Increasing salt intake has substantial negative impacts on human health and well-being. This article focused on the construction of Driver-Pressure-State-Impact-Response (DPSIR) framework for drinking water sodium (DWS) followed by a review on the published studies regarding salinity intrusion, DWS, and their effects on health perspectives in Bangladesh. Saline water is an important factor for hypertension or high blood pressure in the coastal areas. DWS can also lead women, especially pregnant women, to an increased risk of (pre)eclampsia, hypertension, as well as infant mortality. Several interventions, such as rainwater harvesting, pond sand filter (PSF) system, managed aquifer recharge (MAR), and pilot scale solar-powered desalination plants, such as reverse osmosis (RO), were reviewed on the context of their effectiveness in controlling drinking water sodium. Although rainwater consumption has the positive impact of low or no sodium intake, it still possesses negative impacts from not having vital minerals. A steady increment in sodium concentration through the span of the dry season was observed in MAR. It is, subsequently, important to increase awareness on DWS intake by providing and adopting correct technological interventions and training communities on the maintenance of the adaptive measures. Seawater intrusion is a pressing issue in coastal aquifers worldwide. Surface water resources, like rivers and canals, are severely affected by the intrusion of saline water ,2. In th−) were found to be 4044.12 mg/L, 7186.7 mS/cm, and 3143.6 mg/L, respectively in Shyamnagar, and 2313.60 mg/L, 4390.3 mS/cm, and 1402.1 mg/L, respectively in Tala Upazila of Satkhira district, one of the severely affected areas of salinity in Bangladesh. Local people are aware of the safe water scarcity in the mentioned areas and nearly all of them perceive that salinity is the main reason behind it [High salt intake is a major risk factor for increased blood pressure. Approximately 20 million people in Bangladesh are at high risk of hypertension due to the intrusion of saline water caused by climate change . The phy+ consumption has immunological effects on skin tissue, intestinal microbiology, and other organs, as well as cardiovascular disease, inflammation, infection, and autoimmunity [In addition, millions of people on the coastal regions of Southeast Asia experience cumulative sodium concentrations in their sources of potable water, which is partly influenced by climate change . The lonimmunity . Drinkinimmunity . HoweverThe article is aimed identifying the impacts of DWS on the coastal areas of Bangladesh by constructing the Driver-Pressure-State-Impact-Response (DPSIR) framework based on available literature review. The article is structured first by describing the DPSIR framework theory at While there are several theoretical contexts to demonstrate associations between the anthropogenic stresses and scenario deviations in marine and coastal ecosystems, the DPSIR framework is the most extensively applied framework . The DPSWe constructed a DPSIR framework of DWS based on the review of literature and published case studies on the coastal regions of Bangladesh. The map of coastal regions of Bangladesh is shown in This section is a comprehensive review of the available literature concerned with the impacts of salinity intrusion in the community health in order to construct the DPSIR framework. When we discuss the salinity intrusion in coastal areas, it automatically leads to the key point “Drinking or potable water salinity”, which is mainly caused by the presence of sodium in the drinking or potable water. The review is based on the published research through the use of scientific databases, such as Google Scholar, Web of Science, ScienceDirect, Scopus, etc. We used keyword-based screening according to the texts in the abstracts and considered articles published in English. Unpublished data such as our own previous works were used as supporting material. The review protocol steps are shown in To understand the area-wide distribution of salinization over two seasons in the study area, we used the IDW method for the spatial analysis of salinity data that we collected in earlier studies. We used ArcGIS version 10.1 to prepare the map. IDW uses the measured values surrounding the prediction location; wherein, greater weight is assigned to the points in proximity to the prediction location. The general formula for IDW can be presented as the following Equation (1).e points . In thisWe obtained user opinion on rainwater harvesting and solar powered desalination plant from Nilganj and Khaprabhanga Union of Kalapara Upazila, Patuakhali District through a questionnaire survey. Patuakhali District is one of the severely salinity-affected area from the south-central part of Bangladesh. Rainwater harvesting and a solar powered desalination plant in a pilot scale is currently operating in the area. We have randomly collected 120 user opinions according to the method suggested by Cochran, taking 95% of confidence level and a 10% margin of error .The application of the DPSIR framework is substantially pertinent to link the existing gaps between the scientific disciplines and the sciences of the coastal development strategy, as well as the integrated coastal zone management. However, the existing applications of the DPSIR framework in the coastal zones have been inadequate and novel innovative approaches are required to apply the model . DPSIR mDrinking water sources in the coastal regions of Bangladesh vary widely. Potable water shortage is seasonal, occurring during the dry season between November and early May. Owing to less precipitation and diminished river flow, the saltiness of surface water bodies such as waterways and canals increases through dry season. Furthermore, during the dry season, ponds repeatedly dry up, leaving the coastal population with few or no options but to use hand pump-extricated saline groundwater for drinking and cooking. Whereas, amidst the monsoon season (May to October), the coastal population generally gather rainwater through household- or community-level rainwater harvesting schemes . The GanThe intrusion of salinity into surface water and aquifers poses a significant risk to people’s access to potable water . The lik−, Na+, SO42−, HCO3−, etc. throughout the post-monsoon season shows the inward movement of saltwater [+ > Ca2+ > K+ > Mg2+ and Cl− > SO42− > HCO3− > NO3− > CO32− [Investigation of spatial and temporal inclination of surface water salinity in the coastal zones of Bangladesh showed that the maximum salt encroached areas during the monsoon season are: (i) Khulna, Satkhira, Bagerhat, Jessore, and Gopalganj—districts located in the extreme southwestern zones; (ii) Bhola, Noakhali, and Feni—districts positioned in the lower Meghna River floodplain and the Meghna estuarine floodplain; (iii) Chittagong and Cox’s Bazar—districts located in the southeastern portion of the Chittagong coastal plains adjacent to the Bay of Bengal; and (iv) Barisal, Jhalkathi, Patuakhali, and Barguna—the slightly saline diverged mid-south zone districts. All these districts are affected during the dry season . Increasaltwater . The extaltwater ,29. The altwater . Along w > CO32− .The spatial and temporal variation of surface water salinity data collected from the secondary sources were incorporated and the following map was generated . The cri+, K+, Cl−, and higher total hardness (TH) in relation to Ca2+, Mg2+, PO43−, and SO42− [+, Mg2+, and Ca2+, along with major anions Cl− and HCO3−. The spatial distribution of irrigation water quality index (IWQI), electrical conductivity (EC), soluble sodium percentage (SSP), and total hardness (TH) during both seasons confirmed the influence of salinity from the sea. The existing low-flow in the major river system was the driving factor of overall groundwater quality in the study area [As described in the earlier section, Gopalganj Sadar Upazila is one of the coastal districts of Bangladesh that is most affected by salinity. The risk of salinity was investigated for the surface water (ponds and river) and the groundwater samples, from shallow tube wells (STW) and deep tube wells (DTW). The water samples were collected from various irrigation sources in the pre-monsoon season in the month of March 2012. The depth of the STW varied from 100 to 150 feet, while the depth of DTW was more than 600 feet . Correland SO42− . Islam end SO42− . Hydrochudy area .+, Cl−, HCO3−, As, Mn, Fe, B, NO3−, CO3−, etc. surpassed the limits of various potable water standards. The spatial distribution of EC, Cl−, As, Fe, and Mn varied considerably in both pre-monsoon and post-monsoon seasons. From multivariate statistical analysis, high-salinity characteristic of groundwater resulting from seawater intrusion was observed. Strong, moderate, and weak spatial dependences are found for both seasons. The exponential semivariogram model was found to be overriding when considering the best-fit model for both seasons. The exponential semivariogram model is a geostatistical function often used to recognize the spatial distribution of specific water-quality parameters for a specified geographic area. Furthermore, mean values of the hazard quotient  and hazard index  was constructed for As, Fe, Mn, B, NO3−, and F−. The HQ and HI values of the aforementioned chemicals in the groundwater samples varied seasonally and carries a considerable health and well-being hazard to adults and children [Rahman et al. further evaluated the likely human risk of consuming the said groundwater samples to adults and children. Maximum hydrochemical parameters corresponding to pH, EC, TDS, Nachildren .−/Σ(anions) and Na⁺/Na++Cl− specified that the groundwater in the south-central part of Bangladesh, such as the Barguna and Patuakhali districts, was affected by the intrusion of seawater. The groundwater of Barguna and Patuakhali was clearly dominated by the cations and anions of Na+, Mg2+, Ca2+, Cl−, and HCO3− in both wet and dry monsoon seasons [+ concentrations in the groundwater were reported to be 863 mg/L and 825 mg/L in the pre-monsoon and post-monsoon seasons, respectively [+. In addition, the average salinity of the shallow tube wells ranged from 5.11 to 6.48 dS/m, while the pond water salinity ranged from 0.11 to 3.12 dS/m [Molar proportion of the Cl seasons . While t seasons  is 200 mectively . In anot.12 dS/m . It is, Pressures identified in the framework were seawater intrusion, salinization of soil and water resources, as well as shrimp cultivation in the coastal zones; thereby leading to the state of drinking water scarcity and presence of sodium in drinking water. Because of the microbial contamination of surface water and uneven distribution of the water resources, the rural population depends heavily on tube wells for drinking water . In thesCoastal communities in Bangladesh had little consciousness of the dangers related to the excessive salt consumption from their food. Moreover, reducing salt intake tactics were not very important to them . ImpactsPotable water security is one of the principal concerns for the well-being and sustainable development of the residents living within the coastal zones . While tp < 0.1) and 42% (p < 0.05) higher chance of being hypertensive than those who consumed freshwater (<1000 mg/L). It was further found that females have a 31% higher chance to be hypertensive than the males. In addition, interviewees 35 years old and above have approximately 2.4 times higher risk of hypertension compared to the interviewees under 35 years. Moreover, it was found that for ages 35 years and above, pre-hypertension and hypertension risks were 53.8% higher for slightly saline water and 62.5% higher for moderate saline water. In total, the disease risks in saline water-exposed groups were 50.1% higher than national rural statistics. For moderate salinity exposure, the pervasiveness of hypertension among the interviewees was 21%, 60%, and 48% higher than national statistics (23.6%), respectively. Although there was a slight periodical difference in the salinity of potable water, the dry season exhibited an increasing trend of salinity and maximum levels of blood pressure. Average salinity, as well as the relevant pervasiveness of hypertension, were greater among the consumers of deep aquifer water (21.6%) than for the users of shallow aquifer waters (20.8%) [Drinking water sodium has serious implications for the health of the community, particularly for pregnant women. People exposed to slightly saline (1000–2000 mg/L) and moderately saline (≥2000 mg/L) concentrations of drinking water had, respectively, 17% ( (20.8%) .p = 0.001). Adjusted risks for (pre)eclampsia and gestational hypertension considered together increased in a dose-response manner for increasing sodium concentrations  in drinking water (ORs 3.30 (95% CI 2.00–5.51), 4.40 (2.70–7.25), and 5.48 (3.30–9.11), (p trends to 0.001)) [To understand the effect of exposure to DWS on maternal health in the coastal areas, information was obtained from different types of studies. The most notable types of information were water sources and water consumption types , daily urinary sodium concentration of the pregnant women, seasonal variations (dry or wet), and hospital incidence due to eclampsia or (pre)eclampsia, etc. Note that (pre)eclampsia and gestational hypertension is a condition that occurs only during pregnancy and is characterized by one or more convulsions and high blood pressure; while eclampsia is the severe complicated form of (pre)eclampsia. Khan et al. identified an estimated average DWS of 5–16 g/day on dry season compared to 0.6–1.2 g/day on wet season. The daily sodium concentration in the urine was found to be 3.4 g/day (range 0.4 to 7.7 g/day) . It was Consequent data gathering and review on the pressing topic found that DWS concentrations were significantly associated with high blood pressure (hypertension) . It was DWS could be a major factor on infant and newborn death in coastal Bangladesh . AlthougResponses obtained from the DPSIR framework were taken as interventions. Several interventions have been implemented to tackle the shortage of potable water owing to salt intrusion in the coastal regions of Bangladesh. With varying success, southwestern Bangladesh communities currently use drinking water via the following interventions: rainwater harvesting, ponds, pond sand filters, managed aquifer recharge (MAR), tube wells, etc. . From thRainwater harvesting is an ancient technique for collecting water especially when the water scarcity is intense. This technique has been modified by different NGOs that provide drinking water to the needy people of coastal areas of Bangladesh at an affordable cost. For instance, SPS Khulna, an NGO, set up concrete tanks that are used for rainwater harvesting, which costs 15,000 BDT ($180 US) per family, while some locally made large earthen containers  costs only 1000 BDT ($12 US). In the questionnaire survey, it was found that 50% of the respondents in the Kalapara Upazila of Patuakhali District Bangladesh reported rainwater harvesting to be a moderately effective measure, while 20% and 23% respondents thought it was a very effective and highly effective measure, respectively. Consuming rainwater lessens the risk of salinity exposure through lowered sodium intake and is beneficial to cardiovascular health of the coastal communities. However, it also decreases the ingestion of vital cardio-protective minerals such as magnesium and calcium . WHO recDesalination systems remove or reduce salts from saline water (either seawater or brackish groundwater) . ExampleMAR can be applied as a measure to reverse and prevent coastal aquifer salinization related to the overexploitation of groundwater and water table decline . The quaHowever, a recent study undertaken in the southwestern coastal region of Bangladesh by Scheelbeek et al. (2017) reported that a gradual increase in sodium concentration over the course of the dry season was observed in MAR. Median sodium concentrations of the pond and MAR sources were around 400 mg/L toward the end of the dry season, whereas median sodium concentrations in tube wells exceeded 800 mg/L, followed by extremes of >1500 mg/L [DWS is a pressing issue in the present socio-economic, environmental, and climatic condition in the coastal region of Bangladesh, where salinity and seawater intrusion are serious issues. Here, we reviewed the salinity scenario of Bangladesh and constructed the DPSIR framework of DWS. We further reviewed the health impacts of high salinity-contaminated potable water on local people’s health, maternal health, hypertension, and infant mortality in the coastal population of Bangladesh. Several key intervention mechanisms were also recognized to manage the saline water. The list of issues is inevitably extensive such as infant mortality, hypertension among adults, and (pre)eclampsia among pregnant women, which leads to millions of people being affected by heart diseases. Several interventions, such as rainwater harvesting, PSF system, MAR usage, and the integration of mixed sources, were reviewed on the content of DWS. While rainwater has the positive impact of low or no sodium intake on human health, it still possesses harmful impacts on human health for not containing essential micronutrients such as calcium and magnesium. Meanwhile, a gradual increase in sodium concentration over the course of the dry season was observed in MAR and is a serious risk factor for MAR failure. Similarly, RO and other desalination technologies are still in the pilot scale study, which requires further exploration to apply to the mass scale. It is very important to identify the mechanisms by which the above-mentioned interventions may fail. Moreover, it is crucial for coastal people to have increased consciousness regarding DWS and to be involved in the maintenance of the technologies which could aid in the desalinization of water.


Objective: Magnetic resonance imaging (MRI) and cardiac catheterization are diagnostic tools for right ventricle dysfunction (RVD), but those are expensive and often unavailable techniques. Thus, our objective was to identify clinical and/or echocardiographic variables capable of predicting a catheterization-based diagnosis of RVD.Design: This was cross-sectional, diagnostic test accuracy study, considering the catheterization-based diagnosis of RVD as the gold standard.Patients: Pediatric patients with non-repaired CHD with overload pressure were evaluated. Clinical variables , transthoracic echocardiography , and cardiac catheterization (pressures and right ventricle systolic work measurements) were obtained during the same hospitalization.Results: We included 253 patients with tetralogy of Fallot (39.9%), pulmonary atresia with ventricular septal defect (33.9%), type C Ebstein's anomaly (15.8%), or pulmonary stenosis (10.4%). Among clinical  and echocardiographic  variables, the Tei index (defined as the ratio of isovolumetric contraction time to ejection time) was the sole variable that exhibited high diagnostic capability, with 98.5% sensitivity, 97.4% specificity, 97.8% positive predictive value, and 98.3% negative predictive value, with 98.0% overall performance. Multivariate logistic regression confirmed that Tei index alone predicted the catheterization-based diagnosis of RVD.Conclusions: Tei index is the best parameter that can be employed for the non-invasive identification of RVD in patients with CHD. Currently, patients with congenital heart diseases (CHD) achieve more than 85% survival at 45 years of age, and this survival decreases according to the complexity of the cardiopathy . The majSome CHD, such as tetralogy of Fallot, pulmonary atresia with ventricular septal defect (PA+VSD), pulmonary valve stenosis (PVS), and type C Ebstein's anomaly , 5 shareMagnetic resonance imaging (MRI) is the best diagnostic tool for the evaluation of RVD, but it is expensive and not widely available. On the other hand, due to its capability for the evaluation of the morphology, functionality, and segmental pressures of the right ventricle, cardiac catheterization may be considered an equivalent of MRI . BecauseThis was a prospective study carried out at the CHD Service of the Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, in Mexico City during the 2010–2015 period. The protocol was reviewed and approved by our institutional scientific and bioethics committee . During hospitalization, prior to the catheterization procedure, the researcher responsible for the investigation provided the assent and consent letters, and the parents of the patients provided their written informed consent for their child's participation in this study.The study population was composed of patients with a CHD and obstruction of the right ventricle output tract, such as tetralogy of Fallot, PA+VSD, PVS, and type C Ebstein's anomaly. They were inpatients of either sex, aged between 1 and 17 years, who were under preparation for total surgical repair. They were, during the same hospitalization, submitted to clinical evaluation and pre-surgical procedures including TTE and cardiac catheterization. These last procedures were performed by interventional cardiologists and echocardiographers certified in CHD and with ample experience in these procedures. Patients with non-programmed admission due to decompensation, with a prior non-palliative heart surgical procedure, with percutaneous valvuloplasty, or with coronary heart disease were excluded.2. This latter parameter was calculated by the formula proposed by Chemla et al. (before the outflow tract obstruction), instead of MPAP. In this calculation, we utilized the following formula: mean pressure of right ventricle at the infundibulum = (right ventricle systolic pressure at the infundibulum – right ventricle diastolic pressure at the infundibulum)/3 + right ventricle diastolic pressure at the infundibulum.Cardiac catheterization was performed via a femoral vein or, alternatively, by subclavian or jugular vein. RVD was considered to be present when all of the following variables coincided: (1) right ventricle systolic pressure  >30 mmHg; (2) right ventricle diastolic pressure  >12 mmHg, and (3) indexed right ventricle systolic work  < 4 kg/m/ma et al. , i.e., Rsystolic function were obtained and evaluated: (1) Indexed right ventricle diameter, expressed in millimeters (average of triplicate measurement) and considered abnormal when z-value was greater than 2 of reference values adjusted by body surface area (diastolic function were obtained: (1) The wave E′/A′ ratio, which was considered abnormal when <0.08. (2) Deceleration time, referred as abnormal if less than 23 m/s.Clinical evaluation was conducted by pediatric cardiologists not participating in this research. The clinical variables analyzed comprised the derangement of Ross functional class by ≥1 class during the previous year, and congestive data including hepatomegaly  or jugular vein distention above two thirds of the neck. TTE was carried out by experienced pediatric cardiologists or echocardiography cardiologists and according to international guidelines . The folace area . (2) Rigace area . (5) S' ace area . AdditioWe assessed the capability of clinical and echocardiographic variables to correctly diagnose RVD documented through cardiac catheterization. To this end, sensitivity, specificity, positive and negative predictive values, and overall performance were computed. Best cut-off point was evaluated through ROC curves. Multivariate logistic regression was employed to identify best predictor variables. Data was processed in Excel and SPSS v20 (IBM SPSS Statistics).A total of 253 patients  with CHD and obstruction of the right ventricle output tract were studied. The main characteristics of this population can be observed in Table When each potential predictor variable  was evaluated for its capability to predict RVD, it was evident that the Tei index possessed, by far, the highest overall accuracy (>95%) in any of the four CHD studied Table . This hir2 = 0.753.When TTE parameters were entered into a multivariate logistic regression analysis as continuous variables, the final regression model retained Tei index as the sole variable capable of predicting the probability of having RVD (pRVD), with high accuracy, excluding from the model all other variables . The final model was pRVD = −27.563 + 71.766 • Tei index, with a pseudo The frequency of RVD in patients with non-repaired CHD is unknown, but it has been estimated that, during the immediate postoperative period and subsequent follow-up, right ventricle dysfunction can be found in up to 25–30% of patients . In the Among the few studies that have assessed the value of TTE in CHD, Puchalski et al.  evaluateThe Tei index exhibited highest diagnostic accuracy across all types of CHD studied. Song et al.  demonstrr = 0.81) as compared with patients with tetralogy of Fallot (r = 0.65) (r = 0.80) with MRI-derived right ventricle ejection fraction in 36 adult patients submitted for evaluation of ischemia or viability. The authors suggested that this method could be utilized for the assessment of right ventricle function in the clinical setting, a suggestion that has been supported by others  . On the  = 0.65)  found thy others . In our The two echocardiographic measurements employed for evaluating right ventricle diastolic function exhibited lower diagnostic accuracy, probably because the major component of cardiopathies included in the study was obstructive in nature.In the present study, the two clinical variables analyzed  demonstrated low diagnostic accuracy in the majority of CHD. However, both clinical variables yielded a specificity of 100% among patients with type C Ebstein's anomaly. This may be explained because criteria for cardiac catheterization in Ebstein's anomaly comprises functional class derangement and low oxygen saturation (caused by a right-to-left shunt due to high pressures inside the right atrium) . BorgdorThe major limitation of our study was that the comparator for TTE was cardiac catheterization and not MRI, which at present is considered the gold standard for RVD evaluation. Likewise, we did not perform more sophisticated tests, such as strain rate or torsion, and in our RVD definition, we included RVSWi as indicator of contractile deficiency but, though reasonable, applicability of this parameter to CHD has not yet been corroborated. Conversely, advantages of our study included that the methodology employed warranted that both procedures (cardiac catheterization and TTE) were performed with a short lag time , and that patients were devoid of any ventricular damage secondary to surgical procedures, guaranteeing that the evaluation focused only on hemodynamic status conditioned by the CHD.In conclusion, the Tei index is a useful echocardiographic parameter for diagnosing RVD in pediatric population with CHD. This index is non-invasive, relatively easy to obtain, and can be repeated as many times as needed during the patient's follow-up. In countries where RMI and cardiac catheterization are not easily available, the Tei index may help clinicians to perform timely identification of RVD in order to modify treatment and achieve a better prognosis.All authors contributed substantially to the conception and design of the study, and to the critical review of the manuscript. LY-G performed the majority of echocardiographic evaluations. HM-G was the main individual responsible for the project and was involved in the full data collection and, along with MV, in data analysis and in drafting of the manuscript.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. The reviewer GJS and handling Editor declared their shared affiliation.


The Centers for Disease Control and Prevention (CDC), through its Behavioral Risk Factor Surveillance System (BRFSS), collects data on caregivers and the caregiving situation as well as many health behaviors, annually. The BRFSS is the world’s largest ongoing health survey, administered in all 50 U.S. states, as well as the District of Columbia and the three U.S. territories, with data collected from more than 400,000 respondents. In 2015-2017, the 9-item caregiving module was administered in 44 states, DC, and Puerto Rico on the BRFSS. CDC’s Alzheimer’s Disease and Healthy Aging Program has developed many data for action resources for use by states and other partners to help identify populations and communities most at need. This presentation will describe future enhancements with the BRFSS caregiving module and the series CDC developed resources to facilitate date utilization, including state-specific infographics, data briefs, and the online data portal.


Background: Although tyrosine kinase inhibitors (TKIs) are still recommended as the standard therapy in renal cell carcinoma (RCC), the high frequency of adverse events is a weakness of this therapy. Because royal jelly (RJ) possesses anti-inflammatory and antioxidant properties, we assessed its protective effects on TKI-induced toxicities in RCC patients. Methods: We enrolled 33 patients with advanced RCC who were assigned to start TKI therapy in combination with a randomized, double-blinded, placebo-controlled RJ trial consisting of a placebo group with 17 subjects and an RJ group with 16 subjects. Results: Fatigue and anorexia frequencies in the RJ group were significantly lower than in the placebo group . A statistically significant correlation between RJ and fatigue or anorexia was detected in sunitinib-treated patients. The dose reduction- or discontinuation-free periods were significantly longer (p = 0.013) in the RJ group than in the placebo group. Furthermore, similar observations were made in sunitinib-treated patients (p = 0.016). Conclusions: Our clinical trial showed that RJ exerted protective effects against TKI-induced fatigue and anorexia and lowered TKI dose reduction or discontinuation. Hence, RJ is beneficial for maintaining the quality of life and medication compliance in TKI-treated RCC patients. Renal cell carcinoma (RCC) is one of the most common urological cancers, and its incidence has continuously increased over the past few decades . AlthougSunitinib and pazopanib are approved as first-line therapy for patients with RCC, especially in favorable- or intermediate-risk clear cell RCC . In addiApis mellifera, and is the exclusive food for the queen honeybee and larvae. The most important biological effects of RJ are its anti-inflammatory and antioxidative activities, and its ability to exert some control over the immune system [Royal jelly (RJ) is secreted by the hypopharyngeal and mandibular glands of worker honeybees of e system ,23,24. Te system ,26. In fe system ,28,29,30Thus, in recent decades, several studies have examined the biological effects of RJ on cancer cell lines and corresponding animal models. However, despite several clinical trials, not many studies have reported the clinical benefits and limitations of RJ administration in cancer patients ,33,34,35This study protocol was approved by the Human Ethics Review Committee of Nagasaki University Hospital , and it was registered as UMIN000020152. In addition, this trial was conducted according to the Declaration of Helsinki. Patients provided written informed consent to participate in all aspects of the study. Patients with RCC who had been assigned to start TKIs were enrolled by the Nagasaki University Hospital. Eligibility criteria of this trial were age >20 years, Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1, and no honey allergy. This is a randomized, double-blinded, placebo-controlled clinical trial. Patients were assigned to two groups, namely the placebo and RJ groups, at a ratio of 1:1 using computer-generated random numbers. The patient selection process was performed by independent non-medical staff at our hospital who had no information on the aim of this trial, and the process was also hidden from the patients and urologists who provided treatment until the end of all analyses. RJ and the placebo were provided by the Yamada Agriculture Center Inc . RJ and the placebo were prepared as capsules containing 900 mg RJ and starch, respectively, that share the same taste, smell, size, shape, and color. Capsules were orally administered four times per day for three months.All subjects received medical examinations and were checked for clinical symptoms every two weeks. Blood samples were collected simultaneously every two weeks and subjected to laboratory analysis routinely performed in patients treated with TKIs. The initial starting dose of sunitinib, pazopanib, axitinib, and sunitinib was 50 mg/day, 800 mg/day, 10 mg/day, and 800 mg/day, respectively, but if an intolerable AE was observed, the dose was decreased to 37.5 mg/day, 400–600 mg/day, 5 mg/day, and 400 mg/day, respectively. In addition, for the sunitinib regimen, if the dose reduction was necessary, all affected patients were treated with an alternative every other day . FurtherToxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. In this study, toxicities classified as grade 3 and 4, or identified as the cause for discontinued TKI administration, were judged as severe AEs. p ˂ 0.05 were considered statistically significant. Statistical analyses were carried out using StatView for Windows v.5.0 software .Results are expressed as the mean and standard deviation (SD) for normally distributed data and the median and interquartile range (IQR) for non-normally distributed data. The Student’s t-test or Mann–Whitney U test was used to compare continuous variables and Scheffé’s method was used for multiple comparisons. The sustained periods of initial dosage were derived from Kaplan–Meier curves, and statistical significance was analyzed using the log-rank test. Values with All subjects of the placebo and RJ group consumed the respective capsules for three months or until disease progression. In addition, we confirmed that the compliance rate was >95% in both groups and no patient experienced any side effects including allergy due to the trial capsules. Thirty-three patients with RCC were enrolled in this study. The pathological features and basic characteristics of our study population at baseline are presented in The statistical analysis indicated that the baseline parameters did not significantly differ between the placebo and the RJ groups. As shown in p = 0.013) compared to that of the RJ group. However, the remaining parameters did not significantly vary between these two groups. In the other TKI group, the mean age of the RJ group was significantly higher (n = 33), the most common AE was hypertension  followed by fatigue , and anorexia  and hand–foot syndrome . Furthermore, anorexia  was the most common severe adverse event. In the study population . The digestive symptoms varied similarly, but the difference between the RJ and placebo group was not statistically significant (p = 0.077). In addition, none of the other symptoms varied significantly, including hypertension. However, when the same analysis was performed separately on the subgroups of patients treated with either sunitinib or other TKIs, such significant differences in fatigue and anorexia differed significantly between the RJ and placebo groups in patients treated with sunitinib , but not in those treated with other TKIs . The frequencies of the remaining symptoms were similar between the two groups regardless of the TKI regimen. As shown in p = 0.162). When the same analysis was performed with the data of the sunitinib-treated patients, no significant difference was detected (p = 0.117). Overall, none of the laboratory blood test results varied significantly between the placebo and the RJ group (RJ group .p = 0.017) in the RJ group (5/16 = 50.0%) than in the placebo group (15/17 = 88.2%). The Kaplan–Meier survival curves for dose-reduction- or discontinuation-free survival rates in the placebo and RJ group are shown in p = 0.013) in the RJ group than in the placebo group. Furthermore, a similar result was observed in patients treated with sunitinib  required a dose reduction or discontinuation of the TKI regimen due to severe AEs and disease progression within three months of TKI treatment initiation. The frequency of dose reduction or discontinuation was significantly lower (n = 26) were significantly lower than those in the control group  [In this study, we investigated the preventive effects of prophylactic RJ consumption on AEs associated with TKI-induced toxicities because the appropriate management of these AEs is critical for maintaining quality of life in RCC patients treated with TKIs. Various harmful symptoms and abnormal observations are known as adverse events of TKIs ,16,17,18 n = 26) . We beli n = 26) . Thus, t n = 26) . In addi n = 26) . MoreoveIn addition to fatigue, our results demonstrated that RJ suppressed the frequency and severity of anorexia. To our knowledge, this is the first report about the preventive effect of RJ on anorexia in RCC patients. In addition, there is no information on the relationship between RJ and anorexia in patients with malignancies. In general, anorexia in cancer patients is caused by complex interactions involving various factors, such as nausea, constipation, pain, depression, and hypothyroidism . In addiOur results showed that RJ had no significant effect on oral mucositis. However, a preliminary study designed as a randomized, single-blinded (physician-blinded) trial showed that prophylactic RJ use led to a significant reduction in head and neck cancer patients. However, the study population was small  . On the Our results showed that there was no significant relationship between RJ consumption and the blood test results. Several in vivo studies demonstrated RJ administration led to the protection of various organ functions . For exaOur study design has several limitations that restrict the conclusions about the preventive effects of RJ on AEs caused by TKIs in patients with RCC. First, the trial had a relatively small number of patients in each group. However, we emphasize that this trial is a preliminary study on the RJ consumption by patients with malignancy treated with TKIs. In addition, the number of patients in the present study appears to be relatively similar to that reported in previous clinical trials on RJ administration ,33. SecoIn conclusion, our results demonstrated that prophylactic RJ intake is effective for the prevention and suppression of sunitinib-induced fatigue and anorexia. In addition, RJ did not affect treatment safety and compliance. Specifically, we found that the risk of TKI dose reduction or discontinuation was significantly lower in the RJ group than in the placebo group. Sunitinib remains a recommended standard agent used singly or in combination with immune therapy, low molecular weight heparin, and vaccines for the treatment of metastatic RCC ,7. There


Background: Quality of life (QoL) studies in patients with mild to moderate Graves' orbitopathy (GO) are scarce.Methods: The original GO-QoL questionnaire was translated to Portuguese and administered to 323 patients with Graves' disease. The clinically active score (CAS) was used to evaluate GO activity, and the NO SPECS and EUGOGO classifications were used to estimate GO severity.Results: The internal consistency of the GO-QoL, evaluated using Cronbach's alpha, was optimal. In people with Graves' disease and long-duration GO, both visual function and appearance scores were negatively associated with the CAS and NOSPECS and EUGOGO classifications (P < 0.001). Asymmetry and proptosis were significantly associated with the visual function and appearance domains, and diplopia was related to the visual function score. In addition, multivariate regression stepwise analysis revealed that disease severity, according to the EUGOGO classification, was associated with the visual function and appearance scores; asymmetry, presence of proptosis, and young age were associated with the appearance score (P < 0.001). The visual function and appearance scores were negatively correlated with the CAS and NOSPECS and EUGOGO classifications (P < 0.001).Conclusion: Graves' orbitopathy has a negative impact in QoL in patients with mild to moderate disease, even after an extended period, rendering GO a chronic disease. The GO-QoL questionnaire can be helpful in identifying patients in need of attention and support. Graves' orbitopathy (GO) is the most common and important extrathyroidal manifestation of Graves' disease (GD) , 2. It iThe concept of QoL is relatively new and has acquired growing importance in recent decades. Certain guidelines reinforce its use in clinical practice because the inclusion of physical, mental, and social aspects, though difficult to measure, reflects a better approach to patient health management , 8, 9. NThe European Group of Graves‘ Orbitopathy (EUGOGO) consortium recommended that a disease-specific QoL, rather than a general questionnaire, be used. Because most studies include patients with severe forms of GO, we evaluated the influences of mild and moderate GO on QoL by using the GO-QoL with a large cohort of Brazilian GO patients. Additionally, we assessed correlations between inflammatory activity, measured using the clinical activity score (CAS), and clinical severity, as determined by the NOSPECS  classification.The study was carried out in three Brazilian University Hospital centers. After institutional research ethics approval, a total of 323 consecutive GO patients with mild to moderate forms of the disease were eligible . The oriSerum-free thyroxine and thyroid stimulating hormone levels were determined using chemiluminescence assays (DPC Immulite system). Thyrotropin receptor antibody levels were determined using electrochemiluminescence assays .n and percent. Numerical variables were described using the mean, standard deviation, and median. The chi-square test was used to compare categorical variables between classifications and, when necessary, the Fisher exact test was used. The Mann-Whitney and Kruskal-Wallis tests were used with numerical variables. Correlations between the CAS, EUGOGO classification, NOSPECS classification, and the GO-QoL score were determined using the Spearman rank correlation. Univariate and multivariable logistic regression were performed to investigate the influences of age, sex, smoking, diplopia, asymmetry, proptosis, CAS, NO SPECS, EUGOGO classification, and duration of GO reflected in the GO-QoL score. Cronbach's alpha was used to evaluate internal consistency based on correlations between items within a subscale of the QoL questionnaire.Samples were separated according to the variables studied. Frequency tables were constructed for categorical variables and were described using P < 0.05. All analyses were performed using SAS  and BioStat Pro 6.1.7.Statistical significance was recognized when n = 246), NOSPECS classifications of 0 or 1 (n = 204), and mild GO according to EUGOGO classifications (n = 229). Members of the other had moderate GO, CAS of 2 to 5 (n = 77), NOSPECS classifications of 2 to 4 (n = 119), and moderate to severe GO according to EUGOGO classifications (n = 94). About three percent of the sample had diplopia at the time of QoL testing. However, a large majority of patients with diplopia had CAS exceeding 2, NOSPECS classifications of 2 to 4, and were classified as moderate by their EUGOGO classifications (P < 0.001).ications . AdditioThe concept of QoL includes physical, mental, and social aspects , 8. ThusAll datasets generated for this study are included in the manuscript and/or the supplementary files.This study was carried out in accordance with the recommendations of Ethics Committee, with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Instituto de Assistência Médica ao Servidor Público Estadual—IAMSPE Ethics Committee.DV, JR, and JA prepared the manuscript and analyzed the data. JA and RS created the charts and figures. RS, AM, and PT managed and verified the collected data. DV, AM, and PS were responsible for interview the patients. LW and JR provided overall guidance and edited the manuscript. The final manuscript was read and approved by all authors.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.


Children’s average age at T1 was 53 months, with 51% male, 42% Anglo-American, 26% African–American, and 40% Hispanic-American. Children’s EF, social skills, pre-literacy/language, and pre-math skills were assessed by trained child assessors blind to study conditions at T1 and T2. Assessors also rated children’s task behavior in the testing situation at T1 and T2. School records of children’s kindergarten screening scores were obtained on 345 children at T3. It was expected that SSEL would have both direct and indirect effects on kindergarten readiness through improvements in children’s SE and EF skills preschool academic skills and on-task behavior. We found no direct effects of SSEL on either pre-academic or on-task behavior outcomes in preschool, nor on later kindergarten readiness. However, SSEL significantly increased EF, and as expected by SSEL’s theory of change, growth in EF predicted gains in both pre-academics (particularly pre-math), and on-task behavior in preschool. End-of-year pre-academic skills and on task behavior in turn predicted better kindergarten readiness. Further, SE  had direct and indirect effects on kindergarten readiness. Thus, overall, our findings largely support SSEL’s theory of change, particularly in relation to EF.Efforts to improve the achievement gap between low-income children and their more affluent peers has led to the development of classroom interventions and curricula to increase executive functioning (EF) and social-emotional skills (SE), thought to be foundational for learning. The Second Step Early Learning (SSEL) curriculum is a commercially available curriculum designed to improve school readiness by building EF and SE skills. However, although widely used, it has not been widely studied. Modeling SSEL’s underlying theory of change, structural equation modeling (SEM) was used to longitudinally examine the effects of the curriculum on low-income preschool children’s kindergarten school readiness through the hypothesized mediating role of EF and SE skills in improving pre-academic skills and task behavior in preschool. In a cluster randomized trial, 972 children attending 63 preschool classrooms within 13 low-income Head Start or community preschools were individually tested at the beginning (T1) and end of preschool (T2,  In recent decades there has been a heightened attention to addressing the achievement gap between disadvantaged children and their more affluent peers at school entry. For instance, national average math and reading scores of children in the highest SES group are more than a full standard deviation above the scores of the lowest SES group at kindergarten entry . MoreoveExecutive functioning (EF) encompasses cognitive processes thought to support academic achievement through top down control of attention and behavior. While there is no consensus on the definition, EF is commonly referred to as an umbrella term for a set of cognitive control processes necessary for planning, problem solving, and monitoring behavior that is distinct from general intelligence . EF inclSocial emotional skills are thought to be another important contributor to school readiness, although findings in this area are mixed and often show indirect but not direct relationships. In particular, research shows that SE skills such as emotion knowledge and social problem-solving skills are consistently related to social competence and fewer behavior problems , and somEarly childhood is a key time in the development of these self-regulatory skills. Both EF and social emotional skills (SE) show rapid growth during the preschool years, mirroring the neurological growth and connectivity of the prefrontal and anterior cingulate cortices during this time . While tBecause of the rapid developmental growth of SE and EF skills in early childhood, their sensitivity to malleable environmental conditions, and their importance to school readiness and success, the preschool classroom is one obvious setting to directly promote and support the development of these skills, particularly for disadvantaged children who may be at risk before they even begin formal schooling . As suchFor instance, This study examines kindergarten readiness skills, independently assessed by schools, of one commercially available curriculum, Second Step Early Learning SSEL, . SSEL isThe Second Step Early Learning Curriculum  is a preschool curriculum targeted to 4–5-year old’s, but suitable for use in mixed age (3–5-year-old) classrooms. SSEL has 28 weekly themes divided into five units with daily large or small group activities to introduce and practice skills. It is guided by the extensive research base on self-regulation and social competence and their importance for school readiness. It is designed to build EF through both directly teaching EF skills , and through the use of instructional teaching methods that support children’s attentional skills, memory, and impulse control . Social emotional skills are also promoted through directly teaching about emotions, emotion management strategies, and social problem-solving skills, as well as instructional teaching methods that foster child learning engagement , and strategies that promote positive behavior through emotional supportiveness, positive reinforcement and modeling strategies .Although not scripted into the daily activity, teachers are also encouraged to reinforce skills throughout the day/week using strategies such as ‘think ahead’  and ‘think back’ , as well as through creating practice opportunities in the classroom, noticing and reinforcing children when they use learned skills, and creating curriculum connections that extend and support newly learned skills . SSEL also includes a weekly handout for parents that teachers can copy and send home to provide information about what children are learning that week, with activities parents can do with their children at home to reinforce concepts.The curriculum comes in a kit with a teacher manual, a boy and girl puppet, 28 large weekly theme cards with a full-color photo of diverse preschool children in situations relevant to the weekly theme  and instructions for each day’s activity on the back. Materials to support and reinforce skills throughout the week are also provided, such as a cd of theme-related songs, posters to hang in the classroom, and cards with feeling faces that can be used in matching games or for children to use to identify how they are feeling.The underlying theory of change is that SSEL will lead to greater social emotional skills and EF, and that these skills will improve children’s on-task behavior and academic skills, which in turn will result in better kindergarten readiness.Our prior study examined the effects of SSEL on SE and EF and pre-academics but did not include kindergarten data. We found a significant impact of SSEL on EF skills but not on SE or pre-academic skills. The goal of the current study is to use SEM to examine SSEL’s effect on kindergarten readiness and the indirect and direct roles of end of preschool SE, EF, pre-academic skills and task behavior guided by the theory of change.We expected that:(1) Kindergarten readiness will be significantly higher for children from intervention classrooms compared to comparison classrooms.(2) The effects of SSEL on kindergarten readiness will be mediated by end of year SE and EF skills, pre-math skills, pre-literacy/language skills, and on-task behavior.This study was approved by the Internal Review Board of the University of Massachusetts Medical School.Participants were 972 pre-kindergarten children recruited from 63 preschool classrooms within 13 childcare sites serving children aged 3 to 5 . Families were recruited in the fall of each year by human subjects research-trained childcare administrators, at the time of enrollment into the preschool program. Families who could not complete the informed consent process in English or Spanish were not recruited into the study. Only one child per family was maintained in the study. When more than one child from the same family was enrolled in the preschool, the oldest child enrolled was maintained, or a randomly selected child in the case of twins. Classrooms were frequently multi-aged (3–5 years), but only children aged 4–5 years or expected to enter kindergarten the next year were individually assessed by study staff.n = 972) and again in the spring [T2: collected between the end of March and the beginning of June of each year ]. The study included two cohorts of preschool classrooms/teachers that were each involved in the study for 2 years . The present study includes both cohorts. For findings from Cohort 1, see Individual child assessment measures used in the current paper  were collected in the fall  who were blind to study goals and conditions. Assessors were told only that it was a study of children’s development and learning. Debriefing of assessors after study involvement confirmed that none were aware that it was an intervention study. The assessment battery was completed during two, 30-min sessions on two different days . Measures were assessed in the same order across children, with measures ordered to maximize engagement, attention and motivation, and minimize fatigue. Most assessments were conducted in a corner of the classroom because of preschool policies around child safety, but some sites allowed assessments to be conducted outside of the classroom in a common area.n = 526) in 24 different school districts, private or charter schools. Kindergarten screening assessments (T3: collected at the beginning of the kindergarten year) using the Early Screening Inventory-Revised . Random assignment was conducted after children were enrolled and baseline data were collected. After random assignment, teachers in intervention classrooms were trained in the SSEL curriculum, with continued support over the 2 years of study involvement. In Years 2 and 4 new children entered previously randomized classrooms, while children also left the centers, so there was a combination of new and continuing students in many classrooms.Teachers were trained during 2-h evening meetings that provided information on the theoretical importance of the skills taught, reviewed implementation strategies, provided opportunities for practice, and most importantly, included time for teachers to share successes and trouble-shoot difficulties. There were 7 meetings in the 1st year of involvement (November–May) and 5 meetings (bimonthly from October–May) in the second year of involvement. In addition, project staff observed teachers implementing curriculum activities in their classrooms each month and provided written feedback. Fidelity was rated during these observations to monitor implementation  Assessor Report . This isThe Early Screening Inventory-Revised ESI-R,  is a widThe goals of the present analyses were to investigate the longitudinal effects of the SSEL curriculum on kindergarten readiness and to explore the mediating roles of SE, EF, academic skills and task behavior in preschool in predicting children’s kindergarten readiness guided by the curriculum’s ToC, while accounting for children’s nesting within classrooms. SEM was used to test the causal relationship among exposure to the SSEL curriculum, gains in preschool skills, and kindergarten readiness. To handle the multilevel-structured data, we used the TYPE = COMPLEX command in Mplus  to delineate the relationships among indicators and underlying latent variables. In the second step, structural equation models were tested using path analysis to determine the longitudinal associations among EF, SE, academic skills and task behavior in preschool, and later kindergarten readiness. We conducted a cross-lagged model for EF and SE between fall and spring in preschool to test the direction of effects between EF and SE and estimated the structural model for the longitudinal impact of the intervention on the kindergarten readiness at the same time. This process allows for concurrent estimation of longitudinal influences of one construct on another, and vice versa, while controlling for contemporaneous correlations between the constructs and the stability of each construct over time, as well as the relation to distal outcomes.We fitted models using chi-square statistics, as well as the root mean square error of approximation (RMSEA), the comparative fit index (CFI), the Tucker–Lewis index (TLI), and the standardized root mean square residual (SRMR). The overall fit of each model was determined using RMSEA, CFI, TLI, and SRMR as the chi square test is sensitive to relatively large sample size. For the RMSEA and SRMR, values of less than 0.08, and ideally below 0.05, were used to indicate an adequate and reasonable fit to the data . Values 2(34244) = 6298.789, p > 0.10. Data found to be MCAR provides assurance that the overall distributions of variables would remain the same with or without those missing participants, so the remaining participants are representative of the full sample, except for negligible random differences. Accordingly, we retained the entire sample in analyses to maximize statistical power.Missing data were handled by using full information maximum likelihood (FIML) to estimate all relevant models. The FIML parameter estimates result in less bias and are more appropriate than other methods  under the condition of data missing completely at random (MCAR) or missing at random (MAR), . In the Table 1 describes the baseline characteristics for the 972 children and families. The children’s average age was 52.98 months (SD = 4.01), and 51.3% were male. Children were racially diverse . Parents’ average age was 31.32 years (SD = 7.91), and the majority of parents were unmarried (72.5%). Approximately half of parents (51.8%) completed more than high school. The majority of parents (74.3%) reported family incomes less than $30,000. T-tests or Chi-square analyses were used to compare differences between intervention and the control groups across the multiple demographic variables. A Bonferroni correction for Type I error (p < 0.005) indicated no significant group differences.Table 2. In order to estimate the impact of the intervention on individual measures, effect sizes (ES) were calculated in the context of nested data in Mplus. Results revealed that ESs (ranging from 0.02 to 0.28) were small and mostly favoring intervention children except for Letter-Word in preschool fall and spring, which favored controls.Basic descriptive statistics among SE, EF, and academic skills and task behavior measures in preschool fall and spring, as well as the ESI in kindergarten are shown in Table 3. Correlations between the same measure at the fall and spring time points in preschool  were moderate to high (r = 0.33–0.76). Otherwise correlations across measures or between preschool and kindergarten were minimal or small except for one correlation within the CST data. For example, within each time point  correlations among measures ranged from 0.03  to -0.53 . Correlations between preschool measures and kindergarten readiness ranged from 0.01  to 0.24 . In addition, correlations among demographics and condition and preschool and kindergarten measures were also minimal to small, ranging from 0.00 , to -0.23 (Hispanic and Applied Problems in the spring).Correlations for all variables are shown in Table 4).We conducted measurement models to test CFA for estimating the latent variables of EF, SE, and Pre-Literacy/Language (see 2(80) = 524.465, p = 0.000; RMSEA = 0.076 ; CFI = 0.844; TLI = 0.766; SRMR = 0.068. Re-specification by correlating error terms for same indicators across the time points  produced a adequate fit to the data: χ2(74) = 232.913, p = 0.000; RMSEA = 0.047 ; CFI = 0.944; TLI = 0.909; SRMR = 0.061. Compared to the initial model, the fit of the re-specified model was significant: χ2Diff(6) = 291.55, p < 0.001. Therefore, the re-specified model was used as the final measurement model. In the Pre-math model, all factor loadings were statistically significant (p < 0.01).The initial fit of the Pre-Math model was inadequate: χ2(144) = 1188.020, p = 0.000; RMSEA = 0.086 ; CFI = 0.721; TLI = 0.632; SRMR = 0.086. The model was re-specified to improve the model fit by correlating error terms for same indicators across the time points . Results showed an adequate fit to the data: χ2(135) = 326.697, p = 0.000; RMSEA = 0.038 ; CFI = 0.949; TLI = 0.928; SRMR = 0.056. Compared to the initial model, the fit of the re-specified model was significant: χ2Diff(9) = 861.323, p < 0.001. The re-specified model was used as the final measurement model. In the Pre-literacy/language model, all factor loadings were statistically significant (p < 0.01).The test of the initial fit was inadequate: χ2(80) = 558.490, p = 0.000; RMSEA = 0.078 ; CFI = 0.812; TLI = 0.718; SRMR = 0.064. The model was retested after the re-specification by correlating error terms for same indicators across the time points . The resulting model fits were satisfactory: χ2(74) = 250.673, p = 0.000; RMSEA = 0.050 ; CFI = 0.931; TLI = 0.888; SRMR = 0.059. Compared to the initial model, the fit of the re-specified model was significant: χ2Diff(6) = 307.817, p < 0.001. The re-specified model was used as the final measurement model. The task behavior model indicated that all factor loadings were statistically significant (p < 0.01).The initial fit of the task behavior model was inadequate: χFigure 1 for full hypothesized model). All hypothesized paths were included in our test of the full structural model, which included preschool EF, SE, and academic achievement as potential mediators of the relation between the SSEL intervention and the ESI kindergarten readiness scores. Next, the model was trimmed to eliminate non-significant paths. The final models show all statistically significant paths.The structural model was conducted to explore the cross-lagged relationship between EF and SE and the intervention effect on kindergarten readiness through preschool EF/SE, early academic performance, and task behavior (see 2(90) = 252.855, p < 0.001; RMSEA = 0.043 ; CFI = 0.943; TLI = 0.924; SRMR = 0.064. In terms of the longitudinal model testing the relations between EF and SE across time, all paths were statistically significant except the correlation between EF and SE in spring. Both EF and SE were stable across time  and the synchronous correlation between EF and SE in fall was significant . The significant cross-lagged paths between EF and SE  allowed the inference of temporal precedence of EF to SE and vice versa. Preschool spring SE was directly related to ESI kindergarten  .Results of the Pre-math model displayed an adequate fit to the data: χp < 0.001), spring EF positively influenced spring Pre-math , and in turn, spring Pre-math positively predicted ESI in kindergarten . Model results showed the total effect and the direct effect were not significant . However, as p < 0.05), suggesting that the intervention was effective in promoting children’s kindergarten readiness indirectly via gains in EF and Pre-math skills in preschool.Overall, the model showed that controlling for baseline, the intervention directly and positively influenced preschool spring EF  indicated that fall EF significantly predicted spring Pre-math. In fact, fall Pre-math did not significantly predict spring EF in either the reverse model or the full model. Taken together, these analyses suggest that while the direction of effects between spring EF and spring Pre-math cannot be definitively determined due to their concurrent assessment, the cross-lagged relation supports the direction of effects from EF to Pre-math.Finally, given that both EF and Pre-math were assessed at the same time point and cannot be definitively causal in relation to one another, we further investigated whether the path from spring EF to spring Pre-math as hypothesized by the ToC, was justifiable (as opposed to spring Pre-math predicting spring EF). This was explored by comparing a series of cross-lagged models and examining the chi square difference between them to determine the best model fit. In each model, we correlated all fall variables  and all spring variables . Four models were compared. In the first baseline model, EF and SE in the spring were each predicted by their own and each other’s score from the fall, but spring Pre-math was only predicted by fall Pre-math. In the second model, the forward model, we replicated the first model but added paths from fall EF and fall SE to spring Pre-math. In the third model, the reverse model, we again replicated the first baseline model but instead of paths from fall EF and SE to spring Pre-math, paths were tested from fall Pre-math to spring EF and spring SE. The fourth model, the full model, had all fall variables predicting all spring variables. In this exploratory 2(153) = 367.241, p < 0.001; RMSEA = 0.038 ; CFI = 0.943; TLI = 0.929; SRMR = 0.059. In terms of the longitudinal association between EF and SE, we found that all paths were significant except the cross-lagged path from preschool fall SE to preschool spring EF and the correlation between preschool spring EF and SE. Both EF and SE were stable across time  and the synchronous correlation between EF and SE in preschool fall was significant . The significant cross-lagged path  indicated that later SE was predicted by early EF. In addition, preschool spring SE directly predicted ESI kindergarten  .Results of Pre-literacy/Language model exhibited an adequate fit to the data: χp < 0.01), with children in the intervention group showing higher levels of preschool spring EF than those in the control group. Further, preschool spring EF promoted spring Pre-literacy/Language , which in turn, positively influenced ESI in kindergarten . In this model, the total effect and the direct effect were not significant , while the indirect effect from intervention to ESI kindergarten via preschool spring EF and Pre-literacy/Language was significant . The results showed that the intervention influenced children’s kindergarten readiness indirectly through improvements in EF and Pre-literacy/Language in preschool.Again, we found that SSEL participation directly influenced preschool spring EF  nor the models with Pre-literacy Language predicting EF (models 3 and 4) fit the data as well as the simpler model where fall Pre-literacy Language predicted spring Pre-literacy/Language. This suggest that when it comes to Pre-literacy/Language, the causal path from spring EF to spring Pre-literacy/Language may not be valid. Although EF and Pre-literacy/language are correlated in the spring, we cannot from this follow up analysis, have confidence that gains in EF led to gains in Pre-literacy/Language. Therefore, the indirect effect of SSEL on kindergarten readiness through EF and Pre-literacy/Language may also not be justified.2(89) = 261.331, p < 0.001; RMSEA = 0.045 ; CFI = 0.932; TLI = 0.909; SRMR = 0.063. With regard to the path model of the longitudinal relationship between EF and SE across time, all paths were statistically significant except the correlation between preschool spring EF and SE. Both EF and SE were stable across time  and the synchronous correlation between preschool fall EF and SE was significant . The significant cross-lagged paths between EF and SE  allowed the interpretation of reciprocal association from early EF to later SE and vice versa. A path between preschool spring SE and ESI kindergarten was also significant in this model .The test of the Task Behavior model displayed satisfactory fit to the data: χp < 0.01), spring EF improved spring task behavior , and in turn, spring task behavior positively predicted ESI in kindergarten . Model results showed no significant total and direct effects , however, the indirect effect from intervention to ESI kindergarten via spring EF and spring task behavior in preschool was marginally significant  .As with the previous models, SSEL directly and positively influenced preschool spring EF  and examining the chi square difference between them to determine the best model fit. Chi square analyses showed that the second model (the forward model) had the best fit, and the final significant paths in this model (as well as the full model) indicated that fall EF significantly predicted spring Task Behavior. In fact, fall Task Behavior did not significantly predict spring EF in either the reverse model or the full model. Taken together, these analyses suggest that while the direction of effects between spring EF and spring Task Behavior cannot be definitively determined due to their concurrent assessment, the cross-lagged relation supports the direction of effects from EF to Task Behavior.This study examined the direct and indirect effects of the SSEL curriculum on kindergarten readiness guided by the curriculum’s theory of change (ToC). As of 2016, SSEL was being used by an estimated 7,900 preschool classrooms each year . While widely used and grounded in a strong theoretical and empirical base, to date, our study has been the only published randomized trial of its effectiveness  were making a concerted effort to focus on SE skills, based on newly passed state regulations . SSEL had a marginal impact on SE in the first cohort , and perWhile we also did not find that SE was directly related to academic growth in preschool, it was directly related to gains in on task behavior, and had direct effects on kindergarten readiness across all three preschool models , emphasizing its critical importance in preschool education. The literature base is mixed in regards to SE’s effects on academic outcomes, with some finding direct effects , some fir = 0.24) indicating the importance of basic reading skills for kindergarten readiness, and the need to promote pre-literacy/language skills in preschool. It is possible that teachers in the intervention classrooms may have had less of an emphasis on pre-reading or pre-math skills than control classrooms who were not asked to implement a new curriculum. While SSEL includes reading a book about the weekly theme at the end of the week and encourages teachers to link SSEL learning with other curriculum goals , it is not designed to directly build pre-reading or pre-math skills. SSEL is intended to be integrated into program goals and support curriculum standards . As such, other skills building such as literacy and numeracy also need to be continued. However, while further study of the long-term school impacts of SSEL is warranted, it appears all too common that gains from interventions by at-risk preschoolers fade out in later schooling, perhaps because of what kindergarten and elementary school teachers emphasize, or because of entrance into poor quality classrooms overall . Further, our results were congruent with the results of other similar curricula. For instance, in a large randomized trial in Head Start classrooms comparing The Incredible Years, Preschool PATHS, and Tools of the Mind curricula to control classrooms, none of the interventions had direct effects on individually assessed preschool academic skills or teacher-rated kindergarten outcomes . In fact overall .This study has a number of strengths. It includes a large, diverse sample of low-income children in both Head Start and community preschools. It also relies on individual child assessments by staff blind to study goals and condition and follows children into kindergarten, obtaining kindergarten readiness scores from school records. However, the study also has several limitations. First, as mentioned previously, the design of the study , does not allow us to draw conclusions regarding direction of effects between the measures within the same time point. The overall study was not initially designed to test the ToC, but rather to test the efficacy of the curriculum to improve preschool and kindergarten outcomes, and was not funded to enable individual testing of children beyond preschool. However, other similarly designed studies have tested and reported mediational models with concurrently assessed measures e.g., , and ourA second limitation is sample size at the kindergarten follow up. Only children entering the study during the first 3 years were followed into kindergarten, and there were a sizeable number of children for whom we were not able to obtain school kindergarten screening data. It is possible that a larger sample at the kindergarten time point may have improved power; however, it is unlikely that it would have changed the direction of effects or mediational paths, since data were shown to be MCAR. While a larger sample and increased power may have resulted in direct effects on pre-academic and kindergarten readiness outcomes, it is also possible that, similar to other intervention studies e.g., , SSEL doA third limitation of this study is that randomization of classrooms occurred in years 1 and 3 (the 1st year of each cohort), but in year 2, program administrators placed children in classrooms as needed, which could have introduced bias  possibly biasing effects downward. Finally, since the task behavior ratings were based on the child’s behavior during the assessment of the other skills, rather than on teacher report, the relation between task behavior and individually assessed SE and EF may be inflated.Overall, SSEL appears to have the expected effect on EF and the expected paths to kindergarten readiness are supported by this study. Future research with broader populations, and attention to not only the implementation of SSEL, but to other curriculum or instruction , as well as following children beyond kindergarten entry is needed to fully understand the short and long-term impact that this curriculum has for children at socio-economic risk. However, SSEL appears to hold promise for improving school readiness and addressing the achievement gap for disadvantaged children by increasing EF with resulting improvements in pre-academic skills (particularly pre-math) and on-task behavior, leading to school readiness.This study was carried out in accordance with the recommendations of ‘the Human Research Protection Program, Internal Review Board of the University of Massachusetts Medical School.’ The protocol was approved by the Internal Review Board of the University of Massachusetts Medical School.CU and MW-G conceptualized and implemented the study. MW-G wrote the introduction, methods and discussion sections of the manuscript. YY contributed to the coaching of teachers, conducted the data analyses, and wrote the data analyses and results sections. CU assisted in conceptualization of the manuscript and methods, and provided detailed editing of the full manuscript. AG provided significant guidance on the statistical analyses, conducted and reported the results of the follow-up Monte Carlo simulation tests, and assisted with the interpretation and write up of the results.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.


Background: As the principal means of reimbursing medical institutions, the effects of case payment still need to be evaluated due to special environments and short exploration periods, especially in rural China. Methods: Xi County was chosen as the intervention group, with 36,104, 48,316, and 59,087 inpatients from the years 2011 to 2013, respectively. Huaibin County acted as the control group, with 33,073, 48,122, and 51,325 inpatients, respectively, from the same period. The inpatients’ information was collected from local insurance agencies. After controlling for age, gender, institution level, season fixed effects, disease severity, and compensation type, the generalised additive models (GAMs) and difference-in-differences approach (DID) were used to measure the changing trends and policy net effects from two levels (the whole county level and each institution level) and three dimensions . Results: At the whole-county level, the cost-related indicators of the intervention group showed downward trends compared to the control group. Total spending, reimbursement fee and out-of-pocket expense declined by ¥346.59 (p < 0.001), ¥105.39 (p < 0.001) and ¥241.2 (p < 0.001), respectively (the symbol ¥ represents Chinese yuan). Actual compensation ratio, length of stay, and readmission rates exhibited ascending trends, with increases of 7% (p < 0.001), 2.18 days (p < 0.001), and 1.5% (p < 0.001), respectively. The intervention group at county level hospital had greater length of stay reduction (¥792.97 p < 0.001) and readmission rate growth (3.3% p < 0.001) and lower reimbursement fee reduction (¥150.16 p < 0.001) and length of stay growth (1.24 days p < 0.001) than those at the township level. Conclusions: Upgraded case payment is more reasonable and suitable for rural areas than simple quota payment or cap payment. It has successfully curbed the growth of medical expenses, improved the efficiency of medical insurance fund utilisation, and alleviated patients’ economic burden of disease. However, no positive effects on service quality and efficiency were observed. The increase in readmission rate and potential hidden dangers for primary health care institutions should be given attention. With people’s increasing awareness and need for accessible medical services, the prevalence of chronic diseases and the increasing trend of aging, among other factors, rising health expenditures have become a financial challenge for many countries and have increased patients’ economic burden of disease. In 2016, about one-third of OECD (Organisation for Economic Cooperation and Development) countries’ health expenditure accounted for 11% of their GDP (Gross Domestic Product). In the United States, the proportion of health expenditure is as high as 17.2% and may reach 19.6% in 2024 . SolvingGiven the information asymmetry and the absence of a cost control mechanism in the medical service system, the fee for service payment is more inclined to encourage supplier-induced demand, which is widely considered as the main reason for the inexorable growth of health expenditure . TherefoDuring implementation, case payment can be roughly divided into two versions. The elementary version sums the total medical expenses that cover the entire treatment process of a single disease , such asWith universal health insurance coverage (which accounted for 96.3% of the population in 2014 ) and impPrevious studies on the policy effects of case payment in rural China obtained contradictory conclusions on cost control because of the limitations of the elementary version ,23. MoreHenan Province is a highly populous province and has the largest agricultural area in China . Its resEven in situations where patients have the same disease, the costs may be different because of diverse conditions. Therefore, the local insurance department divided diseases into three categories according to their condition: simple , complex (with complications that need to be treated), and extremely complex . Consequently, medical institutions combined the current service capability and treatment norm to perform “localisation” adjustment on the basis of the national clinical pathway. The final A/B/C path  was developed upon the approval of health administrative and insurance departments. The proportion of the three paths was set to 7:2:1 according to “the law of large numbers”  of diseaTo safeguard the effectiveness of the cost control measure, medical institutions and insurance department negotiated expenses based on the localised pathway. A certain profit margin was set to ensure the successful implementation of payment reform . Ultimately, the total spending, reimbursement fees and out-of-pocket expenses were determined for each path of the disease.The reform was implemented throughout Xi County in January 2012 . Therefore, we used 2011 as the baseline period after excluding the few inpatients who were compensated through the upgraded model. To increase the reliability of the results, Huaibin County was chosen as the control group for three reasons. Firstly, its geographic proximity see  and popuWe intend to assess the effects from two levels  and three dimensions :Although the county hospital and the township health centre can provide inpatient services, each of them has an explicit and relatively distinguished functional orientation. Township health centres play a pivotal role between village clinics and county hospitals and are responsible for primary care service of common diseases. County hospitals are the leaders of the three-tier health care delivery system in rural China and are committed to curative care for more complex diseases . HoweverThe original purpose of case payment is to control costs, but its impact on efficiency and quality determines the achievement of its social goal. In the cost dimension, to make the result more specific, we analysed the effects on reimbursement fees, out-of-pocket expenses, and compensation ratio aside from total spending. The changes in length of stay before and after the intervention was compared to verify their effects on efficiency. The indicator of readmission within 30 days was determined to examine the effects on quality. All outcomes were calculated for every individual per inpatient visit . The covThe difference-in-differences model (DID) is a scientific tool that is commonly used to evaluate intervention effects . HoweverGAMs, as semi-parametric extensions of generalised linear models, are applied to establish a relationship between the mean of the response variable and a “smoothed” function of the explanatory variables. Moreover, GAMs can deal with nonlinear and nonmonotonic relationships between the response and the set of explanatory variables with a link function . Few stuhttp://www.R-project.org, The R Foundation, Mountain Ave, Murry Hill, NJ, USA) was used for all analyses. Results are reported with two-tailed p-values.To verify the trends reflected by the splines generated in GAMs and obtain more precise results, we adopted a DID using multivariate linear regressions, adjusted for covariables and time effects. In this part, three independent variables served as policy intervention indicators . Given the hysteresis effects, a post-policy indicator was assigned as 0 for the pre-intervention period (between 1 January 2011 and 31 December 2011) and 1 for the post-intervention period (between 1 January 2013 and 31 December 2013), and their interaction term. The price index of rural health care was used to calibrate all spending figures according to 2013 Chinese yuan values . The sofThe research methods and investigation tools in this study were approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (IORG No: IORG0003571).For consistency with DID analysis, At the whole-county level, the intervention of upgraded case payment resulted in evident changes among the independent variables of the intervention group . Unlike At the county hospital level, the changing trends of independent variables in intervention group were similar to those of the whole county level except for reimbursement fee, which grew consecutively and rapidly over the analysis period . The lenAt the township health centre level, the cost-related indicators in intervention group all showed a decline trend . Total sp < 0.001), which amounted to a 21.63% decline. The contribution of out-of-pocket expense (reduction of ¥241.2 p < 0.001) was higher than that of reimbursement fee . Therefore, compensation ratio increased by 7% (p < 0.001). However, the ungraded case payment reform led to an increase in length of stay and readmission rate by 2.18 days (p < 0.001) and 1.5% (p < 0.001), respectively.The estimation at the whole-county level showed the effectiveness of cost control : the totp < 0.001); the out-of-pocket expense faced the largest decline of ¥792.97 (p < 0.001), which was much greater than that of the whole county and township health centre levels. Compensation ratio increased the most with 14.4% (p < 0.001). The length of stay and readmission rate at the county hospital level also increased by 1.24 days (p < 0.001) and 3.3% (p < 0.001), respectively.The impact of cost control on total spending at the county hospital level was more apparent, with a reduction of ¥943.14 or a 57.88% decline. The reduction of reimbursement fee was slightly higher than that of the whole-county level, which was ¥150.16 (p < 0.001) and ¥818.22 (p < 0.001) at the township health centre level. The change in out-of-pocket expense was significant but lower than that of the county hospital level, with a decline of ¥402.34 (p < 0.001). Compensation ratio also increased by 13.7% (p < 0.001). Length of stay had the largest increase of 4.45 days (p < 0.001), and readmission rate showed an insignificant reduction of 0.5% (p = 0.185). This result may be due to the fact that the increase of readmission rate at the whole-county level was caused by county hospitals.Total spending and reimbursement fee had the biggest drop of ¥1220.55 ; the reduction degrees were 21.63%, 57.88%, and 108.53% at the whole county, county hospital, and township health centre levels, respectively (from DID estimation). However, our findings were inconsistent with two previous studies that also focused on Xi County payment reform; they believed that the reform failed to curb the cost growth, and total spending per capita continued to increase . Three rWith the enhancement of insurance funding, the annual premium per enrolee for the New Cooperative Medical Scheme was raised from ¥30 in 2003 to ¥570 in 2014. We can speculate that reimbursement fee should show an upward trend but still cannot keep up with the rising speed of expenditures, which caused an imbalance in the funding pool ,44. FiguThe value of out-of-pocket expense can indicate patients’ economic burden of disease and shows an increasing trend with the rapid growth of health expenditures. Despite fluctuations, the out-of-pocket expense of the control group increased continually, whereas the out-of-pocket expense at the whole-county and county hospital levels of the intervention group showed a considerable downward trend even when it increased slightly in the second year. The out-of-pocket expense at the township health centre level declined steadily. The DID results were consistent with the GAMs: The county hospital had the largest reduction of ¥792.97, and the township health centre also dropped by ¥402.34. The reform has effectively alleviated inpatients’ economic burden in Xi County. However, this situation may lead to a hidden danger: aggravation of the previously mentioned issue of irrational medical service utilisation, which showed that patients tend to seek higher-level medical institution’s services instead of what they actually need. County hospitals have solved numerous diseases under township health centres’ service capacity , therebyWhether in rural or urban areas, medical institutions, especially high-level hospitals, are trying to shorten length of stay as much as possible and increase bed turnover to gain more benefits. The analysis results for the control group confirm this phenomenon. However, after the implementation of the upgraded case payment reform, the length of stay of the intervention group increased by 2.18 days, and the growth at the township level was higher than that at the county level. This phenomenon may be caused by the implementation of clinical pathways: physicians cannot decide patients’ discharge according to their clinical experience anymore. Rather, they must provide standard services every day based on the clinical path regulations, and they must consent to discharge only when the patients’ clinical condition meets the discharging indications within the specified time. Doing otherwise will be considered a violation, thereby affecting the compensation amount they receive.Although the length of stay of the intervention group manifested a rising trend, we cannot conclude that the service efficiency was reduced, which should combine the changes of quality. The county-level readmission rate of the control group showed no obvious change, whereas that of the intervention group increased significantly. This result may be caused by decomposing hospitalisation, which is a disguised trick of medical institutions who aimed to obtain more insurance compensation . TherefoOur study has several limitations. Firstly, we selected only one county as the intervention group and one county as the control group; both counties are located in one province. Thus, our results may not be generalisable to other counties in rural China. However, the reform in Xi County is representative across the country, and many counties have begun to follow suit. In the context of national promotion of case payment, our research offers reference value for other counties. Secondly, our analysis period lasted from 2011 to 2013 only because of the payment reform in the control group. Finding a county that maintains a unified payment method for a long time is difficult because the vast majority of regions in China are exploring payment reform. Meanwhile, study results confirmed the effectiveness of cost control of the upgraded case payment model and discovered some potentially hidden dangers that will guide future reform. Thirdly, although the reform is aimed at inpatient services, the study can perform a more comprehensive evaluation if it determines whether the reform leads to service transfer to outpatient, which is a subject of concern for future studies.In general, the upgraded case payment reform successfully curbs the growth of medical expenses, improves the efficiency of medical insurance fund utilisation and alleviates patients’ economic burden of disease. Considering the complexity of the disease makes the payment design reasonable, and applying the clinical pathway improves the accuracy of cost calculation and can regulate and guide medical services. This payment reform provides a good inspiration for regions where DRGs are unavailable, especially in rural areas. A detail that should be noted is that the reform did not play a positive role in service quality and efficiency at the whole-county level. Moreover, the increase in readmission rate is an urgent problem that needs to be solved by health administration and medical insurance departments. In addition, the reform has resulted in insurance expenses being directed to county hospitals and may cause patients to opt for treatments at county hospitals. These phenomena go against the long-term development of primary healthcare institutions. Future payment reform should pay more attention to the health service delivery system, particularly with respect to cost, quality, and efficiency.