Heidelberg University Research Articles

Tablet-based sensorimotor home-training system for amnestic mild cognitive impairments in the elderly: design of a randomised clinical trial

IntroductionDementia (particularly Alzheimer’s disease, AD) is a major cause of impaired cognitive functions in the elderly. Amnestic mild cognitive impairment (aMCI) is a prodromal stage of AD, if substantiated by...

Protocol of a prospective, monocentric phase I/II feasibility study investigating the safety of multimodality treatment with a combination of intraoperative chemotherapy and surgical resection in locally confined or borderline resectable pancreatic cancer: the combiCaRe study

IntroductionPancreatic cancer is a devastating disease with an exceptionally poor prognosis. Complete resection of the primary tumour followed by adjuvant chemotherapy is the current standard treatment for patients with resectable...

Association of Immune Cell Subtypes and Phenotype With Subsequent Invasive Candidiasis in Patients With Abdominal Sepsis.

In nonneutropenic intensive care unit (ICU) patients, current risk stratification scores lack specificity to reliably predict the risk of a prospective invasive candidiasis (IC). We aimed to explore possible associations of distinct immunological markers with different degrees of Candida affection in patients with abdominal sepsis. The presented explorative, noninterventional diagnosis study recruited patients admitted to the surgical ICU at Heidelberg University Hospital with abdominal sepsis. Over 5 days, we determined white blood cell count, 1,3-β-D-glucan, and HLA-DR expression; the amount of Th1, Th17, regulatory T, T helper, and cytotoxic T cells; Dectin-1 and TLR2-expression; the amount of T, B, and NK cells; the ex vivo secretion of IL-8 upon stimulation with LPS, flagellin, and zymosan; and the distribution of distinct T-cell cytokines in a daily manner. On day 21, patients' Candida infection status was stratified in no colonization or IC, colonization or IC. A total of 26 patients were included. On day 21, five patients showed no colonization or IC, in 13 patients a colonization was detected, and eight patients were diagnosed with IC. On study inclusion, the stratification groups showed comparable values in standard laboratory parameters and morbidity scores. Decreased B and NK cell counts, as well as reduced IL-8 secretion after ex vivo stimulation with LPS or flagellin seemed to be associated with a higher risk of subsequent Candida colonization. Even lower values could distinguish the therapy-relevant difference between prospective IC from colonization alone. We were able to show distinct immune system impairments in early abdominal sepsis by specific immune-based measurements. A possible association of these impairments with a subsequent Candida affection is shown.

Primary adenoid cystic carcinoma of the trachea: clinical outcome of 38 patients after interdisciplinary treatment in a single institution

BackgroundPrimary adenoid cystic carcinomas (ACCs) of the trachea are rare tumors of the central bronchial system. In patients presenting with unresectable tumors, severe comorbidities, or incomplete surgical resection, definitive radiotherapy is currently the recommended treatment. Irradiation with carbon ions (C12) has shown promising local control (LC) and survival rates in cases of ACCs of the head and neck. No data on the therapeutic efficacy of C12 radiotherapy in treating tracheal ACC has been published.MethodsAll patients with histologically confirmed ACC of the trachea treated with surgery and/or radiation treatment at Heidelberg University Hospital between 1991 and 2017 were included in this analysis. Patient and treatment characteristics, short- and long-term toxicity after radiotherapy, overall survival (OS), freedom from local progression (FFLP), and freedom from distant progression (FFDP) were prospectively acquired and retrospectively analyzed.ResultsThirty-eight patients (23 women and 15 men) with a median age of 51 were treated by surgery (n = 20) and/or radiotherapy with either C12 (n = 7) or photons (n = 24). Of these patients, 61% presented with locally advanced (stage 4) ACC. The median follow-up for all patients was 74.5 months. The 5-year OS for all patients was 95% (10-year: 81%). The 5-year FFLP and FFDP were 96% (10-year: 83%) and 69% (10-year: 53%), respectively. In patients who underwent surgery alone, the 5-year OS was 100% (10-year: 80%). The 5-year FFLP and FFDP were 100% (10-year: 100%) and 80% (10-year: 60%), respectively. In patients who underwent radiotherapy alone, the 5-year OS was 100% (10-year: 83%). The 5-year FFLP and FFDP were 88% (10-year: 44%) and 67% (10-year: 34%), respectively. In patients who received multi-modal treatment including surgery and adjuvant radiotherapy, the 5-year OS was 84% (10-year: 84%). The 5-year FFLP was 100% (10-year: 100%) and the 5-year FFDP was 65% (10-year, 65%).ConclusionsThe long-term prognosis is favorable if surgery is performed. In cases of an incomplete resection, good OS can still be achieved following adjuvant radiotherapy. For radiotherapy, irradiation with C12 shows promising first results. However, more data is needed to prove the long-term advantage of C12 over photons.Trial registrationThe ethics committee of the Heidelberg University Hospital approved the retrospective data analysis (S-174/2019).

The NeMo real-time fMRI neurofeedback study: protocol of a randomised controlled clinical intervention trial in the neural foundations of mother–infant bonding

IntroductionMost mothers feel an immediate, strong emotional bond with their newborn. On a neurobiological level, this is accompanied with the activation of the brain reward systems, including the striatum. However,...

In vitro activity of newer antimicrobials against penicillin non-susceptible strains of Streptococcus pneumoniae.

Background: Since the first isolation of Streptococcus pneumoniae with low penicillin susceptibility in the 1960s, resistant strains have spread over the globe, causing substantial problems in the treatment of pneumococcal infections. However, in Germany, rates of non-susceptibility are still below 5%.Methods: Since 2009 clinical pneumococcal strains have been collected at the Center for Infectious Diseases, Heidelberg University Hospital, Germany. In this study, 56 of these strains were chosen due to their decreased penicillin susceptibility (minimal inhibitory concentration (MIC)≥0.12 µg/mL). Sixteen of these strains even showed an MIC of ≥2 µg/mL. We examined the in vitro activity of newer antimicrobials known to be active against Gram-positive bacteria. For this purpose MICs of ceftaroline, ceftobiprole, dalbavancin, delafloxacin, eravacycline, tedizolid, and telavancin were determined and evaluated.Results: All of the 7 antimicrobial agents inhibited pneumococcal growth at concentrations of 0.5 µg/mL or lower. Currently, clinical breakpoints are only available for two substances, ceftaroline and ceftobiprole. According to these breakpoints, all MICs were below the susceptibility breakpoint; however, there was a correlation between high penicillin MICs (≥2 µg/mL) and MICs near the ceftaroline and ceftobiprole susceptibility breakpoint. The other agents showed very promising effects against all tested strains with the lowest MIC90 of 0.002 µg/mL for telavancin.Conclusion: Consequently, this study demonstrates the promising in vitro activity of newer antimicrobials against penicillin non-susceptible strains of S. pneumoniae.

Smartphone-supported Positive Adjustment Coping Intervention (PACI) for couples undergoing fertility treatment: a randomised controlled trial protocol

IntroductionInfertility generally counts as a profound crisis in the lives of couples and as an emotionally stressful experience. For couples undergoing fertility treatment, this is especially true of the waiting...

Promoting medical competencies through a didactic tutor qualification programme \u2013 a qualitative study based on the CanMEDS Physician Competency Framework

BackgroundIn peer-led tutorial courses, qualified medical students (“tutors”) provide their peers with opportunities to deepen their theoretical knowledge effectively and to practice clinical skills already in preclinical semesters. At the Medical Faculty of Heidelberg University, a structured medical didactic qualification programme prepares and trains future tutors for their responsibilities. This programme consists of four modules: 1. medical didactics and group leadership, 2. subject-specific training, 3. performance of tutorial courses as well as 4. collegial advice and reflection on the tutors’ activities. The aim of this study is to systematically analyse and present the development of role competencies for medical tutors based on the CanMEDS Physician Competency Framework through the didactic qualification programme.MethodsWe applied a qualitative research approach to detect CanMEDS role competencies acquisition within the tutor qualification programme. The CanMEDS framework describes key competencies, grouped thematically under seven professional roles. Two tutors and three training coordinators independently assigned the individual modules of the tutor qualification programme to the key competencies of the CanMEDS framework. Tutors and training coordinators compared and discussed the allocations within the groups in a consensus finding process. All authors analysed the findings in order to find out the so-called “hidden curriculum”. The views of both groups are presented separately.ResultsThe training programme promotes the acquisition of competencies in all seven CanMEDS roles. The roles of the scholar and the leader are promoted in all modules. In addition, the first and fourth module focus predominately on the role of the collaborator, the second on the role of the medical expert and communicator, and the fourth on the role of the professional.ConclusionsThe systematic analysis through assignment of the CanMEDS roles to the individual modules of the tutor qualification programme documents the comprehensive acquisition of competencies, not only with regard to the tutor activity, but generally with regard to the later role of the physician. The reflection on one’s own competency acquisition can support the promotion of corresponding competencies in the qualification programme and their transfer into the professional practice later.

Family of protein fragments promises fresh view of Alzheimer's disease

Neuroscientist Joris de Wit was pretty sure he was on the right track as he homed in on a receptor for a potentially beneficial brain molecule. Known as sAPPalpha (soluble amyloid precursor protein alpha), the molecule is a seemingly benevolent sibling to amyloid beta, the peptide that forms clumps in the brains of people with Alzheimer's disease. De Wit's confidence grew when he received a call from his structural biologist collaborators. “Something is actually happening,” they told him. sAPPalpha (red), expressed here in mice, seems to have beneficial effects on the brain. In experiments in mouse models of Alzheimer’s disease, sAPPalpha expression improves memory (dendritic neuron processes shown in green). Image credit: Heidelberg University Institute of Pharmacy and Molecular Biotechnology/Max Richter and Ulrike Muller. For months, the group had been stymied—the receptor motif they were trying to characterize was floppy and unstructured. Then they decided to add a short peptide corresponding to a region of sAPPalpha. The receptor motif and peptide zipped together, and a model of the structure emerged. The resulting study, recently published in Science (1), shows that sAPPalpha binds to a receptor for the neurotransmitter glutamate, modulating the transmission of neural signals across synapses. The findings suggest that sAPPalpha can quell excess neurotransmission and thereby contribute to brain health. They also offer further clues of the part a special class of protein fragments plays in the development of Alzheimer’s disease. A hardy cadre of researchers is looking to understand the precise inner workings of amyloid precursor protein (APP) and its assorted fragments, including sAPPalpha—and what happens to those fragments when things go awry. Progress is slow and piecemeal in this potentially key subfield of Alzheimer’s research—and has been for years. Slowly, the picture is becoming clearer. One idea is that APP is a regulator of neurotransmission, explains …

Association of Serum Cholesterol Levels With Peripheral Nerve Damage in Patients With Type 2 Diabetes

Lowering serum cholesterol levels is a well-established treatment for dyslipidemia in patients with type 2 diabetes (T2D). However, nerve lesions in patients with T2D increase with lower serum cholesterol levels, suggesting that lowering serum cholesterol levels is associated with diabetic polyneuropathy (DPN) in patients with T2D. To investigate whether there is an association between serum cholesterol levels and peripheral nerve lesions in patients with T2D with and without DPN. This single-center, cross-sectional, prospective cohort study was performed from June 1, 2015, to March 31, 2018. Observers were blinded to clinical data. A total of 256 participants were approached, of whom 156 were excluded. A total of 100 participants consented to undergo magnetic resonance neurography of the right leg at the Department of Neuroradiology and clinical, serologic, and electrophysiologic assessment at the Department of Endocrinology, Heidelberg University Hospital, Heidelberg, Germany. Quantification of the nerve's diameter and lipid equivalent lesion (LEL) load with a subsequent analysis of all acquired clinical and serologic data with use of 3.0-T magnetic resonance neurography of the right leg with 3-dimensional reconstruction of the sciatic nerve. The primary outcome was lesion load and extension. Secondary outcomes were clinical, serologic, and electrophysiologic findings. A total of 100 participants with T2D (mean [SD] age, 64.6 [0.9] years; 68 [68.0%] male) participated in the study. The LEL load correlated positively with the nerve's mean cross-sectional area (r = 0.44; P < .001) and the maximum length of a lesion (r = 0.71; P < .001). The LEL load was negatively associated with total serum cholesterol level (r = -0.41; P < .001), high-density lipoprotein cholesterol level (r = -0.30; P = .006), low-density lipoprotein cholesterol level (r = -0.33; P = .003), nerve conduction velocities of the tibial (r = -0.33; P = .01) and peroneal (r = -0.51; P < .001) nerves, and nerve conduction amplitudes of the tibial (r = -0.31; P = .02) and peroneal (r = -0.28; P = .03) nerves. The findings suggest that lowering serum cholesterol levels in patients with T2D and DPN is associated with a higher amount of nerve lesions and declining nerve conduction velocities and amplitudes. These findings may be relevant to emerging therapies that promote an aggressive lowering of serum cholesterol levels in patients with T2D.

Toward a virtual research environment for the spatial humanities: heiMAP

Abstract This article describes the context and design of heiMAP, a virtual research environment (VRE) currently under development at Heidelberg University. heiMAP is aimed at users from a wide spectrum of disciplines within the Humanities, allowing them to collaborate and share data using space as their common frame of reference by way of a collaborative web platform. We first set out the challenges that spatial research in the Humanities poses for such a working platform, including but not limited to reflecting the often heterogeneous and imperfect nature of Humanities data in a Geographic Information System (GIS). Next, we give an overview of some existing VREs and detail where heiMAP fits into this context and show what makes it a worthwhile addition to the existing research landscape. Finally, we revisit the initially outlined challenges and showcase heiMAP’s approaches to address them.

Performance of tacrolimus in hospitalized patients with steroid-refractory acute severe ulcerative colitis.

Acute severe ulcerative colitis unresponsive to systemic steroid treatment is a life-threatening medical condition requiring hospitalization and often colectomy. Despite the increasing choice of medical therapy options for ulcerative colitis, the condition remains a great challenge in the field of inflammatory bowel diseases (IBD). The performance of the calcineurin inhibitor tacrolimus in this clinical setting is insufficiently elucidated. To evaluate the short and long-term outcomes of tacrolimus therapy in adult inpatients with steroid-refractory acute severe ulcerative colitis. We conducted a retrospective monocentric study enrolling 22 patients at a tertiary care center for the treatment of IBD. All patients who were admitted to one of the wards of the Department of Gastroenterology and Hepatology of the Heidelberg University Hospital with acute severe ulcerative colitis between 2007 and 2018, and who received oral or intravenous tacrolimus for steroid-refractory disease were included. Baseline characteristics and data on the disease courses were retrieved from entirely computerized patient charts. The primary study endpoint was clinical response to tacrolimus therapy, resulting in discharge from the hospital. Secondary study endpoints were colectomy rate and time to colectomy, achievement of clinical remission under tacrolimus therapy, and the occurrence of side effects. In the majority of the 22 included patients (68.2%), tacrolimus therapy was initiated intravenously and subsequently converted to oral administration. The treatment duration was 128 ± 28.5 d (mean ± SEM), and the patients were followed up for 705 ± 110 d after treatment initiation. Among all patients, 86.4% were discharged from the hospital under continued oral tacrolimus therapy. In 36.4% of the patients, the administration of tacrolimus resulted in clinical remission at some point during the treatment. Thirty-two percent of the patients underwent colectomy between 5 and 194 d after the initiation of tacrolimus treatment (mean: 97.4 ± 20.8 d). Colectomy-free survival rates at 1, 3, 6 and 12 mo after the initiation of tacrolimus therapy were 90.9%, 86.4%, 77.3% and 68.2%, respectively. The safety profile of tacrolimus was overall favorable. Only two patients discontinued the treatment due to side effects. The short-term outcome of tacrolimus in steroid-refractory acute severe ulcerative colitis was beneficial, and side effects were rare. In all, tacrolimus therapy appears to be a viable option for short-term treatment of steroid-refractory acute severe ulcerative colitis besides ciclosporin and anti-tumor necrosis factor α treatment.

BMAL1 Links Bevacizumab Resistance in Colorectal Cancer to Circadian Rhythm and Heme Receptor REVERBA

Heme sensor Nuclear Receptor Subfamily 1 Group D Member 1 (NR1D1/REVERBA) and its target gene Aryl Hydrocarbon Receptor Nuclear Translocator-Like (ARNTL/BMAL1) regulate circadian rhythm and angiogenesis. Given their involvement in the interplay between clock disruptions (e.g. by mutations or sleep deprival), cancer risk and vascular biology, we hypothesized that these transcription factors contribute to resistance against anti-angiogenic therapy with vascular endothelial growth factor (VEGFA) neutralizing antibody (bevacizumab, abbrev. Beva) in colorectal cancer (CRC). REVERBA bound to a predicted -672 bp Retinoic Acid Receptor-Related Orphan Receptor Alpha (RORA)-responsive element (RORE) adjacent to a BMAL1 DNA-binding motif (E-box) in the proximal promoter of the human VEGFA gene. REVERBA, indirectly and together with BMAL1, increased VEGFA mRNA and protein expression. Conversely, REVERBA siRNA and REVERBA-antagonist hemin decreased VEGFA synthesis. Beva treatment inhibited CRC growth in a C57BL/6J Apc min/+ genetically modified mouse model (GEMM) and BALB/c nu/nu mouse HCT116 xenografts, without attenuating BMAL1 levels or microvessel density (MVD). In CRC patient tumors (n=74), high BMAL1 protein expression was associated with clinical non-response to combination chemotherapy with Beva (*p=0.0061) and reduced progression-free survival (PFS) [*p=0.0223, Hazard Ratio (HR)=1.69]. In addition, single nucleotide polymorphisms (SNPs) in the BMAL1 (ARNTL) gene correlated with shorter overall survival (OS) [rs11022780, *p=0.014, HR=1.61] and PFS (rs7396943, rs7938307, rs2279287) in patients undergoing combination chemotherapy with Beva. Thus, BMAL1 is associated with Beva resistance in CRC. Since the REVERBA-BMAL1-VEGFA axis can be pharmacologically targeted, interference with this signaling pathway could circumvent resistance to anti-angiogenic therapy in CRC. Funding Statement: This study was supported by grants to EB from the Deutsche Krebshilfe (#108287 and #111086). FE received a fellowship from the “Studienstiftung des deutschen Volkes”. JB was supported by the Translational Physician Scientist (TraPS) Program of the Medical Faculty Mannheim of the Heidelberg University. WW was awarded a fellowship from the Chinese Scholarship Council (#201408080116). ME was supported by the State of Baden-Wurttemberg for “Center of Geriatric Biology and Oncology (ZOBEL) – Perspektivforderung” and “Biology of Frailty - Sonderlinie Medizin”. ATB and ME received funds from the European Commission Seventh Framework Programme (Contract No. 278981 [ANGIOPREDICT]) and are supported by the European Commission Horizon 2020 Programme (Contract No. 754923 [COLOSSUS]). ATB is further supported by Science Foundation Ireland under grant 13/CDA/2183 ”Coloforetell”. HJL was partly funded by the National Cancer Institute (grant number P30CA014089), the Gloria Borges WunderGlo Foundation -The Wunder Project, the Dhont Family Foundation, the San Pedro Peninsula Cancer Guild, the Daniel Butler Research Fund, and the Call to Cure Research Fund Declaration of Interests: The authors declare no conflicts of interest. The reagent mBeva was obtained on the basis of a material transfer agreement (MTA#10082012) from Roche Diagnostics GmbH (Penzberg, Germany). HJL has received clinical trial financial support from Merck Serono and Roche and honoraria for advisory board membership and lectures from Bayer, Boehringer Ingelheim, Genentech, Merck Serono and Roche Ethics Approval Statement: Xenograft studies conformed to the 2010/63/EU guidelines and were approved by the Dept. of Health and Children, Dublin, Ireland (B100/3654) and University College Dublin Animal Research Ethics Committee (P12-27). Therapy studies were conducted in accordance with ethical guidelines (Declaration of Helsinki) and approved by the local ethics committees for each participating site. All patients provided written informed consent for the analysis of molecular correlates.

Automated quantitative tumour response assessment of MRI in neuro-oncology with artificial neural networks: a multicentre, retrospective study.

The Response Assessment in Neuro-Oncology (RANO) criteria and requirements for a uniform protocol have been introduced to standardise assessment of MRI scans in both clinical trials and clinical practice. However, these criteria mainly rely on manual two-dimensional measurements of contrast-enhancing (CE) target lesions and thus restrict both reliability and accurate assessment of tumour burden and treatment response. We aimed to develop a framework relying on artificial neural networks (ANNs) for fully automated quantitative analysis of MRI in neuro-oncology to overcome the inherent limitations of manual assessment of tumour burden. In this retrospective study, we compiled a single-institution dataset of MRI data from patients with brain tumours being treated at Heidelberg University Hospital (Heidelberg, Germany; Heidelberg training dataset) to develop and train an ANN for automated identification and volumetric segmentation of CE tumours and non-enhancing T2-signal abnormalities (NEs) on MRI. Independent testing and large-scale application of the ANN for tumour segmentation was done in a single-institution longitudinal testing dataset from the Heidelberg University Hospital and in a multi-institutional longitudinal testing dataset from the prospective randomised phase 2 and 3 European Organisation for Research and Treatment of Cancer (EORTC)-26101 trial (NCT01290939), acquired at 38 institutions across Europe. In both longitudinal datasets, spatial and temporal tumour volume dynamics were automatically quantified to calculate time to progression, which was compared with time to progression determined by RANO, both in terms of reliability and as a surrogate endpoint for predicting overall survival. We integrated this approach for fully automated quantitative analysis of MRI in neuro-oncology within an application-ready software infrastructure and applied it in a simulated clinical environment of patients with brain tumours from the Heidelberg University Hospital (Heidelberg simulation dataset). For training of the ANN, MRI data were collected from 455 patients with brain tumours (one MRI per patient) being treated at Heidelberg hospital between July 29, 2009, and March 17, 2017 (Heidelberg training dataset). For independent testing of the ANN, an independent longitudinal dataset of 40 patients, with data from 239 MRI scans, was collected at Heidelberg University Hospital in parallel with the training dataset (Heidelberg test dataset), and 2034 MRI scans from 532 patients at 34 institutions collected between Oct 26, 2011, and Dec 3, 2015, in the EORTC-26101 study were of sufficient quality to be included in the EORTC-26101 test dataset. The ANN yielded excellent performance for accurate detection and segmentation of CE tumours and NE volumes in both longitudinal test datasets (median DICE coefficient for CE tumours 0·89 [95% CI 0·86-0·90], and for NEs 0·93 [0·92-0·94] in the Heidelberg test dataset; CE tumours 0·91 [0·90-0·92], NEs 0·93 [0·93-0·94] in the EORTC-26101 test dataset). Time to progression from quantitative ANN-based assessment of tumour response was a significantly better surrogate endpoint than central RANO assessment for predicting overall survival in the EORTC-26101 test dataset (hazard ratios ANN 2·59 [95% CI 1·86-3·60] vs central RANO 2·07 [1·46-2·92]; p<0·0001) and also yielded a 36% margin over RANO (p<0·0001) when comparing reliability values (ie, agreement in the quantitative volumetrically defined time to progression [based on radiologist ground truth vs automated assessment with ANN] of 87% [266 of 306 with sufficient data] compared with 51% [155 of 306] with local vs independent central RANO assessment). In the Heidelberg simulation dataset, which comprised 466 patients with brain tumours, with 595 MRI scans obtained between April 27, and Sept 17, 2018, automated on-demand processing of MRI scans and quantitative tumour response assessment within the simulated clinical environment required 10 min of computation time (average per scan). Overall, we found that ANN enabled objective and automated assessment of tumour response in neuro-oncology at high throughput and could ultimately serve as a blueprint for the application of ANN in radiology to improve clinical decision making. Future research should focus on prospective validation within clinical trials and application for automated high-throughput imaging biomarker discovery and extension to other diseases. Medical Faculty Heidelberg Postdoc-Program, Else Kröner-Fresenius Foundation.

Monocyte HLA-DR Assessment by a Novel Point-of-Care Device Is Feasible for Early Identification of ICU Patients With Complicated Courses-A Proof-of-Principle Study.

Background: Critically ill patients, especially following trauma or extensive surgery, experience a systemic immune response, consisting of a pro-inflammatory as well as a counterbalancing anti-inflammatory response. Pro-inflammation is necessary for the initiation of homeostatic control and wound healing of the organism. However, when the counterbalancing mechanisms dominate, a condition of secondary immunodeficiency occurs, which renders the patient susceptible for opportunistic or secondary infections. However, the incidence of this condition is yet illusive.Methods: For a period of 3 months (May to July 2017), 110 consecutive patients admitted to the surgical ICU of the Heidelberg University Hospital, a tertiary university hospital, were enrolled in the study. Monocyte HLA-DR (mHLA-DR), a long-known surrogate of monocyte function, was assessed quantitatively once on admission utilizing a novel point-of-care flow cytometer with single-use cartridges (Accelix system). Patients were followed up for further 28 days and data on ICU stay, antibiotic therapy, microbiological findings, and mechanical ventilation were recorded. Statistical analysis was performed to evaluate the incidence of immunosuppression—defined by different thresholds—as well as its consequence in terms of outcome and clinical course.Results: Depending on the HLA-DR threshold applied for stratification (≤8,000/≤5,000/≤2,000 molecules/cell), a large group of patients (85.5/68.2/40.0%) already presented with a robust decrease of HLA-DR on admission, independent of the cause for critical illness. Analyzed for survival, neither threshold was able to stratify patients with a higher mortality. However, both thresholds of 2,000 and 5,000 were able to discriminate patients with longer ICU stay, ventilation time and duration of antibiotic therapy, as well as higher count of microbiological findings. Moreover, a mHLA-DR value ≤2,000 molecules/cell was associated with higher incidence of overall antibiotic therapy.Conclusion: Single assessment of mHLA-DR using a novel point-of-care flow cytometer is able to stratify patients according to their risk of a complicated course. Therefore, this device overcomes the technical boundaries for measuring cellular biomarkers and paves the way for future studies involving personalized immunotherapy to patients with a high immunological risk profile independent of their background.Trial Registration: German Clinical Trials Register; ID: DRKS00012348.

Patients' self-reported measures of oral health-A validation study on basis of oral health questions used in a large multi-country survey for populations aged 50.

To assess the validity of patient self-reported oral health measures as used in a large multi-country survey for populations aged 50+. Information on people's oral health status is important for assessing oral health needs within populations. However, clinical examination is not always possible. Patient self-reported measures may provide an alternative when time and other resources are scarce. Using oral health items from the Survey of Health, Ageing and Retirement in Europe (SHARE), self-reported measures were collected from 186 patients receiving treatment at Heidelberg University Hospital. Self-reports were compared with subsequent clinical examinations. Analyses were conducted for patients of all age groups and separately for patients aged 50+ (analogous to the SHARE study population). Diagnostic accuracy, agreement and correlation of patient-reported information were examined using descriptive statistics and Bland-Altman plots. Patient-reported presence or absence of a full tooth count was closely related to clinical measurement, both for all age groups (sensitivity: 93%; specificity: 92%) and persons aged 50+ (sensitivity: 100% specificity: 94%). Bland-Altman plots indicate good agreement between patient- and clinical reports of the number of teeth at age 50+ (Concordance Correlation Coefficient=0.95). Discriminatory power of patient-reporting was good regarding presence vs absence of artificial teeth, but less robust regarding partial vs full replacement of missing teeth. Patient self-evaluations provide reasonable estimates of clinical measures and appear sufficiently accurate for examining variations in the number of teeth, including among populations aged 50+. However, patient reports of the extent of replacement of missing teeth may not constitute reliable reflections of clinical conditions.

The impact of a cervical dysplasia diagnosis on individual cancer prevention habits over time: a bicentric case-control study.

Annual cervical cancer screening is recommended in Germany as a part of the statutory preventive care. Abnormal results can provoke psychological distress and anxiety, compromising women's adherence. Little is known about how a cervical dysplasia impacts adherence follow-up visits and prevention habits over time. To optimize care strategies, this study aims to identify women at risk for nonadherence to follow-up visits after a screening event. Between November 2015 and May 2017, participants with an abnormal Pap smear at the Heidelberg and Leipzig University Hospitals received a four-part questionnaire (sociodemographic data, PHQ-D, self-designed fear and prevention habit questions) at the first consultation (T1) and subsequently after 3 (T2) and 6 (T3) months; healthy controls completed the questionnaire at T1. 132 women with an abnormal Pap smear [with conization: S1 (n = 68, 51.5%), without intervention: S2 (n = 64, 48.5%)] and healthy controls (K, n = 101) generally adhered to gynecological checkups, except S1 6 months after the first diagnosis (S1/T3 - 0.47, signed rank p < 0.0005). Knowledge of primary prevention information, i.e., HPV vaccination, was significantly higher among K (K 58%, S1 29%, S2 44%, Chi-squared p = 0.01) as was vaccine uptake (K 39% versus S1/S2 7% and 17%, respectively, Chi-squared p = 0.0004). Fear of upcoming Pap smears rose significantly over time (S1/T1-S1/T2-S1/T3, Wilcoxon signed-rank test p < 0.001) and was higher among those with conization at T2 (Chi-square test, p = 0.01) and partially accompanied by panic disorders at T1 (Chi-square test p = 0.035). Realization of general preventive habits rose significantly among women without an operative procedure (S2) over the study. This study advances the understanding of non-participation in follow-up visits after a dysplasia diagnosis, identifying post-conization women as a special risk group for decreased adherence.

The people behind the papers - Dongbo Shi and Thomas Greb.

Radial growth in plants is driven by proliferating cells in the cambium that give rise to the vascular tissues of xylem and phloem, and increases plant girth. However, the identity and dynamics of the stem cells that drive this crucial process remain poorly understood. A paper in this issue of Development now characterises cambial stem cell activities in the hypocotyl of Arabidopsis We caught up with first author Dongbo Shi and his supervisor Thomas Greb, Heisenberg Professor at the Centre for Organismal Studies in Heidelberg University, Germany, to find out more about the story.

Cardiometabolic risks in India

In a recent article in this journal, we discussed diabetes and Cardiovascular disease (CVD) risks in Indians living abroad. The article was written to complement the information that was published by an elite group of the American Heart Association (AHA);-”the council members of the various subcommittees.” In the journal Circulation, AHA published a scientific statement about the CVD risk of Indians living in the USA. In the June issue of the journal PLoS Medicine, The George Institute for Global Health (GIGH), Sydney, Australia, with collaborators from; Harvard T. H. Chan School of Public Health, USA; Department of Economics, University of Gottingen, Heidelberg University, Germany; School of Public Health Johannesburg, South Africa; King's College London, UK, Indian Institute of Public Health, and Public Health Foundation of India, have published a one of a kind article on, “Geographic and sociodemographic variation of CVD disease risk in India: A cross-sectional study of 797,540 adults.” I am writing this article, as a complement to the topic reviewed by the George Institutes of Global Health and associates and other expert groups. The specific objectives of this academic exercise by the GIGH were, to determine how the CVD risk- and the factors that determine risk varies among states in India, by rural-urban location, and by individual-level sociodemographic characteristics. Rajeev Gupta and associates from Jaipur, under the aegis of South Asian Society on Atherosclerosis and Thrombosis, did a study in 2012, on “Regional variations in CVD risk in India: India heart watch.” The researchers found a wide regional variation in CVD mortality. They concluded, “that although no nationwide study of risk factors exists, there were significant state-level and rural-urban level differences in major CVD risk factors such as smoking, obesity, central adiposity, hypertension, hypercholesterolemia, and diabetes. They also stressed the need for uniform protocols, to assess the regional differences. Whereas, the report by the GIGH Collaborators group, did pooled analysis of CVD risk for 797,540 adults across India, and identified important variation in risk among individuals living in different States. According to them, CVD risk was the highest in the northern (Himachal Pradesh, Uttarakhand), northeastern (West Bengal, Nagaland, Manipur, and Mizoram), and Southern States (Kerala, Andhra Pradesh) of India. CVD risk was found to be higher in urban areas, that too among males, while mean body mass index was higher among wealthy, blood glucose, high systolic blood pressure was common in poor people of middle and older age. We have access to data from three important studies, related to the variation of CVD risk in Indians living in India, as well as abroad. It is high time, that we use these data to develop guidelines, guidance statements, novel clinical studies for validating safety and efficacy of complementary therapies for early risk factors such as oxidative stress, inflammation, and endothelial dysfunction, put together integrated noninvasive diagnostic platforms for risk assessment, risk prediction, and reduction or reversal of metabolic diseases. Having said that, I would like to emphasize the need for a national platform, to address the issues related to this very important public health problem, and to coordinate the prevention strategies.

XVI Meeting of Physics

PrefaceIt is a great pleasure for the editorial committee to introduce the Proceedings of the XVI Meeting of Physics. This event is an initiative of a team of Peruvian scientists –local and living abroad– in conjunction with various renowned international guests that, since 1999, year after year gather to present and share the results of their latest investigations in physics and related areas. A major objective of these meetings is to provide students with the superb opportunity to closely interact with experts. Moreover, students are also invited and encouraged by their supervisors to present their work in poster sessions and then, within a reasonable time, write an improved version of their results in the form of a scientific article, in such a way that those papers can pass a peer review and become published in proceedings such as this, along with the works of keynote speakers and senior researchers. For some students this is the first time to publish. For this reason, the editorial committee and their supervisors had especial patience and interacted several times with them until their articles reached a publishable level.This XVI edition of the Meeting of Physics is an especial one as we honor the memory of our mentor, teacher and friend, Prof. Holger Valqui, who passed away in Nov 2016. Prof. Valqui was not only a rigorous mathematical physicist but also a highly intuitive scientist, who contributed to popularize classical and new scientific ideas among students and general public. He also thought us the value of skepticism as key part of scientific validation and discovery. Another quality of Prof. Valqui was his sense of humor, which was one more motivation for us to deal with science.Prof. Valqui got two first degrees, one in Electrical Engineering and another in Mathematics from UNI (1954) and UNMSM (1956) respectively. He continued his studies in the Heidelberg University, Germany, graduating as “Diplom-Physiker” in 1962, having as supervisor Prof. J. Hans D. Jensen who in 1963 shared the Nobel Prize with Maria G. Mayer “For their discoveries concerning nuclear shell structure”. Since 1962 when he joined the Faculty of Science of the “Universidad Nacional de Ingeniería” (UNI) and for 54 years until he passed away Prof. Valqui was an extraordinary teacher and researcher, participating in every possible activity related to science. Conferences, seminars, science fairs (e.g. EXPOCIENCIA), students thesis supervision, lectures, etc. In fact, he was the initiator of these Meetings of Physics, which started as a set of seminars in theoretical physics then it was expanded to become a local/international event.At the moment, several former students of Prof. Valqui occupy relevant positions in various research organizations in Peru and around the world. Some of us would like to dedicate our time and efforts to invite our international colleagues and friends to this event and in that way continue his legacy.We would like to thank the Dean of the Faculty of Sciences of UNI, Prof. Orlando Pereyra, for the procedures that lead to the organization of this event, to our colleagues in Peru and abroad that contributed with its realization, to the IOP Publishing members for their patience while waiting for the final versions of the papers and to every author who has contributed with an article in these proceedings.Rosendo OchoaEner SalinasHarold Blas