HCs and six binary classifiers are used to differentiate cases between each pair of four types of retinopathy . The final FC layer integrates soft-target information obtained from all of the classifiers to predict the outcomes. We incorporated Grad-CAM++ to obtain the corresponding heatmap from the class of interest . Essentially, Grad-CAM++ generates the heatmap by a weighted combination of latent feature channels from the last convolutional layer. The weights for feature channels reflect their respective importance in prediction of a given class, which is estimated from the gradient of guided back-propagation. Grad-CAM++ is shown to achieve better localization compared to Grad-CAM,Prior to model training, all input images were augmented by horizontal flipping, rotation Training was implemented in three steps. We first replaced the last three fully connected layer of VGG16 with one binary main-classifier, utilized ImageNetWe performed 2.3The second model proposed in this work was used to monitor and visualize candidate lesion sites based on results from the aforementioned screening model at various time points for each patient. Time-series image registration was adopted to align images acquired from multiple time points from a single participant. For each image, control points were automatically extracted using SURF algorithm, and the time-series images and their corresponding heatmaps were registered to the reference image. Subsequently, a clustering algorithm was used to identify candidate sites based on their relevance to identified abnormalities.2.3.1The schema of the proposed time-series image registration method is shown in –Second, a green channel image extracted from each macula-center image was enhanced using the contrast limited adaptive histogram equalization filtering algorithm,Third, the correspondence between control points 2.3.2,An adaptive clustering algorithm was used to locate potential regions of abnormality  on the heatmap derived from the screening model. The pipeline of our algorithm is shown in 33.1In terms of screening, the proposed multi-binary-classifier model achieved macro-average accuracy of 0.80, precision of 0.81, sensitivity of 0.78, specificity of 0.94,  of 0.79 , AUC of F1 score, The performance of the main classifier was assessed using repeated nested CV with an outer five-fold CV and an inner five-fold CV. The main-classifier for discriminating between patients and HCs achieved high mean-macro-average accuracy of 3.2The proposed model provides diagnostic information from heatmaps pertaining to the retina for use in identifying candidate locations of disease. 3.34,,Locating abnormalities in the retina is crucial to diagnostic decision-making. Previous studies have reported that heatmaps obtained from Grad-CAM++ can be used to highlight such abnormalities in instances of single retinopathy .Our model also demonstrated competitive classification performance when compared to the other retinopathy detection models in the literature, either in distinguishing retinopathy from HCs or discriminating between types of retinopathy. ,,It is worth noting that our study incorporated real-world data with minimal data cleaning and annotations. In the literature, screening models trained in real-world clinical settings are generally outperformed by those trained in a laboratory setting with carefully selected data,,Monitoring disease progression from multiple examinations performed on different days provides quantitative and qualitative information by which to monitor disease progression. This process is critical to ensuring timely treatment; however, the process is time-consuming. Recent studies have reported that the discrimination of disease stage can help to reveal the risk of disease progression, particularly in areas such as the AMD and DR.To the best of our knowledge, this is the first attempt to automate the location and visualization of retinopathic regions in the temporal domain. Our results demonstrates the capability of the proposed PADAr to identify potential retinopathy sites and perform longitudinal follow-ups of disease progression, suggesting its feasibility for facilitating clinicians in their decision-making process and focusing on patient-centered treatment.


Since December 2019 and the first confirmed case of SARS-CoV-2 in Wuhan, China, the world has faced an unprecedent global health crisis. Within 2.5 years, more than six million and counting individuals have died from COVID-19 disease, and at least half a billion cases have been reported. The COVID-19 crisis has been answered with an unprecedent effort of the entire Scientific community that was accompanied by worldwide safety measures and next-generation of mRNA vaccines. By inducing the production of specific neutralizing antibodies against the spike protein of SARS-CoV-2 to prevent virus entry in targeted cells, large-scale vaccination dramatically helped reducing the quick propagation of the virus. Unfortunately, despite all those efforts, individuals may still suffer from many complications that would require oxygen supply and lead to death from SARS-CoV-2.Early on in the pandemic, many co-morbidities and factors – such as age, genetics, pre-existing disease condition– were identified as increasing risks of severe COVID-19 disease and related death. While it helped improving patients’ management and saved many lives, deciphering the biological reaction leading patient’s complications is necessary to provide better care and prevent death. Evidences quickly pointed towards an inappropriate immune response as being, at least in part, responsible for COVID-19 complications. Indeed, many studies conducted throughout the pandemic led to the current understanding of a ‘bipolar’ immune response. If an early inflammation is beneficial to prevent virus entry and its spread throughout the body, it becomes detrimental for the host when the whole system is not properly controlled and shutdown. When happening, overactivation of innate immune system and the subsequent cytokine storm escalates to severe lung injuries and generalized inflammation as observed in Multisystem Inflammation Syndrome (MIS). Based on this understanding, clinical trials and drug-repurposing established that anti-inflammatory treatment (e.g. dexamethasone and tocilizumab) would help lower down escalation of the inflammatory response. However, further studies are still necessary to acquire deeper understanding of the mechanisms at play to develop better targeted therapies and improve our knowledge of SARS-CoV-2 virus.The complement system is part of the innate immunity. It is implicated in many pathological processes, particularly in hemolytic disorders associated with thrombotic microangiopathy (TMA) where monoclonal anti-C5 therapy eculizumab has revolutionized life prognosis . This anIn this Research Topic, we aimed to gather Original Research articles, Reviews and Case Reports which have improved our understanding about the relation between complement system and COVID-19 disease severity, long-COVID-19, and outcomes. A total of fourteen articles were published under this collection addressing how complement system is activated by SARS-CoV-2, but also how complement proteins could be used as biomarkers for COVID-19 disease.Sinkovits et al. described that overactivation and consumption of C3 correlated with other markers of inflammation – such as IL6 and CRP – and can be used as predictive marker of mortality of SARS-CoV-2 infection. This result echoed the meta-analysis performed on 19 studies and more than 3700 COVID-19 patients by Zinellu and Mangoni and determining C3 and C4 as potential predictive factors of COVID-19 severity and mortality at the peak of the disease. Moreover, the study from Senent et al. suggested that complement activation is linked to long-term COVID-19. By analyzing samples from a total of 50 patients over the course of 3 months, authors were able to correlate high levels of circulating C5a with the presence of long-term respiratory symptoms suggesting the use of C5a as a potential biomarker for long-term SARS-CoV-2 infection.Complement system impairment has been documented as directly or indirectly involved in pathophysiological mechanisms of many diseases, including autoimmune and infection diseases . Easy acConsidering the length and complexity of the inflammation caused by COVID-19, complement system activation is likely driven by many different signals leading to activation of the three pathways rather than an exclusive one. Nonetheless, it would be expected that implication of each pathway to be time- and context-dependent.Panteleimon Charitos et al. but authors rather found an association between classical and alternative pathways activities and critically ill patients. Noteworthy, SARS-CoV-2 receptor-binding domain drives IgG1 and IgG3 subclasses response  and Acute Kidney Injury (AKI) in a 46-year-old patient with hypertension and obesity personal history. In this case report, authors successfully resolved AKI and dramatically improved renal function upon treatment with eculizumab, strengthening the therapeutic potential of anti-complement therapies in COVID-19 patients.Thromboinflammation being a key feature associated with COVID-19 death, it is fair to assume that pre-existing hemolytic disease condition would inflate SARS-CoV-2 infection and worsen patients’ complications. This hypothesis is particularly relevant here, considering that complement is usually involved in organ injuries occurring in hemolytic disorders. In this context, vaccination would be critical to prevent exacerbation of pre-existing hemolytic sensitivity. Ali et al. described a cohort of 217 patients with severe COVID-19 disease in which defect in circulating complement proteins induced by the infection seems to predispose to bacterial infections, most frequently K. pneumoniae.Interestingly, Nilsson et al. reviewed the complexity of the inflammatory response and the intricate relationships between the complement, the coagulation and the kallikrein-kinin systems. Authors elegantly summarized how life-threatening COVID-19 ARDS is associated with a strong activation of the intravascular innate immune system (IIIS), and with the recognition of this link future clinical trials involving the use of complement inhibitors may be fueled with observational data.Overall, clinical and basic studies published in this Research Topic and elsewhere revealed that complement system is a key partner of the thromboinflammatory reaction occurring in COVID-19-associated organ injuries. Deciphering the mechanisms and understanding the subtilities of the immune response is a long way to go. However, we hope that the variety of articles published in this Research Topic have provided insights on the link between complement, inflammation, and COVID-19 disease, with promising outcomes and future perspectives. As Editors, we would like to thank all the contributing authors and the people in Frontiers in Immunology for their contribution and excellent editing support.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Climate-adaptive forest management aims to sustain the provision of multiple forest ecosystem services and biodiversity (ESB). However, it remains largely unknown how changes in adaptive silvicultural interventions affect trade-offs and synergies among ESB in the long term. We used a simulation-based sensitivity analysis to evaluate popular adaptive forest management interventions in representative Swiss low- to mid-elevation beech- and spruce-dominated forest stands. We predicted stand development across the twenty-first century using a novel empirical and temperature-sensitive single-tree forest stand simulator in a fully crossed experimental design to analyse the effects of (1) planting mixtures of Douglas-fir, oak and silver fir, (2) thinning intensity, and (3) harvesting intensity on timber production, carbon storage and biodiversity under three climate scenarios. Simulation results were evaluated in terms of multiple ESB provision, trade-offs and synergies, and individual effects of the adaptive interventions. Timber production increased on average by 45% in scenarios that included tree planting. Tree planting led to pronounced synergies among all ESBs towards the end of the twenty-first century. Increasing the thinning and harvesting intensity affected ESB provision negatively. Our simulations indicated a temperature-driven increase in growth in beech- (+ 12.5%) and spruce-dominated stands (+ 3.7%), but could not account for drought effects on forest dynamics. Our study demonstrates the advantages of multi-scenario sensitivity analysis that enables quantifying effect sizes and directions of management impacts. We showed that admixing new tree species is promising to enhance future ESB provision and synergies among them. These results support strategic decision making in forestry.The online version contains supplementary material available at 10.1007/s10342-022-01474-4. Adaptive forest management is pivotal to sustain the provision of multiple ecosystem services and biodiversity (ESB) as well as forest multi-functionality in the face of climate change , dynamic forest development models are often used  and in management strategies on forest development over decades to centuries, and they are highly suitable to support decision making. For operational forest management, forest stands are the major target. For forest models to be accurate at the stand level, high data requirements, parameterisation and calibration efforts and computing time are required. Hence, to date most studies providing detailed stand-scale predictions are typically based on case studies comprising specific sites or relatively small forest landscape –and spruce (Picea abies (L.) Karst.)-dominated stands in Switzerland. We present a simulation-based sensitivity analysis that is both accurate at the stand scale and representative at the regional scale, and allows to quantify the effect sizes and effect directions of climate-adaptive silvicultural interventions. Specifically, we addressed the following questions:How do adaptive silvicultural interventions affect ESB provision under climate warming in representative pole stage and mature spruce- and beech-dominated stands?How do these interventions affect trade-offs and synergies between ESB?The aim of the present study is to systematically evaluate the effects of adaptive forest management interventions on ESB under climate warming in regionally representative, low- to mid-elevation beech . The Growth-And-Yield stands used for model parameterisation cover a broad range of mean annual temperatures (0.2–10.2 °C). Therefore, tree growth and regeneration responses to changes in mean temperature as implied by climate scenarios are likely well captured by SwissStandSim. However, the Growth-And-Yield stands have been little affected by drought events in the past and they were re-measured at best every 5 years, so that potential short-term drought effects could not be included in the model. We thus expect simulated growth, regeneration and, in particular, mortality responses to drought under climate change to be underestimated and associated with a high degree of uncertainty. Hence, we focus on the effects of climate warming and do not account for potential drought effects.A new light- and temperature-dependent ingrowth routine has been implemented based on light availability in the stands  and 52 plots as spruce-dominated forest . The plots were further classified as “pole stage” and “mature” based on the development stage determined by the field teams of the Swiss NFI. This selection of NFI plots was used to calculate median stand attributes  and reduced BAU management intensity by 25% as reference scenarios, for the reasons described below Sect. . This reR version 4.0.3 . In contrast, today’s mean growing stocks north of the Alps are between 350 and 400 m3 ha−1. This overestimate of harvesting may be due to an overrepresentation of salvage cuttings following disturbance events in the NFI data, and perhaps also a general overexploitation of growing stocks on the Swiss Plateau  by reducing the removal probability by 25% . This reference was used for all comparisons to the scenarios of adaptive management.Over the four NFI inventory periods 1983–2017), the observed 10-year single-tree removal probability north of the Alps and below 1200 m is 21.8%. This corresponds well to other European forest inventory data summarised in Schelhaas et al. , yieldin983–2017,The long-term application of the management model in a 10-year interval resulted in the uni- and bimodal diameter distributions of the generic stands to converge towards an inverse J-shaped distribution resembling continuous-cover forests . A harvest interval of 10 years was used in all simulations, as this was approximately the interval the NFI plots have been sampled.http://www.nfp73.ch/en/projects/forestry/ecosystem-services-in-forests), in which stakeholders from federal and cantonal administration , private associations , the School of Agricultural, Forest and Food Sciences (HAFL), forest enterprise (Wagenrain), and conservation  participated. To account for different degrees of adaptation, four levels per silvicultural intervention were defined  planting of Douglas-fir, oak and silver fir, b) increased thinning intensity of climatically unsuited tree species to favour planted trees and natural regeneration, and c) increased intensity of target diameter tree harvest. The selection of silvicultural interventions was inspired by stakeholder workshops within the SessFor project Increased thinning intensity of climatically unsuited speciesThe aim of thinning climatically unsuited tree species with a higher intensity is to foster conversion towards a more climate change-adapted species composition. Hence, in the case of the spruce-dominated forest spruce, and in the case of the beech-dominated forest beech were considered as climatically unsuited. To achieve this active adaptation, the removal probability of spruce and beech derived from the reference management model was increased by 15%, 30%, 45% and 60%, respectively, over the entire simulation period.(c)Increased harvesting intensity of target diameter treesThe goal of an increased harvesting intensity of target diameter trees is to shorten the rotation length and thus to reduce stand vulnerability to disturbances such as windthrow or bark beetle outbreaks. To shorten the rotation length, the removal probability of broadleaved trees with DBH ≥ 60 cm and conifers with DBH ≥ 50 cm was increased by 15%, 30%, 45%, and 60%, respectively, compared to the reference scenario over the entire simulation period.The data for the historical climate scenario were randomly resampled from the reference period 1986–2015 provided by MeteoSwiss at the spatial resolution of the Swiss NFI grid  was used to calculate ten ESB indicators to characterise (1) timber production, (2) carbon storage and (3) biodiversity Table , 10% of The carbon storage indicators comprise carbon content in living above- and belowground tree biomass as a fraction of biomass for conifers (51%) and broadleaves (48%); cf. Lamlom and Savidge , in deadThe biodiversity indicators include indices of tree species diversity  was averaged from the observed lying and standing deadwood at NFI4 sample plots, which were classified as beech- and spruce-dominated in the development stages pole and mature, respectively. The decay of deadwood was calculated by exponential temperature-dependent decay functions specific for deciduous and coniferous trees , stem number (approx. 800 stems) and quadratic mean diameter (~ 44 cm) were reached in scenarios with tree planting  increased on average by 12.5% in beech-dominated and by 3.7% in spruce-dominated stands under the strong climate warming scenario Fig. a. These In the simulations for the pole stage stands, all ESB peaked in the second half of the twenty-first century when the maximum of the growing stock was reached , while in mature stands timber supply and carbon storage typically decreased Fig. . HoweverIn scenarios with planting, timber production increased on average by 44.5% relative to the reference management, and this increase was higher in the mature stands  than in the pole stands  , and harvesting intensity slightly increased timber production in the mature beech-dominated stand (+ 0.4%). Overall, the effects of adaptive silvicultural interventions were stronger when applied in the mature stage than in the pole stage  was generally low Fig. a. When tThe planting of trees led to a pronounced synergy of timber production and carbon storage (Spearman correlation from 2031 on > 0.95) and to synergies between all ESBs towards the end of the twenty-first century, i.e. from 2076 or 2086 on  led to the most substantial changes of ESB provision over the simulation period, irrespective of the stand type used for initialisation. The effects on ESB were always positive (with the exception of carbon storage in the pole stages and biodiversity in the mature stages) and increased with the number of trees planted. These findings correspond to results from other simulation studies conducted at different spatial scales and focused on the effect of climate change. At the plot level, Buma and Wessman  showed tProductivity and thus timber production increased considerably over the entire simulation period in the planting scenarios, whereby the effect was substantially higher in beech-dominated than in spruce-dominated stands. In the short term (20–30 years), however, ESB provision dropped and the biodiversity indicator did not increase until mid-century. These effects may be explained by (1) thinning in preparation of planting that accelerated forest restructuring in the long term, but reduced structural diversity in the short term, (2) an increased tree species diversity with the admixture of Douglas-fir, oak and silver fir, and (3) the relatively fast growth of spruce in our simulations (even under the climate change scenarios). A sufficient number of another fast-growing species, i.e. Douglas-fir, had to be planted to compensate for the losses of spruce during the initial preparation thinnings in the planting scenarios. In contrast, a mixture of just 100 trees was enough to increase timber production in slow-growing beech-dominated stands. The positive effects on productivity of admixing in monospecific stands have been reported in many studies  that was then applied in the simulations. Growing stocks decreased from 441 mWe found a small positive effect of climate warming on ESB provision. This effect was higher in beech-dominated than in spruce-dominated stands. Reflecting the empirical basis of SwissStandSim, rising annual mean temperatures slightly elevated the productivity of beech and thus facilitated forest restructuring and increased biodiversity especially in spruce-dominated stands. These findings correspond to retrospective studies from Forrester et al.  who repoIn particular, spruce outside its natural distribution range  After 50–65 years of simulation, planted Douglas-firs reached the diameters to be classified as habitat trees and immediately increased the biodiversity value. b) Douglas-fir was generally the fastest-growing species in our simulations and thus increased both timber production (harvestable diameters were reached earlier) and carbon storage (living biomass accumulated faster) in comparison with stands without Douglas-fir. c) Increasing the number of planted trees further increased the synergetic effects described in a) and b), while interspecific competition remained low due to thinnings in preparation of planting. d) Planted Douglas-fir, silver fir and oak trees grew at different speeds, which increased biodiversity.These results correspond to findings from Mina et al.  who showA striking result was that in the planting scenarios, trade-offs (carbon storage vs biodiversity and timber production vs biodiversity) occurred in the mature spruce-dominated stand only. This may be due to the generally higher productivity of spruce compared to beech in the study area  Drought has not been a decisive factor for tree mortality in the Growth-And-Yield plots. These plots have been set up on productive, presumably rather moist, sites suitable for the production of high-quality timber. The empirical basis of SwissStandSim would have to be extended to plot data from sites with poorer water availability, where past exposure of spruce and beech to drought has been recorded Below is the link to the electronic supplementary material.


In Latin America, where climate change and rapid urbanization converge, non-optimal ambient temperatures contribute to excess mortality. However, little is known about area-level characteristics that confer vulnerability to temperature-related mortality.Explore city-level socioeconomic and demographic characteristics associated with temperature-related mortality in Latin American cities.The dependent variables quantify city-specific associations between temperature and mortality: heat- and cold-related excess death fractions , and the relative mortality risk (RR) associated with 1 °C difference in temperature in 325 cities during 2002–2015. Random effects meta-regressions were used to investigate whether EDFs and RRs associated with heat and cold varied by city-level characteristics, including population size, population density, built-up area, age-standardized mortality rate, poverty, living conditions, educational attainment, income inequality, and residential segregation by education level.We find limited effect modification of cold-related mortality by city-level demographic and socioeconomic characteristics and several unexpected associations for heat-related mortality. For example, cities in the highest compared to the lowest tertile of income inequality have all-age cold-related excess mortality that is, on average, 3.45 percentage points higher . Higher poverty and higher segregation were also associated with higher cold EDF among those 65 and older. Large, densely populated cities, and cities with high levels of poverty and income inequality experience smaller heat EDFs compared to smaller and less densely populated cities, and cities with little poverty and income inequality.Evidence of effect modification of cold-related mortality in Latin American cities was limited, and unexpected patterns of modification of heat-related mortality were observed. Socioeconomic deprivation may impact cold-related mortality, particularly among the elderly. The findings of higher levels of poverty and income inequality associated with lower heat-related mortality deserve further investigation given the increasing importance of urban adaptation to climate change. •Limited evidence of effect modification of cold-related mortality in Latin American cities.•High income inequality is associated with greater excess mortality from cold for all ages.•Segregation and poverty are associated with higher excess mortality due to cold among the elderly.•Results for heat-related mortality are opposite of expectations .•The results for heat-related mortality require further investigation. An estiAn urgent area of research and a public health opportunity is identifying population characteristics that confer vulnerability to (or protection from) heat or cold-related mortality. Multiple cities in Europe and beyond have adopted heat action plans in the aftermath of the 2003 heatwave in Europe that led to an estimated 70,000 excess deaths . In addiVulnerability to non-optimal temperatures is a function of exposure, physiological sensitivity, and adaptive capacity . SocioecA number of individual factors have been shown to modify vulnerability to non-optimal temperatures including age , sex In, low socThis study uses daily mortality records from 325 cities in nine Latin American countries, combined with daily temperature data and information on cities’ socioeconomic and demographic characteristics to examine the extent to which associations between non-optimal temperatures and mortality are modified by characteristics such as poverty, living conditions, income inequality, and segregation, among others.22.1Salud Urbana en América Latina (SALURBAL) project. The goal of SALURBAL, an interdisciplinary multinational collaboration, is to investigate the social and environmental determinants of health in Latin American cities  classifications . We cond2.2.2Guided by the theoretical frameworks on vulnerability to temperature-related mortality , we extr2.2.3Temperature data was obtained from the land surface component of the 5th generation of European ReAnalysis (ERA5), also known as ERA5-Land, produced by the European Centre for Medium-Range Weather Forecasts (ECMWF) and publicly available . ERA5-LaKephart et al. (2022)We obtained data on the prevailing climate zone in a city from the Köppen climate classification , which g3We estimated effect modification of temperature-related mortality by city characteristics in three stages using an approach similar to that in a priori hypotheses that these variables might confound associations. The modeling was done using packages “dlnm”  among those ages 65+ only. In addition, we also estimated excess deaths associated with hot and cold temperatures for deaths from cardiovascular disease (CVD). Finally, in order to analyze whether effect modification by city characteristics varied depending on the cities’ climatic conditions, we stratified the cities by 1) Köppen climate zones ; and 2) category of inter-annual temperature variation .3.2We undertook several sensitivity analyses to assess the robustness of the results. First, we compared the results from the all-age models to the results with adjustment for the proportion of population 65 and older as the older age group may disproportionally contribute to mortality relative to its population size. Second, we re-estimated the meta-regressions for each socioeconomic and demographic indicator while adjusting for population and population density to assess the robustness of our results to the city size and population distributions in cities. Third, for each effect modifier we re-estimated the meta-regressions including non-linear spline terms for mean daily temperature and temperature range.44.1We observed high variability in socioeconomic indicators between the cities in general, as well as between cities within countries. The highest levels of city income inequality were observed in Brazil (median Gini index = 0.55), while in the rest of the countries it hovered around 0.4. According to the living conditions score , cities with the most suboptimal living conditions in our sample are located in Central America and Peru. Indeed, the median proportion of households with piped water access inside their dwellings in Peruvian cities is 70%; the proportion of households with piped water access is slightly higher in Central American cities – 76%, compared with 97% in Brazil. Peruvian and Central American cities also had the highest levels of overcrowding, with the median city proportion of households with more than three people per room at about 10%.4.1.1The demographic and socioeconomic indicators used in the study describe different aspects of cities’ socioeconomic environments, but they exhibit several correlation patterns . The hig4.22 = 93%) than for heat EDFs (I2 = 78). The inclusion of country group reduced I2 to 92% for cold EDFs and 76% for heat EDFs. The addition of climate zone, temperature range, and mean daily temperature further reduced I2 to 91% for cold EDFs and 72% for heat EDFs.According to a meta-regression of city-specific temperature-mortality associations, 5.75%  of deaths at all ages and from all causes are associated with non-optimal temperatures during the 2002–2015 study period . Out of 4.3In this section, we describe associations between city-level socioeconomic and demographic characteristics and: (1) excess death fractions (EDF) related to cold and heat; (2) relative risk (RR) of mortality due to extreme cold and extreme heat. The estimates in 4.3.1The left panel of Results for the excess mortality associated with extreme cold  of all temperature-related deaths. High population density and higher socioeconomic deprivation as measured by poverty and income inequality were associated with lower excess mortality due to heat . Cities The effect modifications of the EDF attributable to extreme heat  and city characteristics among cities in arid, temperate, and tropical climate zones . Other indicators including segregation and poverty were also associated with higher excess mortality due to cold especially among the elderly (65+). We find no clear pattern of effect modification for the relative risk of mortality associated with a 1 °C decrease in temperature below the 5th percentile.a priori hypothesis, the findings that cities with high population density, low living conditions scores, and medium and high poverty have smaller excess mortality from extreme heat (compared to cities with low population density and cities with desirable living conditions score and low poverty) were not expected. We find no modification of the relative risk of mortality associated with a 1 °C increase in temperature above the 95th percentile.We observe more examples of effect modification of excess mortality associated with heat, however, many of those associations are puzzling and opposite of our expectations. For example, cities with high income inequality and high poverty have lower heat EDFs compared to cities with desirable levels of these indicators. While the finding of high age-standardized mortality rate associated with larger excess mortality due to extreme heat  was in line with our Although we hypothesized that desirable socioeconomic characteristics – such as low levels of poverty, income inequality, residential segregation, and high standards of living conditions, as well as small % built-up, low population, and low population density – would be associated with smaller excess mortality and smaller relative risk of mortality due to non-optimal temperatures, our findings show only limited support for these pathways in the case of cold-related mortality and unexpected directions of the associations for heat-related mortality.5.2While multiple studies have demonstrated the contribution of higher- and lower-than-optimal temperatures to mortality all over the globe , to dateSome of our results are also in contrast to several studies from China , Japan , and FraOur study is among the first to explore city socioeconomic characteristics as effect modifiers of temperature-related mortality in Latin America, so, barring a few exceptions we cannot compare the observed results with other studies in the same region. However, the use of community- or area-wide effect modifiers, which ignore within-city and between-person or -neighborhood heterogeneity in socioeconomic wellbeing, potentially contributes to the findings of no effect modification . Future 5.3The finding of lower heat EDF in cities with high Gini index and high poverty is in contrast to our expectation and requires replication and confirmation. Cities in the highest 30% of income inequality as measured by Gini index are almost exclusively concentrated in Brazil (96 cities in Brazil and 6 cities in Mexico comprise the top tertile of the high-Gini cities). Similarly, 30 cities in Mexico and 71 cities in Brazil account for 98% of the poorest cities in the sample. These highly unequal and poor cities also tend to be the hottest cities in our entire sample. In fact, the correlations between mean daily temperature and city characteristics are the highest for Gini (r = 0.45) and poverty (r = 0.24), of all the city characteristics. Our controls for mean daily temperature, temperature range, and climate zone account for the confounding effect of temperature. It is possible, however, that hotter cities  are more adapted to high temperatures and that adjusting for daily temperature, range and climate zone does not directly capture this adaptation. To explore this, we estimated associations between MMT and city-level predictors . These rAnother potential explanation may lie in the distribution of greenspace. A recent study showed that in the same Latin American cities as in our study, city socioeconomic status   is negatOverall, the observed counterintuitive relationships for heat-related mortality may be due to high levels of acclimatization to higher temperatures among the highly unequal and poor cities. Future research should identify measures of and account for the role of population adaptive capacity in vulnerability to non-optimal temperatures.5.4Seguro Popular was associated with a 30% decrease in cold-related deaths among the poor, possibly by increasing medical assistance in general as well as expanding insurance coverage to include winter-related illnesses such as pneumonia  income inequality and higher cold-related mortality for all ages; 2) poverty and segregation and higher cold-related mortality among the elderly. Population's adaptive capacity to withstand the impact of cold and extreme cold may be bolstered by expanding the use of heaters in dwellings and weatherizing homes.5.5First, between-individual or neighborhood variability in socioeconomic characteristics is likely much higher than the between-city variability exploited in the study. Therefore, an analysis using individual-level mortality outcomes and individual-level socioeconomic characteristics would provide a more robust assessment of effect modification. Relatedly, within-city variability in socioeconomic characteristics is also likely higher than the between-city variability, so an alternative analysis could utilize socioeconomic and demographic data from a level smaller than city – such as neighborhood level, for example. It may be that the temperature-mortality relationship is modified by socioeconomic environment at the neighborhood level, but less so at the highly heterogeneous city level. Second, no variables describing healthcare provision and accessibility were available for this analysis, whereas the number of hospital beds  and acce5.6This work explored effect modification of mortality associated with both hot and cold non-optimal temperatures, using excessive death fractions as well as RR per degree difference at temperatures above the 95th percentile and below the 5th percentile. We used population-weighted air temperature, which enabled a more accurate measurement of city-level exposure compared to temperature measures that do not account for population distribution. Our study based on individual mortality records from a large and diverse sample is among the first studies of temperature-related mortality in Latin America, an extremely understudied region. While many previous studies of temperature-mortality and its effect modification by area-level socioeconomic characteristics considered a limited number of cities in Latin America and the Global South , cities 5.7Overall, we find limited effect modification of cold-related mortality in Latin American cities by city-level demographic and socioeconomic characteristics, and several unexpected patterns of effect modification of heat-related mortality. Cold-related mortality in Latin American cities may be impacted by income inequality, particularly among the elderly. The findings of higher levels of poverty and income inequality associated with lower heat-related mortality deserve further investigation. Future studies should consider measures of adaptive capacity when investigating vulnerability to non-optimal temperatures.All authors conceptualized the analysis. MB and BNS completed formal analysis. MB created the original draft of the manuscript. ADR and DAR are senior investigators and provided supervision. All authors contributed to writing and manuscript editing.Requests for the code used in this study should be made to the corresponding author.The authors declare no competing interests.


Universal varicella vaccination (UVV) in England and Wales has been hindered by its potential impact on exogenous boosting and increase in herpes zoster (HZ) incidence. We projected the impact of ten UVV strategies in England and Wales on the incidence of varicella and HZ and evaluated their cost-effectiveness over 50 years. The Maternal-Susceptible-Exposed-Infected-Recovered-Vaccinated transmission model was extended in a dynamically changing, age-structured population. Our model estimated that one- or two-dose UVV strategies significantly reduced varicella incidence (70–92%), hospitalizations (70–90%), and mortality (16–41%) over 50 years. A small rise in HZ cases was projected with UVV, peaking 22 years after introduction at 5.3–7.1% above pre-UVV rates. Subsequently, HZ incidence steadily decreased, falling 12.2–14.1% below pre-UVV rates after 50 years. At a willingness-to-pay threshold of 20,000 GBP/QALY, each UVV strategy was cost-effective versus no UVV. Frontier analysis showed that one-dose UVV with MMRV-MSD administered at 18 months is the only cost-effective strategy compared to other strategies. HZ incidence varied under alternative exogenous boosting assumptions, but most UVV strategies remained cost-effective. HZ vaccination decreased HZ incidence with minimal impact on the cost-effectiveness. Introducing a UVV program would significantly reduce the clinical burden of varicella and be cost-effective versus no UVV after accounting for the impact on HZ incidence. Varicella, or chickenpox, is an acute and highly contagious disease caused by the varicella-zoster virus (VZV). While usually mild and self-limiting, varicella can lead to severe complications, hospitalizations, and death in rare cases ,2. The mLive-attenuated VZV vaccines are active immunizing agents that offer protection against VZV infection. Randomized clinical trials (RCTs) and observational studies have established the safety and efficacy of these vaccines for the prevention of varicella ,8,9 and The World Health Organization (WHO) recommends UVV in countries that can maintain vaccination coverage rates of ≥80% . One dosIn the United Kingdom (UK), varicella vaccination is not part of the routine childhood immunization program and is only offered to those in close contact with individuals at high risk of varicella and its complications . ConsequIn 2010, the Joint Committee on Vaccination and Immunization (JCVI) in England recommended against a UVV program in children or a combined childhood varicella and adult HZ vaccination program due to its potential impact on exogenous boosting and HZ incidence . It has Since the JCVI’s recommendation, several real-world studies have advanced our understanding of the impact of UVV and exogenous boosting. A recently published self-controlled case series study of 9604 UK adults with both household exposure to varicella and an episode of HZ showed that exposure to varicella is associated with a 33% reduction in risk of HZ over 20 years, suggesting that the impact of exogenous boosting may be lower than predicted in previous models . AnotherModels that consider the interplay between exogenous boosting and demographic changes may more accurately predict the impact of varicella vaccination programs on HZ incidence. The objective of this study was to estimate the long-term clinical and economic impact of UVV strategies in England and Wales as well as their cost-effectiveness, considering exogenous boosting scenarios based on recent real-world evidence, in a population with a dynamically changing age structure.A deterministic, age-structured, continuous-time, nonlinear dynamic transmission model in the form of differential equations was developed  [Vaccine properties are described in the  V-GSK]) ,41,42. T V-GSK]) . We esti V-GSK]) .®  or Priorix-Tetra® ). In the 2-dose strategies, children received a monovalent formulation at 12 months (V-MSD or V-GSK), followed by a second dose of the monovalent or the quadrivalent formulation at 18 months or 4 years of age, and with or without catch-up vaccination. The first and second catch-up dose for teenagers who missed childhood varicella vaccination was aligned with the human papillomavirus vaccine schedule. Catch-up vaccination was only offered during the first two years of the program. Vaccination coverage rates were set to 91% for the first dose and a second dose given at 18 months, 88% for a second dose at 40 months [Ten UVV strategies are included in the model  and MMRV-GSK (GBP 55.13) are calculated from the average list prices in Germany , Spain , and SwiThe key model outcomes projected over time included varicella cases, HZ cases, and related outpatient visits, hospitalizations, and deaths. Outcomes were categorized as those related to natural and breakthrough varicella, and those related to HZ.Incremental cost-effectiveness ratios (ICERs) were computed by comparing each UVV strategy to no UVV from both the payer and societal perspectives. In addition, a frontier analysis was conducted to inform decisions as to which strategy or strategies should be considered when choosing among all feasible ones. In this analysis, strategies dominated by one or several others are removed. The ICER of non-dominated strategies on the frontier is performed by determining whether the additional QALYs gained by the next strategy along the frontier is worth the incremental cost. The threshold for cost-effectiveness of GBP 20,000 per QALYs in the UK was used . For allTo examine the impact of uncertainty in key vaccine and cost parameters on the cost-effectiveness of the UVV strategies that are on the frontier, parameters (or sets of related parameters) were varied one at a time in a deterministic sensitivity analysis (DSA). In addition, a probabilistic sensitivity analysis (PSA) using 500 variates was conducted to assess the variability in ICERs relative to the no-UVV scenario as a function of the uncertainty in key parameters relating to the calibration of HZ incidence and varicella seroprevalence, vaccine strategy, and costs. Scenario analyses were also conducted to investigate the robustness of the cost-effectiveness results under alternative assumptions. Since the impact of UVV on HZ incidence is dependent on the assumptions used for exogenous boosting, three alternative scenarios were evaluated based upon the most recent literature and previous assumptions used in modeling studies. In scenario EB1, the waning period of HZ immunity was 24.4 years, with the effectiveness of contacts being age-dependent  . In scenDetailed results of the model calibration are provided in All proposed UVV strategies are projected to rapidly reduce total varicella incidence after introduction. Two years after introducing a UVV program, incidence decreased from approximately 1100 cases per 100,000 person-years without UVV to around 135–210 cases per 100,000 person-years depending on UVV strategy a. BreaktThe percentage reduction in varicella health outcomes  after 50 years with each UVV strategy in comparison to no UVV is shown in The projected incidence of HZ between 2022 and 2072 following UVV in the base-case scenario is depicted in Results from the cost-effectiveness analysis comparing the UVV strategies over 50 years in England and Wales from a payer perspective and societal perspective are provided in Each UVV strategy resulted in higher costs from the payer perspective, but also resulted in QALYs gained (fewer QALYs lost) due to the decrease in total varicella infections and HZ cases. Compared to no UVV, QALYs gained range from 54,854 (Strategy B: single-dose with MMRV-GSK) to 61,826 (Strategy C: a two-dose strategy including a catch-up with V-MSD). The ICER for each UVV strategy compared with no UVV ranged between 6809 GBP/QALY gained and 16,698 GBP/QALY gained. Thus, each strategy was cost-effective compared to no UVV when using the willingness-to-pay threshold of GBP 20,000 per QALY gained . StrategFrom a societal perspective, Strategy A is cost-saving compared to no UVV, as QALYs were gained while reducing total costs by GBP 86M. All other strategies remained cost-effective, with each ICER at or below GBP 8003 per QALY gained vs no UVV. From the societal perspective, the same UVV strategies are on the frontier . However, unlike the payer perspective, no UVV was strongly dominated by Strategy A, and thus does not lie on the frontier. Using the threshold of 20,000 GBP/QALY gained, only Strategy A would be deemed cost-effective, as the ICERs for Strategy G versus Strategy A and for Strategy C versus Strategy G exceed the threshold.The PSA was conducted on the base case to evaluate the uncertainty in the ICER resulting from variation in the calibration and uncertainty in parameters. Results of the PSA showed that the base-case results are robust. Strategies A, G, and C were compared to no UVV from a payer perspective. For Strategy A and Strategy G, all variates led to ICERs below 20,000 GBP/QALY gained. For Strategy C, 97.4% of the variates led to ICERs below 20,000 GBP/QALY gained. The spread of the points from the randomly generated parameter sets surrounding the base-case estimate of expected costs and QALYs and the likelihood of being cost-effective across a range of willingness-to-pay thresholds for the three vaccine strategies are shown in Results of the scenario analysis are presented in We also assessed the impact of HZ vaccination, which was introduced in the UK NIP in 2013 for adults aged 70–79 years old . Total cFinally, the results of the sensitivity analysis with a 1.5% discount rate for health outcomes are provided in We adapted a dynamic transmission model to estimate the long-term health impact and cost-effectiveness of implementing a UVV program in England and Wales, considering different scenarios of exogenous boosting in a population with a dynamically changing age structure. Overall, ten vaccination strategies were considered using monovalent and quadrivalent formulations of MSD or GSK vaccines with one or two doses, short or medium intervals, and with or without catch-up vaccination. All strategies substantially reduced the clinical and economic burden of VZV. Over 50 years, both one-dose strategies with quadrivalent MMRV formulations administered at 18 months of age with assumed coverage of 91% were projected to reduce varicella mortality by 16–32% and varicella incidence by 70–87% . All two-dose strategies, where the first dose was administered at 12 months and the second dose at 18 or 40 months, were projected to have higher reductions in varicella mortality (37% to 41%) and incidence (89% to 92%). Breakthrough varicella cases were higher for one-dose strategies compared to two doses, and were highest for MMRV-GSK; this could be attributed to lower efficacy of one-dose MMRV-GSK . While the benefits of UVV on reducing the burden of varicella are well-established, the potential impact of UVV on exogenous boosting and HZ incidence has hindered the adoption of the UVV program in the UK and other European countries as this could lead to higher healthcare resource utilization. We thoroughly tested different exogenous boosting assumptions in our model. In the base case, our model used boosting assumptions based upon a 20-year real-world evidence study in UK adults conducted by Forbes et al. that showed the intensity of boosting to be lower (33%) than predicted by previous models . PreviouThe base-case model showed that all one- and two-dose UVV programs are cost-effective compared to no UVV, at a willingness-to-pay threshold of 20,000 GBP/QALY gained, either from the payer or the societal perspective. Further, the single-dose strategy with MMRV-MSD at 18 months is cost-saving from the societal perspective. If a UVV program is to be adopted, the cost-effectiveness frontier provides information on which strategy should be selected from a cost-effectiveness standpoint. Based on both the payer and societal perspective, only the single dose of MMRV-MSD at 18 months (Strategy A) was deemed cost-effective at the willingness-to-pay-threshold of GBP 20,000 per QALY gained. Two-dose strategies with catch-up, Strategy G , and Strategy C (V-MSD at 12 and 18 months) lay on the frontier but are not cost-effective because their ICERs (for Strategy G vs Strategy A and for Strategy C vs Strategy G) exceeded the willingness-to-pay threshold of 20,000 GBP/QALY. The DSA suggests that the results are robust to changes in cost of medical care and vaccine coverage, take, waning, and vaccine cost. However, beyond the cost-effectiveness of vaccination strategies, policymakers should consider several factors when implementing a UVV program, including the ability to maintain high vaccination coverage (>80%) and the flexibility of the vaccination schedule to accommodate an additional vaccination visit, as well as the programmatic goals of the country. To prevent outbreaks and reduce transmission and breakthrough varicella, two-dose strategies are recommended over one-dose strategies . The results of our model are consistent with those from a similar dynamic model adapted for Turkey, Italy, Mexico, Norway, and Switzerland ,64,65,66®  was initiated in 2013 within the model. We observed a modest impact of HZ vaccination on HZ incidence and mortality with increased costs compared to no HZ vaccination. This could be due to the narrow age range (adults 70–80 years) that is recommended to receive HZ vaccination in the current program. Nevertheless, the ICERs for each UVV strategy observed in the base case without HZ vaccination were lower than the ICERs in the HZ vaccination scenarios. The HZ vaccination program could be more effective if it was offered to a broader age group of adults who are at a high risk of HZ infection, similar to recommendations in other countries such as the US [Brisson et al. predicted that UVV would reduce the burden of varicella in England and Wales . Howevers the US .This study has several limitations. Data specific to England and Wales for some parameters such as workdays lost and QALYs lost for HZ and PHN were not available; hence, we used published estimates from other countries in line with other studies. There is currently no pediatric vaccination visit at 18 months in England and Wales, which was the modeled timepoint for the one-dose MMRV strategies and two-dose short-interval strategies. The model did not include any costs associated with implementing  a new vaccination visit. Additionally, the list prices for MMRV formulations are not available for England and Wales; we used international reference pricing, which may differ from the actual list prices. Therefore, this is a conservative estimate of ICERs as the analysis utilizes list prices and not tender prices. There are limited data available comparing V-MSD/MMRV-MSD to V-GSK/MMRV-GSK; however, V-MSD and MMRV-MSD are generally considered immunologically equivalent to each other, as are V-GSK and MMRV-GSK. Finally, we used the temporary immunity model to estimate exogenous boosting and its duration. There is ongoing research on alternative modeling of the exogenous boosting mechanism, such as progressive immunity . DiffereWe estimated the long-term effectiveness and cost-effectiveness of UVV in England and Wales while considering the impact on the burden of HZ using recent real-world evidence on exogenous boosting. We also used a dynamic population in our transmission model to better understand the role of an aging population on HZ incidence. Our model estimated that all UVV strategies, including one or two doses, short or medium intervals, and monovalent or quadrivalent formulations, substantially reduced the clinical burden of varicella in terms of incidence, outpatient visits, hospitalizations, and mortality compared to no UVV. A UVV program was projected to reduce the incidence of HZ after 50 years compared to a no-UVV scenario following an initial increase in the first 20 years of its introduction. Our model also showed a similar increase in the incidence of HZ in the absence of UVV because of the ageing population. All UVV strategies were cost-effective compared to no UVV over 50 years. A one-dose UVV strategy with MMRV-MSD administered at 18 months of age was the most dominant strategy from the payer perspective and was cost-saving from the societal perspective. Our model suggests that policymakers should consider UVV to reduce the clinical and economic burden of VZV in England and Wales.