Segmental zoster paresis (SZP) is a relatively rare neurologic complication of herpes zoster (HZ), and is characterized by focal asymmetric motor weakness in the myotome that corresponds to skin lesions of the dermatome. The upper extremities are the second most commonly involved regions after the face, and predominantly involve proximal muscles. The pathogenesis of SZP remains unclear; however, most of the reports indicate that it is the inflammation because of the spread of the herpes virus.A 72-year-old man without trauma history of the left shoulder joint developed weakness of the left proximal upper extremity 10 days after vesicular eruption of HZ.His left shoulder girdle paresis was diagnosed with the upper truncus of the brachial plexus as a HZ complication according to a series of tests, including cervical magnetic resonance imaging (MRI), cerebral fluid analysis, sonography, and electrophysiological studies.Acyclovir and prednisolone were administered during hospitalization to treat SZP. Meanwhile, analgesics and gabapentin were administered to control the patient's neuralgic pain. He also received inpatient (daily) and outpatient (3 times per week) physical therapy along with range of motion and strengthening exercises.Partial improvement of the strength of the left shoulder girdle, and no improvement of the left deltoid muscle was observed 2 months after the interventions.This case emphasizes that HZ infections may be complicated by segmental paresis and they should be considered in the differential diagnosis of acute paresis in the upper limb. Awareness of this disorder is important because it avoids unnecessary invasive investigations and interventions, leading to suitable treatments with favorable prognosis. SZP is a relatively rare complication, whereby motor involvement can be observed in 0.5% to 5% patients with HZ.,4 SZP typically occurs 2 to 3 weeks after the herpetic rash and affects the myotome that corresponds to the regions of rash distribution. In an electromyographic study, Mondelli et al found that SZP was 19% in 158 cases, and they concluded that the true prevalence of SZP may be underestimated because approximately 70% of the patients develop HZ in regions supplied by the ophthalmic branch of the trigeminal nerve, upper cervical (C2–C3) or thoracic nerve roots; therefore, any motor involvement may be difficult to detect in clinical practice. The existing SZP literature primarily includes case reports and the most commonly involved region is the face, accounting for approximately half the cases. The second most common region of SZP is reported to be the upper extremity with a predominant involvement of the proximal muscles (C5–C7).,7Herpes zoster (HZ) or shingles is a common disease followed by the varicella-zoster virus (VZV) infection. The symptoms include specific dermatomal vesicular skin lesions with burning pain. VZV is latent in the dorsal root ganglia and is reactivated during malfunctioning of the immune system. The commonly involved nerve segments are the thoracic, lumbar, and trigeminal; the incidence of typical HZ is approximately 4 to 4.5 per 1000 person years.,8 However, these findings are still uncertain because the incidence of SZP is rare and the manifestation of both signs and electromyography (EMG) vary from patient to patient.,9The pathogenesis of SZP remains unclear. Viral spread from the dorsal root ganglion to the anterior horn cells or anterior spinal nerve roots was suspected based on the association between the involved myotome and dermatome of the rash. The viral spread may cause inflammation that may cause a neurologic deficit, leading to hypervascularity in the perineural structures or actual disruption of the blood nerve barrier.,7 Proper management of a patient with SZP is undoubtedly based on a correct diagnosis. Given that this is still under-recognized by physicians, misdiagnoses or treatment delays may occur. Therefore, physicians must recognize and include SZP as a differential diagnosis for the acute onset of paresis. For this purpose, we report a case of segmental paresis of the upper extremity that is attributed to HZ to remind physicians of the disease and its rare motor complications.The treatment of SZP is similar to that of HZ and primarily comprises antivirals and corticosteroids. The prognoses for patients with SZP are generally favorable after treatment.2Here we report a case study on a 72-year-old male patient who was consulted for left shoulder pain and weakness upon hospitalization to the Rehabilitation Department of Cishan Hospital. The patient provided informed consent for the publication of this report. We presented a detailed analysis of the SZP disease course and review of the literature based on the CARE guidelines. The patient complained of burning-like pain from his left shoulder to left forearm, followed by a vesicular eruption at the same location 10 days prior to admission. The diagnosis of HZ was made by a neurologist. An oral antiviral therapy with acyclovir was administered. Approximately 1 week later, the pain in the left elbow and forearm subsided. However, the patient was unable to elevate his left arm to the shoulder level, and the pain over the left shoulder persisted. Therefore, he visited our neurologic outpatient department where prednisolone (40 mg) was administered 2 times per day. The patient was admitted for further evaluation and management. His medical history included hypertension, coronary artery disease, and benign prostate hyperplasia. There was no history of trauma related to the left shoulder joint, or any systemic illnesses, including diabetes mellitus, cancer, or immunological disorder.Physical examination of the patient revealed hyperpigmented macular lesions from the left shoulder to left forearm Fig.  and mostNeurological examination revealed that the left biceps and brachioradialis reflexes were hypoactive and the triceps reflex was bilaterally normal. Marked weaknesses were found in the left deltoid, supraspinatus, subscapularis, and infraspinatus muscles [manual muscle testing (MMT) 2/5], whereas slight loss of muscle strength (MMT 4/5) was documented in the left biceps brachii muscles  and left radial (record on the snuffbox) nerves with normal conduction velocities compared with the right side. No response was obtained from the lateral antebrachial cutaneous nerve. Normal motor and sensory responses were obtained from the peripheral nerves, which innervate the lower trunk  and left supraspinatus and infraspinatus (MMT 2/5 to 3/5) muscles showed improvement; however, there was no change in the muscle strength of the left deltoid (MMT 2/5), and no progression of the atrophy was observed in the left deltoid and supraspinatus muscles at the follow-up visit 2 months later. The patient complained of low-intensity pain, and indicated a slight improvement in his left shoulder ROM.3 The reported estimate of segmental limb paresis with cutaneous zoster is approximately 3% to 5%. However, the true incidence of SZP may be underestimated because of the difficulties in clinical diagnosis of thoracic or upper cervical motor weakness, the pain often masking voluntary movements, and the weakness of SZP.We reported a patient who presented with weakness in the left proximal upper extremity after HZ infection, and SZP diagnosis was ascertained after a series of laboratory and imaging examinations. SZP is reflected in a wide spectrum of clinical presentations. Based on the electrophysiological study by Cockerell et al, SZP represents a slow extension of viral inflammation from the sensory ganglion to the spinal cord, roots, plexus, and peripheral nerve. However, in a recent retrospective study of SZP using MRI and electrophysiological studies, Liu et al observed that SZP affected the upper limbs more often. There is a high incidence of HZ in individuals aged > 40 years, but the highest incidence is found in the age group of 60 to 70. Elderly patients with HZ develop motor complications more often than pediatric and young adult patients. However, when younger patients with VZV infections develop SZP, the cranial and truncal muscles are often affected. Immunocompromization, smoking, and diabetes are associated with neurological complications that follow VZV infection.,15 Our patient was 72-year-old with a smoking history  and had no systemic disease other than hypertension and coronary artery disease.In a review of the literature by Sumihiro et al, SZP almost equally affects the upper and lower limbs.,16,17 Motor weakness is the most frequent in segments C5 to C7 in the upper limbs and in segments L1 to L4 in the lower limbs of patients with SZP; the distribution of muscle weakness is common in proximal muscles of the limbs and limb-girdles.,7 In a few cases, HZ resulted in partial or complete involvement of the brachial plexus. Eyigör et al reported a case of SZP in a 54-year-old male patient with partial involvement of the upper, middle, and inferior trunks of the brachial plexus. Rabia et al reported a 57-year-old male patient with SZP and involvement of the upper and middle trunks of the brachial plexus after VZV infection. Liu et al studied SZP in 8 Chinese patients and identified 2 cases with radiculopathy, 2 with plexopathy, 3 with radiculoplexopathy, and 1 with combined radiculopathy and mononeuropathy after electrophysiological testing. Our patient exhibited involvement of the upper trunk of the left brachial plexus after electrophysiological testing.Radiculopathy is a common form of HZ-related motor weakness. However, the interval between the occurrence of the skin lesions and muscle weakness following a VZV infection vary. One case showed development of motor paresis 3 days before that of the skin lesions, whereas a few cases showed that patients exhibited weakness months after the rash.,22 In this case, the patient showed weakness 10 days after vesicular eruption.In cases where paresis follows an HZ infection, the diagnosis is established based on the history of weakness following painful skin lesions after exclusion of other causes of weakness and electrophysiological tests. Usually, the muscle weakness occurs days after occurrence of skin vesicles. Studies from Liu et al and Sachs et al proved that peripheral neuropathy caused by HZ may be primarily attributed to axonopathy. Therefore, needle EMG generally shows abnormal spontaneous activities, such as fibrillations and positive sharp waves, in clinically weakened muscles owing to SZP. However, the pathogenesis of SZP remains unclear. Postmortem observations demonstrated the degeneration of anterior spinal roots with lymphocytic infiltration of the posterior and anterior horns in patients with HZ. Pathologic studies observed demyelination, axon degeneration and lymphocyte infiltration in the affected nerves, dorsal root ganglions, and dorsal horns in patients with HZ.,26 MRI studies revealed that some but not all the patients.,27 with zoster paresis exhibited nerve enlargement and transverse relaxation (T2)-dependent signal hyperintensities in the dorsal horn, brachial plexus, or peripheral nerves. These suggested the hypervascularity or disruption of the blood–nerve barrier caused by viral-induced inflammation.Given that the dorsal root ganglion is the site of VZV before HZ eruption, nerve conduction studies usually disclose reduced sensory nerve action potential amplitudes in the affected segments.,19 Antiviral therapy may reduce peripheral sensory axonopathy and prevent viral spread. Moreover, given that there may be more extensive inflammation in patients who developed SZP than that shown in usual cutaneous zoster, corticosteroids were recommended for use immediately after the diagnosis of SZP.,19,28 However, the efficacy of these treatments lack evidence rooted on controlled clinical trials. Pain relief, prevention of muscle atrophy and contractures, and the strengthening of weak muscles should be considered in the treatment of SZP. Although evidence to support rehabilitation on SZP is lacking currently, they are expected to play an important role in motor recovery. The prognosis for SZP is generally favorable with complete or partial recovery rates up to 75%. The recovery time can vary significantly; however, most of the presented cases varied between 1 and 2 years.,29 The patient in this case was administered antiviral medication on occurrence of the skin vesicles. He was also given prednisolone because of the systemic weakness. Analgesics and gabapentin were used to control his neuralgic pain. Rehabilitation started as soon as his weakness developed. Improvement of muscle strength of most of the left proximal upper limb was detected 2 months after his referral despite the fact that there was no change in the strength of the left deltoid muscle at that time point. A long-term follow-up is expected to yield a more precise determination of the prognosis for this patient.Some case reports suggested that an antiviral treatment following an HZ infection could be effective in reducing the incidence of SZP and the severity of electrophysiological changes.4In conclusion, ZP secondary to HZ should be considered in the differential diagnosis of acute paresis in the upper limb. Awareness for this disorder is important given that it can avoid unnecessary invasive investigations and interventions, and could lead to suitable treatments with favorable prognoses. A good understanding of the neurologic complications secondary to HZ should be emphasized, while the rehabilitation is expected to play an important role in the motor recovery of patients with SZP.Conceptualization: Gaun-Bo Chen, Sheng-Hui Tuan, Ya-Chun Hu.Supervision: I-Hsiu Liou.Writing – original draft: Guan-Bo Chen, Hung-Ya Huang, Shin-Yi Wu.Writing – review & editing: Sheng-Hui Tuan.


Regression analyses showed that autism symptom severity explained 12% of variance in academic progress, which was raised to 36% by adding self-reported daily EF, and to 25% by adding performance-based EF. It is suggested that EF is a candidate marker for academic progress in higher education students with ASD and a candidate target for early intervention.Many students with autism spectrum disorders (ASDs) attending higher education drop out prematurely. The predictive value of self-reported daily executive functioning (EF) and (cognitive) performance-based EF  for academic progress was evaluated in 54 young adults with ASD (M According to estimates in the US, the lifetime prevalence of autism spectrum disorder (ASD) ranges between 1.25% based on 2011–2013 data to 2.24% in 2014  were recruited for this study, which is part of a study measuring cognitive and behavioral functioning, academic progress and quality of life in higher education students with ASD. All participants were postsecondary students enrolled in higher education in the Netherlands. To increase generalizability, both males and females were included . The ASD group was recruited through Stumass; a non-profit organization providing services for students with ASD who are enrolled in university programs or universities of higher professional education. Stumass provides guided living homes where students with autism live together, and ambulatory guidance for students that are able to live on their own. In order to be enrolled in Stumass, applicants are required to have received a formal clinical diagnosis of ASD based on the Diagnostic Statistic Manual of Mental Disorders (DSM) criteria , provided according to Dutch protocols. An additional requirement for enrollment in Stumass is that co-morbid psychopathology, if present at entry, is either in remission or of minimal impact on daily functioning of the student. The research protocol was approved by the Medical Ethics Committee of Leiden University Medical Center (NL39057.058.12) and written informed consent was obtained from all participants.Fifty-four young adults with ASD  and higher vocational education (practice oriented). Each curriculum in higher education consists of 60 European Credit Transfer System (ECTS) per year and it has been found that ‘the number of credits earned’ is an appropriate measure for students’ academic progress  of executive function or self-regulation problems in the everyday environment that have occurred in the last 4 weeks. It is composed of 75 items which are divided over 9 non-overlapping theoretically and empirically derived clinical scales; Inhibit, Shift, Emotional Control, Self-Monitor, Initiate, Working Memory, Plan/Organize, Task Monitor and organization of Materials. See Rabin et al.  for an eANT, the Shifting Attentional Set-Visual (SSV) and the Spatial–Temporal Span (STS) tasks were used. The Shifting attentional Set-Visual (SSV) subtest measures both inhibition and cognitive flexibility. This task consists of three parts in which the participant has to respond to the movement of a square that jumps randomly to the left or right on the screen. In part 1, compatible responding is required: the participant has to follow the movement of the green square (compatible condition—press left/right key on left/right move). In part 2, incompatible responses are required compared to the just trained compatible condition: the square is red and the participant has to move in the opposite direction (incompatible condition), requiring the subject to inhibit the prepotent response. In part 3, a mix of part 1 and 2 trials, cognitive flexibility is required as the participant has to flexibly switch between the two response alternatives, depending on the color of the square. Speed  and accuracy (number of errors) are the main outcome parameters. The task model predicts an increase in errors and/or a decrease in speed when inhibition or flexibility is required. Inhibition is operationalized as the difference in performance between parts 1 and 2, cognitive flexibility is operationalized as the difference in performance between part 1 and the compatible trials of part 3, with larger values denoting poorer functioning (slower speed and/or more errors as a result of higher task demands). The STS subtest of the ANT is designed to measure working memory, using squares in a 3 × 3 visual spatial grid. These squares are pointed out by a hand animation in a specific order, with increasing complexity. The test provides two scores: the number of correctly identified squares irrespective of temporal order and the number of squares that are identified in the correct order, which latter condition imposes larger memory demands. The task model predicts that the memory score will be lower when the order criterion is applied. Working memory is operationalized as the difference between these two scores, with a larger value denoting poorer working memory. For a more detailed description of the tasks, including figures, see De Sonneville et al. , including the ANT and the abbreviated WAIS, was always administered first. The ANT was administered on a laptop computer. At the end of the performance session, the participants were debriefed and received a voucher of 20 Euros for their participation in the first part. In addition, they were asked to fill out online questionnaires afterwards. Subsequently, they received an e-mail with a link to the questionnaires so that they could answer the questions at home at their own convenience. Upon returning these questionnaires, they were rewarded with a written report of their cognitive strengths and difficulties in the study. Approximately half a year after the first assessment, the participants received an e-mail with a link to follow-up questionnaires, including information on their academic progress and ECTS at the moment. Students who participated in this second part of the study, received another voucher of 20 Euros for their participation.p < 0.05.All analyses were conducted in IBM SPSS (v.21). All data was checked for normality of the distributions and outliers. Outliers defined as more than 3 standard deviations (z-scores) from the mean were checked for their influence on the data. One outlier on IQ was found, this individual was excluded from further analysis due to extreme performance anxiety during testing that ruined his performance. Also, one individual was excluded from the ANT flexibility measures analysis, and one individual from the ANT inhibition measures analyses, due to extreme scores. One subject did not complete the STS task of the ANT. Level of significance was set at First, the correlations of age, gender, and IQ with academic progress were calculated as these covariates could potentially influence academic progress. As no significant linear correlations were detected, it was decided not to control for these variables in further analysis. The ANT variables appeared to be skewed which was dealt with by applying a natural log transformation, resulting in acceptable skewness varying between .36 and .69. Academic progress data showed a reasonable skewness with values of − .49. To examine relationships between the variables of interest, Pearson correlation coefficients were computed between academic progress with the SRS-A , the BRIEF-A  and the transformed ANT scores . Pearson correlations coefficients were identified as weak (0.1–0.3), moderate (0.3–0.5) or strong (> 0.5), according to Cohen .p < 0.05. Assumptions for linear regression analysis  were met. To provide more robust statistics, subsequent analyses were performed with 1000 resamples bootstrapping with 95% bias corrected and accelerated confidence intervals (CIs).Next, to answer our research questions, hierarchical multiple regression analyses were performed. Two separate analyses for the self-report and the performance-based EF measures were performed, with the SRS-A total score entered in the first step and those subscales from the EF measures that correlated significantly with academic progress were entered in the second step . Level of significance was set at n = 8), switched to vocational education (n = 4), not attended the follow-up study (n = 1), or because they experienced symptoms of depression at the time of the follow-up (n = 1). When comparing these fourteen drop outs with the rest of the sample (n =39), it was found that they did not significantly differ in terms of IQ, SRS and EF.The sample characteristics for the remaining participants regarding sex, age, estimated IQ, academic progress and autism symptom severity are given in Table ANT. A significant medium correlation with academic progress emerged for the total score of the SRS-A . Significant correlations with academic progress also emerged for some scales of the BRIEF-A, ordered from strong to moderate correlations: plan/organize , initiate , total score , task monitor  and working memory . These negative correlations indicate that a higher autism score and poorer daily EF were associated with poorer academic progress. Correlational analysis showed moderate correlations between academic progress and ANT scores; speed  and accuracy  of cognitive flexibility, and working memory , indicating that poorer cognitive flexibility and working memory were associated with poorer academic progress.Correlational analyses with academic progress were performed with 39 participants for the SRS-A, 37 for the BRIEF-A, and 38 for the prange= .21–.69). It was therefore decided to use only the subscale Plan/Organize from the BRIEF-A in the final regression model, as this subscale correlated highest with academic progress. The final model is shown in Table F = 4.94, p = .033], explaining 12% of the variance in academic progress; the second model adding the subscale plan/organize of the BRIEF-A showed a statistically significant improvement , and tripled the explained variance in academic progress to 36%. In this last model, only plan/organize remained a significant predictor of academic progress . The bootstrapping results showed that in model 1, autism symptom severity was significantly predictive of academic progress . In model 2, autism symptom severity no longer appeared significantly predictive of academic progress , while Plan/organize was significantly predictive of academic progress . Initial regression analysis with the four subscales of the BRIEF-A entered in the second step resulted in a significant model with none of the predictors being significant prange= .1–.69. ItANT, was statistically significant  and the explained variance in academic progress increased from 12 to 25%. However, in this last model, none of the predictors remained a significant predictor of academic success. The bootstrapping results showed that in model 1, autism symptom severity was significantly predictive of academic progress . In model 2, autism symptom severity no longer appeared significantly predictive of academic progress , this was also found for cognitive flexibility accuracy  and working memory . To explore the individual contribution of the two EF predictors to the explained variance, a post hoc three steps multiple regression analysis was conducted. Adding cognitive flexibility to the model raised the explained variance of 12.2% with 7.8% to 20%. By adding working memory in the third step the explained variance increased with 5.4% to 25.4%.Because of a substantial collinearity between the two flexibility subscales of the ANT (accuracy and speed), it was decided to delete flexibility speed from the list of predictors. Initial regression analysis with the remaining subscales of the ANT that correlated significantly with academic progress showed that the model with the subscales cognitive flexibility accuracy and working memory was best in explaining academic progress. The model for predicting academic progress from cognitive EF tasks is shown in Table B are compatible with the idea that poorer performance-based EF is associated with poorer academic progress. For decisions about whether to pursue a research idea further, we concur with Amrhein and Greenland  to 36% (both symptoms and planning/organizing skills). We therefore conclude that, in addition to the severity of autism symptoms, self-reported daily EF is a valuable predictor of academic progress in young adults with ASD. Better performance during tasks that ask for cognitive flexibility and working memory appeared to be related to stronger academic progress as has been demonstrated by the correlational analysis. Together, severity of autism symptoms, cognitive flexibility and working memory performance are significantly predictive of academic progress. This was shown by a significant model in regression analyses, raising the explained variance in academic progress from 12% (ASD symptoms only) to 25% (both symptoms and cognitive performance). However, none of the three predictors in the final model was significant in itself, which is why these results should be interpreted with caution. Nevertheless, referring to the 95% CI from the bootstrap analysis, the point estimates of reenland  and collANT used in the present study, are designed to assess specific, strictly operationalized, aspects of EF under relatively optimal conditions. Also, with performance tasks, the test/tester is ignorant of the individual level of academic progress, which underlines the strength of this study measuring EF in different ways.Problems in planning/organizing reflect impairments that are often reported by clinicians working with children with high IQs and ASD . This result indicates that those students who earned more credits, also had a higher GPA. This seems in line with the Dutch higher education system, in which all studies provide a curriculum of 60 ECTS per year. Not many students take extra courses, and it is not expected of them. Furthermore, in the Netherlands there are no scholarships based on GPA, leading us to assume that GPA is not as important in the Netherlands as it is in other countries. As the correlation of the possible predictors with GPA were lower than with academic progress we did not pursue this issue any further.One might question whether or not the prediction of GPA versus academic progress is more successful. Looking at the GPA at the time of the follow-up in the current study, it was found that number of credits earned and GPA are strongly correlated (Some limitations of our study need to be mentioned. First, academic progress can be measured not only in grades, but also in, for example, increased learning, increased independence and self-determination and positive social experiences. The current study looks at a more global academic progress and these factors were not included in the current study. Also, the current sample consists of higher education students with ASD with mean IQ levels in the high average range, so these results cannot be generalized to autism samples with lower level IQs. However, as these findings are similar to patterns of difficulties found with respect to flexibility, planning and organization in both children and adolescents with autism without intellectual disability (Granader et al. both cognitive performance-based and self-report measures of EF as potential predictors of academic progress in young adults with autism in higher education. Where Shmulsky et al. (and performance-based, resulted in a slower study pace. The results in this study reflect the impact of everyday metacognitive demands that students encounter in higher education. Higher education settings place huge demands on their students’ flexibility as schedules which appear to be “set”, frequently change. In line with Shmulsky et al. (To our knowledge, this is the first study exploring y et al.  found poy et al. , we suggy et al.  EF can py et al. , supporty et al. . They suy et al. . This may et al.  found inThe current study shows that EF potentially plays an important role in academic progress for young adults with ASD. Future research should aim at replicating these findings across different countries and samples of students with ASD, and disentangle the contribution of EF to academic progress compared to other relevant predictors in ASD like IQ and comorbidity. These findings emphasize that clinicians working with children, adolescents and adults with ASD in education settings, should be aware of the impact that EF has on academic progress. Enhancing EF in ASD might not only enhance academic progress, and therefore the chances of graduating, but also overall quality of life and outcome for this group. We urge the field to highly prioritize systematic research into mechanisms related to study drop-out and the development of interventions to promote successful studying for students with ASD.


Both patients and controls were monitored through December 31, 2011, in order to identify the occurrence of adrenal gland disorders (ICD-9-CM code 255.X). We also explored the potential effect of methylphenidate (MPH) and atomoxetine (ATX) treatments on the risk of developing adrenal gland disorders. We found that ADHD patients showed a significantly increased probability of developing an adrenal gland disorder compared to the control group (0.2% of ADHD vs. 0.1% of controls). However, neither MPH nor ATX treatment significantly influenced the patients’ risk of developing adrenal gland dysfunction. We propose that patients with ADHD had greater comorbid rates with adrenal gland dysfunction than the control subjects. Nevertheless, undergoing treatment with MPH or ATX did not significantly influence the risk of developing adrenal gland dysfunction among ADHD patients.This study aims to examine the co-occurrence rate of attention deficit hyperactivity disorder (ADHD) and adrenal gland disorders, as well as whether pharmacotherapy may affect ADHD patients’ risk of developing adrenal gland disorder. One group of patients newly diagnosed with ADHD ( Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder that commonly occurs in children and adolescents, affecting about 7% of all school-age children worldwide , with a Prior studies on children with ADHD that examined overall diurnal cortisol levels and rhythm have shown significantly lower basal cortisol concentrations in the morning ,11,12 anThe management of ADHD includes behavioral therapy and medication, with methylphenidate (MPH), a psycho-stimulant, being the most commonly used drug. The dual mechanism of MPH consists of inhibiting the re-uptake of both dopamine and norepinephrine, leading to treatment effects for not only behavioral but also cognitive aspects . PreviouThe association and comorbidity of ADHD and adrenal gland disorders have yet to be fully explored. Therefore, we conducted this nationwide population-based analysis to explain the co-occurrence rate of ADHD and adrenal gland disorders. We also examined whether certain pharmacotherapy may affect the risk of developing adrenal gland disorder in ADHD patients.The institutional review board of Chang Gung Memorial Hospital has already approved this study, whose data came from the ambulatory claims database of the National Health Insurance Research Database of Taiwan (NHIRD-TW). First implemented in 1995, Taiwan’s National Health Insurance (NHI) program is a mandatory universal health insurance program, for which the NHI Bureau is the sole payer for health care services. Since the launch of the program, the NHI Bureau has contracted 93% of all healthcare providers in Taiwan, and at least 96% of the insured have used healthcare services once or more through those contracted hospitals and clinics. It is required that contracted medical institutions must electronically submit claim documents related to medical expenses every month. The reliability of NHIRD diagnostic codes has been proven in a previous study .The protocol for this study conformed to the Helsinki Declaration, and was approved by the Institutional Review Board (IRB) of Chang Gung Memorial Hospital (No. 102-1297B). Patient records/information was anonymized and de-identified prior to analysis, and the need for written informed consent was waived by the IRB.n = 146,063). To reduce potential misdiagnosis, we defined ADHD as at least two NHI claim records with the International Classification of Diseases, 9th Edition, Clinical Modifications (ICD-9-CM) code 314.X. Moreover, we excluded the patients  born after 31 December 1999, the reason of which will be explained later. After excluding these patients, our data set included 75,247 patients in the ADHD group. We defined the index date as the date when ADHD was first diagnosed and followed these patients’ medical records in the NHIRD-TW from the index date until 31 December 2011.We recruited all patients newly diagnosed with ADHD between January 1999 and December 2011 with records found in the NHIRD-TW , which is composed of the original claim data for one million beneficiaries randomly sampled from the NHIRD-TW’s 2000 Registry of Beneficiaries. The control subjects had no ADHD diagnosis between 1 January 1996, and 31 December 2011. In this study, we used the propensity score matching technique to create a matching control with a ratio of 1:1 for the ADHD group. Propensity scores were determined by multivariate logistic regression analysis, where gender and birth year were confounding covariates ,23. We dWe further identified neurodevelopmental disorders that are commonly comorbid with ADHD, including oppositional defiant disorder (ODD) (ICD-9-CM code 313.81), conduct disorder (ICD-9-CM code 312.X), autism spectrum disorder (ASD) (ICD-9-CM code 299.X), tic disorder (ICD-9-CM code 307.2X), and intellectual disability (ICD-9-CM code 317 to 319).For this study, we defined adrenal gland dysfunction as having a diagnosis of adrenal glands (ICD-9-CM code 255.X) and determined the diagnosis and diagnosis date of adrenal gland dysfunction based on insurance status and outpatient and inpatient claim databases. Adrenal gland disorder (ICD-9-CM 255.X) was classified into Cushing’s syndrome (ICD-9-CM 255.0), hyperaldosteronism (ICD-9-CM 255.1), adrenal genital disorders (ICD-9-CM 255.2), other corticoadrenal overactivity (ICD-9-CM 255.3), corticoadrenal insufficiency (ICD-9-CM 255.4), other adrenal hypofunction (ICD-9-CM 255.5), medulloadrenal hyperfunction (ICD-9-CM 255.6), other specified disorders of adrenal glands (ICD-9-CM 255.8), or an unspecified disorder of the adrenal glands (ICD-9-CM 255.9).Medications were confirmed using the Anatomical Therapeutic Chemical classification system . Methylpp < 0.05 statistically significant.We used the Statistical Package for the Social Sciences (SPSS) Version 16.0  to perform all the statistical analyses in this study. We considered a two-tailed value of 2) test or t-test to compare characteristics between the ADHD group and the control group. Furthermore, we used a Cox regression model to examine the potential influence of ADHD on the comorbidity of adrenal gland dysfunction. A previous study reported that primary and secondary adrenal insufficiency are more frequently in women than in men [We adopted the chi-square  to test whether MPH and ATX exerted differential effects on adrenal gland dysfunction. The multivariate logistic regression model was also used to estimate the potential effects of duration of MPH/ATX in use and the daily doses on the risk of developing disorders of adrenal glands. We calculated both the adjusted odds ratio (aOR) and the 95% confidence interval (CI).The Cox regression models are shown in We used the multivariate logistic regression models to examine the potential influence of pharmacotherapy on the risk of developing adrenal gland dysfunction  in ADHD Using three models , we found that neither MPH  nor ATX  significantly influenced the risk of developing adrenal gland dysfunction. Among ADHD patients, an older age at ADHD diagnosis , being female , and having an intellectual disability  were all associated with a greater risk of adrenal gland dysfunction. In addition, we found that duration of MPH/ATX in use and the daily doses did not affect the risk of developing disorders of adrenal glands .The main results of our study show that the ADHD group had higher comorbidity rates of adrenal gland disorder compared to the control group. Furthermore, among ADHD patients, an older age at ADHD diagnosis, being female, and having an intellectual disability were all associated with a greater risk of adrenal gland dysfunction. Regarding the relationship between the pharmacotherapy of ADHD and adrenal gland disorder, we found that neither MPH nor ATX significantly influenced the risk of developing adrenal gland dysfunction.With regard to the comorbidity rates of ADHD and adrenal gland dysfunction, our results showed a one-fold higher rate in the ADHD group than in the control group (0.2% of ADHD vs. 0.1% of controls). To determine whether this higher rate has clinical significance, we had to recognize the prevalence of adrenal gland disorder in the normal population. A common adrenal gland disorder, adrenal insufficiency, can be classified into primary or secondary  adrenal insufficiency based on its etiology. Primary AI is rare, with a prevalence of approximately 93–140 per 1,000,000 (0.0093–0.014%), and is most commonly caused by congenital adrenal hyperplasia (CAH) in children . SecondaThe pathogenesis of the comorbidity of ADHD and adrenal gland disorder has yet to be determined, but abnormalities in the HPA axis function may be involved. The HPA axis and resulting glucocorticoid levels have been linked to several cognitive functions, including focusing attention, suppressing unwanted impulses and thoughts, and exerting voluntary behavior ,27. Low Possible explanations for the involvement of HPA axis hypoactivity in ADHD children include the following . First, Factors such as being female and having an intellectual disability were found to be associated with a higher risk of adrenal gland dysfunction among ADHD patient in our study. While primary and secondary adrenal insufficiency are both known to occur more frequently in women than in men , compareRegarding the relationship between the pharmacotherapy of ADHD and adrenal gland dysfunction, neither MPH nor ATX significantly influenced the risk of developing adrenal gland dysfunction in our study. Some studies have previously investigated the effects of MPH or ATX administration on cortisol levels. The salivary cortisol level increased after 60 mg atomoxetine use , while cThis study has a number of limitations that should be mentioned at this point. First of all, the inspection of adrenal gland dysfunction was made according to ICD records, so this study lacks relevant laboratory data . Therefore, we were unable to validate the diagnostic accuracy of adrenal gland dysfunction using laboratory data. Second, this study is based on reimbursement data from NHIRD-TW, so the diagnosis of ADHD was identified according to ICD records, instead of validated using structural diagnostic instruments. As a result, the classification of ADHD may not be rigorous enough. Third, the database did not show the severity of the symptoms of the affected individuals, and clinically severe patients are more likely to receive pharmacotherapy. Fourth, patients with adrenal gland disorder (ICD-9-CM 255.X) included in our study may consist of heterogenous disorders. While some of these conditions are related to a low cortisol level, others are caused by excessive corticosteroid, which may be less relevant to ADHD. Furthermore, literature regarding all adrenal gland disorders is scarcer than those focusing on specific diseases like adrenal insufficiency or Cushing’s syndrome, making it more difficult to obtain accurate epidemiology data of adrenal gland disorders. Moreover, ATX served as a second-line treatment choice of ADHD prior to 2017. Patients who received ATX treatment may have special characteristics . Therefore, the study’s results may be influenced by selection bias. Finally, despite applying a propensity score matching strategy, significant differences in age and sex were still found among the ADHD group and the control group. This matter was the result of the recruited number being so large, so the LHID 2000 cohort could not provide enough perfectly matched controls to the given criteria.Patients with ADHD had greater comorbid rates with adrenal gland dysfunction than the control subjects. Nevertheless, receiving pharmacotherapy (MPH or ATX) did not significantly influence the risk of developing adrenal gland dysfunction among ADHD patients. Therefore, continuous efforts are needed to promote public awareness of potential adrenal gland dysfunction among ADHD patients. Furthermore, no current evidence has revealed that MPH or ATX influences long-term adrenal function.


The probability of supporting vaccinations was almost eight-fold lower among respondents believing the vaccine–autism relationship. Chance of supporting vaccination doubled in the group with a higher knowledge level. The individuals not provided with expert information on vaccination were twice as often unconvinced. Age, education and having children significantly affected the attitude toward influenza immunization (p < 0.001). Older, better educated respondents and those having children were more positive about vaccinations. The medical community still exert decisive effects on attitudes toward vaccinations. High-quality information provided by them is of great importance. Skillful and competent provision of evidence-based information disproving the myth about vaccine–autism connection and proper education of medical staff is essential in molding positive attitudes toward vaccinations.Thanks to vaccines, many people are not exposed to the risks associated with vaccine-preventable diseases (VPDs). This, however, results in growing popularity of antivaccine movements and affects global and local epidemiological situation. Vaccine hesitancy has become a significant problem not only for epidemiologists but also for practitioners. Fortunately, the hesitant group seems to be vulnerable to intervention, and studies indicate that these patients can be persuaded to undergo vaccinations. The aim of the present study was to determine the factors most strongly affecting vaccination-related attitudes and decisions. An anonymous, self-administered survey consisting of demographic data and single select multiple-choice questions regarding vaccination was conducted. The voluntary study included secondary school pupils, medical and nonmedical students, healthcare professionals, hospital and clinic patients as well as parents. A total of 7950 survey forms were distributed between January 2018 and June 2019 in south-eastern Poland. A total of 6432 respondents (80.2%) completed a questionnaire that was eligible for analysis. The positive attitude toward vaccination was significantly affected by older age, by the fact of obtaining information on vaccinations from a physician, this information’s higher quality , higher level of knowledge on vaccines and by the fact of denying the association between vaccination and autism in children ( Over the course of two centuries, widespread vaccinations have contributed to the global eradication of smallpox, elimination of poliomyelitis in the majority of countries and a significant decline in overall morbidity and mortality caused by infectious diseases. This accomplishment was placed at the very top of the list of public health achievements of the 20th century published by the Centers for Disease Control and Prevention (CDC) .Paradoxically, vaccines have become a victim of their own success. Due to the popularity and high effectiveness of this form of prevention, many people are not exposed to the risks associated with vaccine-preventable diseases (VPDs). Hence, there are increasingly common opinions of patients and their parents on limited benefits versus high risks of mass and routine vaccination programs . For almConcerns about vaccination have become a global phenomenon and led to the search for answers to the question, who has the greatest influence on the parental attitude toward vaccination—medical professionals, internet or family and social environment . In receIn 2012, the World Health Organization (WHO) Strategic Advisory Group of Experts on Immunization (SAGE) created the Working Group on Vaccine Hesitancy . The purOne of the most frequently attacked vaccines is the measles, mumps and rubella vaccine (MMR) administered in the pediatric population. However, the theories disseminated by opponents of vaccination also result in a decrease in confidence in this form of infectious disease prevention among adults. A consequence of the decline in public confidence in the MMR vaccine is the increased number of measles cases recorded in recent years in both the United States and Europe ,15.The Polish Vaccination Programme is a mixed system composed of mandatory and recommended vaccinations. Compulsory vaccinations for children, adolescents and high risk groups include immunization of infants against tuberculosis (BCG) and viral hepatitis (HBV) at birth, and in the following months vaccinations against: tetanus, diphtheria and pertussis (DTP), Hemophilus Influenzae type b, Streptococcus pneumoniae, Poliomyelitis and against measles, mumps and rubella (MMR). Vaccination against varicella is carried out free of charge only in high-risk groups, and vaccinations against rotaviruses, Neisseria meningitidis type B and ACWY, human papillomavirus (HPV) and hepatitis A (HAV) are recommended but performed privately, without the financial support of the state. In our schedule, whole-cell pertussis vaccines have been used for years, and 5- or 6-in-1 vaccines can also be used alternatively at the expense of the child’s parents. The list of obligatory and recommended vaccinations, as well as details related to the realization of the vaccination program, are published annually by the Chief Sanitary Inspector ,17.In Poland, the number of patients avoiding preventive vaccination is increasingly high, which is consistent with the global trends. According to the Polish Chief Sanitary Inspector, in 2018, about 43,000 individuals avoided compulsory vaccinations [Considering the above data, the aim of the present study was to determine the factors most strongly affecting vaccination-related decisions in the Polish population. This study focuses on the social groups most closely involved in the decision-making process concerning vaccinations—health care workers, medical students, parents of patients and potential future parents.The survey was conducted using an anonymous, self-administered questionnaire consisting of questions about demographic data and single select multiple-choice questions regarding vaccination . The oriThe survey was conducted between January 2018 and June 2019 in randomly selected schools, universities, hospitals, primary care clinics and workplaces predominantly in south-eastern Poland. A total of 7950 questionnaire forms were distributed and the survey was carried out after obtaining the consent of the respective authorities . The study design was approved by the Bioethical Committee of the University of Rzeszow (reference number: 10/12/2018).The analysis included the following demographic data: gender, age , education , financial status  and having children or otherwise.“Do you consider yourself an advocate or opponent of vaccination?”The attitudes of the respondents to vaccination was assessed on the basis of the answers to question B8:“Have you been vaccinated within the last three years?”“Are you vaccinated against seasonal influenza?”The following multiple-choice questions were asked, specifying the respondent’s actions in relation to the declared attitude:“Please indicate one source of information about vaccinations that you find most convincing” (1)-medical sources  (2)-media  (3)-environment “Did you obtain information on vaccination from healthcare professionals during visits to primary care physicians (PCP) or specialist outpatient clinic?”: (1)-Yes, (2)-no.“Using the school grade system, assess the level of vaccination information provided by health professionals” (1 worst–6 best)“What was the most important source of negative opinions about vaccinations?”: (1)-medical sources, (2)-media, (3)-environment“What opinion about vaccination was provided by health professionals?”: (1)-fully positive, (2)-questioning the validity of certain vaccinations, (3)-strongly negating the purposefulness of vaccinationsThe following questions were used to assess the level of knowledge of respondents about vaccinations:“Which of the infectious diseases has been completely eliminated by vaccination?” (1)-measles, (2)-rabies, (3)-smallpox, (4)-whooping cough, (5)-hepatitis C“The statement that “vaccines cause autism” is:” (1)-true, (2)-falseIn addition to demographic variables, the following items concerning the main determinants of respondents’ attitudes toward vaccination were included:2 or exact Fisher’s tests were performed for independent qualitative variables. In this study logistic regression was applied. For the purposes of the logistic regression model, questions with answers represented by dichotomous variables were taken into account. The model was developed for questions B8 and B12. Classification (decision) trees were constructed. The statistical significance level was set to 5% (α = 0.05).All collected data were entered into a database prepared in Excel 16.0. Statistical analysis was conducted using Statistica 13.1 . Summary statistics were presented . The answers to the questions asked in the survey were ranked. Ranks corresponding to particular answers are presented in n = 1721) (95%CI: 25.82–27.99) were undecided and 35 (0.5%) did not respond to the question about vaccination-related attitudes. Since the number of opponents of vaccination was low, only vaccination advocates and undecided respondents were included in the analysis. The study population was therefore divided into two subgroups—convinced of vaccination and undecided. The between-group differences in gender, age, education, financial status and having children or otherwise were found to be statistically significantly different (p < 0.001).Out of 7950 questionnaires distributed, 6432 completed and analyzable forms were returned (the response rate = 80.2%). The demographic characteristics of the study group are shown in p < 0.001) (p < 0.001) (p < 0.001) (p = 0.001) (p < 0.001) , media-65.81% (95%CI: 64.61–66.99), family and friends-19.09% (95%CI: 18.11–20.08). Media information on vaccination favoured indecisive attitudes toward this form of prevention (< 0.001) . Moreove< 0.001) , and mor< 0.001) . The inf< 0.001) . The inc= 0.001) ; a highe< 0.001) .p < 0.001). Considering the odds ratios, the probability of supporting vaccinations was almost eight-fold lower among respondents believing that vaccinations caused autism  significantly affected the answers to this question. The number of individuals receiving vaccinations against influenza increased with age and was also found to be higher among those with children  respondents were annually vaccinated against influenza during the period of the last three years (95%CI: 6.40–7.70), 1104 (17.2%) were vaccinated at least one time (95%CI: 16.38–19.33) and 4875 (75.8%) (95%CI: 74.07–76.05) were never vaccinated against influenza; 29 (0.4%) respondents did not answer this question. The analysis of demographic data demonstrated that age, education and having children , which is a socially marginal group. Therefore, it is essential for physicians to focus on those unconvinced about the benefits of vaccinations. The above has also been strongly emphasized by the experts of the WHO SAGE Vaccine Hesitancy Working Group; undecided individuals can be convinced while declared opponents of vaccinations are resistant to substantive arguments ,12.According to the data published by the Centre for Public Opinion Research , negative attitudes toward vaccination are favored by young age, lower education and lower financial status . The finFurthermore, the vast majority of studies point to the leading role of health professionals in shaping social attitudes toward vaccination, especially specialists in infectious diseases and in internal diseases, pediatricians, family doctors, nurses and pharmacists. Our results demonstrate that both the provision of information by health professionals and the quality of their information are essential for the decision to vaccinate or otherwise . FurtherHealth professionals who provide vaccination-associated information should be alarmed by the conviction/fear of patients and their care givers that vaccines can induce autism. Our results suggest that such a conviction significantly affects negative attitudes toward vaccination . AccordiInfluenza vaccinations are of special interest. Many countries have attempted to increase influenza vaccination coverage, particularly in risk groups and among health professionals. Unfortunately, our results confirm the pessimistic reports. The majority of young people, especially students (75.8%), are not vaccinated against influenza. Similar data are reported by G.Bonaccorsi et al.; 74.6% of health professionals have never been vaccinated against seasonal influenza, 13.1% once or twice in the last 3 seasons and 12.3% each year. Among students, the percentage of nonvaccinated individuals has been even higher, i.e., 79.7% (85% in our survey)  Given thp = 0.001  of respondents gave the correct answers. Importantly, respondents who knew correct answers were much more likely to be supporters of vaccination, as compared to those who gave wrong answers  = 0.001 . It is sTo improve the public perception of vaccinations, clear and balanced media information on the safety and effectiveness of vaccination should be provided. In France, when new mandatory vaccination regulations were introduced (June 2017–May 2018), the media widely publicized the issue, yet the information was often contradictory. This resulted in a partial loss of confidence in vaccination and caused much controversy surrounding the new regulations . The medBased on our findings demonstrating that the most important sources of information are physicians and media (including the internet), possible measures to combine these two forces should be considered. Margaret Stager has formulated some guidelines for physicians who want to share their knowledge through social media . In the As far as the measures to prevent vaccination refusals are concerned, the issue of making vaccinations mandatory through law is increasingly debated. According to K.Kieslich, the priority in the field of public health for the respective authorities and the society should be well-planned and organized education curricula regarding this form of prevention of infectious diseases, rather than further orders and measures of compulsion .A survey carried out in Poland in 2015 concerning knowledge on influenza vaccinations revealed that the level of knowledge on this topic was insufficient. Effective education is needed to increase influenza vaccination rates. Similar to our study, the majority of respondents were women (72%) and young people (78% <35 years) . In the The majority of respondents was a population of young adults, which could affect the external representativeness of our study population, but the statistical methods used allowed for obtaining the results presented and drawing conclusions. Moreover, our analysis did not include opinion on compulsory vaccination in the entire group of children and young people legally obliged to be vaccinated (0–19 years). Many aspects of vaccinations that may affect their perception were not analyzed in our survey study . This is due to the limited capacity of the questionnaire and the care taken to make it as brief and transparent as possible. One thought to bear in mind is that, as with most survey studies, the findings are based on self-reported data. Therefore, there may have been some misrepresentations caused e.g., by the respondents’ desire to present themselves in a more positive perspective. This study has a cross-sectional character, the findings can only be suggestive of causal relationships, such surveys are not able to test or confirm causal relationships.Firstly, physicians and the medical community still exert decisive effects on attitudes toward vaccinations. Moreover, the quality of the information provided by them is of importance. Negative social attitudes toward vaccinations are most strongly determined by the conviction of an alleged relationship between vaccination and autism; therefore, skilful and competent provision of evidence-based information disproving this myth is essential.Physicians, scientists and representatives of health-promoting movements should be increasingly involved in media activities  and social fora to disprove the disinformation about vaccines. Furthermore, in order to mold correct attitudes of society toward vaccination, the substantive preparation of secondary school pupils, medical students, physicians and other healthcare professionals is essential for provision of coherent and uniform data as well as arguments demonstrating the benefits of mass vaccination.The present study analyzed the material concerning the entire study population; further separate reports are planned to analyze and discuss the attitudes toward preventive vaccinations among students, health professionals and parents.


We investigated the usefulness of the left atrial (LA) strain measurement on the prediction of upcoming cancer therapeutics-related cardiac dysfunction (CTRCD) after trastuzumab therapy in patients with breast cancer who did not develop CTRCD after chemotherapy.n = 13) and no CTRCD group (n = 59). Echocardiographic measurements including left ventricular global longitudinal strain (LVGLS) and peak atrial longitudinal strain (PALS) decline were compared.A total of 72 females with breast cancer who did not develop CTRCD after chemotherapy and underwent additional trastuzumab therapy were divided into CTRCD (p < 0.001) and LVGLS decline  were significantly greater in CTRCD than in no CTRCD group. PALS decline at the time of chemotherapy completion could predict future CTRCD after trastuzumab therapy with better sensitivity and specificity  than LVGLS decline .CTRCD was identified in 13 patients (18.1%) after additional trastuzumab therapy. Baseline echocardiographic findings were not different. After the completion of chemotherapy, conventional echocardiographic parameters were not different, but PALS decline (15.0 ± 4.7 vs. 8.9 ± 3.2%, PALS or LVGLS decline developed before developing overt CTRCD after chemotherapy for breast cancer, and PALS decline showed better sensitivity and specificity in predicting future CTRCD than LVGLS decline. Serial measurement of PALS can be used as a useful parameter in the prediction of future CTRCD. With the improvements in early detection and therapeutic advances including chemotherapy, cancer survival rates have been gradually improved . In contRecently, left atrial (LA) GLS using 2-dimensional (2D) speckle-tracking echocardiography has been suggested as a method to represent LA functional state. It is a new promising approach for LA mechanics and electromechanical coupling , and it The present study is a single-center retrospective observational study and the study protocol was approved by the institutional review board of our center (IRB No. 2015–05-092).n = 13, 47.2 ± 7.7 years) versus no CTRCD group . CTRCD was defined as a decrease in LVEF > 10% from the baseline LVEF to an absolute value below 55% on follow up echocardiography .p value < 0.05 was considered as a significant one.Statistical Package for the Social Sciences (SPSS) 22.0 for Microsoft Windows  was used for all statistical analyses. All numerical variables are presented as mean value ± standard deviation and were compared by independent samples t-test or one-way analysis of variance. All categorical variables were shown as their number and percentages, and they were compared using Chi-square or Fisher’s exact test to determine the significance of differences. Receiver operation characteristic (ROC) curve analysis was used to determine optimal cutoff values, sensitivity and specificity of PALS to predict upcoming CTRCD, and to compare them with those of LVGLS. All statistical tests were two-tailed, and a CTRCD was not identified on follow up echocardiography which was performed after the completion of chemotherapy, but identified in 13 patients (18.1%) on echocardiography which was performed during (7 [9.7%] patients) or just after completing trastuzumab therapy (6 [8.3%] patients).Baseline characteristics are summarized in Table Baseline echocardiographic findings are summarized in Table Serial changes of echocardiographic findings in CTRCD group are summarized in Table Serial changes of echocardiographic findings in no CTRCD group are summarized in Table p = 0.002) and PALS decline  were significantly greater in CTRCD group than in no CTRCD group. Significant drop  of LVGLS occurred in 11 patients (84.6%) in CTRCD group, and 25 patients (42.4%) in no CTRCD group.Serial changes of LVEF, LVGLS, and PALS are shown in Fig. To identify the optimal cut-off value and area under the curve (AUC) for the prediction of future CTRCD, ROC curve analysis was performed. The optimal value to predict future CTRCD was 11.79% for PALS decline and 9.9% for LVGLS. PALS decline at the time of chemotherapy completion could predict future CTRCD after trastuzumab therapy with better sensitivity and specificity  than LVGLS decline  Fig. .Fig. 3RThe authors investigated the clinical significance of LA strain analysis in the prediction of future CTRCD after additional trastuzumab therapy in patients with HER2-positive breast cancer who did not develop CTRCD after standard chemotherapy, and the present study demonstrated several clinically important findings. First, CTRCD was not uncommon (18.1%) after additional trastuzumab therapy, even in patients who did not develop CTRCD after chemotherapy for breast cancer. Second, after the completion of chemotherapy, conventional echocardiographic parameters were not changed, but PALS and LVGLS were significantly decreased. Therefore, it is suggested that PALS and/or LVGLS changes can be used as a more sensitive marker for cardiac injury after chemotherapy. Third, PALS decline after chemotherapy could predict upcoming CTRCD with better sensitivity and specificity than LVGLS. Therefore, serial measurement of PALS can be used as a useful parameter in the prediction of future CTRCD in patients with breast cancer.Anthracycline, cyclophosphamide, taxane, and trastuzumab-based chemotherapy is an important and highly effective chemotherapeutic regimen in HER2-positive breast cancer patients, both increasing survival duration of metastatic breast cancer and decreasing cancer recurrence and death after proper surgical treatment . HoweverTo date, the most widely accepted diagnostic criterion of CTRCD is based on LVEF. But its utility for early detection or prediction of CTRCD is somewhat limited by its relatively low reproducibility , and relDiastolic dysfunction and increase in LV filling pressure occur in earlier stages of various forms of HF. Comprehensive evaluation of diastolic function, using conventional parameters is also recommended, and some previous studies reported early changes of diastolic functional parameters , 18. HowIn this study, the patients who did not experience CTRCD also experienced continuous impairment of PALS, although degree of the change was smaller than the patients with CTRCD. In some previous reports, impairment of LVGLS was observed in patients undergoing breast cancer treatment with trastuzumab, suggesting presence of subclinical cardiac dysfunction in those patients . Our resOne possible explanation about why diastolic parameters have not shown consistent and serial changes in cardio-oncology setting to date is because many patients with cancer suffer from disability to have enough oral intake, and they are frequently under a lot of fluid therapy, especially for chemotherapy. We tried to minimize their effect in this study, by checking echocardiography when the patients were at the outpatient setting and free of any intravenous fluid therapy at least for the day of echocardiography. Also, presence of ‘gray zone’ in prediction of LV filling pressure  could haIn many other forms of chronic and progressive HF, LA volume is not necessarily normalized despite reduction of LV filling pressure, by irreversible damage and remodeling process. However, PALS seems to be improved by reduction of LV filling pressure , suggestThis study has some limitations. First, as shown in Fig. In conclusion, this study demonstrated that functional changes of the LA as measured by PALS and functional changes of the LV as measured by LVGLS precede before developing overt CTRCD defined by changes of LVEF. Also, serial changes of PALS showed even better sensitivity and specificity, compared with that of LVGLS. Therefore, the serial measurement of PALS can be used as a useful parameter in the prediction of future CTRCD. As serial changes of the LA in patients undergoing chemotherapy is not clearly defined yet, reversibility of LA structure and function with cessation of trastuzumab and medical HF management should be defined, and further studies are required.


Bioelectrochemical systems (BESs) are ruled by a complex combination of biological and abiotic factors. The interplay of these factors determines the overall efficiency of BES in generating electricity and treating waste. The recent progress in bioelectrochemistry of BESs and electrobiotechnology exposed an important group of compounds, which have a significant contribution to operation and efficiency: surface-active agents, also termed surfactants. Implementation of the interfacial science led to determining several effects of synthetic and natural surfactants on BESs operation. In high pH, these amphiphilic compounds prevent the cathode electrodes from biodeterioration. Through solubilization, their presence leads to increased catabolism of hydrophobic compounds. They interfere with the surface of the electrodes leading to improved biofilm formation, while affecting its microarchitecture and composition. Furthermore, they may act as quorum sensing activators and induce the synthesis of electron shuttles produced by electroactive bacteria. On the other hand, the bioelectrochemical activity can be tailored for new, improved biosurfactant production processes. Herein, the most recent knowledge on the effects of these promising compounds in BESs is discussed. In recent decades, bioelectrochemical systems (BESs) have undergone dynamic development and raised increasing interest of the scientific community. The term BESs applies to several types of devices, where microorganisms play the crucial role of carrying out various types of electrochemical reactions. In a microbial fuel cell (MFC), organic matter is oxidized by heterotrophic, electroactive anodic bacteria and converted into electric current . MicrobiWith these potentials, BESs are in transition to a wide variety of applications. The MFC and MEC technology has already been successfully investigated in scale up experiments and pilot scale studies to treat wastewater . A greatc-type cytochromes , alkyl ammonium chlorides (cationic), betaines (amphoteric), and ethoxylates (non-ionic). Recently, significant scientific attention has been paid to substitute the chemically synthesized surfactants with biosurfactants, which can be produced by microorganisms derstood . Exampleactivity . The aboAlthough synthetic surfactants may have their biological analogs, their functions and applications in biotic and abiotic components of BES may be entirely different. Several types of emerging interactions and applications of synthetic and biosynthesized surfactants in BES were described so far. In high pH, surfactants may prevent the biodeterioration of MFC cathodes . Their p3 (without surfactant) to 187 W/m3 (with surfactant). Many studies also showed that the enhancement of membrane permeability efficiently reduced the internal resistance of the BES, and thus increased the electron transfer efficiency (int) by up to ∼ 40%, whereas int about 43% in MFC. The same conclusion has also been obtained from a study conducted by P. aeruginosa PA01 strain, which endogenously overexpressed rhamnolipid, when compared to the wildtype strain. These mentioned studies indicate the beneficial influence of surfactants on the acceleration of mediated anodic electron transfer and the reduction of energy consumption due to internal resistances in MFCs  formation, which is further converted into pyocyanin (PYO), 1-hydroxyphenazine (1-HP), and phenazine-carboxyamide (PCN). The synthesis of phenazine is encoded by two homologous operons called operon one and operon two. In P. aeruginosa PAO1 and PA14, operon two showed higher activity when compared to operon one in the phenazine synthesis and current production in oxygen-limited BES  produced by Pseudomonas sp. CMR12a in the acetate-fed MFC system. The provision of the phenazine alone did not promote electroactivity. It is likely that the surfactant promoted PCN solubility, which enabled the PCN to cross the peptidoglycan layer of gram-positive Brevibacillus sp. PTH1. Hence, this bacterium was able to employ PCN as electron shuttle through a synergistic interaction with rhamnolipids, eventually enabling these bacteria to discharge electrons to the anode. In another study, reported by P. aeruginosa-inoculated air cathode-MFC (Pseudomonas putida KT2440 has recently been achieved (According to a study conducted by hode-MFC . Despiteachieved . This biachieved . A next achieved . More woP. aeruginosa PAO1– the same strain that authors utilized to determine the effect of biosurfactants on MFC performance (3 (control) up to 0.86 ± 0.06 mg/m3. Lastly, the microbial community composition of the biofilm was also affected by the presence of rhamnolipid. The MFC supplemented with 40 mg/L had an increased ratio of potential electroactive species such as Geobacter, Desulfovibrio, Tolumonas, and Aeromonas, reaching 81% when compared to the control (65%). These shifts in microbial community composition may also be related to either tolerance of some groups of bacteria to specific types of surfactants or activation of the quorum sensing mechanisms caused by surfactants which could give a competitive advantages to some of the species.In BESs, the biofilm plays an essential role in electron transfer between the bacterial cells, as well as in cell-electrode interactions. The microbial ability to form the biofilm is essential in harsh, BES conditions, which are dominated by unfavorable environmental conditions, such as low aeration, substrate limitation, and incidental desiccation. The biofilm formation may be induced by the presence of biosurfactants in MFCs. Such effect was observed by several authors so far. A 96-well plate test revealed that overproduction of rhamnolipids resulted in induced biofilm formation by formance . This maformance . The autformance . A similThe synthetic surfactants have been recently highlighted as compounds, which can react with the surface of both cathode and anode electrodes in MFCs. At high concentrations and pH, the surfactants presence may lead to the death of the bacterial cell through disruption of the cell membrane. This process is known as the alkaline lysis and was used by Brevibacillus sp. to achieve extracellular electron transfer, as discussed previously  in a MFC system  producing glycolipids, cellobiose lipids and mannosylerythritol lipids, Boruta-Zachem (Poland) producing surfactin, and Ecover (Belgium) producing sophorolipids. However, their synthesis in aerobic microbial processes is often hampered by energy demand of the bioprocess as well as extensive foaming and resulting problems with biomass retention and product recovery leading to losses of efficiency . Applyineviously . In anotproducts . FurtherC system . More reC system . The aut2, while the use of non-ionic Triton X-100, resulted in two orders of magnitude lower power performance. The use of surfactants may therefore cause several effects  in biodegradation-oriented bioelectrochemical techniques and the appropriate studies should always precede their utilization.Surfactants are often used to increase bioavailability of recalcitrant compounds during biodegradation processes . The stu2/g VSS (volatile suspended solids), which was the maximum value when compared to the other surfactants and several times larger when compared to the controls. The authors claimed that rhamnolipids led to the highest acidification of the activated sludge, which was the fuel and possibly improved membrane permeability of the electroactive biofilm cells, leading to improved electrochemical parameters. Contrary results were described by Surfactants have also been recognized as methanogenesis inhibiting agents . Such a in-situ production of surfactants in BESs would offer a great advantage of ensuring an energy-neutral bioprocess modification, which positively affects the BES performance in substrate utilization and energy production through various mechanisms. Considering the range of the effects when different types of surfactants and biosurfactants were investigated in BES, such process, however, would require careful and accurate control in order to avoid the occurrence of negative phenomena such as toxic effects on the electroactive community. Since contrary effects of different surfactants were observed on similar processes, identifying these effects for specific types of surfactants and comparative studies, as well as focus on the potential negative effects will be the main challenge to make use of their advantages in the future. The application of bio/surfactants in BES could finally lead to extended lifetime of the functional MFC elements affected by biofouling, thus leading to their increased utilization toward waste and wastewater treatment.Surfactants, either synthetic or biological, appear to be a highly reactive group of compounds in terms of their influence on several parameters, which are determining BES performance. Although a relatively rich number of surfactants were examined, only rhamnolipids and sophorolipid were included as representatives of biological surfactants. The recently emerged studies indicate that bio/surfactants may interfere with electron transfer mechanisms, especially electron shuttles such as phenazines, biofilm attachment and survival at the electrodes, as well as biofilm architecture and composition. These advantages make them an ideal target for a novel circular economy approaches in biotechnology, where the waste is being converted into value-added product. The GP conceptualized the scope and outline of the study. GP, TA, and MR performed the literature screening. GP and TA wrote the first draft of the manuscript. MR and GP critically revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Despite the effectiveness of methylphenidate for treating ADHD, up to 30% of individuals with ADHD show poor responses to methylphenidate. Neuroimaging biomarkers to predict medication responses remain elusive. This study characterized neuroanatomical features that differentiated between clinically good and poor methylphenidate responders with ADHD.Using a naturalistic observation design selected from a larger cohort, we included 79 drug-naive individuals (aged 6–42 years) with ADHD without major psychiatric comorbidity, who had acceptable baseline structural MRI data quality. Based on a retrospective chart review, we defined responders by individuals’ responses to at least one-month treatment with methylphenidate. A nonparametric mass-univariate voxel-based morphometric analysis was used to compare regional gray matter volume differences between good and poor responders. A multivariate pattern recognition based on the support vector machine was further implemented to identify neuroanatomical indicators to predict an individual’s response.63 and 16 individuals were classified in the good and poor responder group, respectively. Using the small-volume correction procedure based on the hypothesis-driven striatal and default-mode network masks, poor responders had smaller regional volumes of the left putamen as well as larger precuneus volumes compared to good responders at baseline. The machine learning approach identified that volumetric information among these two regions alongside the left frontoparietal regions, occipital lobes, and posterior/inferior cerebellum could predict clinical responses to methylphenidate in individuals with ADHD.Our results suggest regional striatal and precuneus gray matter volumes play a critical role in mediating treatment responses in individuals with ADHD.The online version contains supplementary material available at 10.1186/s12888-021-03040-5. Attention-deficit hyperactivity disorder (ADHD), characterized by impaired attention and impulsivity/behavioral control, is a common neurodevelopmental disorder persisting across the lifespan . Among tInvestigating an individual’s neurobiological variations may provide better explanations and have translational potentials to help identify those poor responders before the start of methylphenidate prescription. This endeavor is of clinical significance to reduce the suffering of unnecessary drug-related side-effects, the delay from receiving more effective treatment, and the discouragement of the patients and their families. Methylphenidate binds to the dopamine transporter and norepinephrine transporter and blocks their reuptake, thereby increasing the extracellular levels of these neurotransmitters . EarlierAmong the scarce published reports , structuIn addition to the striatal regions and associated corticostriatal circuitries, the default-mode network (DMN) maybe another brain circuitry involved in methylphenidate effects and responses. The DMN comprises the posterior cingulate/precuneus, medial prefrontal cortex, and lateral inferior parietal cortex . It exhiIn this context, this study aimed to characterize the baseline brain structural correlates that distinguished good and poor responders to methylphenidate in medication-naïve patients with ADHD, who did not have major psychiatric comorbidities. Based on the mass-univariate analysis of voxel-based morphometry (VBM), we first employed a combination of both unbiased exploratory whole-brain and hypothesis-driven approaches targeting striatal and DMN regions. Further, we leveraged a multivariate pattern classification method that takes into account interactions between regions, and is capable of making predictions for individual subjects based on brain imaging patterns . This mapost-hoc investigation on a uni-center ADHD dataset [This study is a  dataset , 38, 39. dataset –42 for p dataset –45. The  dataset –48. Part dataset , respectThe original studies , 38, 39 post-hoc investigation started with pooling cross-sectional [All medication-naïve  individuals with ADHD were referred to the studies from NTUH outpatient clinic. If they agreed to be enrolled in the studies , 38, 39,ectional , 39 or bectional . Those wThe assignment of good responder and poor responder was defined by their treatment responses to methylphenidate after at least one-month follow-up in the outpatient clinics by board-certificated senior child psychiatrists. Notably, all participants received immediate-release methylphenidate during this period, as Taiwan’s National Health Insurance can only reimburse this type of formulation initially for people with ADHD who are first-ever treated with psychostimulant. Most of the participants were followed up in the clinics for more than 6 months. The one-month criterion was intentionally decided because a follow-up shorter than this duration only yields limited clinical profiles to evaluate drug responses and does not allow enough time for dose optimization. Two child and adolescent psychiatrists (JCC and HYL) conducted a retrospective chart review. They agreed with each other’s judgment on the final estimation of the patient’s global functioning using the Clinical Global Impressions–Improvement Scale (CGI-I) . The CGI3; isotropic voxel size = 1 mm3). Individual T1-weighted image was preprocessed using Statistical Parametric Mapping 12 . Images were reoriented to the anterior and posterior axis and segmented to produce native-space GM, WM, and cerebrospinal fluid (CSF) images [High-resolution T1-weighted images were acquired by a 3D Magnetization Prepared Rapid Acquisition Gradient Echo sequence on a 3-T MRI scanner (Siemens Magnetom Tim Trio) with a 32-channel phased-arrayed head coil  images . Native-) images . The norhttp://www.fil.ion.ucl.ac.uk/spm/snpm/) [t-test using an approximate test of 20,000 permutations. Results were deemed significant with a cluster-forming voxel-level height threshold of p < 0.01 (z > 2.33), and a cluster-level correction for multiple comparisons p < 0.05 (familywise error rate). The categorical group variable (good or poor responder to methylphenidate) was used as an independent variable, and sex, total GM volume, age linear and square terms were assigned as nuisance covariates. For the whole-brain hypothesis-free analysis, a mean GM mask was generated using a threshold of > 0.2 in the GM part of the DARTEL template to minimize the contribution of voxels from WM and CSF. According to our hypothesis that the methylphenidate response would be related to GM morphometry of the striatal and DMN regions, we also implemented this nonparametric model restricted within the striatal and DMN masks, respectively . The striatal mask comprising putamen, caudate nucleus, and nucleus accumbens was generated using the Oxford-GSK-Imanova Structural–anatomical Striatal Atlas [Given the imbalanced sample size of the good responder and the poor responder group, nonparametric statistics were employed using the Statistical NonParametric Mapping-13 (SnPM13) toolbox (m/snpm/) . The twoal Atlas . The DMNal Atlas   version 2.1 . Specifip-value to determine the statistical significance of the accuracy, sensitivity, and specificity. Herein, we adopted the balanced accuracy, as it takes into account the different examples in each class, and gives equal weight to the accuracies obtained on test samples of each class [The generalization ability of the model was evaluated using 5-fold cross-validation (CV) in combination with the leave-one-out cross-validation (LOOCV) strategy to ensure that every individual from the dataset had the chance of appearing in the training and test set. Correctly, the dataset was partitioned into five parts at each cross-validation iteration, with 80% of the data to train the model, alongside 20% to test it. LOOCV involved the exclusion of a single instance  and training the classifier using the remaining subjects in each iteration . LOOCV ach class .To increase the interpretability of the multivariate pattern recognition results, we calculated the images summarizing the weights per region of interest (ROI) as defined by the AAL atlas  . The regAmong 79 participants with ADHD, 63 individuals were allocated in the good responder group, and 16 were in poor responder group based on the CGI-I. There were no significant differences among patients with ADHD with good methylphenidate response and those of poor responders in terms of age, sex, handedness, and IQ profiles, core ADHD symptoms, and ratios of ADHD subtypes  than the poor responders. Within the DMN mask, significantly smaller GM in the bilateral precuneus was observed in the good responders than the poor responders   between the volumes of the left putamen and precuneus.Implementing a small-volume correction within the striatum, we identified that the good responders had significantly larger GM volumes in the left putamen cluster (1738 mmp = 0.010), and smaller volumes in the right (p = 0.025) and the left (p = 0.031) precuneus. . The sensitivity of classification for the good responder group was 93.7%, while the specificity of classification for controls was 81.3%. The positive and negative predictive values for the classifier were 90.8 and 86.7%, respectively. The area under the ROC curve  was 0.88 (Supplementary Fig. From the results of the average fold, SVM based on whole-brain analysis differentiated the ADHD-good responder group from the ADHD-poor responder group with 87.4% balanced accuracy (Using a distinct design in a sample free from confounds of psychiatric comorbidities and medication exposure, we found that participants with ADHD with poor methylphenidate responses clinically had smaller regional volumes in the left putamen and larger precuneus volumes at baseline, compared with the good responders. Multivariate pattern recognition also identified that volumetric information among these two regions alongside the left frontoparietal regions occipital lobes and posterior/inferior cerebellum could differentiate between good and poor responders. This regional structural information, especially striatal volume, if replicated, might serve as a potential biomarker for methylphenidate responses in ADHD.The finding of greater left putamen volumes in good responders was largely consistent with the prior study showing smaller striatal volumes concentration in individuals with ADHD-poor responders . SeveralTo the best of our knowledge, this study is the first work demonstrating the poor responder group, relative to the good responder group, had higher GM volumes of the precuneus, a hub of the DMN . The resAlthough the striatum and DMN were specifically targeted revealed in the univariate VBM analysis in this study, we note that methylphenidate-associated brain structural and functional changes also involve other brain systems and areas, which might be associated with treatment responses as well. For example, methylphenidate has effects on modulating the attention network , 85 and Our finding of the regional brain volume difference between different drug responders by using voxel-based morphometry was also supported by using a machine learning approach, which selected the precuneus and left putamen, endorsing the aforementioned mass-univariate findings. In addition to these two regions, the SVM classification identified that regions of the discriminative pattern most predictive of treatment responses were in the left frontoparietal regions, mid and posterior cingulum gyrus, occipital lobes, as well as posterior cerebellum. There is functional connectivity between the striatum and the posterior cingulate, middle/inferior frontal gyrus , and strSeveral limitations must be considered while interpreting the results. First, the drug response was evaluated through a retrospective chart review, which consisted of patients’ current progress and detailed medication profile that were sufficient for rating the CGI-I. But there were no details about further cognitive function or the life quality profile. Of note, this study also was limited by a lack of placebo-controlled design. However, this study is a follow-up analysis based on the cohort originally for the cross-sectional study purpose, and the two child psychiatrists who rated the CGI-I were blinded to the participants and their attending psychiatrists. This approach may account for some extents of this caveat. We acknowledge that a prospective longitudinal design may be a more robust approach, e.g., the MTA study , to answOur findings of the conventional mass-univariate VBM analysis provide evidence that individuals with ADHD having larger precuneus and smaller putamen volumes were more likely to have a poor response to methylphenidate treatment. Such evidence was further confirmed and extended by findings yielded from a multivariate machine learning approach. Our results corroborate the essential role of the striatum in mediating responses to methylphenidate in ADHD , 23. TheAdditional file 1: Figure S1. The masks used to small-volume corrections. Image A shows the masks used to analyze the bilateral striatum in coronal and axial planes. Image B shows the masks used to analyze the default-mode-network in coronal, axial, and sagittal planes.Additional file 2: Figure S2. The area under the receiver operating characteristic curve by machine learning with leave-one-out and 5-folds cross-validation.Additional file 3.


Athyrium distentifolium Opiz collected in the middle of the growing season from glacial cirques in the Karkonosze. Additionally, fronds of the same species turning brown in autumn were collected from the same sampling sites. The health of ferns was impacted by the contents of Co, Cu, Fe, Mn, Ni, Pb and Zn in fronds, which may indicate that A. distentifolium uses elements accumulated in its tissues as defence against pathogens. Individuals from higher altitudes contained higher concentrations of Cd, Cu, Ni, Fe and Pb than those from lower altitudes. Autumn fronds of A. distentifolium contained a significantly higher concentration of Cr, Cu, Fe, Mn and Pb than vital summer fronds, which may indicate sequestration of these elements in senescing fronds probably to remove potentially harmful metals. Non-vital ferns were a better accumulator of Pb than vital ones, while both types of ferns accumulated Mn in a similar way.The Karkonosze National Park is affected by long-distance metal air transport of anthropogenic contamination as well as by tourist activity. Therefore, concentrations of Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb and Zn were evaluated in soil as well as in vital and non-vital fronds of The online version of this article (10.1007/s10661-020-08438-4) contains supplementary material, which is available to authorized users. Athyrium distentifolium Opiz fronds and soil from its sampling sites. The genus Athyrium may be an example of ferns with the above-mentioned abilities  metal contents in summer green fronds of A. distentifolium are significantly lower than those, while they are turning brown in autumn because the excess of metals is withdrawn; and (3) A. distentifolium accumulates certain metals proportionally to their concentration in soil and thus might provide information on the concentration of these elements present in the environment.The Karkonosze is the largest mountain chain in the Sudety, SW Poland, formed by a crystalline massif reaching up to 1603 m a.s.l. . Fronds turning brown were collected in early October (referred to as autumn). Collecting rhizomes in the Karkonosze National Park was not allowed, and the comparison of metal concentrations in summer and autumn fronds was expected to demonstrate which metals were withdrawn to the decaying fronds to protect the fern from their toxic influence. Samples were collected from open space not influenced by throughfall from canopies . Both soil and frond samples were dried (50 °C) until constant weight. Plant available metals  in soil were evaluated by extraction with 1 M ammonium acetate-EDTA (pH 4.65) for 30 min (10 g dry soil in 100 mL)  followed by a post hoc Tukey test was applied to control the statistical significance of differences between sites with respect to the concentration of metals in soils and both types of fronds. Normal distribution was obtained by BoxCox transformation of data  and health status .One-way ANOVA  was the concentration of an element in soil, the dependent variable was the concentration of the same element in fronds of A. distentifolium, and the categorical predictor variable was the health status. The interaction between the health status and concentration of an element in soil tests the hypothesis that the slopes of regression lines were equal between vital and non-vital fronds. If the slopes were not significantly different, we further tested whether the intercepts were equal. When the slopes were significantly different, a model of heterogeneity of slopes was fitted. Interaction between the health status and concentration of an element in soil tests the unequal slopes hypothesis. In this model, the independent variable (covariate) was the concentration of an element in soil, the dependent variable was the concentration of the same element in A. distentifolium, and the categorical predictor variable was the health status  was used for the evaluation of the similarity of Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb and Zn contents in frond samples : Cd < 0.5, Cu < 15, Pb < 25 and Zn < 70 , Cd 0.1–0.5, Co 0.4–3.2, Cu 2.6–21, Mn 8–234 and Zn 13–62, and lower upper concentrations of Cr 1.3–20 and Fe 1416–20,100 : Cd 0.001–0.7, Cr 0.002–4.4, Cu 0.7–4.3, Fe 97–6220, Mn 0.2–46, Ni 0.002–2.1, Pb 12–77 and Zn 0.6–88. The plant available form of Pb in soil in some sites was also higher than the admissible level of this element for cultivated soils  among the sites. The total maximum content of trace elements in soil Table  exceededls Table  and Wojtls Table . Upper pes Table  for soilA. distentifolium from the Karkonosze subalpine belt .The summer fronds of lt Table  containea et al.  from an A. distentifolium in the Karkonosze were performed, the explanation must be speculative. Plants may use elements accumulated in their tissues as defence against pathogens  and concentration of Mn available in soil , indicated by homogeneous slopes of regression lines : the regression line for non-vital ferns was higher than the line for vital ferns. This indicates that non-vital ferns would have higher Mn concentration at any concentration of Mn available in soil. An equal slopes model showed that there was a significant interaction between the health status  and concentration of Pb available in soil , indicating heterogeneous slopes  and a significantly higher concentration of Cr, Fe, Mn, Pb  and Cu (p < 0.05). The autumn fronds contained up to 3.2 times less Zn and up to 24, up to 3, up to 8, up to 7 and up to 65 times more Cr, Cu, Fe, Mn and Pb, respectively, than the fronds collected in summer. Thus, these metals seem to be sequestrated in senescing fronds probably to reduce the concentration of potentially harmful metals , also concentrated Pb in rhizoids. Similarly Athyrium wardii accumulated Pb in rhizoids with restricted translocation to fronds  and significantly lower for Pb (p < 0.01). There was no difference between vital and non-vital plants in BF for all other trace elements. Thus, it may be supposed that the disruption of tolerance mechanisms leading to elevated transport of the trace elements in non-vital fronds was not observed  are presented in Table A. distentifolium fronds. The anthropogenic impact on Polytrichum commune and Polytrichastrum formosum from Karkonosze hotels was also reported by Wojtuń et al. ESM 2(PDF 133 kb)ESM 3(PDF 72 kb)ESM 4(PDF 86 kb)