This study aimed to validate the Persian version of Maslach Burnout Inventory for Medical Personnel (MBI-HSS-MP), an instrument developed to capture burnout for health professionals. The specific aims were to psychometrically assess the Persian MBI-HSS-MP in relation to its structure, test-retest reliability, and item properties.The study setting was all eight hospitals in Qazvin province, Iran (study period from 10 September to 16 November 2020). Health professionals of physicians (n = 106) and nurses (n = 200) participated in the study. The psychometric properties of the 22-item MBI-HSS-MP was then examined for its factor structure via confirmatory factor analysis (CFA) and Rasch models, test-retest reliability, item fit, and differential item functioning (DIF).The MBI-HSS-MP was verified as having a three-factor structure and each item was embedded well in its belonging construct . Test-retest reliability of each MBI-HSS-MP item was satisfactory and no substantial DIF items were displayed across gender or across health professionals.The MBI-HSS-MP has good psychometric properties to assess burnout accurately among healthcare professionals in the three dimensions of emotional exhaustion, personal accomplishment, and depersonalization. •The study confirmed the three-factor structure for the Maslach Burnout Inventory.•Policymakers and managers can use this inventory to assess burnout and identify barriers.•Different genders and health professionals interpret this inventory similarly. Burnout; Factor analysis; Physician; Nurse; Validation. HoweverBurnout may lead to serious consequences if health professionals cannot cope with it , 15, 16.Given the importance of assessing burnout for health professionals in a precise way , empiricIn order to assess burnout among human service workers, the Maslach Burnout Inventory Human Services Survey (MBI-HSS) was developed using the three aforementioned dimensions of burnout . The MBIAlthough the MBI-HSS is a promising instrument to assess burnout for human services workers, it may not precisely capture the burnout for a specific type of human services workers . Researchers and healthcare providers are extremely interested in understanding the issue of burnout among health professionals because this particular human service is important and related to human life. Indeed, a number of recent papers have discussed burnout among health professionals using the MBI-HSS , 16, 17.Although the MBI-HSS-MP may share similar psychometric properties found in the MBI-HSS , 10, 11,22.1The present methodological study was conducted between 10 September 2020 and 16 November 2020 in Qazvin, Iran. The study setting was all hospitals in Qazvin province. Study participants were physicians and nurses who were working in eight hospitals in Qazvin province. A convenience sampling approach was used to collect data from 400 physicians and nurses. After providing information on study aims and procedure, 94 physicians and nursed declined to participate in the study. The remaining 306 participants (106 physicians and 200 nurses), had a mean age of 45.12 years (SD = 6.42) and a larger proportion of females (62.4%).The two types of health professions were recruited because of the following reasons: (1) nurses and physicians usually work in the same scenarios and contexts. Therefore, they may share some burnout factors similarly and it is important for researchers and policymakers to know if the MBI-HSS-MP can be applied to both nurses and physicians; and (2) when the psychometric features of the MBI-HSS-MP can be supported in the two types of health professionals, researchers, policymakers, and healthcare providers can use the MBI-HSS-MP scores to make further decisions regarding how to take care of burnout among these two types of health professionals. The participants were eligible to be included in the study if they worked full-time or part-time, providing direct care to patients, and provided written consent form to participate in the study.2.2The ethics committee of Qazvin University of Medical Sciences approved the study . The study complies with all regulations and written informed consent was obtained.2.32.3.1The MBI-HSS-MP is a specific version of the MBI Human Services Survey. The MBI Human Services Survey was designed to assess how individuals working in human services feel exhausted or burnt out. However, given that medical personnel are one of the most studied occupational among all human services professions, the MBI-HSS-MP was further developed by slightly changing some of the wording from the MBI Human Services Survey. The MBI-HSS-MP contains 22 seven-point items distributed across three dimensions: Emotional Exhaustion (nine items), Personal Accomplishment (eight items), and Depersonalization (five items). The response scales are defined as follows: 0 = never, 1 = a few times a year or less, 2 = once a month or less, 3 = a few times a month, 4 = once a week, 5 = a few times a week, and 6 = every day. Higher scores indicate a higher level of burnout. The dimension scores can be calculated using two methods. The first method sums the item scores for each dimension and the second method calculates the average item scores for each dimension. The present study adopted the second method to calculate the MBI-HSS-MP dimension scores because this method provides a more straightforward interpretation of the dimension scores. More specifically, a mean dimension score of 3.5 can be interpreted as the participant feeling emotionally exhausted several times a month rather than emotionally exhausted every week. Psychometric properties of the MBI-HSS-MP have not been previously investigated. However, the MBI Human Services Survey has been tested among health professionals and has demonstrated a consistent three-factor structure [2.3.2A.Forward translationThe translation procedure was performed in several steps based on Beaton et al.‘s (2000) recommendations . MoreoveB.Backward translationTwo independent bilingual translators whose mother tongue was Persian, translated the English MBI-HSS-MP into Farsi/Persian. A session was then held with the corresponding author to synthesize all translations. The first stage attempted to develop an interim Persian version of the MBI-HSS-MP.C.Expert committeeThe interim Persian version was then translated back into English by two other bilingual translators who were blinded to the original English version. These back-translated versions were then compared with the original English versions.D.Pilot testingA panel session with several health professionals  was held to consolidate all the versions of MBI-HSS-MP versions. The committee members assessed all translated items in terms of semantic equivalence, idiomatic equivalence, experiential equivalence, and conceptual equivalence. The pre-final Persian MBI-HSS-MP was then piloted on 20 nurses and 11 physicians to ensure that the target population could understand the items, responses, and instructions.2.4The demographics of the participants were analyzed using descriptive statistics before the psychometric testing of the MBI-HSS-MP was carried out. Two types of psychometric testing were utilized in the psychometric testing . Following this, LPA was used to classify the participants into different levels of burnout. Demographics and MBI-HSS-MP dimension scores were compared between the participants with different levels of burnout using analysis of variance (ANOVA).Psychometric testing from CTT includes the following analyses. Normal distribution of each MBI-HSS-MP item score was assessed using skewness  and kurtosis  . Test-rePsychometric testing utilizing Rasch analyses included the following. Inlier-sensitive mean square (infit MnSq) and outlier-sensitive (outfit) MnSq were used to assess MBI-HSS-MP item score with acceptable value between 0.5 and 1.5 . DiffereLatent profile analysis (LPA) was used to classify the participants into different levels of burnout according to their underlying latent structures of MBI-HSS-MP performance. With the use of goodness of fit, including AIC, Bayesian Information Criteria (BIC), and Sample Size Adjusted Bayesian Information Criterion (SSABIC), the LPA can help determine how many levels of burnout exist among the participants. More specifically, the lowest values of AIC, BIC, and SSABIC indicate better model fit and lead to the decision of group numbers . FurtherRegarding the statistics software, IBM SPSS AMOS was used for performing CFA; WINSTEPS for performing Rasch analyses; Mplus for performing LCA; IBM SPSS and Excel for performing the rest of the analyses.3The participants were health professionals either as a physician  or a nurse . The mean age of the participants was 45.12 years (SD = 6.42) with nearly half of the sample having extensive clinical experience of over 10 years (49.0%). In addition, slightly more than one-third of the participants were males (37.6%) and most of the participants were married (88.2%) .Table 1PThe scale properties of the MBI-HSS-MP were also promising. In the CTT findings, The CFA fit indices indicated that the all the three tested models were supported: CFI = 0.941, TLI = 0.929, RMSEA (90% CI) = 0.046 , and SRMR = 0.069 for three-factor structure model; CFI = 0.915, TLI = 0.901, RMSEA (90% CI) = 0.055 , and SRMR = 0.071 for second-order structure model; CFI = 0.920, TLI = 0.906, RMSEA (90% CI) = 0.054 , and SRMR = 0.076 for bifactor structure model . AccordiThe LPA suggested that the present sample should be classified into three groups  are accAt the scale level, all three models  of the MBI-HSS-MP were confirmed by the CFA. However, the fit indices were only borderline satisfactory . According to the latest recommendation, CFI and TLI should be higher than 0.95 . MoreoveThere are some limitations in the present study. First, there were no external outcome measures. Therefore, the convergent validity and discrimination validity of the MBI-HSS-MP was only examined using the CFA rather than using external outcome measures. Future studies may consider using different outcome measures  to provide additional validity evidence for the MBI-HSS-MP. Second, only two types of health professional  were recruited in the present study. Therefore, the present findings cannot necessarily be generalized to other types of health professional. Future studies may want to examine the psychometric properties of the MBI-HSS-MP among other types of health professional . Third, all the participants were Iranians and the present findings cannot be generalized to other ethnic groups. Fourth, the present sample size was relatively small, and this can sometimes be a limitation in advanced psychometric testing such as CFA. Finally, all the participants were in full-time work employment, therefore the findings cannot necessarily be generalized to those in part-time work employment. Future studies could therefore investigate measurement invariance comparison based on type of employment.5Given that the psychometric properties of the MBI-HSS-MP were rigorously examined and produced satisfactory results, clinical and nursing practitioners may use the MBI-HSS-MP to assess the levels of burnout among health professionals. Subsequently, early treatments or interventions can be applied to prevent serious health problems caused by burnout among those in the health profession. More specifically, the present findings have nursing implications in the following aspects. First, healthcare providers’ burnout can be assessed in a better and more accurate way according to the satisfactory psychometric properties found in the present study. Consequently, this could be helpful for improving mental health among those in the nursing profession. Second, the results of the present study can be used to better understand latent profiles of nursing staff with any level of burnout. That is, the findings support the use of the MBI-HSS-MP in the early detection of the initial stage of burnout among nursing staff. This could also be helpful for improving mental health among nursing professionals. Third, it is estimated that over 120 million people speak Persian worldwide . Therefore, the results of the study can especially assess burnout among Persian-speaking nursing staff. Finally, the results of the present study can be used by policymakers and managers to assess burnout and to identify barriers to improve nursing mental health at the governmental level.6In conclusion, the present study demonstrated the promising psychometric properties of the MBI-HSS-MP, an instrument for assessing burnout among health professionals. The factor structure of the MBI-HSS-MP was verified to be a three-factor structure and all the items in each factor fitted their embedded constructs well. Therefore, in future studies, researchers and healthcare providers may use MBI-HSS-MP to assess three dimensions of burnout  among health professionals.Chung-Ying Lin: Conceived and designed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.Zainab Alimoradi: Performed the experiments; Contributed reagents, materials, analysis tools or data; Wrote the paper.Mark D. Griffiths: Analyzed and interpreted the data; Wrote the paper.Amir H Pakpour: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Data will be made available on request.The authors declare no conflict of interest.No additional information is available for this paper.


Background and Objectives: 18F-fluorodeoxyglucose (FDG) positron emission tomography/X-ray computed tomography (PET/CT) represents the mainstay diagnostic procedure for suspected ovarian cancer (OC) recurrence. PET/CT can be integrated with contrast medium and in various diagnostic settings; however, the effective benefit of this procedure is still debated. We aimed to compare the diagnostic capabilities of low-dose and contrast-enhanced PET/CT (PET/ldCT and PET/ceCT) in patients with suspected ovarian cancer relapse. Materials and Methods: 122 OC patients underwent both PET/ldCT and PET/ceCT. Two groups of nuclear medicine physicians and radiologists scored the findings as positive or negative. Clinical/radiological follow-up was used as ground truth. Sensitivity, specificity, negative/positive predictive value, and accuracy were calculated at the patient and the lesion level. Results: A total of 455 and 474 lesions were identified at PET/ldCT and PET/ceCT, respectively. At the lesion level, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were not significantly different between PET/ldCT and PET/ceCT . At the patient level, no significant differences in these parameters were identified . Smaller peritoneal/lymph node lesions close to physiological FDG uptake sources were found in the cases of misidentification by PET/ldCT. PET/ceCT prompted a change in clinical management in four cases (3.2%) compared to PET/ldCT. Conclusions: PET/ceCT does not perform better than PET/ldCT but can occasionally clarify doubtful peritoneal findings on PET/ldCT. To avoid unnecessary dose to the patient, PET/ceCT should be excluded in selected cases. Even th PET/CT) ,21. In psegments ,23,24, asegments . Recentlsegments .18F-FDG PET/CT is performed using “low-dose” settings in the CT component: this allows performing a CT-based attenuation correction of the PET data and anatomically localizing the FDG accumulation while avoiding the increased radiation burden, which is associated with a “full-dose” CT. Some reports indicate that performing an 18F-FDG PET with a full-dose CT and contrast medium might grant a better accuracy than 18F-FDG PET with low-dose, non-contrast CT [18F-FDG PET/CT [Under normal circumstances, trast CT ,28,29. HG PET/CT . In geneG PET/CT ,32.18F-FDG PET/CT (PET/ldCT) with the contrast-enhanced 18F-FDG PET/CT with standard radiological dose settings (PET/ceCT) retrospectively. Moreover, we tried to identify the specific clinical scenarios in which PET/ceCT could significantly outperform PET/ldCT.To try and clarify the role of contrast-enhanced, full-dose PET/CT in the setting of OC recurrence, we planned this present study, in which we aimed to compare the diagnostic capability of standard “low-dose” 18F-FDG PET/CT with both ceCT and ldCT in the same sitting, because of suspected recurrence of a pathologically proven ovarian cancer. At our institution, the standard imaging procedure of suspected OC recurrence is represented by an 18F-FDG PET/ldCT and ceCT; whenever possible, however, the two examinations are performed at the same time, to accelerate the diagnostic process and to limit the patients’ discomfort.The local database was searched for patients who had undergone an 18F-FDG PET/CT included unclear or suspicious findings at conventional imaging , an increase of tumour markers (at least two consecutive determinations), suggestive signs of recurrence at a physical examination, or any combination of these.Indications for Patients were excluded in case of concomitant further oncological conditions, insufficient quality of any series of the combined examination, and in presence of ongoing treatment .Each patient signed informed consent before the examination. Due to the study’s retrospective nature, the local review board waived the need to get specific consent for this study. 18F-FDG  [A Discovery ST  PET/CT was used for the acquisition. After at least 4 h of fasting, the patients received an intravenous bolus injection of delines) ,34. The 18F-FDG PET/ldCT, any focal, non-physiological uptake higher than that of the surrounding background corresponding to any solid tissue was considered pathological [All PET/ldCT examinations were grouped after anonymization, and two expert nuclear medicine physicians (MM and GB), blinded to ceCT results, interpreted the exams, with a third senior reader (AP) being referred to whenever a consensus was needed. On ological . Referen18F-FDG PET/ceCT, any focus of non-physiological uptake corresponding to a suspicious ceCT finding was deemed suggestive for recurrence. Reference tissues were the same as described above. Enlarged lymph nodes (>10 mm) without FDG uptake were classified as negative findings [PET/ldCT studies were interpreted visually and semi-quantitatively by using the SUVmax, on a patient-by-patient and lesion-by-lesion basis. No SUVmax cut-off values were introduced to assess tumour lesions, whereas these parameters were calculated as support to visual interpretation. All PET/ceCT results were interpreted in consensus by an experienced radiologist (FP), and by an experienced nuclear medicine physician (MC). On findings .The final diagnosis was obtained from a multidisciplinary follow-up of at least 18 months , based on tumour marker levels, contrast-enhanced CT findings, and PET/ceCT findings. We classified the findings of the cases as true positive (TP); the study revealed findings compatible with a recurrence, and the patient underwent chemotherapy resulting in a decrease in size and FDG uptake or a complete disappearance in the follow-up study. Likewise, lesions progressing under chemotherapy, or remaining initially stable under treatment but ultimately showing progression were also labelled as TP. Furthermore, lesions displaying growth in size or FDG uptake in the absence of treatment were considered TP.True negative cases were defined as those in which no abnormal CT or PET findings were detected, and the follow-up imaging showed neither an appearance of FDG uptake nor a morphological growth or alteration of FDG-negative findings. A false positive was defined in cases in which an abnormal finding was seen at baseline imaging, with later disappearance in the absence of intercurrent treatment. Finally, the evolution in size of an FDG-negative lesion was deemed as a false negative. These criteria are summarized in p values of less than 0.05 were considered to indicate statistical significance. Statistical analyses were performed using SPSS software Advanced Models 24 .Sensitivity, specificity, and accuracy were calculated, after dichotomous interpretations of the readers  and considering the above defined standard of reference. Differences between the two imaging modalities were tested with the McNemar. In the case of multiple comparisons, a Bonferroni correction was applied. One hundred and twenty-two subjects  fit the inclusion criteria .Most of the cases (72%) were referred to our centres because of rising tumour marker; roughly a quarter of them had undergone a CT or MR, which had shown unconducive findings. The selected patients were affected by a generally aggressive or advanced form of OC: almost four-fifth of them had a stage III or IV at the first diagnosis, as well as a grade three clonal proliferation. The most frequent histology was serous OC, followed by the mucinous one; the other histologies made up one-fifth of the sample. Median follow-up was three years, with some patients still attending their regular follow-up visits nine years after the recurrence diagnosis. The overall patients’ characteristics are listed in A total of 56 patients (46%) had at least one finding at PET/ldCT; at PET/ceCT, 57 patients with positive findings were identified (47%). At PET/ldCT, 43 patients (35%) had at least one peritoneal lesion; among them, two had evidence of a pararectal lesion, and nine presented with a diffuse peritoneal spread. In total, 380 peritoneal lesions were identified . Twenty-seven subjects (22%) had at least a positive lymph node; five had ten or more nodal manifestations. A total of 262 lesions were detected . PET/ceCT detected peritoneal nodules in 44 patients (36%) and a positive lymph node in 28 subjects (23%). Overall, contrast-enhanced PET/CT identified 393 peritoneal and 263 nodal lesions. Of all the 122 patients, PET/ldCT failed to identify peritoneal lesions in five patients and lymph node metastases in two. Moreover, it identified false-positive findings in the peritoneum and the lymph node stations of four and one patients, respectively. Its overall accuracy was 92.6% and 98.4% for the peritoneum and the lymph nodes, respectively. PET/ceCT performed slightly better, missing peritoneal lesions in two patients only, and lymph node lesions in one. However, the difference between the two methods did not reach statistical significance. See In keeping with the patient-based setting, the lesion-based analysis could not find a significant difference in the performance of the two methods. PET/ldCT was not able to identify nine lesions  while PET/ceCT had only five false negatives. Similarly, false positives lesions amounted to twelve and eight for PET/ldCT and PET/ceCT, respectively.See The course of therapy was altered due to the contrast-enhanced, full-dose PET/CT in four cases. In one case, a false-positive peritoneal finding in PET/ldCT was correctly characterized by PET/ceCT, and unnecessary treatment was avoided. In two cases, the presence of active disease (one lymph node and one paracolic relapse) was unmasked by PET/ceCT, whereas the unenhanced, low-dose PET/CT had not indicated any clear positivity. Because of that, treatment was initiated. The correct identification by PET/ceCT in the case of paracolic recurrence is depicted in In one case, however, PET/ceCT detected a peritoneal finding which was deemed as disease-related, even though PET/ldCT did not indicate any evident positivity . As the 18F-FDG-PET/CeCT could be of value, allowing to correctly interpret as faint positive uptake close to the physiological activity of the bowel but corresponding to small lesions of peritoneal carcinomatosis. Besides, contrast enhancement can help the physician in identifying a small amount of abdominal and pelvic ascites whose presence often requires the physician better weigh and evaluate microscopic peritoneal lesions characterized by minimal FDG activity. Finally, using full-dose protocols can improve the grey-scale contrast and the spatial resolution in the lymph node station, thus allowing the identification of small-scale nodal disease. This consideration might be especially valid when the suspected lymph nodes are located in the proximity of physiological FDG uptake sources, such as vessels or urinary tract, where the interpretation of tracer uptake within small structures is more challenging.In this paper, we tried to evaluate the impact of full-dose, contrast-enhanced CT within a PET/CT examination in patients affected by OC and suspected relapse. Our results show that adding the diagnostic quality and the contrast medium has a limited impact on the method’s accuracy. The diagnostic parameters of the PET/ldCT were already very satisfactory; adding the contrast and the full dose only marginally improved these figures. However, we observed that in specific cases, a PET/ceCT could be of value. Indeed, it appears that, in selected patients with a suspected low burden of peritoneal disease, due to, e.g., marginally increase levels of tumour markers, In all other cases, there appears to be no compelling reason to switch to PET/ceCT. Using a full-dose setting entails a significant escalation of the absorbed dose, with a difference that can range from five- to tenfold, depending on the used protocol ,36. MoreTo date, only a few research papers have tried to tackle this issue. The study by Kitajima et al. analysed a similarly sized sample and did not detect any significant difference between PET/ldCT and PET/ceCT at the patient level . At the On the other hand, there is vast evidence that FDG PET/CT has an irreplaceable role in the setting of suspected OC recurrence ,41. MoreMoreover, protocols requiring morphometric evaluations of the disease-related findings might require having a full-dose, contrast-enhanced CT to work with; diagnostic-quality imaging is in fact preferred in the context of standardized morphologic evaluations  .Clarification of unclear findings using PET/ceCT might be decided after the execution of PET/ldCT so that the additional exposure due to the full-dose CT ensues only when necessary. Given the available evidence, such occurrences should be relatively rare. In all other cases, given the excellent accuracy of PET/ldCT, contrast medium and diagnostic CT could be skipped, reducing the radiation burden and the patients’ discomfort.This study had certain limitations. It represents a single-centre retrospective analysis, thus incurring potential information or selection bias. In particular, such a bias could have been introduced by a high prevalence of patients with a high disease burden. Moreover, the majority of the included population suffered from a high-grade disease, limiting our knowledge of the PET/ceCT usefulness in less aggressive ovarian neoplasms. However, these limitations are present in most studies on this subject, given the generally advanced disease status at diagnosis in OC patients ,28. MoreThe ideal gold standard for any analysis would be histological confirmation of the findings. However, clinical follow-up is a valid way to evaluate diagnostic accuracy and response to therapy, and it would have been questionable to investigate all PET/CT-detected lesions using invasive procedures. Positive findings are easy to confirm, but negative findings need to be confirmed over an extended follow-up period. Therefore, sensitivity in this series may have been overestimated. Our data confirm the excellent sensitivity, specificity, and accuracy of PET/CT; moreover, they clarify the role of an integrated PET with ceCT, which might be used to clarify equivocal findings in suspected cases. However, the lack of clear indications on the superiority of PET/ceCT in terms of sensitivity, specificity, or accuracy does not support its routine use. Accordingly, the application of PET/ceCT could be decided on a case-by-case basis, according to the principle of personalized medicine.


Primary aldosteronism (PA) is one of the common causes of secondary hypertension, increasing the risk of cardiovascular disease and renal events as compared to essential hypertension, independently of blood pressure control –3.Primary aldosteronism (PA) is one of the common causes of secondary hypertension, and is associated with higher risks of cardiovascular, renal, and metabolic sequelae, including left ventricular hypertrophy, myocardial infarction, atrial fibrillation, stroke, microalbuminuria, osteoporosis, as well as metabolic syndrome , 4–7.The present Research Topic highlights the interplay between clinical diagnosis, underlying genetic etiologies, and clinical outcome PA. Overall, it focuses on the histopathologic findings, gene mutation, the coexistence of cortisol, cosecretion, and targeted treatments of PA.Nanba et al. provide a template for researchers to study aldosterone-producing adrenal using formalin-fixed paraffin-material embedded sections for DNA capture, sequencing, and mutation determination.Inoue et al. summarize the current state of knowledge about cortisol cosecretion with PA. They conclude, there is increasing evidence about the relatively high prevalence of cortisol cosecretion in PA and its potential influence on adverse health outcomes.Although cortisol cosecretion in aldosterone-producing adenoma (APA) has been reported , the cliOkamoto et al. assess 1586 PA patients without apparent adrenal tumors in the multicenter study and conclude adrenal venous sampling should be considered for male hypokalemic PA patients with high ARRs because of the rates of the lateralized subtype and cardiovascular events are high in these patients.Adrenal venous sampling (AVS) is the test of choice to identify patients with a surgically curable subtype of PA . OkamotoPauzi and Azizan reviewed APCCs associated aldosterone-stimulating somatic gene mutations  and their accumulation during the aging process, raising the possibility that APCCs may play a role in the development of PA and age-related hypertension.The major advance of understanding PA pathophysiology is the identification of several somatic driver mutations in ion channels and ATPases in lateralized aldosterone-producing adenoma (APA) . UtiliziKCNJ5 gene could be identified in 34 to 73% of APAs  and lesion to the contralateral ratio of bilateral adrenal glands (CON)] and provided more information in an individualized treatment plan.Lim et al. study.In regarding possible variations in response to hormonal stimuli, APAs with ATPase-mutations are more responsive to ACTH than KCNJ5-mutated APAs was found in Pan et al. demonstrate extensive cardiac remodeling in APA patients through hemodynamic and non-hemodynamic causes. Adrenalectomy improved both hemodynamic and non-hemodynamic components of left ventricular remodeling, which also correlated with decreases in blood pressure and ARR.PA patients also have a higher risk of cardiovascular diseases and greater cardiac remodeling compared to those with essential hypertension , 12. PanZhou et al. report the severity of diastolic dysfunction independently relates to the degree of diffuse myocardial fibrosis in PA patients with elevated aldosterone level.Tsai et al. performed a meta-analysis and showed different effects of PA treatment on NOAF risk. The PA patients receiving MRA treatment had a higher risk of NOAF compared to the PA patients receiving adrenalectomy and the patients with essential hypertension.The excess aldosterone causes atrial structural and electrical remodeling, which induce atrial fibrillation genesis, and PA was associated with a higher incidence of new-onset atrial fibrillation (NOAF) that could ameliorate after adrenalectomy . Tsai etChen et al. provide new insights into the relationship between adipose tissue and aldosterone excess in patients with APA and idiopathic hyperaldosteronism (IHA). Abdominal adiposity indexes were similar in patients with IHA and those with essential hypertension but were markedly lower in patients with APA. Aldosterone-to-renin ratio (ARR) was negatively correlated with abdominal adiposity indexes in patients with APA but not in patients with IHA.Liu et al.The endocrine-gut interaction show PA patients had fewer short-chain fatty acids-producing genera and more inflammation-associated genera than healthy controls. Alteration of gut microbiota may contribute to the obesity and diabetics status in PA, as shown by Huang et al. show superior performance of surgical treatment over medical treatment for patients with lateralized PA on both composite and individual clinical cardiovascular outcomes in this meta-analysis. An interesting study presented by Tezuka and Turcu on targeted treatment, they identified that lower baseline serum potassium, lower mineralocorticoid receptor antagonist (MRA) doses, and beta-blocker use was independently associated with lower odds of achieving target renin in PA. Their findings suggest that renin targets, when PRA was <1.0 ng/mL/h and DRC was <8.0 pg/mL, are followed in very few and are achieved in under half of such PA patients seen in an academic setting, with possibly even lower rates in community practices.Some studies showed similar long-term cardiac effects of surgical or medical treatment in PA patients . HoweverWang C. et al. conclude international collaboration on the clinical and molecular mechanism of PA will be important to improve the investigation and therapy of patients with PA.In the future, Highlighting the novel insights into the possible mechanism and outcome of PA, all the studies in this special issue fill some gaps of knowledge and give future challenges for research in this field.W-CW wrote the draft of the article. V-CW and QW supervised the results. All authors contributed to the article and approved the submitted version.This study was supported by MOST 107-2314-B-002-026-MY3, 108-2314-B-002-058, 109-2314-B-002-174-MY3], National Taiwan University Hospital  Grant MOHW110-TDU-B-212-124005 and Mrs. Hsiu-Chin Lee Kidney Research Fund. The NGS experiments were performed by the NGS Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Taiwan (grant CLRPD1J0012).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.


Amblyomma testudinarium larvae. Further epidemiological surveillance and etiological studies are necessary to assess the status and risk of jingmenvirus infection in Japan.Jingmen tick virus (JMTV) and the related jingmenvirus-termed Alongshan virus are recognized as globally emerging human pathogenic tick-borne viruses. These viruses have been detected in various mammals and invertebrates, although their natural transmission cycles remain unknown. JMTV and a novel jingmenvirus, tentatively named Takachi virus (TAKV), have now been identified during a surveillance of tick-borne viruses in Japan. JMTV was shown to be distributed across extensive areas of Japan and has been detected repeatedly at the same collection sites over several years, suggesting viral circulation in natural transmission cycles in these areas. Interestingly, these jingmenviruses may exist in a host tick species-specific manner. Vertical transmission of the virus in host ticks in nature was also indicated by the presence of JMTV in unfed host-questing  Ticks are hematophagous ectoparasites that infest various animals and can transmit a variety of pathogens, including protozoa, bacteria, and viruses, to their hosts during the blood-feeding process. Tick-borne viruses have become the focus of public health attention with the re-emergence of highly pathogenic viruses such as Crimean-Congo hemorrhagic fever virus (CCHFV) and the emergences of new viruses such as severe fever with thrombocytopenia syndrome virus and Bourbon virus .Advances in next-generation sequencing (NGS) technologies have dramatically facilitated the study of tick-borne viruses. A series of recent studies have revealed the ticks harbor a wide variety of viruses through comprehensive analyses utilizing next-generation sequencers . This haRhipicephalus microplus) collected in China in 2010  and was passed through sterile 0.45-μm filters , and then mixed in equal amounts up to a total of 380 µL . This sample was then used for library preparation for NGS analysis as described previously ,26. In b2. A fresh culture medium was then added to each well, and the incubation was continued for seven days, followed by two subsequent blind passages under the same conditions. Culture supernatants after the incubation period were analyzed using next-generation sequencers (as described previously)  or BHK-21 cells  as described by Kobayashi et al. . In brieviously) ,26 to co4], as described previously [Previously, we used BHK-21 cells to isolate viruses from field-caught ticks from various parts of Japan during 2013 to 2014 . The blieviously . The coneviously . Libraryeviously .To identify virus-positive tick pools, reverse transcription polymerase chain reaction (RT-PCR) was performed on total RNA extracted from each filtered tick pool homogenate, as described previously . RT-PCR The virus-positive pools were then used to determine the complete viral genome sequence. Sequence gaps between contigs obtained using RNA virome analyses were filled with subsequent RT-PCRs using primers specific for the viral sequences. The resultant amplicons were analyzed using direct Sanger sequencing using an ABI 3130 Genetic Analyzer  or Genewiz, Inc. , as previously described ,26. The Jingmenviral open reading frames and their encoded amino acid sequences were determined using Genetyx version 14 software .Attempts to isolate Takachi virus (TAKV) in cell cultures failed, which raised the possibility that the TAKV sequence was derived from an EVE in the host tick genome. DNA extracted from the homogenate of TAKV-positive pool was analyzed through PCR using the following four virus-specific primer sets: IMOI-Js1-F and IMOI-Js1-R for segment 1, IMOI-Js2-F and IMOI-Js2-R for segment 2, IMOI-Js3-F and IMOI-Js3-R for segment 3, and IMOI-Js4-F and IMOI-Js4-R for segment 4 , as descMultiple sequence alignments were performed using the MAFFT online service . The GblAmblyomma testudinarium, Haemaphysalis flava, Hae. formosensis, Hae. hystricis, Hae. longicornis, Hae. megaspinosa, Haemaphysalis sp., Ixodes ovatus, I. persulcatus, and I. turdus, were collected in 2018–2020 in Ehime and Ishikawa Prefectures, Japan . Eight pools derived from Am. testudinarium ticks were identified as JMTV-positive using RT-PCR screening , all of which were biting on the skin, in Tsushima City in 2013; the JMTV strains were named T281 and T285 . Thus, the novel jingmenvirus genome likely exists as RNA but is not derived from the EVE in the host tick genome. Therefore, we tentatively named the new virus as Takachi virus (TAKV) after the Japanese name of the host tick species Am. testudinarium ticks, although virus detection was performed on diverse unfed ticks from nine species across three genera. Remarkably, JMTV was detected not only in nymphs but also in unfed larva, indicating the vertical JMTV transmission in Am. testudinarium ticks in nature. In a previous study, an infectious JMTV was isolated from Am. javanense, and JMTV infection experiment in Am. javanense ticks has confirmed the virus accumulation and replication in the salivary glands, suggesting Am. javanense may be a potential vector of JMTV [Amblyomma genus may be important as vectors and reservoir hosts of JMTV. Three Amblyomma species are known to be distributed in Japan [Am. testudinarium, where we detected JMTV in this study, is considered to be critical species as a JMTV vector because of its high preference for humans [Amblyomma testudinarium is widely distributed from India to Southeast Asia and East Asia, including Japan ; this sAm. testudinarium infestation have been described in a resident bird species, Scolopax mira  was shown to be genetically related to wild boar distributed in China and the Indochinese Peninsula, including Laos [The JMTV strains detected in this study were shown to be phylogenetically related to strains from southern China and Laos. This suggests that virus-infected ticks can be transported over a long distance by migratory birds as reported for CCHFV . In JapaYamauchi ), and in species . This tild boars , ticks ming Laos . This sting Laos . Furthering Laos ,14, it iWhile attempting to isolate the virus, we detected JMTV RNA in the supernatant of BHK-21 cell cultures after two blind passages. Although this indicates possible virus replication in the cells, we cannot rule out the detection of viral RNA carryover from the virus-positive tick homogenates for inocula. According to the first report describing JMTV , JMTV geHae. formosensis ticks. This suggests a specific and stable virus-tick host relationship similar to those between JMTV and Am. testudinarium ticks, also demonstrated in this study. TAKV occupies a phylogenetically intermediate position between human-pathogenic JMTV and ALSV . FurtheAm. testudinarium larvae, suggesting the vertical transmission of the virus in host ticks in nature. Further epidemiological surveillance and etiological studies are necessary to assess the status and risk of jingmenvirus infection in Japan.JMTV and a novel jingmenvirus, TAKV, were detected in host-questing ticks for the first time in Japan. JMTV was also detected in the supernatant of BHK-21 cells inoculated with the tick sample. Interestingly, these jingmenviruses may exist in a host-tick species-specific manner. This study also revealed that JMTV was distributed across an extensive area in Japan and was detected at the same collection site for several years. Moreover, JMTV was found in


Novel psychoactive substances (NPS) represent a rising public health threat due to the associated side effects and the lack of success on their control policies. NPS are freely sold, mostly on the internet, as legal and safe replacements of controlled drugs of abuse. Synthetic cannabinoids (SCs) represent one of the largest groups of NPS and are designed as mimetics of Δ9-tetrahydrocannabinol from cannabis . After twww.chem.eu). THJ-018 and EG-018 were purified through HPLC/DAD and confirmed by GC/MS. Pure SCs stock solutions were prepared in 100% DMSO accordingly to the stipulated final concentrations and diluted into the culture medium prior addition to cells. The neuroblastoma human cell line SH-SY5Y was exposed, for 24 h, to several concentrations of each SC. Cell toxicity was evaluated through MTT assays.The SC JWH-018 was obtained as >98.5% pure powders from Lipomed AG Switzerland. SCs THJ-018 and EG-018 were bought through an internet website (Discussion and conclusions: The results from the present study points THJ-018 and EG-018, JWH-018 analogues of 2nd and 3rd generations, as more toxic to the neuroblastoma cells than JWH-018, the first SC found on the street market. These results suggest that emerging modified SCs, to avoid the law, are becoming more toxic and dangerous. Given the emergence of this situation, it is time to rethink current legislation to prevent rise on public health issues derived from consumption of molecules of unknown toxicological profile.


Background: Basal ganglia perivascular spaces are associated with cognitive decline and cardiovascular risk factors. There is a lack of studies on the cardiovascular risk burden of basal ganglia perivascular spaces (BG-PVS) and their relationship with gray matter volume (GMV) and GM cerebral blood flow (CBF) in the aging brain. Here, we investigated these two issues in a large sample of cognitively intact older adults.Methods: A total of 734 volunteers were recruited. MRI was performed with 3.0 T using a pseudo-continuous arterial spin labeling (pCASL) sequence and a sagittal isotropic T1-weighted sequence for CBF and GMV analysis. The images obtained from 406 participants were analyzed to investigate the relationship between the severity of BG-PVS and GMV/CBF. False discovery rate-corrected P-values (PFDR) of <0.05 were considered significant. The images obtained from 254 participants were used to study the relationship between the severity of BG-PVS and cardiovascular risk burden. BG-PVS were rated using a 5-grade score. The severity of BG-PVS was classified as mild (grade <3) and severe (grade ≥3). Cardiovascular risk burden was assessed with the Framingham General Cardiovascular Risk Score (FGCRS).Results: Severe basal ganglia perivascular spaces were associated with significantly smaller GMV and CBF in multiple cortical regions (PFDR <0.05), and were associated with significantly larger volume in the bilateral caudate nucleus, pallidum, and putamen (PFDR <0.05). The participants with severe BG-PVS were more likely to have a higher cardiovascular risk burden than the participants with mild BG-PVS .Conclusion: In cognitively intact older adults, severe BG-PVS are associated with smaller cortical GMV and CBF, larger subcortical GMV, and higher cardiovascular risk burden. Perivascular spaces, also known as Virchow–Robin spaces, are interstitial fluid-filled spaces surrounding the wall of small penetrating vessels , and a written informed consent was obtained from all the participants, who were recruited from two ongoing cohort studies (cohort A and cohort B). Cohort A is a community-based study that comprises elderly subjects from Beijing, China. Cohort B is a large-scale willed body donation program in the Chinese Academy of Medical Sciences and PUMCH . The exclusion criteria of participants were as follows: (1) under 55 years old; (2) a Mini-Mental State Exam (MMSE) score of <27 who might have apparent cortical hypoperfusion and atrophy  were eligible for the subsequent analysis. Participants with inferior image quality (n = 18), unavailable pseudocontinuous arterial spin labeling (pcASL) data (n = 117), and/or incomplete clinical data (n = 287) were also excluded. Finally, the MRI images obtained from 406 participants were used to investigate the relationship between the severity of BG-PVS and GMV/CBF, while the MRI images obtained from 254 participants were used to investigate the relationship between the severity of BG-PVS and cardiovascular risk burden.2), an axial pCASL sequence , and a sagittal 3D BRAVO sequence . The MRI studies of cohort B were performed with another 3.0 Tesla GE MRI scanner . The MRI protocols used for cohort B were as follows: an axial T2-PROPELLER sequence , an axial pCASL sequence , and a sagittal T1-weighted 3D BRAVO sequence . The MR sequences and parameters used with cohort B were similar to those used with cohort A, which could greatly reduce the potential differences between the MRI scanners . The MRI protocols used with cohort A comprised three serial sequences: an axial T2-PROPELLER sequence  , diabetes, and smoking history  value.Statistical analysis was performed using SPSS . Categorical variables were tested by χP-values (PFDR) of < 0.05 were considered significant. Logistic regression analysis was performed to assess the difference in cardiovascular risk burden between the mild and severe BG-PVS groups.Using age, sex, scanner, and total intracranial volume (TIV) as covariates, the difference in GMV between the mild and severe BG-PVS groups was analyzed using univariate linear models. Using age, sex, scanner, and regional GMV as covariates, the difference in CBF between the mild and severe BG-PVS groups was analyzed using univariate linear models. The Benjamini–Hochberg procedure was performed to control for false discovery rate (FDR). FDR-corrected The inter-rater consistency was high for assessing the severity of BG-PVS (κ =0.883). The two raters reached a consensus on the classification of 81 images.A total of 406 participants  were included in the GMV and CBF analysis  that did not belong to the gray matter were excluded, and the remaining 58 brain regions were used for morphological and metabolic analysis.PFDR < 0.05, corrected for age, sex, scanner, and TIV, PFDR < 0.05, corrected for age, sex, scanner, and TIV, The gray matter volume analysis revealed that the severe BG-PVS group had a significantly smaller GMV than the mild BG-PVS group, in the bilateral lateral occipital lobe, bilateral rectus gyrus, right orbitofrontal gyrus, right posterior temporal lobe, and right inferior middle temporal lobe  and age (P < 0.001). Those in the severe BG-PVS group were more likely to have hypertension (P = 0.032), higher SBP (P = 0.001), and higher total cholesterol (P = 0.001). The participants with severe BG-PVS were twice as likely to have a high cardiovascular risk burden than the participants with mild BG-PVS .A total of 254 participants  were included in the analysis between the severity of BG-PVS and cardiovascular risk burden. This study showed that BG-PVS were associated with cardiovascular risk burden and regional differences in CBF and GMV. This study advanced those of several groups Kalaria, , which aPrevious MRI studies have shown no association between BG-PVS and whole-brain atrophy , consistent with previous studies (Zhu et al., This study focused on cognitively intact individuals and presented some new findings that might suggest directions for future research. There is a growing body of evidence that cerebral microvascular dysfunction and brain hypoperfusion play critical roles in the pathogenesis of dementia Kalaria, . HoweverThere are some limitations to this study. First, the visual scoring system was an observer-dependent task (Dubost et al., This study indicated that for cognitively intact older adults, the presence of severe BG-PVS is associated with smaller cortical GMV and CBF, larger subcortical GMV, and a higher cardiovascular risk burden. This study suggested that early identification is crucial for understanding the evolution of BG-PVS-related diseases.The datasets generated during the current study are available from the corresponding author on reasonable request.The studies involving human participants were reviewed and approved by Institutional review board of Peking Union Medical College Hospital. The patients/participants provided their written informed consent to participate in this study.SL, HY, ZZ, and FF: conception and design of the study. SL, BH, YCZ, and CM: acquisition of data. SL, YWZ, and ZZ: analysis and interpretation of data and SL, ZZ, and FF: drafting of the article. 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.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.


Peritoneal dialysis (PD) is an important, if underprescribed, modality for the treatment of patients with end-stage kidney disease. Among the barriers to its wider use are the deleterious effects of currently commercially available glucose-based PD solutions on the morphological integrity and function of the peritoneal membrane due to fibrosis. This is primarily driven by hyperglycaemia due to its effects, through multiple cytokine and transcription factor signalling—and their metabolic sequelae—on the synthesis of collagen and other extracellular membrane components. In this review, we outline these interactions and explore how novel PD solution formulations are aimed at utilizing this knowledge to minimise the complications associated with fibrosis, while maintaining adequate rates of ultrafiltration across the peritoneal membrane and preservation of patient urinary volumes. We discuss the development of a new generation of reduced-glucose PD solutions that employ a variety of osmotically active constituents and highlight the biochemical rationale underlying optimization of oxidative metabolism within the peritoneal membrane. They are aimed at achieving optimal clinical outcomes and improving the whole-body metabolic profile of patients, particularly those who are glucose-intolerant, insulin-resistant, or diabetic, and for whom daily exposure to high doses of glucose is contraindicated. The increasing worldwide number of patients suffering from end-stage kidney failure (ESKF) who require a chronic renal replacement therapy (RRT) represents a significant economic burden on health systems globally . Among RCompared with hemodialysis, PD offers a similar survival rate and is less expensive; in addition, it preserves residual kidney function better and removes solutes and fluid more gradually . HoweverDevelopment of a more biocompatible, efficient dialysate for routine clinical use is of utmost importance for the future of PD. Many factors have been claimed  as contrIn this article, we review established and novel approaches aimed at improving the biocompatibility of PD solutions, and hence the viability of the technique and optimization of clinical outcomes.The peritoneal membrane is a structure that comprises mesothelial cells  attached to a basement membrane. Underneath the basement membrane, there is the submesothelial layer composed of connective tissue, fibroblasts, and a dense vascularization. In PD, the peritoneum acts as an efficient semipermeable dialysis membrane when a hypertonic solution is introduced into the peritoneal cavity. Hypertonicity is generally obtained with glucose-based solutions, and thus the peritoneum is continuously exposed to unphysiologically high concentrations of glucose, resulting in cellular stress.The rate of removal of metabolites, uremic toxins, electrolytes, and water from the systemic circulation is proportional to the vascular surface area in contact with PD fluid in the peritoneal cavity . It has Overall, peritoneal fibrosis can be considered as the final step of peritoneal injury, and is regulated by several related processes: inflammation, angiogenesis, and epithelial-to-mesenchymal transition (EMT) . In the It has been shown that long-term exposure to high glucose concentrations causes changes in mesothelial membrane permeability and structure and, in particular, induces mesothelial cells to produce transforming growth factor-beta (TGF-beta) . TGF-betPeritoneal injury causes the activation of macrophages, neutrophils, and endothelial and mesothelial cells, which are the main sources of proinflammatory cytokines . SimilarThe balance between rates of glycolysis, glutaminolysis, and fatty acid oxidation determines the deposition and breakdown of collagen and other ECM components that result in fibrosis . This ocHyperglycaemia results in the upregulation of TGF-beta and hypoxia-inducible factor 1 subunit alpha (HIF1α) expression . Indeed,Another substrate that is increasingly utilized by cells that make the epithelial-mesenchymal transition to myofibroblasts is glutamine. This amino acid is itself important for collagen synthesis, and glutaminolysis gives rise to NH2 groups—which can be used in amino acid synthesis—as well as to another amino acid, glutamate. Conversion of glutamate to ketoglutarate (α-KG) provides a substrate for the generation of NADH and FADH2 through the oxidation of α-KG as a TCA cycle intermediate. These provide ATP through oxidative phosphorylation, which becomes increasingly important in the absence of substantial oxidation of pyruvate for this purpose in myofibroblasts, in a similar manner to the use of glutamine for ATP formation by neoplastic tissues . HoweverConversely, ECM degradation is favoured by mitochondrial oxidation of fatty acids. This is promoted by activation of the energy-sensing kinase AMPK, which, through its phosphorylation and inhibition of the acetyl-CoA carboxylases, lowers the concentration of the unique inhibitor—malonyl-CoA—of the rate-limiting enzyme of mitochondrial long-chain FA oxidation, carnitine palmitoyltransferase 1 . HoweverThe relationship between FAO and pyruvate oxidation is regulated primarily at the level of intramitochondrial acetyl-CoA  and cytosolic malonyl-CoA, which inhibits CPT1 and thus lowers FAO . ImportaRaising the intracellular concentration of carnitine would shift the equilibrium catalysed by the intramitochondrial enzyme CAT towards acetyl-carnitine formation, thus lowering mitochondrial matrix acetyl-CoA and enhancing the release of the resulting acetyl-carnitine from the mitochondria in exchange for cytosolic carnitine. Such increases in intracellular carnitine would be difficult to achieve under normal physiological conditions, as dietary carnitine  is efficiently excreted by the kidney. However, it is possible to raise plasma concentrations of carnitine by many-fold in patients with end-stage kidney disease on peritoneal dialysis, in which residual kidney function is greatly decreased, through the use of carnitine-supplemented PD solutions .Since PD patients experience fibrosis of the peritoneal membrane, such a strategy would be particularly appropriate to prevent fibrosis of the peritoneal membrane itself. Increased availability of carnitine to the cells that make up the peritoneal membrane would be anticipated to divert more pyruvate towards oxidation and away from lactate formation, thus decreasing the profibrotic profile of the myofibroblasts in the membrane.Alternative pharmacological strategies aimed at preventing/alleviating fibrosis could therefore be based on promoting fatty acid and/or pyruvate oxidation, or even by inhibiting glycolysis. In the former instance, the activity of CPT1 could either be increased directly pharmacologically; e.g., with compounds that, like C75, directly activate CPT1 . AlternaIn summary, several metabolic mechanisms , as well as extracellular factors  and intracellular signalling (HIF-1α), are involved in mesothelial fibrosis, and their regulation should be considered in the development of new biocompatible PD solutions.Strategies devised to reduce or eliminate PD-solution-associated toxicity without jeopardizing the patient’s health represent a major challenge in present-day PD therapy .The results obtained with the various strategies are reported in the following sections.n = 11 for each group) at the time of catheter removal. Loss of glycocalyx of the peritoneal endothelium was found in patients treated with conventional dialysate, and was associated with UF failure and severe vasculopathy. These results suggest that neutral-pH, low-GDP solutions could help to protect peritoneal vasculature [The introduction of novel, glucose-based dialysates characterized by neutral- or physiological-pH and low-GDP fluids using multichamber bags was a major advance in the development of PD . Use of culature ; furtherSignificant peritoneal damage is still observed with neutral-pH, low-GDP solutions, which suggests that the high glucose content in the dialysate (required for UF) is the main culprit of the peritoneal changes occurring over time in PD patients regardless of other possible causal factors . The effTherefore, minimising the glucose-associated toxicity (glucose sparing) may be fundamental to improving the biocompatibility of PD solutions . SeveralIcodextrin is a water-soluble glucose polymer derived from starch. It allows for a slow but sustained peritoneal UF, and is therefore indicated for use during a single long dwell per day [ per day ,78. Icod per day . A recen per day . Indeed, per day ,82. Some per day ,84.A combined crystalloid (glucose) and colloid (icodextrin) PD solution has been used as a glucose-sparing strategy, with positive results. It increased peritoneal ultrafiltration while protecting the peritoneal membrane and diminishing the systemic consequences, namely systemic absorption of glucose in high and high-average transport APD patients. Freida et al.  evaluateIn terms of biocompatibility, despite being glucose-free and with a low content of GDPs, conventional icodextrin solutions have a low pH, which can result in increased local and systemic inflammation ,87. A poamino acids. It has a pH of 6.7 and is free of GDPs. In addition, this approach offers the possibility of improving the nutritional status of some malnourished PD patients. Use of amino-acid-based PD fluids has been shown to increase muscle amino acid uptake [The other commercially available glucose-free PD solution is based on the use of d uptake  and imprd uptake  while cod uptake . The gluThe biocompatibility of PD solution containing amino acids remains uncertain . ExperimAs a glucose-sparing approach, a low-glucose regimen based on the use of amino acids, icodextrin, and dextrose was examined in two randomized studies in PD diabetic patients . The intglycerol (molecular weight 92 Da), a small three-carbon alcohol used as the backbone of triglyceride (TG) and phospholipids. As glycerol becomes available in the circulation, either after hydrolysis of dietary fat (TG), lipolysis of adipocyte stored TG, or glycerol-based PD solution, it is primarily metabolized by the liver due to the presence of aquaporin 9, which facilitates its transport into the hepatocyte, and a very active glycerol kinase that phosphorylates it to glycerol-3-phosphate [An interesting low-molecular-weight osmolyte that has been tested either alone or in combination with amino acids is hosphate . The fathosphate .Van Biesen et al. used an alternative strategy to reduce the daily peritoneal exposure to glucose by formulating a PD solution with a mixture of 0.6% amino acids and 1.4% glycerol that was tested in a randomized, 3-month trial in nondiabetic CAPD patients . The daiThe biocompatibility profile of glycerol-containing PD solution was examined in a rat model. A bicarbonate/lactate-buffered solution with a mixture of osmotic agents  (GLAD) was used daily for 16 weeks in a randomized study in a rat model of chronic renal failure . As compOther compounds that have been tested for a potential use in the PD solution as osmotic agents to replace glucose include taurine and hyperbranched polyglycerol, both still under experimental development.Taurine has a molecular weight of 125 Da and is a sulfonic beta-amino acid with high water stability that is present in high concentrations in mammalian cells, where it regulates osmotic balance and ion transport. Peritoneal transport and biocompatibility of a new PD solution containing taurine instead of glucose as the osmotic agent were examined in a rat PD model [PD model . The newPD model . HoweverPD model . This haPD model . NeuroloHyperbranched polyglycerol is a polyether polymer synthesized by polymerization of glycidol that is hydrophilic, highly water-soluble, and chemically stable in aqueous solution. Du et al. [u et al.  comparedu et al. . Moreoveu et al. . A more u et al. . Metabolu et al.  and is au et al. . After tu et al. . Resultsu et al. .The use of additives in PD dialysate to prevent, treat, or arrest bioincompatibility has been proposed as a strategy to attenuate the bioincompatible effects of the glucose-based PD solutions. Among potential additives, the use of glycosaminoglycans , heparinsulodexide [In one study, sixteen CAPD patients received lodexide  for 30 dheparin during PD has been considered. Clinical experience with peritoneal rest and intermittent heparin administration has offered some limited success [The potential of the use of  success . A coupl success  conclude success  did not The apparent lack of effect of bemiparin on anti-FXa activity in the Spanish study may suggest noncompliance in some patients, although low peritoneal absorption is a plausible alternative explanation. On the other hand, the Danish study  presentesodium citrate was chosen as a suitable candidate as an alternative inhibitor of complement [® dialysate (2.5% glucose) in 28 stable outpatients from the PD unit. Comparisons were made between single dwells of each fluid. The addition of citrate (5 mM/L) to the PD solution significantly improved UF and small-solute clearances. The side effects of the use of citrate on calcium metabolism and acid–base balance were minimal.In line with the application of heparin as an additive in PD, mplement . The promplement  promptedmplement  to initiCarnosine and related compounds are associated with an effective regression in AGE formation in both long- and short-term exposures in vitro [in vitro .dipeptide-based PD solutions in 2001. Their results indicated that the hydrolysis rate of dipeptides in the peritoneal cavity is much lower than the dipeptide diffusive transport rate from the PD solution into blood, thereby providing more sustained UF when compared to amino-acid-containing PD solutions. Another interesting finding was that dipeptide-containing solutions may deliver amino acids across the epithelium with a smaller change in plasma amino acid concentrations [Werynski et al.  reportedtrations .alanyl-glutamine (Ala-Gln) to glucose-based PD solutions. The addition of Ala-Gln to the PD dialysate reduced peritoneal thickness, αSMA expression, and angiogenesis; prevented peritoneal extracellular matrix deposition; and attenuated the IL-17 pathway expression induced by glucose-based PD solutions. The results of two different dipeptide-based PD solution rat/mice studies, within 15 years of each other, have provided evidence that the use of PD solutions containing dipeptides may have a local protective effect , as well as positive systemic effects , resulting in better biocompatibility [Fifteen years later, Ferrantelli et al.  publishetibility . More retibility .n = 50 randomized; eight Austrian PD centres) treated with Ala-Gln or placebo added to the PD solution for eight weeks. They concluded that Ala-Gln supplementation in PD solution improves biomarkers of peritoneal membrane integrity, immune competence, and systemic inflammation when compared to nonsupplemented PD solution with neutral pH and low-glucose degradation [Two early clinical trials performed by an Austrian study group on the addition of the dipeptide Ala-Gln to glucose-based PD solutions showed that it restored the stress response and improved immune competence of the peritoneal cells ,125. Vycradation . Consistradation ,125,126,radation . Howevermolecular hydrogen (H2). Its unique biological action as an antioxidant ameliorates tissue injury [Another potential PD solution additive to be explored in the prevention/arrest of PD solution bioincompatibility impacting the peritoneal membrane and cavity is e injury . Moreovee injury , in an ee injury . Terawake injury  could ree injury  recentlyThe wealth of data, information, and experience published with commercially available glucose-sparing PD solutions  indicates that the future of PD depends largely on finding new osmotic agents, improving their biocompatibility and the fluid balance, but also, and no less important, its effect on the metabolism of the patient. The osmo-metabolic approach to PD solutions represents a novel tool to antagonize glucose-associated toxicity, which is based on the replacement of most of the glucose load with other osmolytes. Osmo-metabolites can be defined as those compounds that exhibit both osmotically and metabolically favourable properties ,134. WhiL-carnitine (LC) and xylitol are two examples of osmo-metabolic agents. LC is a naturally occurring compound known to be essential for fatty acid oxidation in the mitochondria [chondria . Xylitolchondria . Exogenechondria . These tchondria . Studieschondria , human uchondria , and murchondria , and in chondria .Clinical studies demonstrated excellent tolerability and feasibility of xylitol  or L-carClinical use of xylitol- or LC-containing dialysate in CAPD patients has also been shown to induce favorable metabolic effects. The PD xylitol regimen described above  significMore recently, in the search for dialysates that minimize the negative effects of PD, we developed a new PD solution containing LC, xylitol, and low glucose, to achieve a favorable synergistic combination of the two osmo-metabolic agents. The biocompatibility of the experimental solution was first examined in cultured HUVECs obtained from the umbilical cords of either healthy or gestational diabetic mothers, and compared to a normal-pH, low-GDP PD solution . The capWe recently tested the biocompatibility of the new experimental PD solution by recreating in vitro a mesothelium-like structure, exploiting a cell line of human mesothelium grown to confluence on porous cell culture inserts previously coated with a layer of an extracellular matrix . Using tMore recently, further in vitro data showed that the use of a PD solution containing carnitine and xylitol could prevent or mitigate the adverse effects produced by standard glucose-based PD solutions . ResultsA phase II, prospective, open, multicenter study to investigate the tolerability and the efficacy of osmo-metabolic agent-based PD solutions in CAPD patients is currently underway (NCT04001036). The study consists of three study periods  in two group of patients. Patients in group A were treated with a 2.5% glucose dialysate for the nocturnal exchange and, during the intervention period, received the experimental solution IPX15, while patients in group B received the experimental solution IPX07 replacing 1.5% glucose dialysate for two diurnal exchanges, maintaining icodextrin for the nocturnal exchange. Experimental bags differed in their xylitol content , but were otherwise identical in their composition, including L-carnitine 1.24 mM and glucose 27.7 mM.n = 6; group B, n = 4), and no adverse safety signals were observed. During the study, several efficacy parameters were assessed, including total weekly urea Kt/V, weekly total creatinine clearance, peritoneal equilibration test , residual kidney function, daily diuresis, and daily peritoneal UF. The results indicate the noninferiority of the osmo-metabolic agent-based PD solutions compared to standard solutions as far as adequacy and peritoneal transport characteristics are concerned [Though the study has been greatly hampered and delayed by the COVID-19 pandemic and related implications, it is currently ongoing. Results obtained in the first cohort of patients completing the whole study period have been recently reported . Use of oncerned . The comIn PD, there is the unmet need for more biocompatible but efficacious dialysates to improve the clinical outcome and prolong the survival of the treatment. The ideal biocompatible PD solution should encompass three features: prolonged and sustained ultrafiltration capacity; preservation of the peritoneal membrane morphology and physiology; and, if its solutes are absorbed, they should not impact negatively on systemic metabolism and/or nutrition. By these criteria, little progress has been achieved in PD fluid technology over the last 30 years, and by the continued use of glucose-based fluids, PD treatment still confers major peritoneal and systemic toxicity . Main adInitial clinical experience with some new approaches to improve the biocompatibility of fluids for PD is promising in terms of safety in the short- and mid-terms. More detailed and longer studies, some of which are already planned, are now warranted to establish whether the encouraging results obtained with the proposed novel PD solutions translate into important clinical outcomes.


Background: Many patients who have been suffering by Covid-19 suffer of long-Covid syndrome, with symptoms of fatigue and muscular weakness that characterize post-acute sequelae SARS-CoV-2 infection (PASC). However, there is limited knowledge about the molecular pathophysiology, and about the serum profile of these patients.Methods: We studied the blood serum profile of 75 selected patients, with previous confirmed Covid-19, 2 months after hospital discharge, who reported new-onset fatigue, muscle weakness and/or dyspnea not present prior to the virus infection and independently from concomitant diseases and/or clinical conditions.Results: All patients had very high serum concentrations of ferritin and D-Dimer. 87 and 72% of patients had clinically significant low levels of hemoglobin and albumin, respectively. Seventy three percentage had elevations in erythrocyte sedimentation rate and CRP. Twenty seven percentage had elevations in LDH.Conclusions: The co-existence of patient symptoms along with blood markers of coagulation, protein disarrangement and inflammation suggests ongoing alterations in the metabolism, promoting an inflammatory/hypercatabolic state which maintains a vicious circles implicated in the persistence of PASC. The persistence of altered D-Dimer levels raises the possibility of long-term risks of thromboembolic disease. All these markers levels should be accurately evaluated in the long-term follow-up, with individualized consideration for prophylactic nutritional, anti-inflammatory and/or anticoagulant therapy if indicated. Covid-19 infection has risen to a global pandemic with important sanitary and socio-economic consequences  is an enveloped mRNA beta-coronavirus causing coronavirus disease 2019 , after 60 days from hospital discharge, who reported new-onset fatigue not present prior to the virus infection. Patients with symptoms of fatigue were seen in our private ambulatory setting from July to September 2020. Based on the fundamental guidance of “good medical practice” (www.gmc-uk.org) we performed tests and blood analyses according to professional and ethical standards. For these reasons, ethical approval was not required under local legislation. Written informed consent was obtained from all patients for blind management of the data.This study is a prospective cohort study of previously hospitalized patients with laboratory confirmed mild-moderate CIn an effort to exclude any potentially confounding factors, we studied selected patients with fatigue, muscle weakness and/or dyspnea independently from concomitant diseases and/or clinical conditions which could influence physical performance, including thrombotic episodes.Clinical data and demographic characteristics were collected from the patients' electronic medical records. At the follow up visit, all patients were interviewed face-to-face. Specific standardized and validated self-reported symptoms and the Fatigue Assessment Scale (FAS) were administered . The FASAdditional exclusion criteria were: major cardiac arrhythmias and hemodynamics instability, enable to sitting down independently, and FAS score <22.t-test was applied to compare means. The normality of distribution data was assessed by Shapiro-Wilk Test (https://www.statskingdom.com).Patient's clinical data were presented as mean ± standard deviation or expressed as absolute values with percentages of total. Hematological data were expressed as mean ± standard deviation and Welch's Clinical data of patients, including length of hospitalization (from diagnosis to discharge) and time from hospital discharge are presented in ovid-19 infection, selected patients with reported fatigue and muscular weakness independent from concomitant diseases continued to exhibit elevated indexes of altered cell proteins machinery as ferritin, hemoglobin and albumin, as well as inflammatory markers as CRP, ESR, LDH and marker of activated coagulation as DD, suggesting ongoing impairment in the global metabolism of affected patients. Covid-19 replication and Covid-19-induced metabolic disarrangements are discussed in further detail in the following section.This study demonstrates that, at 2 months after hospital discharge for acute CIt is well-known that SARS-CoV2 is obligate intracellular pathogen which cannot replicate without macromolecules and metabolic machinery of the host cell. The spike proteins of the virus bind receptors identified as angiotensin-converting enzyme-2 (ACE2) present on the cell membranes of many organs. This binding causes conformational changes of the viral capsid and its fusion with the cellular membrane and release of the viral genome inside the host cell. The viral nucleic acid (mRNA) starts to synthesize the encoded proteins using the host cell ribosomes and needs of molecules, mainly proteins, and energy of the infected cell in order to replicate the viral genome and synthetize his progeny. Then, the newborns virions are released from the host cell , 12.per se hijacks and alters cellular metabolism to fulfill its needs for replication, it predominantly targets the amino acids (AAs) to meet such needs. Indeed, AAs are vital biomolecules for viral protein synthesis and are precursors for viral nucleotide metabolism because they are the unique molecules with the ability to provide nitrogen , nucleocapsid (NP), envelope (EP), proteins, as well as nonstructural viral proteins named OFR-6, 7 s and 9b proteins are pro-apoptotic in the host cell –24. In dIn addition, data suggest that phosphorylation of MAPKs cascade occurs in the SARS-CoV2 infected cells . MAPKs aThe presence of virus-activated inflammation and cellular stress promoting an hypercatabolic/hypermetabolic state was also confirmed by our finding of a significant reduction in circulating albumin . Furtherovid-19  early restoration of the metabolic cell's molecules and machinery providing proteins and/or AAs with enzymatic cofactors as anabolic vitamins and ions to stimulate protein synthesis in order to restore the body metabolism, and (ii) activation of the cell's anabolic metabolism by personalized physical rehabilitation as we have previously demonstrated in patients with chronic diseases .We observed consequences of a protracted hypermetabolic-hypercatabolic condition in our patients, easily detected both by physical exam and laboratory findings. Correction of these needs by optimizing nutritional care and supporting personalized nitrogen intake to counteract inflammation and promote tissue repair , should ovid-19 infections  we performed tests and blood analyses according to professional and ethical standard. Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Informed consent for blind management of the data was obtained from all subjects involved in the study.Patients were seen in the private ambulatory setting. Based on the fundamental guidance of good medical practice (EP, GC, and FD: conceptualization. EP and GC: methodology, formal analysis, writing—original draft preparation, project administration, and investigation. GC and CR: software and data curation. FD, TS, and LS: validation. GC: resources. TS and CC-S: writing—review and editing. FD and LS: supervision. 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.


Growing evidence suggests that ADHD, an early onset neurodevelopmental disorder, is associated with poor somatic health in adulthood. However, the mechanisms underlying these associations are poorly understood. Here, we tested whether ADHD polygenic risk scores (PRS) are associated with mid-to-late life somatic health in a general population sample. Furthermore, we explored whether potential associations were moderated and mediated by life-course risk factors. We derived ADHD-PRS in 10,645 Swedish twins born between 1911 and 1958. Sixteen cardiometabolic, autoimmune/inflammatory, and neurological health conditions were evaluated using self-report (age range at measure 42–88 years) and clinical diagnoses defined by International Classification of Diseases codes in national registers. We estimated associations of ADHD-PRS with somatic outcomes using generalized estimating equations, and tested moderation and mediation of these associations by four life-course risk factors . Results showed that higher ADHD-PRS were associated with increased risk of seven somatic outcomes  with odds ratios ranging 1.07 to 1.20. We observed significant mediation effects by education, BMI, tobacco use, and alcohol misuse, primarily for associations of ADHD-PRS with cardiometabolic outcomes. No moderation effects survived multiple testing correction. Our findings suggests that higher ADHD genetic liability confers a modest risk increase for several somatic health problems in mid-to-late life, particularly in the cardiometabolic domain. These associations were observable in the general population, even in the absence of medical treatment for ADHD, and appear to be in part mediated by life-course risk factors. Attention-deficit/hyperactivity disorder (ADHD) is an early onset neurodevelopmental disorder with an estimated prevalence of 5–7% in childhood . There iTwo recent reviews concluded that ADHD is robustly associated with obesity, sleep disorders, epilepsy, migraine, and asthma. Further, increasing evidence supports associations of ADHD with cardiovascular disease, neurodegenerative disorders, and certain autoimmune/inflammatory conditions , 7. SomeOne approach to partly circumvent these limitations is to study the effect of ADHD genetic liability in population-based samples that are untreated for ADHD, using polygenic risk scores (PRS), which capture the sum of an individual’s common autosomal genetic variant liability for ADHD based on independent genetic discovery data . Such apN = 52,080) were contacted for a telephone interview between 1998 and 2002 in the Screening Across the Lifespan Twin (SALT) study. In total, 44,919 individuals completed the SALT interview (response rate 85%). Study design and data collection has been described in detail elsewhere  = 1) across the p-value thresholds, retaining the first PC to derive a single (PC-)PRS used in subsequent analyses. This approach has been shown to maximize the amount of variance captured across PRS p-thresholds, whilst avoiding overfitting and maintaining a correct Type I error rate , mean centered and scaled), tobacco use (ever/never for snuff and cigarettes), and alcohol misuse . For alcohol misuse, we also included information regarding lifetime alcohol use disorder from the NPR . Life-course risk factors were assessed by self-report in the SALT interview and asked in a lifetime perspective.We identified four life-course risk factors previously associated with ADHD  as potenData collections in SALT/TwinGene and linkage to national registers were approved by the Swedish Ethical Review Authority in Stockholm. Informed consent was obtained from all participants.R2 was estimated for the full model  and the null model (not including ADHD-PRS). Percentage variance explained by ADHD-PRS for each outcome was calculated as the difference between the two (ΔR2). To evaluate differential associations by ascertainment source, we ran sensitivity analyses for self-reported and register-based outcomes separately. Further, we explored potential sex differences in the association of ADHD-PRS with each somatic outcome by running sex stratified analyses.We estimated associations between ADHD-PRS and each somatic health outcome separately using generalized estimating equations (GEE) implemented in the R-package DrGEE , and adjWe tested whether the four life-course risk factors  were associated with ADHD-PRS, using the same statistical model as above. As all factors showed evidence of association, we further tested for moderation and mediation effects by each life-course risk factors on the ADHD-PRS-outcome associations. Moderation effects were tested by including an interaction term to the main analyses  between ADHD-PRS and each life-style risk factors, in separate models. Finally, we ran a regression-based causal mediation analysis using the counterfactual approach  to explop-values using the Benjamini–Hochberg method to safeguard against multiple testing within each set of analyses. Data management was performed using SAS software version 9.4  and analyses ran using R 4.1.0 [All analyses were adjusted for birth year, sex, the first six PCs, and length of follow-up in register data . We obtained false-discovery rate (FDR) corrected  R 4.1.0 .N. The number of cases and prevalence rates for somatic health outcomes are presented in Table Among the 10,645 included individuals, 5587 (53%) were female. The mean age was 59 years (range 42–88) at self-report data collection, and 72 years (range 53–100) at the end of register-based follow-up (31st December 2013). In total, 1016 (10%) individuals had died and 9 (0.1%) emigrated after donating DNA in the TwinGene data collection (2004–2008) and before the end of register-based follow-up. Only 11 individuals had an ADHD diagnosis and/or an ADHD medication dispensation in register data, in line with evidence that ADHD is often underdiagnosed and untreated in older adult populations [p-values and ΔR2 are presented in Table R2 for the combined, register-based, and self-reported outcomes can be found in Fig. Associations between ADHD-PRS and somatic health outcomes defined by combined register and self-reported data are presented Fig. Descriptions of the four life-course risk factors and their associations with ADHD-PRS are presented in Table No interaction effects survived multiple testing correction. Results from the moderation analyses are presented in Table p < 0.05) after FDR correction. An overview of the mediation results and FDR corrected p-values can be found in Table Table We evaluated the role of ADHD genetic liability, as captured by PRS, on somatic health conditions in mid-to-late life in a general population sample. Our results suggest that polygenic risk for ADHD confers modestly increased risks for a range of somatic health problems in adulthood, particularly in the cardiometabolic domain. These associations were evident in a general population sample untreated and undiagnosed for ADHD. Further, we present novel, albeit tentative, findings to suggest that part of the association between ADHD genetic liability and primarily cardiometabolic outcomes may be mediated by life-course risk factors .Higher ADHD-PRS were associated with four out of seven cardiometabolic outcomes, including obesity, peripheral vascular disease, heart failure and cerebrovascular disease. There is an extensive body of literature linking ADHD to obesity . Furtherrg 0.16 and 0.23, respectively) were reported in one prior study, whereas the association to Type 1 diabetes was not found to be statistically significant [Overall, we found less evidence for genetic links between ADHD-PRS and diseases in the autoimmune/inflammatory and neurological domains. Among the autoimmune/inflammatory diseases, ADHD-PRS were associated with a small increased risk for type 1 diabetes and rheumatoid arthritis, but not psoriasis or inflammatory bowel disease. Some prior studies have found associations of clinical ADHD with type 1 diabetes and rheumatoid arthritis, both within-individual and across relatives, suggesting a possible common genetic vulnerability between ADHD and certain autoimmune diseases , 44. Hownificant . More rerg ~ 0.2 to 0.4) [Within the neurological domain, migraine was the only outcome associated with ADHD-PRS, with no significant associations observed for epilepsy, dementia, Parkinson disease, or sleep disorders. Although there are well-established phenotypic links between ADHD and certain neurological diseases , evidence of genetic overlap with ADHD are mixed . Large-s to 0.4) , 46. A q to 0.4) . Togethe to 0.4) , in part to 0.4) .We found no evidence for moderation of ADHD-PRS associations by the investigated life-course risk factors , with minor differences observed between exposure groups. The few available studies investigating interaction effects using ADHD-PRS have focused on ADHD as the outcome and largely reported null findings , much liIn contrast, we did find support for a mediating role of lower education, higher BMI, tobacco use, and alcohol misuse, on the relationship between ADHD-PRS and several somatic outcomes. Mediation effects were observed for nearly all cardiometabolic outcomes, for multiple mediators. For example, the main effect of ADHD-PRS on peripheral- and cardiovascular diseases showed significant mediation by all four life-course risk-factors. Further, BMI and alcohol misuse showed evidence of mediation on all significant ADHD-PRS main effects in the cardiometabolic domain . Further, BMI also mediated part of the association of higher ADHD-PRS with type 1 diabetes and migraine. The mediating effect of higher BMI across disease domain could either reflect the broad systemic effect that obesity can have on health and the strong link between ADHD and obesity. It may also in part be because BMI was the only mediator modeled as a continuous variable, thus increasing the power to detect even very small mediation effects. It is important to note that the life-course risk factors were asked about in a lifetime manner, meaning they did not necessarily precede the outcomes and mediation effects should therefore be cautiously interpreted. Further, it is important to note that both the main and mediation effects of ADHD-PRS were modest across all three disease domains, and our findings are thus far from clinical utility . This is unsurprising given that the current ADHD-PRS only explains about 5% of variance in ADHD diagnosis, and considerably less in related traits and comorbidities , 20. HowOur results add to a growing body of evidence suggesting that ADHD common variant genetic liability confers a small increased risk for several mid-to-late life somatic health condition , 22. MorThere are several strengths but also important limitations of this study. First, assessment of somatic health outcomes by both self-report and national medical registers represents an advantage of this study, yet the two data sources may capture partly different case definitions. Self-report provides information on somatic health problems that are untreated or mostly treated in primary care (which we did not have information from), and for symptoms below the diagnostic threshold. Conversely, register data from specialist care captures more severely affected patients and has excellent coverage for diseases requiring specialist treatment  . As suchOur study suggests an overall pattern whereby higher ADHD genetic liability is linked to a modest risk increase for several somatic health problems in adult life, particularly in the cardiometabolic domain. These associations were observable in the general population, even in the absence of medical treatment for ADHD, and may in part be mediated via life-course risk factors.Supplementary materials


The demand for adult education and training (AET) opportunities throughout the life course is substantial as labor markets often require workers to obtain advanced skills. AET opportunities are more often pursued by high-income and high-skilled workers than low-skilled or low-income workers. With the increased prominence of job automation and technological advances in the workforce, low-skilled workers are at risk for fewer opportunities within the labor market. These factors emphasize the importance of providing learning opportunities throughout the life course. In this mixed-methods study, we analyzed 2012/2014 data from the Program for the International Assessment of Adult Competencies (PIAAC) for the U.S., Canada, the Netherlands, Norway, and Sweden to compare participation rates in non-formal education (NFE) by high and low-skilled adults. Countries were selected based on qualitative findings that inform best practices. Additionally, to gain insights of policies and programs that promote NFE, international key informant interviews (n = 33) were conducted. AET policies and programs, along with barriers such as cost, motivation, and time, were explored with key informants. Findings include (1) aging and skills are negatively correlated in all nations of interest; (2) low-skilled adults are less likely to participate in NFE than their high-skilled counterparts; (3) low-skilled workers in Norway and the Netherlands are more likely to participate in NFE than their U.S. counterparts; and (4) NFE is often more acceptable to low-skilled adults due to previous negative experiences with formal education. Using these findings, we discuss successful AET programs in Nordic countries for overcoming barriers.