Ulm University
  • Ulm, Baden-Württemberg, Germany
Recent publications
Due to the constant use of smartphones in daily life, mHealth apps might bear great potential for the use in health care support. In this chapter the potentials, limitations, current quality and future directions of mHealth apps will be discussed. First, we describe potential benefits like quicker facilitation of information, patient empowerment and inclusion of undersupplied population groups. Furthermore, the use of mHealth apps for diverse somatic and mental health conditions will be discussed. Beyond, the chapter provides the reader with a short overview on the efficacy of mHealth apps for different indications: Exemplary, we provide evidence for the efficacy of mHealth apps in the realm of asthmatic disease, depression and anxiety disorder. Despite the availability of mHealth solutions, the acceptance of among health care providers is still moderate to low. This represents a substantial problem, as health care providers are important gate keepers for intervention uptake. In this context we describe methods to foster acceptance. Furthermore, we address potential risks of mHealth app use including low responsiveness towards critical situations (e.g. self-harm) or the difficulty for users to assess the quality of the app’s content. Here we refer to standardized instruments to assess app quality. With respect to the massive amount of sensitive data already being collected through such mHealth apps, we also reflect on the latest current legal situation in Europe and the United States.
The aim of this chapter is to introduce and describe how digital technologies, in particular smartphones, can be used in research in two areas, namely (i) to conduct personality assessment and (ii) to assess and promote physical activity. This area of research is very timely, because it demonstrates how the ubiquitously available smartphone technology—next to its known advantages in day-to-day life—can provide insights into many variables, relevant for psycho-social research, beyond what is possible within the classic spectrum of self-report inventories and laboratory experiments. The present chapter gives a brief overview on first empirical studies and discusses both opportunities and challenges in this rapidly developing research area. Please note that the personality part of this chapter in the second edition has been slightly updated.
Smartphones allow for several daily life enhancements and productivity improvements. Yet, over the last decade the concern regarding daily life adversities in relation to excessive smartphone use have been raised. This type of behavior has been regarded as “problematic smartphone use” (PSU) to describe the effects resembling a behavioral addiction. In addition to other problems in daily life, research has consistently shown that PSU is linked to various psychopathology constructs. The aim of this chapter is to provide an overview of some findings in PSU research regarding associations with psychopathology. We also discuss some of the theoretical explanations that may be helpful in conceptualizing PSU. We then take a look at self-reported PSU in relation to objectively measured smartphone use, and, finally, provide some insight into current findings and future opportunities in objectively measuring smartphone use in association with psychopathology measures. This chapter may be useful as an introductory overview into the field of PSU research.
Introduction: Although evidence-based treatments for posttraumatic stress disorder (PTSD) in adolescents and young adults exist, affected youth do not have sufficient access to these treatments due to structural and attitudinal barriers. Internet- and mobile-based interventions (IMIs) can help fill this healthcare gap, but such programmes have not yet been sufficiently evaluated in youth with PTSD. Aim: This study aims to investigate the feasibility of an IMI for youth with PTSD in a one-arm, non-randomised, prospective proof-of-concept feasibility study. Methods: We aim to recruit 32 youth between 15 and 21 years old with clinically relevant posttraumatic stress symptoms (CATS ≥ 21), who will receive access to the IMI. The IMI consists of nine sessions involving psychoeducation, emotion regulation and coping skills, written-based imaginal exposure, cognitive restructuring and relapse prevention. Participants will be guided by an eCoach, who provides weekly semi-standardised written feedback on completed sessions and adherence reminders. We will use a formal feasibility framework to assess different dimensions of feasibility: (1) recruitment capability and resulting sample characteristics, (2) data collection procedures and outcome measures, (3) acceptability of the IMI and study procedures, (4) resources and ability to manage and implement the study and IMI and (5) participants' responses to the IMI in terms of symptom severity and satisfaction. Additionally, potential negative effects related to the intervention will be assessed. Assessments take place pre-, mid- and post-intervention and at follow-up, including semi-structured clinical telephone interviews for PTSD diagnostics at pre- and post-intervention assessment. Qualitative interviews will be conducted to investigate the youth perspectives on the IMI. Discussion: This study aims to determine the feasibility of a guided IMI for youth with PTSD to adapt the IMI as closely as possible to youth needs and to inform the design, procedure and safety management of a large-scale efficacy RCT. Trial registration: German Clinical Trials Register identifier: DRKS00023341. Highlights: Evidence-based care for adolescents after trauma is not widely available.• This study evaluates the feasibility of a guided trauma-focused Internet intervention as a time- and location-independent low-threshold treatment option for adolescents and young adults with posttraumatic stress disorder.
Background: The study examined the psychometric properties of the Child and Adolescent Trauma Screen 2 (CATS-2) as a measure of posttraumatic stress disorder (PTSD) according to DSM-5 and (Complex) PTSD following the ICD-11 criteria in children and adolescents (7-17 years). Methods: Psychometric properties were investigated in an international sample of traumatized children and adolescents (N = 283) and their caregivers (N = 255). We examined the internal consistency (α), convergent and discriminant validity, the factor structure of the CATS-2 total scores, latent classes of PTSD/Complex PTSD (CPTSD) discrimination, as well as the diagnostic utility using ROC-curves. Results: The DSM-5 total score (self: α = .89; caregiver: α = .91), the ICD-11 PTSD total score (self: α = .67; caregiver: α = .79) and the ICD-11 CPTSD total score (self: α = .83; caregiver: α = .87) have proven acceptable to excellent reliability. The latent structure of the 12-item ICD-11 PTSD/CPTSD construct was consistent with prior findings. Latent profile analyses revealed that ICD-11 CPTSD was empirically distinguishable from ICD-11 PTSD using the CATS-2. ROC-analysis using the CAPS-CA-5 as outcome revealed that CATS-2 DSM-5 PTSD scores of ≥21 (screening) to ≥25 (diagnostic) were optimally efficient for detecting probable DSM-5 PTSD diagnosis. For the ICD-11 PTSD scale scores of ≥7 (screening) to ≥9 (diagnostic) were optimally efficient for detecting probable DSM-5 PTSD diagnosis. Conclusions: The CATS-2 is a brief, reliable and valid measure of DSM-5 PTSD, ICD-11 PTSD and CPTSD symptomatology in traumatized children and adolescents, allowing crosswalk between diagnostic systems using one measure. Highlights: The CATS-2 screens for potentially traumatic events (PTEs) and PTSD symptoms.The CATS-2 captures DSM-5 and ICD-11 criteria for PTSD and CPTSD and enables clinicians and researchers to crosswalk between both diagnostic systems.International validation has proven good psychometric properties and presents cut-off scoresThe CATS-2 is a license-free instrument and is freely accessible.
Background: Type II germ cell tumors (GCT) are the most common solid cancers in males of age 15 to 35 years. Treatment of these tumors includes cisplatin-based therapy achieving high cure rates, but also leading to late toxici-ties. As mainly young men are suffering from GCTs, late toxicities play a major role regarding life expectancy, and the development of therapy resistance emphasizes the need for alternative therapeutic options. GCTs are highly susceptible to interference with the epigenetic landscape; therefore, this study focuses on screening of drugs against epige-netic factors as a treatment option for GCTs. Results: We present seven different epigenetic inhibitors efficiently decreasing cell viability in GCT cell lines including cisplatin-resistant subclones at low concentrations by targeting epigenetic modifiers and interactors, like histone deacetylases (Quisinostat), histone demethylases (JIB-04), histone methyltransferases (Chaetocin), epigenetic readers (MZ-1, LP99) and polycomb-repressive complexes (PRT4165, GSK343). Mass spectrometry-based analyses of the his-tone modification landscape revealed effects beyond the expected mode-of-action of each drug, suggesting a wider spectrum of activity than initially assumed. Moreover, we characterized the effects of each drug on the transcriptome of GCT cells by RNA sequencing and found common deregulations in gene expression of ion transporters and DNA-binding factors. A kinase array revealed deregulations of signaling pathways, like cAMP, JAK-STAT and WNT. Conclusion: Our study identified seven drugs against epigenetic modifiers to treat cisplatin-resistant GCTs. Further , we extensively analyzed off-target effects and modes-of-action, which are important for risk assessment of the individual drugs.
Obsessive-compulsive disorder (OCD) is a highly disabling mental illness that can be divided into frequent primary and rarer organic secondary forms. Its association with secondary autoimmune triggers was introduced through the discovery of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute onset Neuropsychiatric Syndrome (PANS). Autoimmune encephalitis and systemic autoimmune diseases or other autoimmune brain diseases, such as multiple sclerosis, have also been reported to sometimes present with obsessive-compulsive symptoms (OCS). Subgroups of patients with OCD show elevated proinflammatory cytokines and autoantibodies against targets that include the basal ganglia. In this conceptual review paper, the clinical manifestations, pathophysiological considerations, diagnostic investigations, and treatment approaches of immune-related secondary OCD are summarized. The novel concept of “autoimmune OCD” is proposed for a small subgroup of OCD patients, and clinical signs based on the PANDAS/PANS criteria and from recent experience with autoimmune encephalitis and autoimmune psychosis are suggested. Red flag signs for “autoimmune OCD” could include (sub)acute onset, unusual age of onset, atypical presentation of OCS with neuropsychiatric features (e.g., disproportionate cognitive deficits) or accompanying neurological symptoms (e.g., movement disorders), autonomic dysfunction, treatment resistance, associations of symptom onset with infections such as group A streptococcus, comorbid autoimmune diseases or malignancies. Clinical investigations may also reveal alterations such as increased levels of anti-basal ganglia or dopamine receptor antibodies or inflammatory changes in the basal ganglia in neuroimaging. Based on these red flag signs, the criteria for a possible, probable, and definite autoimmune OCD subtype are proposed.
Background Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design. Methods A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72 , 41 GRN , and 28 MAPT mutation carriers with CDR® plus NACC-FTLD ≥ 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR® plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR® plus NACC-FTLD ≥ 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR® plus NACC-FTLD = 0.5 to ≥ 1 (and therefore how long a trial would need to be). Results The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72 , GRN , and MAPT ). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR® plus NACC-FTLD 0.5 to ≥ 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR® plus NACC FTLD 0.5 to ≥ 1 without treatment over that time period. Discussion We created gene-specific cognitive composite scores for C9orf72 , GRN , and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.
Background: This study aims at describing the imaging features of the metastatic presentation of clear cell renal cell carcinoma (ccRCC) in arterial (AP) and portal venous phase (PVP) of contrast-enhanced-computed-tomography (CECT) during clinical follow-up (FU) and to evaluate the necessity of a dual phase approach for metastasis detection. Methods: We identified a total of 584 patients that were diagnosed with ccRCC between January 2016 and April 2020. Inclusion criteria were histologically proven ccRCC with metastatic spread, proven by histology or interim follow-up of at least 2 years and follow-up CT examination with AP and PVP CECT including thorax/abdomen and pelvis. Exclusion criteria were defined by missing or incomplete CT-scans or lack of sufficient follow-up. CT studies of 43 patients with histologically proven ccRCCs were analyzed in retrospect. AP and PVP images were analyzed by two radiologists for metastases, two additional independent radiologists analyzed PVP images only. A 5-point Likert scale was used to evaluate the likelihood off the presence of metastasis. Imaging patterns of the metastases were analyzed visually. Results: 43 patients (16 female; mean age: 67±10 years) with recurrent ccRCC and metastatic disease were included. Three imaging patterns were observed (solid, heterogeneous or cystic metastases), which rarely exhibited calcifications (2%). All metastases showed hyperenhancement in AP and PVP. Inter-reader agreement was substantial (Fleiss' κ 0.6-0.8, p<0.001). No significant differences in sensitivity or specificity between readers (AP and PVP images vs. PVP images only) were present (79.4-85.2%, 97.1-99.6%, p ≥ 0.05). The area under the receiver-operating-characteristic (ROC) curve was between 0.901and 0.922 for all four radiologists. Conclusions: Similar rates for detection, sensitivity and specificity of metastasis and local recurrence in ccRCC were observed irrespective of using a dual-phase protocol with AP and PVP or a single PVP protocol only. Thus, a single-phase examination of PVP can be sufficient for experienced radiologists to detect metastatic disease in the follow-up of ccRCC patients.
Introduction Individuals with proopiomelanocortin (POMC) or leptin receptor (LEPR) deficiency are young and experience severe obesity, hyperphagia, and comorbidities, which can impair quality of life (QOL). Methods Two pivotal Phase 3 trials explored the effect of setmelanotide on body weight and hunger in individuals with obesity due to POMC (NCT02896192) or LEPR (NCT03287960) deficiency. QOL and depression were investigated in parallel using the disease-specific, age-appropriate Impact of Weight on Quality of Life-Lite (IWQOL-Lite), Pediatric Quality of Life Inventory (PedsQL), and Patient Health Questionnaire-9 (PHQ-9). Results In total, the POMC and LEPR trials enrolled 21 patients. Adults (≥ 18 years old; n = 7) had moderate-to-severe impairment in QOL at baseline, with mean (standard deviation [SD]) IWQOL-Lite total score 60.3 (13.2; maximum IWQOL-Lite total score = 100). The effect of setmelanotide on IWQOL-Lite total score was observed as soon as Week 5. Among those with scores at Week 52, 5 of 6 adults experienced a clinically meaningful improvement, with mean (SD) total scores increased from baseline by 24.2 (12.1) points. Children (6–12 years old; n = 2) and adolescents (13–17 years old; n = 4) had impaired QOL at baseline, with mean (SD) self-reported PedsQL total scores 53.3 (6.2) and 63.3 (29.1), respectively (maximum PedsQL total score = 100). Three of 5 patients experienced clinically meaningful improvement in PedsQL, with 2 children whose PedsQL total score increased by 28.3 and 3.3 points and 3 adolescents whose mean (SD) total score increased from baseline by 5.8 (18.3) points. Baseline mean (SD) PHQ-9 score (in those ≥ 12 years old) was 5.3 (3.8) and was generally maintained through Week 52. Conclusions Patients with POMC or LEPR deficiency had impaired, and in some cases severely impaired, QOL before setmelanotide treatment. Setmelanotide improved QOL in patients as early as Week 5, with some patients no longer experiencing impaired QOL at Week 52. Improvements in QOL may be related to a reduction in hunger and body weight associated with setmelanotide. Because of the highly complex psychological consequences of rare genetic diseases of obesity, some patients may require a long period of treatment to improve QOL and benefit from interdisciplinary care.
Background There is a need for a comprehensive evaluation of the associations between varieties of weather conditions on the time spent out-of-home (TOH) and on walking duration (WD) among older adults. We aim to investigate the extent to which various weather parameters (temperature, solar radiation, sunshine duration, humidity, windspeed, and rain) determine daily WD the TOH in older adults. Methods The ActiFE (Activity and Function in Older People in Ulm) study is a prospective study of participants aged 65 years or older who wore an accelerometer and kept a movement diary in up to three temporally separated waves from 2009 to 2018 for a duration up to seven days per wave (up to three weeks in summary). We used weather data from a weather station near the participants‘ homes. Age-adjusted and gender-stratified generalized mixed models were used to predict WD and TOH (with 95% confidence interval (CI)) within and between weather categories. Generalized additive models were computed for the single predictions at the weather quartile boundaries. Cubic splines (with 95% pointwise confidence bands (CB)) visualized the continuous course of the weather values. Results Higher temperatures, solar radiation and more hours of sunshine, led to an increase in WD and TOH, while higher precipitation, humidities and windspeeds led to a decrease. Women had in general higher WD and TOH times than men. Conclusions Our data suggest that weather parameters have a considerable influence on PA and TOH. Future analyses and interpretation of PA data should therefore account for weather parameters.
Background In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process. Study design This multi-center, prospective controlled study has a two-phase cohort design. Methods Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD’s outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2). Outcomes Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients’ quality of life and evaluation of care; and f) physicians’ satisfaction with the innovative care approach. Conclusions This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease. Trial registration ClinicalTrials.gov; Identifier: NCT03563677; First posted: June 20, 2018, https://clinicaltrials.gov/ct2/show/NCT03563677 .
Background The COVID-19 outbreak has taken a heavy toll on the mental well-being of healthcare workers, even those who have not been directly involved in the care of acutely ill patients. The aims of this study were to identify the overall burden and mental health status of healthcare workers in pediatric developmental services under the influence of the COVID-19 pandemic, and to identify the risk and protective factors associated with mental health. Methods This cross-sectional web-based study was part of a large multicenter VOICE study conducted among employees ((neuro-)pediatricians, psychologists, speech therapists, occupational therapists, etc.) from various pediatric developmental services between June and July 2020. A total of 1291 questionnaires regarding overall burden, mental health status (depression, generalized anxiety disorder and emotional exhaustion) and risk and protective factors for mental health (working conditions, potential problems during the COVID-19 pandemic and psychological resources) were analyzed. Descriptive statistics and multiple linear regression were used for data analysis. Results A total of 44.5% (574/1291) participants felt a high or very high overall burden during the COVID-19 pandemic. Of all the participants, 14.6% (171/1173) reported clinically significant levels of depressive symptoms, 17.0% (199/1173) reported generalized anxiety disorder symptoms and 44.6% (532/1192) reported emotional exhaustion. Multiple linear regression analyses identified several common risk and protective factors for mental health status variables. The burden of an increase in the quantity of work, fear of work and fear of becoming infected showed the strongest negative associations, whereas psychological resources and sufficient relaxation in leisure time exhibited the strongest positive associations. Conclusion Employees who were not directly involved in the care of acutely ill patients were also exposed to considerable stress, some of which was not different from that experienced by professionals who were directly affected. These employees should not be lost sight of and must be offered appropriate support.
Background Pain occurs in the majority of patients with late onset Pompe disease (LOPD) and is associated with a reduced quality of life. The aim of this study was to analyse the pain characteristics and its relation to a small nerve fiber involvement in LOPD patients. Methods In 35 patients with LOPD under enzyme replacement therapy without clinical signs of polyneuropathy (19 females; 51 ± 15 years), pain characteristics as well as depressive and anxiety symptoms were assessed using the PainDetect questionnaire (PDQ) and the hospital anxiety and depression scale (HADS), respectively. Distal skin biopsies were analysed for intraepidermal nerve fiber density (IENFD) and compared to age- and gender-matched reference data. Skin biopsies from 20 healthy subjects served as controls to assure validity of the morphometric analysis. Results Pain was reported in 69% of the patients with an average intensity of 4.1 ± 1.1 on the numeric rating scale (NRS; anchors: 0–10). According to PDQ, neuropathic pain was likely in one patient, possible in 29%, and unlikely in 67%. Relevant depression and anxiety symptoms occurred in 31% and 23%, respectively, and correlated with pain intensity. Distal IENFD (3.98 ± 1.95 fibers/mm) was reduced in 57% of the patients. The degree of IENFD reduction did not correlate with the durations of symptoms to ERT or duration of ERT to biopsy. Conclusions Pain is a frequent symptom in treated LOPD on ERT, though a screening questionnaire seldom indicated neuropathic pain. The high frequency of small nerve fiber pathology in a treated LOPD cohort was found regardless of the presence of pain or comorbid risk factors for SFN and needs further exploration in terms of clinical context, exact mechanisms and when developing novel therapeutic options for LOPD.
The quantum Cramér–Rao bound sets a fundamental limit on the accuracy of unbiased parameter estimation in quantum systems, relating the uncertainty in determining a parameter to the inverse of the quantum Fisher information. We experimentally demonstrate near saturation of the quantum Cramér–Rao bound in the phase estimation of a solid-state spin system, provided by a nitrogen-vacancy center in diamond. This is achieved by comparing the experimental uncertainty in phase estimation with an independent measurement of the related quantum Fisher information. The latter is independently extracted from coherent dynamical responses of the system under weak parametric modulations, without performing any quantum-state tomography. While optimal parameter estimation has already been observed for quantum devices involving a limited number of degrees of freedom, our method offers a versatile and powerful experimental tool to explore the Cramér–Rao bound and the quantum Fisher information in systems of higher complexity, as relevant for quantum technologies.
Prognosis of patients with parkinsonism varies greatly between the various parkinsonian syndromes. However, it is often difficult to distinguish the different forms, particularly in early stages. We examined predictors of mortality and functional outcome in patients with recent-onset parkinsonism with an initially uncertain diagnosis ( n = 156). Patients were recruited between 2003 and 2006, comprehensively investigated, and followed prospectively (up to 15 years, mean 7 years). A final clinical diagnosis was established after follow-up. Independent predictors of mortality were investigated with multivariable Cox regression and combined into a simple prediction model. Model performance to predict 5- and 10-year mortality and functional outcome after 3 years was evaluated and externally validated in a second cohort of 62 patients with parkinsonism with an initially uncertain diagnosis. Ninety-one patients died (58%). Orthostatic hypotension, impaired cognition, abnormal tandem gait, and elevated neurofilament light chain concentration in serum or CSF were associated with mortality. A simple model that combined these factors showed excellent performance for prediction of functional outcome after 3 years and mortality after 5 and 10 years ( c -statistic ~0.90 for all models). Model performance was confirmed after external validation: prediction of functional outcome after 3 years ( c -statistic 0.89, 95% CI 0.80–0.98) and mortality after 5 years ( c -statistic 0.91, 95% CI 0.84–0.99) were comparable to the results in the discovery cohort. These findings help clinicians to estimate a patient’s prognosis, irrespective of the specific diagnosis.
Background Thyroid hormone responsive protein (THRSP) is a lipogenic nuclear protein that is highly expressed in murine adipose tissue, but its role in humans remains unknown. Methods We characterized the insulin regulation of THRSP in vivo in human adipose tissue biopsies and in vitro in Simpson-Golabi-Behmel syndrome (SGBS) adipocytes . To this end, we measured whole-body insulin sensitivity using the euglycemic insulin clamp technique in 36 subjects [age 40 ± 9 years, body mass index (BMI) 27.3 ± 5.0 kg/m ² ]. Adipose tissue biopsies were obtained at baseline and after 180 and 360 min of euglycemic hyperinsulinemia for measurement of THRSP mRNA concentrations. To identify functions affected by THRSP, we performed a transcriptomic analysis of THRSP-silenced SGBS adipocytes. Mitochondrial function was assessed by measuring mitochondrial respiration as well as oxidation and uptake of radiolabeled oleate and glucose. Lipid composition in THRSP silencing was studied by lipidomic analysis. Results We found insulin to increase THRSP mRNA expression 5- and 8-fold after 180 and 360 min of in vivo euglycemic hyperinsulinemia. This induction was impaired in insulin-resistant subjects, and THRSP expression was closely correlated with whole-body insulin sensitivity. In vitro, insulin increased both THRSP mRNA and protein concentrations in SGBS adipocytes in a phosphoinositide 3-kinase (PI3K)-dependent manner. A transcriptomic analysis of THRSP-silenced adipocytes showed alterations in mitochondrial functions and pathways of lipid metabolism, which were corroborated by significantly impaired mitochondrial respiration and fatty acid oxidation. A lipidomic analysis revealed decreased hexosylceramide concentrations, supported by the transcript concentrations of enzymes regulating sphingolipid metabolism. Conclusions THRSP is regulated by insulin both in vivo in human adipose tissue and in vitro in adipocytes, and its expression is downregulated by insulin resistance. As THRSP silencing decreases mitochondrial respiration and fatty acid oxidation, its downregulation in human adipose tissue could contribute to mitochondrial dysfunction. Furthermore, disturbed sphingolipid metabolism could add to metabolic dysfunction in obese adipose tissue.
Background The oral, selective SMN2 -splicing modifier risdiplam obtained European approval in March 2021 for the treatment of patients ≥ 2 months old with a clinical diagnosis of 5q-associated spinal muscular atrophy (SMA) 1/2/3 or with 1–4 SMN2 gene copies. For the preceding 12 months, this compassionate use program (CUP) made risdiplam available to patients with SMA1/2 in Germany who could not receive any approved SMA therapy. Patients and methods Patients with SMA1/2, aged ≥ 2 months at enrollment, could be included if they were not eligible for, no longer responsive to, or not able to tolerate nusinersen or not able to receive onasemnogene abeparvovec. Oral risdiplam dosing ranged from 0.2 mg/kg to 5 mg depending on age and weight. All treatment decisions were made by the attending physicians, who were required to report all adverse events (AEs). Results Between March 12, 2020 and March 30, 2021, 36 patients with SMA1 and 98 patients with SMA2 were enrolled, with 31 patients and 80 patients receiving ≥ 1 risdiplam dose, respectively. The median (range) age was 10.5 (3–52) years in the SMA1 cohort, and 26.5 (3–60) years in the SMA2 cohort. 22.2% of patients with SMA1 and 48.0% with SMA2 were treatment-naïve. Most patients were not eligible/could not continue to receive nusinersen due to scoliosis/safety risk (SMA1: 75.0%; SMA2: 96.9%), risks associated with sedation (77.8%; 63.3%), or loss of efficacy (30.6%; 12.2%). Safety data were generally in line with the safety profile of risdiplam in ongoing clinical studies. Gastrointestinal disorders were the most common AEs. For patients with SMA1, 30 AEs were reported in 13 cases with 2 serious AEs in 1 patient. For SMA2, 100 AEs were documented in 31 case reports, including 8 serious AEs in 2 patients. Conclusions We present the first real-world safety data of risdiplam in patients with SMA in Germany. Our observations indicated no new safety signals under real-world conditions. Real-world SMA1/2 populations comprise considerable numbers of patients who are not eligible for gene therapy and cannot tolerate or have failed nusinersen treatment. This medical need may be addressed by oral risdiplam.
We examine the prospects of utilizing matter-wave Fabry–Pérot interferometers for enhanced inertial sensing applications. Our study explores such tunneling-based sensors for the measurement of accelerations in two configurations: (a) a transmission setup, where the initial wave packet is transmitted through the cavity and (b) an out-tunneling scheme with intra-cavity generated initial states lacking a classical counterpart. We perform numerical simulations of the complete dynamics of the quantum wave packet, investigate the tunneling through a matter-wave cavity formed by realistic optical potentials and determine the impact of interactions between atoms. As a consequence we estimate the prospective sensitivities to inertial forces for both proposed configurations and show their feasibility for serving as inertial sensors.
The design and construction of high-nuclear polyoxometalate (POM) clusters remain a severe challenge, but attract significant interest on account of their impressive structural versatility and outstanding properties in nanosized dimensions. With continuous exploration, diverse synthetic strategies have been developed that open multiple windows for constructing and engineering abundant high-nuclear POM species with function-oriented applications. Remarkably, the unique behaviors of Mo, W, V, Nb and Ta have demonstrated the promise of POMs in fabricating distinct architectures (from giant molecular metal oxides to metal–organic polyhedra) and applications (from catalysis, electrode materials, proton conductivity, magnetism, luminescence to molecular recognition and gas separation, etc.). This review summarizes recent advances on high-nuclear POM clusters, highlighting synthetic strategies, structural classifications and relevant applications in different areas. Furthermore, challenges and prospects of high-nuclear POM clusters are presented.
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