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BackgroundThe COVID-19 pandemic affected university students' mental health worldwide. International students were presenting high levels of stress, anxiety, and depressive symptoms before the pandemic. This study aimed to investigate (i) differences between various timepoints of the COVID-19 pandemic (2020, 2021, and 2022) in mental health outcomes and social and emotional aspects in domestic and international students, separately, (ii) differences between international and domestic students between the three timepoints on mental health outcomes and social and emotional aspects, and (iii) possible moderation effects of timepoints on mental health outcomes and social and emotional aspects of domestic and international students.Material and methodsData from three cross-sectional anonymous online surveys conducted in German universities were analyzed and compared. Data were collected in 2020, 2021, and 2022, respectively, with a total N = 14,498. Depressive symptoms, hazardous alcohol use, social support, self-efficacy, resilience, perceived stress, and loneliness were assessed through standardized self-report instruments. Differences between domestic and international students in mental health outcomes, and social and emotional aspects across three timepoints were assessed with one-way and two-way ANCOVAs.ResultsRegardless of the timepoint, international students presented more depressive symptoms and perceived stress, lower perceived social support and resilience, but higher levels of self-efficacy and less alcohol consumption compared to domestic students. A significant interaction effect between timepoint and student status emerged only for loneliness.ConclusionsInternational students generally presented poorer mental health outcomes than domestic students. Mental health care and prevention such as low-threshold, online counseling should address university students, especially international students.

BackgroundThe COVID-19 pandemic caused significant disruption to education systems worldwide, increasing pre-existing concerns regarding university students' mental health. Brazil was among the countries most affected by COVID-19 cases and deaths and was considered a pandemic epicenter. This study aimed to investigate Brazilian university students' mental health status and perceived burdens during the COVID-19 pandemic.Material and methodsFrom November 2021 to March 2022, a cross-sectional and anonymous online survey was conducted among students of a Brazilian federal university. Mental health status (depressive symptoms, alcohol and drug consumption) and social and emotional aspects in the pandemic context (social support, perceived stress, loneliness, resilience, and self-efficacy) were assessed with standardized measures. Students' attitudes toward the COVID-19 pandemic and vaccination and perceived burdens of the pandemic were also investigated.ResultsA total of N = 2,437 students completed the online survey. The PHQ-9 mean sum score was 12.85 (SD = 7.40), while n = 1,488 (61.10%) participants reported a sum score of 10 or more, indicating clinically relevant depressive symptoms. Further, n = 808 (33.1%) of the total sample reported suicidal thoughts. Levels of depressive symptoms, perceived stress, and loneliness were higher among undergraduate/bachelor students than doctoral students. Almost all participants (97.3%) reported being fully vaccinated against COVID-19. Multiple regression analyses showed that being single, having an income decreased during the pandemic, having a previous mental illness, having a chronic somatic condition, not finding positive aspects in the pandemic, lower self-efficacy, lower social support, lower resilience, and higher experienced loneliness were significantly associated with higher levels of depression.ConclusionsThe study showed high levels of depressive symptoms and suicidal ideation among Federal University of Parana students. Therefore, health care providers and universities need to recognize and address mental health issues; psychosocial policies must be enhanced to mitigate the impact of the pandemic on students' mental health and wellbeing.

BackgroundDespite traumatic experiences and persistent psychosocial stressors, many refugees and migrants display resilience and strength in the midst and aftermath of hardships. 'Value Based Counseling' (VBC), a low-threshold, short-term and culturally sensitive psychological intervention avoids the stigmatization and pathologization of mental health problems, and, in line with latest research calling for a rethink of mental health care for migrants and refugees, focusses on the resilience and resources of clients.MethodThis pragmatic, assessor-blinded randomized controlled trial employed a pre-post control group design to assess the effectiveness of VBC in the development of psychological assets. Refugees and migrants aged 18 or above were randomly assigned to either VBC sessions delivered by counselors matched with their clients according to gender and native language, or to a waiting list.ResultsPer protocol and intention-to-treat (ITT) analyses revealed that compared with participants in the waiting-list group (n = 50), the VBC group (n = 53) experienced a greater improvement in resilience (adjusted difference 11.59, 95% CI 8.35 to 14.84, effect size .49, p < .001) and perspective taking (adjusted difference 3.98, 95% CI 2.12 to 5.84, effect size .39, p < .001) after four sessions on average. These positive results remained consistent until a 3-month follow-up assessment within the VBC group.ConclusionVBC with a focus on personal resources in the Here and Now, and with a culturally sensitive approach, helps clients exposed to persistent psychosocial stressors to develop strength and to increase agency over their lives.

IntroductionInterim PET (iPET) assessment is important for response adaptation in Hodgkin lymphoma (HL). The current standard for iPET assessment is the Deauville score (DS). The aim of our study was to evaluate the causes of interobserver variability in assigning the DS for iPET in HL patients and to make suggestions for improvement.MethodsAll evaluable iPET scans from the RAPID study were re-read by two nuclear physicians, blinded to the results and patient outcomes in the RAPID trial. The iPET scans were assessed visually according to the DS and, thereafter, quantified using the qPET method. All discrepancies of more than one DS level were re-evaluated by both readers to find the reason for the discordant result.ResultsIn 249/441 iPET scans (56%) a concordant visual DS result was achieved. A "minor discrepancy" of one DS level occurred in 144 scans (33%) and a "major discrepancy" of more than one DS level in 48 scans (11%). The main causes for major discrepancies were 1) different interpretation of PET-positive lymph nodes-malignant vs. inflammatory; 2) lesions missed by one reader and 3) different assessment of lesions in activated brown fat tissue. In 51% of the minor discrepancy scans with residual lymphoma uptake, additional quantification resulted in a concordant quantitative DS result.ConclusionDiscordant visual DS assessment occurred in 44% of all iPET scans. The main reason for major discrepancies was the different interpretation of PET positive lymph nodes as malignant or inflammatory. Disagreements in evaluation of the hottest residual lymphoma lesion can be solved by the use of semi-quantitative assessment.

BackgroundThe international collaboration study PRICOV-19 -Primary Health Care in times of COVID-19 aims to assess the impact of the COVID-19 pandemic on the organisation of primary health care. The German part focuses on the subjective perceptions of general practitioners on primary health care and the impact of political measures during the second wave of the COVID-19 pandemic. Within this survey, the "open text field" of the questionnaire was utilised remarkably frequently and extensively by the respondents. It became clear that the content that was named needed to be analysed in an exploratory manner. Accordingly, this paper addresses the following question: What preoccupies general practitioners in Germany during COVID-19 that we have not yet asked them enough?MethodsThe data collection took place throughout Germany from 01.02.2021 to 28.02.2021with a quantitative online questionnaire consisting of 53 items arranged across six topics as well as an "open text field" for further comments. The questionnaire's open text field was analysed following the premises of the qualitative content analysis.ResultsThe topics discussed by the respondents were: insufficient support from health policies, not being prioritised and involved in the vaccination strategy, feeling insufficient prepared, that infrastructural changes and financial concerns threatened the practice, and perceiving the own role as important, as well as that health policies affected the wellbeing of the respondents. One of the main points was the way general practitioners were not sufficiently acknowledged for their contribution to ensuring high-quality care during the pandemic.DiscussionGerman general practitioners perceived their work and role as highly relevant during the COVID-19 pandemic. In controversy with their perception, they described political conditions in which they were the ones who contributed significantly to the fight against the pandemic but were not given enough recognition.

Background The COVID-19 pandemic was associated with far-reaching changes all over the world. Health care systems were and are also affected. Little is known about the impact of these changes and the duration of the pandemic on people with mental disorders. The aim of this longitudinal follow-up study was to investigate the mental health status, medical care provision, and attitudes towards the pandemic of these people at the end of the second pandemic lockdown in Germany in 2021, and to compare these findings with the results of 2020. Methods People with mental disorders currently receiving treatment in the psychiatric outpatient department of the University Hospital Leipzig, Germany, were asked about depressive symptoms (PHQ-9), self-reported medical care provision, attitudes and social and emotional aspects of the pandemic (social support [ESSI], perceived stress [PSS-4], loneliness [UCLA-3-LS], and resilience [BRS]) using structured telephone interviews. Results In total, N = 75 participants who had already participated in the first survey in 2020 took part in the follow-up telephone interviews. The most frequent clinician-rated diagnoses were attention deficit disorder/attention deficit hyperactivity disorder (n = 21; 28.0%) and obsessive-compulsive disorder (n = 16; 21.3%). In comparison to 2020, a significantly higher proportion of participants reported no problems in receiving medical care provision. Compared to the previous year, the resilience of the participants had significantly decreased. Depressive symptoms, social support, perceived stress, and loneliness remained stable. Significantly more participants felt restricted by the pandemic-related government measures in 2021 than in 2020. Conclusions This study highlights the importance for continued efforts to maintain stable medical care provision for people with mental disorders during the COVID-19 pandemic, as except for a decrease in resilience, mental health status remained stable. Nonetheless there is still a need for continued treatment to stabilise and improve this status.

IntroductionThe automatic classification of lymphoma lesions in PET is a main topic of ongoing research. An automatic algorithm would enable the swift evaluation of PET parameters, like texture and heterogeneity markers, concerning their prognostic value for patients outcome in large datasets. Moreover, the determination of the metabolic tumor volume would be facilitated. The aim of our study was the development and evaluation of an automatic algorithm for segmentation and classification of lymphoma lesions in PET.MethodsPre-treatment PET scans from 60 Hodgkin lymphoma patients from the EuroNet-PHL-C1 trial were evaluated. A watershed algorithm was used for segmentation. For standardization of the scan length, an automatic cropping algorithm was developed. All segmented volumes were manually classified into one of 14 categories. The random forest method and a nested cross-validation was used for automatic classification and evaluation.ResultsOverall, 853 volumes were segmented and classified. 203/246 tumor lesions and 554/607 non-tumor volumes were classified correctly by the automatic algorithm, corresponding to a sensitivity, a specificity, a positive and a negative predictive value of 83%, 91%, 79% and 93%. In 44/60 (73%) patients, all tumor lesions were correctly classified. In ten out of the 16 patients with misclassified tumor lesions, only one false-negative tumor lesion occurred. The automatic classification of focal gastrointestinal uptake, brown fat tissue and composed volumes consisting of more than one tissue was challenging.ConclusionOur algorithm, trained on a small number of patients and on PET information only, showed a good performance and is suitable for automatic lymphoma classification.

The herpes simplex virus 1 (HSV-1) virion host shut-off (vhs) protein cleaves both cellular and viral mRNAs by a translation-initiation-dependent mechanism, which should spare circular RNAs (circRNAs). Here, we show that vhs-mediated degradation of linear mRNAs leads to an enrichment of circRNAs relative to linear mRNAs during HSV-1 infection. This was also observed in influenza A virus (IAV) infection, likely due to degradation of linear host mRNAs mediated by the IAV PA-X protein and cap-snatching RNA-dependent RNA polymerase. For most circRNAs, enrichment was not due to increased circRNA synthesis but due to a general loss of linear RNAs. In contrast, biogenesis of a circRNA originating from the long isoform (NEAT1_2) of the nuclear paraspeckle assembly transcript 1 (NEAT1) was induced both in HSV-1 infection–in a vhs-independent manner–and in IAV infection. This was associated with induction of novel linear splicing of NEAT1_2 both within and downstream of the circRNA. NEAT1_2 forms a scaffold for paraspeckles, nuclear bodies located in the interchromatin space, must likely remain unspliced for paraspeckle assembly and is up-regulated in HSV-1 and IAV infection. We show that NEAT1_2 splicing and up-regulation can be induced by ectopic co-expression of the HSV-1 immediate-early proteins ICP22 and ICP27, potentially linking increased expression and splicing of NEAT1_2. To identify other conditions with NEAT1_2 splicing, we performed a large-scale screen of published RNA-seq data. This uncovered both induction of NEAT1_2 splicing and poly(A) read-through similar to HSV-1 and IAV infection in cancer cells upon inhibition or knockdown of CDK7 or the MED1 subunit of the Mediator complex phosphorylated by CDK7. In summary, our study reveals induction of novel circular and linear NEAT1_2 splicing isoforms as a common characteristic of HSV-1 and IAV infection and highlights a potential role of CDK7 in HSV-1 or IAV infection.

BackgroundCerebral arteriovenous malformations (AVMs) are challenging lesions, often requiring multimodal interventions; however, data on the efficacy of stereotactic radiosurgery for cerebral AVMs are limited. This study aimed to evaluate the clinical and radiographic results following robotic radiosurgery, alone or in combination with endovascular treatment, and to investigate factors associated with obliteration and complications in patients with AVM.MethodsWe retrospectively analyzed the clinical and imaging characteristics of 123 patients with AVMs of all Spetzler-Martin grades treated at two institutions by robotic radiosurgery in single-fraction doses (CyberKnife). Embolization was performed before radiosurgery in a subset of patients to attempt to downgrade the lesions. Factors associated with AVM obliteration and complications (toxicity) were identified via univariate and multivariate analyses.ResultsThe median follow-up time was 48.1 months (range, 3.6-123 months). Five patients were lost to follow-up. The obliteration rate in the 59 patients with a follow-up period exceeding four years was 72.8%. Complete obliteration and partial remission were achieved in 67 (56.8%) and 31 (26.3%) cases, respectively, whereas no change was observed in 20 cases (17.8%). Embolization was performed in 54/123 cases (43.9%). Complete and partial obliteration were achieved in 29 (55.7%) and 14 (26.9%) embolized patients, respectively. In the multivariate analysis, the factors associated with obliteration were age (p = .018) and the Spetzler-Martin grade (p = .041). Treatment-induced toxicity (radiation necrosis and/or edema) was observed in 15 cases (12.7%), rebleeding occurred in three cases (2.5%), and the rate of mortality associated with rebleeding was 1.7%.ConclusionsCyberKnife radiosurgery is a valid approach for treating AVMs of all Spetzler-Martin-grades, with satisfactory obliteration rates, low toxicity, and a relatively rare incidence of rebleeding.

BackgroundThe role of non-invasive ventilation (NIV) in severe COVID-19 remains a matter of debate. Therefore, the utilization and outcome of NIV in COVID-19 in an unbiased cohort was determined.AimThe aim was to provide a detailed account of hospitalized COVID-19 patients requiring non-invasive ventilation during their hospital stay. Furthermore, differences of patients treated with NIV between the first and second wave are explored.MethodsConfirmed COVID-19 cases of claims data of the Local Health Care Funds with non-invasive and/or invasive mechanical ventilation (MV) in the spring and autumn pandemic period in 2020 were comparable analysed.ResultsNationwide cohort of 17.023 cases (median/IQR age 71/61-80 years, 64% male) 7235 (42.5%) patients primarily received IMV without NIV, 4469 (26.3%) patients received NIV without subsequent intubation, and 3472 (20.4%) patients had NIV failure (NIV-F), defined by subsequent endotracheal intubation. The proportion of patients who received invasive MV decreased from 75% to 37% during the second period. Accordingly, the proportion of patients with NIV exclusively increased from 9% to 30%, and those failing NIV increased from 9% to 23%. Median length of hospital stay decreased from 26 to 21 days, and duration of MV decreased from 11.9 to 7.3 days. The NIV failure rate decreased from 49% to 43%. Overall mortality increased from 51% versus 54%. Mortality was 44% with NIV-only, 54% with IMV and 66% with NIV-F with mortality rates steadily increasing from 62% in early NIV-F (day 1) to 72% in late NIV-F (>4 days).ConclusionsUtilization of NIV rapidly increased during the autumn period, which was associated with a reduced duration of MV, but not with overall mortality. High NIV-F rates are associated with increased mortality, particularly in late NIV-F.

Gait analysis using foot-worn inertial measurement units has proven to be a reliable tool to diagnose and monitor many neurological and musculoskeletal indications. However, only few studies have investigated the robustness of such systems to changes in the sensor attachment and no consensus for suitable sensor positions exists in the research community. Specifically for unsupervised real-world measurements, understanding how the reliability of the monitoring system changes when the sensor is attached differently is from high importance. In these scenarios, placement variations are expected because of user error or personal preferences. In this manuscript, we present the largest study to date comparing different sensor positions and attachments. We recorded 9000 strides with motion-capture reference from 14 healthy participants with six synchronized sensors attached at each foot. Spatial gait parameters were calculated using a double-integration method and compared to the reference system. The results indicate that relevant differences in the accuracy of the stride length exists between the sensor positions. While the average error over multiple strides is comparable, single stride errors and variability parameters differ greatly. We further present a physics model and an analysis of the raw sensor data to understand the origin of the observed differences. This analysis indicates that a variety of attachment parameters can influence the systems' performance. While this is only the starting point to understand and mitigate these types of errors, we conclude that sensor systems and algorithms must be reevaluated when the sensor position or attachment changes.

This paper describes the conceptual design of a virtual reality-based stress management training tool and evaluation of the initial prototype in a pilot efficacy study. Performance Edge virtual-reality (VR) was co-developed with the Australian Defence Force (ADF) to address the need for practical stress management training for ADF personnel. The VR application is biofeedback-enabled and contains key stress management techniques derived from acceptance and commitment and cognitive behavioural therapy in a modular framework. End-user-provided feedback on usability, design, and user experience was positive, and particularly complimentary of the respiratory biofeedback functionality. Training of controlled breathing delivered across 3 sessions increased participants' self-reported use of breath control in everyday life and progressively improved controlled breathing skills (objectively assessed as a reduction in breathing rate and variability). Thus the data show that a biofeedback-enabled controlled breathing protocol delivered through Performance Edge VR can produce both behaviour change and objective improvement in breathing metrics. These results confirm the validity of Performance Edge VR platform, and its Controlled Breathing module, as a novel approach to tailoring VR-based applications to train stress management skills in a workplace setting.

BackgroundGeneral practitioners (GPs) play a significant role in depression care. Recognition of depression is crucial for adequate treatment but is impeded by a high portion of depressed patients only reporting physical symptoms to their GP. Among the many reasons for this phenomenon is mental health stigma. We investigated how patients with depression differed from patients without depression regarding the types and number of complaints presented to their GP, as well as their depression stigma. For the subgroup of patients with depression, potential associations between perceived depression stigma and number and types of presented complaints were investigated to see if these might reflect the patient's intention to conceal mental health symptoms due to fear of being stigmatized by others. Further, we investigated if perceived depression stigma is related to depression treatment.MethodsData on depressive symptoms (assessed by the Depression Screening Questionnaire; DSQ), depression stigma (assessed by the Depressions Stigma Scale; DSS), type of complaints reported to the GP and treatment-related factors were collected from 3,563 unselected primary care patients of 253 GPs in a cross-sectional epidemiological study ("VERA study") in six different German regions. Data of a total of 3,069 patients was used for analysis on complaints reported to the GP (subsample of the VERA study), and for 2,682 out of 3,069 patients data on a stigma questionnaire was available.ResultsNearly half of the primary care patients with depression (42.2%) reported only physical complaints to their GP. Compared to patients without a depression diagnosis, patients with depression reported twice as many complaints to their GP with a mean of 2.02 (1.33) vs. 1.2 (0.69), including a more frequent combination of physical and mental symptoms (28.8% vs. 3.5%). Patients with depression showed higher total stigma compared to patients without depression, Mdn = 48 (IQR 40-54) vs. Mdn = 46.3 (IQR 29-53), due to higher perceived stigma, Mdn = 27 (IQR 21-32) vs. Mdn = 25.9 (IQR 20-29). Perceived stigma was associated with male gender (beta -.14, p = .005) and a lack of pharmacological treatment (beta -.14, p = .021) in patients with a depression diagnosis.ConclusionThe number of complaints presented to the GP might function as a marker to actively explore depression in primary care patients, in particular when both physical and mental symptoms are reported. Perceived depression stigma should also be addressed especially in male patients. Further research should clarify the role of perceived stigma as a potential inhibitor of pharmacological treatment of depression in primary care.

BackgroundPrimary care consultation is significantly influenced by communication between the General Practitioner (GP) and their patients. Hypothesising that patient satisfaction can be tested based on an expectation-experience comparison, the aim of this article is to discuss the influence of communication on patient satisfaction.MethodsA standardised questionnaire was developed striving for a universal primary care survey tool that focuses on patient satisfaction in the context of patient-centred-communication. The sample consisted of 14 German GPs with 80 patients each (n = 1120). Due to the inclusion in an overarching cluster-randomised-study (CRT), the medical practices to be examined were divided into intervention and control groups. The intervention was developed as a reflective training on patient-centred communication.ResultsThe results in the present sample show no correlation between patient-centred-communication and patient satisfaction. There are also no significant differences between the intervention and control group.DiscussionThe results raise the question to what extent patient satisfaction can be shaped significantly through patient-centred-communication. The presented project represents part of the basic research in general medical care research and contributes to the transparent processing of theoretical assumptions. With the results described here, communication models with a focus on patient centredness can be evaluated with regard to their practical relevance and transferability.

Digital mobility assessment using wearable sensor systems has the potential to capture walking performance in a patient's natural environment. It enables monitoring of health status and disease progression and evaluation of interventions in real-world situations. In contrast to laboratory settings, real-world walking occurs in non-conventional environments and under unconstrained and uncontrolled conditions. Despite the general understanding, there is a lack of agreed definitions about what constitutes real-world walking, impeding the comparison and interpretation of the acquired data across systems and studies. The goal of this study was to obtain expert-based consensus on specific aspects of real-world walking and to provide respective definitions in a common terminological framework. An adapted Delphi method was used to obtain agreed definitions related to real-world walking. In an online survey, 162 participants from a panel of academic, clinical and industrial experts with experience in the field of gait analysis were asked for agreement on previously specified definitions. Descriptive statistics was used to evaluate whether consent (> 75% agreement as defined a priori) was reached. Of 162 experts invited to participate, 51 completed all rounds (31.5% response rate). We obtained consensus on all definitions ("Walking" > 90%, "Purposeful" > 75%, "Real-world" > 90%, "Walking bout" > 80%, "Walking speed" > 75%, "Turning" > 90% agreement) after two rounds. The identification of a consented set of real-world walking definitions has important implications for the development of assessment and analysis protocols, as well as for the reporting and comparison of digital mobility outcomes across studies and systems. The definitions will serve as a common framework for implementing digital and mobile technologies for gait assessment and are an important link for the transition from supervised to unsupervised gait assessment.

BackgroundAlthough obsessive-compulsive disorder (OCD) is one of the most common mental disorders, it takes up to 17 years for patients with OCD to receive adequate therapy. According to existing outdated literature, this study aimed to investigate the current duration between symptom onset and diagnosis and between diagnosis and the beginning of therapy separately.MethodsIn a cross-sectional study, N = 100 patients diagnosed with OCD undergoing treatment in a psychiatric outpatient department were assessed, using self-report questionnaires on sociodemographic and clinical variables. Based on self-reported information, the durations between age at symptom onset and age at diagnosis, and between age at diagnosis and beginning of therapy were calculated. To investigate associated factors, two subgroups of patients, one with a short duration between symptom onset and diagnosis < 7 years, and another with a long duration between symptom onset and diagnosis ≥ 7 years, respectively, were compared.Results and conclusionPatients reported first symptoms of OCD at a mean age of 18.72 years. The mean duration between age at symptom onset and age at diagnosis was 12.78 years and the mean duration between age at diagnosis and the beginning of therapy was 1.45 years. Subgroup comparison indicated that patients with a short duration between symptom onset and diagnosis were significantly younger than patients with a long duration. However, patients with a short duration between symptom onset and diagnosis were at an older age when they reported first symptoms of OCD. Further, they showed less severe symptoms of OCD, higher functioning levels, and less self-stigmatization than patients with a long duration. It can be concluded that the duration until patients with OCD are diagnosed correctly and receive adequate treatment is still very long. Therefore, the duration between symptom onset and diagnosis should be shortened. Further, the duration between diagnosis and the beginning of therapy could be a good additional approach to reduce the overall duration of untreated disorder.

BackgroundWeb-based treatments and online self-management interventions extend the range of therapeutic supply. Since the number of online self-management interventions is steadily increasing, we aimed to examine, how web-based services currently influence mental health care, asking about previous internet use and future interests of patients with mental disorders.MethodsWe consulted patients (n = 400) from all services of the Department of Psychiatry and Psychotherapy of the University of Leipzig using a 28-item questionnaire. Overall, 301 questionnaires could be used for analysis. The data were analysed by means of descriptive statistics and group comparisons.ResultsThe majority of patients (98.3%) were using the internet. Data revealed younger patients were searching for information on diseases (p < .001; M = 35.7 ±13.2), psychiatrists (p < .001; M = 34.6 ±11.6) and exchange with other patients (p < .001; M = 32 ±10.6) more often than older patients. We also found the internet was consulted more often regarding the search for information (p = .011; M = 58.3 ±10.9) and psychiatrists (p < .001; M = 35.7 ±13.2) the lower the patients' level of functioning was. While only a small proportion (10.1%) of the sample had used online self-management interventions before, there is a far greater number (46.1%) who stated an interest to use online self-management interventions in the future. This interest was greater in patients who were younger (p < .001; M = 33.8 ±13.2) had a higher education level (p = .003; university degree = 59.2%, high school degree = 52.3%; mandatory school degree: 34.8%).ConclusionsWhile only a small percentage of patients uses online self-management interventions, there is a far greater interest to include them into the treatment. Further research has to investigate how the integration of web-based services into the whole treatment process can be optimized. In addition, standardized diagnostic methods have to be found to evaluate the needs and experiences of patients.

AimqPET is a quantitative method used to assess FDG-PET response in lymphoma. qPET was developed using 898 scans from children with Hodgkin Lymphoma (HL) in the EuroNet-PHL-C1 (C1) trial. The aim of this study was to determine if qPET could be applied as an alternative response method in adults in the RAPID trial.MethodsPET-CT scans performed after 3 cycles of ABVD in RAPID were re-evaluated by an independent reader, blinded to PET results and outcome in RAPID. All initially involved regions were assessed visually and by qPET. The distribution of qPET measurements was compared for RAPID and C1 patients. Previously published qPET thresholds corresponding to visual DS (vDS) of 1-5 in C1 were used to derive quantitative DS (qDS) for RAPID patients.ResultsPET-CT scans were available for 450 patients from RAPID. vDS were 1 (171 scans), 2 (153 scans), 3 (72 scans), 4 (31 scans) and 5 (23 scans) respectively. The distribution of qPET values was similar to C1 patients, with a unimodal 'normal' distribution and a long tail to the right, suggestive of favorable response in the majority and less favorable response in the minority with outlying values. qPET thresholds from C1 applied in RAPID patients gave 86% concordance for vDS and qDS. There was 97% concordance for complete metabolic response (CMR; DS 1-3) vs. no-CMR using the Lugano classification.ConclusionqPET which was developed in pediatric patients receiving more intensive OEPA chemotherapy, was a suitable quantitative method for assessing response in adult patients treated with ABVD in a response-adapted setting in the RAPID trial.

BackgroundAndrogen deprivation therapy (ADT) remains the standard therapy for patients with oligometastatic prostate cancer (OMPC). Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT)-based stereotactic body radiotherapy (SBRT) is emerging as an alternative option to postpone starting ADT and its associated side effects including the development of drug resistance. The aim of this study was to determine progression free-survival (PFS) and treatment failure free-survival (TFFS) after PSMA-PET/CT-based SBRT in OMPC patients. The efficacy and safety of single fraction radiosurgery (SFRS) and ADT delay were investigated.MethodsPatients with ≤5 metastases from OMPC, with/without ADT treated with PSMA-PET/CT-based SBRT were retrospectively analyzed. PFS and TFFS were primary endpoints. Secondary endpoints were local control (LC), overall survival (OS) and ADT-free survival (ADTFS).ResultsFifty patients with a total of 75 metastases detected by PSMA-PET/CT were analyzed. At the time of SBRT, 70% of patients were castration-sensitive. Overall, 80% of metastases were treated with SFRS (median dose 20 Gy, range: 16-25). After median follow-up of 34 months (range: 5-70) median PFS and TFFS were 12 months (range: 2-63) and 14 months (range: 2-70), respectively. Thirty-two (64%) patients had repeat oligometastatic disease. Twenty-four (48%) patients with progression underwent second SBRT course. Two-year LC after SFRS was 96%. Grade 1 and 2 toxicity occurred in 3 (6%) and 1 (2%) patients, respectively. ADTFS and OS rates at 2-years were 60.5% and 100%, respectively. In multivariate analysis, TFFS significantly improved in patients with time to first metastasis (TTM) >36 months (p = 0.01) and PSA before SBRT ≤1 ng/ml (p = 0.03).ConclusionFor patients with OMPC, SBRT might be used as an alternative to ADT. This way, the start/escalation of palliative ADT and its side effects can be deferred. Metastases treated with PSMA-PET/CT-based SFRS reached excellent LC with minimal toxicity. Low PSA levels and longer TTM predict elongated TFFS.

Bryophytes have been proposed as ideal indicators of ecosystem change, because they are important components of forest integrity, and considerable research indicates that some groups are sensitive to the changes associated with specific human disturbances. Bryophyte richness and abundance have been found to vary predictably along elevational gradients, but the role of human impacts on these distribution patterns remains unclear. The aim of this study is to explore the impact of human disturbance on the elevational patterns of bryophyte diversity, along an elevational gradient. Along the gradient we collected three datasets in the following sites: preserved (P), forest track roadsides (R) and disturbed by agriculture/silviculture practices (D). Two survey plots of 100 m2 were established at every 200 m elevational step for each sites P, R, D, and in each plot bryophytes were sampled in a stratified manner. At each plot we recorded all species on available substrates and estimated their percentage cover. Our results showed that species number did not differ among studied sites, but that species diversity pattern differs among the three gradient types and species life strategy composition along the elevational gradient showed a clear response to the disturbance of mature communities. We conclude that human impact has strongly changed the elevational pattern of diversity, and that these changes vary depending on the ecological and taxonomical group considered.

The high temporal and intensity resolution of modern accelerometers gives the opportunity of detecting even tiny body movements via motion-based sensors. In this paper, we demonstrate and evaluate an approach to identify pulse waves and heartbeats from acceleration data of the human wrist during sleep. Specifically, we have recorded simultaneously full-night polysomnography and 3d wrist actigraphy data of 363 subjects during one night in a clinical sleep laboratory. The acceleration data was segmented and cleaned, excluding body movements and separating episodes with different sleep positions. Then, we applied a bandpass filter and a Hilbert transform to uncover the pulse wave signal, which worked well for an average duration of 1.7 h per subject. We found that 81 percent of the detected pulse wave intervals could be correctly associated with the R peak intervals from independently recorded ECGs and obtained a median Pearson cross-correlation of 0.94. While the low-frequency components of both signals were practically identical, the high-frequency component of the pulse wave interval time series was increased, indicating a respiratory modulation of pulse transit times, probably as an additional contribution to respiratory sinus arrhythmia. Our approach could be used to obtain long-term nocturnal heartbeat interval time series and pulse wave signals from wrist-worn accelerometers without the need of recording ECG or photoplethysmography. This is particularly useful for an ambulatory monitoring of high-risk cardiac patients as well as for assessing cardiac dynamics in large cohort studies solely with accelerometer devices that are already used for activity tracking and sleep pattern analysis.

BACKGROUND:In South Africa, access to second-trimester abortion services, which are generally performed using medical induction with misoprostol alone, is challenging for many women. We aimed to estimate the costs and cost effectiveness of providing three safe second-trimester abortion services (dilation and evacuation (D&E)), medical induction with mifepristone and misoprostol (MI-combined), or medical induction with misoprostol alone (MI-misoprostol)) in Western Cape Province, South Africa to aid policymakers with planning for service provision in South Africa and similar settings. METHODS:We derived clinical outcomes data for this economic evaluation from two previously conducted clinical studies. In 2013-2014, we collected cost data from three public hospitals where the studies took place. We collected cost data from the health service perspective through micro-costing activities, including discussions with site staff. We used decision tree analysis to estimate average costs per patient interaction (e.g. first visit, procedure visit, etc.), the total average cost per procedure, and cost-effectiveness in terms of the cost per complete abortion. We discounted equipment costs at 3%, and present the results in 2015 US dollars. RESULTS:D&E services were the least costly and the most cost-effective at $91.17 per complete abortion. MI-combined was also less costly and more cost-effective (at $298.03 per complete abortion) than MI-misoprostol (at $375.31 per complete abortion), in part due to a shortened inpatient stay. However, an overlap in the plausible cost ranges for the two medical procedures suggests that the two may have equivalent costs in some circumstances. CONCLUSION:D&E was most cost-effective in this analysis. However, due to resistance from health care providers and other barriers, these services are not widely available and scale-up is challenging. Given South Africa's reliance on medical induction, switching to the combined regimen could result in greater access to second-trimester services due to shorter inpatient stays without increasing costs.

To determine the spectrum of infections with multidrug-resistant Gram-negative bacteria (MDR-GNB) and the clinical impact of the newly available betalactam/betalactamase inhibitor combinations ceftolozane/tazobactam and ceftazidime/avibactam in a German academic tertiary care center.Retrospective analysis.Between September 1, 2015 and August 31, 2016, 119 individual patients (0.22% of all hospital admissions) were colonized or infected with carbapenem-resistant MDR-GNB. The species distribution was Pseudomonas aeruginosa, n = 66; Enterobacteriaceae spp., n = 44; and Acinetobacter baumannii, n = 18. In 9 patients, carbapenem-resistant isolates belonging to more than one species were detected. Infection was diagnosed in 50 patients (total: 42.0%; nosocomial pneumonia: n = 23, 19.3%; bloodstream infection: n = 11, 9.2%). Antimicrobial treatment with broad-spectrum antibiotics prior to detection of a carbapenem-resistant isolate was documented in 105 patients (88.2%, prior administration of carbapenems: 62.2%). Nosocomial transmission was documented in 29 patients (24.4%). In 26 patients (21.8%), at least one carbapenem-susceptible, third-generation cephalosporin non-susceptible isolate was documented prior to detection of a carbapenem-resistant isolate belonging to the same species (median 38 days, IQR 23-78). 12 patients (10.1%) had documented previous contact to the healthcare system in a country with high burden of carbapenemase-producing strains. Genes encoding carbapenemases were detected in 60/102 patient isolates (58.8%; VIM-2, n = 25; OXA-48, n = 21; OXA-23-like, n = 10). Susceptibility to colistin was 94.3%. Ceftolozane/tazobactam and ceftazidime/avibactam were administered to 3 and 5 patients, respectively (in-hospital mortality: 66% and 100%). Development of drug-resistance under therapy was observed for both antimicrobials.i) The major predisposing factors for acquisition of carbapenem-resistant MDR-GNB were selective pressure due to preceding antimicrobial therapy and nosocomial transmission. ii) Colistin remains the backbone of antimicrobial chemotherapy for infections caused by carbapenem-resistant MDR-GNB. iii) Novel β-lactam/β-lactamase inhibitor combinations are of limited usefulness in our setting because of the high prevalence of Ambler class B carbapenemases and the emergence of nonsusceptibility under therapy.

INTRODUCTION:Cardiac surgery with the use of cardiopulmonary bypass is known to induce distinct metabolic changes. Respective changes in acid-base status including increased systemic lactate levels were previously related to clinical outcomes, but data remain controversial. Therefore, we aim to investigate the relevance of lactate and base excess (BE) levels on ICU-mortality in patients admitted to the ICU after cardiac surgery. MATERIALS AND METHODS:Perioperative data of patients treated in a tertiary care academic center admitted to the ICU after on-pump surgery were analyzed in a retrospective fashion. Receiver operation characteristic (ROC) curves were constructed for admission lactate-levels and BE with calculation of optimal cut-off values to predict ICU mortality. Univariate followed by multivariate regression models were constructed to identify potential outcome-relevant indices. RESULTS:Data from 1,058 patients were included in the analysis. Area under the curves for prediction of ICU mortality were 0.79 for lactate levels at ICU admission (sensitivity 61.9%/ specificity 87.5%; optimal cut-off level 3.9mmol/l), and 0.7 for BE (sensitivity 52.4%/ specificity 93.8%, optimal cut-off level -6.7), respectively. Multivariate regression identified BE < -6.7 as the single metabolic predictor of ICU-mortality (HR 4.78, 95%-CI 1.4-16.33, p = 0.01). Explorative subgroup analyses revealed that the combination of lactate ≤3.9mmol/l and BE ≤ -6.7 has stronger impact on mortality than a combination of lactate of >3.9mmol/l and BE > -6.7 (HR 2.56, 95%-CI 0.18-37.17). CONCLUSIONS:At ICU-admission, severely reduced BE appears superior to hyperlactatemia with regard to prediction of ICU-mortality in patients after cardiac surgery.

[This corrects the article DOI: 10.1371/journal.pone.0164863.].

Pancreatic cancer (PC) remains one of the most challenging solid tumors to treat with a high unmet medical need as patients poorly respond to standard-of-care-therapies. Prominent desmoplastic reaction involving cancer-associated fibroblasts (CAFs) and the immune cells in the tumor microenvironment (TME) and their cross-talk play a significant role in tumor immune escape and progression. To identify the key cellular mechanisms induce an immunosuppressive tumor microenvironment, we established 3D co-culture model with pancreatic cancer cells, CAFs and monocytes. Using this model, we analyzed the influence of tumor cells and fibroblasts on monocytes and their immune suppressive phenotype. Phenotypic characterization of the monocytes after 3D co-culture with tumor/fibroblast spheroids was performed by analyzing the expression of defined cell surface markers and soluble factors. Functionality of these monocytes and their ability to influence T cell phenotype and proliferation was investigated. 3D co-culture of monocytes with pancreatic cancer cells and fibroblasts induced the production of immunosuppressive cytokines which are known to promote polarization of M2 like macrophages and myeloid derived suppressive cells (MDSCs). These co-culture spheroid polarized monocyte derived macrophages (MDMs) were poorly differentiated and had an M2 phenotype. The immunosuppressive function of these co-culture spheroids polarized MDMs was demonstrated by their ability to inhibit CD4+ and CD8+ T cell activation and proliferation in vitro, which we could partially reverse by 3D co-culture spheroid treatment with therapeutic molecules that are able to re-activated spheroid polarized MDMs or block immune suppressive factors such as Arginase-I.

Sepsis is defined as a dysregulated immune response to infection. Impaired immune response in sepsis, often described as endotoxin tolerance, is characterized by unresponsiveness of monocytes on lipopolysaccharide (LPS) stimulation to release tumor necrosis factor α (TNFα). Furthermore, decreased monocyte surface protein expression of human leucocyte antigen DR (HLA-DR) is a marker for changes of the innate immune response during sepsis. Quantitative polymerase chain reaction (qPCR) and flow-cytometry (FACS) have been used to measure protein or gene expression of HLA-DR. We aimed to determine whether changes in mRNA expression of HLA-DR are associated with impaired TNFα response in human sepsis.Surface protein together with mRNA expression of HLA-DR were measured by FACS and qPCR in a cohort of 9 sepsis patients and compared to 10 pre-operative control patients in a prospective study. In addition, 20 patients with post-surgical inflammation, 20 patients with sepsis or septic shock were included and TNFα was determined following ex vivo stimulation of whole blood with 500 pg/mL LPS. Total RNA was prepared from whole blood and subjected to qPCR analysis for expression analysis of HLA-DR alpha (HLA-DRA) to correlate TNFα response with HLA-DRA expression.Patients with sepsis presented higher numbers of monocytes in peripheral blood (P

Conventional magnetic resonance imaging (MRI) of patients with hemolytic uremic syndrome (HUS) and neurological symptoms performed during an epidemic outbreak of Escherichia coli O104:H4 in Northern Europe has previously shown pathological changes in only approximately 50% of patients. In contrast, susceptibility-weighted imaging (SWI) revealed a loss of venous contrast in a large number of patients. We hypothesized that this observation may be due to an increase in cerebral blood flow (CBF) and aimed to identify a plausible cause.Baseline 1.5T MRI scans of 36 patients (female, 26; male, 10; mean age, 38.2±19.3 years) were evaluated. Venous contrast was rated on standard SWI minimum intensity projections. A prototype four-dimensional (time resolved) magnetic resonance angiography (4D MRA) assessed cerebral hemodynamics by global time-to-peak (TTP), as a surrogate marker for CBF. Clinical parameters studied were hemoglobin, hematocrit, creatinine, urea levels, blood pressure, heart rate, and end-tidal CO2.SWI venous contrast was abnormally low in 33 of 36 patients. TTP ranged from 3.7 to 10.2 frames (mean, 7.9 ± 1.4). Hemoglobin at the time of MRI (n = 35) was decreased in all patients (range, 5.0 to 12.6 g/dL; mean, 8.2 ± 1.4); hematocrit (n = 33) was abnormally low in all but a single patient (range, 14.3 to 37.2%; mean, 23.7 ± 4.2). Creatinine was abnormally high in 30 of 36 patients (83%) (range, 0.8 to 9.7; mean, 3.7 ± 2.2). SWI venous contrast correlated significantly with hemoglobin (r = 0.52, P = 0.0015), hematocrit (r = 0.65, P < 0.001), and TTP (r = 0.35, P = 0.036). No correlation of SWI with blood pressure, heart rate, end-tidal CO2, creatinine, and urea level was observed. Findings suggest that the loss of venous contrast is related to an increase in CBF secondary to severe anemia related to HUS. SWI contrast of patients with pathological conventional MRI findings was significantly lower compared to patients with normal MRI (mean SWI score, 1.41 and 2.05, respectively; P = 0.04). In patients with abnormal conventional MRI, mean TTP (7.45), mean hemoglobin (7.65), and mean hematocrit (22.0) were lower compared to patients with normal conventional MRI scans (mean TTP = 8.28, mean hemoglobin = 8.63, mean hematocrit = 25.23).In contrast to conventional MRI, almost all patients showed pathological changes in cerebral hemodynamics assessed by SWI and 4D MRA. Loss of venous contrast on SWI is most likely the result of an increase in CBF and may be related to the acute onset of anemia. Future studies will be needed to assess a possible therapeutic effect of blood transfusions in patients with HUS and neurological symptoms.

PURPOSE:The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised. METHODS:Five international expert readers scored 100 interim PET/CT scans from paediatric HL patients. Scans were acquired in 51 European hospitals after two courses of OEPA chemotherapy (according to the EuroNet-PHL-C1 study). Images were interpreted in direct comparison with staging PET/CTs. RESULTS:The probability that two random readers concord on the five point D score of a random case is only 42% (global kappa = 0.24). Aggregating to a three point scale D1,2 vs. D3 vs. D4,5 improves concordance to 60% (kappa = 0.34). Concordance if one of two readers assigns a given score is 70% for score D1,2 only 36% for score D3 and 64% for D4,5. Concordance for the binary decisions D1,2 vs. D3,4,5 is 67% and 86% for D1,2,3 vs D4,5 (kappa = 0.36 resp. 0.56). If one reader assigns D1,2,3 concordance probability is 92%, but only 64% if D4,5 is called. Discrepancies occur mainly in mediastinum, neck and skeleton. CONCLUSION:Inter-reader reliability of the five point D-scale is poor in this interobserver analysis of paediatric patients who underwent OEPA. Inter-reader variability is maximal in cases assigned to D2 or D3. The binary distinction D1,2,3 versus D4,5 is the most reliable criterion for clinical decision making.

The Brazilian South coast seasonally hosts numerous marine species, observed particularly during winter months. Some animals, including fur seals, are found dead or debilitated along the shore and may harbor potential pathogens within their microbiota. In the present study, a metagenomic approach was performed to evaluate the viral diversity in feces of fur seals found deceased along the coast of the state of Rio Grande do Sul. The fecal virome of two fur seal species was characterized: the South American fur seal (Arctocephalus australis) and the Subantarctic fur seal (Arctocephalus tropicalis). Fecal samples from 10 specimens (A. australis, n = 5; A. tropicalis, n = 5) were collected and viral particles were purified, extracted and amplified with a random PCR. The products were sequenced through Ion Torrent and Illumina platforms and assembled reads were submitted to BLASTx searches. Both viromes were dominated by bacteriophages and included a number of potentially novel virus genomes. Sequences of picobirnaviruses, picornaviruses and a hepevirus-like were identified in A. australis. A rotavirus related to group C, a novel member of the Sakobuvirus and a sapovirus very similar to California sea lion sapovirus 1 were found in A. tropicalis. Additionally, sequences of members of the Anelloviridae and Parvoviridae families were detected in both fur seal species. This is the first metagenomic study to screen the fecal virome of fur seals, contributing to a better understanding of the complexity of the viral community present in the intestinal microbiota of these animals.

OBJECTIVE:So-called cold physical plasmas for biomedical applications generate reactive oxygen and nitrogen species and the latter can trigger DNA damage at high concentrations. Therefore, the mutagenic risks of a certified atmospheric pressure argon plasma jet (kINPen MED) and its predecessor model (kINPen 09) were assessed. METHODS:Inner egg membranes of fertilized chicken eggs received a single treatment with either the kINPen 09 (1.5, 2.0, or 2.5 min) or the kINPen MED (3, 4, 5, or 10 min). After three days of incubation, blood smears (panoptic May-Grünwald-Giemsa stain) were performed, and 1000 erythrocytes per egg were evaluated for the presence of polychromatic and normochromic nuclear staining as well as nuclear aberrations and binucleated cells (hen's egg test for micronuclei induction, HET-MN). At the same time, the embryo mortality was documented. For each experiment, positive controls (cyclophosphamide and methotrexate) and negative controls (NaCl-solution, argon gas) were included. Additionally, the antioxidant potential of the blood plasma was assessed by ascorbic acid oxidation assay after treatment. RESULTS:For both plasma sources, there was no evidence of genotoxicity, although at the longest plasma exposure time of 10 min the mortality of the embryos exceeded 40%. The antioxidant potential in the egg's blood plasma was not significantly reduced immediately (p = 0.32) or 1 h (p = 0.19) post exposure to cold plasma. CONCLUSION:The longest plasma treatment time with the kINPen MED was 5-10 fold above the recommended limit for treatment of chronic wounds in clinics. We did not find mutagenic effects for any plasma treatment time using the either kINPen 09 or kINPen MED. The data provided with the current study seem to confirm the lack of a genotoxic potential suggesting that a veterinary or clinical application of these argon plasma jets does not pose mutagenic risks.

In addition to its role as an essential protein component, leucine (Leu) displays several other metabolic functions such as activation of protein synthesis. This property makes it an interesting amino acid for the therapy of human muscle atrophy and for livestock production. However, Leu can stimulate its own degradation via the branched-chain keto acid dehydrogenase complex (BCKDH). To examine the response of several tissues to excessive Leu, pigs were fed diets containing two- (L2) and four-fold (L4) higher Leu contents than the recommended amount (control). We found that the L4 diet led to a pronounced increase in BCKDH activity in the brain (2.5-fold, P < 0.05), liver (1.8-fold, P < 0.05) and cardiac muscle (1.7-fold, P < 0.05), whereas we found no changes in enzyme activity in the pancreas, skeletal muscle, adipose tissue and intestinal mucosa. The L2 diet had only weak effects on BCKDH activity. Both high Leu diets reduced the concentrations of free valine and isoleucine in nearly all tissues. In the brain, high Leu diets modified the amount of tryptophan available: for serotonin synthesis. Compared to the controls, pigs treated with the high Leu diets consumed less food, showed increased plasma concentrations of 3-hydroxybutyrate and reduced levels of circulating serotonin. In conclusion, excessive Leu can stimulate BCKDH activity in several tissues, including the brain. Changes in cerebral tryptophan, along with the changes in amino acid-derived metabolites in the plasma may limit the use of high Leu diets to treat muscle atrophy or to increase muscle growth.

Dairy cows mobilize large amounts of body fat during early lactation to overcome negative energy balance which typically arises in this period. As an adaptation process, adipose tissues of cows undergo extensive remodeling during late pregnancy and early lactation. The objective of the present study was to characterize this remodeling to get a better understanding of adaptation processes in adipose tissues, affected by changing metabolic conditions including lipid mobilization and refilling as a function of energy status. This was done by determining adipocyte size in histological sections of subcutaneous and retroperitoneal adipose tissue biopsy samples collected from German Holstein cows at 42 days prepartum, and 1, 21, and 100 days postpartum. Characterization of cell size changes was extended by the analysis of DNA, triacylglycerol, and protein content per gram tissue, and β-actin protein expression in the same samples. In both adipose tissue depots cell size was becoming smaller during the course of the study, suggesting a decrease in cellular triacylglycerol content. Results of DNA, triacylglycerol, and protein content, and β-actin protein expression could only partially explain the observed differences in cell size. The retroperitoneal adipose tissue exhibited a greater extent of time-related differences in cell size, DNA, and protein content, suggesting greater dynamics and metabolic flexibility for this abdominal depot compared to the investigated subcutaneous depot.

Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of Neurodegeneration with Brain Iron Accumulation (NBIA) associated with mutations in the pantothenate kinase 2 gene (PANK2). Pantothenate kinases catalyze the rate-limiting step of coenzyme A synthesis and Pank2 is the only pantothenate kinase isoform in humans that is localized to mitochondria. Acanthocytosis, the occurrence of spiculated erythrocytes, is observed in about 10% of the PKAN patients. Therefore PKAN is also classified together with other rare neurodegenerative diseases like Chorea Acanthocytosis (ChAc) and McLeod syndrome (MLS) into the Neuroacanthocytosis (NA) syndromes. It has not been investigated yet whether acanthocytosis in PKAN is associated with a specific subset of Pank2 mutations. In this study, we analyzed acanthocytosis of a cohort of 25 PKAN patients from the Dominican Republic that are homozygous for the c.680 A>G mutation in the PANK2 gene as compared to control donors that are heterozygous or wild-type with respect to this mutation. 3D modeling of this mutation indicated that the replacement of a tyrosine by a cysteine at position 227 in Pank2 disrupts a polar interaction within the A domain of the enzyme. Mean acanthocyte count was elevated in the cohort of patients, however, acanthocytosis varied among the patients with nearly half of them showing high (>20%) or elevated acanthocytosis and the rest showing mild (6-10%) or no (

To demonstrate the feasibility of simultaneous acquisition of 18F-FDG-PET, diffusion-weighted imaging (DWI) and T1-weighted dynamic contrast-enhanced MRI (T1w-DCE) in an integrated simultaneous PET/MRI in patients with head and neck squamous cell cancer (HNSCC) and to investigate possible correlations between these parameters.17 patients that had given informed consent (15 male, 2 female) with biopsy-proven HNSCC underwent simultaneous 18F-FDG-PET/MRI including DWI and T1w-DCE. SUVmax, SUVmean, ADCmean, ADCmin and Ktrans, kep and ve were measured for each tumour and correlated using Spearman's ρ.Significant correlations were observed between SUVmean and Ktrans (ρ = 0.43; p ≤ 0.05); SUVmean and kep (ρ = 0.44; p ≤ 0.05); Ktrans and kep (ρ = 0.53; p ≤ 0.05); and between kep and ve (ρ = -0.74; p ≤ 0.01). There was a trend towards statistical significance when correlating SUVmax and ADCmin (ρ = -0.35; p = 0.08); SUVmax and Ktrans (ρ = 0.37; p = 0.07); SUVmax and kep (ρ = 0.39; p = 0.06); and ADCmean and ve (ρ = 0.4; p = 0.06).Simultaneous 18F-FDG-PET/MRI including DWI and T1w-DCE in patients with HNSCC is feasible and allows depiction of complex interactions between glucose metabolism, microcirculatory parameters and cellular density.

Previous non-simultaneous PET/MR studies have shown heterogeneous results about the correlation between standardized uptake values (SUVs) and apparent diffusion coefficients (ADCs). The aim of this study was to investigate correlations in patients with primary and recurrent tumors using a simultaneous PET/MRI system which could lead to a better understanding of tumor biology and might play a role in early response assessment.We included 31 patients with histologically confirmed primary (n = 14) or recurrent cervical cancer (n = 17) who underwent simultaneous whole-body 18F-FDG-PET/MRI comprising DWI. Image analysis was performed by a radiologist and a nuclear physician who identified tumor margins and quantified ADC and SUV. Pearson correlations were calculated to investigate the association between ADC and SUV.92 lesions were detected. We found a significant inverse correlation between SUVmax and ADCmin (r = -0.532, p = 0.05) in primary tumors as well as in primary metastases (r = -0.362, p = 0.05) and between SUVmean and ADCmin (r = -0.403, p = 0.03). In recurrent local tumors we found correlations for SUVmax and ADCmin (r = -0.747, p = 0.002) and SUVmean and ADCmin (r = -0.773, p = 0.001). Associations for recurrent metastases were not significant (p>0.05).Our study demonstrates the feasibility of fast and reliable measurement of SUV and ADC with simultaneous PET/MRI. In patients with cervical cancer we found significant inverse correlations for SUV and ADC which could play a major role for further tumor characterization and therapy decisions.