To determine whether the nationwide program ‘Reducing maternal mortality and eliminating neonatal tetanus’ contributed to the rapid decline in China’s maternal mortality ratio (MMR) and neonatal tetanus elimination by enhancing hospital delivery, we compared MMR and neonatal tetanus incidence rate (NTR) reductions by province from 2000 to 2013. The difference-in-difference method was used to analyze the program effect. Long-term effects were analyzed relative to MMR and NTR in 2000 and 2002, respectively, while short-term effects in a given year were analyzed relative to MMR and NTR in the preceding year. The national program was associated with a faster decline in MMR in the long term. The rate of decline showed an inverse ‘U’ shape from 2000 to 2013, peaking in 2009. The program had a short-term effect in MMR reduction in 2005, 2007, and 2009. The program was also associated with faster decline in NTR in the short term at some time points, but this association was not consistent and was not found in the long term. In conclusion, the program accelerated decline of MMR from 2000 to 2013 but did not clearly reduce NTR at the province level. Therefore, this targeted program worked efficiently in resource-poor areas. Unfortunately, the global 2015 goal for the reduction in maternal mortality was not met. A World Health Organization (WHO) report released at the end of 2015 showed that the global maternal mortality ratio (MMR) fell by 44% from 385 to 216 deaths per 100,000 live births between 1990 and 2015, which fell short of the 75% decline stipulated in Millennium Development Goal 5 (MDG 5)2. In addition, no region of the world achieved that. Reducing maternal mortality in resource-scarce areas such as Africa and remote areas of China is even more difficult.Reducing maternal mortality is challenging. It requires comprehensive changes in policy support, health financing, health workforce, health infrastructure and maternal care coverage3, which is less than the 5.5% that WHO estimated to be needed in order to achieve MDG 5. One of the challenges to reduce maternal death in China is the regional inequity in healthcare infrastructure and access. For example, MMRs are nearly three times higher in western areas than eastern areas4, and the annual MMR reduction in western areas was only half that in eastern areas3. Estimates suggest that more than 95% of maternal deaths in western areas and 76% in eastern areas are preventable, with obstetric hemorrhage accounting for 59% of preventable maternal deaths in western regions and 35% in eastern regions5.Annual MMR reduction rate in China was only 2.8% from 1996 to 19996. However, a study of 30 counties from six provinces in China found that the average neonatal mortality rate was 22‰ in 1996. Of the neonatal deaths, 16.3% were attributed to neonatal tetanus, and this was still the third most frequent cause of neonatal death in 1996. In total, 89% of tetanus-related deaths involved births at homes, where family members assisted7. These deaths would have been preventable if the births had occurred with skilled attendants under disinfected and sanitary conditions.In addition to reducing maternal mortality, the Chinese government also aimed to reduce neonatal death. The Plan for China's children's development in the 1990s, which was released in 1992, stated that China aimed to decrease MMR by 50%, decrease neonatal mortality by 33% by 2000, and eliminate neonatal tetanus by 19958.In order to reduce preventable maternal and neonatal deaths, the Chinese government launched the nationwide program ‘Reducing maternal mortality and eliminating neonatal tetanus’ in 2000. The goal of this program was to reduce the national MMR and neonatal tetanus incidence rate (NTR) in remote, poor areas in the central and western parts of the country. The program aimed to increase hospital births and provide skilled attendants and disinfectant birth environment. It involved eliminating the ‘four inaccessibilities’: (1) eliminate the culture inaccessibility, by providing health education to maternal and child health (MCH) workers and women of reproductive age and their families. Health education aims to persuade women to give birth in a hospital. It includes information on maternal health, the benefits of hospital delivery, and possible risks of traditional delivery; (2) eliminate economic inaccessibility by providing financial assistance to poor families for hospital births; (3) eliminate territory inaccessibility by providing maternal emergency centers, referral networks and ‘green channels’ for first aid; and (4) eliminate service inaccessibility, by training grass roots clinicians or sending them to provincial hospitals for further training. Training was mainly provided for midwifery skills, including manual removal of the placenta, repair of vaginal lacerations, cesarean section, and first aid skills. Besides, the program also provide basic and emergency obstetric equipment, blood supplies and medicine to village, township and county medical hospitals to improve the quality and accessibility of obstetric services11. Therefore the present study examined the program’s outcomes at provincial level in both the short and long terms.It is likely that this nationwide program helped reduce MMR and NTR in China; however, most studies focused on county-level outcomes and did not examine later stages of the programThis government-initiated program was started in 2000 in 378 counties across 12 provinces where MMRs were > 80 per 100,000 live births . In 2004, the program was expanded to include another 62 counties in Jilin, Hubei, Guangxi, Shaanxi and Xinjiang provinces and was expanded again in 2005 to another 560 counties from Hebei, Shanxi, Heilongjiang, Anhui, Henan, Hainan and Xinjiang provinces. Except for resource-rich provinces along the east coast, the program included all provinces by 2005. In 2008, 182 counties were added to the program. The program included all counties in the enrolled provinces for a total of 2,288 counties from 22 provinces by 2010. Starting in 2014, the program was integrated into the National Essential Public Health Programs (NEPHPs), which subsidized hospital births to ensure long-term effects. Figure 12.Data on provincial MMRs were collected through China’s Provincial MCH Surveillance system (PMCHSS) from 2000 to 2013. No data were available for 2001. MMR was calculated as The PMCHSS is a five-level network that involves villages, townships, counties, municipalities, and provinces. Data on the numbers of live births and deaths in women of reproductive age in the village are initially collected by village doctors who are responsible for health management. The village doctors then report the data to township MCH workers. The process for data collection is as follows: data are collected from township MCH institutions by provincial MCH institutions level by level. The accuracy of number of live births and maternal deaths, as well as authenticity of cause of maternal death, are checked before being reported to higher levels. Most provinces have electronic reporting systems and collect data online. The provincial MCH institution finally report the maternal death and live birth data to the National Office for MCH Surveillance every year using a standardized form.Cases of maternal death and deaths in women of reproductive age are required to be reported to township MCH institutions within 24 h by village doctors. The deceased woman’s family members are visited by an obstetrician or MCH worker from the township hospital within three days to inquire about the cause of death and to determine if the woman was pregnant. If the woman was pregnant, relevant information is reported to MCH institutions at county level. MCH staff at county then conduct a further, more comprehensive investigation that includes collecting information from family members, midwife, anesthetist, fellow physicians and nursing staff of the deceased woman through standardized forms, and by obtaining a copy of the medical records. Standardized forms are completed within seven days and submitted to the commission at county level.3.All maternal deaths are reviewed by the relevant commission at county, municipal, and provincial levels. After reviewing the deaths, the commission first determines whether they met the criteria for a maternal death and then identifies the main cause of death, factors that contributed to the death, and preventive measures that were subsequently implemented. The death review results are submitted to the National Office for MCH Surveillance, which reviews the data to rectify possible errorsTo ensure the quality of collected data, all the data go through a quality control process each year. The quality control process, which aims to investigate missing reports and data quality, is multisource and multilevel. All the data and information for deaths of woman in reproductive age from hospitals, Centers for Disease Control (CDC), police and crematoriums are collected and cross-checked. After excluding reported maternal deaths and deaths of women who were not pregnant, the remaining possible maternal death cases are investigated by inquiring the hospital or local community to determine the cause of death. If deaths was confirmed as pregnant woman, a supplement or missing case report is initiated. The quality control procedures occur from bottom to top, starting at the county level, then progressing to municipality, province, and national levels. Quality control procedures occur once per year at provincial and national levels, four to six times per year at county levels, and twice per year at all other levels. There is a permitted threshold of < 15% missing reports for maternal deaths and < 10% for live births. If the reported data fails to meet the requirements during the quality control procedure at each level, MCH institutions reinvestigate the missing report and resubmit reports to meet requirements. When quality control occurs at each level, the missing report rate is approximately 5%, which is far below the permitted threshold.The data collection and quality control details are shown in Fig. NTR data at provincial level was collected through the yearbook of National Health Statistics from 2002 to 2013. Data were not available for 2000 or 2001. NTR data at county levels from 2000 to 2013 were collected from the ‘Reducing and Eliminating’ program and quality control measures information as described above for PMCHSS.Data on the following covariates were collected through the yearbook of China Statistics from 2000 to 2013: licensed physicians per 1,000 people, illiteracy rate, regional GDP (Gross Domestic Product), and miles of highways per 1,000 miles.13.Neonatal tetanus elimination was a binary variable and was defined as less than one neonatal tetanus case per 1,000 live births at district level, in accord with WHO criteriaThe program’s effects were analyzed for the long-term effects on reducing maternal death and neonatal tetanus , the short-term effect on reducing maternal death and neonatal tetanus , and the trend in neonatal tetanus elimination among counties in the program .15. To control for other potential confounders, analyses were conducted with the following covariates: licensed physicians per 1,000 people, illiteracy rate, regional GDP and miles of highways per 1,000 miles.Provinces outside the program were used as the control. In the long-term analysis, MMR in 2000 and NTR in 2002 were taken as the baseline. In the short-term analysis, MMR and NTR in the year before the year being analyzed were used as the baseline. The difference-in-difference method (DID) was used for the long- and short-term analyses. This method uses data from before and after the intervention and controls to assess the program’s effects while avoiding selection biasUit is the MMR or NTR of province i at time t, βpost and βexp are binary variables indicating whether the province I was in the postinclusion period or was or was not enrolled in the program at time t, the interaction is for the DID estimates, and Xit captures the covariation of province i with time t.The model used for long- and short-term analysis can be summarized as.Provinces were categorized into four groups according to whether they were never included in the program (group g0) or were included in 2000 (g1), 2004 (g2) or 2005 (g3). Box plots were used to illustrate the dispersion of MMR and change in MMR over time.Logistic regression was used in the elimination analysis to examine neonatal tetanus elimination. A binary variable of neonatal tetanus elimination at county level served as the dependent variable in the model; year, as the independent variable; and hospital birth rate, as the covariate. The Mantel–Haenszel test was used to analyze neonatal tetanus elimination trends from 2000 to 2013.yit = αi∗ + βixit + uit, where MMR or NTR at county level was the only independent variable, MMR or NTR at provincial level was the dependent variable, and all other variables were assumed to be uncorrelated and invariant through different time and units. The county contribution was estimated using R216.We also analyzed how much individual counties participating in the program contributed to provincial MMR and NTR reduction. The model of panel data analysis was SAS 9.4  was used for data analysis, and significance was defined at the 0.05 level.β = − 54.03, P = 0.0036). In the short-term analysis, the program significantly reduced MMR in 2005 , 2007  and 2009 .Table Figure The annual data in Fig. β = − 0.26, P = 0.0140).Table Z = − 39.76, P < 0.0001). The rate of hospital births increased from 55.2% in 2000 to 99.2% in 2013 in counties included in the program. This increasing rate was associated with a significant increase in neonatal tetanus elimination at county level .Table R2 values of 0.1569 , NTR had already fallen to low levels . In addition, the NTR may be relatively high in some counties, but low at provincial level. While NTR varied largely between provinces , the program aimed to eliminated the NT at county level, Therefore, it is even harder to achieve statistically significant results at provincial level. These findings were confirmed by another study that compared the NTR between program counties and counties outside the program and showed that the program significantly reduced NTR in the early years of the program23, but their MMR reduction from 1990 to 2015 was smaller than China’s24. Although both countries provided birthing facilities and offered economic incentives for mothers, Nepal did not initially target disadvantaged areas. In contrast, China initially introduced the program to impoverished counties with the highest MMRs in 2000, then expanded the program in 2004 and 2005. This suggests that interventions aimed at the most vulnerable areas can have impressive effects25.China’s success in reducing MMR may reflect its decision to focus efforts on disadvantaged areas from the beginning. Nepal, like China, implemented a targeted program to address high maternal and neonatal mortality16.Our study is one of the first to separately assess the national program on its long and short term effect separately. In addition, we also assessed the program effect over its whole lifespan from 2000 to 2013. However, there were still limitations to this study, including the lack of NTR data from counties that were not in the program and the lack of baseline data from provinces before their inclusion in the program. In addition, by failing to take into account potentially relevant variables such as institutional first aid capability and first aid equipment quality, our analysis may overestimate the contribution of each county to provincial MMR and NTR reduction26 and the MMR in 2019 is 17.8 per 100,000 live births27. Available evidence suggests that the program has paid off for MMR reduction not only in China but in all of East Asia. This is because China accounts for roughly 85% of the population in East Asia, and the great reduction in MMR of China contributed to the reduction in the entire region, which had the second largest MMR reduction in the world2. The program has supported maternal and child health in impoverished areas in China through health education, training, infrastructure and financial incentives. In addition, it has helped change attitudes about giving birth in a hospital, where mothers have access to hygienic conditions and medical assistance when necessary. These experiences may be useful for other countries, especially those in resource-poor areas that struggle with reducing maternal death and improving perinatal safety.The ‘Reducing maternal mortality and eliminating neonatal tetanus’ program is one of the largest programs in maternal and child health that the Chinese government has funded (approximately 4 billion USD), and is also one of the longest with a lifespan of 13 years. The cumulative effect of the program and sustainment hospital births subsidies  resulted in a current hospital delivery rate over 99% and a steadily decreasing MMR in China. China achieved MDG5 in 2014


Aspergillus sp. TS-A, and the recombinant Lac (69 kDa), MnP (45 kDa) and LiP (35 kDa) were secretory expressed in Pichia pastoris GS115, with enzyme activities of 34, 135.12 and 103.13 U l−1, respectively. Dyes of different structures were treated via the recombinant ligninolytic enzymes under the optimal degradation conditions, and the result showed that the decolourization rate of Lac on Congo red (CR) in 5 s was 45.5%. Fourier-transform infrared spectroscopy, gas chromatography–mass spectrometry analysis and toxicity tests further proved that the ligninolytic enzymes could destroy the dyes, both those with one or more azo bonds, and the degradation products were non-toxic. Moreover, the combined ligninolytic enzymes could degrade CR more completely compared with the individual enzyme. Remarkably, besides azo dyes, ligninolytic enzymes could also degrade triphenylmethane and anthracene dyes. This suggests that ligninolytic enzymes from Aspergillus sp. TS-A have the potential for application in the treatment of contaminants.Ligninolytic enzymes, including laccase (Lac), manganese peroxidase (MnP) and lignin peroxidase (LiP), have attracted much attention in the degradation of contaminants. Genes of Lac (1827 bp), MnP (1134 bp) and LiP (1119 bp) were cloned from  Most Aspergillus  pyrazine-1, 4-dione, hexahydro-3-(phenylmethyl), and l-proline-N-allyloxycarbonyl-tetradecyl ester were detected; (ii) the asymmetric cleavage of the C–N bond, removing N in the aromatic ring, and yielding several intermediate products, such as 9-octadecenamide, (Z)- and phenylethyl alcohol, and p-xylene; and (iii) the breakage of benzene ring opening and the transformation of long-chain compounds into low-molecular-weight and less-toxic stable products, such as butanoic acid, 3-methyl- and 4-methyl-2-oxovaleric acid. The azo and SO3 groups were lost in degradation. Some of these results were found in previous studies. For example, in one study, LiP could mineralize various recalcitrant aromatic and halogenated phenolic compounds [3 group in the CR. The degradation pathway of Lac was similar to that of MnP, and diphenylolpropane was detected, which proves that the CR dye was degraded and mineralized by Lac. The degradation pathway may be as follows: first, the asymmetric cleavage of one N=N bond occurs, then the other N=N bonds are broken. Previous studies have reported that Lac could catalyse the ring cleavage reaction of aromatic compounds [et al. reported a similar pathway involving asymmetric cleavage [For CR degradation, the possible degradation pathway is shown in figure 5ompounds . A similompounds . The degompounds ,15. In tcleavage . This cu3.6.Vigna radiata confirmed the toxic nature of the untreated dye solutions [The decolourization rate of CR degraded by the recombinant enzymes could reach 90% after 24 h . As shown in olutions . Moreove4.Aspergillus sp. TS-A were cloned and expressed in P. pastoris, a system that afforded a relatively high enzyme production. The three recombinant enzymes were found to exhibit strong activities over a wide range of pH and temperature, and the recombinant enzymes showed enhanced activity in the presence of certain metal ions. In addition, the recombinant enzymes also had a fast decolourization ability. The analysis of metabolites proved the degradation and detoxification of the azo dye, and the possible degradation pathways were estimated. The combination of the three recombinant enzymes could provide a highly efficient catalytic reaction system.In summary, Lac, MnP and LiP genes from


The demand for professional training, mentorship, and research in the field of aging is expected to increase remarkably. Recent statistics indicate less than 8% of social work students nationwide specialize in gerontology; however, a significant amount of social work graduates, regardless of their specialization at school, serve older adults in various social and health care settings. As a panel, former fellows present experiences as participants of the AGESW Pre-Dissertation Fellows Program. The program helps students comprehend basic principles of doctoral education and develop strong professional networks with other gerontology-focused colleagues and mentors across the country. Doctoral students are also trained to be competent working with older adults through research, teaching, and professional development. Many fellows move into faculty positions and their accomplishments are varied and impressive. It is difficult to separate these from the education, connections, mentorship, and support received from the AGESW network and through participation in this program.


ARID1A and CTNNB1/β-catenin analysis. The integrated clinicopathologic and molecular approach developed in this study could represent a workable and useful method in routine clinical practice for improving risk stratification and patient management.Translation of the molecular characterization of endometrial cancer into the clinical practice is emerging as a challenge. This study investigates the feasibility and the prognostic impact of the novel surrogate TCGA molecular classification of endometrial carcinoma into the clinical setting proposing an immuno-molecular algorithm supplemented with POLE mutated (POLE) cases; (ii) the hypermutated subtype, characterized by MisMatch Repair deficiency (MMRd); (iii) the copy-number high subtype, with p53 abnormal/mutated features (p53abn); (iv) the copy-number low subtype, known as No Specific Molecular Profile (NSMP). Although the prognostic value of TCGA molecular classification, NSMP carcinomas present a wide variability in molecular alterations and biological aggressiveness. This study aims to investigate the impact of ARID1A and CTNNB1/β-catenin alterations by targeted Next-generation sequencing (NGS) and immunohistochemistry (IHC) in a consecutive series of 125 molecularly classified ECs. NGS and IHC were used to assign surrogate TCGA groups and to identify molecular alterations of multiple target genes including POLE, PTEN, ARID1A, CTNNB1, TP53. Associations with clinicopathologic parameters, molecular subtypes, and outcomes identified NSMP category as the most heterogeneous group in terms of clinicopathologic features and outcome. Integration of surrogate TCGA molecular classification with ARID1A and β-catenin analysis showed NSMP cases with ARID1A mutation characterized by the worst outcome with early recurrence, while NSMP tumors with ARID1A wild-type and β-catenin alteration had indolent clinicopathologic features and no recurrence. This study indicates how the identification of ARID1A and β-catenin alterations in EC represents a simple and effective way to characterize NSMP tumor aggressiveness and metastatic potential.The collaborative Cancer Genome Atlas (TCGA) project identified four distinct prognostic groups of endometrial carcinoma (EC) based on molecular alterations: (i) the ultramutated subtype that encompasses  POLE exonuclease domain mutated (POLE) cases (excellent prognosis); (ii) the hypermutated subtype, characterized by MisMatch Repair deficiency (MMRd) (intermediate prognosis); (iii) the copy-number high subtype, with p53 abnormal/mutated features (p53abn) (poor prognosis); (iv) the copy-number low subtype, also known as No Specific Molecular Profile-NSMP (intermediate prognosis) . iagnosis .POLE group, such as endometrioid-type histology and abundance of tumor-infiltrating lymphocytes. However, MMRd ECs have an intermediate prognosis, which significantly differs from that of the POLE group tumors.The MMRd group (approximately 30% of our cases) shows morphological characteristics similar to those of the Tumors of the p53 abnormal group (approximately 20% in our series) have aggressive histologic characteristics including high grade, non-endometrioid features, and significantly higher FIGO stage. NSMP ECs represent approximately 40% of the cases in our cohort and are predominantly low-grade endometrioid carcinomas with low proliferative activity. Although our results are consistent with literature, the classification into four molecular TCGA groups alone did not achieve statistical significance in prognostic stratification.ARID1A and CTNNB1 mutations and their predictive-prognostic impact with particular reference to the NSMP group.Our study was not limited only to surrogate TCGA subtyping, but it also aimed to investigate the relevance of CTNNB1 mutations/β-catenin abnormal expression (found in approximately 20% of NSMP tumors) identify a subset characterized by young age at diagnosis, high BMI, low mitotic rate, low Ki67 proliferative index, and low TILs counts. As reported in the literature, CTNNB1 mutated tumors are predominantly low grade and low stage, but in our cohort this molecular alteration is not linked to unfavorable prognosis.ARID1A and PI3K mutations promote epithelial transdifferentiation associated with epithelial-to-mesenchymal transition (EMT) [MLH1, ARID1A is a causative, instead of a target gene for microsatellite instability. However, in our MMRd group, ARID1A loss is usually a subclonal event—both by IHC and NGS—suggesting that the alteration of ARID1A follows, instead of preceding microsatellite instability. In our study we have confirmed that ARID1A alterations occur in both MMRd as well as POLE group tumors, while they are inversely related to p53 mutated tumors. In the entire cohort, ARID1A mutated carcinomas are prevalently endometrioid, undifferentiated/dedifferentiated and exhibit histopathologic features such as MELF, presence of TILs and high proliferative index. We have explored the role of ARID1A in the β-catenin altered and NSMP subgroups to determine its impact on clinical features and prognosis. In both subgroups ARID1A alteration is associated with novel and distinctive histological features: (1) in β-catenin altered tumors, ARID1A loss correlates with high histologic grade, necrosis, tumor budding, TILs and high proliferative activity; (2) in the NSMP group, ARID1A mutation correlates with increased proliferative activity and, interestingly, it identified all NSMP with recurrent disease. This remarkable finding can improve the surrogate molecular EC classification differentiating the biological heterogeneity of NSMP tumors and identifying a subset of ECs (NSMP_A) at higher risk of relapse. By integrating conventional ESMO 2016 clinicopathologic criteria and narrowing the analysis to high risk groups, our immuno-molecular classifier implemented with β-catenin and ARID1A alterations proved to be statistically associated with recurrence. In order to test the performance of our immuno-molecular classification with an external case series we tried our algorithm using TCGA data , indicating conformity with TCGA data. However, as also shown in previous studies, surrogate molecular classification is similar to—but does not simply overlap with—the TCGA scheme for endometrial cancer [ARID1A and CTNNB1/β-catenin. In addition, our study has included immunohistochemical analysis for ARID1A on whole slides in order to identify subclones and to guide subsequent molecular sequencing. Moreover, our cases have been enrolled consecutively, without selection bias, from a referral center for gynecologic oncology, with survival time and follow-up different from the TCGA cases. These points may explain some of the differences in survival patterns when our classifier is applied to TCGA data  . These fon (EMT) ,17, suggdata see . The logdata see .POLE/MMRd tumors.The multistep classification approach proposed in our study allows to better discriminate NSMP tumors by the simple addition of two markers to the already known PORTEC/ProMisE algorithms. In particular, the assessment of ARID1A in NSMP group could change the clinical management of these patients: i.e., a closer follow-up could be proposed for an early detection of possible recurrence. In addition, ARID1A is emerging as a potential therapeutic target. Recent studies have showed that ARID1A loss is associated with improved response to immunotherapy across diverse tumor types ,45. ConsARID1A and CTNNB1 status granted a more reliable risk assessment and it resulted to be particularly informative in the group of high-risk patients. Our data indicates that ARID1A analysis may be a useful biomarker to identify patients who have worse prognosis in the NSMP group and may therefore require more aggressive forms of treatment and closer follow-up. The evolution of EC classification from being purely based on morphology, to classification incorporating molecular profile promises for more accurately subtyping endometrial carcinoma to better reflect patient prognosis and outcome. This study confirms the feasibility of surrogate molecular TCGA classification of EC into routine clinical practice. Our immuno-molecular classification scheme supplemented with NSMP tumor sub-grouping based on the However, this classifier does not replace risk assessment based on conventional clinicopathologic parameters that will remain essential in prognostic stratification . It is reasonable that molecular and clinicopathologic prognostic grouping systems will likely work better together.


Evaluation of the degree of concordance between an artificial intelligence (AI) program and radiologists in assessing malignant lesions in screening mammograms.The study population consisted of all consecutive cases of screening-detected histopathologically confirmed breast cancer in females who had undergone mammography at the NU Hospital Group  in 2018 to 2019. Data were retrospectively collected from the AI program  and from medical records (independent assessments by two radiologists). Ethical approval was obtained.p = 0,002).Altogether, 120 females with screening-detected histopathologically confirmed breast cancer were included in this study. The AI program assigned the highest overall malignancy risk score 10 to 86% of the mammograms. Five cases (4%) were assigned an overall malignancy risk score ≤5. Lack of consensus between the two radiologists involved in the initial assessment was associated with lower overall malignancy risk scores (The AI program detected a majority of the cancerous lesions in the mammograms. The investigated version of the program has, however, limited use as an aid for radiologists, due to the pre-calibrated risk distribution and its tendency to miss the same lesions as the radiologists. A potential future use for the program, aimed at reducing radiologists’ workload, might be to preselect and exclude low-risk mammograms. Although, depending on cut-off score, a small percentage of the malignant lesions can be missed using this procedure, which thus requires a thorough risk–benefit analysis.This study conducts an independent evaluation of an AI program’s detection capacity under screening-like conditions which has not previously been done for this program. The detection capacity of the Transpara program has been reported to be comparable to that of radiologists in several studies.4–6 If simultaneously used to aid radiologist’ assessments, the program increases the detection capacity of the radiologist.4 However, cancer rates in the studied cohorts have been high, 25–42%, compared to the expected prevalence of 0.5–0.8% in a population screened for breast cancer.3 Moreover, one of the studies showed that radiologists perform better than the program when the number of false-positive cases was increased.5 Few studies undertake an independent investigation of this and similar program’s detection capacity under real screening-like conditions.1–3TransparaThis study was conducted with the aim of evaluating the degree of concordance between the Transpara program and radiologists in assessing malignant lesions in screening mammograms.A retrospective study design was used, which included consecutive cases of screening-detected histopathologically confirmed breast cancer in females. The females had undergone screening mammography at the NU Hospital Group  during the period of April 23, 2018–March 3, 2019. Cases of interval cancer were not possible to include since the study period encompassed one round of screening only. Two criteria for exclusion were deployed. Firstly, for females with bilateral breast cancers, one side was excluded in order to perform analyses on a patient/examination level. Secondly, cases missing data on the overall malignancy risk score were excluded, which was due to technical unavailability . Having All data were obtained from medical records at the Mammography Department at the NU Hospital Group  and from the Transpara program. Data were collected after mammography had been carried out and assessed both by radiologists and the program. The radiologists’ independent assessments, the female’s age and the pathoanatomical diagnosis were obtained from the mammography records. The overall malignancy risk score, delineation of the lesion and, when available, lesion risk score for the respective mammographic projection were obtained from the program. Lesion delineation by the program was regarded as successful when the program had visually marked the histopathologically confirmed lesion.Mammography screening at the NU Hospital Group  includes two image projections of each breast, one craniocaudal (CC) and one mediolateral-oblique (MLO) view. Mammograms are independently assessed by two radiologists, who categorise the mammography findings as either ”normal” or ”suspected malignancy”. In the next step, two radiologists (who might have participated in the first assessment) reassess mammograms labelled as “suspected malignancy” and determine cases requiring further investigation. These females undergo additional X-ray imaging and ultrasound as well as fine needle aspiration cytology and/or 14-Gauge core needle biopsy. In this study, the breast cancer diagnosis was based on post-operative histopathological analysis of surgically removed tissue and/or core needle biopsy in all cases.4 It can be used either to aid manual assessments or to make independent assessments. The program visually delineates lesions in the mammogram and assigns a risk score in percent for each detected lesion (lesion risk score). Moreover, an overall malignancy risk is obtained (Transpara score). The Transpara score ranges from 1 (low risk) to 10 (high risk) and is distributed in a pre-calibrated manner in which the program is designed to categorise mammograms in ten groups of equal size .Descriptive statistics are given as mean ± standard deviation, median and range for all variables. Percentages were calculated based on the number of patients in the entire study population, if not otherwise stated. Differences between groups and relationships between variables were analysed with Wilcoxon’s Signed Rank test and regression analyses. A two-sided During the study period, 26,373 females underwent mammography in the screening program at the NU Hospital Group , of whom 159 (0.6%) were diagnosed with histopathologically confirmed breast cancer. Bilateral breast cancer was diagnosed in two females. Technical limitations regarding the program’s availability and server storage capacity resulted in exclusion of 39/159 (25%) cases due to missing data on the overall malignancy risk score. Characteristics of the final study population of 120 females and the excluded cases are shown in n = 5), score 8 (n = 2), score 7 (n = 3), score 6 (n = 2), score 5 (n = 1), score 4 (n = 2), score 3 (n = 2).The program assigned score 10 in 103/120 (86%) mammograms . The remp = 0.02, The program successfully delineated the cancerous lesion in 100/120 cases 83%, . The meavs 9.7 ± 1.2; p = 0.002; The cancerous lesion was detected by both radiologists in 105/120 cases 88%, . The AI n = 103) and ≤5 (n = 5) showed a similar distribution of cancer types as the study population as a whole: invasive ductal cancer (72% and 80% vs 70%), invasive lobular cancer (11% and 0% vs 11%) and other cancer types (17% and 20% vs 19%).The distribution of cancer types in the study population is shown in In this study, we have compared the ability of the AI program Transpara to detect malignancy-suspect lesions with that of radiologists in 120 mammograms with screening-detected histopathologically confirmed breast cancer at the NU Hospital Group  in 2018 to 2019.4–6 It is, therefore, reasonable to expect that most cancers in our study would be assigned an overall malignancy risk score of 10. However, that did not correspond with our findings and can suggest deficiencies in the program’s performance when applied to a real screening population. We also found that the same lesion often was assigned a higher lesion risk score in the CC projection than in the MLO projection. This indicates that the program has some built-in systematic differences with respect to image projection. Since AI-based programs are calibrated for the material they have been trained on, clinical usefulness will be impaired if a limited or non-representative case selection is used in its construction or validation process.1,3We found that the program assigned the highest overall malignancy risk score (10/10) in 86% of the mammograms and that the program successfully delineated the lesion in 83% of the cases. Consequently, 14% of the cancer cases were assigned lower scores than 10, although not the lowest scores (1–2) and the lesion was not delineated in 17% of cases. Previous studies have found that Transpara detects malignancy-suspect lesions to an extent comparable to that of radiologists, measured as area under the receiver operating characteristic curve, as sensitivity and specificity or as true positive fractions.3 Three commercially available AI algorithms have recently been subject to an external, independent evaluation in a case–control setting.7 One of the studied algorithms showed a significantly higher performance compared with the other two algorithms, highlighting the importance of construction and training data for external validity. Interestingly, combining the best performing AI with the first reader/radiologist was more successful than combining the first and second readers regarding cancer detection rate, however, at the cost of increasing false-positive cases.7 Another study, also evaluating a different AI program than Transpara, illustrates the complexity both in calibrating and in evaluating AI algorithms based on retrospective data.8 For instance, reasonable cut-off levels must be chosen for the AI assessments  to enable comparison with the human assessments . This study also provides evidence for the potential complementary roles played by AI systems and radiologists, as both are expected to miss a small proportion of cancers, but not necessarily of the same type. However, this study, as well as many other AI evaluations, are limited by the retrospective setting and the lack of follow-up/biopsy-verification of mammograms with AI-detected lesions which were classified as “normal” by radiologists.3,9 This impairs the possibility for evaluation of AI-detected lesions and makes it difficult to determine the amount of actual AI-detected cancers versus false-positive cases.9There is a general need for external validation of AI programs in large representative screening populations.10 If a cut-off score of 5  is applied, scores ≤5 by the program will be regarded as “normal”. The radiologists’ workload would then decrease by 47% while the rate of missed cancer cases would reach 7%.10 In our material, there were five cancer cases (4%) with scores ≤5, which would have been missed if relying on the program alone . Applying an alternative cut-off score of 2 was discussed in the same study,10 which would lead to less decrease in workload (17%) but fewer missed cancer cases (1%). Reducing radiologists’ workload by excluding low-risk cases was also evaluated in a retrospective simulation study concerning another AI program.11 This study concluded that using sole AI assessments in 60–80% of the cases would result in only a proportion of ≤2.6% missed cancers with a substantial workload reduction.11 Moreover, the study showed a potential increase in cancer detection (12% vs 27%) if 1% vs 5% of females with the highest AI risk scores were selected to an enhanced assessment group, which for instance would include supplemental imaging with magnetic resonance tomography.11 In comparison, the Transpara program includes 10% of all mammograms in the top-risk category, potentially leading to a large number of cases selected for radiologists’ assessment or recalls if it is used alone in a real screening population.Another important finding in our study was that lesions missed by radiologists at single-reading were associated with both lower overall malignancy risk scores and with lesion delineation to a lower extent. This is important when discussing the possibility for stand-alone assessments by this and similar programs to reduce workload for radiologists. It has been suggested that Transpara could be used to exclude low-risk cases from the radiologist’s assessment.i.e. cases with a score ≤2. By excluding normal cases, the need for manual double-reading would thereby be reduced.With account to all above-mentioned aspects, remembering that all of the histopathologically confirmed cancerous lesions in our data had an overall malignancy risk score ≥3, a safe alternative (given that this can be confirmed in future studies) would be to only trust the scores for the low-risk group, The main strength of this study is the investigation of cases with screening-detected histopathologically confirmed breast cancer in a large unselected consecutively screened population. The main limitation of this study is the case-only setting which prevents evaluation of false-positive cases and assessment of sensitivity and specificity. The case-only design also risks biasing the study in favour of radiologists. Other limitations include the relatively small study population which resulted from limitations in the program’s availability and server storage capacity and a risk of data collection bias. It cannot fully be ruled out that the radiologists were influenced by the program’s results when making their own assessments. Another minor limitation is not to have included the program’s risk score of any other lesions (in addition to the verified cancers).AI is increasingly utilised in radiology and has now also been available for mammography screening at the NU Hospital Group . Transpara, an AI-based CAD program, detected the majority of cancerous lesions in the mammograms, also assigning high malignancy risk scores. However, the program in the investigated version is of limited use as an aid for radiologists, due to the pre-calibrated risk distribution and its tendency to miss the same lesions as the radiologists. Moreover, our findings indicated an unexpected discrepancy in lesion risk scores between the two studied image projections, which suggests that the program suffers from a systematic built-in difference with respect to image projection. A potential future use for the program, aimed at reducing radiologists’ workload, might be to preselect and exclude low-risk mammograms from radiologists’ assessment. Although, depending on cut-off score, a small percentage of the malignant lesions can be missed using this procedure, which thus requires a thorough risk–benefit analysis.


The purpose of this study is to examine the factors of disaster experience that impact the effectiveness of disaster education on school students (children and teens). Following the magnitude 5.4 Pohang earthquake in 2017, Pohang City Hall conducted a school earthquake disaster education program over a period of four months (August to November) in 2018. Professors and graduate students from the Ulsan National Institute of Science and Technology taught around 5000 middle and high school students, while also conducting surveys. The experiences of the Pohang earthquake were analyzed and divided into cognitive responses and emotional responses. Students who felt activated emotional responses, surprise and fear, but not joy, tended to have more effective educational experiences. On the other hand, unpleasant emotional reactions, such as anger and sadness, had a negative effect on educational effectiveness. The cognitive response, which is perceived intensity in this research, did not impact educational effectiveness significantly. These results imply that the emotional responses of students are more important than their cognitive responses in providing a disaster education program. This means that even though an earthquake may be small in magnitude and may not cause physical damage, we still need to provide immediate disaster education to the children and teens if they are surprised and afraid of future disasters. The frequency of earthquakes in Korea has historically been low, and their size has been relatively small. Therefore, up until 2016, the contents of Korea’s disaster education program did not include how to respond to earthquakes, because people viewed the country as being safe from such incidents. However, two seismic, unprecedented events then took place in Korea. In 2016, an earthquake of Magnitude 5.8 (M 5.8) occurred in Gyeongju, which was followed by the Pohang earthquake of M 5.4 about one year later, on 15 November 2017 see . The disThe seismic waves of the Pohang earthquake shocked the entire population of Korea, causing the Korean government to postpone the National College Scholastic Aptitude Test, which had been scheduled for November 16. Following this decision, Korean schools felt the need to offer earthquake response education to students, and the first steps toward offering earthquake disaster education were put in place . For exaThe effects of disasters can be substantially reduced if people are well-informed about how to respond to them. Disaster education plays an important role in improving students’ disaster awareness and preparedness level . FurtherIn the Republic of Korea, schools and public institutions have provided many different forms of disaster educations. They offer knowledge of hazards, causes of injury, protective actions, and mitigation actions, and these activities can help people improve resilience, survival, and mental trauma recovery. Despite these efforts, many children and teens still either do not know how to respond to disasters  or fail Having disaster experience is one of the key factors affecting an individual’s disaster preparedness behaviors, as people who have experienced disasters either directly or indirectly face different levels of intensity and damage compared to those who have not. In the case of children and teens, it is more important to investigate their emotional reactions to disaster experiences, as such feelings linger in their minds for a long time and affect their subsequent behavior . TherefoThe purpose of this study is to analyze the earthquake experiences of children and teens and evaluate the effects of their experiences on disaster education. Educational effectiveness in this study will be measured using the students’ knowledge level regarding earthquake drills and their levels of training satisfaction.Experiencing a disaster when you have an immature psyche can be more stressful, leaning toward having a negative effect on a young person’s growth. Although the disaster may have occurred a long time ago, children can still remember such events vividly . AccordiVarious forms of disaster education were conducted: lectures ,15,16, dDisaster education can be conducted across several levels. The individual level tends to improve the awareness of the disaster risk, and the community level, including home-based education, increases the adjustment and preparedness activities . HoweverTo provide effective disaster education for children and teens, it is important to determine how the effectiveness of education can be measured. Usually, the measurement indices are devised by methodologies such as surveys, interviews, and observations. These indices include fear and risk perception ,28, disaIn the case of applying new teaching methods, the methods itself were mainly used as factor ,22. AmonHowever, there are not many studies about individual factors that can increase the effectiveness of disaster education, given the importance of individual attributes . This maPrevious studies examined disaster experience as a factor that motivates people to prepare for future incidents ,31. MoreDisaster experience is a major factor in promoting preparedness ,36. ThisHowever, such an experience can also have negative effects on levels of preparedness. For example, experiencing a moderate disaster or less traumatic exposure can cause “a false sense of confidence” or normalcy bias ,37. WhenSeveral attempts have been made to interpret or define disaster experiences, which can be measured using their intensities and the level of physical, emotional, and financial damage inflicted . Becker In this study, the earthquake experiences of children and teens were analyzed using both their emotional and cognitive response. The cognitive response factor includes the participants’ perceived Modified Mercalli Intensity Scale degree. The measurement of the Modified Mercalli Intensity  is a mechanism of intelligent judgement and observation that can be determined by the observation of each case, such as the building or geologic condition . In contIn disaster situations, negative emotions constitute the principal response to risks and threats . HoweverThe common emotional reactions to a disaster are fear, anger, guilt, and sadness . To undeEmotions represent the strongest system for motivating an individual’s behavior , with eaIn 2018, Pohang City Hall’s “Earthquake Damage Settlement Association” and “Disaster Prevention Policy” department established a joint plan to provide a customized earthquake disaster educational program for children and teens. The purpose of the program, which was based on the earthquake response manuals of the Korean government, was to ensure the safety of school students from future earthquakes. As part of the plan, the “2018 school earthquake disaster education program in Pohang” was conducted over a period of four months (August to November) in 2018. The content was taught by professors and graduate students from the Ulsan National Institute of Science and Technology (UNIST), who also conducted surveys regarding the program’s effectiveness. Fourteen schools (six middle and eight high schools) in Pohang city participated, and the number of students who joined the program was about 5000. The training content consisted of three parts. The first part focused on earthquake science, including the phenomena of earthquakes and seismic waves. When describing seismic waves, students were taught the difference between P waves and S waves using experiments and video materials. The second part concerned earthquake-resistant and earthquake-proof construction, with key elements and goals regarding the seismic design explained. In the final section, the general protective action and strategy regarding earthquakes was introduced, as well as memorization skills designed to help students remember key actions easily.This study examined factors relating to the disaster experience increase the effectiveness of earthquake response education for the students who experienced the Pohang earthquake. The experience was measured by two responses to the earthquake: cognitive response and emotional response. The cognitive response was determined by the perceived scale of the earthquake. The emotional response was measured by five emotions: fear, joy, surprise, sadness, and anger. The variables for the effectiveness of education were measured by the knowledge level of the earthquake protection drills and the level of satisfaction of the education program. The structural equation model (SEM) was conducted to find the statistically significant factors from students’ previous disaster experience that impacted educational effectiveness.The hypothesis of this study is that cognitive response and two emotional responses , stemmiHypothesis 1 (H1).Cognitive response will positively influence educational effectiveness.Hypothesis 2 (H2).Activated emotional response will positively influence educational effectiveness.Hypothesis 3 (H3).Unpleasant emotional reaction will negatively influence educational effectiveness.Two responses to the earthquake were used both to analyze the previous disaster experience and identify the factors influencing educational effectiveness. The latent endogenous variable was educational effectiveness, which was measured through a combination of knowledge level and level of satisfaction. The latent exogenous variables were cognitive response, activated emotional response, and unpleasant emotional response. The observed exogenous variables for emotional response included five emotions , which were classified into two latent variables. The activated emotional response was measured using fear, joy, and surprise, while the unpleasant emotional response was measured using sadness and anger.The survey data were collected as a part of the “2018 school earthquake disaster education program in Pohang” developed by Pohang City Hall. The survey was conducted from August to November (four months) in 2018, about a year after the Pohang earthquake. The respondents were about 5000 students from six middle schools and eight high schools in Pohang. Prior to the survey, the earthquake response education was conducted by members of UNIST. The data of 3316 respondents were analyzed after eliminating insincere answers and missing values from among the initial ~5000 questionnaires. M5.4) earthquake and the level of damage. The scales are “1 = Not felt,” “2 = Felt only by a few persons at rest,” “3 = Felt quite noticeably. Windows and furniture shook,” “4 = Flowerpots or furniture fell down or windows shook violently,” “5 = Some windows broken or walls cracked,” “6 = Walls or buildings collapsed” [The question designed to gauge students’ cognitive response concerned how they perceived or observed their surroundings and intensity during the shock . The statement about magnitude was based on the Modified Mercalli Intensity scale, developed by Harry O. Wood and Frank Neumann. Several additional features were also included in the survey, such as the middle size . These items were measured using a five-point Likert-type scale .The respondents answered six right or wrong questions concerning earthquake response actions. To measure the educational effectiveness, the six questions were based on the content of the education program . The six questions were as follows: (1) “If you are indoors, right away, you must try to get under a desk or table to protect your head and torso” (correct answer: yes); (2) “During the shaking, you must evacuate outside of buildings immediately” (no); (3) “During the shaking, you must use an elevator to evacuate the building as fast as possible” (no); (4) “When the earthquake occurs, you must evacuate to open space, such as a park or a ground” (yes); (5) “If you are driving, you must use a vehicle to move to a safe place” (no); and (6) “If you are outside, you must stay next to the walls” (no). The questions and their contexts are based on the manual of the Ministry of the Interior and Safety.The level of educational effectiveness was assessed by the students. They answered questions regarding their level of satisfaction with the training (“I am satisfied with this earthquake response training.”) using a five-point Likert-type scale .The analysis was conducted using the IBM SPSS Statistics  and The R Project for Statistical Computing . The basic statistical characteristics and correlations among the variables were found through frequency analysis, correlation analysis, and regression analysis. The Structural Equation Model was applied to evaluate the causal relationship between earthquake experience and training effectiveness. The five emotional response variables were converted into two factors through Principal Component Analysis (PCA). The internal consistency, Construct Reliability, and Average Variance Extracted were then determined to confirm the validity of the PCA results.p = 0.000). According to the ANOVA test results, there were no significant differences between male high vs. male middle school students (p = 0.807). The same is also true of female high vs. female middle school students (p = 0.912).All of the respondents to this survey had experienced the Pohang earthquake. The result shows that the respondents perceived an intensity of 3.7 MMI (Mean (M) = 3.71, Standard Deviation (SD) = 0.89) on average. The perceived MMI tended to decrease as the distance from the epicenter increases see . When cop-value = 0.000), and joy and other emotions show an opposite tendency. While most emotional responses are more strongly experienced by females, males rated joy higher than females. The correlation between respondents’ emotional responses and proximity to the epicenter is significant. The nearer the location of the respondent, the stronger the level of emotion other than joy. By contrast, the correlation coefficient between the level of joy and distance is positive . Age has a statistically significant relationship with joy  and anger .In contrast, the survey results show that the strongest emotional response during the Pohang earthquake was surprise , while the weakest emotion was anger . The mean values of the other emotions are fear , sadness , and joy . According to the result of the independent group t-test between emotional responses and gender, there are significant differences  out of 6.00. Satisfaction levels regarding the earthquake response training were measured using a five-point Likert-type scale, from “1 = not at all” to “5 = strongly agree.” The mean value was 4.61 (SD = 0.71) out of 5.00.The SEM  was formed on the hypothesis that the factors relating to earthquake experience will enhance the effectiveness of the emergency training. As we can see in  χ2/d.f. ,53,54. Hp = 0.000), while for H3 it was −0.033 (p = 0.03). Therefore, we can accept hypotheses H2 and H3: namely, that the activated (unpleasant) emotional response will positively (negatively) influence educational effectiveness. However, the standardized estimate of H1 was only 0.004 (p = 0.721). As this was not a statistically significant result, we rejected the H1 hypothesis, which stated that the cognitive response (perceived MMI) would positively influence educational effectiveness. This result shows that an individual’s emotional response is more relevant to the effectiveness of disaster training than the recognized scale by witnessing or experiencing such incidents. More specifically, activated emotions  have the greatest influence among the factors, while unpleasant emotions (anger and sadness) have a statistically significant but opposite influence. In other words, sadness and anger demotivate students to learn about the disaster.The experiences of the Pohang earthquake of M 5.4 in 2017 were analyzed and divided into cognitive responses and emotional responses. The cognitive responses of the students did not impact educational effectiveness significantly. This factor was measured using the earthquake intensity that the students perceived, which was measured to be around 3.7 MMI on average. The measured intensity result differed according to the individual’s proximity to the epicenter; students who were further away from the epicenter tended to experience weaker shaking. The reason why the effects of cognitive responses are not statistically significant may be due to the characteristics of the Pohang earthquake. Although its size was M 5.4, the second strongest event recorded in South Korea since 1978, it was only a mid- or minor-sized earthquake compared to the large magnitude earthquakes witnessed in Japan or other countries around the world. Consequently, in spite of the respondents’ surprise and fear, which were based on the unfamiliarity of experiencing earthquake, the physical damage inflicted by the earthquake was not very serious. Consequently, students might think that they do not need additional preparation because there was no notable damage.p < 0.01), with activated emotional responses identified as most significant factor. Students who felt surprise and fear, but not joy, tended to have more effective educational experiences. On the other hand, the unpleasant emotional reactions, such as anger and sadness, had a negative effect on educational effectiveness.Students felt various emotional reactions, including both negative and positive responses. The two emotional responses, activated emotional response and unpleasant emotional response, were statistically significant in terms of educational effectiveness . As shown in the results, the “2018 school earthquake disaster education program in Pohang”, developed by Pohang City Hall, was meaningful. The M 5.4 Pohang earthquake in 2017 was a mid-sized earthquake compared with larger incidents, such as the M 8.0 Sichuan earthquake in China in 2008 or the M 9.0 Tohoku earthquake in Japan. However, the Pohang earthquake was the second largest earthquake in Korean history, and almost all people in Pohang were shocked by it because it was so unfamiliar. In particular, the surprise and fear of children and teens in Pohang city was severe. These activated emotional states motivated students in Pohang to learn about disaster science and how to take protective actions effectively. Although the education program started nine months after the earthquake, the vivid emotions of surprise and fear still lingered in the hearts of children and teens in Pohang city.Educational institutions need to clearly understand the importance of students’ emotional conditions when planning a disaster education program. Furthermore, it is also important to change students’ perceptions regarding the controllability of the disaster. The message that preparedness can reduce the resulting damage may induce students to prepare more thoroughly , especia


The North American cheetah population serves as a reservoir for the species, and acts as a research population to help understand the unique biology of the species. Little is known about the intrauterine physiology of the cheetah, including embryo differentiation, implantation, and the development of the placenta. After mating, cheetah females frequently experience (30–65% of matings) a non-pregnant luteal phase where progestogen metabolite levels match those found in pregnant females for the first ~55 days of gestation, but parturition does not occur. Immunoglobulin J chain (IgJ) is a molecule that is involved in the activation of the secretory immune response and has been found to be indicative of pregnancy in the cheetah using fecal monitoring. In this study, western blotting was employed to track IgJ abundance in pooled weekly fecal samples following natural breeding or exogenous stimulation to ovulate, and IgJ levels were compared between individuals undergoing a pregnant (n = 12) and non-pregnant (n = 19) luteal phase. It was revealed that IgJ abundance was increased in pregnant females compared to non-pregnant females at week 4 and week 8 post-breeding, indicating the potential modulation of maternal immunity in response to sensitive events such as implantation and the increased secretory activity of the placenta. IgJ levels also tended to be higher early after breeding in females that were bred naturally with intact males compared to exogenously stimulated females with no exposure to seminal plasma, potentially indicating a response to the act of intromission or the stress of breeding, or possibly demonstrating an immune response resulting in the promotion of maternal tolerance to seminal antigens present upon embryonic implantation. Monitoring fecal IgJ may be a potential method to determine gestational status in the cheetah and will aid future conservation efforts of the species. Acinonyx jubatus) is listed as vulnerable by the International Union for Conservation of Nature (IUCN), with an estimated population of ~7100 individuals in the wild, and numbers continuously decreasing due to habitat fragmentation and human conflict [ex situ population is critical to serve as an insurance population should the wild cheetah’s numbers diminish further. The ex situ population can serve as a reservoir for the species and could potentially be used for reintroduction efforts in the future. The insurance population is also invaluable for research purposes, allowing for studies that cannot be conducted on in situ populations due to the scarcity of the species in the wild.The cheetah . The animals included in the study were female adults from 2 to 12 years of age (mean ± standard error of the mean (SEM) = 6.0 ± 0.6 y). Several females included in this analysis bred multiple times throughout the course of the study, and as a result have multiple breeding periods included. The animals in this study were fed a diet of commercial beef or horse-based meat product  a minimum of five days per week, with supplements that included whole rabbit, beef and horse bone, or organ meat. Water was available ad libitum.This study was conducted according to the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The female cheetahs included in this study  were all housed at accredited Association of Zoos and Aquariums (AZA) institutions within the United States. All subjects were born Fecal samples were collected opportunistically from females that were naturally bred according to SSP breeding management recommendations and from females receiving exogenous gonadotropins to stimulate ovulation. Exogenous gonadotropin therapy was conducted under IACUC approval for separate projects according to previously published methods , 15, and3H-progesterone prior to shaking extraction. The mean extraction efficiency (±SEM) was found to be 73.6% ± 0.2% for all samples.Fecal samples were collected non-invasively from enclosures approximately 3–4 times weekly. Only fresh samples (deposited within 24 h) were chosen. Samples, about 50g in size, were collected in individual plastic bags and immediately stored in a -20°C freezer. Individual fecal samples were then lyophilized , crushed, and transferred to individually labeled tubes. Reproductive cyclicity and ovulation were confirmed by steroid hormone metabolite analysis. Fecal samples underwent a steroid hormone metabolite extraction protocol according to previously published methods , 10. Extg for 30 min. The supernatant was filtered using a 0.22 μm syringe driven filter unit (Millipore Sigma), and the proteins were then precipitated from the supernatant using a 60% ammonium sulfate saturation. The ammonium sulfate solution was shaken for 30 min and centrifuged at 7000 x g for 30 min. The protein extract pellet was collected and resuspended in 400 μL of phosphate buffered saline with protease inhibitor. This protein extract solution was then desalted using a 3 kDa Millipore spin column (Amicon Ultra-0.5) and centrifugation at 7400 x g. All extraction steps were performed at 4°C. Extracted samples were then run on a Bradford assay  to determine total protein concentration. Briefly, standards for the assay were created by serial dilution of bovine serum albumin at 0.388 mg/mL to 0.012 mg/mL. Fecal protein samples were diluted to 1:30, and 10 μL of each sample was added to a well in duplicate. 200 μL of Bio-Rad Quick Start™ Bradford Dye Reagent was added to each well, and after 5 minutes protein concentrations were determined using a Molecular Devices Filtermax F5 plate reader. Coefficients of variation for all samples in duplicate were <10%. Differences in steroid hormone and total protein concentrations between pregnant and non-pregnant groups were determined using a Student’s T-test in R (version 3.3.2) [Weekly pooled fecal samples of 0.5g were created by combining approximately 0.125g of four individual dried samples in a 15 mL centrifuge tube. Individual samples from day 1–7 post-breeding were used to create the pooled sample for week 1. Individual samples from day 8–14 post-breeding were used to create the pooled sample for week 2, etc. Because samples were collected opportunistically, some weekly time periods had insufficient samples for analysis. In these cases, no IgJ information was available for that week, making the number of replicates per week variable. Total protein was subsequently extracted from pooled dried samples as follows. 6 mL of 0.1 M phosphate buffered saline  with protease inhibitor (1:1000) was added to the pooled fecal sample, and the mixture was shaken for 30 min and centrifuged at 4600 x n 3.3.2) , with di2PO4, 3.5 M Na2HPO4, 0.3 M NaCl, H2O; pH, 7.0) and were analyzed by enzyme immunoassay (EIA). Estrogen metabolites in diluted fecal extracts were used to determine reproductive cyclicity using an estradiol EIA that has been validated for use in the cheetah [Steroid hormone neat extracts were diluted 1:20 to 1:16,000 in phosphate buffer  was used as a positive control at 16.67 μg/mL. 18 μg of each sample, and 0.15 μg of positive control were loaded into wells on a 4–20% Mini-PROTEAN TGX gel . Samples were then separated by SDS-PAGE, transferred to a PVDF membrane, blocked with 5% milk, and incubated overnight at 4°C with a primary antibody (Aviva Systems Biology ARP55440_P050) diluted 1:1000 in 1% milk. This polyclonal antibody was developed in a rabbit against human recombinant IgJ and was previously found to be reactive to cheetah IgJ in western blot .Intensity of IgJ abundance was determined using GeneSys Spot Blot analysis (Syngene) of the band occurring within each lane at 18 kDa for each weekly pooled sample. GeneSys Total Lane analysis (Syngene) for each sample of the Coomassie image was used to determine the total protein in the sample as a loading control. A ratio of IgJ intensity to Coomassie intensity was calculated for each pooled sample, as well as for the positive control. Relative intensity for each pooled sample was calculated by dividing the ratio for each pooled sample by the ratio of the positive control, in order to control for inter-blot variation. A pre-breeding relative intensity value specific to each individual luteal phase was then subtracted from each weekly post-breeding relative intensity value to control for pre-breeding IgJ levels. If relative intensity values were not normally distributed, then the data was subjected to a log transformation. After transformation, 15 of 18 groups describing weekly IgJ abundance  and both groups describing early post-breeding IgJ response  were verified for normality using a Shapiro-Wilk test in R (version 3.3.2) . DiffereFecal estrogen metabolite profiles confirmed the cyclicity of monitored females. Examples of the estrogen metabolite concentrations of cycling females prior to natural breeding can be seen in Detection of IgJ by western blotting with the use of a commercially available antibody was confirmed by the use of a positive control. IgJ was confirmed in the positive control and in fecal samples at a molecular weight of ~18 kD . FemalesPregnant females tended to have higher IgJ levels (P = 0.081) in week 4 post-breeding  compared to females experiencing a non-pregnant luteal phase  . Pregnanin situ and ex situ. However, cheetahs in the wild are in decline, as habitat fragmentation and human conflict have reduced the natural range of the species [ex situ insurance population. However, creating a sustainable ex situ population with the goal of improving genetic diversity and ensuring future health and adaptability of the species has become a challenge, as many cheetahs struggle to successfully reproduce in human care. The low genetic diversity of the species as a whole, and high levels of inbreeding depression, have contributed to many health and reproductive issues that affect the cheetah, including the impairment of genes mediating immune defenses [ex situ environmental factors may be having a negative effect on reproductive capacity. Of importance to animal managers is understanding the relatively high incidence of non-pregnant luteal phase that occurs in the ex situ population, whether this represents failure to conceive or early embryo loss.The reproductive biology of the cheetah has been studied for decades, with great advances in the understanding of this species both  species , 20. Becdefenses , low fecdefenses , 23. Whidefenses , 25, indTemporal tracking of IgJ abundance over the first 9 weeks post-breeding provided insight into the intrauterine events that result in the success or failure to establish pregnancy in the cheetah. Females in our study that were bred with an intact male demonstrated an elevation of IgJ early post-breeding compared to exogenously stimulated females with no exposure to a male. This increase in IgJ could be the result of multiple factors. Exposure to a new male, as well as the act of copulation can be a stressful event for the female. While this may provoke a stress response, it is unclear what effect this stress has on secretory immunity or IgJ expression. Intromission may also result in the introduction of bacteria or other foreign substances into the reproductive tract of the female, increasing the expression of IgJ and provoking an immune response at the mucosal surface. Another possible explanation is that a secretory immune response was stimulated by the presence of seminal plasma in the reproductive tract which, as a foreign substance interacting with a mucosal surface, could induce an upregulation in IgJ. An immune response to semen has been documented previously in mice, as lymphocyte synthesis and cytokine activation is triggered in response to the constituents of seminal plasma . The immThe timing of early intrauterine events, including implantation and the development of the placenta, is unknown in wild felids. In the domestic cat, fertilization takes place in the oviduct up to 48 h after ovulation, and implantation occurs at day 13–14 post-breeding . These f2ɑ (PGF2ɑ) by the placenta during week 8 post-breeding, as levels of a fecal PGF2ɑ metabolite (PGFM) were found to be elevated in the pregnant cheetah beginning at day 48 post-breeding and increased through parturition [2ɑ is known to have a strong luteolytic effect in many species [Pregnancy in the cheetah first becomes distinguishable from a non-pregnant luteal phase using progestogen metabolite monitoring at ~day 55 post-breeding, as progestogen levels in fecal samples drop to pre-ovulatory levels in non-pregnant individuals. It can be theorized that around this time in non-pregnant individuals a regression of the corpora lutea (CL) occurs which results in a subsequent decrease in progesterone production, followed by a plateau at lower basal levels. It is unknown whether luteal regression occurs in pregnant females as well, or if the CL is maintained until parturition. Recent studies have suggested that the placenta is a source of progesterone production in the domestic cat , 30, andturition . While P species , suggestIt is possible that the presence of external immune stressors, which potentially could alter the production of systemic IgJ, could influence the results and interpretation of our experiment. IgJ is a protein that is upregulated in response to an activation of the secretory immune system, which is present in all mucosal surfaces of the body in order to protect from foreign pathogens. An immune challenge to a mucosal surface that is independent of pregnancy could increase expression of IgJ, resulting in high IgJ values in our assay that do not correspond to intrauterine events and could affect the accuracy of the assay. Inter-individual variability in IgJ expression was controlled for here by assessing relative changes in concentration from pre-breeding levels within each individual. Because the assay in this study utilizes fecal material, the IgJ that is being measured is likely excreted by the cells of the intestinal mucosa. Immune stressors, whether related to pregnancy or not, likely increase IgJ expression across all mucosal surfaces, allowing for excreted IgJ abundance to be a useful indicator of pregnancy related events. A future goal is to extend the Western analysis to a reliable benchtop enzyme-linked immunosorbent assay (ELISA) for measuring fecal IgJ levels after breeding, allowing for the confirmation of pregnancy at week 4 post-breeding. Daily quantification using this method would improve the accuracy and efficiency of IgJ monitoring and may be able to reveal moments of immune challenge that impact establishment of pregnancy with greater precision. The occurrence of a non-pregnant luteal phase is common in other species, indicating the potential for a felid-wide or carnivore-wide assay for determining pregnancy using IgJ monitoring.ex situ management of the species, and further research will continue to advance the understanding of cheetah reproductive physiology following breeding, aiding future conservation efforts for the species.In summary, this study detailed IgJ levels throughout the first 9 weeks of pregnancy and non-pregnant luteal phase in the cheetah. Females that were bred naturally with intact males tended to have a higher immediate IgJ response than females that were exogenously stimulated to ovulate, indicating a potential immune response to the constituents of seminal plasma or other foreign substances introduced by the act of breeding that may have the effect of promoting maternal tolerance of fetal tissue upon implantation. There was a tendency towards increased IgJ abundance at week 4 post-breeding in pregnant cheetahs compared to non-pregnant cheetahs, indicating an activation of the secretory immune system in response to implantation and the invasion of the maternal endometrium by the fetal trophoblast. A significant increase in IgJ abundance was also found in week 8 post-breeding in pregnant cheetahs compared to non-pregnant cheetahs. Taken together, these data support the suggestion that the window of implantation in the cheetah is between 19–21 days post-breeding, and that the placenta is a source of extragonadal progesterone during the third trimester. Further refinement of this assay will allow for fecal IgJ monitoring to become a reliable non-invasive tool for determining pregnancy in the cheetah at week 4 post-breeding, much earlier than current methods. These findings will help to improve S1 Fig(TIF)Click here for additional data file.S1 File(PDF)Click here for additional data file.


After upgradation, the performance of the network was observed using the latest recorded earthquakes in the country. The experimental results in the present work demonstrate that the new parameters shakemaps added in the current work provide promising outputs, and are comparable with the shakemaps given by the official agency CWB. These shakemaps are helpful to delineate the earthquake-hit regions which in turn is required to assist the needy well in time to mitigate the seismic risk.Using low-cost sensors to build a seismic network for earthquake early warning (EEW) and to generate shakemaps is a cost-effective way in the field of seismology. National Taiwan University (NTU) network employing 748 P-Alert sensors based on micro-electro-mechanical systems (MEMS) technology is operational for almost the last 10 years. This instrumentation is capable of recording the strong ground motions of up to ± 2g and is dense enough to record the near-field ground motion. It has proven effective in generating EEW warnings and delivering real-time shakemaps to the concerned disaster relief agencies to mitigate the earthquake-affected regions. Before 2020, this instrumentation was used to plot peak ground acceleration (PGA) shakemaps only; however, recently it has been upgraded to generate the peak ground velocity (PGV), Central Weather Bureau (CWB) Intensity scale, and spectral acceleration ( In Eastern Taiwan, the Philippine Sea plate subducts under the Eurasian plate along the Ryukyu Trench , EEW parameters, site corrections, and partial observation values . HoweverP-Alert network till 2019 has published near real-time PGA shakemaps during and after the occurrence of an earthquake. In general, P-Alert starts plotting shakemaps once 10–12 instruments confirm PGA to be 0.012g. These maps provide an idea about the rupture directivity, as well as radiation patterns [aS at different periods, and the CWB Intensity scale shakemaps. The CWB Intensity scale represents the damage patterns or felt intensity by the human. Also, aS maps at different periods , corresponding to different story buildings are plotted. aS represents the maximum force experienced by the buildings having a particular natural vibration period.The patterns ,26. Initpatterns  than theP-Alert system also publishes the earthquake information and the resulting shakemaps to social media within a few seconds after the earthquake origin. We believe that with upgradation in the present network, such real-time and needed information is easily available, and with the help of this information, the disaster relief resources can be delivered to disaster-hit areas in a fast and appropriate way.This L 6.2. This earthquake caused the highest fatalities in recent times, most of them from a multi-storied hotel building. The 0.6g PGA corresponding to the CWB Intensity VII was recorded at one or two stations during this earthquake. The PGA shakemaps during the earthquake were available within 2 min of the occurrence of the earthquake. Another Hualien earthquake having ML 6.3 occurred in 2019, exactly 14 months later of the 2018 earthquake. The CWB rapid-reporting system, located this earthquake 10 km northwest of Hualien County with a focal depth of 18.8 km. The recorded PGA during this earthquake reached 0.5 g.In the eastern part of Taiwan, near Hualien County, two earthquakes having almost the same magnitude occurred in 2018 and 2019. The CWB rapid-reporting system located the 2018 earthquake 18 km northeast of the Hualien city having MThe higher PGA values (˃ 0.4 g) were observed at a few stations in the epicentral region during the 2018 earthquake. The higher PGV values (PGV ≥ 75 cm/s) are expected in the epicentral region corresponding to higher PGA values (PGA ≥ 0.4 g). However, looking at the PGV contour map for this earthquake , a smallThe present work related to shakemaps upgradation uses the data collected by the P-Alert network. The research system is based on the Earthworm platform ,29 that palert2ew. It is used as a server-side program waiting for connections from P-Alert sensors across Taiwan and then receives the waveform data packets through TCP/IP protocol. Besides, the module can also be used as a client-side program connecting to the main P-Alert server to request the waveform data from all online P-Alert sensors. The main process inside this program is parsing the raw P-Alert packet, and then transforming it to the Trace Buffer format in the Earthworm platform. Once the data is processed, it is transferred to the first shared memory, Wave Ring I.Firstly, the data receiving part includes only one module, Wave Ring I, two different additional actions are performed in the data processing part. In the first action, the data is handled by the differential and integral module, diffint. This module first cooperates with the conversion parameters in the database to convert integer records into real physical quantities  and then using integral, convert the original acceleration waveforms into velocity and displacement waveforms. To avoid the noise-induced drifting, we also apply the high pass filter that is two poles Butterworth filter at 0.075 Hz corner frequency. Finally, output the results to the next shared memory (Wave Ring II) in the Earthworm platform. The other action is performed by the calculation module, spectra. This module calculates the corresponding response aS based on the defined period and damping ratio. This process is more complicated than the previous due to the real-time transformation between acceleration and aS signal. Conventionally, the transformation is performed using Fourier transform and Inverse Fourier transforms but it takes too much time and computing power. Therefore, we use another method that is similar to the recursive filter [For data in e filter . The deth is the damping ratio that is set to 0.05 as usual. After this recursive processing, we will derive the spectral displacement record. After applying another double differential, the aS is obtained. The output from this module is also transferred to the Wave Ring II. Next, the scanning module, peakup, scans all of the waveforms including acceleration, velocity, displacement, and aS inside the Wave Ring II once per second, corrects the zero offsets, finds the maximum value of the waveform per second, and finally, outputs the results to the next shared memory (Peak Ring).The peak2trig. This module will collect the peak value information generated by the previous module to determine whether a possible earthquake event has occurred. Once the triggering stations reach more than five, it is defined as an earthquake event. The optimum condition for the triggering station is that the maximum acceleration reaches 0.0015 g in one second, and the other two stations within 30 km also report 0.0015 g within 6 s. Once triggered, this module will continue to update the trigger information and output the trigger information to the shared memory (Trig Ring). A simple linked list data structure is used inside this module to implement this algorithm. In this way, we can manage the triggered station list easily such as removing the obsolete triggered station or attaching the incoming triggered station. To this portion, all the data for generating shakemap are ready.Following is the trigger process part which includes only one module, shakemap, it will receive the peak value information from the Peak Ring continuously and simultaneously detect whether there is trigger information from Trig Ring. Once it is triggered, the shakemap module will enter the triggered mode and save the peak value of each station. Also, it will perform the spatial interpolation calculation using inverse distance weighting [Map Ring), it also sends the output to the local hard disk in a text format for archiving. The second module is the drawing and publishing module, postshake. It firstly draws the image file (png format) of regional shakemap according to the data generated by the previous module; once all required shakemaps are drawn, this module will send the emails with earthquake message notifications to the address on the list. Also, the message is posted to social media, such as Facebook, Twitter (started posting on Twitter in October 2020) by calling external scripts . dP calculation from instruments is a two-staged process that is followed continuously. A 0.08g PGA value in Taiwan equals seismic Intensity V as per the old Intensity scale and IV according to the new scale. These values of PGA, PGV, and Intensity are supposed to cause light damage in the epicentral region [The upgraded P-Alert system was officially launched in early 2020. Since its operation, only a few earthquakes with a magnitude greater than 5.5 have occurred and were successfully recorded by this network. The functioning of this network is described in terms of one such earthquake having a magnitude MdP values recorded by instruments were lower than the predefined thresholds, so the EEW system was not initialized. The earthquake started at 12:52:29 (UTC) and the first shakemaps were generated at 12:52:42 just 13 s after the origin time. Then every 30 s, the P-Alert system generated a series of shakemaps continuously. The stable shakemaps were first generated at 12:54:12, and then the final shakemaps were available at 12:54:39 with a total triggering of 631 stations  or second floors (about 19%) of the buildings. However, most of the P-Alert instruments are mounted vertically on the walls, so the measurements may be affected by the soil-building interaction. To compute the difference in measurements, Wang et al. [P-Alerts and found the difference in values by dividing PGA values recorded by both of them. They found that the PGA values recorded by the P-Alert instruments placed on the ground floor were the same as TSMIP instruments and for instruments at the first and second floor they were 1.07 and 1.52 times, respectively. Therefore, the amplified seismic waveforms from P-Alert instruments installed on a wall of different floors can be adjusted directly using the factor mentioned above. After removing the building amplifying effect, the hesitation of the overestimation in shakemaps generated by P-Alert is also eliminated.The NTU research team started establishing the NTU network in 2010 when the first g et al.  collecteIn P-Alert instruments, there are still some upgrades that need to be done. To provide more high-quality waveform data and improve the sensitivity. The advanced P-Alert plus instruments which belong to Class-B type [Although the NTU network already becomes a robust and dense network with the s-B type  will be P-Alert instrumentation has been proven to be very effective in generating the various shakemaps and immediately issuing an earthquake early warning to the various lifeline structures including schools. After the upgradation, the P-Alert system can provide the PGV, aS of various periods, and the CWB Intensity scale shakemaps in addition to PGA shakemaps. These additional shakemaps will benefit significantly the end-users which are mainly the disaster management authorities and administrative planners of the country. The upgradation of the network to generate additional shakemaps will be helpful to delineate the earthquake-hit areas and to provide help at the earliest to mitigate the earthquake disaster. The addition of the new instruments regularly and instrumenting on the known faults ensures that the near-fault properties are captured very precisely on this network. This leads to this instrumentation always to be ahead in generating various value-added products to be circulated on social media and delivering them to the disaster-relief agencies at the earliest using a strong communication system.The The next step is to expand this network on the eastern side of Taiwan where the mountainous area and the scarcity of the proper logistics pose difficulty in expanding the network. Though a few instruments have already been added, still, there is room for many other instruments. In the future, we plan to expand the network and to combine the resultant shakemaps with several building components related to construction and design to further generate complete seismic hazard maps for important cities in Taiwan.


Chiikiwaku is a measure to improve the maldistribution and shortage of physicians in rural areas in Japan. Although Chiikiwaku quota seats have been on the rise, a considerable number of young physicians and medical students return their loans and do not fulfill their duty periods for several important reasons, including an obligation term lasting for 9 years. The number of medical students who do not apply for admission to the Chiikiwaku quota has increased, and vacancies have developed in some medical schools. Urgent modification of this program is therefore required to make it suitable for actual situations of both rural medical care and the education of young physicians. The Japanese government has taken various measures to improve this situation.The unequal geographical distribution of doctors is a serious problem in several developed countries. Doctors concentrate in urban cities, and their shortage is serious in rural areas Chiikiwaku, a program combining a student loan and a regional admission quota (1). All applicants have to be engaged in the medical practice in rural areas falling under their alma mater’s prefecture immediately upon graduation.One of these measures is Chiikiwaku quota seats have been on the rise. According to the Ministry of Education, Culture, Sports, Science and Technology, these seats reached 1,674 in 2017, accounting for 20% of all the medical school enrollees . Some researchers reported that this program has contributed to alleviating the physician maldistribution in Japan (1). Yet, the limitations of this program have not been sufficiently acknowledged.Since the introduction of this program in 2009, (2). The interest rate associated with this loan is higher than 10% in some prefectures, and students also have to repay USD 80,000 as the interest cost (2).The most serious problem is that the obligation term is as long as 9 years. To leave the program, enrollees have to repay the entire loan amount taken for meeting the cost of the program. The amount, which covers the enrollment fee, tuition fees, and living expenses, reaches approximately USD 100,000 over a 6-year student period Chiikiwaku would increase to 7% in the future. In 2018, the proportion of vacancy seats exceeded 20% of the total seats in the Chiikiwaku programs of 22 medical schools. The Chiikiwaku program has not functioned in an actual clinical setting.Nonetheless, a number of young doctors do not fulfill their duty periods, preferring to return their loans. According to the Ministry of Health, Labor and Welfare (MHLW), 123 of 5,290 medical students (2.3%) enrolled in this program withdrew from it during 2008–2018. MHLW reported that the number of students leaving Chiikiwaku program and strengthened regulation by delivering a notice to hospital directors not to hire physicians who left this program. As a result, only 9 of 805 doctors (1.1%) who were enrolled in the Chiikiwaku program withdrew from it in 2018. However, such a compulsive approach of MHLW has been pointed out as being illegal (2), and there is a problem concerning its sustainability. If doctors enrolled in the Chiikiwaku program are forced to engage in medical practice in rural areas, they might quit the job (3).The Japanese government raised concerns about the withdrawal of several young doctors from the (4). The loan is offered to those who are determined to pursue a career in primary care. Despite its similarity with the Chiikiwaku program in making applicants who fail to meet the obligations of this program repay their loans at 15% interest, it is more flexible than the Japanese program in terms of career choice (4). For instance, applicants are allowed to finish the residency program before they engage in their practice, which is the return on the program. The scheme also enables program enrollees to attain a certification. Furthermore, the period of compulsory practice under the program obligation is approximately 9–12 months, which is shorter than that in Japan’s regional quota system program (2). In Chiikiwaku, the period of compulsory practice under the program is 3–12 years, and a 9-year duration is the most popular.It is imperative to overcome the limitations of this system and make it sustainable. As a model case that can be emulated, we would like to present a US program. Students admitted to the University of Kansas School of Medicine are eligible to apply for the Kansas Medical Student Loan program, which gives them a maximum of USD 2,000 per month Chiikiwaku(5). In this respect, a good starting point for reform of the program could be to offer it only to those medical students who are determined to engage in primary care in the future.We realize that it may be difficult to directly import this example into Japan, given the differences in the medical education system in the two countries. However, the importance of postgraduate medical education should at least be taken into account when designing a regional quota system. There is a case where the number of physicians has increased in a hospital in a remote area in Japan without relying on Dr. Yamamoto received personal fees from NAGATANIEN Co., Ltd. and ROHTO Pharmaceutical Co., Ltd., outside of the submitted work; Dr. Ozaki received personal fees from MNES Inc., outside of the submitted work; Dr. Tanimoto received personal fees from MNES Inc., outside of the submitted work; Dr. Saito received personal fees from TAIHO Pharmaceutical Co., Ltd., outside of the work; Dr. Masahiro Kami received a donation from AIN HOLDINGS Inc. and is remunerated as outside director of SBI Biotech Co., Ltd., SBI Pharmaceuticals Co., Ltd., and Y’s Inc.; he is also an advisor of MNES Inc. and MRSO Inc.All authors conceived and designed the study and are responsible for the integrity and accuracy of the data. KY, AO, MT and MK drafted the manuscript. All authors critically reviewed the manuscript for important intellectual content and provided final approval.