Parent relationship satisfaction and parental reflective functioning (PRF) are significant factors in the transition to first-time parenting and are likely to affect a child’s later wellbeing. However, little is known about their joint longitudinal effects from pregnancy onward. Starting in the prenatal period, this follow-up study of 1016 Finnish first-time parents (358 fathers and 658 mothers at baseline) examined the stability and the reciprocal associations between relationship satisfaction and PRF in predicting child behavioral problems (CBCL) at age 2. First, the results of the random-intercept cross-lagged panel models showed that both relationship satisfaction and PRF were stable from pregnancy onward for both mothers and fathers, with the exception of mothers’ prenatal PRF. Second, there were significant reciprocal associations between low prenatal PRF and low relationship satisfaction at age 1, and vice versa. Third, for both mothers and fathers, a low level of relationship satisfaction, but not PRF, predicted consistently higher levels of child behavioral problems at age 2. These results suggest that parent relationship satisfaction and PRF are stable but largely independent parental factors during the transition to parenthood. In addition, our results highlight the significant role of parent relationship satisfaction in predicting toddler behavior problems, which indicates the relevance of early relationship-orientated help for first-time parents. Toddlerhood is a challenging developmental period that is often characterized by an increase in externalizing and internalizing behavioral problems . These eThe transition to first-time parenthood changes a parental couple’s romantic relationship. Although research has indicated that relationship satisfaction increases during pregnancy for first-time parents, most couples report a decline in relationship satisfaction during the 1st year of their infant’s life . ParentsConsequently, it is not surprising that relationship dissatisfaction can have direct negative consequences for the child: children may learn maladaptive behaviors to protect themselves against negative emotions  or parenThe significant role of reflective parenting skills, i.e., the parental capacity to show coherent and appropriate appreciation of the child’s internal states, has recently been underlined in the transition to parenthood . The devReflective parents are open, curious, and interested; rather than simply responding to observable behaviors, reflective parents make accurate interpretations about their child’s internal experiences. Parents who are characterized as having low PRF seem unaware of their own or their child’s thoughts or feelings, and they overlook the emotional experiences associated with parenting . As suchFamily systems theory further postulates that there is a reciprocal association between the functioning in the spousal and parental subsystems. Behaviors and emotions experienced in one subsystem  may be transferred to another subsystem , or vice versa . AccordiEarly childhood behavior problems are categorized within two broad domains: externalizing and internalizing. Externalizing problems include under-controlled, acting-out behaviors, such as conduct difficulties, hyperactivity, and impulsivity. Internalizing problems involve experiences of distress  that are represented by inwardly directed reactions . LongituFinally, parenting literature has frequently called for the systematic inclusion of both mothers and fathers. Indeed, the few parenting studies that have produced reports from both fathers and mothers on relationship satisfaction have used either the total or average relationship satisfaction scores of both spouses  or used This study aimed to add to the extant research by utilizing a longitudinal data set of first-time parents to examine the stability and interrelations between relationship satisfaction, PRF, and child behavioral problems from pregnancy to 2 years postpartum. Based on previous research and theory, we first hypothesized that both relationship satisfaction and PRF measured prenatally, and at 3, 12, and 24 months postnatally would show stability over time. Second, according to the spill-over hypothesis, we predicted that relationship satisfaction and PRF would interact together. However, few empirical studies have addressed the longitudinal interrelations between relationship satisfaction and PRF; therefore, we hypothesized that the crossover effects would be indicated at an early age by the presence or absence of indirect effects from either relationship satisfaction or PRF on a child’s behavior problems at age 2, each mediated by the other. We therefore regarded these tests as exploratory. Third, we hypothesized that both relationship satisfaction and PRF would predict child behavior symptoms at age 2. Finally, as there has been little research studying PRF and relationship satisfaction in both mothers and fathers, no hypotheses were set regarding the differences in the associations between the study variables.via the system of maternity and well-baby clinics between January 2011 and October 2015  about the study at a regular visit during the third trimester of pregnancy. The average gestational week the mothers answered the first survey was 34.4 (SD 3.2). The nurses were specifically instructed not to select families for the study, but to offer the opportunity to all first-time parents during a regular check-up. Either the mother or the father, or both, received written information about the study as well as informed consent forms with a prepaid envelope. The mothers and fathers who took part in the study separately filled in the same questionnaires. All parents gave their voluntary, informed consent for treatment and were instructed that they could leave the study or treatment at any time.The background information used in the present study included parental age, marital status , and parental level of education. The questionnaire included a nine-point list of alternatives to assess the level of education, with a higher number indicating a higher education level. The education levels ranged from the lowest category of less than the compulsory 9 years of school to the highest category of university doctorate degree. For descriptive purposes, To assess relationship satisfaction, we used the Index of Marital Satisfaction (IMS) . The IMSoptimal PRF, 1 and 7 = low PRF; i.e., scoring is 1, 3, 5, 7, 5, 3, 1). In this study, we used the total sum score comprising all the subscales. Internal consistency for the total PRFQ  was α = 0.90 for mothers and α = 0.88 for fathers.The P-PRFQ  consistsTo assess PRF, we used the Finnish shortened version of the original Parental Reflective Functioning Questionnaire PRFQ;  called tM = 50, SD = 10) on seven different syndrome scales , as well as five different DSM-oriented scales . These scores combine to yield an internalizing problems, externalizing problems, and total problems composite score, and this method was used in the present study. The manual for the CBCL reports adequate reliability and validity for the scale scores . Descriptive statistics were then conducted to evaluate the distribution, mean, and standard deviation (SD) of each study variable, and comparisons were made to assess whether there were differences between mothers and fathers (Student’s t-tests). We also conducted bivariate correlations (Pearson’s r) between the study variables. We applied structural equation modeling to the analyses of the temporal associations between PRF, relationship satisfaction, and CBCL. We used random intercept cross-lagged panel data modeling (RI-CLPM) with the lavaan R-package (n = 106).The preliminary analyses for the means, standard deviations, and bivariate correlations of the study variables were performed using the SPSS version 25. We determined whether there were differences between mothers and fathers in the background variables using Student’s -package , as this-package . To incrM = 29.17, SD = 4.62 and for fathers M = 30.94, SD = 4.91), and had received an education beyond the 9 years of compulsory school (96.3% of mothers and 91.2% of fathers). Mothers and fathers differed in terms of age, t(844) = −5.09, p < 0.01, and educational level, χ2(3) = 23.29, p < 0.001, with mothers being younger and more educated than fathers. There was no difference in the matrimonial status, χ2(4) = 7.04, ns (M = 39.7 SD = 1.76), with birth weight M = 3441.5 (SD = 495), and Apgar M = 8.54 (SD = 1.47).The vast majority of the participants were married or cohabiting (96.8% of mothers and 98.9% of fathers), were between the ages of 17 and 49 . The data was checked to ensure that there were no statistical differences between the three groups  in relation to the other background or study variables; the participants who were single parents were then excluded from the analyses to keep the group sizes equal. The results indicated associations with a higher educational level and PRF in all the different study phases for mothers and at 3 and 12 months for fathers , and the study variables  using Student’s t-tests. We also examined the association between child birth characteristics and study variables using correlations. For the purposes of these analyses, categorical variables  were dichotomized to maintain adequate cell sizes . The number of single parents was very low . Only the IMS showed significant correlations with child behavioral symptoms, r = 0.14−0.28 for both mothers and fathers.Significant small to large size correlations , 6 were 2(55) = 66,65, RMSEA = 0.000 (0.035), CFI = 1.00 (0.983), TLI = 1.020 (0.978)]. With the exception of mothers’ pre- to postnatal PRF, both relationship satisfaction and PRF showed stability across time for both mothers and fathers. Furthermore, there were significant cross-related associations between a low level of prenatal relationship satisfaction and low PRF at 3 months, and vice versa. Finally, a low level of relationship satisfaction, but not PRF, was associated with child behavioral problems at 2 years of age. Additionally, with only using a subsample of those parents who entered the study together (n = 106 parents), the results showed a similar pattern of associations  for the statistical analyses which is useful as it explicitly take into account stable between-person differences so that their autoregressive and cross-lagged paths exclusively pertain to within-person associations. This result is expected, as a large number of studies, conducted particularly among older children, have shown that relationship dissatisfaction is linked to the CBCL-DP . The negIn the study of relationship satisfaction and PRF, it is important that researchers consider the various contextual factors, such as the SES and marital status . Our resvia interview-based measures, such as the PDI-RF (The first limitation of the present study relates to the use of self-reports for the assessment of all the study variables; thus, the findings may in part reflect shared method variance. The high correlations between the independent variables also make estimation vulnerable to multicollinearity, leading to an increase in the possibility of Type II error, which means that the data does not reveal significant relationships that should be present. Furthermore, questionnaires cannot provide information that is as detailed and idiosyncratic as the data gathered e PDI-RF . Second,Despite the limitations, the longitudinal results of the present study both confirm and extend previous findings on relationship satisfaction and PRF and their relevance for child behavioral problems across the transition into parenthood. Our study highlighted the significance of relationship satisfaction, rather than PRF, as a predictor of toddler behavioral problems; this finding suggests that supporting first-time parents’ relationships with their partners may have preventive clinical value. Furthermore, the results indicated a significant interrelationship, over a period of time, between high prenatal PRF and high relationship satisfaction at 3 months, and vice versa, which underlines the importance of focusing on both PRF and relationship satisfaction during the significant transition from pregnancy to life with a young baby. In addition, our study builds on previous research by showing that parents’ PRF and relationship satisfaction are highly stable from pregnancy to 2 years postpartum; thus, our research emphasizes the importance of extending the understanding of their role in early parenting. Further longitudinal follow-up study phases at school-age will provide additional data on the present sample; the analyses will show whether the stability of PRF and relationship satisfaction is maintained and whether they are related to a wider range of child outcomes.saara.z.salo@helsinki.fi.The datasets presented in this article are not readily available because permission to share data was not asked from the participants. Requests to access the datasets should be directed to SS, The studies involving human participants were reviewed and approved by the Finnish National Institute of Health and Welfare. The patients/participants provided their written informed consent to participate in this study.MK and MP contributed to the original design of the study. SS and JL analyzed the data. SS and JS wrote the manuscript. All authors contributed to the manuscript revisions and have read and approved the submitted version.


Strict and repeated lockdowns have caused public fatigue regarding policy compliance and had a large impact on several countries’ economies. We aimed to evaluate the effectiveness of a soft lockdown policy and the strategy of active community screening for controlling COVID-19 in Taiwan. We used village-based daily confirmed COVID-19 statistics in Taipei City and New Taipei City, between May 2, 2021, and July 17, 2021. The temporal Gi* statistic was used to compute the spatiotemporal hotspots. Simple linear regression was used to evaluate the trend of the epidemic, positivity rate from community screening, and mobility changes in COVID-19 cases and incidence before and after a level three alert in both cities. We used a Bayesian hierarchical zero-inflated Poisson model to estimate the daily infection risk. The cities accounted for 11,403 (81.17%) of 14,048 locally confirmed cases. The mean effective reproduction number (Re) surged before the level three alert and peaked on May 16, 2021, the day after the level three alert in Taipei City (Re = 3.66) and New Taipei City (Re = 3.37). Mobility reduction and a lower positive rate were positively associated with a lower number of cases and incidence. In the spatiotemporal view, seven major districts were identified with a radial spreading pattern from one hard-hit district. Villages with a higher inflow degree centrality among people aged ≥ 60 years, having confirmed cases, specific land-use types, and with a higher aging index had higher infection risks than other villages. Early soft lockdown policy and detection of infected patients showed an effective strategy to control COVID-19 in Taiwan. In 2020, most countries had non-pharmaceutical approaches to slow down the epidemic, such as lockdowns3, social distancing4, mask-wearing5, and controlling international borders6. However, the strict and repeated lockdown caused resident fatigue on policy compliance and had a large impact on economies7. At the early stage of the pandemic, a social distancing policy was supported by residents and this significantly reduced the spread of severe acute respiratory coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, worldwide8. Nevertheless, the high transmissibility and high mutation rate of SARS-CoV-2 variants continue to pose global public health threats9. In 2021, enhancing vaccination coverage to cope with the pandemic became a major public health priority in countries.From January 2020, the COVID-19 pandemic has swept over the world, causing high morbidity and mortality10. Nonetheless, Taiwan never enforced strict lockdowns, nor did it resort to drastic restrictions on civil freedom. Instead, a more lenient approach was adopted, encouraging residents to stay at home and follow protocols, including mask-wearing and limits on gatherings. Since Taiwan has not reached the level four alert criteria , a full lockdown was unnecessary. The soft lockdown measures were more sustainable as people voluntarily stayed at home and adhered to the regulations.Given that COVID-19 spread through contact between humans, a full lockdown, including restricted social contact and keeping open essential businesses only, places everyone in quarantine and minimizes the risk of community transmission. Evidence showed that a 2-week lockdown successfully reduced the number of daily diagnosed cases, intensive care unit admissions, and mortality in Italy and Spain11, and personal protective behavior, including the wearing of masks and alcohol handwashing12. These policies successfully suppressed the local COVID-19 epidemic from January 2020 to April 2021. On May 15, 2021, the Central Epidemic Command Center (CECC) of Taiwan declared a level three alert in Taipei City and New Taipei City because of community outbreaks. On May 19, 2021, CECC issued a nationwide level three alert and downgraded to level two alert on July 27, 2021. During the level three alert period, there were no strict regulations on the suspension of work; however, all schools were closed. People had to wear masks at all times, and indoor gatherings were limited to five people, while outdoor gatherings were restricted to 1013. A wide spectrum of specific businesses and public venues were to be closed, except for essential services, such as police departments, hospitals, and government buildings. In those businesses and public institutions that remained open, crowd control, masks, and social distancing were required. Workplaces had to abide by epidemic prevention requirements, implement personal and workplace hygiene management, and initiate continuous corporate operation response measures, such as remote work and flexible working hours. Restaurants and coffee shops could only provide take-out services. In contrast to the “hard” lockdown in other countries where there was restricted freedom of movement15, the residents in Taiwan were not restricted to move but were encouraged to stay at home. Therefore, we named this type of level three alert as “soft” lockdown.In Taiwan, the government has also implemented significant efforts to implement border control, quarantine policy, contact tracing, social distancing policyIn addition, the campaign for extensive polymerase chain reaction (PCR) testing in the communities was launched in mid-May 2021, the early phase of this outbreak. The local governments in Taipei and New Taipei City encouraged residents who lived close to the hotspot areas or had any influenza-like symptoms  to undergo a PCR testing at community screening stations.With a soft lockdown policy and extensive rapid screening, the effectiveness of controlling the COVID-19 outbreak within 2 months was to be evaluated. To balance socio-economic development and disease control, timely and precise intervention was needed to lower the socioeconomic impact and flatten the curve of the epidemic. The study area was the two metropolitan cities of Taipei City and New Taipei City in northern Taiwan with 6.44 million residents, accounting for 27.78% of the total Taiwanese population, which also represented the political and economic centers of the country. The wave in mid-2021 started in these two cities, accounting for 81.17% of the total confirmed COVID-19 cases at the time. This study was based on epidemic, mobility, and land-use data in Taipei and New Taipei City, as well as information on policy interventions, to evaluate the policy effect on COVID-19 at different spatial resolutions.During our study period (from weeks 18 to 28 in 2021), the cumulative incidence and cases were high and clustered in northern Taiwan  and New Taipei City (R0: 3.37) . Positive associations between cases (p = 0.69)/incidence (p < 0.001) and positive rate and between cases (p < 0.001)/incidence (p < 0.001) and mobility were observed.To measure the effectiveness of extensive screening in communities and mobility changes in the COVID-19 epidemic, we stratified the analyses into two periods: one before the level three alert was issued (May 2 to May 14) and the other after this alert . On the contrary, villages with a higher number of outflow degree centrality among people aged ≥ 60 years had a significant negative association with the increase in confirmed cases than other villages .1), Group 2 (Q1 to Q2), Group 3 (Q2 to Q3), and Group 4 (≥ Q3), where Group 1 of the two predictor variables was used as the reference group. The model parameter estimates revealed that the four population density groups had no significant effect on the daily number of confirmed cases. Furthermore, positive mean effect differences between the other three groups and the reference one were observed in aging index groups. This indicated that the number of confirmed cases increased with an increased aging index.In addition to the mobility effect, villages composed of different land-use types may have different infection risks. We found that there were three major types of land use associated with the increase in confirmed cases in this outbreak  and three with their decrease . Population density and aging index were equal-frequency discretization into four groups: Group 1  model21, the focused approaches and the epidemic situation were entirely different in this study. The mentioned studies were conducted during a period of low numbers of cases in 2020 in Taiwan. They found that the two successful approaches to slow down the transmission and flatten the epidemic curve included case-based, such as case detection, contact tracing, and 14-day quarantining of close contacts, and population-based interventions, such as physical distancing and mask-wearing. However, this study focused on a large outbreak in 2021 which was the first COVID-19 epidemic affecting Taiwanese communities. When facing the surging number of infected cases, the soft lockdown strategy and extensive community screening were first introduced and bundled with individual and population-based interventions. We provided combinatorial evidence regarding aggregated mobility data and corresponding mean effective reproduction number to ascertain the efficacy of soft lockdown and mass testing after the local COVID-19 outbreak.Our study provided spatiotemporal evidence that a soft lockdown accompanied by clear guidelines, public discipline, and extensive testing can serve as a disease-mitigating intervention to curb community transmission. Although the estimated effectiveness of public health interventions in Taiwan was previously described22. These findings provide insights into the geo-statistical analysis of COVID-19 clusters, which may assist public health agencies in predicting spatiotemporal transmission dynamics and formulating control strategies.Wanhua District, which had the highest COVID-19 cumulative incidence, and its surrounding six districts were identified as significant hotspots, indicating the geospatial dynamics of the spread of the virus to peripheral districts and the persistent effects on the epidemic. A similar spatiotemporal pattern of COVID-19 was also seen in Bangladesh, indicating that cases were first confined within the central region of the country, Dhaka, and subsequently spread to the surrounding six districts, which were later also identified as significant hotspots23, the average stringency index of Taiwan before May 1, 2021, was 24.04 and the one during the level three alert period in 2021 was 70.29. Between May and July 2021, the number of countries, with an average monthly stringency index exceeding 70, was 27 worldwide. We chose five countries with similar stringency indexes for comparison: Germany (70.13), Canada (71.07), Vietnam (76.29), Argentina, 78.51, and India (80.44). The stringency index was composed of eight containment and closure policy indicators plus one indicator recording public information campaigns. The comparison of policy differences in these six countries is briefly listed in Supplementary Appendix According to the policy stringency index provided by the Oxford COVID-19 government response trackerRegarding school closures (C1), cancellation of public events (C3), restrictions on gatherings (C4), and public information campaigns (H1), six countries had a consistent policy on school closures, cancellation of public events, restrictions of gatherings involving ≤ 10 people, and had coordinated public information campaigns. For the rest of the five indicators in the stringency index, the six countries had different policy strengths, which related to human movement and social activity. Regarding workplace closures (C2), Taiwan only required the closure of some businesses, but other countries such as India and Canada require closing for all-but-essential workplaces. Closure of public transport (C5) was the major difference between Taiwan and other countries. There was no measure on closing public transport and residents were recommended to stay at home (C6) and not to travel between cities (C7) in Taiwan. Compared to other countries, they adopted required and recommended closures to reduce the human flow and social contacts. For this reason, we termed this policy in Taiwan a soft lockdown, as residents could adjust their behavior to adhere to the policy, while maintaining their flexibility and freedom to move. The last stringency index indicator was international travel (C8), which related to the imported risk from other countries. In Argentina, Canada, Taiwan, and Vietnam, strict border control was applied. In Germany and India, they banned arrivals only from some regions. In addition to the stringency index, the open testing policy (H2), comprehensive contact tracing (H3), and the mandatory facial covering outside the home (H6) were also successful strategies applied in Taiwan to combat the mid-2021 COVID-19 outbreak.24, but our study revealed that villages with a higher aging index were associated with a higher susceptibility to infection. This was also due to the deteriorating immune system and underlying medical problems that predispose them to more severe infections25. In addition to the mobility effect, villages with different land-use types had distinct impact on infection risks. We found that there were three major types with higher infection risk in this outbreak: social welfare facilities, commercial and mixed-use housing, which were associated with cluster infections in the long-term care facilities, and higher mobility of crowds. Such findings shed light on demographic and land-use heterogeneities associated with infection risk, which could enable precise disease prediction and prevention.The findings of this study have unique implications for the combinatory analysis of land-use and demographic data, along with the COVID-19 epidemic in Taiwan. Interestingly, villages with a higher inflow population aged over 60 years were associated with higher infection risks compared to other villages. This could be explained by the Wanhua transmission chain, in which senior citizens accounted for a substantial part. Not only were age-related variables, that is, aging index and percentage of the population aged 65 years and older, proven to be significant to the spread of COVID-19 in a previous studyThis study had some limitations. First, despite large-scale testing, an underestimation of incidence was expected because of undetected asymptomatic cases. However, the study has extended over a time span of 11 weeks , in which asymptomatic carriage and transmission clusters could still be reflected in the cases and incidence we collected. In hindsight, given the downward epidemic trend in Taiwan, the impact of this underestimation was minimal. Second, with the ongoing COVID-19 pandemic, the data might change over time, but the spatiotemporal pattern of COVID-19 presented in this study could still serve as a vital reference for lockdown decision-making and aggregated mobility applications. Third, when we modeled the mobility data with different age groups on the villages’ incidences, we could not differentiate the age distribution of the confirmed cases in that village. However, infected patients might not only transmit the virus to the same age group but also to different age groups. Therefore, risk can be treated as the overall infection risk in the community. Fourth, the representativeness of the telecommunication data was not comprehensive. The aggregated mobility data we used was from FarEastern telecommunication company, which accounted for 23.86% of the market share in Taiwan. As we could not apply the data from other four companies, we could not ascertain the representativeness of all residents in these two cities.In conclusion, the soft lockdown policy was considered to balance socio-economic activity and the mitigation of COVID-19 transmission. Despite extensive studies focused on the relationship between lockdown and mobility, there is a paucity of research regarding the effectiveness of COVID-19 outbreak control by a soft lockdown policy. An advantage of this study was the utilization of finer spatiotemporal disease surveillance data and estimation of the structure and quantity change of human mobility from telecommunication data. Capturing the spatiotemporal dynamics of epidemics could become a forecasting tool. During outbreaks, the evaluation of the effectiveness of policy interventions is important. In our findings, we found that a soft lockdown policy and extensive screening played a role in slowing down the transmission. The control measures used in this study aimed to allow society to operate normally, without forbidding the freedom of movement of the residents along with other public health interventions. This might provide an alternative to traditional lockdown measures in containing COVID-19 and preventing future epidemics.This study was approved by the Research Ethics Committee of the National Taiwan University (202007HM008). The data used in this study were all aggregated and anonymized, and thus the requirement for informed consent was waived by the Research Ethics Committee of the National Taiwan University. This study was performed in accordance with the declaration of Helsinki and followed by the approved protocol.https://data.gov.tw/dataset/120711). The confirmed COVID-19 cases at the village level were from the Department of Health in Taipei and New Taipei City. There are 456 villages in Taipei City and 1032 villages in New Taipei City. The study period was defined from May 2, 2021, to July 17, 2021. The positive rate of community PCR testing in Taipei and New Taipei City is from press releases. The expense for the test was entirely covered by the government. The mobility data at the village level were provided by the local commercial telecommunication company, Far EasTone Telecommunications. The land use data in 2019 and demographic data including population density and aging index in June 2021 at the village level were obtained from the socio-economic database maintained by the Ministry of Interior, Taiwan . According to the land-use classification system in Taiwan (https://www.rootlaw.com.tw/LawContent.aspx?LawID=A040040100025100-1080328), there are nine categories in the first tier, 41 subcategories in the second tier, and 103 subcategories in the third tier. In this study, we subjectively selected 13 subcategories from the second tier into the model selection. Finally, we obtained nine types of land-use in the final model, including government agencies, schools, medical facilities, social welfare facilities, parks and green spaces, commercial, residential, mixed-use housing, and manufacturing areas.The confirmed COVID-19 cases and their age distribution at the township level are from open data maintained by the Taiwan Centers for Disease Control and Prevention (CDC)  to display the weekly incidence at the district level for 11 weeks. To detect the spatiotemporal hotspots of confirmed COVID-19 incidence, we applied a modified spatiotemporal Getis-Ord Gi* statistic26 to consider their spatiotemporal dependence. The detailed procedure is listed in Supplementary Appendix  To visualize the spatiotemporal dynamics of the COVID-19 outbreak in Taipei and New Taipei City, we used ArcGIS  and our developed ring map toolbox 28 and the EpiEstim (v2.2-4) package29.Following the meta-analysis results from Challen et al.https://covid19.apple.com/mobility). The mobile phone data used in this study were collected and aggregated by Far EasTone Telecommunications in Taiwan. During the study period, we obtained a three-day mobility flow matrix by four age groups  from 7753 villages. Three days included May 10 , May 16 , and May 20 . The observed population was defined as the users of FarEasTone telecommunication. The telecommunication company first defined their observed population by computing their mobile phone users aged ≥ 18 years old and staying in the villages overnight in the previous month. We computed the inflow and outflow weighted degree centrality by the mobile phone data as the measure of mobility structure change before and after the level three alert. The detailed computation method is listed in Supplementary Appendix The mobility data on transit in both cities were obtained from the Apple Mobility Report  and the second period after level three alert . The explanatory variables included linear temporal trend, positive rate from community screening, weekend effect, and Apple mobility data on transit.30 with spatial and nonspatial structured random effects was constructed to estimate the effects in each village of Taipei and New Taipei City using R software28 and the package of INLA (www.r-inla.org)31.In the second part, the Bayesian hierarchical zero-inflated Poisson model (type 0)i in Bayesian modelling is given by:i, and i. i, respectively. The i, including the cumulative cases from the previous 3 days, in-degree centrality and out-degree centrality by four age groups, and the percentage of nine types of land utilization within the village, population density, and aging index. The The likelihood models combining spatially structured and unstructured effects of village Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.


Until now, strategies used to treat cancer are imperfect, and this generates the need to search for better and safer solutions. The biggest issue is the lack of selective interaction with neoplastic cells, which is associated with occurrence of side effects and significantly reduces the effectiveness of therapies. The use of nanoparticles in cancer can counteract these problems. One of the most promising nanoparticles is magnetite. Implementation of this nanoparticle can improve various treatment methods such as hyperthermia, targeted drug delivery, cancer genotherapy, and protein therapy. In the first case, its feature makes magnetite useful in magnetic hyperthermia. Interaction of magnetite with the altered magnetic field generates heat. This process results in raised temperature only in a desired part of a patient body. In other therapies, magnetite-based nanoparticles could serve as a carrier for various types of therapeutic load. The magnetic field would direct the drug-related magnetite nanoparticles to the pathological site. Therefore, this material can be used in protein and gene therapy or drug delivery. Since the magnetite nanoparticle can be used in various types of cancer treatment, they are extensively studied. Herein, we summarize the latest finding on the applicability of the magnetite nanoparticles, also addressing the most critical problems faced by smart nanomedicine in oncological therapies. Cancer is one of the most common causes of human death. In 2020 there were approximately 19.3 million cancer cases, and it is estimated that this number could increase to 28.4 million in 2040 . Due to One of the proposed alternative approaches in cancer treatment is magnetic hyperthermia . HyperthMagnetic hyperthermia is based on the use of magnetic nanoparticles. Among the dozen or so magnetic nanoparticles, the most promising is magnetite. Magnetite nanoparticles are already in clinical use: they have found application as a diagnostic tool for contrasting . In addiIn the presented work, we summarize the research and achievements to date in the field of medicine, biology, and chemistry that concentrate on therapeutic use of magnetite nanoparticles in oncology. In the presented context, magnetite research faces problems typical for translational medicine, i.e., in laboratory  and in clinics as well. Here, we describe the problems related to the medical use of magnetite nanoparticles and future research directions.Nanoparticles (NPs) are defined as solid particles in the size range 10–1000 nm . In addiMedicine is one of the branches of science where nanoparticles are expected to have the most significant impact. First and foremost, nanoparticles are planned to be used in so-called smart nanomedicine . Here, tCurrently, they are used in cancer medicine, mainly in diagnostics. In addition, nanoparticles serve as a stabilizing factor for therapeutics when used in therapies. According to the authors’ knowledge, about 10 types of nanoparticle-based therapies have been approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency(EMA) .Nanoparticles that have been used in medicine can be divided into three groups: metal, nonmetallic, and composite nanoparticles. The most commonly used are metal and metal-oxide nanoparticles . Because2O3), hematite (α-Fe2O3), and magnetite (Fe3O4) [3O4 nanoparticles have a large surface area needed for adsorption and immobilization of molecules or drugs. They can be easily modified to improve absorption [3O4 nanoparticles, in which other compounds cover magnetite nanoparticles, such as SiO2, or even by the biodegradable polymers [Within the group can be found such iron oxides as maghemite (γ-Fe (Fe3O4) . From a  (Fe3O4) . Fe3O4 nsorption . Moreovesorption . It is ppolymers ,57,58.3O4 nanoparticles can also be covered by LDHs to form nanostructures with different morphology and properties [Therapeutic magnetite nanoparticles usually consist of three essential components: magnetite core, which serves as a carrier for therapeutic agents; a coating on the iron-oxide nanoparticle, which promotes beneficial interactions in the body; and a therapeutic load that performs a designated function in vivo . In addioperties . This floperties  have shooperties ,63.Hyperthermia is defined as an increase in body temperature by ≥1 °C  or as anIncreasing temperature in a limited-body region allows maximizing therapeutic effect in the appropriate parts of the body while minimizing undesirable effects of heating in other body regions . There aIn the 18th century, it was noticed that tumors shrank in patients with fever. Since then, hyperthermia has been intensively studied as a potential cancer treatment . HoweverSo far, many studies have been carried out to confirm the effects of hyperthermia . InitialCurrently, oncological hyperthermia is used primarily as an adjunctive method in treating many cancer types, along with chemotherapy or radiotherapy ,71,78. IAlthough many studies show the positive effect of hyperthermia in cancer treatment, this method is still controversial, and the results of clinical trials have been criticized ,91. In aAlthough many studies confirmed the effectiveness of hyperthermia, the exact mechanism of its action is not fully understood ,91. The Moreover, hyperthermia can help overcome the problem of drug resistance by modulation of different pathways . HoweverHowever, hyperthermia can affect tumors by modulation of blood flow . In healFurther temperature increase (above 42 °C) is connected with additional effects. High temperature damages chaotically connected blood vessels and reduces blood perfusion in the cancerous tissue. This causes local hypoxia and acidification of the tumor, and eventually necrosis. However, the increase does not strongly affect healthy tissue . In addi3O4) [3O4 nanoparticles that can be used in treatment. These include targeting them to neoplastic cells through increased permeability and retention [There are several problems associated with hyperthermia nowadays. The main problems are related to nonselective heating up of tissues and not reaching a high enough temperature ,103. The3O4) . There aetention  and enabetention . In addietention . In addietention .3O4 nanoparticles. The specific absorption rate (SAR), defined as the power transformed into heat per unit of mass of nanoparticles, strongly depends on the alternative current (AC) fields parameters (frequency and field strength) and the magnetic fluid concentrations. However, the size and shape of magnetite also play a crucial role in the efficiency of magnetic hyperthermia. For example, magnetite nanorings are characterized by higher SAR values than nanotubes, while spherical-shaped magnetite nanoparticles can achieve SAR values of about 11 W/g for two times lower concentrations than magnetite-truncated octahedrons in similar AC magnetic fields parameters  completed clinical phase 2a, and the NoCanTher project has started final clinical trials  [The effect of ferrites has been studied in in vitro cell cultures, as well as in in vivo models, both in the case of magnetically induced hyperthermia ,124 and rcinoma) .Besides the application of magnetite in magnetic hyperthermia, there are other proposed applications of these nanoparticles in cancer therapies. The nanoparticle’s properties allow use for targeting cancer. Interaction between the magnetite particle and magnetic field is the backbone of targeting. Magnetite-carrying drugs can be pulled to the desired location in the body by the magnetic field. Thus, the magnetite nanoparticles described here are carriers for therapeutics. Several studies have been made to test the possible use of magnetite in the controlled delivery of drugs or gene and protein therapy .Nowadays, the main problem of cancer treatments is nonselectivity toward cancer cells; interactions with healthy tissue cause numerous side effects . In chemAdditionally, new disease entities may develop even long after the end of chemotherapy, e.g., pulmonary tissue fibrosis, infertility, cardiac arrhythmias, and peripheral neuropathies ,135. PreThe magnetic particle can serve as a carrier in controlled drug delivery ,133,138.Therapeutics can then be directed to the desired location through a magnetic field . The magHowever, the magnetic field could be used in drug delivery another way . It was Gene therapy aims to modify genetic material or correct genetic errors that cause diseases. It can be performed by injecting foreign genetic material into the body (in vivo gene therapy) ,148 and Several proposed oncological therapies are based on the modification of nucleic acids . These iThe introduction of therapeutic nucleic acids into the target cell can be done only using appropriate vectors. So far, several methods of delivering genetic material to the patient’s body have been proposed. Among them are distinguished methods based on viral vectors and physical and chemical methods ,151. TheAdditionally, easy surface modification of the nanoparticles enables immune-system-response modulation . NanoparNanovectors based on magnetite nanoparticles are also considered a potential vector in gene therapies. Initially, magnetite was tested with an adenoviral vector . One of In cancer therapies, the goal of protein therapy is to deliver a sufficient dose of the therapeutic protein to cancer cells . It is cAccording to the authors’ knowledge, magnetite nanoparticles were not clinically used in protein therapy, and magnetite was tested in in vivo conditions. In the mouse model, the therapy based on magnetite nanoparticles and the combination with chlorotoxin inhibited the invasiveness of glioblastoma . In addiThe development of new cancer therapies, especially selective strategies, is connected with several well-known problems that make it challenging to develop a uniform methodology. These include heterogeneity of tumors, differences between the human and mouse models used in in vivo studies and differences between neoplastic lesions . In addiIn recent years, hyperthermia has been used to support radiotherapy, chemotherapy, and immunotherapy, increasing their effectiveness ,173. HowAlthough the properties of nanoparticles show promise from a clinical point of view, they require further research. Unfortunately, nanotechnology develops faster than legislature and it creates problem of lack of standardization of nomenclature and test methodology. There is great need for guidelines for safety assessment of nanomaterials . DetaileMoreover, they can enter the blood cells, which can damage morphotic elements of the blood. There are also reports of an allergic reaction following the use of nanoparticles ,181. NanCytotoxicity of nanomaterials depends on the concentration, proportion, porosity, aggregation tendency, a chemical affinity for biological structures, chemical surface reactivity and even the shape, size of nanoparticles, and environmental conditions ,184. So The synthesis of magnetite is a leading technical problem and requires improvement . It is cOn the other hand, methods based on the high-temperature decomposition of organic precursors allow for the obtaining of monodisperse nanoparticles, albeit with low efficiency compared to the reaction time ,192. TheAnother noteworthy obstacle connected with a large-scale synthesis of therapeutic is fact that this is clinically useful only when the quality of obtained therapeutic is unchanged between batches of manufactured product. Therefore, a reproducible, scalable-production-method nanoparticle-based therapeutic must be developed and validated . Here, gThe clinical methodology also needs improvement. The main problem limiting the effectiveness of magnetic hyperthermia is low penetration of the magnetic field, i.e., up to 5 cm into the body due to the loss of the magnetic field gradient . As a reAdditionally, in the case of prostate cancer, the temperatures typically reached inside the tumor were generally in the range of 40–41 °C. Only a few of these studies have reached maximum intraprostate temperatures of 42.5 °C or exceeded the critical temperature of 43.0 °C. The temperature distribution in the prostate gland is heterogeneous, so reliable temperature calculations during prostate-cancer hyperthermia are challenging to obtain. Due to local differences in tissue properties, excessive temperature rise can occur, resulting in burns, blisters, pain, thrombosis, bleeding, and other undesirable effects . TherefoTumor-selective therapies should be the main oncological strategies in the future. Nanoparticles’ properties could be helpful in the development of such methods. Magnetite seems to be one of the most promising nanoparticles in oncology. This is mainly because the nanoparticle can be used in different ways, and all of the proposed magnetite-based strategies selectively interact with tumors. The therapeutic application of magnetite nanoparticles has been under investigation for many years with no success. Most of the tests ended at the preclinical phase . There a


Introduction: Depression is a commonly experienced psychological disorder among patients undergoing hemodialysis and has a strong association with insomnia and fatigue. The purpose of the present study was to explore the factors related to depression in dialysis patients and the impact of insomnia and fatigue on depression.Methods: In this cross-sectional study, one hundred (n=100) patients on hemodialysis from one hemodialysis center in Greece participated. Data collection was carried out by interviews using the Zung Self-rating Depression Scale (SDS) for the evaluation of depression; the Athens Insomnia Scale (AIS) for the evaluation of insomnia; the Modified Fatigue Impact Scale (MFIS) for the evaluation of fatigue; and a questionnaire which was created by the researchers. The Kruskal-Wallis, the Mann-Whitney tests, and the Spearman's rho criterion were used to evaluate the relationship between depression score and patient characteristics. Multiple linear regression was performed to assess the effect of characteristics on patients' depression.Results: Statistically significantly high levels of depression were found in patients over the age of 70 years old (p=0.001), in divorced/widowed patients (p = 0.001), in pensioners (p = 0.002), in patients who had other diseases (p = 0.001), in those who felt tired after hemodialysis or at night and those who felt constantly tired , in those who had physical and mental fatigue , in those who had changes in body image (p = 0.009), itching, stiffness, and nausea/vomiting , in patients who had restrictions in clothes they could wear (p = 0.001), in patients who had insomnia (p = 0.001), and in patients who did not wish to receive written information about the management of their disease (p = 0.025). A statistically significant positive linear association was detected between physical/mental fatigue and depression levels  and between the score of insomnia and depression levels (rho = 0.707). An increase in fatigue  and an increase in insomnia score also indicated an increase in depression levels.Conclusions: The findings of this study showed that depression had a strong association with a variety of demographic factors. Additionally, an increase in fatigue score and an increase in insomnia score indicated an increase in depression levels. Therefore, depression, insomnia, and fatigue should be early assessed and effectively treated by renal professionals in order to improve the quality of life in hemodialysis patients and reduce their morbidity and mortality. Depression is a mental disturbance that includes sadness, loss of interest or pleasure, feelings of guilt, interrupted sleep, decreased desire for food, feelings of tiredness, and low concentration . DepressMoreover, depression is strongly associated with insomnia and fatigue in hemodialysis patients . More spThe aim of this study was to investigate the factors related to depression in patients undergoing hemodialysis and the impact of insomnia and fatigue on depression.Study sampleThe study sample is a convenience sample and consists of 100 dialysis patients in a hemodialysis center in Athens, Greece. Inclusion criteria were: age over 18 years old and less than 85 years old, on hemodialysis for at least three months, and capability to speak, read, and write in Greek. Exclusion criteria were inadequate language skills, age over 85 years old, cognitive decline, and drug or alcohol abuse. Patients who met the inclusion criteria were informed during their treatment about the aim and procedure of the study and the anonymity of the data. Before collecting data, we obtained approval from the Ethics Committee of General Hospital of Athens "Evangelismos - Athens Ophthalmology Clinic - Polyclinic" . The study was carried out from November 2020 to January 2021.Data collection was carried out by interviews using the Zung SDS for the evaluation of depression, the Athens Insomnia Scale (AIS) for the evaluation of insomnia, the Modified Fatigue Impact Scale (MFIS) for the evaluation of fatigue, and a questionnaire which was created by the researchers and included (a) socio-demographic characteristics: gender, age, marital status, number of children, educational level, occupation; (b) clinical characteristics: whether they suffered from another disease, the degree of information about their health problem, values of urea, creatinine, phosphorus, the level of stress they experienced due to their disease if they wished to receive written information about the management of their disease, fatigue after hemodialysis and its duration, pain after hemodialysis, changes in body image, muscle cramps, stiffness, nausea, vomiting; (c) information about patients' concerns: changes in social and personal life, changes in the volume of fluids and the amount of food they used to take, fear of the possibility of the hemodialysis machine shutting down, difficulties in movement, and in the clothes they could wear. The study was conducted according to the Declaration of Helsinki (1989).Zung self-rating depression scaleThe Zung Self-Rating Depression Scale (SDS) was used to assess depression in patients undergoing hemodialysis. The SDS scale includes 20 questions evaluating the feelings of respondents during the previous week. Participants are able to answer each question on a four-point Likert-type scale. The final score ranges from 20 to 80. Higher scores point out higher scores of depression [Athens insomnia scaleThe AIS is a self-assessment psychometric scale assessing difficulty in sleeping. It includes eight questions, the first five of which are related to the onset of sleep, the night's awakenings, the final awakening, the total duration of sleep, and the quality of sleep. The other three questions are associated with wellness, functionality, and fatigue during the day. The total score of insomnia ranges from 0 to 24. Higher scores point out higher scores of insomnia. AIS has high consistency, reliability, and validity in Greek people and is a significant tool in clinical practice .Modified fatigue impact scaleThe MFIS is a self-assessment questionnaire and includes 21 questions. Respondents indicate the fatigue they have felt during the last four weeks on a 5-point Likert scale. Ten of the 21 items evaluated the mental fatigue of participants, and the other 11 evaluated physical fatigue. The scores of mental and physical fatigue are summed up separately and range from 10 to 50 for mental fatigue and from 11 to 55 for physical fatigue. High scores point out high levels of mental and physical fatigue, respectively. The MFIS has high reliability and validity among Greek people [Statistical analysisNominal data are presented with absolute and relative (%) frequencies, while the continuous data are presented with mean, standard deviation, median, and interquartile range (IQR). The normality of the data was checked with the Kolmogorov-Smirnov criterion and graphically with histograms and Q-Q plots. The Kruskal-Wallis test, the Mann-Whitney test, and Spearman's rho criterion were used to estimate the relationship between depression levels and patient characteristics, insomnia, and fatigue. Multiple linear regression was carried out to evaluate the effect of characteristics, insomnia, and fatigue on patients' depression. The results are presented with β regression coefficients and 95% confidence intervals (CI). The observed significance level of 5% was considered statistically significant. All statistical analyses were performed with version 25 of the SPSS program .Sample characteristicsA total of 100 patients took part in the research study. Men accounted for 75% of the sample, while 73% were over 60 years old. Additionally, 65% were married, 42% had a primary school education, and 65% were pensioners. The majority of participants had two or more children (63%) , marital condition (p = 0.001), job (p = 0.002), comorbid diseases of patients (p = 0.001), patients' beliefs that regular updating was helpful in reducing stress (p = 0.016), patients’ desire to receive written information about the management of their illness (p = 0.025), whether they felt tired after dialysis, when they felt tired and for how long , whether they had changes in body appearance (p = 0.009), whether they had itching, stiffness and nausea/vomiting , whether they had restrictions in clothing (p = 0.001), physical and mental fatigue  and insomnia (p = 0.001).More specifically, patients over the age of 70 had statistically significantly higher levels of depression (median 48) than younger patients (median 45 and 37). Divorced/widowed patients had statistically significantly higher levels of depression (median 52) than married (median 44) and single (median 39). Pensioners had higher levels of depression (median 47) than employees (median 37) and unemployed patients (median 41). Patients who had another disease had higher levels of depression (median 51) than those who did not have another disease (median 41). Patients who had the opinion that regular updating did not help decrease stress had statistically significantly high scores of depression (median 53).Additionally, statistically significantly high scores of depression were found in patients who did not wish to receive written information about the management of their disease (median 51), those who felt tired after hemodialysis (median 54), and those who had increased tiredness at night (median 48), and those who felt constantly tired (median 57), those who felt that they had a change in body appearance (median 48), those who experienced frequent itching (median 53), stiffness (median 56), and sometimes nausea (median 50), and those who had restrictions in clothing (median 48).Finally, a statistically significant positive linear association was detected between physical/mental fatigue and depression levels  as well as between the score of insomnia and depression (rho = 0.707). An increase in fatigue score , as well as an increase in insomnia score, indicated an increase in depression levels . In addition, patients who sometimes had tiredness after hemodialysis had a statistically significantly lower depression score of 2.8 points than those who had tiredness after each session . Participants who did not believe that they had a change in body image had a 3.3 points lower depression score than those who believed that they had . In addition, 1-point increase in the score of fatigue either physically or mentally indicated an increase of depression score by 0.35 and 0.31 points, respectively . Likewise, a 1-point increase in the score of insomnia indicated an increase of depression score by 2.5 points  (Table In the present study, it was found that participants over the age of 70 had a statistically significantly higher score of depression than younger participants. Similarly, in a previous study, it was found that old age was strongly related to increased levels of depression among patients on hemodialysis .It can be assumed that elderly patients on hemodialysis usually suffer from chronic diseases such as diabetes, hypertension, and heart failure , leadingMoreover, the findings of this study showed that high levels of depression were experienced by patients who did not wish to receive written information about the management of their disease. It can be assumed that a lack of information can lead to low levels of understanding of medical instructions . Thus, pAdditionally, the findings of this study indicated that divorced/widowed patients had statistically significantly higher levels of depression. This can be attributed to the fact that patients undergoing hemodialysis often experience disorders in marital relationships since the chronic disease causes tension, negative emotions, and changes in marital roles . In a siThe present study also found that patients who had comorbid diseases had statistically significantly high levels of depression. It can be assumed that frequent hospitalizations are an important factor in depression in these patients  due to vThe present study also found that pensioners had statistically high levels of depression. This can be attributed to the fact that retirement usually leads to social isolation in older adults, which is a significant factor in depression . AdditioThis study also showed that an increase in physical or mental fatigue and an increase in insomnia score indicated an increase in depression levels. Insomnia causes daytime sleepiness and lack of energy, which is regarded as a significant factor for fatigue . It can The results of this study offer significant information to health professionals about the factors related to depression in patients undergoing hemodialysis. Therefore, regular psychiatric evaluation of these patients and evaluation of risk factors are essential for the early diagnosis of depression and for reducing morbidity and mortality in these people.Limitations of the studyThe sample used in this study is a convenience sample since it comes from one renal unit in Athens, Greece. Thus, the findings cannot be generalized. Additionally, further investigation of the factors related to depression in hemodialysis patients can be achieved with more qualitative approaches.Depression is a common problem among hemodialysis patients and has a strong association with insomnia and fatigue. The findings of this study showed that depression had a strong association with a variety of demographic factors. Additionally, an increase in fatigue score and an increase in insomnia score indicated an increase in depression levels. Therefore, depression, insomnia, and fatigue should be early assessed and effectively treated by renal professionals in order to improve the quality of life of these people and reduce their morbidity and mortality.


Chronic obstructive pulmonary disease (COPD) is a major and difficult disease of the chronic respiratory system that is common and frequent, with a huge disease burden. The aim of this study was to investigate the efficacy and safety of budesonide/glyburide/formoterol fumarate (BGF) in the treatment of COPD.  A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. The basic features of the seven pieces of literature were identified using the search strategy. The sample size range was 130∼1264. p < 0.00001). The effects of BGF improved in patients with ≥1 TEAE in patients with COPD, and was not statistically significant after treatment . The effects of BGF increased in patients with TEAEs related a to study treatment in patients with COPD . The effects of BGF in decreased patients with serious TEAEs in patients with COPD . The effects of BGF decreased the death rate in patients with COPD, and were not statistically significant after treatment . The effects of BGF decreased the hypertension rate in patients with COPD , and was not statistically significant after treatment. The effects of BGF increased pneumonia in patients with COPD , and were not statistically significant after treatment. The effects of BGF increased FEV1, increased patients with TEAEs related a to study treatment, and decreased patients with serious TEAEs in patients with COPD.  The effects of BGF increased FEV1 in patients with COPD (mean difference = 2.86, 95%CI: 2.71–3.01,  This study elucidates the efficacy and safety of BGF in the treatment of COPD with a view to providing a clinical reference. Chronic obstructive pulmonary disease (COPD) is a common, frequently occurring, major, and difficult disease of the chronic respiratory system . It has With the development of the social economy, air pollution has become a serious public health problem all over the world, which seriously endangers the health of residents and leads to a heavy burden of disease . AtmosphCOPD is a disease that can be prevented and treated with the characteristics of airflow restriction . Airflow∗), urinary symptoms , and limb pain, chest pain, caries, rash, headache, insomnia, and cognitive impairment [Budesonide is a steroid hormone which can increase the level of endogenous corticosteroids and has a significant anti-inflammatory activity . It is apairment –21.Formoterol fumarate is a bronchodilator, which can effectively relax the airway smooth muscle, relieve airway obstruction, and quickly improve symptoms such as dyspnea . RelevanThe experiment was searched from PubMed, Embase, and Web of Science, and the last search was performed on March 2022. The free words adopted were as follows: “budesonide/glycopyrronium/formoterol fumarate,” “chronic obstructive pulmonary disease,” “budesonide,” “glycopyrronium,” “formoterol fumarate,” and their combinations. The reference lists of previous relevant reviews were manually checked to find additional publications of interest. The language of publications was restrained to English.The following inclusion criteria were used to select eligible studies: (i) the diagnosis of cerebral infarction was pathologically confirmed; (ii) the forced expiratory volume in one second (FEV1) and safety population  were evaluated in this study. The exclusion criteria were as follows: (i) abstract, review, case report, or comment letter; (ii) animal studies; (iii) duplicate publications; (iv) published not in English or Chinese.Q test in which I2 indicates the level of heterogeneity. I2 < 50% or pheterogeneity>0.1 represented low heterogeneity. p < 0.05 was considered statistically significant.Two independent reviewers using a standardized form extracted relevant data from eligible studies as literature . Data weThis study was identified through systematic literature searching. 531 pieces of literature were identified and evaluated. The literature selection process is shown in The quality of literature was evaluated using the Cochrane Collaboration's tool for assessing risk of bias Figures . The nump < 0.00001), as shown in The study analyzed the effects of BGF on FEV1 of COPD. As shown in p=0.97). As shown in p=0.02). The effects of BGF decreased in patients with serious TEAEs in patients with COPD . As shown in p=0.81), and were not statistically significant after treatment. The effects of BGF increased pneumonia in patients with COPD  has been widely concerned by medical circles all over the world because of its high prevalence, high mortality, and high disability rate . At presp < 0.00001).Population aging is one of the main problems China is facing at present . It is ep=0.02). The effects of BGF decreased in patients with serious TEAEs in patients with COPD .The development of chronic obstructive pulmonary disease is a complex, multielement, and multiring process . ChronicWith the growth of age, the incidence of many lung diseases is also gradually increasing, among which chronic obstructive pulmonary disease and pulmonary fibrosis are the most significant . At presThe present study has some limitations. First, all citations only researched that the effects of BGF increased FEV1 in patients with COPD. Second, due to a relatively low number of studies included depicted the relationship between BGF and the treatment of COPD, which is an important reason for the heterogeneity of this results. It is necessary to develop high-quality large-scale studies with more complete patients' types to verify our results. Finally, significant heterogeneity was detected for several parameters, however, we used the fixed-effect model according to heterogeneity, which also existed due to the difference in included studies.


The preoperative prediction of lateral pelvic lymph node (LPLN) metastasis is crucial in determining further treatment strategies for advanced lower rectal cancer patients. In this study, we established a nomogram model to preoperatively predict LPLN metastasis and then externally validated the accuracy of this model.A total of 287 rectal cancer patients who underwent LPLN dissection were included in this study. Among them, 200 patients from the Peking University First Hospital were included in the development set, and 87 patients from the First Affiliated Hospital of Xi’an Jiaotong University were included in the independent external validation set. Multivariate logistic regression analysis was used to develop the nomogram. The performance of the nomogram was assessed based on its calibration, discrimination, and clinical utility.Five factors  were identified and included in the nomogram. The nomogram developed based on the analysis showed robust discrimination with an area under the receiver operating characteristic curve (AUC) of 0.878 . The validation set showed good discrimination with an AUC of 0.863 . Decision curve analysis showed that the nomogram was clinically useful.The present study proposed a clinical-imaging nomogram with a combination of clinicopathological risk factors and imaging features. After external verification, the predictive power of the nomogram model was satisfactory, and it is expected to be a convenient, visual, and personalized clinical tool for assessing the risk of LPLN metastasis in advanced lower rectal cancer patients. Lateral pelvic lymph node (LPLN) metastasis has been reported as the major cause of local recurrence after curative resection in patients with advanced lower rectal cancer (ALRC), given that approximately 50% of the local recurrences occur in the lateral pelvic sidewall area , 2. It iSeveral studies have reported some clinicopathological factors that predict LPLN metastasis before surgery , 8. AlthNomograms are considered reliable graphical calculating models that can accurately quantify and predict individual risk events by combining all known independent risk factors . NomograHence, in this study, we sought to develop a comprehensive nomogram incorporating MRI imaging features and clinicopathologicak factors to help quantify the individual risk of LPLN metastasis in patients with ALRC. Additionally, we assessed the predictive accuracy and clinical utility of the nomogram and validated it in an external cohort.This retrospective multicenter study was performed at two public tertiary medical centers in China . All consecutive patients who underwent TME+LPLND for rectal cancer were screened between January 2010 and January 2022. The inclusion criteria were patients who (a) underwent TME and LPLND for histologically confirmed primary rectal cancer and (b) had a clinical stage of stage II or III. The exclusion criteria included patients (a) with the distal margin of the tumor above the peritoneal reflection; (b) lacking other relevant clinicopathological data in their medical records; and (c) without preoperative MRI. A total of 200 eligible patients at Peking University First Hospital were enrolled and allocated to the model development cohort. Within the same time period, a total of 87 patients who underwent TME+ LPLND at the First Affiliated Hospital of Xi’an Jiaotong University were enrolled as the external validation cohort Figure 1To identify variables associated with LPLN metastasis, the following preoperative clinicopathological characteristics were reviewed and collected from both hospitals: age, sex, body mass index (BMI), grade of tumor differentiation, gross classification of tumor, extramural vascular invasion (EMVI), tumor size, distance from anal verge, cT stage, perirectal lymph node status, short-axis diameter of the largest LPLN, preoperative carcinoembryonic antigen (CEA) level, and preoperative carbohydrate antigen 19-9 (CA19-9) level. The gross classification and differentiation grade of the tumor were assessed by colonoscopy and tissue biopsy. The preoperative imaging features of the tumor were assessed by MRI. All patients had undergone 1.5 or 3.0 T pelvic MRI with pelvic phased-array coils before surgery. If the patient underwent nCRT, the MRI assessment was based on preneoadjuvant MRI. The images were taken in the sagittal, coronal, and axial planes. The cranial border of the field of view was L5, and the caudal border was below the anal canal. The diameter of the lymph node was measured on T2-weighted axial MRI scans of the pelvis, acquired in 4- to 5-mm slices.The MRIs of all included patients were re-evaluated by two experienced gastrointestinal radiologists. They were asked to make the diagnosis of T stage (T1/T2/T3/T4), tumor size, perirectal lymph node status (positive/negative), the distance of the tumor from the anal verge, and EMVI (positive/negative) for each patient, and a consensus for each disagreed case was determined after discussion. Perirectal lymph nodes with a short-axis diameter of ≥5 mm were defined as positive. Moreover, we measured the short-axis diameter of the largest lymph node located in the lateral pelvic region. The optimal cutoff value of the short-axis diameter in the present study was set at 7 mm, which was determined by the maximum Youden index of the receiver operating characteristic (ROC) curve and is shown in the The treatment strategies for the patients with ALRC were similar in both centers. The standard surgical approach includes open or minimal TME+LPLND. Some of the patients were discussed in a multidisciplinary treatment meeting to decide on the application of nCRT. Unilateral or bilateral LPLND depends on the preoperative imaging findings in the lateral pelvic region. The procedure involved the complete removal of the lateral pelvic lymph nodes and fatty tissues, including the internal iliac nodes, obturator nodes, common iliac nodes, and/or external iliac nodes, with preservation of the bilateral hypogastric nerve and the pelvic nerve plexus. All lymph nodes were dissected from the fresh specimen, and their locations according to the classification by the Japanese Society of Cancer of the Colon and Rectum were documented prospectively.t-test was used for continuous variables, and the 2χ test was used for categorical variables.Age, BMI, and tumor size were considered continuous variables. Sex, grade of differentiation, EMVI, the distance of the tumor from the anal verge, cT stage, perirectal lymph node status, preoperative CEA level, preoperative CA19-9 level, and short-axis diameter of LPLN were considered categorical variables. For comparisons between groups, Student’s p-value <0.05 was considered statistically significant. Statistical analysis was performed by using SPSS® version 25.0  and R software version 3.4.0 .To develop a well-calibrated and convenient nomogram model for predicting the risk of LPLN metastasis, our nomogram was built using the model development cohort with 200 patients and then validated using 87 patients in the external validation group. We performed a univariate analysis in the development set to determine significant covariates of LPLN metastasis. Significant covariates were then used in a backward stepwise multivariate logistic regression model to determine predictors of pathologically positive LPLN. The nomogram was built based on the results of multivariate logistic regression. The model’s performance was assessed using a calibration curve and the area under the ROC curve (AUC). Decision curve analysis (DCA) was used to evaluate the clinical utility of the nomogram based on net benefits at each risk threshold probability in the development and validation datasets. A p = 0.016), there were no significant differences in age, sex, BMI, grade of differentiation, EMVI, the distance of the tumor from the anal verge, cT stage, perirectal lymph node status, preoperative CEA level, preoperative CA19-9 level, or largest short-axis diameter of LPLN (p = 0.497).A total of 287 patients with ALRC were enrolled in this study, 200 of whom comprised the development cohort and 87 of whom comprised the external validation cohort. All clinicopathological characteristics of both cohorts are summarized in  of LPLN Table 1.p = 0.019), EMVI , distance of the tumor from the anal verge <5 cm , positive perirectal lymph nodes  and largest short-axis diameter of LPLN ≧7 mm  , with the highest AUCs of 0.878  in the training cohort and 0.863  in the validation cohort  of the nomogram score, which was determined by the maximum Youden index of the nomogram ROC curve, and the patients were divided into high-risk  and low-risk  groups. In the low-risk group, the LPLN metastasis proportions in the development and external validation sets were 5/108 (4.6%) and 4/53 (7.5%), respectively, whereas the proportions were 51/92 (55.4%) and 17/34 (50.0%) in the high-risk group  has been reasonably shown to be an important risk factor for LPLN metastasis . Based oIt is well known that treatment modalities should be based on detailed pretreatment assessment and an individualized approach that considers all options to optimize the treatment of patients with rectal cancer. However, the best approach to diagnosing LPLN metastasis is unknown because the study results were inconsistent. Therefore, improvements in approaches to qualitative assessment are needed. Nakanishi et al. reported that radiomics-based prediction modeling provides an individualized risk estimation of LPLN metastasis in rectal cancer patients treated with (chemo)radiotherapy . Amano eThis study has some limitations. First, the sample size of the model development set, including 200 patients, was not large enough. A more extensive and prospective dataset is needed to generalize the performance of the LPLN metastasis prediction model. Second, nCRT caused a decreased number of LPLNs detected and pathological transformation of LPLNs, which may lead to a certain bias. However, the sample of patients who underwent nCRT+TME+LPLND was too small to allow further subgroup analysis. Therefore, the change in LPLNs before and after nCRT was not further assessed. Moreover, if the changes in LPLNs after nCRT were used as indicators, the predictive power of the model, especially its specificity, may be further improved.Despite these drawbacks, we believe our study findings are valuable. In our study, LPLN metastasis was predicted preoperatively through a combination of imaging assessment and clinicopathological characteristics, which provides a new perspective for the comprehensive diagnosis and treatment of LPLN metastasis. Patients should be classified depending on their risk of developing LPLN metastasis to select the best option to manage the pelvic compartment. In patients who have a low risk of LPLN metastasis, undergoing nCRT+TME may be sufficient to avoid overtreatment. Patients who have a high risk of LPLN metastasis may need to undergo nCRT + TME + LPLND to achieve better local control.In conclusion, we present a novel, externally validated model to predict the risk of LPLN metastasis, which could provide an individual prediction of LPLN metastasis with good accuracy and serve as a useful guide in patient management.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study was reviewed and approved by The First Affiliated Hospital of Xi’an Jiaotong University Ethics Committee, 2019-ZD-04 and Peking University First Hospital Biomedical Sciences Ethics Committee, 2021-351. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.LZ and FS: data collection, formal analysis, investigation, methodology, project administration, software, validation, and writing original. CH, ZZ, JL, and RL: data curation, formal analysis, investigation, methodology, review, and editing. JS and JT: project administration, validation, review, editing, and supervision. All authors contributed to the article and approved the submitted version.The study was supported by the National Natural Science Foundation of China .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.


We investigated the risk of stroke according to statin medication compliance in older people with chronic periodontitis.Chronic periodontitis patients were extracted from the National Health Insurance Service-Senior Cohort Database from 2002 to 2014. Among 255,056 chronic periodontitis patients, 41,412 patients with statin prescriptions for 28 days or more were included. The study population was divided into the top 25% of medication compliance group (TSG) and the lower 25% of medication compliance group (BSG). After 1:1 propensity score matching was performed, the final number of patients in the BSG and TSG was 6,172 each. To analyze the risk of stroke, a Cox proportional hazard model was performed to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjusting for age, sex, income level, hypertension, diabetes, and Charlson comorbidity index.In the Kaplan-Meier curve, the disease-free probability was prominently lower in the BSG than in the TSG (p for log-rank= 0.001). The HR in the multivariable-adjusted model for stroke occurrence in the TSG compared to the BSG was 0.79 . Subgroup analyses showed significant associations between compliance to statin medication and stroke, especially in female, people 85 years or older, and patients with comorbidities.Increasing compliance to statins may reduce stroke risk in older adults with chronic periodontitis. Therefore, in order to increase medication compliance among older people with chronic periodontitis, it is necessary for medical staff to make efforts to provide effective medication guidance. Periodontal disease causes inflammation in the tissues around the teeth, forming periodontal pockets and ultimately causing tooth loss by resorption of the alveolar bone . Periodostatin. Statins are widely used drugs for dyslipidemia and hyperlipidemia, and they are known to significantly reduce cardiovascular abnormalities and mortality caused by these diseases [Statins, also known as β-hydroxy β-methylglutaryl-CoA reductase inhibitors, refer to a group of anti-hyperlipidemic drugs whose names end in -diseases . These ediseases ,9, antibdiseases , skeletadiseases ,12, and diseases . Statinsdiseases ,15.Stroke is a collective term for local neurological deficits that are suddenly caused by abnormalities in cerebral blood flow . As suchWhen considering the effect of a particular treatment, it is often thought the result depends on whether the patient has properly taken the relevant medication. The full therapeutic effect of a drug can be achieved when the patient takes the drug according to the doctor’s prescription—that is, when the medication compliance is high .Medication compliance is generally defined as “the extent to which a patient is taking medications as prescribed by their healthcare provider” . Poor meMedication compliance figured prominently in the present study due to its importance in treatment. We compared the risk of stroke between two groups: the top 25% of statin compliance group (TSG) and the bottom 25% of statin compliance group (BSG) among older people diagnosed with chronic periodontal disease. The information came from the Senior Cohort Database provided by the NHIS. Consequently, this study aimed to provide basic data on the risk of stroke according to statin medication compliance among older Korean patients with chronic periodontal disease.This study utilized the Senior Cohort Database provided by the NHIS. The Korea National Health Information Database (NHID) is a public database on healthcare services maintained by the NHIS of Korea, which is a universal health insurance system that covers the medical expenditures of approximately 98% of all Korean citizens . The datThe MPR is calculated as the proportion of the number of days of treatment during the follow-up period from the first to last prescription. In this study, having the medication dispensed at the pharmacy was considered to indicate medication compliance. This measurement method has a limitation in that it is impossible to determine whether the patient actually took the drug or took it at the appropriate time. However, this method is known to provide a relatively accurate estimate of medication compliance in large patient groups using cohort data ,27. TherThe considered covariates were age, sex, income level, hypertension, diabetes, and Charlson comorbidity index (CCI). Chronic periodontitis was identified as an International Classification of Diseases, 10th revision (ICD-10) code of K053  and the To ensure the homogeneity of the 2 groups, age, sex, income level, hypertension, diabetes, CCI, and disease to medication interval were applied as variables in 1:1 PSM. The PSM analysis was carried out on the sampled cohort with logistic regression to consider selection bias and the presence of potential confounding variables. The standardized difference in potential confounding variables was confirmed to be less than 0.025, indicating the homogeneity of the 2 groups .https://www.r-project.org/) and SAS version 9.4 . The baseline characteristics according to the TSG and BSG among patients with chronic periodontitis were compared using the Student t-test and the chi-square test. A Kaplan-Meier curve was presented for stroke risk analysis, and the log-rank test was performed. The incidence rate of ischemic stroke was presented in units of 1,000 person-years for the total follow-up period of the TSG and BSG. To analyze the risk of stroke, a Cox proportional-hazard model was performed to calculate the hazard ratio (HR) and 95% confidence intervals (CIs) after adjusting for age, sex, income level, hypertension, diabetes, and CCI. A p-value < 0.05 was considered to indicate statistical significance.The Senior Cohort Database provided by the NHIS was analyzed using R version 3.6.0  of Silla University (IRB No. 1041449-202102-HR-001). The requirement for informed consent was waived by the IRB since personal information that can be used to identify individuals registered to NHID was removed.The total number of study subjects was 12,344, and 687 stroke occurrences (5.6%) were confirmed during the median follow-up period of 5.3 years. No significant demographic characteristics between the TSG and BSG were found in age, sex, income level, hypertension, diabetes, and CCI (p>0.05). In addition, the interval from diagnosis of chronic periodontitis to taking statins was approximately 3 months, without a significant difference between the 2 groups (p=0.78). However, the MPR was significantly higher in the TSG than in the BSG (p<0.001). The stroke incidence was significantly lower in the TSG (4.5%) than in the BSG (6.6%) (p<0.001) .In the Kaplan-Meier curve, the disease-free probability was prominently lower in the BSG than in the TSG (p=0.001 by the log-rank test) . Of the Subgroup analyses were performed according to sex, age, and comorbidities including hypertension and diabetes . In the In this large-scale and long-term follow-up cohort study, we confirmed the association between statin medication compliance and ischemic stroke in older people with chronic periodontitis. Previous studies reported that chronic periodontitis and stroke were related ,32, but In Korea, which is aging rapidly, medication compliance among older people suffering from chronic diseases is a very important issue, both for preventing disease and improving treatment and for reducing the economic costs borne by the individual and national health system . MedicatThe subgroup analysis according to sex in this study showed that females had a lower incidence of stroke in the TSG than in the BSG, although without a statistically significant difference. However, females showed a statistically significantly lower incidence of stroke in the TSG than in the BSG. The clinical results after stroke treatment are generally known to be worse in females than in males . Among pAs with all research, it is valuable to examine the limitations and strengths of the present study. Despite having found results similar to other previous scholarly works, this study has some limitations to consider. First, the disease codes might not have accurately reflected patients’ medical conditions, as they are sometimes exaggerated to receive reimbursement due to a fee-for-service payment system . Second,In summary, there was a significant association between compliance with statins and stroke in older people with periodontitis. Accordingly, older people with chronic periodontitis should increase their medication compliance when taking statins in order to lower the risk of stroke. This is recommended especially for female patients and other older patients with a high risk for stroke. To best increase medication compliance among older people with chronic periodontitis, it is necessary for medical staff to make efforts to provide effective medication guidance. Additionally, caregivers who make home visits for older patients with reduced mobility will need to develop their capacity to provide effective medication guidance. Only with support from national health organizations and institutions will future efforts engender positive change.


Breast cancer is the most common type of cancer in women and the second leading cause of cancer death in female. Triple-negative breast cancer has a more aggressive proliferation and a poorer clinical diagnosis than other breast cancers. The most common treatments for TNBC are chemotherapy, surgical removal, and radiation therapy, which impose many side effects and costs on patients. Nanobodies have superior advantages, which makes them attractive for use in therapeutic agents and diagnostic kits. There are numerous techniques suggested by investigators for early detection of breast cancer. Nevertheless, there are fewer molecular diagnostic methods in the case of TNBC due to the lack of expression of famous breast cancer antigens in TNBC. Although conventional antibodies have a high ability to detect tumor cell markers, their large size, instability, and costly production cause a lot of problems. Since the HER-2 do not express in TNBC diagnosis, the production of nanobodies for the diagnosis and treatment of cancer cells should be performed against other antigens expressed in TNBC. In this review, nanobodies which developed against triple negative breast cancer, were classified based on type of antigen. According to oncology studies in most countries, breast cancer is the most prevalent cancer in women, and this malignancy is the 2nd leading reason for cancer death in women , 2. The Of the numerous breast cancers, TNBC (triple-negative breast cancer) has a more aggressive proliferation and a poor clinical diagnosis and prognosis . TNBC isE. coli, S. cerevisiae, P. pastoris, and tobacco plants . A–7. A5–7]o plants . VHH, oro plants . In facto plants . Nanobodo plants . VHHs cao plants . Nanobodo plants . Since HIn this article, we summarize and review and nanobodies designed and produced against triple negative breast cancer (TNBC). The use of these nanobodies in designing new diagnostic and treatment methods will be very promising for the effective treatment and early detection of TNBC patients.By chance, a novel class of antibodies was discovered in camelids in the early 1990s that naturally lack light chains and the first constant domain (CH1) in the heavy chain , 14. It Pichia pastoris expression system. In their experiment, proliferation of the hTNFα-induced MCF-7 breast cancer cell line was inhibited by TNFα-specific nanobody. Moreover, in a micro-invasion model, the TNFα-specific nanobody inhibited the migration of the MDA-MB-231 and MCF-7 cell lines. In a mouse model experiment, once-daily subcutaneous dosing was performed in the 4 T-1 metastatic breast cancer mouse model. The TNFα level was lower than it was during the earlier stages of tumor formation. Their research emphasized the importance of neutralizing low levels of TNF in the tumor microenvironment in order to sensitize the potential of chemotherapy response for medical use [Among the important factors for the progression of breast cancer, TNFα plays an essential role in promoting the growth of the tumor and metastasis; so that it is proven that anti-TNFα antibodies can prevent the proliferation of breast cancer cells and metastasis , 19. Ji In another study that was later conducted by Ji et al.  a fusionToday, the use of quantum dots in various fields has been widely used in diagnosis and treatment due to their dual nature. Wang et al.  used quaThe combination of nanobodies with another ligand or molecule has been used in many studies, and its benefits in the treatment of various diseases have been investigated. In a landmark study by Kitamura et al. , a combiOne of the most important ways to activate immune responses is to use anti-CD3 monoclonal antibodies. After binding of the T cell receptor (TCR) to a particular antigen, CD3, as a part of the TCR, is required for activation of T cells. Studies have shown that anti-CD3 antibodies are able to induce T cell proliferation and promote chemokine secretion in the absence of antigen interacting with T cells . ConsequCTLA-4 is an important negative stimulatory agent in T cells, and the interaction of this molecule with B7 prevents further activation of T cells. CTLA-4 is expressed in some cancerous cells. The anticancer role of the CTLA-4 molecule makes it a perfect target in the treatment of tumors . Tang etSTAT is a transcription factor, which shows expression in nearly 75% of human cancers, such as breast cancer . ResearcThe most commonly over-activated pathway in malignancies is the PI3K-AKT pathway . AKT  in tumorigenesis and metastatic dissemination, these proteins have been extensively studied –40. In mECM is a major component of the tumor microenvironment and plays an important role in cancer cell survival, metastasis, and angiogenesis . ECM is Abnormal circulation of the actin cytoskeleton is thoroughly associated with the invasion and migration of cancer cells. Proteomic studies have shown that one of the components of the actin cytoskeleton, called CapG, is overexpressed in breast malignancy. Previous studies propose that CapG is involved in the proliferation and metastasis of tumor cells and therefore can be considered as one of the drug targets in breast cancer , 46. ImpAram and colleagues  developeTNBC tumor heterogeneity, as a reason for the different clinical consequences of this malignancy, has led to different responses to traditional therapies. As a result, it often leads to different survival times . HoweverHowever, nanobodies have some disadvantages, including rapid renal clearance and induced nephrotoxicity . In the Nanobodies or VHHs have good properties such as small size, facile and low-cost production, and high stability. These advantages make them attractive as a cancer therapeutic or diagnostic agent. These nanobodies produced against antigens expressed in TNBC such as TNF-α, EGFR, CD3, CTLA-4, STAT3, AKT2 and other antigens can be used for the purpose of detecting, targeting, or sensing cancerous cells.