Objective: Serum magnesium (Mg2+) levels are associated with insulin resistance, hypertension, lipid abnormalities, and inflammation. However, limited studies have indicated the relationship between Mg2+ and multiple system indexes. The purpose of this study was to investigate the association between Mg2+ and allostatic load (AL) in hemodialysis patients.Methods: A cross-sectional survey was conducted on hemodialysis patients from different centers in Anhui Province, China, between January and December 2020. A total of 3,025 hemodialysis patients were recruited. Their clinical data were measured before hemodialysis. Information was collected by an online self-reported questionnaire and medical record. Serum Mg2+ was divided into three groups by tertiles. A score of AL greater than or equal to 3 was defined as high AL. A binary logistic regression model was applied to examine the relationship between serum Mg2+ and AL.Results: A total of 1,222 patients undergoing hemodialysis were included, 60% of whom were males . The mean (standard deviation) age of patients was 55.90 (12.75). The median level of serum Mg2+ was 1.22 mmol/L. The rate of high AL levels was 23.4%. Serum Mg2+ was negatively correlated with body mass index, fasting blood glucose (Glu), and C-reactive protein and positively correlated with high-density lipoprotein, low-density lipoprotein, total cholesterol, diastolic blood pressure (DBP), and serum phosphorus. After adjusting for gender, anxiety, diabetes, family residence, lipid-lowering agents, antihypertensive medications, albumin, and Glu, the binary logistic regression model showed that patients with lower levels of serum Mg2+ were more likely have high AL .Conclusion: Our data support the hypothesis that higher serum Mg2+ concentrations may contribute to lower health risk in hemodialysis populations. Further randomized controlled trials and cohort studies are warranted to verify whether Mg2+ supplementation could be part of routine examinations in hemodialysis populations. Hemodiaf uremia . Every yf uremia . More thf uremia . Poor prf uremia . HoweverThe concept of allostatic load (AL) was proposed by 2+) is the fourth most abundant cation in the human body, which is found primarily in bone and skeletal muscle  data, which was a biological marker of AL. Finally, 1,222 patients were analyzed in the study.This study was approved by the Ethics Committee of the Second Hospital of Anhui Medical University (No. PJ-YX2020-006). Electronic informed consent was obtained from all participants before completing the survey. The study was conducted in accordance with the principles of the Declaration of Helsinki.An online platform named “h6world” supported by the Clinical Big Data Platform Research Group of Peking University was used to collect data. Before the survey, doctors, nurses, or graduate students of each center were trained. Each center logged into the platform for investigation data entry. All data were summarized to the project leader and were checked by a quality controller, including the demographic characteristics , behaviors , hemodialysis status, psychological states, medications, comorbidities, and clinical data.2).For all patients, anthropometric parameters such as body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and blood samples were collected before hemodialysis. Height measurement is accurate to 0.01 m, and weight measurement is accurate to 0.1 kg, measured with a calibrated electronic scale. The BMI was calculated as weight (kg) divided by height squared (square meters) , high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), and BMI; autonomic nervous system (SBP and DBP); immune system containing CRP and white blood cells (WBCs). The cut-off points for blood pressure and BMI were based on the KDOQI Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients  and WHO criteria . These dEach biomarker was assigned a value according to the threshold value standard, and the value exceeding the threshold value  is assigned a value of 1, otherwise, it is assigned a value of 0. The total scores of AL were obtained by adding up all the indexes, ranging from 0 to 8. High scores mean that patients were suffering a more serious imbalance of the biological system. The 75th percentile of the AL scores was 2. Therefore, participants with total scores ≥3 are defined as the high-AL group, as found in previous studies .t-tests and rank sum tests were used to examine the difference in clinical information between high-AL and low-AL groups. Categorical data were expressed as frequencies (n) and percentages (%). The chi-square test was used to calculate the difference in the percentage of high AL between different groups. Spearman’s correlations were applied to analyze the correlations between serum Mg2+ and clinical index in patients undergoing hemodialysis. AL scores were counted by the cut-off points of eight biomarkers and calculated by numerical transformations. It was not a distribution of probability and was presented as a dichotomous variable. Therefore, binary logistic regression was used to analyze the association between serum Mg2+ and AL. These data were processed by SPSS 26.0. All statistical tests were two-sided, and the significance was set at p < 0.05.The measurement data were represented by the mean and standard deviation (SD) for normally distributed data and by median and quartile for skewed distribution data. Two independent p < 0.05).2+ and clinical indexes in patients undergoing hemodialysis. Serum Mg2+ was positively correlated with HDL , LDL , TC , DBP , and P  and negatively correlated with Glu , BMI , and CRP . All the aforementioned indexes had statistical significance (p < 0.05). There was no correlation between serum Mg2+ and TG, Ca, iPTH, WBC, or SBP.2+ was divided into three groups by tertiles. The T1 group was defined as having serum Mg2+ concentration <1.00 mmol/L, the T2 group was defined as having serum Mg2+ concentration of 1.00–1.28 mmol/L, and the T3 group for serum Mg2+ concentration ≥1.28 mmol/L. The proportion of high AL levels in the T1 group (34.0%) was higher than that of the T2 (25.4%) and T3 (16.6%) groups, and the difference was statistically significant (p < 0.001).As seen in 2+ in comparison with that of the reference group (T3 group) for AL. In model 1, the univariate logistic regression results showed that compared with the T3 group, the ORs for the T1 and T2 groups were 2.593 (95% CI: 1.871–3.594) and 1.715 (95% CI: 1.239–2.373), respectively. In model 2, after adjusting for gender, anxiety, diabetes, family residence, antihypertensive and hypolipidemic medications, and Alb and Glu, the results showed that compared with the T3 group, the ORs for the T1 and T2 groups were 1.945 (95% CI: 1.365–2.773) and 1.556 (95% CI: 1.099–2.201), respectively.A sensitivity analysis was performed on the excluded samples and included samples. As shown in 2+ and AL. The results showed that a high AL level was common in patients undergoing hemodialysis and was inversely related to serum Mg2+ concentration. The proportion of patients with high levels of AL was 23.4% in our study. Compared with other studies, patients undergoing hemodialysis had almost the same proportion in high levels of AL. For example, a recent pilot study found that the percentage of higher AL levels was 25% among female outpatients with fibromyalgia (via change” (This is the first study to analyze the correlation between serum Mgomyalgia . Howeveromyalgia . AL is t change” . Previou change” , unexpla change” , and ove change” , which s change” . Thus, w2+ was negatively correlated to AL levels in patients undergoing hemodialysis, which was the main novel finding in our study. Mg2+ loss in patients undergoing hemodialysis is less likely to attract the attention of clinicians, which has also been called a “neglected cation” (2+ plays an important role in the homeostasis of organisms. It is not only a cofactor for several enzymes involved in most cellular processes (2+ are also involved in a variety of pathological conditions (It has been found that lower serum Mg cation” . In factrocesses . Changesnditions . Due to nditions . A largenditions .2+. Mg2+ was strongly linked to the cardiovascular system, inflammation, insulin resistance, and metabolic syndrome (2+ is an essential cofactor for many enzymes involved in glucose metabolism. In animal experiments, the onset of diabetes appears to be delayed in model rats supplemented with Mg2+, whereas animals with low Mg2+ levels show elevated serum glucose levels and altered lipid patterns (2+ and blood glucose was found, which is consistent with previous findings. In addition, Mg2+ has been found to be associated with dyslipidemia in the general population, and our study also indicated that Mg2+ was strongly correlated to related blood lipid indexes in the hemodialysis population. Our results also proved the evidence for the effect of Mg2+ on dyslipidemia, similar to a previous study (2+ also had a strong correlation with diastolic blood pressure. However, no studies have focused on the connection between Mg2+ and blood pressure, but there are some studies reporting the effects of different magnesium concentrations in the dialyzate on blood pressure. For example, a study in Greece showed that hypotensive episodes during dialysis were least common in using the highest magnesium dialyzate and most common in using the lowest magnesium dialyzate. In addition, studies in Egypt and Iran also support this view (2+ concentrations in the dialyzate have no significant effect on blood pressure in dialysis patients (2+ concentration has a protective effect on blood pressure control. Interestingly, we found that CRP was negatively correlated with Mg2+. Low Mg2+ status was accompanied by an elevation of CRP, and Mg2+ supplementation reduces CRP levels (Increasing risks for AL were connected to low serum Mgsyndrome . Some stsyndrome , diabetesyndrome , and morsyndrome . As mentpatterns . Other spatterns . In our us study . Moreovehis view . Howeverpatients . Future P levels .2+ and AL in the future. Second, patients without complete biomarkers of AL were excluded, which may influence the results. To determine the impact of the excluded samples on the results, a sensitivity analysis was performed. The results revealed that there were some differences in age, family residence, hypertension, diabetes, cardiovascular disease, and antihypertensive and hypolipidemic medication. Consistent with the findings, participants included in this study may have overestimated the percentage of high AL. Therefore, the inclusion criteria which strictly controlled and stratified the analysis of patients with comorbidity are warranted. Third, the components of AL in different studies were not unified, which commonly consisted of the metabolic system, autonomic nervous system, and immune system. The neuroendocrine index of AL was lacking in the present study, but the indicators selected in our study were well-validated in the different biological systems, and the results were in line with those of our original hypothesis and previous studies. At last, it should also be mentioned that the generalizability of our findings to different ethnicities is unknown due to significant worldwide disparities in the clinical pattern and prognosis of hemodialysis patients.The present large-scale, multi-center study contributed to high reliability of the findings. However, some limitations should be addressed. First, a cross-sectional design could not provide causal associations, and prospective cohort studies are needed to verify causal associations between serum Mg2+ and AL in the hemodialysis population. Patients undergoing hemodialysis with lower levels of serum Mg2+ are more likely to be at higher health risks. In addition, this study also provides evidence for the effects of serum Mg2+ on blood lipids, glucose metabolism, blood pressure, and immunity. The findings could provide empirical evidence for the intervention of Mg2+ supplements on reducing the health risk of the hemodialysis population.This is the first study to examine serum Mg


The thymus is a crucial organ for the development of T cells. T cell progenitors first migrate from the bone marrow into the thymus. During the journey to become a mature T cell, progenitors require interactions with many different cell types within the thymic microenvironment, such as stromal cells, which include epithelial, mesenchymal and other non-T-lineage immune cells. There are two crucial decision steps that are required for generating mature T cells: positive and negative selection. Each of these two processes needs to be performed efficiently to produce functional MHC-restricted T cells, while simultaneously restricting the production of auto-reactive T cells. In each step, there are various cell types that are required for the process to be carried out suitably, such as scavengers to clean up apoptotic thymocytes that fail positive or negative selection, and antigen presenting cells to display self-antigens during positive and negative selection. In this review, we will focus on thymic non-T-lineage immune cells, particularly dendritic cells and macrophages, and the role they play in positive and negative selection. We will also examine recent advances in the understanding of their participation in thymus homeostasis and T cell development. This review will provide a perspective on how the thymic microenvironment contributes to thymocyte differentiation and T cell maturation. The thymus is an essential organ for T cell development . It is hProper TCR-MHC interactions predicate whether DP cells are allowed to differentiate to the next stage of αβ-T cell development. Conversely, DPs with non-functional TCR-MHC interactions undergo death by neglect, which occurs for over 95% of DPs . FollowiThe two-step selection process is repeated every day in the thymus and is only diminished during thymus aging or due to external injuries, such as irradiation and inflammatory stress , 15, 16.+SIRPα- (CD8+ DCs), and CD8-SIRPα+ (SIRPα+ DCs)   into the thymus medullary through CCR7:CCL19 and CCR4:CCL17/CCL22 interactions, respectively. Interestingly, some aDCs also expressed AIRE, which validated other group’s previous findings , CD8Pα+ DCs) . SIRPα+ e thymus –26. Typion (CMJ) –29. A reon (CMJ) . These afindings , 32. It findings . Combine+ DCs have been shown to transport antigens through blood and induce Treg development in mice (+SIRPα+ monocyte DCs (moDCs) subset in the thymus that was important for the generation of Tregs , which are absent in the SIRPα+ DC subset, indicating that moDCs are likely a distinct population. Their findings suggested that the TLR9/MyD88 pathway induced mTECs to express chemokines that promoted the recruitment of moDCs to the thymus. These moDCs could also acquire antigens from mTECs. However, whether these or other DCs are able to transfer self-antigens expressed by medullary fibroblast, which were recently shown to express TRAs that contribute to central tolerance was not addressed  and IEd (an MHC class II antigen), the authors found thymic DCs, compared with splenic DCs, had a higher efficiency in acquiring H2-Dd and IEd. The capacity for MHC molecules uptake by thymus CD8+ DCs and SIRPα+ DCs were similar. However, this intercellular transfer ability was only found between thymic DCs and TECs, and not with other APCs, such as B cells, when cocultured with thymic DCs. Using qRT-PCR, the authors identified that this intercellular antigen transfer process was correlated with the unique expression of the epithelial marker EpCAM only in DCs found in the thymus. Thymic DCs were previously thought to acquire EpCAM protein from TECs, while this paper showed that both thymic CD8+ DCs and SIRPα+ DCs can express EpCAM, while SIRPα+ DCs expressed the highest level of EpCAM compared with all other DC subtypes in the thymus   . Using m(TE-DCs) Figure 2xpansion . AltogetIt has been shown that the generation of mature T cells from the thymus is attenuated during and post infections , 46. SinDuring T cell development, cells that do not pass positive or negative selection undergo apoptosis . It is e+ and CX3CR1+) in the thymus of adult mice using scRNA-seq , and genes involved in antigen presentation   in mice  –66. Thes in mice .+ macrophages are found mainly in the cortex, while CX3CR1+ macrophages are localized in the CMJ. In combination with their transcriptomic profile, this suggests that Timd4+ thymic macrophages are the main cells performing efferocytosis of apoptotic thymocytes. Their findings were also supported by Catherine C. Hedrick’s group who demonstrated that Timd4+F4/80+ thymic macrophages have the highest phagocytic efficiency compared with other macrophage subsets, and that the depletion of these macrophages accelerated thymic involution, suggesting an important role in thymic homeostasis  mouse to demonstrated that MafB expressing cells in the thymus play a crucial role in thymus repair after irradiation. When comparing thymus recovery post irradiation between MafB+/+ and MafB+/GFP, the authors found that there was a decrease in immature TECs (Krt5+FoxN1+) generated in the MafB+/GFP thymus. The organization of the medulla was also found to be abnormal post-irradiation injury, where mTECs in the MafB+/GFP thymus formed only one prominent medullary compartment, while MafB+/+ maintained multiple medullary compartments after recovery. Since MafB is a common marker used to identify macrophage populations, it stands to reason that a majority of the cells expressing MafB in the thymus are likely macrophages , each of which appears to serve distinct functions. Macrophage heterogeneity in the thymus was also elucidated using this technology, and we can now appreciate that there are two macrophage populations in the thymus, Timd4+ and CX3CR1+. However, there are still many questions remaining, such as which thymic macrophage subset plays a role in thymus repair? Do thymic macrophages play a role in the negative selection of T cells, if so, which subset? By addressing these questions, we can pave the way to promoting new clinical therapies for the repairing of the thymus post injuries.The thymus is a sophisticated organ that is important for generating T cells, which play a critical role in immune function. As a result, severe consequences can arise if thymic homeostasis is not properly regulated. This therefore demands the need to have a thorough understanding of the thymus environment that induces and support T cell development. Although the T cell selection process by TECs has been well studied, whether thymic DCs and macrophages are important players in T cell development, selection and thymus homeostasis remain to be further elucidated. With scRNA-seq technology, several groups have been able to identify new populations of DCs in the thymus .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The aim of this study is to evaluate teachers' perceptions of online seminars during COVID-19 pandemic to improve future courses in pharmacology. The study was performed as a questionnaire survey. A questionnaire that included 11 questions was used. A total of 14 online seminar teachers, of which 9 were senior teachers and 5 were PhD students, filled out the questionnaire. PhD students’ and senior teachers’ answers to questions 1–5 were compared statistically. The results of questions 6–10 were analysed qualitatively through thematic content analysis. There were no significant differences between senior teachers and PhD students in regard to the scores given to questions 1–5 in the questionnaire. Most (65%) teachers scored the online seminars lower than in person seminars. Interaction, communication, and group dynamics were mostly perceived to be less effective at online seminars compared to in person seminars. The main advantages of online seminars were time saving and flexibility. The main disadvantages of online seminars were reduced student interest, risk of monologue discussion and poorer communication without body language. Most teachers experienced minor technical problems with internet connection and sound quality. The teachers mentioned that better group dynamics, smaller groups, better chat functionality and clearer guidelines could help to improve online seminars. As an alternative to online seminars, blended-learning could be used. This way, one could appreciate both the richness of interactions in a face-to-face environment as well as the flexibility and convenience of online learning. Further studies comparing blended-learning and online teaching at seminars are needed to investigate this issue. Seminars are a prominent feature of university education and a way to encourage active student participation , 2. In oAs evident by the transition to online education during the COVID-19 pandemic and with the latest technological improvements, new methods for university education have led to altered ideas about learning . EducatiIt is possible that face-to-face interaction with students is required to optimize teaching and discussion during seminars. In addition, there is a risk that a teacher may not be able to fulfil all necessary tasks during online seminars. The design sometimes needs to be different during online seminars, as compared to in person seminars, which requires other and sometimes more advanced teacher skills .The Department of Pharmacology at the University of Gothenburg, Sweden, is responsible for several courses that include teaching seminars. Based on the learning objectives, seminars have an extremely important function when it comes to student-activating teaching. Prior to the COVID-19 pandemic, all seminars were given at in person. However, because of restrictions, all seminars were performed online during the COVID-19 pandemic. In the current study, we aimed to investigate pharmacology teachers’ perspectives on improving online seminars.Bernard et al. defined that distance education/online learning refers to teaching/learning conditions where students and teachers are physically separated from each other but have two-way communication that connects them . They fuPlanned online learning is meaningfully different from emergency remote instruction . SeveralThe review of the current literature on online learning and emergency remote instruction demonstrates the importance of the current study. The main research questions we aimed to address were what teachers’ perceptions of online seminars during the COVID-19 pandemic are and how we can improve online seminars that were designed as an emergency remote instruction. We believe that the results of the present study can guide teachers in university education to make online seminars more effective in the future, especially in emergency situations like during a pandemic.www.freeonlinesurveys.com). It was only possible to see if the origin of the comment was from a senior teacher or a PhD student. The teachers who answered the survey could only see a summary of the overall results, not any result for individual participants. Zoom was the online platform used during online seminars. It was decided to use Zoom since both the teachers and students had most previous experience with Zoom. In addition, Zoom was assumed to be perceived as easy to use, and there are many functions in Zoom, such as chat function and break-out rooms, that help teachers to perform effective online seminars.In the current study, an anonymous questionnaire that contained 11 questions  and took approximately 20 min to complete was used to examine teachers’ reflections and perceptions to online seminars during the COVID-19 pandemic . In totaU test was used for statistical comparisons. Statistical significance was considered for p values < 0.05. The total number of comments that were analysed for each question regarding questions 6–10 in the questionnaire was 13 . The results of questions 6–10 were presented on the basis of a qualitative inductive method with a thematic content analysis that made it possible to evaluate the teachers' perceptions to online seminars. The six steps developed by Braun and Clarke  were followed for analysis of teachers’ answers to questions 6–10  to interact with”.Three senior teachers and 3 PhD students suggested having even smaller groups by using breakout rooms. The main reasons for this were to improve group dynamics and have more interactive discussions:“Better chat function. Add time for possible questions at the end”.A PhD student mentioned the importance of the chat function and additional time for possible questions at the end of the seminar to improve online seminars in the future:Some teachers (3 senior teachers and 1 PhD student) mentioned the need for clear guidelines during online seminars:“Clear guidelines for students and teachers”.It seems that two senior teachers became annoyed with online seminars and would prefer to do seminars on in person:“That they are only used in emergencies = in connection with a pandemic or similar. Otherwise, I definitely prefer in person seminars”“Remove them”.Table Four teachers (29%), of which three senior teachers and one PhD student, evaluated the online seminars much worse in relation to in person seminars while only one PhD student (7%) thought that online seminars were much better compared to in person seminars. Four teachers (29%), of which two senior teachers and two PhD students, meant that there was no difference between online seminars and in person seminars. Five (36%) teachers, of which four senior teachers and one PhD student, evaluated the online seminars as slightly worse, in comparison to in person seminars. PhD students and senior teachers mentioned similar pros and cons of online seminars.This study showed that the interaction/communication and group dynamics became worse at online seminars compared to in person seminars, even though 3 PhD students believed the opposite. A common problem during online seminars was getting students involved in the discussion. According to the teachers, the main advantages of online seminars were time saving and flexibility. The current study also showed that some students who usually didn’t dare to ask at in person seminars asked more questions and participated more during online seminars. The main disadvantages of online seminars were reduced student interest, risk of monologue discussion and poorer communication without body language. Most of the online seminar teachers experienced minor technical problems with Internet connection and sound quality. To improve online seminars in the future, the teachers suggested to improve group dynamics, to have even smaller groups with the help of breakout rooms and better chat function and to have clear guidelines for both students and teachers. Most  teachers evaluated the quality of online seminars worse than in person seminars.The current study showed that group dynamics, the interaction between students and student participation were worse during online seminars compared to in person seminars. These results differ from some previous studies. It has previously been shown that communication during online teaching, like online seminars, was evenly distributed and most students participated in the discussion during online teaching . Two graCommunication/interaction between students at online seminars is generally accepted as a key factor and active student participation leads to the birth of various interesting ideas . Khine eMason stated that the constructivist idea could be encouraged through the active participation of students in online discussions and through the changing role of the teacher into a guide . As a goPrevious studies showed that students would be more likely to attend online seminars if they receive feedback and advice from their classmates , 27. StuAccording to the teachers that participated in this study, time saving and flexibility were the most important advantages of online seminars. This is in accordance with previous research that showed that most students appreciate the flexibility, convenience and reduced costs associated with online learning . In our Previous studies have shown that a particular disadvantage of online discussions is that they take place without the rich mix of speech and body language that helps to convey emotions , 31. In The current data revealed that the teachers suggested having smaller groups, a better chat function and clearer guidelines for both students and teachers to improve online seminars in the future. One way to generate smaller groups is to use breakout rooms. By using this, students would have the opportunity to experience simplified social interactions and improved information exchange. However, it may be more difficult for some teachers to have control over the discussion when having to monitor several groups. The chat function is also considered important because some students who do not dare to ask questions orally could type questions. A chat function can also play a role in creating friendship, group identity and social support. Similarly, Haythornthwaite showed that students preferred to use special tools, such as the chat function in Zoom, to ask for help that they would not otherwise ask in front of the whole group . When itCompared to planned online learning, the current situation with emergency remote instruction could potentially have led to worse communication and group dynamics, less student participation and ineffectiveness of online seminars compared to in person seminars. Since emergency remote instruction frequently lacks a theoretical framing in guiding its design, the findings in the current study can be understood better by looking closer into the entities described within the community of inquiry framework. In an online learning/teaching environment, community of inquiry has three components: social presence, cognitive presence and teaching presence –36. ThesThe current study showed that online seminar teachers experienced several challenges that can be observed in emergency situations like the COVID-19 pandemic. Ferri et al. divided the potential challenges of emergency remote instruction into three categories: technological, pedagogical and social challenges . TechnolAlthough we received satisfactory answers for the topic we wanted to investigate, the present study has some limitations. The questionnaire was kept as short and clear as possible to increase the number of answers from teachers. The results could have been different if we had done interviews or had more questions in the questionnaire. The aim of this study was to examine teacher’s perceptions of online seminars, but student’s perceptions should also be examined in future studies.That most of the seminar teachers (65%) evaluated the quality of online seminars worse than in person seminars might be due to most teachers longing for profound interactions, as previously experienced in a face-to-face environment. However, online seminars have some benefits that cannot be ignored. It may be a good idea to do online seminars in conjunction with face-to-face discussions on in person (blended-learning). This way, students and teachers can enjoy the richness of communication and social interactions in a face-to-face environment as well as the flexibility and convenience of online learning.The most common problems during online seminars, as compared to in person seminars, are worse communication and group dynamics as well as less student participation. However, online seminars have some advantages, such as being time saving and having greater flexibility. The existing functions in Zoom, such as break-out rooms and a chat function, can be used more efficiently to improve online seminars. Clear guidelines for both teachers and students can also help to improve online seminars in the future. Allowing students to take responsibility for their own learning can also promote a deeper understanding of the subject and improve interaction during online seminars. After the COVID-19 pandemic, blended-learning can be an excellent alternative to take advantage of the benefits of both a face-to-face environment and online learning.


With the continuous improvement of the power density of the power delivery (PD) adapter, switching frequency increases and volume decreases. The EMI issues caused by magnetic near-field coupling effects have become bottlenecks in the PD adapter’s EMI suppression. In this paper, the coupling characteristics of the magnetic field are deeply analyzed, and the equivalent circuit considering near-field coupling effects is derived. According to the electromagnetic field theory, the mathematical models of near-field coupling between transformer as well as power PCB circuits and the input plug are established. Based on this, the influence of the structure parameters of the input plug is studied. Finally, a new input plug loop structure is proposed, which can reduce the near-field coupling effects between the transformer as well as power PCB circuits and input plug. The experimental results verify the theoretical analysis to be correct and effective. The near-field coupling effects are hard to understand and deal with.With the continued increasing power density of the power delivery (PD) adapter, the distance among devices is getting closer and closer. The electromagnetic coupling between two components is becoming enormous. Furthermore, electromagnetic interference (EMI) caused by near-field coupling effects has become a bottleneck in PD adapter’s design8. In Ref.6, the leakage magnetic field distribution of power factor correction (PFC) choke and the sensitivity of common-mode (CM) choke in a PFC converter are analyzed. It reveals that the insertion loss of the EMI filter may be deteriorated by the magnetic field coupling between PFC and CM chokes. In Ref.7, the magnetic field distribution of planar transformer and the influence on CM choke coil in power supply have been analyzed. Moreover, the layout, shielding, and CM choke design method are proposed to reduce the effects of magnetic near-field coupling to suppress EMI noise.As for the influence of magnetic near-field coupling on EMI, research results mainly focus on the effect of near-field coupling between magnetic power components and EMI filter11. In Ref.8, near-field coupling between two shunt capacitors in the EMI filter is analyzed, and a negative mutual coupling method is proposed to offset the equivalent series inductance (ESL) of capacitors. In Ref.9, the electromagnetic coupling of a CLC EMI filter is analyzed. A method is proposed to balance the parasitic inductive and capacitive coupling between two capacitors. It can optimize the performance of the EMI filter. In Ref.10, magnetic field coupling in a two-stage EMI filter is analyzed. A series inductor integration method using near-field coupling effects is proposed to improve the low-frequency performance of the DM EMI filter.Besides, the characteristic of the EMI filter can also be affected by magnetic near-field coupling between components inside EMI filter14. A double-wire parallel wound CM choke in the PD adapter is usually adopted to reduce near-field coupling effects between power magnetic components and CM choke. In this case, near-field coupling paths in the compact PD adapter are pretty different from traditional ones.However, the input plug close to the high-frequency power circuits is also a possible noise propagation path due to near-field coupling effects, especially in high power density applicationsTherefore, this paper analyzes near-field coupling characteristics in a compact PD adapter and studies the influence of near-field coupling on DM conducted EMI noise. Magnetic field coupling between transformer as well as PCB power current loops and input plug loop are intensely studied. The mathematical coupling models are built, then a near-field coupling optimization method is proposed. Finally, experiments verify the theory analysis to be correct and flexible.The topology of the PD adapter is shown in Fig. Near-field coupling between transformer and CM choke can be analyzed by the electromagnetic theory, in which the transformer is usually seen as an interference component. In contrast, CM choke is deemed as a sensitive component. The propagation path of DM noise coupled to the CM choke is shown in Fig. The leakage magnetic field generated from the transformer and coupling to CM choke can be divided into three directions .ux1 and ux2 are the induced voltage generated in part 1 and part 2 of the live wire, ux3 and ux4 are the induced voltage generated in part 1 and part 2 of the naught wire, respectively. Both windings have a symmetrical structure and are tightly wound together. Therefore, the total induced voltages are offset. The CM choke is insensitive to the magnetic field along the x-axis.Figure uy1–uy4 are the induced voltage generated in four parts of the live wire, uy5–uy8 are the induced voltage generated in four parts of the naught wire, respectively.Figure uz1 and uz2 are the induced voltage generated in live wire and naught wire, respectively.Figure Above all, the double-wire parallel wound CM choke has high immunity to external magnetic field interference. Therefore, near-field coupling between transformer and CM choke is usually at a low level and can be neglected. Similarly, the magnetic field coupling between DM choke and CM choke can also be analyzed by the same method. It can usually be neglected too.LAcin is the parasitic inductance of the input plug, LCM is the inductance of CM choke, L1 is the inductance of DM choke, Lpcb1 and Lpcb2 are the parasitic inductance of the primary and secondary power PCB loops. Near-field coupling between other devices and these three devices is taken into consideration. M1–M12 are the mutual inductance between every two components or loops, respectively.As to near-field coupling in PD adapter, not only magnetic components in the circuits need to be considered, but also input plug and high-frequency power PCB circuits. The complete near-field coupling model of the PD adapter is shown in Fig. L1 can be simplified into a corresponding current-controlled voltage source, and its equivalent circuit is shown in Fig. Near-field coupling between magnetic components in the PD adapter and the primary and secondary power PCB loops and DM choke C1 and C2 at both ends of the DM choke, the noise coupled to L1 can be bypassed by C1.Since there are two X capacitors LCM and magnetic components in the PD adapter, as well as the primary and secondary power PCB loops, is shown in Fig. The equivalent circuit diagram of near-field coupling between CM choke LCM has high immunity to the interference of near-field coupling, so near-field coupling between CM choke and other components, or loops can be neglected.The two-wire parallel wound CM choke Near-field coupling between the input plug and magnetic components in the PD adapter, as well as the primary and secondary power PCB circuits, can be simplified into a corresponding current-controlled voltage source, and its equivalent circuit is shown in Fig. LACin of the input plug can directly flow into LISN and form DM noise.From Fig. Above all, near-field coupling between high-frequency power PCB circuits and other components of the PD adapter and the input plug will be the critical factor, and it may affect the EMI performance of the PD adapter.Mtrans, calculated by Eq.  simulation model is shown in Fig. However, the established equivalent model of the near-field coupling between the transformer and the input plug loop is different from the actual structure. The magnetic core and winding turns cannot be infinite, and some other components are close. Hence, the actual mutual inductance Mtrans varying with the plug structure parameters can be obtained through simulation analysis, as shown in Fig. The mutual inductance Mtrans obtained by simulation with l and s1 is the same as model calculation results. However, the variation trend of Mtrans obtained by simulation with d is somewhat different from the model calculation result. The model calculation result have shown that Mtrans increases linearly with the distance d between plug pins. Actually, the transformer windings are not infinite, and the leakage flux generated by the transformer decreases with the distance from the transformer. Therefore, the mutual inductance between the transformer and the input plug loop will not increase infinitely with d, but will tend to a constant value. For the above reasons, the values of simulation and calculation have some differences too.As shown in Fig. Mloop can also be used to represent the influence of near-field coupling effects. It can be seen from Eq. .The mutual inductance of two rectangular loops in the same plane can be calculated using the Neelman equation. The Cartesian coordinate system is established, as shown in Fig. Coordinate transformation is carried out for formula  to calcuMloop of two rectangular loops is as follows:According to Eqs. –10), th, th10), Mpri is calculated as:Theoretically, a PCB loop with an arbitrary shape can be equivalent to a limited number of rectangular loops. For the convenience of calculation, several rectangle loops with key influences are usually taken to approximate the primary power PCB loop with an equivalent irregular shape. As shown in Fig. PCB traces have a specific width in actual applications, and the current does not flow at the centerline of the PCB traces. They are different from the above theoretical assumptions. Meanwhile, if two loops are not in the same plane, the calculation method is different. The loop needs to be projected to xoy, xoz, and yoz planes.The simulation was carried out to explore the influencing factors of mutual inductance between the PD adapter’s power current loops and the input plug loop. Moreover, the influences of different plug structure parameters on near-field coupling are analyzed. The FEA simulation model is shown in Fig. l, width d between plug pins and loop spacings s2 unchanged, the mutual inductance between the primary power PCB loop and input plug loop under different lengths l, widths d, and distance s2 can be obtained through simulation. Where l is 80 mm, d is 25 mm, s2 is 1.94 mm. The trends of mutual inductance Mpri between the two loops with d, s2, and l are plotted in Figs. By keeping two parameters of length Mpri between the primary power PCB loop and the input plug loop increases with plug length l, and the change rate of Mpri decreases with l. When l reaches 50 mm, the increment of Mpri with l is not apparent. The simulation results are consistent with the theoretical calculation results. Therefore, in this near-field coupling model, the effective length influenced by near-field coupling is 50 mm.It can be seen from Fig. d between plug pins, Mpri increases, and when d is in the range of 0–25 mm, Mpri increases linearly. When d reaches 50 mm, it continues to grow, but the increment of Mpri is not apparent. It is consistent with the theoretical calculation results. Therefore, the effective width influenced by near-field coupling is 50 mm.It can be seen from Fig. Mpri decreases with the increase of the distance s2, and when the distance s2 increases above 20 mm, the decreasing trend of Mpri of two loops slows down. It is consistent with the theoretical calculation results. Therefore, the effective distance influenced by near-field coupling is 20 mm.As shown in Fig. Mtotal of the PD adapter to the input plug loop is equal to the sum of the mutual inductance of the transformer and the primary and secondary PCB loops to the input plug loop.Similarly, magnetic field coupling between the secondary power PCB loop and the input plug loop can be theoretically calculated and simulated by the same method. Then, the total mutual inductance According to the above analysis, it can be known that the effects of near-field coupling on the input plug loop can be suppressed by increasing the distance between the input plug loop and transformer as well as power PCB loops. However, considering the volume of the PD adapter, the application of this method is limited.Mtotal can be reduced by reducing plug length l and width d between plug pins. However, there are specific requirements for the charger plug length l and width d in practical application.On the other hand, the mutual inductance Mtotal is related to the shape of the input plug loop. In this situation, the magnetic field distribution needs to be analyzed firstly. The flux lines generated by the primary power PCB loop and transformer can be obtained through simulation, as shown in Fig. Besides, the Therefore, considering the distribution of the magnetic field generated by the transformer and the primary power PCB loop and the influence of the effective length on the near-field coupling, a new input plug structure is proposed. The horizontal distance between two plug pins within the effective length range can be reduced, and the vertical distance between two plug pins is increased to satisfy the safety requirements. If necessary, the live and naught wires can be separated at the end, as shown in Fig. By dividing the projection of the designed structure into several equivalent rectangles, the influence of near-field coupling on the input plug loop can be calculated by a complete near-field coupling model, and total mutual inductance is equal to the sum of mutual inductance. Because the distance between plug Loop 3 and adapter is far, the influence of near-field coupling on plug Loop 3 usually can be neglected. Therefore, the mutual inductance of the designed structure is simplified as follows:M1 and M2 are the mutual inductance between the adapter and rectangular plug Loop 1, Loop 2, respectively. Hence, the structure of the input plug can be optimized by adjusting the size of rectangular plug loops. The first method is adjusting the structure of rectangular plug Loop 2 to achieve negative coupling between adapter and Loop 2. Therefore M1 and M2 cancel each other out, as shown in Fig. M1 and M2 approaches 0.In this paper, a structure with a minimum size of rectangular plug loops is designed to suppress the influence of near-field coupling. The prototype’s original and proposed structure is shown in Fig. 16 is used to measure mutual inductance between the primary power PCB loop and the input plug loop. After the MOSFET and bus capacitor Cin in the primary power PCB loop are short-circuited, the primary power PCB loop is connected to the TG output port of the network analyzer, and the input plug loop is connected to the RF input port, respectively, as shown in Fig. K) and mutual inductance is as follows:Lpcb1 and LACin are the self-inductances of the primary power PCB loop and the input plug loop, respectively. The insertion loss K(f) curve between the primary power PCB loop and plug loop is shown in Fig. The insertion loss methodf = 550 kHz are shown in Table When the near-field coupling between the transformer and the input plug loop is evaluated, the secondary side of the transformer needs to be short-circuited. The mutual inductance between the transformer leakage inductance and the plug loop is calculated. The measurement results at A PD adapter is taken as the prototype for the experiment. The specification is shown in Table According to standard EMI measurement principles CISPR22, the prototype’s noise spectrums are tested in an electromagnetic shielding chamber. It is mainly composed of the device under test (DUT), ESH2-Z5 linear impedance stabilization network (LISN), and R&S ESCI EMI receiver.The noise spectrums under the original and proposed structure are shown in Fig. As shown in Fig. In this paper, possible magnetic near-field coupling between components and loops in the PD adapter is analyzed, and the complete coupling model of the PD adapter is proposed. Then the mathematical model of the near-field coupling between plug loop and magnetic components as well as PCB traces is established. Based on it, a new structure is proposed which can effectively reduce the near-field coupling. Finally, a 40 W PD adapter is used as a prototype to verify the effectiveness and feasibility of the proposed optimization scheme.


Neurosurgical Focus in 2012, the interest in this educational platform and number of submissions for publication have risen dramatically. Recognizing this need for an enhanced platform for video materials, we have increased our capacity in this arena. Initially published twice per year, our video supplement issues are currently published quarterly.Since the advent of video supplements introduced by Neurosurgical Focus: Video. This new periodical will capitalize on the current technological video enhancements available in an open-access web-based publication. Under the outstanding leadership of Neurosurgical Focus Associate Editor Aaron Cohen-Gadol, the new journal will utilize the advantages of video to demonstrate the following themes of operative intervention:•Operative anatomy•Surgical technique•Novel or enhanced surgical approaches•Surgical complications•New technology and instrumentationThe growing international interest for this media has demonstrated to the Journal of Neurosurgery Publishing Group (JNSPG) the need for an enhanced platform for its dissemination. In this regard, it is my absolute pleasure to announce the establishment of the inaugural issue of In addition, in future issues we wish to initiate an operative forum for open feedback and discussion of material published. We intend this new journal to function as a world platform and encourage submissions accordingly. The quarterly format will continue, with topic-specific editors with additional experience in video editing to offer the most contemporary peer review. We invite video submissions that demonstrate both macro- and microscopic and endoscopic techniques.Neurosurgical Focus: Video! We have compiled a remarkable set of videos that include anatomic correlative enhancements of surgical principles and technique with the management of patients with symptomatic cavernous malformations.We hope you enjoy the inaugural issue of


In this paper we introduce a new representation for the multistationarity region of a reaction network, using polynomial superlevel sets. The advantages of using this polynomial superlevel set representation over the already existing representations  is discussed, and algorithms to compute this new representation are provided. The results are given for the general mathematical formalism of a parametric system of equations and so may be applied to other application domains. Many problems in applied sciences can be modelled by a parametric polynomial system, and therefore to solve such problems we must be able to explore the properties of these systems. In particular, we often seek to identify areas of the parameter space where a property holds. The contribution of this paper is a new methodology for exploring these.We are motivated by the problem of understanding the multistationarity behavior of a Chemical Reaction Network (CRN). In a CRN, variables represent the concentrations of the species. These change as time passes and are studied as part of the field of dynamical systems. This is of polynomial type when the kinetics is assumed to follow the mass action rules. The equilibria of such a dynamical system are therefore the solutions to a system of polynomial equations. However, the coefficients of the terms on the polynomials may involve some parameters. These parameters are usually the rates under which a reaction occurs and the total amounts .Both the variables and parameters can only attain non-negative real values. A network is called multistationary if there exists a choice of parameters for which the network has more than one equilibrium. There are already many algorithms developed for answering the binary question of whether a system can exhibit multistationarity –9. The iIn the case where multistationarity can exist it then becomes important to determine the parameters where the network has this behavior. There has been less progress in this direction in the literature to date: the present paper offers a promising new development for this problem.Reviewing the state of the art in the literature, we see one vein of work focused on specific reaction networks, with success following heuristic or manual calculations to find a suitable parameter which may not work in generality , 11. TheRecently in  a new apIn this work, we propose using polynomial superlevel sets to approximate the union of the hyperrectangles from  as a setThe organization of this paper is as follows. The mathematical framework of reaction networks and the definition of the multistationarity region is given first followed by a section containing the notations regarding parametric functions and definitions of the sampling and the rectangular representations of the multistationarity region from  is used to show the hyperractangle S of a hyperrectangle S with respect to B, i.e.X is distributed by a normal distribution with mean g(X) when X is distributed by a probability distribution q is denoted by The cardinality of a set All computations for the examples of this paper were done on a computer with the following information. Processor: Intel(R) Core(TM) i7-10850H CPU @2.70GHz 2.71 GHz. Installed memory (RAM): 64.0 GB (63.6 GB usable). System type: 64-bit Operating System, x64-based processor.The software and programming languages used for the computations reported in this paper had the following version numbers: Maple 2021, Matlab R2021a, YALMIP, SeDuMi 1.3, Julia 1.6.2, MCKR 1.0.In this section, we introduce the concepts of reaction network theory that are needed throughout the rest of the paper, with the help of a simple gene regulatory network example.One can think of a gene as a unit encoding information for the synthesis of a product such as a protein. First, a group of DNA binding proteins called transcription factors bind a region of the gene called promoter. Now an enzyme called RNA polymerase starts reading the gene and produces an RNA until it arrives in the terminator region of the gene. The process until here is called the transcription step. After transcription is completed, the resulting RNA leaves the nucleus (in eukaryotes) and reaches ribosomes. In ribosomes, the second step, called translation, gets started. Ribosomes assemble a protein from amino acids using the manual guide written in the RNA. A gene encoding of a protein recipe is said to be expressed when it gets transcribed to an RNA, and the RNA translated to the protein. A gene is not always expressed in a constant rate. There might be proteins that bind the transcription factors or the promoter region and, as a result, inhibit the RNA polymerase starting the transcription process. On the other hand, there might be other proteins in which their binding to the transcription factors or the promoter region enhances the transcription.A, B, and C as their final products. Denote their concentrations at time t by [A](t), [B](t) and [C](t) respectively. The concentration of these proteins will not remain constant all the time, and we have an Ordinary Differential Equation (ODE) system describing the variation of the concentrations as time passes, see Fig. A activates the expression of the second gene with Michaelis-Menten kinetics with the maximum rate A and B together with the product of two Michaelis-Menten kinetics, with maximum rate C,  and protein C has an inhibitory effect on the expression of the first gene, captured by the denominator Consider a simple example from  then a grid on B is achieved by dividing B along each axis to equal parts. Then for each sub-hyperrectangle of B in this rectangular division we assign the average of the number of solutions of k coming from the sub-hyperrectangle. This approach hereafter is referred as the rectangular representation approach. See Fig. A different discretization can be done using a rectangular division of Consider the gene regulatory network in  to 100 equal sub-rectangles and then solving the system for 10 points superlevel set of f is the set of the formU(f). Naturally, a polynomial superlevel set is a superlevel set of a polynomial.Consider d. A sum of squares (SOS) polynomial of degree 2d is a polynomial d by Polynomial sublevel sets are defined similarly as in Definition K a closed subset of B. For  where U(p)  of degree d can be written as p(x) which are the variables of the optimization problem.Let p(x) has to be nonnegative on B. This can be enforced by lettingK or in other words K. This holds if and only if Now let us look at the constraints. First of all d YALMIP , 32 whicd YALMIP .K be the union of rectangles B, 9 of them satisfy this condition. These sub-rectangles are colored orange in Fig. p of the PSS representation of degree 2. Figure U(p).We continue with the example from Fig. $B= and then transforming the PSS polynomial back to the original B allows a better PSS approximations via YALMIP. For degrees 2 and 6 the numerical problem message is avoided but for degree 10 it remains. The results are shown in Fig. Let us illustrate this with our ongoing example. Consider the sampling representation of the multistationarity region of the network of Example 3.4 given at Fig. B takes the same amount of time as solving the system at 1000 random points with only 2 of their coordinates varying took time in the previous case. It took about 1.5 s to compute the 45 coefficients of the polynomial of the PSS representation of degree 2. The polynomial found is the following.To demonstrate that the number of free parameters need not be 2 to be able to compute the PSS representation, we repeated the above process with all 8 parameters of the system being free in the following hyperrectangle:p is a polynomial of degree d. K is impossible. In order to save or show the sampling representation one needs to use a matrix of the size When K using the sampling representation is not a straightforward task. However, using the PSS representation one needs to verify only one condition of the evaluation form, To test if a point K, using the sampling representation, if K and then take the minimum. Using the PSS representation, whether To compute the distance of a point In a typical example from CRN theory, r is usually much higher than 2, and therefore item 1 is really important. When rm, one can use less memory by saving the PSS representation instead of keeping all the points of the sampling representation in the memory. Further, as items 2 and 3 show, this will not cause a loss of information about the multistationarity region.Let us address why one should find a PSS representation of the multistationarity region using the sampling representation if one already has a sampling representation. Let We showed earlier  that the PSS representation can be generated for examples with a higher number of parameters than two. There, we let all 8 parameters of the network in Fig. Consider a gene expression system with 4 species me as in :5\documeIn  it is sh,,5,14]$$\,,5,14]$$\As shown in the previous section, it is possible to get the PSS representation both from the sampling and the rectangular representations. If one needs to solve the system at random points and take an average in order to get the rectangular representation, then using the rectangular representation does not have much advantage over using the sampling representation for the purpose of finding the PSS representation.m equal parts, then the number of sub-hyperrectangles in the rectangular representation becomes B to equal sub-hyperrectangles. When using a bisection algorithm, the rectangular decomposition usually contains fewer number of sub-hyperrectangles .But in some cases it is possible to compute the average number of the solutions without solving the system. One such case is introduced in . InsteadB. The goal is to express B. One of the shapes of multistationary networks, observed often for realistic models, are bistable networks with a folding type of bifurcation, such as in dual phosphorylation cycle [Let us simplify the question. There is a hyperrectangle on cycle .(i)This can happen if and only if for almost every (ii)This can happen if and only if for almost every (iii)This can happen if and only if The proof is straightforward by noting thatB is a subset of B is a subset of B along only one axis into two equal sub-hyperrectangles. We continue in this fashion until each sub-hyperrectangle is inside two-value bisection search hereafter. This algorithm is formally written in Algorithm 1.In our settings these networks have one steady state for some choices of parameters and threeA similar algorithm was presented in  is not nB are of different scales, then it is better to replace the termination condition of Algorithm 1 with the following:If the length of the edges of q is a distribution on S and then find a rectangular representation using two-valued bisection search and afterwards a PSS representation.We are not going to explain how to use the Kac-Rice integral in the CRN framework as it is not the topic of this paper. All algorithms in this paper are independent from the choice of the algorithm to compute the expected number of solutions of a parametric system on a given parameter region. A simple algorithm to achieve this is to solve the system for several random points from the given hyperrectangle according to a random distribution of interest and take the average. Thus we may assume the existence of a method capable of computing To illustrate this method we use Example 2.1 of , shown halues in ), the gogiven in  it takesgiven in  as the fS in the process of this algorithm. Then the total number of expectations that are needed to be computed until the termination of this algorithm is equal to B along each axis to Note that having fewer hyperrectangles in the rectangular representation obtained by the two-valued bisection search does not guarantee a faster speed than the simple approach for finding a rectangular representation discussed in the previous section. Consider the setting in Algorithm 1. Assume length of all edges of S is an almost subset of S to Now consider a more general case where S which has the same zero measure sets as Lebesgue measure’s we have Note thatq on S we have q one can attain any point in q, we will not get Returning to our goal assume B is almost subset of q on B with the same zero measure sets as Lebesgue measure’s.Let two-step bisection search.Note that in  it is meConsider the following univariate polynomial of degree 5 with two parameters from [lication  which co


Miliaria is a self-limiting cutaneous disease that may develop from skin exposure to humid climates, occlusion, or raised temperatures, forming groups of 1-3-mm-sized sweat-filled vesicles in the epidermis due to obstruction of the eccrine sweat duct. Here, we describe the first case of extensive bullous miliaria reported in a 47-year-old female with no comorbidities or significant medical history. Miliaria crystallina occurs when sweat ducts in the most superficial layer of the epidermis, the stratum corneum, are obstructed. Miliaria rubra occurs when sweat ducts get blocked at the mid-epidermal level, and miliaria profunda is noted when the block occurs at the dermo-epidermal junction . Risk faThe vesicular lesions are typically 1-3 mm in diameter and self-resolve after removal of the triggering factors. Typically, patients experience superficial desquamation, but post-inflammatory hyper or hypopigmentation can also occur. The most serious complications include impaired thermoregulation and secondary bacterial infection.To our knowledge, this is the first reported case of miliaria presenting with multiple bullous skin lesions admixed with smaller vesicles.A 47-year-old female, known to have glucose-6-phosphate dehydrogenase deficiency but otherwise healthy, presented to the emergency room with a five-day history of pruritic, elevated lesions all over the trunk, abdomen, and back that appeared one day after an episode of high-grade fever. Initially, the lesions appeared as grouped vesicles, which later became enlarged and/or coalesced, forming clear bullae with associated pruritus. The itch worsened during nighttime, impacting the patient’s ability to sleep. Along with the lesions on her abdomen, the patient presented with multiple erythematous maculopapular lesions on all four extremities. Apart from fever and itchiness, there were no other associated signs or symptoms.Before presenting to the emergency department, the patient received topical and intravenous (IV) corticosteroids at the local health center; however, the lesions failed to subside.Upon admission, a general physical examination and laboratory testing were done. On examination, the patient had stable vitals and clinically presented with multiple vesicles and bullae, on an erythematous base, mainly on the trunk, abdomen, and back Figures , 2. WhenThe differential diagnosis at the time of admission included miliaria crystallina/rubra, bullous pemphigoid, viral exanthems, allergic dermatitis, disseminated herpes, varicella, and vasculitis.A 4 mm skin punch biopsy was obtained from the abdominal lesions for further characterization of the nature of the skin lesions and to assist in making the diagnosis. Hematoxylin and eosin staining of the epidermis revealed hyperkeratosis, focal parakeratosis, spongiosis, and exocytosis of lymphocytes and neutrophils. The dermis showed moderate perivascular lymphohistiocytic infiltrate without eosinophils or neutrophils. Histopathological evidence of vasculitis or viral infection was absent Figure .While waiting for the serology, laboratory, and pathology results, the patient was initially managed with IV acyclovir, topical steroids, cetirizine, paracetamol, cool compresses, and IV fluid support.Over the next few days, while the patient was on empiric and supportive therapy, she did not develop any new lesions. She did have a single episode of hypotension, which was corrected by adjusting IV fluids.The diagnosis of miliaria induced by fever was made based on the clinicopathological correlation and response to treatment; the type of miliaria was considered to be an overlap between crystallina and rubra. After allergic and infectious causes were ruled out, acyclovir was discontinued, and the patient was treated with antihistamines and topical steroids to control pruritus, as well as oral paracetamol with cold compresses to cool the body and reduce the fever.A couple of days after admission, as the fever subsided, almost all the blisters receded; some ruptured and were replaced by serous crust, and the background erythema disappeared. The patient was subsequently fit for discharge with no medications. On the first follow-up visit a week later, all the previously persistent and crusted lesions had healed completely.Although miliaria is common in newborns and infants due to the immaturity of sweat glands, it is also common in adults exposed to hot and humid environments. As detailed above, there are three main types, namely, crystallina, rubra, and profunda. Miliaria crystallina involves the eccrine ducts within the stratum corneum. The lesions are superficial, self-limiting, and can easily rupture. Miliaria rubra, the most common form, involves the eccrine ducts in the mid-epidermis, which usually shows an inflammatory response and tends to form larger vesicles with an erythematous base. These lesions are typically associated with pruritus and may form pustules. Miliaria profunda affects the eccrine ducts at the dermal-epidermal junction, forming non-pruritic, skin-colored papules, and is the rarest among all three types .Our patient’s presentation with a sudden-onset pruritic fluid-filled vesicular and bullous eruption on her trunk, back, and abdomen was most consistent with a miliaria crystallina/rubra overlap.What was unusual in this case presentation was that many of the lesions were bullae with a diameter larger than 1 cm. Miliaria usually is described as small vesicles and pustules that rarely reach sizes over 3 mm, making our case the first of its kind in describing bullous lesions in miliaria that were larger than 1 cm and reached up to 2 cm in some areas of the abdomen.While allergic reactions, vasculitis, viral exanthems, and herpetic infections can have similar presentations as miliaria and had to be included in the differential diagnosis, history taking, physical examination, laboratory investigations, serology, and histopathology all helped in ruling out these entities and confirming the diagnosis of miliaria.Miliaria with multiple bullous lesions in a healthy individual is noteworthy, and our case is the first one describing this unusual presentation of a common skin disorder, which will help dermatologists as well as histopathologists in reaching a correct diagnosis when faced with a similar presentation. Through this article, we wish to emphasize the importance of keeping a broad differential diagnosis in approaching such unsuspected cases.


Modest drinking has been repeatedly discussed in scientific papers as protective against certain diseases, such as cardiovascular diseases, but in most cases, alcohol worsens health conditions, especially when consumed at high risk levels. The complexity of the risk relationship between alcohol and health conditions has confused clinicians as to whether it should be recommended. The study aims to balance the risks and benefits of modest drinking. This retrospective cohort study of 430,016 adults recruited from a standard health-screening program since 1994, with 11,031 deaths identified as of 2008. Drinking distinguished “modest drinker” (no more than one drink a day) from “regular drinker”. Mortality risks including all-cause mortality and diseases-specific mortality with hazard ratio (HR) were calculated by adjusting for 15 confounders. Life table was used for life expectancy. Risk predictors were subjected to Cox proportional hazards regression analysis to identify significant predictors in multivariate models and life expectancy analysis. Nearly one out of 4 males (23%) was a modest drinker, who gained 0.94 year (95% CI 0.65–1.23 year) in life over non-drinker and had 8% reduction in adjusted all-cause mortality . In contrast, regular drinkers had 43% increase in overall mortality  and shortened life by 6.9 years (95% CI 6.6–7.1 years). As most drinkers also smoked, 59% in modest and 75% in regular, the combined effect shortened life by 2.0 years (95% CI 1.6–2.4 years) in modest drinker and 10.3 years (95% CI 9.8–10.7 years) in regular drinker. Cancer were increased in modest drinkers for oral  and esophageal  cancer. The gain of one year by modest drinkers was erased by a two to fourfold increase in oral and esophageal cancer and that drinking beyond modest amount led to a large loss of life expectancy. Given that drinkers are prone to cross the line of drinking, clinicians should balance the risks and benefits of drinking, as well as the understanding of whether the patient is at risk for addiction. A recurring theme is that although high doses of alcohol are harmful to the heart and causes cancer of multiple sites along the gastrointestinal tract , breast and larynx, mild to modest alcohol consumption has been associated with reductions in coronary artery diseases, diabetes, and even all-cause mortality4. In several systematic reviews and meta-analyses, modest alcohol consumption was found to be beneficial for various disease mortality and incidence risks12, especially in reducing cardiovascular disease (CVD) mortality and coronary heart disease incidence and mortality16. Furthermore, several epidemiological theories have been proposed to criticize the benefits of modest drinking, including abstainer bias, insufficient confounding factors adjustment, and “sick quitter hypothesis” means that individuals stop drinking due to serious illness17. The health outcome related to modest alcohol intake continues to be debated until now.Drinking alcohol appears to have a complex and controversial relationship with health outcome. The “J-shaped” relationship between drinking and mortality has been well cited in the scientific literature18. In other words, the cumulative evidence is that modest drinkers had lower all-cause mortality and survived better than never drinkers, even after confounders were considered. A more recent review of 83 prospective cohorts also found consuming alcohol at 100 g/week (around one drink a day) with the lowest cardiovascular disease risks19. Limited to the studying of 600,000 drinkers, authors in this study justified their report overlooking or not mentioning the risk of non-drinker. However, it was pointed out that data found in that study indicated a hidden 20% higher risk among non-drinker than the modest drinkers. The results were consistent with earlier studies but the concept of modest drinking is novel and against main stream thinking to accept “a little drinking is better than no drinking”. Furthermore, this review indicated that the all-cause mortality and hear failure risk were positively association with alcohol consumption19. However, other studies have suggested a J-type relationship between these two and alcohol consumption6. This demonstrates the complexity and inconclusive findings of past studies on the topic of modest drinking.An important meta-analysis of 34 prospective cohort with one million subjects found 1–2 drinks for women and 2–4 drinks for men inversely associated with total mortality, with an estimated 16–19% benefit18, the results may vary depending on the subjects included in the reference group, and the protective effect was reduced when ex-drinkers and light drinkers were excluded from the reference group. Comparison of relative risk is difficult and could be misleading. Another problem is whether a hidden trade-off was involved in that accepting benefits are associated with a possibility of crossing the line of drinking into excess, where a much larger increase in mortality, like 50% or 100%, maybe involved. In this study, in addition to the use of relative risks, we used absolute risk (life expectancy), and tried to present a balanced view of both sides of the issue. Life expectancy is an absolute risk that is well understood by the general public. The public may be vaguely aware that alcohol consumption may be harmful to health, but to date there is a lack of reports of its effects on life expectancy in modest drinkers.Mortality reduction between 16 and 20% may look simply to cheer about, but it is actually difficult for the public to appreciate its magnitude. As a relative risk, 20% could be high or low depending on which reference group was used. As described in the meta-analysis22. However, changes in the official recommendation are not always well known to consumers, and physicians may be confused about the definition of “modest” when conducting nutritional health counseling.Another controversy surrounding what constituted the amount in modest drinking. In the U.S. and Australia, the drinking recommendation used to be up to 2 drinks for men and 1 drink for women, with an acceptable risk of one death per 100 people in their lifetime. However, in the last 2–3 years, both the US and UK called for lowering the amount from 2 to 4 drinks to one drink a dayWith the availability of a large cohort of nearly half a million subjects followed between 1996 and 2008, we compared modest drinkers (no more than one drink a day) or regular drinkers with non-drinker. Because a large number of drinkers also smoke, we analyzed the risks individually and in combinations.During study period, 430,016 participants were analyzed. Table After adjusted 15 confounders, modest drinker had an 8% decrease in mortality risk , 34% decrease in diabetes mellitus mortality risk, 14% decrease in expanded CVD mortality risk and 26% decrease in respiratory system mortality risk compared to non-drinker  also smoked, further analysis of non-smoking drinking HRs were needed to avoid the mixing effect of smoking and drinking. Besides most smokers were male in this study cohort. Table As shown in Table In this cohort study of 430,270 adults in Taiwan, the results suggested that modest drinking is associated with significantly reduced risk of all-cause mortality, diabetes mellitus, expanded CVD , respiratory system disease (include COPD), and suicide; whereas a 2 to 4 folds increased risk of oral cancer and esophageal cancer. The results also showed that male modest drinkers gain 0.94 years (95% CI 0.65–1.23 years) and male modest drinkers who were never smokers gain 3.97 years (95% CI 3.65–4.29 years) compared to non-drinker. It appears that a little drinking could be better than none. However, drinking beyond modest amount led to a large loss of life expectancy of 7–10 years in males. Given that drinkers are prone to cross the line from limited benefits to grave consequences, clinicians should cautious in their recommendations.24. To avoid the mixing effect of smoking and drinking, the subgroup analysis was conducted to make the results closer to real world because of the high co-use rate, 72.2% of males in our study. Moreover, in order to clarify the previously proposed methodological problems of abstainers’ misclassification, sick quitter hypothesis, and potentially confounding factors17, we categorized drinking status of ex-drinkers into regular drinker to avoid misclassifying the former drinkers as abstainers and controlled 15 confounders to minimize confounding. There were still some limitations in this study. First, we collected the self-reported responses at baseline, but the participants might change their consumption behavior during follow-up. Recall bias may also exist in these self-report materials. Changes in drinking behavior, whether increasing or decreasing, and underreporting of alcohol use may affect the quality of drinking data used in this study. All subjects in this study aged 20 years or older were recruited by the MJ Health Group, Taiwan, to participate in a standard health-screening program between 1994 and 2008. A total of 11,031 deaths were identified with a median follow-up period of 8.8 years. According to the previous study25, women were more likely than men to be former rather than current drinkers in 87 of 96 age-specific comparisons, and in the majority of age groups in 30 of the 32 countries, meaning that men are less likely to quit alcohol than women. Take Japan as an example, the rate of former drinker in men was only 3.5%. The period of our study is from 1994 to 2008, and the average follow-up period was 8.8 years. According to previous literature, the rate of drinkers who quit alcohol is not high, we speculate that the impact on the results should be limited. However, the inability to continuously track drinking status is indeed one of the main limitations of this study, and we must make improvements in future study design. Secondly, there might be residual confounding factors in addition to the 15 confounders we controlled, such as the mental and socioeconomic status in suicide analysis. Lastly, the case numbers in certain death categories were too small, such as breast and bladder cancer, and may affect the statistical accuracy.This large population-based cohort study is the first study to use the life expectancy to assess the absolute risk from the different levels of alcohol consumption. The mortality risks of various diseases in males were analyzed from the data of the National Cancer Registry and National Death File. On the other hand, the co-use of smoking in drinkers is common26 indicated that the prevalence of abstainers in Taiwan was 82% in females and 56% in males in 2016, and was 84% in females and 61% in males in 1990. The prevalence of abstainers in our study was 91.9% in females and 65.4% in males, higher than the global statistics. Such a difference has no obvious explanation. Underreporting of alcohol consumption may lead the risks to be biased toward the null hypothesis18. The alcohol-attributable fraction (AF) of all cancers was highest in the Western Pacific region around the world, with 7.1% for incidence and 7.8% for mortality, which was higher than the global rates of 5.5% and 5.8% in 201226. However, the opposite research indicated that modest drinking may be beneficial to health within Asia population29. Although there is no global consensus on alcohol consumption recommendation, countries usually have their own standards. According to the Dietary Guidelines for Americans 2015–2020, women can drink up to 14 g of pure alcohol per day and men can drink 28 g per day. Previous research had also indicated that the light to modest drinking could decrease the all-cause mortality30. However, the Korean meta-analysis proposed that mild alcohol consumption have no benefit for all-cause, cancer-related, and cardiovascular mortality31. Zaitsu et al. indicated that the light to modest drinking elevated the all-cancer incidence32. Another Japanese pooled analysis revealed an increased dose–response relationship between alcohol and colorectal cancer incidence, and the relation was more apparent in Japanese than in Western populations33. It’s well known that East Asians had higher proportion of genetic variant of the aldehyde dehydrogenase 2 (ALDH2) enzyme, identified as ALDH2*2, which cause lower metabolic efficiency of reactive aldehyde carcinogens34. These results of previous studies showed that the harm of alcohol might be greater in Asia. Our study shows only 0.94 years of life gain in modest drinking group, and the benefits will be eliminated to 1.49 year life loss if smoking. About two thirds of modest drinkers smoke, meaning that only a small percentage of people can benefit from modest drinking. Moreover, alcohol is addictive and affects judgment, making it difficult to control the amount within two drinks. Once more than two drinks each time and three times a week, the life expectancy in males may reduced by 6.86 years compared with nondrinkers in this study.This study of Asians is similar to previous studies of Asian alcohol consumption, in that the effects of alcohol on Asians cannot be underestimated. The systematic analysis for the Global Burden of Disease Study 201636. The possible mechanisms might be the biologic and molecular pathways include enhanced insulin sensitivity, increased high-density lipoprotein (HDL) cholesterol, and improved endothelial function by decreased tissue injury via limited ischemia/reperfusion ratio induced by ethanol37. In contrast, Holmes et al. indicated that there were no protective effects toward CVD in low-moderate alcohol consumption group based on the Mendelian randomization analysis38. Our study also reveals non-significant CVD risk between modest-drinker and non-drinker  monograph also showed that the cancers with the highest PAFs were cancers of oesophagus, pharynx, and lip and oral cavity47. The risks are much higher than 1.17 times of oropharyngeal cancer and 1.30 times of esophageal cancer in previous meta-analysis43. The potential cause might be the high prevalence of ALDH2*2 allele in East Asians, and the evidence of the carcinogenic effect is strong in esophageal cancer and head and neck cancer48. In addition, the concurrent use of tobacco and alcohol is common and increasing over time, especially among socioeconomically disadvantaged population49. The mortality risk of esophageal cancer is more than 5 times in modest drinkers who smoke compared to non-drinker. This is an important issue about cancer prevention we must pay attention to.Our study proposed that the modest-drinking group has no significant effects on cancer mortality, both generally or in any particular cancer. The effects on the different types of alcohol related cancers in previous research were still controversialIn conclusions, modest drinkers, no more than one drink a day, had benefits and could gain nearly 1 year in life expectancy, in contrast to a loss of nearly 7 years if drinking more than that. The loss exceeded 10 years if drinkers also smoked, as did majority (65–80%) of drinkers. Given the reality that drinkers are prone to cross the line, clinicians should balance the risks and benefits of drinking, as well as the understanding of whether the patient is at risk for addiction.The study was approved by the Institutional Review Boards at the China Medical University (CRREC-107-092) and National Health Research Institutes (EC0981201-E), Taiwan. The requirement for written informed consent was waived by the Institutional Review Board. All analyses adhered to the guidelines and regulations of the ethics committee of National Health Research Institutes.All subjects aged 20 years or older were recruited by the MJ Health Group, Taiwan, to participate in a standard health-screening program between 1994 and 2008. Excluding individuals without drinking data, a study cohort of 430,270 individuals was established. Participants had tests for blood, urine, body measurements, functional tests, physical examination and completed a comprehensive health history questionnaire to collect medical history and epidemiological data. Drinking status was defined from questionnaire according to not only self-report never or occasional drinker, ex-drinker and drink alcohol three times or more a week and two or more drinks a week, the amount of alcohol each time was estimated by number of drinks. Drinking status was categorized into four levels: “non-drinker”, “ex-drinker”, “modest drinker”  and “regular drinker” . Smoking was defined according to answer “Do you now smoke cigarettes?” and categorized into 2 groups: “never smokers” and “smokers”. Considering the portion of ex-drinkers and ex-smokers were very small (3% and 6% respectively) but hazard ratios (HRs) were large and were comparable with regular drinkers and current smokers in this study cohort. In additions, most ex-drinkers and ex-smokers might quit because alcohol and cigarettes had led some health problems. That was why we combined ex-drinker and ex-smokers into “regular drinker” and “current smoker”. Leisure time physical activity (LTPA) volume was ascertained by three multiple choice questions. The duration and intensity of weekly physical activity were converted into MET -hour/week. LTPA = METs  × time (h) and was classified into three levels: “inactive” (< 3.75 MET-h/week), “low active”  and “fully active”, with ≧ 7.5 MET-hour/week or ≧ 30 min/day, met the current exercise recommendation of ≧ 150 min/week. Causes of death were classified according to International Classification of Diseases, 9th version (ICD-9). Health outcome variables were all causes mortality (ICD-9 codes 001–998), all cancer (ICD-9 codes 140–208), oral cancer (ICD-9 codes 140–149), esophageal cancer (ICD-9 codes 150), stomach cancer (ICD-9 codes 151), colon rectum cancer (ICD-9 codes 153–154), liver cancer (ICD-9 codes 155), pancreas cancer (ICD-9 codes 157), lung cancer (ICD-9 codes 162), breast cancer (ICD-9 codes 174), prostate cancer (ICD-9 codes 185), bladder cancer (ICD-9 codes 188), Diabetes mellitus (ICD-9 codes 250), cardiovascular disease (CVD) (ICD-9 codes 390–459), ischemic heart disease (ICD-9 codes 410–414), stroke (ICD-9 codes 430–438), respiratory system disease (ICD-9 codes 460–519), COPD (ICD-9 codes 491–496), digestive system disease (ICD-9 codes 520–579), cirrhosis (ICD-9 codes 571), kidney disease (ICD-9 codes 580–589), accidents (ICD-9 codes 800–949) and suicide (ICD-9 codes 950–959). Expanded CVD was CVD plus diabetes plus kidney disease.Using the unique national identification numbers, subjects were each matched with the National Cancer Registry and National Death File between 1997 and 2008. A total of 11,031 deaths were identified with a median follow-up period of 8.8 years. Informed consent was obtained to authorize the processing and analyzing of the data. The study was approved by the Institutional Review Boards at the National Health Research Institutes, Taiwan. A detailed description of this method has been reported earlier.51. HRs were adjusted for 15 confounding variables, including 2 continuous and 13 categorical variables. The continuous confounding variables were age, and C-reactive protein level; the categorical variables were gender, education , BMI , smoking , physical activity , anemia, fasting glucose , Systolic blood pressure , total cholesterol , High-density lipoprotein , Low-density lipoprotein , triglycerides , proteinuria , and uric acid level . Life expectancy was calculated based on Chiang52. LE1 for drinkers and LE2 for nondrinkers. LEV2-LEV1 = lost years of life. After adjusted for age and gender, we found the odds ratio between smoking and drinking is much larger than odds ratios between BMI and drinking or physical activity and drinking. Therefore, we performed further analysis of mortality risks by smoking status rather than other important lifestyle risk factors of health-related outcomes such as BMI or physical activity. All statistical tests were two-sided with the alpha level set at 0.05 and all statistical analyses were performed with SAS 9.4 .Risk predictors were subjected to Cox proportional hazards regression analysis to identify significant predictors in multivariate models. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for each variable. HRs were calculated using Cox proportional hazards model, with adjustments made, when appropriate, for confounders. We selected confounders based on literature that address the increase risk for drinking, with most of them similar to confounders we used in other studiesSupplementary Tables.