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Abstract The impact of ustekinumab (UST) on mucosal- and fistula healing and extraintestinal manifestations (EIM) in Crohn’s disease (CD) were not fully elucidated in the registration trials. In this prospective, multicenter study (EudraCT number: 2017-005151-83) we evaluated the German label real-world-effectiveness of UST to achieve the primary endpoint of combined clinical and endoscopic response at week 52 and several secondary endpoints. Of 79 screened we enrolled 52 patients (female n = 28, bionaïve n = 13, biologic n = 39). At week 52 (per protocol analysis), 52% (n = 13/25) of patients achieved the primary endpoint [50% (n = 3/6) in the bionaïve, 45.5% (n = 5/11) biologic, 62.5% (n = 5/8 ) multiple biologics cohorts, respectively with age as independent predictor [OR 95% CI 0.933 (0.873, 0.998) p = 0.043], 60% (n = 15/25) achieved endoscopic response [50% (n = 3/6) in the bionaïve, 54.5% (n = 6/11) biologic, 75% (n = 6/8) multiple biologics cohorts, respectively], 36% (n = 9/25) achieved endoscopic remission [50% (n = 3/6) in the bionaïve, 27.3% (n = 3/11) biologic, 37.5% (n = 3/8) multiple biologics cohorts, respectively], 48% (n = 12/25) achieved mucosal healing [50% (n = 3/6) in the bionaïve, 36.4% (n = 4/11) biologic, 62.5% (n = 5/8) multiple biologics cohorts, respectively]. All achieved a fistula response and 33.3% (n = 1/3) in the multiple biologics group fistula remission at week 52. EIM decreased (week 0 28.2% vs. week 52 8%). CRP, FCP, PRO-2, EQ-5D-5L improved throughout. 36 patients (69.2%) experienced ≥ 1 treatment emergent adverse event, in 8 (15.4%) cases rated as severe and in 5 (9.6%) leading to UST discontinuation, but no very severe events or deaths. The effectiveness of UST was better than in the registration trials.

Abstract Background Pre-exposure prophylaxis (PrEP) with oral emtricitabine/tenofovir disoproxil (FTC/TDF) proved highly efficient in preventing HIV. Since 09/2019, FTC/TDF-PrEP is covered by health insurances in Germany, if prescribed by licensed specialists. However, methods to longitudinally monitor progress in PrEP implementation in Germany are lacking. Methods Utilizing anonymous FTC/TDF prescription data from 2017-2021, we developed a mathematical model to disentangle HIV-treatment from PrEP prescriptions, as well as to translate PrEP prescriptions into number of PrEP users. We used the model to estimate past- and future PrEP uptake dynamics, to predict coverage of PrEP needs and to quantify the impact of COVID-19 on PrEP uptake on a national and regional level. Results We identified significant (p

Summary: Background: In care of people living with human immunodeficiency virus (HIV), early diagnosis of infection is one of the greatest challenges remaining. A promising approach to increase early diagnosis could be optimized HIV testing in persons with indicator conditions (ICs). ICs are conditions which are AIDS-defining in people living with HIV, conditions that may have significant adverse consequences for the individual's clinical management if the presence of HIV infection is not detected, and conditions with an (undiagnosed) HIV prevalence of ≥0.1%. Methods: In this cohort study, anonymous routine healthcare data of German statutory health insurances from 07/01/2016 to 06/30/2021 based on insured persons with an ICD-10-based diagnosis of selected ICs were analyzed. In a primary analysis, two stratifications (gender and age), and four sensitivity analyses HIV prevalence/incidence were calculated for persons with at least one of 26 IC described in international literature. This study is registered in the German Clinical Trials Register (identifier: DRKS00028743). Findings: Routine healthcare data from 513,509 insured persons were selected for analysis. In the primary analysis, only in malignant neoplasm of bronchus and lung a HIV prevalence was observed with a 95%-CI < 0.1%. ICs with particularly high HIV prevalence were pneumocystosis (40.33%), oral hairy leukoplakia (36.71%), and Kaposi's sarcoma (29.86%). When stratified by gender, it was observed that in female patients, the 95%-CI of HIV prevalence fell below 0.1% for seven ICs. No such effect was observed in male patients. Stratified by age, among patients aged 30 to

BackgroundIn Europe, the combination of cabotegravir (CAB) with rilpivirine (RPV) has been approved as a dual injection long-acting (LA) therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections in adults since December 2020. Studies have shown that between 36 and 61% of people living with HIV (PLWHIV) prefer LA therapy. However, there are no real-world data on the number of people receiving LA therapy, in Germany or internationally. The aim of this study was to assess the current situation and trends in usage of LA therapy for the treatment of HIV-1 in Germany.MethodsBased on pharmacy prescription data derived from Insight Health, the monthly number of prescriptions for oral CAB, CAB-LA, and RPV-LA over the entire period of availability in Germany was analyzed and evaluated (May 2021 to December 2023). The number of 1st and 2nd initiation injections and subsequent maintenance injections was calculated on the basis of the prescriptions for oral CAB initiation.ResultsThe bimonthly schedule resulted in two growing cohorts from September 2021 with an estimated 14,523 CAB-LA prescriptions over the entire period. Accordingly, in December 2023, there were approximately 1,364 PLWHIV receiving LA therapy, of whom 1,318 were receiving maintenance therapy. Only treatments with bimonthly regimens were carried out. Accounting for people not covered by statutory health insurance (~13%), a total of ~1,600 PLWHIV were receiving LA therapy in Germany in December 2023. The average rounded annual cost of therapy in 2023 was €11,940 (maintenance therapy with initiation) and €10,950 (maintenance therapy without initiation).ConclusionTo our knowledge, this is the first study of real-world use and number of people receiving LA therapy. A strength of our study is the nearly complete coverage of people with statutory health insurance in Germany. The predicted demand for LA therapy does not match the actual number of people receiving LA therapy. Although the number of PLWHIV receiving LA therapy increased steadily, they accounted for just under 2% of the estimated total number of people receiving HIV therapy in Germany in 2023, almost 2 years after the market launch. No significant increase in prescriptions is expected; on the contrary, the trend is leveling off and is unlikely to change drastically in the near future. Hence, the need for this mode of therapy in Germany appears to be limited. Follow-up studies at regular intervals on the further course would be useful and are recommended, as well as investigations into the possible reasons for the slow uptake to inform public health experts and possibly broaden treatment options.

Abstract Understanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, we created a strategy based on synthetic, high diversity, Designed Ankyrin Repeat Protein (DARPin) libraries. We show that DARPin Antigenicity Analysis (DANA), a purely in vitro screening tool, has the capability to extrapolate relevant information of antigenic properties of Env immunogens. DANA screens of stabilized, soluble Env trimers revealed that stronger trimer stabilization led to the selection of highly mutated DARPins with length variations and framework mutations mirroring observations made for bnAbs. By mimicking heterotypic prime-boost immunization regimens, DANA may be used to select immunogen combinations that favor the selection of trimer-reactive binders. This positions DANA as a versatile strategy for distilling fundamental antigenic features of immunogens, complementary to preclinical immunogenicity testing.

Abstract Background Despite the potentially accompanying negative clinical, epidemiologic, and health economic effects, a large proportion of persons living with the human immunodeficiency virus (HIV) are diagnosed late. Internationally, numerous diseases are known to be HIV indicator diseases. Adequate HIV testing in the presence of HIV indicator diseases could help to diagnose unknown HIV infections earlier. The objective of the HeLP study is to validate published HIV indicator diseases for the German setting and to identify guidelines in terms of these indicator diseases in order to reduce knowledge gaps and increase HIV testing when HIV indicator diseases are diagnosed. Methods A mixed methods approach is used. In a first step, published HIV indicator diseases will be identified in a systematic literature review and subsequently discussed with clinical experts regarding their relevance for the German setting. For the validation of selected indicator diseases different data sets (two cohort studies, namely HIV-1 seroconverter study & ClinSurv-HIV, and statutory health insurance routine data) will be analyzed. Sensitivity analyses using different time periods will be performed. Guidelines of HIV indicator diseases validated in the HeLP study will be reviewed for mentioning HIV and for HIV testing recommendations. In addition, semi-standardized interviews (followed by a free discussion) with guideline creators will identify reasons why HIV testing recommendations were (not) included. Subsequently, a random sample of physicians in medical practices will be surveyed to identify how familiar physicians are with HIV testing recommendations in guidelines and, if so, which barriers are seen to perform the recommended tests in everyday care. Discussion The HeLP-study adopts the challenge to validate published HIV indicator diseases for the German setting and has the potential to close a knowledge gap regarding this objective. This has the potential to improve targeted HIV testing for patients with HIV indicator diseases and consequently lead to earlier HIV diagnosis. Trial registration DRKS00028743

The purpose of this article is to identify opportunities that digital transformation in post-harvest activities offers to an engineering solution provider. The research method is a simple case study. The object is a company based in southern Brazil that provides engineering-integrated digital solutions to grain producers, including products and services. The specific objectives are to describe the company’s digital products and services, identify opportunities and players, and discuss how players can take advantage of opportunities owing to business process digitalization. The main results include separating products into three technological layers and identifying five types of opportunities (financing, commercialization, operation, logistics, traceability, and insurance), eight types of players, and the main opportunities for each player. The most significant opportunities are risk reduction in insurance contracts, improvement in grain quality, increments in food safety, and accurate information on grain movements. The main implication of the study is that grain producers and other players can explore opportunities, and solution providers can evolve toward complete digitalization by integrating service into the current offerings of post-harvest engineering solutions.

Introduction: Hereditary haemorrhagic telangiectasia (HHT) is a rare multi-organ vascular disease. It is characterised by mucocutaneous telangiectasia, epistaxis, and arteriovenous malformations. Some 70% of patients with HHT are thought to have issues with gastrointestinal (GI) bleeding. Traditional management of GI bleeding in HHT includes monitoring for iron deficiency anaemia, iron replacement, antifibrinolytic therapy and control of identifiable bleeding sites with argon photocoagulation during gastrointestinal endoscopy. Blood transfusion may also be required. Case description: Our case describes a man in his 40s with confirmed HHT, with transfusion-dependent anaemia secondary to GI bleeding. He was commenced on fortnightly bevacizumab (5 mg/kg) for 12 weeks in an attempt to reduce his blood transfusion requirement and manage his anaemia. In the months prior to starting bevacizumab, our patient’s transfusion requirement ranged from 3–5 units of packed red cells per month to maintain an Hb >8 g/dl. He had a marked improvement in his symptoms within the first month of treatment and did not require any further blood transfusion during the three months of treatment. He was given one further IV iron infusion in the final month of his 3-month bevacizumab treatment and did not experience any adverse side effects from bevacizumab. Discussion: HHT results from alterations to genes which encode proteins involved in blood vessel formation. This provides the rationale for using anti VEGF drugs such as bevacizumab. Current evidence for this treatment approach is limited. Conclusion: Bevacizumab can be an effective treatment option in patients with HHT refractory to traditional management.

Background: In 2019, Germany introduced a law to reimburse high-incidence populations for pre-exposure prophylaxis (PrEP), prescribed as tenofovir-disoproxil/emtricitabine (TDF/FTC), via statutory health insurance (SHI). We studied changes in TDF/FTC-prescriptions after the implementation of this law and during the COVID-19 pandemic.Methods: We performed an interrupted time series analysis with monthly prescriptions per defined time period as the outcome. We considered the introduction of SHI-covered PrEP (09/2019) as an interruption, and four COVID-19 waves and two national lockdowns (2020–2021) as explanatory variables. We extrapolated prescriptions had the lockdowns not occurred, and compared this to the actual prescriptions. We performed sub-analyses based on stratification by five federal states with the highest proportion of PrEP users. We assessed the models’ goodness-of-fit based on the adjusted R-squared using RStudio.Results: The best fitting model included SHI-covered PrEP and the first COVID-19 lockdown (04/2020). The decrease in prescriptions during the first lockdown was significant nationally, and in the five federal states for single-month prescriptions. The first lockdown resulted in reductions of 57.7% (95% prediction interval (PI): 23.0%–92.4%) for single-month prescriptions, while 17.4% (95% PI: 0.28%–34.5%) nationally, and 13.9% (95% PI: -3.67%–31.5%) for 3-month prescriptions.Conclusion: Introduction of SHI-covered PrEP resulted in a doubling of TDF/FTC-prescriptions nationwide in the first month alone. A drop in prescriptions was most apparent after the first lockdown, and particularly affected PrEP initiations, possibly due to reduced healthcare access and behavioural changes. Ongoing monitoring of TDF/FTC-prescriptions is needed to safeguard access to preventative care such as PrEP and particularly PrEP initiation during public health crises like COVID-19.

Background Skin is the largest organ of the human body and fulfills many important functions, like detecting mechanical stimuli. Skin can be divided into glabrous (non-hairy) and hairy skin. These two skin types differ with regard to their mechanical properties and in the distribution of mechanoreceptors. Although many investigations focus on glabrous skin, hairy skin still plays a fundamental role in various activities, e.g., with regard to the perception of pleasantness or for developing wearable vibrotactile devices for pattern recognition in persons with disabilities. Unfortunately, investigations on influencing factors, like vertical contactor force, are scarce for hairy skin. Similarly, it would also be interesting to investigate whether regional vibratory sensitivity differences are present across the human torso. Hence, this study investigated the effects of vertical contactor forces and different anatomical locations on vibration perception. Four anatomical torso regions were studied. Based on findings in glabrous skin, we generally hypothesized improved vibration perception with increasing contactor forces and regional sensitivity differences between the anatomical locations. Methods Forty young and healthy individuals participated (23.0 ± 2.0 yrs), and vibration perception thresholds (VPTs) were determined at 30 Hz for three vertical force levels (0.6, 2.4, and 4.8 N) at four torso locations (sternum, deltoid/shoulder, lower back, middle lateral torso side). Results Higher contactor forces resulted in lower VPTs corresponding to improved vibration perception, regardless of anatomical location. In addition, the sternum region was more sensitive than the remaining three regions, regardless of force level. The reasons for these findings may be a varying number and activation pattern of afferents activated under the different conditions. The findings of this study complement the understanding of vibrotactile sensitivity in hairy skin and may offer implications when developing vibrotactile devices or clothing/textiles, for example.

Structural martensitic transformations enable various applications, which range from high stroke actuation and sensing to energy efficient magnetocaloric refrigeration and thermomagnetic energy harvesting. All these emerging applications benefit from a fast transformation, but up to now their speed limit has not been explored. Here, we demonstrate that a thermoelastic martensite to austenite transformation can be completed within 10 ns. We heat epitaxial Ni-Mn-Ga films with a nanosecond laser pulse and use synchrotron diffraction to probe the influence of initial temperature and overheating on transformation rate and ratio. We demonstrate that an increase in thermal energy drives this transformation faster. Though the observed speed limit of 2.5 × 1027 (Js)1 per unit cell leaves plenty of room for further acceleration of applications, our analysis reveals that the practical limit will be the energy required for switching. Thus, martensitic transformations obey similar speed limits as in microelectronics, as expressed by the Margolus – Levitin theorem.

Electron and lattice heat transport have been investigated in bilayer thin films of gold and CoSb _3 after photo-excitation of the nanometric top gold layer through picosecond x-ray scattering in a pump-probe setup. The kinetics of heat transfer are detected by thermal lattice expansion and compared to simulations based on the two-temperature model of coupling of electron and phonon degrees of freedom. The unexpected observation of a larger portion of the deposited heat being detected in the underlying CoSb _3 layer before the topmost gold layer is heated supports the picture of transport of the photo-excited electrons from gold to the underlying layer to be converted into lattice heat. The change of partition of heat between the gold and CoSb _3 layer with laser fluence and wavelength (either exciting intraband transitions or additionally interband transitions) is rooted in the amplitude of electron temperature. Higher electron temperatures result in a longer equilibration time with the lattice and thus a larger proportion of ballistic electron transport across the interface.

Martensitic transformations enable various emerging applications like the shape memory effect and elastocaloric applications in NiTi. Increasing the speed of this transformation can shorten the response time for actuation and increase the power density of caloric cooling systems. Up to now, research on the speed and possible time limits of the martensitic transformation in NiTi has been limited to milli- and microsecond experiments. The dynamics of the transformation for shorter time scales are therefore unknown. Here, we report the fastest transformations in NiTi so far by heating an epitaxial NiTi film with a ns laser pulse and tracking the martensitic transition with in - situ synchrotron x-ray diffraction. We find that the martensite to austenite transition upon heating can proceed within the 7 ns pulse duration of the laser, but it requires substantial overheating as the rate of the transformation increases with the driving energy. The austenite to martensite transition is slower because cooling proceeds by conductive heat transfer, but with appropriate undercooling, the complete transformation from martensite to austenite and back only takes 200 ns. We compare our results to previous experiments on the Heusler alloy Ni–Mn–Ga and (K, Na)NbO _3 and find very similar trends, which reveal that fast martensitic transformations in general follow a universal scaling law.

Effectively treating hepatitis C viral (HCV) infections prevents sequelae and onward transmission. In Germany, HCV drug prescriptions have declined since 2015. During the COVID-19 pandemic, lockdowns impacted the access to HCV care services and HCV treatment. We assessed if the COVID-19 pandemic further decreased treatment prescriptions in Germany. We built log-linear models with monthly HCV drug prescription data from pharmacies from January 2018 - February 2020 (pre-pandemic) to calculate expected prescriptions for March 2020-June 2021 and different pandemic phases. We calculated monthly prescription trends per pandemic phase using log-linear models. Further, we scanned all data for breakpoints. We stratified all data by geographic region and clinical settings. The number of DAA prescriptions in 2020 (n = 16,496, −21%) fell below those of 2019 (n = 20,864) and 2018 (n = 24,947), continuing the declining trend from previous years. The drop in prescriptions was stronger from 2019 to 2020 (−21%) than from 2018 to 2020 (−16%). Observed prescriptions met predictions from March 2020 to June 2021, but not during the first COVID-19 wave (March 2020–May 2020). Prescriptions increased during summer 2020 (June 2020-September 2020) and fell below the pre-pandemic numbers during the following pandemic waves (October 2020 – February 2021 and March 2021 – June 2021). Breakpoints during the first wave indicate that prescriptions plummeted overall, in all clinical settings and in four of six geographic regions. Both, outpatient clinics and private practices prescribed overall as predicted. However, outpatient hospital clinics prescribed 17–39% less than predicted during the first pandemic wave. HCV treatment prescriptions declined but stayed within the lower realms of predicted counts. The strongest decline during the first pandemic wave indicates a temporary HCV treatment gap. Later, prescriptions matched predictions despite of pronounced decreases during the second and third waves. In future pandemics, clinics and private practices need to adapt more rapidly to maintain a continuous access to care. In addition, political strategies should focus more on continuously providing essential medical care during periods of restricted access due to infectious disease outbreaks. The observed decrease in HCV treatment may challenge reaching the HCV elimination goals in Germany by 2030.

Abstract Background Recent patent losses for antiretroviral drugs (ARV) have led to the debate of cost-saving through the replacement of patented drugs with generic drugs. The split of recommended single-tablet regimens (STR) into their single substance partners is one of the considerations mentioned in said debate. Particularly, generic tenofovir disoproxil/emtricitabine (TDF/FTC) is expected to hold untapped cost-saving potential, which may curb increasing overall expenditures for combined antiretroviral therapy (cART) within the statutory health insurance (SHI) of Germany. Methods Data of ARV reimbursed by the SHI were used to describe the trends of defined daily doses (DDD) as well as the revenue within the German ARV market. They were also used to determine the cost-savings of moving to generic drugs. The time period observed was between January 2017 and June 2019. The potential cost-savings were determined with following assumption in mind: the maximum possible use of generic ARV, including 1) the split of STR and replacing all substance partners with generic ones, and 2) replacing patented tenofovir alafenamide/emtricitabine (TAF/FTC) with generic TDF/FTC. Results Throughout the observation period, the DDD of generic ARV increased nearly five-fold while their revenue increased more than four-fold. Total cost-saving showed a sharp increase over the same period, with generic TDF/FTC accounting for a share of around 70%. The largest potential cost-saving could have been achieved through replacing patented TAF/FTC with generic TDF/FTC, peaking at nearly 10% of total revenue, but showing decreasing trends in general. Conclusion The progressive distribution of generic ARV ensured increasing cost-savings, but consequently curbed the potential cost-savings. Unique price reductions of generic TDF/FTC have played a pivotal role for these effects. In any case, substituting with generic ARV should not fail to adhere to the treatment guidelines and continue to consider the medical requirements for the treatment.

Here, the authors perform a large-scale, high-throughput biochemical assay to determine the compatibility of over 300,000 domain recombination variants of the inward rectifier K+ channel Kir2.1. They derive rules for designing domain insertion variants that fold and traffic to the cell surface and conclude that the insertion of domains at protein termini is evolutionary favoured.

This contribution addresses the impact of tempering processes on the emissivity of LowE glass. The current status of a measurement series conducted at various tempering sites on different types of LowE glass is presented. Emissivity measurements using inductive eddy current sensors have been made on glass before and after tempering. The obtained data shows an improvement by factor 2 in emissivity depending on coating type. Effects from tempering recipes and the resulting emissivity homogeneity have been analyzed. Measurements also show significant worsening of the emissivity by the use of wrong tempering settings where too little convection occurs during heating that cause glass bending leading to the well-known white marks in the center of the glass along with significant loss in emissivity. Assessment of the glass emissivity properties as well as the negative effects of poor furnace recipe optimization on coatings were measured by eddy current systems, which rely on inductive methods for contact or non-contact real-time emissivity assessment. Comparison to thermographic images are shown and discussed. Finally, the status of measurement and analysis are summarized and the potentials to use of these phenomena are discussed.

Internationalization in higher education is essential, and although active learning methodologies are increasing and allow students to develop transversal skills, most still have a very local scope. In this context, the Collaborative Online International Learning (COIL) methodology is an interesting approach to benefit the students' development. It consists of an online program that involves creating multicultural teams to develop a specific learning project. Although this methodology is expanding, its use in physiology is still scarce. This paper aims to show an example of applying COIL methodology in physiology topics to enhance higher-education students' innovation and business skills. Our example project developed a sports-assessment service concept focused on physiology and biomechanics assessments. The program involved teams from Brazil, Germany, and Spain, comprising undergraduate and master students. Over 7 weeks, these teams, mentored by professors and researchers, engaged in workshops covering COIL methodology, business model design, executive summary planning, economic analyses, and communication techniques. Key outcomes included learning new concepts, developing soft skills, building confidence in innovative solution proposals, and experiencing diverse cultures. Challenges faced were language barriers, scheduling, task complexity, and logistical issues. This experience confirms the effectiveness of incorporating programs using COIL methodology into educational curriculums. Doing so exposes physiology students to innovation, entrepreneurship, and business creation while strengthening their professional connections and opening up postgraduation opportunities.

Abstract Background The aim of this study was to develop a standardized method to reconstruct persons’ individual viral load (VL) courses to determine viral suppression and duration of viremia for the HIV care continuum in Germany using longitudinal cohort data. Methods We analyzed data from two large, multi-center German cohort studies under the direction of the Robert Koch Institute. We included data from 1999 to 2018 of all diagnosed people and of people who initiated antiretroviral treatment (ART). We developed a model generating virtual VL values and an individual VL course corresponding to real VL measurements with a maximum distance of 180 days, considering ART status and VL dynamics. If the distance between VL measurements was > 180 days, the time between was defined as gap time. Additionally, we considered blips, which we defined as a single detectable VL 1000 copies/ml decreased from 37% in 1999 to 3% in 2018. The proportion of people with gap time fluctuated and ranged between 18 and 28%. An analysis of the first VL after gap time showed that 90% showed viral suppression, 5% VL between 50- 1000 copies/ml. Conclusion We provide a method for estimating viral suppression and duration of viremia using longitudinal VL data. We observed a continuous and remarkable increase of viral suppression. Furthermore, a notable proportion of those with viremia showed low-level viremia and were therefore unlikely to transmit HIV. Individual health risks and HIV drug resistance among those with low-level viremia are problematic, and viral suppression remains the goal. In 2018, 93 and 96% of people after ART initiation showed VL

A long-standing goal in protein science and clinical genetics is to develop quantitative models of sequence, structure, and function relationships to understand how mutations cause disease. Deep mutational scanning (DMS) is a promising strategy to map how amino acids contribute to protein structure and function and to advance clinical variant interpretation. Here, we introduce 7429 single-residue missense mutations into the inward rectifier K+ channel Kir2.1 and determine how this affects folding, assembly, and trafficking, as well as regulation by allosteric ligands and ion conduction. Our data provide high-resolution information on a cotranslationally folded biogenic unit, trafficking and quality control signals, and segregated roles of different structural elements in fold stability and function. We show that Kir2.1 surface trafficking mutants are underrepresented in variant effect databases, which has implications for clinical practice. By comparing fitness scores with expert-reviewed variant effects, we can predict the pathogenicity of ‘variants of unknown significance’ and disease mechanisms of known pathogenic mutations. Our study in Kir2.1 provides a blueprint for how multiparametric DMS can help us understand the mechanistic basis of genetic disorders and the structure–function relationships of proteins.

Abstract Background Dementia and cognitive decline are serious social and economic burdens. An increase in the population of older people, as well as longer lifespans mean that numbers of dementia cases are exponentially rising. Neuropathological changes associated with dementia are thought to appear before the clinical manifestation of cognitive symptoms, i.e., memory impairments. Further, some older adults (OA) experience cognitive decline before it can be objectively diagnosed. For optimal care of these patients, it is necessary to detect cognitive decline and dementia at an early stage. In this vein, motor, sensory, and neurophysiological declines could be promising factors if found to be present before the onset of cognitive impairment. Hence, the objective of the SENDA study is to develop a multi-dimensional sensor-based instrument that allows early detection of cognitive decline or dementia in OA with the help of cognitive, sensory, motor, and neurophysiological parameters before its clinical manifestation. Methods/design In the cohort sequential study, participants are assigned to one of three study groups depending on their cognitive status: 1. cognitively healthy individuals (CHI), 2. subjectively cognitively impaired persons (SCI), or 3. (possible) mildly cognitively impaired persons (pMCI, MCI). All groups take part in the same cognitive (e.g., executive function tests), motor (e.g., gait analyses, balance tests), sensory (e.g., vibration perception threshold test, proprioception tests), and neurophysiological (e.g., electroencephalograms) measurements. Depending on the time at which participants are included into the study, all measurements are repeated up to four times in intervals of 8 months within 3 years to identify associations with cognitive changes over time. Discussion This study aims to detect possible motor, sensory, neurophysiological, and cognitive predictors to develop an early screening tool for dementia and its pre-stages in OA. Thus, affected persons could receive optimal health care at an earlier time point to maintain their health resources. Trial status The study is ongoing. The recruitment of participants will be continued until May 2020.

Background & Aims: Treatment options remain limited for patients with autoimmune hepatitis (AIH), while there are still concerns over the consequences of long-term corticosteroid use. A few studies have suggested a role for B cell-driven autoimmune liver injury in AIH. This multicentre, international retrospective cohort study from the International Autoimmune Hepatitis Group aims to evaluate the clinical efficacy and safety of rituximab in difficult-to-manage AIH. Methods: Clinical data from 22 patients who received rituximab between 2007 and 2017 were collected from centres in the United Kingdom, Germany and Canada. Clinical response was assessed using changes in biochemical and immunological parameters up to 24 months post-rituximab infusion. In addition, we compared the doses of prednisolone used 3 months before and 12 months after treatment, and assessed freedom from AIH flares over the post-treatment period. Results: Twenty-two patients with type-1 AIH were included, with a median age of 40 years at diagnosis (range 19–79); 15/22 (68%) were female and 18/22 (82%) were Caucasian. The median period from diagnosis to the end of follow-up in these patients was 11 years (range 3–28). Values of alanine aminotransferase, aspartate aminotransferase and albumin improved significantly following rituximab therapy, and were sustained for up to 2 years (all p ≪0.001). Prednisolone doses were significantly reduced by 12 months post-treatment (p = 0.003), with 13/21 (62%) patients having a dose reduction. Over a median post-treatment follow-up period of 6 years (range 1–10), 5 patients developed AIH flares at a median of 22 months post-treatment, giving an estimated 71% freedom from AIH flare at 2 years. Four of these patients received a second course of treatment, of whom 2 had subsequent further flares. No serious adverse events attributable to rituximab were recorded. Conclusion: In patients with difficult-to-manage AIH, rituximab appears to be clinically effective and well tolerated. Rituximab was associated with sustained improvements in serum liver tests, an absence of clinical disease flares, and a reduction in prednisolone dose. Controlled trials are warranted to further evaluate B cell-targeting therapies in patients with AIH. Lay summary: Autoimmune hepatitis is an autoimmune condition of the liver, usually treated with medications that suppress the immune system, such as steroids. However, some patients do not respond to this treatment. We analysed the safety and efficacy of rituximab in patients who were not responding to first- or second-line therapies. Rituximab was safe and improved liver blood tests in 70% of patients over a 2-year follow-up period, while enabling steroid doses to be reduced in two-thirds of patients, which is a very positive clinical outcome. Keywords: Autoimmune hepatitis, Prednisolone, Difficult-to-manage, B cell depletion therapy, Rituximab

With the recent redefinition of the SI base units in terms of constants of nature, the race is on to maximize achievable precision by developing primary standards based on quantum metrology, thereby to realize the Quantum SI. For the becquerel (Bq) and gray (Gy), the derived SI units for activity and absorbed dose, respectively, this is especially challenging because production and detection of ionizing radiation is difficult to manage at the atomic scale, and quantum coherences are easily lost in the cascade of inelastic processes that accompany the slowing of energetic particles in matter. This would not preclude a secondary role for quantum metrology in the pursuit of single-event detection and resolution of radiation effects at microscopic scales, where we are beginning to apply new transition-edge sensors, silicon photonics, and link to quantum electrical standards. Here we summarize recent results for microcalorimetry in activity and dosimetry measurements and discuss their potential as next-generation standards.

Allostery is a fundamental principle of protein regulation that remains challenging to engineer. Here authors screen human Inward Rectifier K + Channel Kir2.1 for permissibility to domain insertions and propose that differential permissibility is a metric of latent allosteric capacity in Kir2.1.

Fluctuations of surfaces that harbor reactive molecules interacting across the intervening space strongly influence the reaction kinetics. One such paradigmatic system is the cell membrane, with associated proteins, binding to an interior or an exterior scaffold—for example, the cytoskeleton in the former and the extracellular matrix in the latter case. Given that membrane fluctuations are significant and regulated by the activity of the cell, we hypothesize that these active fluctuations can be tuned to influence ligand-receptor-mediated adhesion. However, a comprehensive model, deriving both binding and unbinding rates from first principles, has not yet been established, and as such, the effect of the membrane activity on the rates remains an open problem. Here, we solve this issue by establishing a systematic coarse graining procedure, providing a cascade of expressions for rates appropriate for the observed timescale, and present a scale-free formulation of rates. In the first step, we introduce a minimal model to recover the so-called Bell-Dembo rates from first principles, where the binding and unbinding rates depend on the instantaneous position of the membrane. We then derive the analytical coarse-grained rates for thermal fluctuations, recovering a result that has previously been successfully used in the literature. Finally, we expand this framework to account for active fluctuations of the membrane. In this step, we develop a mechanical model that convolutes Gauss and Laplace distributed noise. This choice may have universal features and is motivated by our analysis of measurements in two very different cell types, namely, human macrophages and red blood cells. We find that cell activation enables the formation of bonds at much larger separations between the cell and the target. This effect is significantly greater for binding to a surface on the extracellular compared to the intracellular side. We thus show that active fluctuations directly influence protein association and dissociation rates, which may have clear physiological implications that are yet to be explored.

Subliminal electrical noise (SEN) enhances sensitivity in healthy individuals of various ages. Diabetes and its neurodegenerative profile, such as marked decreases in foot sensitivity, highlights the potential benefits of SEN in such populations. Accordingly, this study aimed to investigate the effect of SEN on vibration sensitivity in diabetes. Vibration perception thresholds (VPT) and corresponding VPT variations (coefficient of variation, CoV) of two experimental groups with diabetes mellitus were determined using a customized vibration exciter (30 and 200 Hz). Plantar measurements were taken at the metatarsal area with and without SEN stimulation. Wilcoxon signed-rank and t tests were used to test for differences in VPT and CoV within frequencies, between the conditions with and without SEN. We found no statistically significant effects of SEN on VPT and CoV (p > 0.05). CoV showed descriptively lower mean variations of 4 and 7% for VPT in experiment 1. SEN did not demonstrate improvements in VPT in diabetic individuals. Interestingly, taking into account the most severely affected (neuropathy severity) individuals, SEN seems to positively influence vibratory perception. However, the descriptively reduced variations in experiment 1 indicate that participants felt more consistently. It is possible that the effect of SEN on thick, myelinated Aβ-fibers is only marginally present.

Background Studies demonstrated that the older adults can be more susceptible to balance instability after acute visual manipulation. There are different manipulation approaches used to investigate the importance of visual inputs on balance, e.g., eyes closed and blackout glasses. However, there is evidence that eyes open versus eyes closed results in a different organization of human brain functional networks. It is, however, unclear how different visual manipulations affect balance, and whether such effects differ between young and elderly persons. Therefore, this study aimed to determine whether different visual manipulation approaches affect quasi-static and dynamic balance responses differently, and to investigate whether balance responses of young and older adults are affected differently by these various visual conditions. Methods Thirty-six healthy participants (20 young and 16 older adults) performed balance tests (quasi-static and unexpected perturbations) under four visual conditions: Eyes Open, Eyes Closed, Blackout Glasses, and Dark Room. Center of pressure (CoP) and muscle activation (EMG) were quantified. Results As expected, visual deprivation resulted in larger CoP excursions and higher muscle activations during balance tests for all participants. Surprisingly, the visual manipulation approach did not influence balance control in either group. Furthermore, quasi-static and dynamic balance control did not differ between young or older adults. The visual system plays an important role in balance control, however, similarly for both young and older adults. Different visual deprivation approaches did not influence balance results, meaning our results are comparable between participants of different ages. Further studies should investigate whether a critical illumination level may elicit different postural responses between young and older adults.

Background: Germany is a low prevalence country for hepatitis B virus (HBV) infection with higher prevalence in vulnerable groups. The number of treated chronic hepatitis B (CHB) patients is unknown. We aimed to determine the number of CHB patients treated with nucleos(t)ide analogs (NUCs), the treatment costs within the statutory health insurance (SHI) in Germany and per patient per month.Methods: Data on pharmacy bills of NUCs to patients with SHI between 2008 and 2019 were purchased from Insight Health™ and described. Negative binomial regression was used for trend analysis.Results: Number of patients increased between 2008 and 2019 (4.9% per year) with little changes in treatment options. Overall prescription costs were increasing (6.7% per year on average) until the introduction of tenofovir and entecavir generics in 2017 after which costs decreased by 31% in 2019. Average therapy costs peaked at 498 Euro per patient per month in 2016 and decreased to 214 Euro in 2019. Prescriptions changed from 30 to 90 pills per pack over time. HBV therapy was prescribed to 97% by three medical specialist groups, mainly specialists in internal medicine (63%), followed by hospital-based outpatient clinics (20%) and general practitioners (15%). Contrary to guideline recommendation, adefovir was still prescribed after 2011 for 1–5% of patients albeit with decreasing tendency. Prescriptions per 100,000 inhabitants were highest in Berlin and Hamburg.Conclusion: Our data shows, that the number of treated CHB patients increased steadily, while NUC therapy costs decreased. We recommend continued testing and treatment for those eligible to prevent advanced liver disease and possibly decrease further transmission of HBV.

Background In research, assessing vibratory cutaneous sensitivity is an important research branch to quantify various diseases or to develop devices for pattern recognition. The measured vibration perception thresholds (VPTs), however, are subjective and usually result in a large data variability. This might induce difficulties to detect differences, for example, when comparing different anatomical locations. Hence, a higher ability to detect changes is desirable. Another feature of VPTs is spatial summation, but in the literature it is controversially discussed whether or not this phenomenon is also present in the lower frequency range. For these reasons, the present study aimed to investigate whether an enlarged matrix contactor area (measured at the hairy skin) induces improvements in subjective sensitivity using high and low frequencies, and whether a large contactor area is better able to identify changes of VPTs than a small contactor area of a single contactor. For each frequency, we hypothesized an increased sensitivity for the matrix compared to the single contactor. We also hypothesized that changes can be better-detected between the anatomical locations when using the matrix than the single contactor. Methods Twenty healthy and young participants voluntarily took part in this study. Three anatomical locations at the torso were measured at the middle aspect of the lower back, middle lateral aspect of the upper arm, and the region just below the armpit. At each location, two frequencies (30, 200 Hz) and two contactor conditions (single contactor: 0.48 cm2 , contactor matrix: 9 × 0.48 cm2 = 4.32 cm2) were tested in a randomized order. Results Supporting our hypothesis, we found that improved cutaneous sensitivity after increasing the contactor size occurs not only at high, but also at low frequencies at all anatomical locations. Large contactor sizes resulted in higher sensitivity and in a superior ability to detect changes. The superior behavior of the matrix to exhibit a lower variability could not always be proven. This work may be relevant for future studies aiming to identify changes of VPTs in various patient groups, for example.

Paratya australiensis Kemp (Decapoda: Atyidae) is a widely distributed freshwater shrimp in eastern Australia. The species has been considered as an important stream organism for studying genetics, dispersal, biology, behaviour and evolution in atyids and is a major food source for stream dwelling fishes. Paratya australiensis is a cryptic species complex consisting of nine highly divergent mitochondrial DNA lineages. Previous studies in southeast Queensland showed that “lineage 4” favours upstream sites at higher altitudes, with cooler water temperatures. This study aims to identify putative selection and population structure between high elevation and low elevation populations of this lineage at relatively small spatial scales. Sample localities were selected from three streams: Booloumba Creek, Broken Bridge Creek and Obi Obi Creek in the Conondale Range, southeast Queensland. Six sample localities, consisting of 142 individuals in total were sequenced using double digest Restriction Site Associated DNA-sequencing (ddRAD-seq) technique. Among the 142 individuals, 131 individuals shared 213 loci. Outlier analysis on 213 loci showed that 27 loci were putatively under selection between high elevation and low elevation populations. Outlier analysis on individual streams was also done to test for parallel patterns of adaptation, but there was no evidence of a parallel pattern. Population structure was observed using both the 27 outliers and 186 neutral loci and revealed similar population structure in both cases. Therefore, we cannot differentiate between selection and drift here. The highest genetic differentiation was observed between high elevation and low elevation populations of Booloumba Creek, with small levels of differentiation in the other two streams.

Genetic variants in FOXO3 are associated with longevity. Here, we assessed whether blood DNA methylation at FOXO3 was associated with cancer risk, survival, and mortality. We used data from eight prospective case–control studies of breast (n = 409 cases), colorectal (n = 835), gastric (n = 170), kidney (n = 143), lung (n = 332), prostate (n = 869), and urothelial (n = 428) cancer and B-cell lymphoma (n = 438). Case–control pairs were matched on age, sex, country of birth, and smoking (lung cancer study). Conditional logistic regression was used to assess associations between cancer risk and methylation at 45 CpGs of FOXO3 included on the HumanMethylation450 assay. Mixed-effects Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with cancer survival (total n = 2286 deaths). Additionally, using data from 1088 older participants, we assessed associations of FOXO3 methylation with overall and cause-specific mortality (n = 354 deaths). Methylation at a CpG in the first exon region of FOXO3 (6:108882981) was associated with gastric cancer survival (HR = 2.39, 95% CI: 1.60–3.56, p = 1.9 × 10−5). Methylation at three CpGs in TSS1500 and gene body was associated with lung cancer survival (p < 6.1 × 10−5). We found no evidence of associations of FOXO3 methylation with cancer risk and mortality. Our findings may contribute to understanding the implication of FOXO3 in longevity.

The goal of this work is to evaluate a deep learning algorithm that has been designed to predict the topological evolution of dynamic complex non-Euclidean graphs in discrete–time in which links are labeled with communicative messages. This type of graph can represent, for example, social networks or complex organisations such as the networks associated with Industry 4.0. In this paper, we first introduce the formal geometric deep lean learning algorithm in its essential form. We then propose a methodology to systematically mine the data generated in social media Twitter, which resembles these complex topologies. Finally, we present the evaluation of a geometric deep lean learning algorithm that allows for link prediction within such databases. The evaluation results show that this algorithm can provide high accuracy in the link prediction of a retweet social network.

Abstract Background In Germany, medical care of prisoners is completely separated from extramural health care. The extent and quality of medical care among prisoners in Germany are therefore largely unknown. We performed a secondary data analysis of pharmacy sales data for tuberculosis (TB), HIV, hepatitis C (HCV) and opioid substitution treatment (OST) delivered to prisons in 11 federal states (FS) in Germany between 01/2012 and 03/2013. The aims of this study were to assess (i) the treatment availability for the selected diseases and OST in German prisons, (ii) the proportion of prisoners treated per FS and overall for TB, HIV, HCV and OST during the study period. Methods Substances unique to or typically used for the treatment of each disease were defined as marker substances with defined daily doses (DDD). For each marker substance we assessed the cumulative number of DDD, the average daily number of DDD (DDDd) and average treatment prevalence per day in percent (adTP). Accordingly, the DDDd represents one person treated per day and the adTP means the proportion of prisoners treated per day. We compared the adTP of the diseases with previously measured prevalences. Results We obtained data from pharmacies supplying prisons in 11 of 16 German FS. Of the included prisons, 41% were supplied with medicines for TB, 71% for HIV and 58% for HCV and OST. Twice as many delivered marker substances for TB were indicated for the continuation phase and chemoprevention than the intensive phase. The HIV adTP ranged from 0.06% to 0.94%, HCV adTP ranged from 0.03% to 0.59% and OST adTP ranged from 0% to 7.90%. The overall adTP for the respective treatment was 0.39% for HIV, 0.12% for HCV and 2.18% for OST. Conclusions According to our findings treatment rates for TB were consistent with the expected TB prevalence, at least in Berlin. HIV treatment seems to be offered to an adequate proportion of estimated infected prisoners. In contrast, the HCV treatment prevalence was low. High variation among FS in provision of all treatments, particularly of OST, point to inconsistent treatment practices, although nationwide extramural treatment guidelines for Germany exist.

Conventional plasmons in metals often suffer from high plasmonic loss in the optical range. Here, the authors report a distinct form of tunable correlated plasmons in Mott-like insulating Sr1−xNbO3+δfilms, with multiple plasmon frequencies and low loss in the visible-ultraviolet range.

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 – A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F – were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.

Objective: Skin temperatures are known to increase cutaneous sensitivity. However, it is unclear whether the amount of improved sensitivity differs depending on the protocol of heat application. Therefore, this study aimed to investigate the effects of active (treadmill walking) and passive (infrared radiator) warming of the foot sole on vibration perception thresholds. Methods: Sixty healthy and injury-free subjects voluntarily participated in this study. Vibration perception thresholds (200 Hz) and plantar temperatures were measured at the hallux and 1st metatarsal head. In experiment 1, warming and mechanically stimulating the skin was achieved by walking on a treadmill for 30 min. In a follow-up study (experiment 2), external plantar heat was administered via an infrared radiator (30 min). Results: In both experiments, increasing temperatures led to increased plantar sensitivity. However, the amount of improved sensitivity was greater in experiment 1, although plantar temperature increases were lower compared to experiment 2. Conclusions: Warming in conjunction with mechanical stimulation seems to have a greater potential to enhance plantar sensitivity compared to external heat supply only. Significance: The possible influence of mechanical stimulation and warming towards superior plantar afferent feedback highlights its importance regarding human posture and fall prevention. Keywords: Plantar temperatures, Plantar sensitivity, Mechanical stimulation, VPTs

The prevalence of transmitted drug resistance (TDR) in antiretroviral therapy (ART)-naïve individuals remains stable in most developed countries despite a decrease in the prevalence of acquired drug resistance. This suggests that persistence and further transmission of HIV-1 that encodes transmitted drug resistance mutations (TDRMs) is occurring in ART-naïve individuals. In this study, we analysed the prevalence and persistence of TDRMs in the protease and reverse transcriptase-sequences of ART-naïve patients within the German HIV-1 Seroconverter Study Cohort who were infected between 1996 and 2017. The prevalence of TDRMs and baseline susceptibility to antiretroviral drugs were assessed using the Stanford HIVdb list and algorithm. Mean survival times of TDRMs were calculated by Kaplan-Meier analysis. The overall prevalence of TDR was 17.2% (95% CI 15.7-18.6, N = 466/2715). Transmitted NNRTI resistance was observed most frequently with 7.8% (95% CI 6.8-8.8), followed by NRTI resistance (5.0%, 95% CI 4.2-5.9) and PI resistance (2.8%, 95% CI 2.2-3.4). Total TDR (OR = 0.89, p = 0.034) and transmitted NRTI resistance (OR = 0.65, p = 0.000) decreased between 1996 and 2017 but has remained stable during the last decade. Viral susceptibility to NNRTIs (6.5%-6.9% for individual drugs) was mainly reduced, while

In many clinical disciplines, especially in subjective sensitivity research, data are collected on the ratio scale. This is also true for vibration perception thresholds (VPTs). Hence, such data may be of heteroscedastic nature, where the amount of measurement error increases as the values increase. Heteroscedastic data is a great scientific concern, since many standard inferential statistical tests assume homoscedasticity and may, therefore, lead to incorrect interpretations. Unfortunately, only few studies even address heteroscedasticity, and even if they do, in many cases this is achieved inappropriately. Therefore, in this paper, we first show a simple approach for how to detect heteroscedasticity in VPTs measured at the plantar aspect of the hallux. Second, we show how to correct for heteroscedasticity by means of logarithmizing the raw data. Finally, we also demonstrate the importance of how data benefits from this transformation. Hence, if data takes benefit from the transformation, we recommend using logarithmized data to conduct further statistical approaches. We also interpret the results presented here. Furthermore, we briefly mention alternatives in case the transformation is not successful in eliminating heteroscedasticity.

The goal of this work is to explore how the relationship between two subordinates reporting to a leader influences the alignment of the latter with the company’s strategic objectives in an Industry 4.0 environment. We do this through the implementation of quantum circuits that represent decision networks. In fact, through the quantum simulation of strategic organizational design configurations (QSOD) through five hundred quantum circuit simulations. We conclude that the alignment probability of the leader is never higher than the average alignment value of his subordinates, i.e., the leader never has a better alignment than his subordinates. In other words, the leader cannot present asymptotic stability better than that of his subordinates. The most relevant conclusion of this work is the clear recommendation to the leaders of Industry 4.0 not to add hierarchical levels to their organization if they have not achieved high levels of stability in the lower levels.

Structural health monitoring (SHM) is a promising technique for in-service inspection of technical structures in a broad field of applications in order to reduce maintenance efforts as well as the overall structural weight. SHM is basically an inverse problem deriving physical properties such as damages or material inhomogeneity (target features) from sensor data. Often models defining the relationship between predictable features and sensors are required but not available. The main objective of this work is the investigation of model-free distributed machine learning (DML) for damage diagnostics under resource and failure constraints by using multi-instance ensemble and model fusion strategies and featuring improved scaling and stability compared with centralised single-instance approaches. The diagnostic system delivers two features: A binary damage classification (damaged or non-damaged) and an estimation of the spatial damage position in case of a damaged structure. The proposed damage diagnostics architecture should be able to be used in low-resource sensor networks with soft real-time capabilities. Two different machine learning methodologies and architectures are evaluated and compared posing low- and high-resolution sensor processing for low- and high-resolution damage diagnostics, i.e., a dedicated supervised trained low-resource and an unsupervised trained high-resource deep learning approach, respectively. In both architectures state-based recurrent artificial neural networks are used that process spatially and time-resolved sensor data from experimental ultrasonic guided wave measurements of a hybrid material (carbon fibre laminate) plate with pseudo defects. Finally, both architectures can be fused to a hybrid architecture with improved damage detection accuracy and reliability. An extensive evaluation of the damage prediction by both systems shows high reliability and accuracy of damage detection and localisation, even by the distributed multi-instance architecture with a resolution in the order of the sensor distance.

The photophysics of lead halide perovskites is under intense investigation. Here, the authors use force microscopy on single crystals to show that light induces drastic lattice changes, and propose that the weakening of the hydrogen coupling under illumination is responsible for the lattice dilatation.

Achieving the shift towards Industry 4.0 is only feasible through the active integration of the shopfloor into the transformation process. Several shopfloor management (SM) systems can aid this conversion. They form two major factions. The first includes methodologies such as Balanced Scorecard (BSC). A defining feature is rigid structures to fixate on pre-defined goals. Other SM strategies instead concentrate on continuous improvement by giving directions. An example of this group is the “HOSHIN KANRI TREE” (HKT). One way of analyzing the dissimilarities, the advantages and disadvantages of these groups, is to examine the neurological patterns of workers as they are applying these. This paper aims to achieve this evaluation through non-invasive electroencephalography (EEG) sensors, which capture the electrical activity of the brain. A deep learning (DL) soft sensor is used to classify the recorded data with an accuracy of 96.5%. Through this result and an analysis using the correlations of the EEG signals, it has been possible to detect relevant characteristics and differences in the brain’s activity. In conclusion, these findings are expected to help assess SM systems and give guidance to Industry 4.0 leaders.

In the near future, value streams associated with Industry 4.0 will be formed by interconnected cyber−physical elements forming complex networks that generate huge amounts of data in real time. The success or failure of industry leaders interested in the continuous improvement of lean management systems in this context is determined by their ability to recognize behavioral patterns in these big data structured within non-Euclidean domains, such as these dynamic sociotechnical complex networks. We assume that artificial intelligence in general and deep learning in particular may be able to help find useful patterns of behavior in 4.0 industrial environments in the lean management of cyber−physical systems. However, although these technologies have meant a paradigm shift in the resolution of complex problems in the past, the traditional methods of deep learning, focused on image or video analysis, both with regular structures, are not able to help in this specific field. This is why this work focuses on proposing geometric deep lean learning, a mathematical methodology that describes deep-lean-learning operations such as convolution and pooling on cyber−physical Industry 4.0 graphs. Geometric deep lean learning is expected to positively support sustainable organizational growth because customers and suppliers ought to be able to reach new levels of transparency and traceability on the quality and efficiency of processes that generate new business for both, hence generating new products, services, and cooperation opportunities in a cyber−physical environment.

Monitoring skin sensitivity is studied to clarify its relationship on balance. Measuring skin sensitivity is performed when subjects are sitting or lying, whereas balance tests are measured during standing. However, afferent signal processing and subsequent efferent responses can be altered by different body positions. Therefore, this study investigated whether vibration perception thresholds (VPTs) are influenced by body positions. Sixty-six healthy subjects (41♀; 25♂) participated in this study. Five measurements of VPTs were performed at each of the three analyzed anatomical locations (heel, first metatarsal head, hallux) of the right plantar foot under two randomized conditions: during sitting and standing. The contact force applied to the probe was measured and controlled within the five trials. Contact forces between the probe and the foot were higher during standing. However, no differences in VPTs were found between conditions. This indicates that VPTs are not different during standing compared to sitting, contrary to our expectations. We conclude that higher forces did not induce increased receptor activity. Since no differences were found between thresholds, future clinical studies can implement plantar VPT tests during sitting in association with balance tests during standing.

Rapid and accurate industrial inspection to ensure the highest quality standards at a competitive price is one of the biggest challenges in the manufacturing industry. This paper shows an application of how a Deep Learning soft sensor application can be combined with a high-resolution optical quality control camera to increase the accuracy and reduce the cost of an industrial visual inspection process in the Printing Industry 4.0. During the process of producing gravure cylinders, mistakes like holes in the printing cylinder are inevitable. In order to improve the defect detection performance and reduce quality inspection costs by process automation, this paper proposes a deep neural network (DNN) soft sensor that compares the scanned surface to the used engraving file and performs an automatic quality control process by learning features through exposure to training data. The DNN sensor developed achieved a fully automated classification accuracy rate of 98.4%. Further research aims to use these results to three ends. Firstly, to predict the amount of errors a cylinder has, to further support the human operation by showing the error probability to the operator, and finally to decide autonomously about product quality without human involvement.

Industry 4.0 leaders solve problems all of the time. Successful problem-solving behavioral pattern choice determines organizational and personal success, therefore a proper understanding of the problem-solving-related neurological dynamics is sure to help increase business performance. The purpose of this paper is two-fold: first, to discover relevant neurological characteristics of problem-solving behavioral patterns, and second, to conduct a characterization of two problem-solving behavioral patterns with the aid of deep-learning architectures. This is done by combining electroencephalographic non-invasive sensors that capture process owners’ brain activity signals and a deep-learning soft sensor that performs an accurate characterization of such signals with an accuracy rate of over 99% in the presented case-study dataset. As a result, the deep-learning characterization of lean management (LM) problem-solving behavioral patterns is expected to help Industry 4.0 leaders in their choice of adequate manufacturing systems and their related problem-solving methods in their future pursuit of strategic organizational goals.

The Posturomed device is used as a scientific tool to quantify human dynamic balance ability due to unexpected perturbations, and as a training device. Consequently, the question arises whether such measurements are compromised by learning effects. Therefore, this study aimed to analyze inter- and intra-day reliability of dynamic balance responses using the Posturomed. Thirty healthy young subjects participated (24.3±3.2 years). The Posturomed was equipped with a triggering mechanism to enable unexpected, horizontal platform perturbations. A force platform was used to quantify Center of Pressure (COP) excursions for two time intervals: interval 1 (0-70 ms post perturbation) and interval 2 (71-260 ms post perturbation). Dynamic balance tests were performed in single leg stances in medio-lateral and anterior-posterior perturbation directions. Inter- and intra-day reliability were assessed descriptively using Bland-Altman plots and inferentially using tests for systematic error and intra-class-correlations. With regard to the mean COP excursions for every subject and all intervals, some cases revealed significant differences between measurement sessions, however, none were considered relevant. Furthermore, intra class correlation coefficients reflected high magnitudes, which leads to the assumption of good relative reliability. However, analyzing inter- and intra-day reliability using Bland-Altman plots revealed one exception: intra-day comparisons for the anterior-posterior direction in interval 2, which points towards possible learning effects. In summary, results reflected good overall reliability with the exception of certain intra-day comparisons in the anterior-posterior perturbation direction, which could indicate learning effects in those particular conditions.