Asprosin physiologically increases in fasting conditions and decreases with refeeding and has been implicated in glucose homeostasis. An alteration of meal-related circadian oscillation of asprosin has been suggested in adults affected by type 2 diabetes mellitus.Aims of this study were to test the hypothesis of an alteration in the meal-related variation of asprosin levels in non-diabetic children and adolescents with obesity and to assess which metabolic variables condition this variation in non-diabetic children and adolescents with obesity. This is a cross-sectional study which included 79 children and adolescents with obesity. Children underwent clinical and biochemical assessments, including oral glucose tolerance test (OGTT), and liver ultrasound evaluation. Asprosin serum levels were measured by an enzyme-linked immunosorbent assay at a fasting state and at the 120-minute OGTT timepoint . Fasting and 2h-postprandial asprosin serum levels did not significantly differ in the entire study population . 55.7% of patients had a significant increase in 2h-postprandial asprosin compared with fasting levels. The asprosin level increase condition was significantly associated with HOMA-IR , fasting glycaemia  and HOMA-B . Moreover, the IFG condition was associated with the increase in asprosin levels , even after adjustment for HOMA-IR, BMI SDS, sex and pubertal stage. Insulin resistance and IFG influence meal-related changes of asprosin serum levels in our study population of obese, non-diabetic, children. Alteration of asprosin circadian secretion might be an early biomarker of impaired glucose regulation in obese children with insulin resistance. Childhood obesity represents one of the most important health issues worldwide and is associated with an increased risk of metabolic complications, such as insulin resistance (IR) and impaired glucose regulation (IGR), including impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) , 2. IR hAsprosin is a recently identified adipokine, produced mainly by white adipose tissue , implicaPrevious studies described asprosin involvement in glucose homeostasis as consisting of appetite regulation through orexigenic AgRP+ neurons and promotion of hepatic gluconeogenesis under fasting conditions , 7. AccoSeveral studies have documented a positive correlation between asprosin levels and HOMA-IR –10 whileBased on these findings, although partly contrasting, asprosin seems to play a role in glucose homeostasis regulation, but no data are available on meal-related asprosin level changes in children and adolescents with obesity.Aims of this single-center cross-sectional study were to test the hypothesis of an alteration in the meal-related variation of asprosin levels in non-diabetic children and adolescents with obesity and to assess which metabolic variables condition this variation.This is a single-center, cross-sectional study carried out from October 2020 to May 2021. Inclusion criteria were age between 5 and 16 years; BMI ≥ +2 standard deviation score (SDS), in accordance with definition of obesity by the World Health Organization (WHO) for children from the age of 5 years; Caucasian ethnicity; born as healthy full-term infant adequate for gestational age. Exclusion criteria were genetic and/or endocrine causes of obesity; diabetes; chronic diseases; chronic pharmacological therapies; smoking. All procedures were performed in accordance with the Declaration of Helsinki and were approved by the Ethics Committee of Messina (N.552-17/04/2019). Written informed consent was obtained from all parents or legal tutors.At recruitment, physical evaluation was performed according to standardized procedures, including assessment of height, weight, BMI, BMI SDS, waist circumference (WC), WC-to-height ratio (WHtR), systolic and diastolic blood pressure . PubertaHomeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of β-cell function (HOMA-B), Matsuda-index, insulinogenic-index (IGI) were calculated, as previously detailed . Areas ui/AUCg-ratio. Model 2: age, sex, BMI SDS, fasting and 2h-postprandial glycaemia, fasting and 2h- postprandial insulin. Model 3: age, sex, BMI SDS, Triglycerides/HDL-ratio, Total Cholesterol/HDL-ratio. Model 4: age, sex, BMI SDS, Triglycerides, LDL, HDL, Total Cholesterol. Model 5: age, sex, BMI SDS, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), hepatic steatosis). In addition, further logistic regression models were estimated to assess the influence of IFG on the asprosin level increase condition, even after adjustment for HOMA-IR, BMI SDS, sex and pubertal stage ; in this analysis, pubertal stage, rather than age, was chosen as an independent variable because of the well-known significant implications of puberty on metabolic changes.Numerical data were expressed as mean and SDS and categorical variables as absolute frequency and percentage. The non-parametric approach was used since most numerical variables were not normally distributed, as verified by the Kolmogorov-Smirnov test. The Wilcoxon test for dependent samples was applied to identify possible significant differences between fasting and 2h-postprandial glycaemia, insulin and asprosin, both in the entire study population and in subgroups defined according to sex, pubertal stage, BMI SDS (BMI SDS ≤ or > 2.5) and the presence of IR, IFG and hepatic steatosis. To compare clinical and metabolic parameters between the two groups of patients identified according to meal-related asprosin variation the Mann-Whitney test  and the Chi Square test  were applied. The Spearman correlation test was used to assess the existence of significant interdependence between asprosin levels  and clinical and biochemical parameters; in addition, partial correlation was also estimated in order to check for sex, pubertal stage and BMI SDS. A stepwise multiple logistic regression analysis was carried out to identify which metabolic predictors significantly affect the variation of asprosin levels considering the dichotomous variable asprosin increase/non-increase between fasting and 2h-postprandial status, through the estimation of different models . A p-value < 0.05 was considered to be statistically significant.Seventy-nine children (aged 11.5 ± 2.6 years) were consecutively recruited, 40 males and 39 females; 64.5% of them were in a pubertal stage. Clinical and biochemical characteristics of the study population are shown in As expected, a significant increase in blood glucose and insulin levels was documented from fasting to 2h-timepoint of OGTT Table 2.vs 380.75 ± 83.16; p=0.000), whereas in the remaining 44.3% of patients asprosin levels decreased . Patients had a significant increase in 2h-postprandial asprosin had significantly higher fasting blood glucose levels and more frequently an IFG condition compared to patients who had a significant decrease in 2h-postprandial asprosin levels  had a significant increase in 2h-postprandial asprosin compared with fasting levels  was not documented (data not shown).Correlation analysis documented a significant positive relation between asprosin and lipid profile parameters. In particular, after adjustment for sex, pubertal stage and BMI SDS, fasting asprosin levels were correlated to triglycerides  and triglycerides/HDL-ratio , while 2h-postprandial asprosin levels were correlated to LDL , triglycerides  and triglycerides/HDL-ratio . A correlation between asprosin and BMI, BMI SDS, and glucose metabolism parameters -protein kinase A (PKA) pathway (Asprosin is a glucogenic adipokine that stimulates hepatic glucose release  pathway . Under p pathway .For the first time, in our study we have demonstrated, differently than expected, no significant variation between fasting and 2-h postprandial asprosin levels in obese, non-diabetic children, suggesting an alteration in the meal-related regulation of asprosin secretion in these subjects. Furthermore, in the group of patients who had an increase in asprosin between fasting and 2-hour postprandial levels, the IFG condition was significantly more frequent than in patients who had a decrease in asprosin levels. HOMA-IR, fasting glycaemia and IFG significantly influenced the asprosin increase condition in 2-h postprandial evaluation, suggesting that IR and IFG may affect the physiological meal-related variation in asprosin levels.IR plays a central role in the relationship between obesity and the associated risk of IGR, T2DM, metabolic syndrome and cardiovascular disease , 16, 21.Our study found that asprosin levels did not significantly decrease at 2h-postprandial assessment in obese non-diabetic children and that this trend was significantly influenced by the presence of IR and IFG. We speculate that in obese children and adolescents with IR and IFG there may be an altered production of asprosin which in turn may promote IR worsening by stimulating hepatic glucose secretion and subsequent hyperinsulinemia. The asprosin increase condition and, in particular, alteration of its circadian secretion, might be an early biomarker of IGR in obese children with IR.Asprosin may also be implicated in the pathogenesis of the well-known association between IR and lipid profile alteration . Zhang eSample size represented a limitation of our study. For ethical reasons, it was not possible to have healthy children undergo an OGTT to perform the same assessments conducted on the study population. Data on liver ultrasound were available for 71 patients as 8 patients discontinued follow-up before undergoing ultrasound. Due to the cross-sectional design of the study, it is not possible to generalize the findings of the present study. On the other hand, our study has significant strengths. First, our study population consisted in a homogeneous sample of obese Caucasian children with equal distribution according to sex. Second, the assessment of both fasting and meal-related asprosin levels through standardizing the evaluations by performing an OGTT. This type of assessment, compared with a random asprosin measurement, allowed us to verify an alteration of the physiological meal-related fluctuation of asprosin levels in a pediatric population with obesity. The assay standardization is useful in the interpretation of results as it partly compensates for the lack of plasma reference values for asprosin.In conclusion, this is the first study to demonstrate a non-significant variation between fasting and 2h-postprandial asprosin levels in obese, non-diabetic children and to document an influence of IR, fasting glycaemia and IFG on meal-related changes of asprosin serum levels. The alteration of asprosin circadian secretion might be an early biomarker of IGR in obese children with IR. Further studies on a larger study population are needed to confirm and verify these findings.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the ethics committee of Messina. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.DC and MW contribute to conception and design of the study. DC, TA, GP, SC, and AL organized the database and prepared the tables. RI and MC performed asprosin measurements. AA performed statistical analysis. DC and MW wrote the first draft of the manuscript. MW and RI supervised the work. DC and MW wrote the final version of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.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.


In recent years, mesenchymal stem cells (MSCs) have been used to improve cardiac function and attenuate adverse ventricular remodeling of the ischemic myocardium through paracrine effects and immunoregulation functions. In combination with cell sheet technology, MSCs could be more easily transplanted to the ischemic area. The long-term retention of MSCs in the affected area was realized and significantly improved the curative effect. In this review, we summarized the research and the applications of MSC sheets to the treatment of ischemic heart tissue. At present, many types of MSCs have been considered as multipotent cells in the treatment of heart failure, such as bone marrow-derived mesenchymal stem cells (BM-MSCs), adipose-derived mesenchymal stem cells (AD-MSCs), umbilical cord-derived mesenchymal stem cells (UC-MSCs), and skeletal myoblasts (SMs). Since UC-MSCs have few human leukocyte antigen-II and major histocompatibility complex class I molecules, and are easy to isolate and culture, UC-MSC sheets have been proposed as a candidate for clinical applications to ischemic heart disease. Heart failure is the leading cause of death worldwide, despite improvements in management through mechanical and surgical therapeutic strategies. Heart transplant is the standard curative therapy for end-stage heart failure. However, the shortage of donor hearts limits the application of this procedure, which also requires lifelong immunosuppression. Other surgical interventions, such as the implanting of mechanical ventricular assist devices, have high associated medical costs and can easily cause bleeding, infection, and other complications. Recently, stem cell therapy has been developed and extensively investigated as an alternative therapeutic strategy for heart failure. It is well-known that heart tissue is difficult to repair itself, and adult cardiac cells tend not to divide, so it may be possible to repair ischemic areas by transplanting mesenchymal stem cells (MSCs). MSCs have been used to treat damaged hearts as they offer a low immunogenic property, paracrine effect, and immunosuppression. MSCs secrete growth factors and chemokines which induce cardio-protection, stimulate angiogenesis, and reorganize the extracellular matrix in ischemic scar areas. Several clinical studies have described how the use of MSCs improved cardiac function and the regeneration of heart tissue in damaged hearts –3.High colonization rates and long survival times after transplanting are two key points in the curative effects of MSCs. Suspensions of MSCs injected into the ischemic area of the heart often present underwhelming results, because of cell loss and a low retention of transplanted cells. Cell sheet technology eliminates the problem of retention, as all MSCs remain at the implantation site. In addition, a cell sheet is a scaffold-free composition of cells, avoiding the potential inflammatory response to scaffold degradation.A cell sheet engineering technology was developed by Okano’s team, using thermo-responsive culture dishes coated with poly (N-isopropylacrylamide) (PIPAAm) , 5. WithNormally in cell therapy, suspension cells are used though injection and intravenous infusion. Studies have hypothesized that poor retention as a result of blood flow causes decreased effectiveness, because it is a zero-dimensional application . A cell In this review, we mainly summarized the application of MSC-derived cell sheets on the ischemic heart tissue. MSCs from various tissues share many characteristics. Several types of MSC sheets were classified, and the characteristics and applications of each kind of cell were analyzed. We also summarized the research and applications of human-induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) in pre-clinical study.MSCs are adult stem cells that can be isolated from various tissues. They originate from mesodermal lineages and have been differentiated into connective tissues, such as osteoblasts, chondrocytes, cardiomyocytes, and adipocytes . The IntBM-MSCs are one of the most popular cell sheets for use in cases of MI, because of their convenient isolation and culture in vitro. BM-MSC populations were increased through the repeated passages of the cells by trypsinization. In primary culture, non-adherent cells were removed by medium changes, and the remaining purified BM-MSCs were further expanded in continuous culture. Usually, purity will improve after two or three passages .+ cells and upregulation of IL6. However, substantial numbers of allogenic BM-MSCs survived for a certain early period and improved cardiac function [Narita et al. reported that syngeneic BM-MSC sheets transplanted onto the heart epicardium had effective retention within 1 month, compared to intramyocardial injection in an MI rat model . The inifunction .A cell sheet improves the efficiency of transplanted BM-MSCs. Research into BM-MSC sheet adhesion over time to porcine heart tissue showed that the basal side of the cell sheet has more ECM components, including some collagens, fibronectin, and specialized proteins, making it more likely to adhere to the surface of heart tissue without any mechanical device such as suturing. Chang et al. identified a minimum time of 30 min for adhesion of the basal side of a cell sheet to heart tissue . To enhaThe adipose tissue has also been considered as a source of MSCs for use in cell therapy, because it is one of the most abundant human tissues. Zuk et al. identified the existence of MSCs with self-renewal and multipotent capacities in adipose tissue . The isoSimilar to BM-MSCs, these studies showed that the use of AD-MSC sheets preserves cardiac function, improves cardiac perfusion, and reduces scar tissue size and cardiac remodeling, compared to intramyocardial injection . Kim et AD-MSCs are also used to co-culture with other cells and to prepare multilayered cell sheets. Sasagawa et al. used double-layered AD-MSC sheets sandwiching pre-vascularized human umbilical vein endothelial cells (HUVECs) to form multilayered cell sheets . The exiUC-MSCs are appearing in cardiac tissue engineering, with the assistance of differentiating agents. UC-MSCs are isolated from Wharton’s jelly of the umbilical cord, by enzyme digestion or explant method . UC-MSCs2 and IL-6 than the other two kinds of cell sheets [Compared to BM-MSC and AD-MSC sheets, the number of reports on the UC-MSC sheet is limited. However, its advantages and clinical application potential have attracted more and more attention from researchers –42. Nakal sheets . UC-MSC Human UC-MSCs are a non-intrusive acquisition with good ethical availability as a population of multipotent cells . They arAlthough MSCs have been used to produce cell sheets for the heart tissue repair because of their cardiomyocyte differentiation potency and paracrine action, it will be some time before MSC sheets are used clinically. Skeletal myoblast (SM) sheets and induced pluripotent stem cell (iPSC) sheets have already been used in patients, pioneering the clinical application of cell sheets in ischemic heart disease.bcl2 gene or hepatocyte growth factor (HGF) gene were studied in a rat model and showed a higher improvement in heart function [SMs are derived from a satellite cell or cell lying beyond the myofiber, with a similar method of differentiation of cardiomyocyte , 46. Thefunction –52. Autofunction . Three mfunction . Since tfunction . No sevefunction . LVEFs ifunction . The resfunction . In 2020function . A 6-monfunction .The differentiation ability of MSCs and SMs has been considered too limited to produce sufficient functioning cardiomyocytes for heart tissue repair. Pluripotent stem cells, including embryonic stem cells (ESCs) and iPSCs, are highly advantageous cell sources for cell sheets, for regeneration of cardiac myocytes (CMs).Matsumoto et al. fabricated a cell sheet composed of CMs, endothelial cells, and mural cells differentiated for ESCs. They demonstrated that a multilayered sheet attenuated cardiac dysfunction at 1 week after transplantation in a rat model, due to neovascularization mediated by paracrine effects. However, the engraftment efficiency of the ESC-derived cardiac tissue sheet was rather low at 4 weeks after transplantation . CompareiPSC sheets were transplanted onto myocardial infarcts in an ICM porcine model and a rat MI model –63 and sWhen using iPSC sheets in combination with the omentum flap, the cell survival percentage on an implanted iPSC sheet can be improved significantly because of increased angiogenesis , 65. BesBeyond enhancing angiogenesis, other basic researches were conducted . EliminaiPSC-derived MSCs have become another cell source for MSC therapies in recent years. Compared to BM-MSCs, iPSC-derived MSCs have better proliferative capacity and differentiation potential, being little affected by cellular senescence. Research has demonstrated that the immunomodulation and paracrine effects of iPSC-derived MSCs can improve the cardiac function of a porcine HF model . iPSC-decell homing. It is characterized by a molecular axis resulting from the interaction of the chemokine SDF-1 or CXCl-12 with its specific receptor, the CXCR chemokine receptor type 4 (CXCR-4) [In this review, we have described the application of many types of cell sheets in the repair of ischemic heart tissue. Cell sheets from various cell sources can be fabricated and transplanted to improve cardiac function. However, the high cost and the time required to manufacture each patient-derived cell sheet hinder the dissemination of cell sheet-based regenerative medicine. Figure (CXCR-4) . This papostpartum and with lesser complications of ethical clearance, as well as self-renewal capacity, than MSCs from other origins. Compared to the complicated separation operation, these advantages are overwhelming. Thus, UC-MSCs are the emerging cell source in cell sheet technology for cardiac tissue regeneration.Although MSCs have been widely used as therapeutics in cellular therapy, their clinical effectiveness remains limited. MSCs have limited ability to proliferate during in vitro culture. Cellular senescence was observed in MSCs from various sources, such as the bone marrow  and dentSM sheets and iPSC-derived cardiomyocyte sheets have already been used clinically. Autologous SM sheet transplantation can improve cardiac function and avoid rejection –55. HoweMany factors influence and modulate the effectiveness of cellular therapy in tissue recovery after damage to ischemic heart tissue, especially the source of the stem cells and the method of stem cell transplantation. Fully automatic processing is a reliable and effective way to eliminate deviation caused by individual operators. In this way, UC-MSC sheets have the potential to become an “off-the-shelf” product with batch-to-batch consistency. The efficiency of UC-MSC sheets is improved because of UC-MSCs as a prospective source. The application of UC-MSC sheets can also convert the use pattern from individual medical technology to a “live medicine,” which could be regulated in a good manufacturing practice (GMP) system. The feasibility and safety of UC-MSC sheets have been tested in animal models of myocardial infarction . More cl


Globally, major depressive disorder (MDD) is considered to be a leading cause of disability. In this article, we aim to investigate the sex difference in global burden of MDD by year, age, and socioeconomic development, utilizing disability-adjusted life-years (DALYs).Global and national sex-specific DALY estimates caused by MDD from 1990 to 2019 and in different age groups were obtained from the Global Burden of Disease (GBD) Study 2019. Human development index (HDI) was used as an indicator of national socioeconomic development. Spearman correlation and linear regression analyses were performed to explore the relationship between national socioeconomic development and sex difference in MDD burden.P < 0.001). National age-standardized DALY rates among both sexes were negatively related to HDI. However, female-to-male age-standardized DALY rate ratios were positively associated with HDI .Sex difference in global burden of MDD persisted between 1990 and 2019, with age-standardized DALY rates being 352 among males vs. 593 among females in 1990 and 354 vs. 564 in 2019. Females had higher burden of MDD than males at the same age. Disability-adjusted life-years numbers and rates among both sexes rapidly increased with age for those aged 10–24 years, along with gradually enlarging sex difference. Age-standardized DALY rates among females were higher than that among males for each HDI-based country group (Although some improvement in sex difference in global burden of MDD has been achieved, it still persists in the past three decades, with females bearing more burden than males. To reduce sex difference in global MDD burden, more attention should be paid to young people and people in developed countries. The findings highlight the importance of making sex-specific health policy to manage mental impairment caused by MDD. Depression is a common mental disorder affecting approximately 300 million people of all ages worldwide . It is aBased on DALY data for depressive disorders from the GBD study 2015, significant correlations between gender disparity in depressive disorders and diverse aspects of social inequality  have been detected –8. DespiInternational Classification of Diseases or the Diagnostic and Statistical Manual of Mental Disorders  is a composite index developed by the United Nations to evaluate the socioeconomic development of countries around the world . Human dP < 0.05 was considered statistically significant.Globally, national age-standardized DALY rates among female population and among male population were compared using Wilcoxon signed ranks test. Such comparisons were also performed for each HDI-based country group. Spearman correlation analyses and linear regression analyses were conducted to assess the association of national age-standardized DALY rates among female population, age-standardized DALY rates among male population, and female-to-male age-standardized DALY rate ratios with HDI. SPSS 23  was used for statistical analyses, and Sex difference in global burden of MDD persisted between 1990 and 2019 . Sex difGlobally in 2019, female population had higher burden of MDD than male population at the same age . DisabilZ = −12.367, P < 0.001). Human development index data were available for 187 countries, including 64 very-high-HDI countries, 53 high-HDI countries, 37 medium-HDI countries, and 33 low-HDI countries. Age-standardized DALY rates among female population were higher than that among male population for very-high-HDI , high-HDI , medium-HDI , and low-HDI  countries , as well as age-standardized DALY rates among male population , were negatively related to HDI .Wilcoxon test showed that for 204 countries included in the GBD study 2019, age-standardized DALY rates caused by MDD among female population (median [interquartile range]: 642 [476–782]) were significantly greater than that among male population (378 [295–293]) .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.


Background: Huntington's disease (HD) leads to altered gait patterns and reduced daily-living physical activity. Accurate measurement of daily-living walking that takes into account involuntary movements (e.g. chorea) is needed.Objective: To evaluate daily-living gait quantity and quality in HD, taking into account irregular movements.Methods: Forty-two individuals with HD and fourteen age-matched non-HD peers completed clinic-based assessments and a standardized laboratory-based circuit of functional activities, wearing inertial measurement units on the wrists, legs, and trunk. These activities were used to train and test an algorithm for the automated detection of walking. Subsequently, 29 HD participants and 22 age-matched non-HD peers wore a tri-axial accelerometer on their non-dominant wrist for 7 days. Measures included gait quantity , gait quality  metrics, and percentage of walking bouts with irregular movements.Results: Measures of daily-living gait quantity including step counts, walking time and bouts per day were similar in HD participants and non-HD peers (p > 0.05). HD participants with higher clinician-rated upper body chorea had a greater percentage of walking bouts with irregular movements compared to those with lower chorea (p = 0.060) and non-HD peers (p < 0.001). Even after accounting for irregular movements, within-bout walking consistency was lower in HD participants compared to non-HD peers (p < 0.001), while across-bout variability of these measures was higher (p < 0.001). Many of the daily-living measures were associated with disease-specific measures of motor function.Conclusions: Results suggest that a wrist-worn accelerometer can be used to evaluate the quantity and quality of daily-living gait in people with HD, while accounting for the influence of irregular (choreic-like) movements, and that gait features related to within- and across-bout consistency markedly differ in individuals with HD and non-HD peers. Huntington's disease (HD) is an inherited neurodegenerative disease that results in impairments in motor, cognitive, and behavioral domains . ExcitinThere is increasing interest in wearable, remote monitoring sensors to evaluate walking and daily-living physical activity with minimal operator input in a range of neurological disorders including Parkinson's disease –5, multiChoreic movements are a hallmark symptom of HD and are often the first motor symptom, affecting almost any part of the body . While sAs a step forward towards the use of wearable, 24/7 measurement of daily-living physical activity and mobility in HD, we aimed to evaluate everyday walking and activity taking into account irregular  movements. We specifically addressed the following questions: (1) What percent of walking during the day is spent with irregular (upper-extremity) movements in HD and age-matched non-HD peers? (2) Is daily-living gait quantity and quality different among individuals with HD compared to non-HD peers? and (3) How are measures of daily-living walking quantity and quality related to HD disease-specific measures including clinician ratings of motor function, chorea, and dystonia?n = 42) and age-matched non-HD peers (n = 22) from clinical centers in four countries were recruited for this study. Inclusion criteria for HD participants were: (1) aged 18 years or older; (2) genetically confirmed HD; (3) Total Functional Capacity (TFC)≥7; and (4) able to walk 10 meters independently without assistive device. Exclusion criteria were: (1) diagnosis of juvenile-onset HD; (2) history of co-morbid neurological conditions such as stroke or multiple sclerosis; and (3) acute orthopedic conditions . Inclusion criteria for non-HD peers were: (1) aged 18 years or older; and (2) able to walk 10 meters independently without assistive device. Exclusion criteria were: (1) history of neurological conditions such as stroke or multiple sclerosis; and (2) acute orthopedic conditions .HD participants  was collected and, for the HD participants, disease-specific assessments were completed or were obtained from clinical records. Disease-specific status was quantified through the Unified Huntington's Disease Rating Scale (UHDRS)  includinn = 42) and age-matched non-HD peers (n = 14) completed the in clinic assessment. We used a research-grade inertial measurement unit with a tri-axial accelerometer, magnetometer and gyroscope  Activinsights; 43.7 mm × 39.7mm × 13.7 mm; weight: < 25 grams; 128 Hz sampling rate) to quantify movement parameters during the performance of a standardized laboratory-based circuit of functional activities, required for independent activities of daily living in the home. This included quiet sitting for 30 sec, writing a sentence, drinking a 100 ml glass of water, 5-repetition chair stand test, Timed Up & Go (TUG) Test, 2-min walk test, step-ups, and quiet standing with eyes open and closed. These activities were used to train and test an algorithm for the automated detection of walking. All activities were videorecorded using a GoPro camera. The algorithm is described in the HD participants  to wear on their wrist for 24 h over the next 7 days. To minimize the impact of everyday movements like hand-writing, teeth-brushing and gestures that are typically conducted with the dominant hand, the accelerometer was placed on the wrist of the non-dominant hand and participants were asked to continue their activities as usual. Upon completion of the 7-day period, participants removed the device and sent it back to the local clinical site, using a provided addressed, stamped and padded envelope.Using the automated algorithm that is described below in section Automatic Identification of Walking Bouts and in further detail in the The first stage in the automatic detection of the walking bouts included low pass filtering and removal of the DC component of the accelerometer signals. The Euclidean norm of the 3D accelerometer signal was computed to minimize any effects of the placement of the sensor on the wrist and angle or orientation dependency. An activity threshold was set to 0.10 [g] to eliminate areas in the recording with no activity. The remainder of the areas that crossed the threshold was divided into windows with a duration of 6 sec, with 5-second overlap, for further processing. A second threshold based on a standard deviation of minimum a 0.10 [g] was applied to each window of the acceleration signal. Using power spectral density (PSD) as computed with Welch's method in each window, the frequency at the maximum power was calculated and examined. Windows with a peak frequency within a “gait” range 0.5–3 [Hz] were further examined to evaluate the consistency during the walking bout using autocorrelation. Windows that passed all the thresholds and conditions mentioned above were identified as windows that contain walking see . The algThe algorithm for detecting “irregular” walking was developed to detect walking bouts that likely contain irregular (chorea-like) wrist movements. The detection was based on four features from the recorded accelerometer signals using empirically derived thresholds that were based on 2-min walk trials that were performed in laboratory settings in non-HD peers and people with HD with varying degrees of upper extremity chorea. Based on video recordings of these walks, segments with no chorea, mild chorea, and severe upper extremity chorea were identified to determine the threshold for defining the presence or absence of irregular (chorea-like) walking bouts  daily walk time and step counts were calculated. Total daily-living physical activity was defined by calculating the signal vector magnitude (SVM) of the measured acceleration signal from three axes of each 60 second window during the day . For eacSeveral domains of gait quality were evaluated, adapting those proposed previously when other sensor locations were used , 18–20. t-tests were used for normal distribution. For the within-bout and across-bout walking gait quality measures, we used a Bonferroni correction to define the level of significance ; otherwise, a two-tailed p-value < 0.05 was considered statistically significant. Effect sizes were calculated by dividing the test statistic (Z) by the squared number of observations (N) for results that were not distributed normally and Cohen's d for normal distributions , for non-normal distributions. Spearman's correlations assessed the relationship between daily-living walking measures and HD clinical scores. To compare groups, Mann-Whitney tests were used for non-normal distributions and independent ibutions . Statistp > 0.05) . The number of all walking bouts (or windows) per day also did not differ in the two groups (p = 0.24); however, there was a trend for participants with HD to have fewer long walking bouts (>30 sec) during daily-living (p = 0.053). The total daily-living physical activity was significantly greater for non-HD peers compared to HD participants (p = 0.006).p = 0.060) and almost twice as large as that seen in the non-HD peers (p < 0.001).p(f) = 0.06) than in the non-HD peer (p(f) = 1.67). The autocorrelation plots (2C) show that the step and stride regularity was significantly lower in the HD participants compared to non-HD peers, reflecting a less consistent and more variable gait pattern.p = 0.04). Within-bout walking consistency, as represented by amplitude, width, step regularity, stride regularity and step time variability were significantly different between HD and non-HD peers . These differences indicate that the within-bout gait of the people with HD was more variable and less consistent than that of the non-HD peers (similar to the example shown in p = 0.347) and for the SD of the width of the dominant frequency, which was higher in HD than in non-HD peers (p = 0.003). In contrast, to the other measures of consistency, higher width reflects lower consistency, so essentially this latter finding is consistent with the other results, which indicate lower bout-to-bout consistency in the HD participants compared to the non-HD peers.Group differences in daily-living gait quality are summarized in Relationships between clinical measures and accelerometer-derived daily-living measures are summarized in This study reports accelerometry-derived measures of everyday walking in people with manifest HD. Uniquely, we used wrist-worn devices to assess daily-living walking in people with HD in the community while accounting for involuntary, irregular movements. This study considered the potential influence of involuntary movements during walking when using accelerometry-derived measures for remote monitoring in HD. We found that daily-living step counts and time spent walking among a heterogeneous group of HD participants were not different from that of non-HD peers; nonetheless, these measures were inversely correlated with disease severity (UHDRS-TMS). HD participants also tended to have fewer long walking bouts  compared to non-HD peers, perhaps reflecting fatigability  or limitIn this study, we were able to develop an algorithm, validated by in-person clinical assessments, to identify irregular movements to quantitatively characterize walking behavior in individuals with HD and non-HD peers. Not surprisingly, we found that irregular movements were more common in HD compared to non-HD peers. Interestingly the percentage of irregular movements was almost twice as great in people with relatively high clinician-measured chorea as compared to those with low chorea recall . This fiImportantly, measures of within-bout and across-bout walking consistency and variability were different in HD participants and non-HD peers, even after considering the irregular, chorea-like movements. This suggests that chorea alone does not account for differences in consistency and variability seen in individuals with HD. Previous research has suggested that parameters of gait variability are a particularly relevant digital biomarker for gait impairment with high sensitivity to differentiating individuals with and without HD mutation . ConsistHere, we extend earlier work on stride-to-stride variability in HD , 34 and The group differences for several of the gait quality measures (both within and across bouts) had relatively high effect sizes (>1.0). They were higher than the effect sizes for daily-living gait quantity and for those obtained for in-lab gait speed. This suggests that these measures may be more useful as clinical endpoints than the amount of daily-living walking and conventional in-lab measures. Larger effect sizes could potentially allow for smaller sample sizes in clinical studies. In particular, step regularity, which represents the within-bout walking consistency of the step pattern, had a very large effect size. Replicating the effect sizes seen in our data (which were between HD and non-HD peers) longitudinally in HD intervention studies would further support the utility of these metrics as clinical endpoints.This study has several limitations. The sample included only individuals with early-mid stage HD and did not include individuals with premanifest or prodromal HD. This would be useful to determine if differences in gait quantity and quality can be detected earlier in the disease process. It would also be interesting to examine if the observed changes in daily-living are related to CAG mutation length. We also only evaluated upper extremity movements in relation to their impact on gait. It is possible the irregular movements of the trunk or lower extremity could further impact quality or quantity. However, adding additional sensors on other extremities would increase participant burden and potentially change or limit regular movement in the home environment .This was also a cross-sectional study with a relatively small number of participants. Initial validity was demonstrated; however, other clinimetric properties of these wrist-worn derived measures still need to be established . Future research should evaluate the algorithm in another set of patient data and monitor individuals longitudinally to evaluate the trajectory of changes in gait quality and quantity over time and in response to interventions.This study provides proof of concept demonstrating the utility of metrics representative of daily-living gait quantity and quality in individuals with HD over 7 days while accounting for the influence of irregular movements. This is the first study to evaluate wrist-worn accelerometry to evaluate daily-living physical activity and gait in HD, with ground truth established from clinical measures. Gait impairments are a salient feature of HD, and with the use of wrist-worn devices, we generated measures of gait quality and quantity that may be useful clinical endpoints for a range of clinical interventions. This study also provides useful information about the importance of gait quality as a sensitive measure of motor impairment in HD. Activities that address gait adaptability in daily living, as well as the consistency and regularity of gait patterns, may be important targets of rehabilitation interventions. In summary, the present results suggest that multiple measures of daily-living walking are altered in people with HD and that a subset of these measures is associated with clinician-based tests of chorea and disease severity. These findings set the stage for larger-scale, follow-up studies to further evaluate these possible digital biomarkers and their potential as measures of therapy and disease progression in HD.We aim to make our research data available wherever possible, subject to regulatory approvals, any terms and conditions placed upon us from external providers, patient confidentiality and all laws concerning the protection of personal information.We received Institutional Review Board/Ethics approval at all sites: Cardiff University, Cardiff, UK , Teachers College, Columbia University, New York, NY, USA (IRB 17-322), New York State Psychiatric Institute, New York, NY, USA (IRB 7488), Wayne State University, Detroit, MI, USA (IRB 1701000248), George Huntington Institute, Münster, Germany (2017-079-fs), and Tel Aviv Medical Center, Tel Aviv, Israel (0090-17-TLV). The patients/participants provided their written informed consent to participate in this study.All authors made substantial contributions to the conception or design of the work or the acquisition, analysis or interpretation of data or the creation of new software used in the work, drafted the work or revised it critically for important intellectual content, approved the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.This study was funded by the Jacques and Gloria Gossweiler Foundation and sponsored by Cardiff University. Centre for Trials Research, Cardiff University received infrastructure funding from Health and Care Research Wales and Cancer Research UK.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.


Introduction: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disease associated with the NMDA receptor. This paper describes a patient who presented with bilateral hearing loss as the initial symptom of anti-NMDAR encephalitis.Case Report: We describe a 31-year-old young female with anti-NMDAR encephalitis who presented with bilateral severe hearing loss after brief loss of consciousness and then accompanied by other symptoms, such as generalized tonic–clonic seizures, manic episodes, excessive salivation, severe cognitive impairment, and complex non-convulsive status epilepticus. Great improvement was achieved by a combined treatment of steroid, IVIG, and plasmapheresis, especially after surgical removal of the ovarian teratoma. When she was discharged on hospital day 43, her hearing loss obtained a significant improvement.Conclusion: This case study and literature review investigated the impairment of hearing loss and its subsequent treatment in patients with anti-NMDAR encephalitis. N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disease associated with IgG antibodies against the NR1 subunit of the NMDA receptor  with a lymphocytic predominance and normal protein and glucose levels. On hospital day 3, the symptoms of this patient were progressing rapidly, developing manic episode, language impairment, and increased salivation. Her manic symptom was gradually controlled when treated with midazolam or diazepam intravenous infusion and risperidone tablets (1 mg twice daily). Since our patient had such signs, the diagnosis of autoimmune encephalitis was suspected. A 5-day course of IV methylprednisolone (1 g/day) and intravenous immunoglobulin (IVIG) (25 g/day) were administered empirically. On hospital day 4, the patient showed significant cognitive dysfunction and even did not know where she came from. CSF PCR for herpes simplex virus (HSV) 1 and 2 was unremarkable. Serum and CSF anti-NMDAR antibodies returned positive by immunofluorescence , confirming the diagnosis of definite anti-NMDAR encephalitis  showed an increased white blood cell (WBC) count  in the right-side ovary . BecauseIn the 1-month follow-up, her hearing was normal and cognitive function improved significantly, just presenting with mild memory deterioration. During this period, no seizures were observed. The MMSE score was 29 and the MoCA score was 27. Regular follow-up will be carried out for our patient. The clinical course is summarized in Anti-NMDAR encephalitis was first identified in 2007 by Dalmau et al. . The cliParaneoplastic syndrome has also been reported in some literature associated with hearing loss. The most frequent is Kelch-like (KLHL) 11 encephalitis that is associated with testicular germ cell tumors, benign teratomas, small-cell lung cancer, and ovarian cancer . The typThe strongest pathogenic evidence of bilateral fluctuating hearing loss is that of an immune-mediated disease. The inner ear is not an immunologically privileged site and may mount an immune response against foreign and self-antigens damaging sensory structures within it –26. BothIn this case, the patient presented with bilateral severe hearing loss when she visited our hospital. Serum and CSF anti-NMDAR antibodies were positive, confirming the diagnosis of definite anti-NMDAR encephalitis. During the treatment with methylprednisolone, gamma globulin, and plasmapheresis intravenously, the hearing showed a degree of volatility. Occasionally, sound could be heard in the left ear, but it did not sustain. Starting from the second day after the surgical excision of ovarian teratomas, binaural hearing of this patient showed some extent of retrieval, especially after the following three sessions of plasmapheresis. Fortunately, the hearing loss in this young patient recovered substantially after 43 days of treatment. So far, the hearing loss in anti-NMDA receptor encephalitis associated with ovarian teratoma has not been reported. Taraschenko et al.  reportedIn summary, our case, as the first episode of anti-NMDAR encephalitis, initially presented with bilateral hearing loss after brief loss of consciousness and then accompanied by other symptoms, such as generalized tonic–clonic seizures, manic episodes, excessive salivation, severe cognitive impairment, and complex non-convulsive status epilepticus. Great improvement was achieved by a combined treatment of steroid, IVIG, and plasmapheresis, especially after surgical removal of ovarian teratoma. An awareness of diverse and uncommon primary manifestations is conducive to early and accurate diagnosis of anti-NMDAR encephalitis.The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by Jincheng people's Hospital, Jincheng, China. The patients/participants provided their written informed consent to participate in this study.LJ: put forward research ideas. FY: took the responsibility of communicating with the patient's family and obtaining the authorization in this paper. HC and JZ: responsible for drafting articles. All authors contributed to the article and approved the submitted version.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.


Self-compassion recognises a meaning of life’s suffering, aligning with existential positive psychology. Although this construct is known to protect our mental health, how to augment self-compassion remains to be evaluated. Social work students suffer from high rates of mental health problems; however, research into self-compassion in this population remains to be developed. This study aimed to evaluate (i) relationships between self-compassion and more traditional positive constructs—resilience, engagement and motivation, and (ii) differences of these constructs between the levels of studies to inform how self-compassion can be enhanced in social work students. A total of 129 Irish social work students completed self-report scales regarding self-compassion, resilience, engagement and motivation. Correlation, regression and one-way MANOVA were conducted. Self-compassion was associated with gender, age, resilience, engagement and intrinsic motivation. Resilience and intrinsic motivation were significant predictors of self-compassion. There was no significant difference in the levels of these constructs between the levels of studies. Findings suggest that social work educators across different levels can strengthen students’ resilience and intrinsic motivation to cultivate the students’ self-compassion. Moreover, the close relationships between self-compassion, resilience and intrinsic motivation indicate that orienting students to the meaning of the studies helps their mental health. There is a significant commonality between self-compassion and Existential Positive Psychology (EPP). EPP is an integrative, holistic model, which conceptualises people as bio–psycho–social–spiritual beings and seeks to integrate the strengths and flourishing focused perspectives of positive psychology with the focus on meaninglessness, death and alienation prevalent in existential psychology . Thus, ESelf-compassion is having awareness of and bringing compassion to one’s own and others’ suffering and is conceptualised as encompassing three components: (i) self-kindness, (ii) common humanity and (iii) mindfulness . Self-kiSelf-compassion is aligned with Existential Positive Psychology (EPP) in that it recognises the suffering inherent in living while also finding meaning and connection with others in that suffering. Self-compassion is a holistic approach in that it is concerned with both mitigating suffering or psychopathological symptoms and also with fostering flourishing and meaningful living. Indeed, research supports the connection of self-compassion to both reduced psychopathology and psychological flourishing . FurtherThough still nascent, self-compassion has begun to be regarded as essential in social work for self-care and empathetic client care. Self-care was predicted by self-compassion among professional social workers , and selUnderstanding the relationship between self-compassion and other constructs is important in developing varied approaches for cultivating self-compassion, as self-compassion interventions remain to be further developed . ExistinSelf-compassion is associated with increased wellbeing and decreased symptoms of poor mental health . Having While poor mental health is common among UK university students generally , poor mePoor mental health is associated with lower achievement and dropout among university students  and, morWhile there is no agreed-upon definition of resilience , the AmeCultivating resilience has been identified as an important goal for social work training. High levels of resilience are associated with lower levels of mental health problems among students  and decrSelf-Determination Theory (SDT), aligning with EPP’s concerns, articulates the roles of autonomy and authenticity in motivating human behaviour and their potential impact on flourishing and psychological wellbeing . SDT posEngagement is another construct relevant to mental health. Engagement describes the effort and determination students exhibit in learning or mastering skills and in acquiring knowledge . SchaufeAccordingly, this study aims to evaluate relationships between self-compassion, resilience, engagement and motivation (Aim 1), identify significant predictors of self-compassion (Aim 2), and appraise differences in the levels of these psychological constructs between different levels of studies (Aim 3). Aims 1 and 2 were designed to identify which of these more established constructs were associated with this relatively new construct, self-compassion. Aims 3 was designed to provide insights into whether the current curriculum may significantly impact self-compassion and the other variables across different levels.p H1 = 0.30, α = 0.05, Power = 0.80, p H0 = 0) [Participants were 18 years old or older and enrolled in a social work programme at two universities in the Republic of Ireland. An online survey was disseminated to the students via module announcement by their tutors (authors were not involved); therefore, students who were on a study break were excluded. Based on convenience sampling, 140 students in total were approached, of which 129 undergraduate students , 16 males (12%), 4 did not answer (3%); Age M = 25.12, SD = 7.68, Range = 18–47 years old; 68 first-year, 40 third-year and 21 fourth-year students (second-year students were not approached as they were introduced to other research)) agreed to take part (92% response rate), and completed self-report scales regarding self-compassion, resilience, engagement and motivation. The required sample size per power analysis was satisfied  . The gen H0 = 0) .Four scales were used regarding self-compassion, resilience, engagement and motivation.Self-compassion was measured using the Self-Compassion Scale-Short Form (SCS-SF), a shortened version of the full 26-item Self-Compassion Scale . SCS-SF Resilience was assessed using the 6-item Brief Resilience Scale   was usedThe 17-item Utrecht Work Engagement Scale for Students (UWES-S) appraised the level of engagement . The 17 Lastly, motivation was assessed using the Academic Motivation Scale , which ap < 0.05), square-root-transformation was used to satisfy the assumption of normality [First, data screening was performed to detect any outliers and check the assumptions of parametric tests. Second, correlation and regression analyses were performed to identify correlates with and predictors for self-compassion. Finally, one-way MANOVA was conducted to appraise whether the levels of self-compassion, resilience, engagement and motivation were different by their levels of studies. As self-compassion, resilience, extrinsic motivation and amotivation were not normally distributed  was reported. Resilience, engagement and intrinsic motivation yielded 14% of the variance for self-compassion, indicating a medium effect size [To identify significant predictors of self-compassion from significant correlates, namely resilience, engagement and intrinsic motivation, multiple regression analyses were performed . At stepect size . Resilieect size  confirmep = 0.058). There was not a statistically significant difference between the levels on the combined dependent variables, F  = 1.18, p = 0.30; Wilks’ Λ = 0.89; partial η2 = 0.06.A one-way MANOVA was run to determine the effect of the students’ level of studies on self-compassion, resilience, engagement and motivation . There wThere is little research in the literature on the mental health of social work students, despite high academic expectations being a major cause of stress in this particular group . We inveIn the present study, a positive relationship between self-compassion, gender, age, resilience, engagement and intrinsic motivation was noted, consistent with previous findings showing the positive impact of self-compassion in academic settings ,83,84,85Contextualising our findings in social work, indeed, social work does require a high level of self-compassion for practitioners to maintain wellbeing and performance . Social The study found that the level of studies on self-compassion was not significantly different; that is, the year of the study did not appear to affect levels of self-compassion among participating students. Conflicting results have been reported in the literature by Gunnell et al. , who sugLastly, the results of our study can inform the field of EPP. Intrinsic motivation and resilience were particularly strongly associated with self-compassion. These constructs share qualities of EPP. Intrinsically motivated students find meaning in their studies and enjoy their learning, as opposed to extrinsically motivated students who recognise the value of studying in an external reward they are after . This, somewhat, materialistic motivation was not associated with self-compassion, whereas more meaning-oriented intrinsic motivation was. Likewise, resilience refers to the adaptable process of dealing with stress in a healthy way by employing positive coping mechanisms ,98,99. NAlthough this study offers useful insights into the self-compassion of social work students, some limitations of the current study should be noted. First, because correlation and regression analyses were employed in this study, causality could not be determined. A longitudinal design could prove useful in future studies. In addition, the study relied on self-reported measures, which restricts the reliability of participant responses and may influence results . Future Though the importance of self-compassion to the mental health of social work students has been reported, how this relatively new construct could be cultivated remained to be evaluated among Irish social work students. Our results indicated that resilience and intrinsic motivation—more traditional constructs—were strongly associated with self-compassion, suggesting effective means to improve self-compassion. The meaning orientation of both resilience  and intrinsic motivation  may mean that EPP approaches can be helpful to enhance self-compassion, leading to better mental health. For example, educating students to identify and embrace the meaning of their studies may be helpful to protect their mental health. Future research is warranted to implement and evaluate the effects of EPP interventions to improve self-compassion among Irish social work students.


Introduction: According to the cognitive reserve and use-it-or-lose-it hypotheses, engagement in stimulating activities seems to benefit cognition, with engagement often associated with more education or higher occupational position. However, whether retirement may modify the association between education/occupation and cognition is unclear. We aimed to assess how age at retirement may modify the relationship between education/occupation and cognition. Methods: Older adults (n=360) from the Alzheimer’s Disease Neuroimaging Initiative who were cognitively normal and retired at baseline participated. Linear regression was used to assess how educational attainment (high/low) or occupational position  related to executive functioning (EF) or memory, controlling for age, sex, depressive symptoms, and health status. Effect modification by retirement . Results: High education , intermediate  and managerial  occupations  were associated with better EF and memory performance. High education was significantly associated with better EF and memory for participants who retired early  or on-time , but not for participants who retired late . Intermediate occupations were associated with EF only for participants who retired on-time . Conclusion: Education and occupational position may influence cognition after retirement differently based on retirement timing, with effects most apparent for on-time retirement and substantially reduced for late retirement.


As of September 2021, twenty-one anti-COVID-19 vaccines have been approved in the world. Their utilization will expedite an end to the current pandemic. Besides the usual vaccine formats that include inactivated viruses (eight approved vaccines) and protein-based vaccines (four approved vaccines), three new formats have been validated: recombinant adenovirus (six approved vaccines), DNA (one approved vaccine), and messenger RNA . The latter was the fastest . Most Western countries have reserved or use the protein vaccines, the adenovirus vaccines, and mRNA vaccines. I describe here the different vaccine formats in the context of COVID-19, detail the three formats that are chiefly reserved or used in Europe, Canada, and the USA, and discuss why the mRNA vaccines appear to be the superior format. Finally, since the end of the 1990s, companies (starting with the one I cofounded: CureVac) are developing vaccines based on synthetic, in vitro-transcribed mRNA (ivt mRNA) [https://ec.europa.eu/commission/presscorner/detail/en/IP_14_229 accessed on 7 October 2021). Still, the prejudice that mRNA would be instable remained strongly present in the psyche of the scientific and medical communities, which plagued the development of mRNA-based drugs for the last thirty years. The COVID-19 pandemic created a definitive U-turn in this bias and allowed the mRNA vaccine to showcase its potential , which made it the first vaccine format approved against SARS-CoV-2 infections, less than one year after the publication of the viral sequence [https://covid19.trackvaccines.org/vaccines/ accessed on 7 October 2021).Since the validation by Jenner of the principle of vaccination (using cow- (“vacca”) pox virus as a prophylaxis for smallpox), attenuated and inactivated viruses have been the components of efficacious vaccines. Their production, which requires usually animal cells (or eggs), can be difficult (particularly if the virus is lytic), and their purification cannot be too stringent as it would destroy their integrity. As a consequence, the vaccines based on whole viruses contain impurities from the production process that may cause problems, in terms of the induction of irrelevant immunity and intolerance/allergies. Subunit vaccines have proven to be safe and efficacious and somewhat easier to produce, purify, and store. They, however, must be complemented with adjuvants. More recently, recombinant attenuated viruses have been generated that rely on robust production, safety, and efficacy features established for modified attenuated viruses . This type of vaccine was first approved in summer 2020 for protection against Ebola Concerning safety, as they all passed the evaluation processes, they all have been approved as safe . However, are there also theoretical concerns that should be mentioned?Concerning efficacy, all approved vaccines protect well against COVID-19 . Although all current recombinant vaccines use the SARS-CoV-2 spike protein as a target, some use the wild-type protein , while others use a mutated version of it , in particular one that contains two consecutive prolines . This was previously shown for the SARS-CoV and MERS-CoV spikes to keep the protein in a prefusion conformation (the conformation at the virus surface) .Vaccines based on ivt mRNA developed primarily in Europe and the U.S. by BioNTech/Pfizer and Moderna;Vaccines based on recombinant deficient adenoviruses optimized and produced in different countries and by companies including AstraZeneca, Johnson & Johnson/Janssen, and CanSino;Protein-based vaccines mostly advanced in the U.S. and Russia;Inactivated SARS-CoV-2 viruses developed mostly in China and India;A DNA vaccine only approved in India.Five vaccine platforms are currently providing approved vaccines against SARS-CoV-2:In addition, promising new experimental vaccination approaches such as, for example, aerosolized adenovirus , adeno-ahttps://clinicaltrials.gov/ct2/show/NCT04527575 accessed on 7 October2021). Nevertheless, it could be of interest as it is not produced by cells, but chemically synthesized. The chemical peptide antigens corresponding to the SARS-CoV-2 protein are conjugated to a carrier protein and adsorbed on an aluminum hydroxide. These types of chemically synthesized vaccines would not contain contaminants such as proteins from the producing cells in vitro and therefore present less risk of inducing allergies or irrelevant immunity.A safety advantage of proteins is that they are inert and naturally eliminated. However, when produced in cell culture, they contain contaminants coming from the cultures . This muAdenoviruses are nonenveloped viruses that are particularly resistant to chemical or physical agents. Replication-defective adenoviruses are used to generate recombinant vaccines . The rec10 particles per injection, which means approximately 1.5 µg of DNA) is administered intramuscularly in two doses, given between 4 wk and 12 wk apart. It was reported to give a different level of protection , but the overall efficacy was above 70% [https://www.fda.gov/media/146265/download accessed on 7 October 2021).Among the approved adenovirus-based vaccines, the one primarily utilized and most widely distributed so far is from AstraZeneca and named ChAdOx1 nCoV-19 AZD1222). It is a recombinant replication-deficient chimpanzee adenovirus in which a promoter from cytomegalovirus was introduced before a gene sequence from the tissue plasminogen activator (the leader sequence); it also contains the cDNA coding for the full-length wild-type spike and, at the end, a bovine growth hormone polyadenylation sequence. The vaccine . Thus, it can be expected that anticancer mRNA vaccines, particularly when used in combination with other treatments , will soon be approved.Although the utilization of synthetic mRNA in vaccines is relatively new , and one by Moderna . The reth spike , allowinth spike . The adjth spike ). Whetheth spike ; (ii) tyth spike ). Thus, ®) in December 2020. These two mRNA vaccines give over 90% protection against COVID-19 [https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3911826 accessed on 7 October 2021). In the age group of 18 to 60, protection against moderate to severe disease was calculated to be 77%. The company seeks regulatory approval in the segment of the population where it provides protection (https://www.curevac.com/en/2021/08/31/curevacs-cvncov-phase-2b-3-study-data-published-in-preprints-with-the-lancet/ accessed on 7 October 2021). In Israel, where a majority of the population has been vaccinated using the BioNTech/Pfizer or Moderna vaccine, a study on over 10,000,000 persons  demonstrated a vaccine efficacy of 92% against infection, 94% against symptomatic COVID-19, 87% against hospitalization, and 92% against severe disease (determined 7 d or more after the second dose). Thus, the approved mRNA vaccines are highly efficacious, not only in preventing the disease, but also transmission [Although the first injections of an anti-SARS-CoV-2 ivt mRNA vaccine  in volunteers was conducted by Moderna on March 16 2020, the first approval was for the mRNA vaccine of BioNTech in association with Pfizer , it is expected that there will be enough synthetic mRNA vaccine doses to fully, safely, and efficiently vaccinate a large part of the Western world’s population before the end of 2021.Although, as expected for vaccines that strongly activate the immune system, the approved vaccines against SARS-CoV-2 have frequent side effects , they all provide efficient protection against COVID-19 and are widely administered in order to end the pandemic. Three vaccine formats are largely approved in the world. The ivt mRNA vaccine combines the safety aspects of the traditional protein-based vaccines (inert and quickly eliminated), while it has the versatility of recombinant viruses. However, as opposed to recombinant adenoviruses, ivt mRNA-based vaccines do not have the risk of evolving, recombining, or integrating in genomes, and as opposed to proteins, the risk of inducing immunity against contaminants is limited. The safety and flexibility aspects of the ivt mRNA vaccines have turned them into the winners of the race to develop vaccines against COVID-19. These features also keep this format optimal in terms of the design and production of vaccines that might be needed in case variants of SARS-CoV-2 resisting the current vaccine-induced immune response emerge (this is so far not the case even if the beta variant is less well recognized than other variants by mRNA-vaccine-induced antibodies). As the vaccines induced immune response declines over time , a third


Background: Smartphones comprise a promising tool for symptom monitoring in patients with unipolar depressive disorder (UD) collected as either patient-reportings or possibly as automatically generated smartphone data. However, only limited research has been conducted in clinical populations. We investigated the association between smartphone-collected monitoring data and validated psychiatric ratings and questionnaires in a well-characterized clinical sample of patients diagnosed with UD.Methods: Smartphone data, clinical ratings, and questionnaires from patients with UD were collected 6 months following discharge from psychiatric hospitalization as part of a randomized controlled study. Smartphone data were collected daily, and clinical ratings  were conducted three times during the study. We investigated associations between (1) smartphone-based patient-reported mood and activity and clinical ratings and questionnaires; (2) automatically generated smartphone data resembling physical activity, social activity, and phone usage and clinical ratings; and (3) automatically generated smartphone data and same-day smartphone-based patient-reported mood and activity.Results: A total of 74 patients provided 11,368 days of smartphone data, 196 ratings, and 147 questionnaires. We found that: (1) patient-reported mood and activity were associated with clinical ratings and questionnaires (p < 0.001), so that higher symptom scores were associated with lower patient-reported mood and activity, (2) Out of 30 investigated associations on automatically generated data and clinical ratings of depression, only four showed statistical significance. Further, lower psychosocial functioning was associated with fewer daily steps (p = 0.036) and increased number of incoming (p = 0.032), outgoing (p = 0.015) and missed calls (p = 0.007), and longer phone calls (p = 0.012); (3) Out of 20 investigated associations between automatically generated data and daily patient-reported mood and activity, 12 showed statistical significance. For example, lower patient-reported activity was associated with fewer daily steps, shorter distance traveled, increased incoming and missed calls, and increased screen-time.Conclusion: Smartphone-based self-monitoring is feasible and associated with clinical ratings in UD. Some automatically generated data on behavior may reflect clinical features and psychosocial functioning, but these should be more clearly identified in future studies, potentially combining patient-reported and smartphone-generated data. Unipolar depressive disorder is a common and serious mental disease with a lifetime prevalence of 15–20%  as well Currently, no objective biomarkers are available to monitor illness activity in patients with unipolar depressive disorder. Monitoring of symptoms is essential for patients and clinicians, i.e., as part of measurement-based care . FurtherThus, monitoring methods to assess patients regularly, on both subjective changes in mood and detectable changes in behavior and psychomotor function, are warranted. Remote monitoring of patients could potentially help to allocate the right treatment to the right patient at the right time to distribute the limited treatment resources appropriately and possibly detect relapse in high-risk groups.Smartphones comprise an available platform for remote real-time monitoring of patient-reported symptoms such as mood, activity, and anxiety through Ecological Momentary Assessments (EMAs) , 12. FurPatient reportings are often easier to interpret; however, they require the patient's active action to provide data. Automatically generated data allow for large-scale data collection without efforts to the patients, but often with several technical challenges and more complex interpretation.Several relevant reviews within the field , 17–21 iThe present study aims to add important knowledge to the field by (1) investigating associations between daily smartphone-based patient-reported mood and activity and clinical ratings of depression measured using the Hamilton Depression Rating Scale 17-items (HDRS-17), psychosocial functioning measured using the Functional Assessment Short Test (FAST), and standardized questionnaires using Beck's Depressive Inventory (BDI-21); (2) investigating associations between automatically generated smartphone measures of social and physical activity as well as phone usage with validated clinical ratings (the HDRS-17 and the FAST) and (3) investigating associations between automatically generated smartphone data of social and physical activity as well as phone usage with same-day smartphone-based patient-reportings of mood and activity.Based on available studies and clinical experience, we hypothesized that (1) higher symptom scores on the HDRS-17, the FAST, and the BDI-21 would entail lower smartphone-based patient-reported mood and activity; (2) higher symptom scores on the HDRS-17 and FAST would entail lower physical and social activity and higher smartphone phone usage, measured by automatically generated smartphone data, and (3) lower smartphone-based patient-reported mood and activity would entail lower physical and social activity and higher phone usage measured by automatically generate smartphone data.The data included in the present study were collected as part of a large Randomized Controlled Trial (RCT) called the RADMIS trial, investigating the effect of smartphone-based monitoring and treatment in patients with unipolar depressive disorder following discharge from a psychiatric hospital. The results from the RCT study have been published elsewhere .The RADMIS trial included 120 patients diagnosed with unipolar depressive disorder when discharged from psychiatric hospitals in The Capital Region in Denmark from May 2017 to August 2019. The present study includes data from 74 of these patients, as they provided relevant smartphone data for the analysis.Inclusion criteria: Age over 18 years; unipolar depressive disorder diagnosis according to the International Classification of Diseases, version 10 (ICD-10) using Schedules for Clinical Assessments in Neuropsychiatry (SCAN) (y (SCAN)  , −2 (moderate depression), −1 (mild depression), −0.5 (lowered mood), 0 neutral mood). Activity was scored as one of the following scores: −3, −2, −1, 0, 1, 2, 3 with negative values resembling low activity; zero is the patient's normal activity level, and positive score resembling higher than usual activity. Once a day, at a self-chosen time, the smartphone reminded the patient to conduct the evaluations. If several days were missing, patients were contacted by the study nurse.Automatically generated smartphone data: The automatically generated smartphone data were collected from patients in both the intervention and control groups. The smartphone app was available for Android and iOS. Due to technical constraints on iOS, fewer automatically generated data were available from iOS users . The automatically generated smartphone data were collected and summarized to daily measures and reflected physical activity, social activity, and phone usage:Physical activity: The number of steps per day; The total distance moved per day , Wifi signals, and mobile cell towers).Smartphone usage: The total screen-on time per day (seconds per day) and the number of times the screen was turned on per day.Social activity: The number of incoming, outgoing, and missed calls per day; the duration of calls per day (seconds per day); The number of incoming and outgoing text messages per day .No specific instructions on how and when to carry the phone were given.Ethical permission was obtained from the ethics committee in The Capital Region of Denmark (H-16046093) and the Data Agency . The law on handling personal data, as well as the European General Data Protection Regulation (GDPR), was respected. All data collected by researchers was stored in the Research Electronic Data Capture (REDCap) electronic data capture tools , 40. EleThe statistical analyses for the present study were defined a priori. For aims 1 and 2, we calculated the averages of the daily smartphone data  for the days surrounding the ratings and questionnaires. We used the day of the rating/questionnaire and, respectively, 3 days before the HDRS-17 ratings and BDI-21 questionnaires and 14 days before the FAST ratings. This resembles the period in which the symptoms were evaluated. In a few cases, relevant smartphone data were not available in the 3/14 days before an assessment. In such cases, we used the 3/14 following days as a pragmatic solution to use the valuable data surrounding the clinical data points. Missing items from ratings and questionnaires were not included in the summed scores, and no imputations or assumptions on missing items were made.For aim 3, we used all smartphone-based patient-reported data with same-day corresponding automatically generated smartphone-based data without any averages or summed scores.Linear mixed-effects models accounting for repeated measurements within each participant were employed. For aims 1 and 2, we used averages of smartphone data as the dependent variable and the clinical ratings/questionnaires as independent variables handled as fixed factors. For aim 3, we used automatically generated smartphone data as the dependent variable and patient-reported data as the independent variable handled as fixed factors. Individual ID number was used as a random factor for all analyses to account for individual differences.All analyses were conducted first in an unadjusted model and secondly in models adjusted for age and sex. As there were only minor differences among adjusted and unadjusted models, only the models adjusted for age and sex are presented. Model assumptions with analyses of residuals and covariance were calculated and assessed graphically  and discussed by MFJ and MLT for all models and were acceptable. Further, all automatically generated smartphone variables were logarithm transformed and square-root transformed and included in all analyses without significant improvement of models and therefore omitted. All models had sufficient amount of data to fulfill the model assumptions.P-values of ≤0.05 were considered statistically significant. We used SPSS  version 25 for all analyses.The sample size was defined according to the RCT. As this is the first study on smartphone data in this well-characterized and severely ill group, it is explorative by nature. Therefore, in the present study, the statistical models were not corrected for multiple analyses. Thus, results should be interpreted with caution due to the risk of chance findings when multiple analyses are conducted. . Patient-reported data was provided by 58 patients for 7,509 days , automatically generated smartphone data was provided by 46 patients for 7,063 days , and 30 patients provided 3,204 days of same-day smartphone-based patient-reported data and automatically generated smartphone data . The 74 patients participated in 196 clinical ratings  and completed 147 questionnaires . The amount of data included in the individual analyses varies depending on available data and the temporal context of clinical ratings and smartphone data. This information is presented in the corresponding tables. The data collected had a large variance for both smartphone-based patient-reported symptoms and clinical ratings, including cases of both mild, moderate, and severe symptoms, although, fewer cases of severe symptoms. Data examples are displayed in A total of 74 patients provided data to the present study, with 11,368 days of available smartphone data Sociodemographic and clinical characteristics are presented in Data on the association between smartphone-based patient-reported data on mood and activity with clinical ratings and questionnaires are presented in p < 0.001; HDRS item 1: B = −0.44, 95% CI , p < 0.001; FAST: B = −0.013, 95% CI , p < 0.001; BDI-21: B = −0.034, 95% CI , p < 0.001]. Thus, for every increase in the HDRS-17 score of one point there was decreased in smartphone-based patient-reported mood of 0.057 points.As hypothesized, smartphone-based patient-reported mood was negatively associated with severity of symptoms in clinical ratings and questionnaires: Higher scores on the HDRS-17, the FAST and the BDI-21 was associated with lower smartphone-based patient-reported mood: . Thus, for every increase in the HDRS-17 score of one point, there was a decreased smartphone-based patient-reported activity of 0.053 points.As hypothesized, smartphone-based patient-reported activity were negatively associated with severity of symptoms in clinical ratings: Higher severity of symptoms scores on the HDRS-17 and the FAST were associated with lower smartphone-based patient-reported activity: . Thus, for every increase in the FAST of one point, there was a decreased number of daily steps of 51. There were no other statistically significant results concerning step counts or total distance traveled as proxy measures for physical activity.As hypothesized, higher scores on the FAST was associate with lower daily step count: . Thus, for every increase in the HDRS-17 of one point, there was a decrease in the number of times the patient turned on their smartphone screen per day by 0.71. There were no other statistically significant results on the daily number of times the screen was turned on or the screen-on duration, as proxy measures for smartphone usage.Higher scores on the HDRS-17 were associated with fewer times the screen was turned on: . Thus, for every decrease of patient-reported mood by one point, there was an increase of daily screen time by 1,344 s (22 min).As hypothesized, smartphone-based patient-reported mood was negatively associated with automatically generated measures of social activity and phone usage: Lower patient-reported mood was associated with higher automatically generated measures. . Further, Smartphone-based patient-reported activity was negatively associated with screen time and number of incoming calls: Lower patient-reported activity was associated with an increase of , p < 0.001; and the number of incoming calls: B = −0.088; 95% CI , p = 0.0082.) Thus, for every decrease in patient-reported activity by one point, there was a corresponding decrease in the daily length traveled by 4,949 m and an increase in the daily screen time by 784 s (13 min).As hypothesized, smartphone-based patient-reported activity was positively associated with automatically generated measures of physical and social activity as well as phone usage: Lower patient-reported activity was associated with a decrease in [adjusted models: number of steps: B = 178.58, 95% CI , We systematically investigated smartphone-based monitoring tools for patients with unipolar depressive disorder against validated clinical ratings and questionnaires.As hypothesized, smartphone-based patient-reported mood and activity were associated with total scores on the HDRS-17 and the FAST. Further, smartphone-based patient-reported mood was statistically significantly associated with mood according to item 1 of the HDRS-17 and with the BDI-21. These findings emphasize that patient-reported mood and activity are feasible and with high clinical validity in patients with unipolar depressive disorder. This is consistent with similar studies on patients with bipolar disorder , 15, 29.The associations of clinical ratings of depression (including subscores) with behavioral changes detected through automatically generated smartphone data were not as compelling as expected. We found four statistically significant results among 30 analyses, with a high risk of chance findings: As hypothesized, higher HDRS-17 total scores were associated with a higher number of times the screen was turned on and longer duration of phone calls, whereas, higher scores on HDRS item 9 (agitation) were associated with more outgoing calls and longer duration of phone calls.Lower levels of psychosocial functioning resulted in fewer daily steps, an increased number of incoming, outgoing, and missed calls, and increased duration of phone calls. Thus, several detectable changes in behavior were found to be associated with the FAST. However, the increase of phone-call-activity possibly represents an increased concern and help from family, friends, or caretakers, rather than changes in symptoms.The recent technological development has shifted our digital life toward smartphones , providiAs hypothesized, when combining the daily smartphone-based patient-reported data with the same-day automatically generated smartphone data, we found that patient-reported mood and activity were associated with several changes in behavior reflected by automatically generated smartphone data. The changes were in line with our hypotheses, findings from previous studies, and clinical experience.Thus, smartphone usage could be a proxy measure for sedentary behavior. Lower patient-reported mood was associated with an increase in smartphone usage (as a possible sign of more sedentary behavior) and an increase in missed calls as a possible sign of less social engagement. The prolonged call duration could be caused by the increase in incoming calls. Along with an increase of incoming text messages, the increased incoming communication may reflect increased concern/care from surroundings when patients report low mood.Lower smartphone-based patient-reported activity was associated with a decrease in the number of steps and distance traveled as a sign of lower physical- and travel activity. As with patient-reported mood, the corresponding increase of total screen time, the number of missed and incoming calls may reflect an increase in sedentary behavior, social withdrawing, and concern from surroundings, respectively.As such, same-day patient-reported mood and activity were associated with specific behavioral changes. Thus, a large amount of non-intrusive, fine-grained same-day smartphone data can be collected and may reflect changes in symptoms and behavior caused by the severity of the disease.The data in the present study is obtained from an RCT study. Participation in the study might have affected the patients' smartphone behavior when planning and showing up for assessments. Further, automatically generated smartphone data may have been influenced by the intervention to some degree as patients were contacted on text message or telephone by the study-nurse in case of concern. Due to different technological and methodological reasons, not all data was collected from all patients. There are constant technological changes to smartphone technology and to how we use and interact with our smartphones. These changes may influence the future generalizability of our findings, especially concerning the type of data collected and how it is processed. We only collected data on old school text messages, not including common messenger apps or social media. Future studies may include more broad sources of smartphone-based information . The facThe combination of smartphone-based technology and thorough clinical assessments in a clinical population is a major advantage of the present study. Rating scales were conducted by research-trained medical doctors in well-tested clinical setups and with high attrition among included patients. Patients underwent thorough clinical examinations, and researchers had access to their electronic medical records. The data were collected in a population of patients with an indisputably need for psychiatric support and treatment, and thus, findings from the current study can more easily be generalized to patient populations in psychiatric treatment settings. Finally, the system used in the study had been thoroughly tested in multiple studies in patients with bipolar disorder , 43, 44.The ongoing COVID-19 crisis, with worldwide and local lock-down(s), has accelerated and emphasized the need for new ways of conducting outpatient psychiatry assisted by technology. Smartphone-based solutions could likely improve telephone and online courses by supplying clinicians with important information about patients' symptoms and behavior. Moreover, methods to adapt to the constant technological changes to smartphone technology faster are needed. Machine-learning algorithms might detect such patterns , and tecSmartphone-based symptom monitoring in patients with unipolar depressive disorder was feasible and associated with clinical ratings of depression and psychosocial functioning. Patient-reported mood and activity were highly statistically significantly associated with standardized clinical ratings and questionnaires. The results concerning the association of automatically generated smartphone data with clinical ratings of depression were less appealing, and only 4/30 associations were statistically significant. Lower levels of clinically rated psychosocial functioning were associated with fewer daily steps, increased number of incoming, outgoing, and missed calls, and increased duration of phone calls. Finally, the associations of smartphone-based patient reportings and same-day automatically generated smartphone data were more consistent and showed that the daily patient reportings were associated with several automatically generated smartphone features likely reflecting behavioral changes. Taken together, findings from this study suggest that smartphone-based patient-reported data on mood and activity and some smartphone-based automatically generated data on behavior may assist and supplement the clinicians in the monitoring of unipolar depressive disorder, and hereby provide patients and healthcare professionals relevant and timely information to improve decision making and treatment. A combination of data could potentially increase the use of smartphone data in clinical settings and should be investigated further using more advanced machine learning models in future studies, i.e., focusing on individual patterns and generating composite scores.Lars.Vedel.Kessing@regionh.dk.The datasets presented in this article are not readily available because data are still being used for internal research purposes, and we do not have the approvals for data sharing. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by the ethics committee in the Capital Region of Denmark (H-16046093). The patients/participants provided their written informed consent to participate in this study.MT, MF-J, JB, and LK conceived the study. MT, MF-J, and LK did all statistical analyses and wrote the first draft of the manuscript. JB and MF provided the technical content. All authors contributed to the manuscript and approved the final version.JB and MF are co-founders and shareholders of Monsenso. LK has, within 3 years, been a consultant for Lundbeck and Teva. The remaining 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.