Evaluation of Clinical Meaningfulness of Fortasyn Connect in Terms of "Time Saved".

Assessment of meaningfulness in randomized clinical trials (RCTs) in Alzheimer's disease (AD) is challenging, particularly in early disease. Converting clinical outcomes to disease progression time allows assessment of treatment effects using a metric that is understandable and meaningful: time. We demonstrate time savings assessments using meta time component tests (TCTs) in the LipiDiDiet multinutrient RCT. Dietary patterns are important for dementia prevention, likely due to individual cumulative nutrient effects. LipiDiDiet used a multinutrient (Fortasyn Connect) formulation in patients with prodromal AD, benefitting cognition (5-item composite NTB, effect 0.089), cognition and function (CDR-SB, -0.605), and slowing hippocampal atrophy (0.122 cm3). Meaningfulness of point differences is unclear. However, a combination TCT showed 9-month disease time savings at 24 months (38% slowing of disease time): 9.0, 10.5, and 7.2 months for NTB, CDR-SB, and hippocampal volume, underscoring the value of TCTs in AD RCTs and the need for continued validation of this approach.

Combined Evidence for a Long-Term, Clinical Slowing Effect of Multinutrient Intervention in Prodromal Alzheimer's Disease: Post-Hoc Analysis of 3-Year Data from the LipiDiDiet Trial.

The LipiDiDiet randomized clinical trial is evaluating the long term effects of a multinutrient intervention (Fortasyn Connect) compared with control in participants with prodromal AD. In this post-hoc analysis we used the Alzheimer's Disease Composite Score (ADCOMS) as a measure of cognition and global function, together with a global statistical test (GST) and Bayesian hierarchical modelling (BHM) to evaluate the totality of evidence for an effect of the intervention over 36 months. The analysis includes 67 participants (39 active, 28 control) with change from baseline data after 36 months intervention. All outcome measures showed a statistically significant effect for the intervention: ADCOMS (P =0.045), GST (P <0.001), and BHM (P =0.008 based on 3 outcomes and P <0.001 including all primary and secondary quantitative clinical outcomes). Fortasyn Connect was associated with significantly less clinical decline over 36 months, suggesting the long-lasting beneficial effects of the multinutrient in prodromal AD.

Hurdles and signposts on the road to virtual control groups-A case study illustrating the influence of anesthesia protocols on electrolyte levels in rats.

Introduction: Virtual Control Groups (VCGs) represent the concept of using historical control data from legacy animal studies to replace concurrent control group (CCG) animals. Based on the data curation and sharing activities of the Innovative Medicine Initiatives project eTRANSAFE (enhancing TRANSlational SAFEty Assessment through Integrative Knowledge Management) the ViCoG working group was established with the objectives of i) collecting suitable historical control data sets from preclinical toxicity studies, ii) evaluating statistical methodologies for building adequate and regulatory acceptable VCGs from historical control data, and iii) sharing those control-group data across multiple pharmaceutical companies. During the qualification process of VCGs a particular focus was put on the identification of hidden confounders in the data sets, which might impair the adequate matching of VCGs with the CCG. Methods: During our analyses we identified such a hidden confounder, namely, the choice of the anesthetic procedure used in animal experiments before blood withdrawal. Anesthesia using CO2 may elevate the levels of some electrolytes such as calcium in blood, while the use of isoflurane is known to lower these values. Identification of such hidden confounders is particularly important if the underlying experimental information (e.g., on the anesthetic procedure) is not routinely recorded in the standard raw data files, such as SEND (Standard for Exchange of Non-clinical Data). We therefore analyzed how the replacement of CCGs with VCGs would affect the reproducibility of treatment-related findings regarding electrolyte values (potassium, calcium, sodium, and phosphate). The analyses were performed using a legacy rat systemic toxicity study consisting of a control and three treatment groups conducted according to pertinent OECD guidelines. In the report of this study treatment-related hypercalcemia was reported. The rats in this study were anesthetized with isoflurane. Results: Replacing the CCGs with VCGs derived from studies comprising both anesthetics resulted in a shift of control electrolyte parameters. Instead of the originally reported hypercalcemia the use of VCG led to fallacious conclusions of no observed effect or hypocalcemia. Discussion: Our study highlights the importance of a rigorous statistical analysis including the detection and elimination of hidden confounders prior to the implementation of the VCG concept.

Multimodal Preventive Trial for Alzheimer's Disease: MIND-ADmini Pilot Trial Study Design and Progress.

BACKGROUND: Interventions simultaneously targeting multiple risk factors and mechanisms are most likely to be effective in preventing cognitive impairment. This was indicated in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) testing a multidomain lifestyle intervention among at-risk individuals. The importance of medical food at the early symptomatic disease stage, prodromal Alzheimer's disease (AD), was emphasized in the LipiDiDiet trial. The feasibility and effects of multimodal interventions in prodromal AD are unclear. OBJECTIVES: To evaluate the feasibility of an adapted FINGER-based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD. METHODS: MIND-ADmini is a multinational proof-of-concept 6-month randomized controlled trial (RCT), with four trial sites (Sweden, Finland, Germany, France). The trial targeted individuals with prodromal AD defined using the International Working Group-1 criteria, and with vascular or lifestyle-related risk factors. The parallel-group RCT includes three arms: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); 2) multimodal lifestyle intervention+medical food (Fortasyn Connect); and 3) regular health advice/care (control group). Primary outcomes are feasibility and adherence. Secondary outcomes are adherence to the individual intervention domains and healthy lifestyle changes. RESULTS: Screening began on 28 September 2017 and was completed on 21 May 2019. Altogether 93 participants were randomized and enrolled. The intervention proceeded as planned. CONCLUSIONS: For the first time, this pilot trial tests the feasibility and adherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. It can serve as a model for combination therapy trials (non-pharma, nutrition-based and/or pharmacological interventions).

Acute electroencephalography responses during incremental exercise in those with mental illness.

Introduction: Depression is a mental illness (MI) characterized by a process of behavioral withdrawal whereby people experience symptoms including sadness, anhedonia, demotivation, sleep and appetite change, and cognitive disturbances. Frontal alpha asymmetry (FAA) differs in depressive populations and may signify affective responses, with left FAA corresponding to such aversive or withdrawal type behavior. On an acute basis, exercise is known to positively alter affect and improve depressive symptoms and this has been measured in conjunction with left FAA as a post-exercise measure. It is not yet known if these affective electroencephalography (EEG) responses to exercise occur during exercise or only after completion of an exercise bout. This study therefore aimed to measure EEG responses during exercise in those with MI. Materials and methods: Thirty one participants were allocated into one of two groups; those undergoing management of a mental health disorder (MI; N = 19); or reporting as apparently healthy (AH; N = 12). EEG responses at rest and during incremental exercise were measured at the prefrontal cortex (PFC) and the motor cortex (MC). EEG data at PFC left side (F3, F7, FP1), PFC right side (F4, F8, FP2), and MC (C3, Cz, and C4) were analyzed in line with oxygen uptake at rest, 50% of ventilatory threshold (VT) (50% VT) and at VT. Results: EEG responses increased with exercise across intensity from rest to 50% VT and to VT in all bandwidths (P < 0.05) for both groups. There were no significant differences in alpha activity responses between groups. Gamma responses in the PFC were significantly higher in MI on the left side compared to AH (P < 0.05). Conclusion: Alpha activity responses were no different between groups at rest or any exercise intensity. Therefore the alpha activity response previously shown post-exercise was not found during exercise. However, increased PFC gamma activity in the MI group adds to the body of evidence showing increased gamma can differentiate between those with and without MI.

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience.

In 2016, the European Commission launched the EU-ToxRisk research project to develop and promote animal-free approaches in toxicology. The 36 partners of this consortium used in vitro and in silico methods in the context of case studies (CSs). These CSs included both compounds with a highly defined target (e.g. mitochondrial respiratory chain inhibitors) as well as compounds with poorly defined molecular initiation events (e.g. short-chain branched carboxylic acids). The initial project focus was on developing a science-based strategy for read-across (RAx) as an animal-free approach in chemical risk assessment. Moreover, seamless incorporation of new approach method (NAM) data into this process (= NAM-enhanced RAx) was explored. Here, the EU-ToxRisk consortium has collated its scientific and regulatory learnings from this particular project objective. For all CSs, a mechanistic hypothesis (in the form of an adverse outcome pathway) guided the safety evaluation. ADME data were generated from NAMs and used for comprehensive physiological-based kinetic modelling. Quality assurance and data management were optimized in parallel. Scientific and Regulatory Advisory Boards played a vital role in assessing the practical applicability of the new approaches. In a next step, external stakeholders evaluated the usefulness of NAMs in the context of RAx CSs for regulatory acceptance. For instance, the CSs were included in the OECD CS portfolio for the Integrated Approach to Testing and Assessment project. Feedback from regulators and other stakeholders was collected at several stages. Future chemical safety science projects can draw from this experience to implement systems toxicology-guided, animal-free next-generation risk assessment.

['Hip-in-a-Day']. / Hüftgelenkersatz im tagesklinischen Setup.

BACKGROUND: In 2017, the average length of stay for primary hip replacement patients in Germany was 10.2 days. In our hospital, we have been able to reduce the length of stay in the last 10 years to an average of 3.8 days. OBJECTIVES: Since September 2015, we offer the 'Hip-in-a-Day' program. This ultra-fast-track pathway consists of a hip arthroplasty procedure with the same day discharge of a well-prepared and explicitly selected patient with maximum intensive interdisciplinary care. The aim is to present the philosophy, treatment principles and daily routine during the pre-, intra- and postoperative phase. The challenges in the German health care system will be discussed. MATERIAL AND METHODS: From September 2015 to November 2019, we operated on 97 patients (50 F: 47 M, ages: 43-77 years, ⌀ 55 years) who had undergone the Hip-in-a-Day pathway. All 97 patients received general anesthesia. Surgery was performed via the direct anterior approach (DAA) to the hip. Patients stayed in the day clinic less than 24 h after surgery. Of these, 30 patients were discharged on the day of surgery (⌀ 12 h stay), and 67 patients left the clinic the day after the operation (⌀ 20 h stay). Due to integrated health-care contracts with health-care providers, we were eligible to receive bundled reimbursement for this patient population. RESULTS: All 97 patients completed the Ultra-Fast-Track pathway and were able to meet the discharge criteria within 24 h after surgery. 96 of the 97 (98.9%) patients were able to complete Hip-in-a-Day without readmission. One patient had to undergo revision surgery after 10 days due to cup loosening. All patients (100%) were very satisfied with the routine of the day and the fast discharge from the hospital. CONCLUSION: The aim of Hip-in-a-Day is to discharge patients within 24 h after surgery. The implementation of the setup at the day clinic is intensive interdisciplinary care of all participating departments, as well as the three cornerstones of anesthesiological management, minimally invasive surgical techniques and patient compliance. In our clinic, ultra-fast-track arthroplasty is routinely feasible and has produced great patient satisfaction. Statutory health-care providers should include short-stay hip arthroplasty into the DRG system, so that this care concept can be reimbursed and practiced nationwide in Germany.

Alzheimer's Disease Composite Score: A Post-Hoc Analysis Using Data from the LipiDiDiet Trial in Prodromal Alzheimer's Disease.

As research evolves in prodromal AD, the need to validate sufficiently sensitive outcome measures, e.g. the Alzheimer's Disease Composite Score (ADCOMS) is clear. In the LipiDiDiet randomized trial in prodromal AD, cognitive decline in the study population was much less than expected in the timeframe studied. While the primary composite endpoint was insufficiently sensitive to detect a difference in the modified intention to treat population, the per-protocol population showed less decline in the active than the control group, indicating better treatment effects with regular product intake. These results were further strengthened by significant benefits on secondary endpoints of cognition and function, and brain atrophy. The present post-hoc analysis investigated whether ADCOMS could detect a difference between groups in the LipiDiDiet population (138 active, 140 control). The estimated mean change in ADCOMS from baseline (standard error) was 0.085 (0.018) in the active and 0.133 (0.018) in the control group; estimated mean treatment difference -0.048 (95% confidence intervals -0.090, -0.007; p=0.023), or 36% less decline in the active group. This suggests ADCOMS identified the cognitive and functional benefits observed previously, confirming the sensitivity of this composite measure.

An adaptable two-lens high-resolution objective for single-site resolved imaging of atoms in optical lattices.

In this paper, we present a high-resolution, simple, and versatile imaging system for single-site resolved imaging of atoms in optical lattices. The system, which relies on an adaptable infinite conjugate two-lens design, has a numerical aperture of 0.52, which can in the ideal case be further extended to 0.57. It is optimized for imaging on the sodium D2-line but allows us to tune the objective's diffraction limited performance between 400 nm and 1000 nm by changing the distance between the two lenses. Furthermore, the objective is designed to be integrated into a typical atomic physics vacuum apparatus where the operating distance can be large (>20 mm) and diffraction limited performance still needs to be achieved when imaging through thick vacuum windows (6 mm to 10 mm). Imaging gold nanoparticles, using a wavelength of 589 nm which corresponds to the D2-line of sodium atoms, we measure diffraction limited performance and a resolution corresponding to an Airy radius of less than 0.7 µm, enabling potential single-site resolution in the commonly used 532 nm optical lattice spacing.

Epidermal-specific deletion of CD44 reveals a function in keratinocytes in response to mechanical stress.

CD44, a large family of transmembrane glycoproteins, plays decisive roles in physiological and pathological conditions. CD44 isoforms are involved in several signaling pathways essential for life such as growth factor-induced signaling by EGF, HGF or VEGF. CD44 is also the main hyaluronan (HA) receptor and as such is involved in HA-dependent processes. To allow a genetic dissection of CD44 functions in homeostasis and disease, we generated a Cd44 floxed allele allowing tissue- and time-specific inactivation of all CD44 isoforms in vivo. As a proof of principle, we inactivated Cd44 in the skin epidermis using the K14Cre allele. Although the skin of such Cd44Δker mutants appeared morphologically normal, epidermal stiffness was reduced, wound healing delayed and TPA induced epidermal thickening decreased. These phenotypes might be caused by cell autonomous defects in differentiation and HA production as well as impaired adhesion and migration on HA by Cd44Δker keratinocytes. These findings support the usefulness of the conditional Cd44 allele in unraveling essential physiological and pathological functions of CD44 isoforms.

CD44: More than a mere stem cell marker.

CD44 is a cell adhesion molecule that plays an important role in tumor progression and metastasis. The role of CD44 in tumorigenesis is due to its binding to extracellular matrix components, including hyaluronan (HA) and osteopontin (OPN), and to messenger molecules, such as growth factors present in the tumor microenvironment. HA and OPN are highly abundant in the leukemic stem cell niche and in solid tumors of various cancer types, where they contribute to the maintenance of the stemness of malignant cells. CD44 has consequently been recognized as a cancer stem cell marker in several types of cancers, which has been a topic of much recent research. In this review we have addressed the question of how CD44 might promote cancer cell stemness by interacting with extracellular matrix components, growth factors and cytokines.

Ready to use bioinformatics analysis as a tool to predict immobilisation strategies for protein direct electron transfer (DET).

Direct electron transfer (DET) to proteins is of considerable interest for the development of biosensors and bioelectrocatalysts. While protein structure is mainly used as a method of attaching the protein to the electrode surface, we employed bioinformatics analysis to predict the suitable orientation of the enzymes to promote DET. Structure similarity and secondary structure prediction were combined underlying localized amino-acids able to direct one of the enzyme's electron relays toward the electrode surface by creating a suitable bioelectrocatalytic nanostructure. The electro-polymerization of pyrene pyrrole onto a fluorine-doped tin oxide (FTO) electrode allowed the targeted orientation of the formate dehydrogenase enzyme from Rhodobacter capsulatus (RcFDH) by means of hydrophobic interactions. Its electron relays were directed to the FTO surface, thus promoting DET. The reduction of nicotinamide adenine dinucleotide (NAD(+)) generating a maximum current density of 1µAcm(-2) with 10mM NAD(+) leads to a turnover number of 0.09electron/s/molRcFDH. This work represents a practical approach to evaluate electrode surface modification strategies in order to create valuable bioelectrocatalysts.

[Participation in Preventive Medical Examinations for Children in Saxony-Anhalt (Germany) at the Time of School Entry Medical Examination]. / Inanspruchnahme von Früherkennungsunter-suchungen bei Kindern aus Sachsen-Anhalt zum Zeitpunkt der Schuleingangsuntersuchung.

OBJECTIVE: The aim of this study is to present data concerning children's participation in the German preventive medical examinations for children ("U2" to "U8") in accordance with sections 26 and 92 of the German Social Code (Book V) as retrospectively recorded by the Public Health Service ("Öffentlicher Gesundheitsdienst") of the German Province of Saxony-Anhalt during school entry medical examinations. Also we wanted to analyse the additional variables recorded per child in the areas of social factors, diagnostic findings and levels of therapeutic care in connection with their degree of participation in the preventive medical examinations. METHODOLOGY: The statistical analysis of 73 628 anonymised data sets from the health monitoring system of the German Province of Saxony-Anhalt that were collected by the 14 health authorities in Saxony-Anhalt during school entry medical examinations between 2008 and 2012. An analysis of the data for 20 variables per child was performed with regard to the influence of their degree of participation in the U2 to U8 medical examinations using differences in frequency in the examination groups and checking the significance of these differences by means of the chi-squared test. RESULTS: 99-96% of children in Saxony-Anhalt underwent the 5 preventive medical examinations U2-U6. As the children get older, the participation rates decrease (U2=98.7% down to U8=88.5%). By the time the school entry medical examinations are carried out (at an average age of 63 months), 83% of the children have -undergone all 7 preventive medical examinations for children, while 0.4% have not -undergone one single "U" examination. A child's gender has no influence on its parents' decision as to whether or not it should undergo the examinations. The results also reveal that children who attend day care -facilities are significantly more likely to have undergone all of the U examinations (84.8%) than children who are cared for at home (55.1%). CONCLUSION: The retrospective comprehensive collection of data concerning the children's degree of participation in preventive medical examinations using the school entry medical examination is suitable for identifying connections between participation rates and the social factors, diagnostic findings and levels of therapeutic care of the children in question.

Outbreak of Tuberculosis in a Colony of Rhesus Monkeys (Macaca mulatta) after Possible Indirect Contact with a Human TB Patient.

Simian tuberculosis is one of the most important bacterial diseases of non-human primates. Outbreaks of tuberculosis have been reported in primate colonies almost as long as these animals have been used experimentally or kept in zoological gardens. Significant progress has been made in reducing the incidence of tuberculosis in captive non-human primates, but despite reasonable precautions, outbreaks continue to occur. The most relevant reason is the high incidence of tuberculosis (TB) amongst the human population, in which tuberculosis is regarded as an important re-emerging disease. Furthermore, many non-human primate species originate from countries with a high burden of human TB. Therefore, Mycobacterium tuberculosis remains a significant threat in animals imported from countries with high rates of human infection. We report an outbreak of tuberculosis among a group of rhesus monkeys (Macaca mulatta) living in a closed, long-term colony. The outbreak coincided with reactivation of a TB infection in a co-worker who never had direct access to the animal house or laboratories. Eleven of 26 rhesus monkeys developed classical chronic active tuberculosis with typical caseous granulomata of varying size within different organs. The main organ system involved was the lung, suggesting an aerosol route of infection. Such an outbreak has significant economic consequences due to animal loss, disruption of research and costs related to disease control. Precautionary measures must be improved in order to avoid TB in non-human primate colonies.

Vitamin E: Curse or Benefit in Alzheimer's Disease? A Systematic Investigation of the Impact of α-, γ- and δ-Tocopherol on Aß Generation and Degradation in Neuroblastoma Cells.

OBJECTIVES: The E vitamins are a class of lipophilic compounds including tocopherols, which have high antioxidative properties. Because of the elevated lipid peroxidation and increased reactive oxidative species in Alzheimer's disease (AD) many attempts have been made to slow down the progression of AD by utilizing the antioxidative action of vitamin E. Beside the mixed results of these studies nothing is known about the impact of vitamin E on the mechanisms leading to amyloid-ß production and degradation being responsible for the plaque formation, one of the characteristic pathological hallmarks in AD. Here we systematically investigate the influence of different tocopherols on Aß production and degradation in neuronal cell lines. MEASUREMENTS: Beside amyloid-ß level the mechanisms leading to Aß production and degradation are examined. RESULTS: Surprisingly, all tocopherols have shown to increase Aß level by enhancing the Aß production and decreasing the Aß degradation. Aß production is enhanced by an elevated activity of the involved enzymes, the ß- and γ-secretase. These secretases are not directly affected, but tocopherols increase their protein level and expression. We could identify significant differences between the single tocopherols; whereas α-tocopherol had only minor effects on Aß production, δ-tocopherol showed the highest potency to increase Aß generation. Beside Aß production, Aß clearance was decreased by affecting IDE, one of the major Aß degrading enzymes. CONCLUSIONS: Our results suggest that beside the beneficial antioxidative effects of vitamin E, tocopherol has in respect to AD also a potency to increase the amyloid-ß level, which differ for the analysed tocopherols. We therefore recommend that further studies are needed to clarify the potential role of these various vitamin E species in respect to AD and to identify the form which comprises an antioxidative property without having an amyloidogenic potential.

Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia.

The initiation and maintenance of a malignant phenotype requires complex and synergistic interactions of multiple oncogenic signals. The Hedgehog (HH)/GLI pathway has been implicated in a variety of cancer entities and targeted pathway inhibition is of therapeutic relevance. Signal cross-talk with other cancer pathways including PI3K/AKT modulates HH/GLI signal strength and its oncogenicity. In this study, we addressed the role of HH/GLI and its putative interaction with the PI3K/AKT cascade in the initiation and maintenance of chronic lymphocytic leukemia (CLL). Using transgenic mouse models, we show that B-cell-specific constitutive activation of HH/GLI signaling either at the level of the HH effector and drug target Smoothened or at the level of the GLI transcription factors does not suffice to initiate a CLL-like phenotype characterized by the accumulation of CD5(+) B cells in the lymphatic system and peripheral blood. Furthermore, Hh/Gli activation in Pten-deficient B cells with activated Pi3K/Akt signaling failed to enhance the expansion of leukemic CD5(+) B cells, suggesting that genetic or epigenetic alterations leading to aberrant HH/GLI signaling in B cells do not suffice to elicit a CLL-like phenotype in mice. By contrast, we identify a critical role of GLI and PI3K signaling for the survival of human primary CLL cells. We show that combined targeting of GLI and PI3K/AKT/mTOR signaling can have a synergistic therapeutic effect in cells from a subgroup of CLL patients, thereby providing a basis for the evaluation of future combination therapies targeting HH/GLI and PI3K signaling in this common hematopoietic malignancy.

Separation anxiety disorder in adult patients with obsessive-compulsive disorder: prevalence and clinical correlates.

OBJECTIVE: Individuals with obsessive-compulsive disorder (OCD) and separation anxiety disorder (SAD) tend to present higher morbidity than do those with OCD alone. However, the relationship between OCD and SAD has yet to be fully explored. METHOD: This was a cross-sectional study using multiple logistic regression to identify differences between OCD patients with SAD (OCD+SAD, n=260) and without SAD (OCD, n=695), in terms of clinical and socio-demographic variables. Data were extracted from those collected between 2005 and 2009 via the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders project. RESULTS: SAD was currently present in only 42 (4.4%) of the patients, although 260 (27.2%) had a lifetime diagnosis of the disorder. In comparison with the OCD group patients, patients with SAD+OCD showed higher chance to present sensory phenomena, to undergo psychotherapy, and to have more psychiatric comorbidities, mainly bulimia. CONCLUSION: In patients with primary OCD, comorbid SAD might be related to greater personal dysfunction and a poorer response to treatment, since sensory phenomena may be a confounding aspect on diagnosis and therapeutics. Patients with OCD+SAD might be more prone to developing specific psychiatric comorbidities, especially bulimia. Our results suggest that SAD symptom assessment should be included in the management and prognostic evaluation of OCD, although the psychobiological role that such symptoms play in OCD merits further investigation.