In 1994, Piccoli The purpose of this study is to develop an approach to data analysis in body composition bioimpedance research in two-dimensional representations.The data of 1.124.668 patients aged 5 to 85 years who underwent a bioimpedance study in Russian Health Centers from 2009 to 2015 were used. Statistical programming in the R Studio environment was carried out to estimate two-dimensional distribution densities of pairs of body composition parameters for each year of life.The non-Gaussian distribution is found in most parameters of bioimpedance analysis of body composition for most ages . The slices of the actual two-dimensional distribution pairs of body composition parameters had an irregular shape. The authors of the article propose using the actually observed distribution for populations where numerous bioimpedance studies have already been carried out. Such technology can be called two-dimensional bioimpedance analysis of human body composition (2DBIA). The 2DBIA approach is clearer for practitioners and their patients due to the use of body composition parameters in addition to electrical impedance parameters. The development and practical application of the technology of bioimpedance analysis of human body composition (BIA) began four decades ago. The forms of BIA data presentation have improved and developed: the result sheets have been repeatedly supplemented with new parameters, the ranges of normal values have been refined, the age range of the subjects has been expanded, and centile evaluations have been used.The tabular representation of bioimpedance estimates of body composition parameters in both static (for one-time examination) and dynamic (for numerous examinations of one person) BIA result sheets have, naturally, evolved into a graphical one. The current representation of the primary BIA result sheets demonstrates the geometric position of the current value markers of the BIA parameters against the background of graphic scales with gradations of “normal”, “below normal”, and “above normal”. The boundaries of the normal value area for each parameter were repeatedly revised, as a result of obtaining more and more representative samples of experimentally obtained data and localized for ethnic populations. A similar trend can be observed in dynamic result sheets: the appearance of graphs and diagrams presented against the background of norm zones and centile curves. Further development and sophistication of BIA result sheets has continuously increased the saturation of information and the speed of data reception by the physician .The number of parameters calculated for body composition analysis in modern analyzers has slightly increased. In addition to the traditional estimates of body fat mass (FM), fat free mass (FFM), total, extra and intracellular fluid , estimates of active cell mass (ACM), skeletal muscle mass (SMM), and mineral mass (MM) have been added. Metabolic correlates have also been added to the list of calculated parameters: basal metabolic rate (BMR) and phase angle (PA) .According to early 2000–2010 publications, samples of hundreds of thousands of people have already been received in some countries ,4,5,6. Ohttps://www.tanita.com, . The same trend is present for different parameters for all ages of both male and female parts of the population. In this case the non-Gaussian multivariate distributions are explained by the high prevalence of obesity: more than 52% of the group have BMI > 30 kg/mThe most notable deviations from the elliptic form of dispersion in many ages were found for the 95% tolerance curve. This phenomenon is due to the large variability of rarely occurring combinations of initial parameters in the raw data and, as a result, in general, the form of data dispersion is far from elliptical. Thus, the usage of Gaussian multivariate distributions with two-dimensional elliptic representation to describe the entire population does not seem reliable enough. The volume of bioimpedance research data collected at Russian Health Centers allows us to construct a planar representation of two-dimensional distributions without using a pre-selected curve shape.Using the specially developed Animation software , on the basis of native bioimpedance data of more than 1.1 million people, two-dimensional centile curves for several pairs of body composition parameters were constructed. The software allows selecting any pair of parameters and setting any age range from 5 to 85 years. To assess body composition at the individual level in a single study as well as to learn about the population age dynamics of the parameters, a fairly narrow age range can be chosen, for example, within one year. This step clearly shows age-related changes in the dynamics of body composition parameters, and the typicity of individual patient indicators are evaluated accurately. Any combination of BIA parameters can be selected when drawing two-dimensional centile curves. Colored numbers in the right upper corner show population value inside the corresponding closed curves. The upper left corner displays population age and population value used for constructing each centile curve. Also, the overall age structure of data used is visible.It is clear that the centile graphs of all parameter pairs are not concentric ellipses and all two-dimensional distributions are non-Gaussian . The observed shape of the centile curves is specific for each pair of parameters.The 2DBIA centiles curves  were connd week of gestation  it was found that the distribution of bioimpedance data in the Russian population shows significant difference from Gaussian. The authors of the article propose using the actually observed distribution for populations where numerous bioimpedance studies have already been carried out.Parameters of body composition, already familiar to physicians through their courses of normal and pathological physiology, can be used as a basis for a two-dimensional bioimpedance analysis of human body composition. It means the 2DBIA can help improve the quality of medical care and patient adherence to therapy. Since the parameter values of body composition bioimpedance analysis and their distribution in the population undergo significant changes with age, the image of 2DBIA, built for narrow age intervals, should be considered for clinical use.et al. [Data visualization, containing more than two dimensions, entails difficulties in graphical construction, and, more significantly, information perception. A compromise solution is proposed to place four two-dimensional images of eight basic body composition parameters on the background of two-dimensional centile curves on one screen and on one sheet of the result sheet. The technique of constructing two-dimensional curves of 2DBIA was considered in work by Nikolaev D.V. et al. . FiguresApparently, the irregularity of the curves’ shape is explained by the features and the size of the population. In this case from 20% to 80% of the Russian population depending on sex and age are overweight or obese . 95% tolPatients with diabetes  differ lth to 37th weeks of gestation, bioimpedance analysis registers an increase in iFM against the background of a less pronounced increase in iFFM and a pronounced increase in BMI and extracellular fluid volume. In general, there is an undeniable tendency for the indicators to go beyond the internal curves of tolerance.th day.A two-week follow-up examination of a pregnant woman  with preDuring the development of the fetus, the fat mass experienced fictitious increases in order to increase the body weight of the woman's fetus, amniotic water and increasing uterine weight: in the lower right quadrant a sharp decrease iFM on the third day after birth  is visibThe idea of compressing BIA data in two-dimensional representations may be useful. Visual representations of the 2DBIA allow analyzing the selected combinations of body composition parameters. It is shown that such visual representations can be used for both single and dynamic studies of body composition. A simultaneous image of several pairs of parameters allows a more complete assessment of the patient's condition and its change during a dynamic observation. Thus, the possibility of a real multivariate estimation of body composition parameters is excluded. Considering the volume of bioimpedance data accumulated in different countries, localized reference images of 2DBIA can be constructed for each sex and age, which will increase the adequacy of patient assessment and minimize the probability of errors. Time will show whether this technology will be in demand.


The purpose of this brief communication is to make publicly available three unpublished manuscripts on the organization of retinal ganglion cells in the tree shrew. The manuscripts were authored in 1986 by Dr. Edward DeBruyn, a PhD student in the laboratory of the late Dr. Vivien Casagrande at Vanderbilt University. As diurnal animals closely related to primates, tree shrews are ideally suited for comparative analyses of visual structures including the retina. We hope that providing this basic information in a citable form inspires other groups to pursue further characterization of the tree shrew retina using modern techniques. Tupaia belangeri or Tupaia chinensis) (Northern tree shrews (inensis)  are smalinensis) . They arIn the early 1980s, Dr. Edward DeBruyn, then a PhD student in the laboratory of Dr. Vivien Casagrande, produced a characterization of the organization, morphology, and projections of RGCs in the tree shrew retina. The findings were documented in the first three chapters of Dr. DeBruyn’s doctoral thesis DeBruyn, . ManuscrThe purpose of this communication is to make these unpublished manuscripts on the organization of RGCs in the tree shrew available to the neuroscience community. Here we briefly describe the central findings of the works, place them in the context of current knowledge of cross-species retinal properties, and refer the reader to the three manuscripts in Supplementary Material. Although they did not complete the peer-review process, the manuscripts contain the majority of our current morphological knowledge about tree shrew RGCs. We hope their availability inspires future studies using modern techniques that may confirm or refine the main findings. To cite any of these manuscripts, please follow the format used in this brief communication both for in-text citations and for the full reference as listed in the reference section.area centralis,” a small region in the temporal retina with the maximum cell density of approximately 20,000 cells/mm2  of RGCs backfilled with horseradish peroxidase (HRP) injected into the optic tract or superior colliculus (SC). The authors concluded that tree shrew RGCs could be grouped into three major classes based on morphological criteria . Though versus OFF-center (laminae 4 and 5) cells into paired ipsi- and contralateral layers in the dorsal lateral geniculate nucleus (LGNd)  in different brain structures and analyzed the spread, soma size and dendritic arborization of retrogradely labeled RGCs. These results highlight unique features of the tree shrew visual system, as also reported by other groups including : (1) segAlthough these manuscripts provide fundamental data on the organization of the tree shrew retina, much work remains. For instance, studies of the morphological, functional, and molecular properties of RGC cell types in the mouse, their distribution across the retina, and their contribution to behavior, have produced major advances in our understanding of visual processing in this species. These studies were critically dependent on advances in genetic and molecular tools for the measurement and manipulation of neuronal structure and function such as large-scale electrophysiological recording and single cell RNAseq (Baden et al., Improved understanding of the tree shrew retina will benefit visual neuroscientists as well as the broader community of scientists who study species-specific retinal properties and their relationship to ecological niche and behavior. Given the tree shrew’s proximal position to primates, in the evolutionary tree  these da


Amongst odontogenic cysts, keratocystic odontogenic tumor (KOT) is a benign intra-osseous lesion, characterized by corrugated parakeratinized uniform stratified squamous epithelium,with potential for aggressive behavior and high tendency to recur. There are multiple treatment modalities for this cyst.Some surgeons prefer the conservative treatments such as marsupialization while the others prefer invasive treatments such as radical resection.The aim of this study was to present a case of KOT involving the right mandibular premolar area with an impacted tooth in a 9-year-old boy treated by marsupialization.The treatment resulted in eruption of the mandibular first premolar, and no signs of recurrence were observed after two years.Marsupialization was found to be an effective treatment in inducing the eruption of mandibular premolar associated with KOT in preadolescents and can be a reliable procedure to reduce recurrence tendency of KOT In 1956, the word odontogenic keratocyst (OKC) was originally named by Phillipsen until it was classified as keratocystic odontogenictumor (KOT) by WHO in 2005  .KOTs are more prevalently seen in the posterior region of the mandible than in maxilla  .This leIn histological examination, KOTs are characterized by a fibrous wall, lined with corrugated parakeratinized stratified squamous epitheliumof 6-10 cell layers in thickness without rete pegs, which makes a flat interface between the epithelium and the connective tissue , 9.The A 9-year-old boy referred to the department of oral and maxillofacial surgery of Rajaei Acute Care Surgical Hospital affiliated to ShirazUniversity of Medical Sciences with a chief complaint of swelling in the right body of mandible.The history of papilloma in the dorsal region of the tongue and familial multiple KOTs were reported.Extra oral examination revealed a non-tender, firm swelling on the same side.Intra oral examination revealed a painless, firm swelling in the buccal vestibule, extending from distal aspect of canine to the mesialaspect of the first molar. No systemic pain was observed and the patient’s general condition was good.The panoramic image showed a multilocular well-defined radiolucent lesion in the right side of mandible from the right canineto mesial of the non-erupted second premolar. The lesion had expanded from alveolar crest to inferior border of the mandible, and therewere some septa inside. Displacement of the first premolar and root resorption of the primary firstmolar were observed .The cone beam computed tomography (CBCT) images showed a large multilocular expansile radiolucent lesion in the right side of mandiblethat had caused displacement and impaction of permanent first premolar, root divergence of canine and second premolar as well as rootresorption of the primary first molar. Loss of continuity of cortical borders of mandibular canal at the affected site was seen.Thinning and expansion of mandibular buccal and lingual cortical plates as well as perforation of buccal mandibular cortex were observed and 3.There was another expansile lytic lesion in the left mandibular molar area, causing destruction or failure to develop tooth bud of the left third molar.Based on clinical and radiographic findings, the differential diagnosis was compatible with dentigerous cyst and then KOT.The treatment possibilities were discussed with his parents. For histopathologic findings, two incisional biopsies were initially performed to approve the diagnosis. Microscopic examination showeda cystic lesion lined by corrugated parakeratotic uniform stratified squamous epithelium with hyperchromic palisaded basal layer,and the connective tissue revealed mild infiltration of inflammatory cells .Treatment started with prep and drape under general and hypotension anesthesia in supine position.First, right sulcular incision was made and musculomucosal flap was reflected. Inferior alveolar nerve was explored and preserved.Next, marsupialization of pathologic lesion was done and obturator was applied.Afterward, mucoperiosteal flap was replaced and sutured with vicryl 3/0. Another sulcular incision in the left side of the mandiblewas made and mucoperiosteal flap was reflected. Then, unerupted tooth No. 7 was extracted and pathologic lesion in this site was excised.Mucoperiosteal flap was replaced and sutured with vicryl 3/0. After discharging from hospital, the patient returned periodically for the follow-up. After one year, the lesion size had decreased and the first mandibular premolar had completely erupted.After two years, the panoramic radiograph showed adequate bone healing and no evidence of lesionrecurrence was observed . The firet al.[ Various approaches are utilized to treat KOTs. The conservative treatments for KOTs are marsupialization and decompression. The invasive treatments are resection, peripheral osteotomy,and enucleation . Due to high recurrence of KOTs, the best treatment plan is stillcontroversial  , 10.It et al. , marsupiA recent study   evaluateThe authors   claimed A written informed consent was obtained from patient's parents.In our case study, marsupialization was found to be an effective treatment in inducing the eruption of mandibular premolar associatedwith KOT in preadolescent. It seems that this treatment modality can be a reliable procedure to reduce recurrence tendency of KOT.


As of late 2019, the COVID-19 pandemic has been a challenge to health care systems worldwide. Rapidly rising local COVID-19 incidence rates, result in demand for high hospital and intensive care bed capacities on short notice. A detailed up-to-date regional surveillance of the dynamics of the pandemic, precise prediction of required inpatient capacities of care as well as a centralized coordination of the distribution of regional patient fluxes is needed to ensure optimal patient care. In March 2020, the German federal state of Saxony established three COVID-19 coordination centers located at each of its maximum care hospitals, namely the University Hospitals Dresden and Leipzig and the hospital Chemnitz. Each center has coordinated inpatient care facilities for the three regions East, Northwest and Southwest Saxony with 36, 18 and 29 hospital sites, respectively. Fed by daily data flows from local public health authorities capturing the dynamics of the pandemic as well as daily reports on regional inpatient care capacities, we established the information and prognosis tool DISPENSE. It provides a regional overview of the current pandemic situation combined with daily prognoses for up to seven days as well as outlooks for up to 14 days of bed requirements. The prognosis precision varies from 21% and 38% to 12% and 15% relative errors in normal ward and ICU bed demand, respectively, depending on the considered time period. The deployment of DISPENSE has had a major positive impact to stay alert for the second wave of the COVID-19 pandemic and to allocate resources as needed. The application of a mathematical model to forecast required bed capacities enabled concerted actions for patient allocation and strategic planning. The ad-hoc implementation of these tools substantiates the need of a detailed data basis that enables appropriate responses, both on regional scales in terms of clinic resource planning and on larger scales concerning political reactions to pandemic situations. The COVID-19 pandemic affects societies worldwide. It began spreading across Europe and North America in early 2020. From the very beginning, the COVID-19 pandemic has been a significant challenge to health care systems worldwide. The health care capacities of many countries reached their limits in regions with particularly high SARS-CoV-2 infection numbers due to a fast acceleration of the infection dynamics . The actThe aims of this paper are as follows:Description of the regional Saxonian model of care for pandemic responsePresentation and validation of our mathematical model for predictions of regional demands of bed capacities.Germany is a federal republic with strict separation of power and responsibilities between the federal government and its 16 states, such that non-pharmaceutical interventions (NPIs) and most regulations concerning COVID-19 are established at the state level and are only coordinated by the federal government. Thus, in principle every state has its one set of regulations that depends on the local pandemic situation and respective political measures taken on the state level. During the second wave of the pandemic between October 1 and December 24, 2020, the state of Saxony readjusted its regulations five times tightening restriction with each subsequent set of regulations to counteract the increasing number of cases –15. AmonIn October 2020, light restrictions introduced during the first wave early 2020 were still in place, e.g., a ban of public gatherings of more than two households plus family members and ten additional people as well as mandatory masks in shops and public transport, with additional regional restrictions depending on the number of new cases per week and the overall population.On November 2, 2020, these counter measures became significantly stricter. Shops, bars, restaurants, sport facilities and most public meeting places were closed, non-private public events were generally restricted in their number of participants and the allowed number of simultaneous private contacts was reduced. Schools were mostly unaffected by these regulations.This changed on December 14, 2020, when the state of Saxony entered into an extended shutdown, which further reduced the allowed number of private and public contacts and facilitated the closing of schools and essential educational institutions. These were thereupon closed.Both shutdowns, moderate and extended, had a significant effect on the infection dynamic and bed occupancy rates but did not prevent the number of cases from increasing.2) and with more than 4 million inhabitants the sixth most populous state [Saxony is the tenth largest of Germany’s sixteen states  was necessary to ensure a structured distribution of patients. These clinic coordination centers are located at three hospitals of maximum care, which are the large university hospitals in Dresden (East), Leipzig (North) and the clinic of Chemnitz (West). The distribution of COVID-19 patients based on severity of disease and needed treatment  is organized by a graduated scheme:Level I: inside of the three clusters East, North and West SaxonyLevel II: inside Saxony between different clustersLevel III: nationwide in Germany On a daily basis, the individual hospitals report their actual occupancy of COVID-19 beds as well as free beds to the clinic coordination center of their cluster. Their coordination center then provides this information to be fed into the DISPENSE database (see below for abbreviation). In return, the DISPENSE tool provides a daily report on free and occupied clinic beds for each cluster as well as a prognosis and in this way enables the clinic coordination centers to allocate COVID-19 patients to clinics with free treatment capacities. Video conferences with all heads of each of the clinics provide a planning, information dispersal and mutual discussion platform. These conferences were held up to twice a week during November and December 2020.On another scale of surveillance, thirteen local health departments oversee and monitor SARS-CoV-2 outbreaks. They all report their information to the State Health and Veterinary Research Institute , a subordinate authority of the Saxon State Ministry for Social Affairs and Social Cohesion at the next higher state-level of organization, which in turn relays this data to the DISPENSE database.The data, e.g. information about age, gender, and date of death of Saxonian COVID-19 patients, is also reported to the Robert-Koch-Institute at the federal state-level. Note that in contrast to the DISPENSE tool, which has been established as a local solution as part of a sudden demand during the pandemic, this structure of reporting from the local authorities to the federal state level is part of the German public health service.COVID-19: Dresdner Informations- und Prognosetool für Erkrankungsverlauf und Bettenauslastung in Sachsen, in English: COVID-19: Dresden’s information and prognosis tool for the disease course and hospital bed demand) model of care was initiated by the University Hospital Dresden together with its 35 partner hospitals and the local public health institutions. The acronym comprises the idea of an online tool including infection surveillance and prognosis of bed capacity requirements in Saxon regions. The clusters East, North and West Saxony had agreed on and established a collection of data for bed occupancies. Those data were subsequently integrated into the DISPENSE tool. The project was undertaken in accordance with the GCP and data protection legislation. The institutional review board of the TU Dresden approved the study protocol (EK number: 235062020). Note that as no patient data was used, no consent was required.In March 2020, the German federal state of Saxony, in the course of a general ruling, assigned the regional responsibility for the provision of appropriate inpatient care facilities for COVID-19 patients in East Saxony to the University Hospital Carl Gustav Carus in Dresden  where the clinic coordination center is situated alongside the 35 hospital. On these legislative grounds, the DISPENSE  capacity needs for the upcoming 2 weeks. It consists of individual components to handle data automatically at various stages of the process of extraction, transfer and loading (ETL).The The extraction of data from several heterogeneous sources is funneled through a custom-made system of post-processing steps and culminates in a complementary database as is shown in ◦ the local and communal level ◦ the regional Saxony-wide level (statewide information on a fast track data download to avoid reporting delays to the Robert-Koch-Institute)◦ the federal Germany-wide level (data is sourced from an open data source provided by the Robert-Koch-Institute) ◦ the European level (data is sourced from John Hopkins University data set) The COVID-19 infection spread onThe normal ward and ICU ward bed occupancy from all three Saxon hospital clusters centrally managed by the University Hospital Dresden , University Hospital Leipzig , and the hospital Chemnitz The front-end, a tool implemented in R Shiny displays plots and key figures to the end-users of the crisis management and infection monitoring teams, i.e. decision makers at regional hospitals, health administration authorities, and ministries. For this purpose, the most suited dataset is utilized for each visualization, e.g. state-provided data for Saxony and the John Hopkins University data set for a European overview. The presentation is both in electronic form of an internet dashboard see  and mateThe dynamic mathematical model to predict near future bed occupancies in Saxony is driven by the most recent and accurate data sources for incidences and current bed occupancies in Saxony, i.e. the state provided infection data and detailed bed occupancy data provided by the three clusters. A prototype of the mathematical model for prognosis was set up and used by decision makers in East Saxony as of early April 2020. The prognosis was implemented as a fully automatized version for all three clusters in a development phase from summer 2020.The DISPENSE tool is regularly used by the central clinic coordination centers and regional clinics for strategic decisions in pandemic management for the graduated distribution scheme, creation of additional treatment capacity by the reduction of elective medical treatment and data reports in video conferences of the cluster clinics. The reliable prediction of COVID-19 patient numbers on a two-week horizon via DISPENSE prognoses allows for proactive and tailored disaster management.In order to estimate the course of the pandemic at the population and health care level we used a variant from the Susceptible-Exposed-Infected-Removed (SEIR) model class –24. Fig Like in classical SEIR-models, susceptible individuals in the compartment (S) are transferred to the compartment (E) whenever they are exposed and infected by contact with an infectious individual in compartment (I). Exposed individuals in compartment (E) are infected but incapable of infecting others as, for example, their viral load is still too low. They then transition to the compartment (I) after a pathogen specific waiting time and become infectious themselves.Unlike the number of infectious individuals in compartment (I), the amount of people in compartment (E) cannot be measured robustly with standard PCR or rapid antigen test.During the course of the infection, the infectious person then leaves this state by transitioning to the removed (R) or normal ward state (H). Please note that the removed state (R) comprises all people who have either recovered from the disease or passed away as a result from or during the disease. Whether a person is removed from or enters into the normal ward state depends on a specific probability. This probability encapsulates several risk factors to enter the hospitalized stage, e.g. age, comorbidities, or overall fitness. As these factors are both complex and/or not known, they do not enter into the model explicitly, but are contained in the model parametrization.The hospitalized patients then transition from the normal ward (H) either to the removed state (R) or to the ICU state (B). The choice of this route is random with probabilities that again depend on the aforementioned risk factors. Since the direct admission form infectious (I) to ICU ward (B) played a secondary and negligible role in Saxony for the largest part of the pandemic and parameter estimation for this transition proved impossible with the provided data set, we decided against modeling this transition.Thus, parameters of this model are the transition rates between compartments, transition probabilities and the overall infection parameter R0. Aiming at predicting the occupancy of acute care, the input occupancies for the model are patient counts in the acute hospitals. Emergency reserves available in alternative medical facilities help keep up medical care during overburdening but are not an object of the regional coordination in tense but not overloaded periods.On the day of prognosis the three free model parameters were fitted via the least squared error method to data from eight days prior to the prognosis day. Implicitly, this assumes that the trend for these parameters of the dynamics and people requiring attendance at hospitals remains unchanged during the prediction horizon. The model was then run from the day of prognosis with these parameters to forecast to seven days and give a trend line for 14 days in the future.The fitting procedure was applied to each of the three hospital clusters individually. The sum of each of these regions then yields the state-wide prognosis for Saxony.We validated our mathematical model for near-future regional bed capacity prognosis using two different approaches. At first, we scatter plot prognosis data against measured reality to visually guide the search for abnormalities in our prognosis across the orders of magnitude of the time series. An unbiased prediction across value ranges shows a symmetric cloud around the identity diagonal.Secondly, we looked at the relative errors R(t) given byPersistently positive values as well as negative values of R(t) reveal systematic over- or underestimation and are thus an indicator of bias.By treating the three clusters as an ensemble of statistically independent processes subject to the same time-dependent forcing of the pandemic, we get a picture of our model’s performance over time.mean and the standard deviation Rstd of this distribution characterize the accuracy and the precision of the prediction. For an unbiased prediction, we expect Rmean≈ 0. The predictions are only informative for small Rstd.The distribution of relative errors summarizes the performance in a given time window T. The mean relative error Rmean and Rstd for different time windows T.Since the infection dynamic is non-stationary and subject to sudden changes in the population’s behavior and the implementation of NPIs, we expected the performance to be time dependent. Thus, for a fair analysis of the prediction quality it is necessary to compute Rmean and Rstd for all of Saxony and for each individual regional cluster to evaluate the overall and regional performance.Finally, we computed RIn the following, we will present key figures as well as the model evaluation during the so-called second wave of infections in the federal state of Saxony. We briefly summarize the overall numbers of detected cases in Saxony and of occupancies in Saxonian hospitals, and present how the distribution of age, an important risk factor of hospitalization, has changed during the wave. This distribution provides an intuitive connection to the need of hospital beds, as the probability of hospitalization rises with age. The age distribution thus–if reported immediately—poses, in addition to the prognosis, an important source of information for medical management.Finally, we will evaluate the performance of the model prediction on bed occupancy for Saxonian acute hospitals and the clusters by comparing our predicted and the true occupancies.By December 31, 2020, a total number of 138,549 individuals tested positive for SARS-CoV-2 since the beginning of the pandemic in Saxony . Of thesAcross all age groups more women than men were tested positive with prominent peaks in the age groups 50–59 and above 80 years, respectively . In the The trajectory of registered individuals infected with SARS-CoV-2 in Saxony exhibited an exponential increase in October 2020, a slowing down and a plateau in November 2020 followed by a second almost linear increase in December 2020, a slowing down in late December 2020 and a rapid decrease before Christmas see .The incorporated SEIR-model provides a seven-day estimate of the bed demand on ICU and normal ward in each of the three Saxon clusters. Since the qualitative infection dynamic was the same in all three clusters  and since the resulting effects in our prognosis were analogous, we restricted our model evaluation to the cluster East Saxony and the whole state of Saxony. The performance evaluation of the two remaining clusters can be found in the Our seven-day prognosis for bed demand in East Saxony reflected the behavior of the actual time series in general . The proThe scatter plot revealed that the errors of the employed forecasting model form a uniform corridor and exhibited no visible biases for different ranges of predicted values see .As we outlined in the Section Statistical Methods for Model Validation, we computed the time series of relative errors in bed demand for each of the three clusters and investigated their joint mean and standard deviation to assess the models performance over time as well as possible temporal biases see . The aveMotivated by these different performances during different time windows, we computed the mean and the standard deviation of relative errors for three periods. First, (A) during the complete three months October, November and December 2020, then (B) starting from the exertion of shutdown measures at November 3, 2020 until end of December 2020, and finally (C) in the time window starting at November 19, 2020, right after the overestimation period of ICU bed demand predictions, until end of December 2020. In every time window the prognosis errors (standard deviation of relative errors) for the cluster East Saxony was lower than for the entire state of Saxony. We found that our model yields an expected error of 21% in normal bed occupancy and 38% in ICU bed occupancy for all of Saxony between October 1, 2020, and December 31, 2020, however, less than 15% during the critical phase of the second wave in November and December 2020.In principle, Surveillance of SARS-CoV-2 spreading allows inferring the emergence of near-future COVID-19 cases by mathematical modeling. Numerous well-established epidemiological studies state a broad theoretical background for the modeling of infection dynamics. A common approach to this question are SEIR-type compartment models  along wiThe limitations of our current study manifest mainly in the available data to faithfully predict unknown model parameters. For instance, given the age-dependent severity of the disease course for a population requires exact knowledge of each individual’s exact age at each point in time. To circumvent this problem we implicitly modelled this parameter dependence by adjusting free parameters over time to reflect severity and current mean age of the infected individuals without actually requiring to know these exact variables. This goes in line with the principle of parsimony  to only use a minimal number of variables to model a process. In addition, SEIR-models are a simplified view of complex disease dynamics and only have limited validity under stochastic effects such a low number of infected individuals. In order to reduce parameters even further, we omitted to model the transition between the infected and the ICU compartment because of its negligible role in Saxony during this study’s time frame. However, despite its limitations, as we showed, our approach suffices to predict hospital bed demand and guide the hospital planning process especially under a surge in Corona virus cases.Accurate prognoses of near-future hospital capacity demands require an appropriate modeling of both infection dynamics and patient stays in hospital treatment. Predictions of infection dynamics help quantifying future patient influx into the healthcare system. Super-spreading events such as outbreaks in care homes, institutions of common education or collective accommodation or during other gatherings of larger groups of people notably accelerate infection spreading by a high number of affected people at the same time. Mathematical models cannot predict the occurrence of such events due to the complexity of human behavior. Prognoses can nonetheless account for and properly incorporate such observations if a detailed surveillance and reporting of detected cases and hotspots is provided. For the estimation of hospital capacity demands at specific points in time additional knowledge about the outflow of patients is necessary. This in turn requires information about the current occupancy of normal wards and intensive care units as well as the patient flow rates between model compartments.The course of the pandemic during the spreading phase since the beginning of October 2020 is subject to non-pharmaceutical interventions and other changes of human behavior. Interventions systematically change both the dynamics of the pandemic and hospital admission and hence the requirements on mathematical models for health care demands. Until the end of 2020 the impact of the worldwide vaccination program due to immunization was still negligible in Germany. The exponential growth of reported infections was suspended by the implementation of light shutdown measures during November . The agaThe specific dynamical features were also visible to a lesser extent in the number of hospital beds occupied by COVID-19 patients on normal ward and ICU ward see .Legal regulation affected the amount of hospital bed capacities in Germany due to financial reimbursements and interruption of elective medical treatment. During the Christmas holidays and on weekends the burden for the Saxon clinics in treating COVID-19 patients was even higher because of reduced outpatient medical treatment by general practitioners. For the future, the cooperation of outpatient and clinical treatment of COVID-19 patients has to be intensified to avoid unnecessary admissions and crowding in clinics.The overall pandemic situation is obviously non-stationary, in the sense that the dynamics of infections and hence hospital admissions underlie different forces and characteristics during different temporal periods. Our model evaluation shows periods of better and worse forecast accuracy for hospital bed demands. The origin of the underestimation of bed demands  seems toFurthermore, decreased outpatient treatment capacity and local out-breaks in rest homes may explain this haziness.The temporal overestimation of ICU beds is most probably caused by the introduction of NPIs in the beginning of November. This is indicated by the start of the overestimation period around November 12, 2020, i.e. nine days after NPIs were introduced, which is the delay expected for such effects to be noticeable at ICU . AlsTaken together, in particular, these points illustrate that in the critical phase of increasing daily infection numbers, the predicted numbers of hospital demand reflect not the real development but rather a scenario that would have occurred if no counter measures had been introduced. As a remark, the prognosis for the entire state of Saxony is smoother cp. Figs  and 7 si0 (controls infections), pIR and pHR  in our modeling allow for a flexible and quick adjustment of our prognoses to the aforementioned systematic changes in the daily live application. The non-stationary setting of variable data influx , systematic changes  and prognoses that possibly induce interventions itself makes an overall model evaluation difficult. Considering the entire period of increasing incidence from October until December 2020, the error of our prognoses was 21% nonetheless. During November and December 2020, the critical phase of the high healthcare capacity demands and still ongoing growth of case numbers after the implementation of moderate NPIs, we achieved a prognosis precision of 15% at best. Considering sudden surges in hospitalization numbers caused by correlated infections in residence homes as well as planned German-wide redistribution of patients [The free parameters Rpatients , this isThe utilization of the DISPENSE tool by the central clinic coordination centers was essential to avoid crowding and secure medical treatment in Saxony during the Christmas holidays at the peak of the second wave. Because the tool predicted exhausted treatment capacities within two weeks, the central COVID-coordination in Saxony decided on December 18 to launch LEVEL III of the aforementioned graduated distribution scheme and allocated COVID-19 beds nationwide in Germany. Because of large transportation distances in Germany, weather dependent flight conditions (rescue helicopter) and high logistical demands, these additional two weeks were valuable and helped to secure free hospital beds at any time in Saxony. According to this successful disaster management, the Saxonian concept of patient distribution located at university hospitals and based on close collaboration between political and clinical decision makers, data providers and mathematical modeling is a “best-practice” example among the German healthcare system.The DISPENSE project in the German Federal State of Saxony put a regional data-based patient steering system into practice during the COVID-19 pandemic. The online tool comprises a comprehensive quantification and visualization of the regional pandemic situation. A strong cooperation between the inpatient coordination centers, the data scientists in charge of the prognosis and the medical informatics department crucially strengthens the Saxon health care system by integrating the activities into each individual player’s work routine.The resulting dashboard visually integrates data that would be otherwise disperse. The end-users and decision-makers have key information at their fingertip to adjust their course of actions to, for example, coordinate management teams to plan political social distancing interventions as in the case of the state ministry and to provide additional hospital resources as in the case of hospital overburdening.The present case study brings together theoretical modeling of bed capacity demands and real bed occupancy data of the second pandemic wave in Saxony. Experiences from the daily live application of the model prognoses propose some improvements of the forecasting procedure such as adjustments to unexpected behavior in both the spreading and bed dynamics.Modeling the course of expected hospital capacity demands during a pandemic benefits hospitals with more balanced workloads and resource demands.S1 File(PDF)Click here for additional data file.


Complex regional pain syndrome (CRPS) is a disabling condition that is usually preceded by trauma or surgical procedure. Involvement of the motor system is a well-known phenomenon in CRPS, though the pathophysiologic mechanisms of motor system affliction in CRPS are poorly understood. Graded motor imagery (GMI) has been proposed to be one of the therapeutic interventions to help improve pain and other disabling symptoms associated with CRPS, though the benefits noted are modest and inconsistent. The neurophysiological mechanisms implicated in motor imagery are intended to target the aberrant prefrontal and sensorimotor integration areas, which may potentially help restore the aberrant cortical plasticity in CRPS. Detailed well-controlled experiments using insights from the existing body of literature on motor system reorganization in CRPS are required to better understand this complicated disorder. Attempts to gain pathophysiologic insights about complicated disorders like CRPS based on case reports with poorly performed and uncontrolled interventions are misguided. They additionally performed TMS during the follow-up visits and noted a serial increase in delta scores based on motor evoked potential (MEP) amplitudes and interpreted that as being evidence for motor system reorganization. The current case, which occurred after a radial fracture was classified as CRPS type I; however, the authors do not report any findings of electromyography (EMG)/nerve conduction studies, which would be essential for this diagnosis, especially in the setting of a fracture. Absence of baseline and follow-up nerve conduction studies to rule out the possibility of any axonotmesis or neurapraxia makes the interpretation of the findings of the current case report difficult. The authors correctly noted many limitations in their performance and interpretation of the TMS experiments. To note a few, they used delta scores derived using resting motor threshold (RMT) as a surrogate for corticospinal strength, which is incorrect. They did not perform an input-output (IO) curve, which involves giving TMS pulses of varying strengths in a random order to measure the MEPs at the different stimulation intensities. Additionally, using the same swim cap to locate the hotspot for follow-up visits is an erroneous technique. Though using swim caps may be reasonable technique for a single session, it is certainly not appropriate for multiple follow-up visits, and imaging-based guidance should have been used to ensure stimulation of the same cortical site.In the present issue of the 27 There is no clear evidence that any of the interventions performed by the authors influence either of these mechanisms. Mechanisms of graded motor imagery, though poorly understood, implicate influencing the prefrontal and sensorimotor integration cortices.30 Studying the influence of a complicated therapeutic intervention using measures based on RMT does not have any clear rationale. The authors claim improvements in the MEP recorded as evidence of strengthening of corticospinal projections; however, the clinical improvements in strength are clearly lacking.The authors suggested improvements noted in delta scores that are based on RMT obtained at follow-up visits as suggestive of strengthening of corticospinal projections. RMT is increased by drugs blocking the voltage-gated sodium channels and decreased by drugs that enhance non-N-methly-D-aspartate (NMDA)-mediated glutamatergic transmission.31 Another possible explanation could be the resolution of the nerve damage, which may have occurred due to the fracture and would follow a similar timeline for improvement.32 Improvement in the strength of corticospinal projections is an unlikely explanation for the findings noted in the current report.The findings of the current case report can be best interpreted as improved recording of the surface EMG as the vasomotor and sudomotor changes associated with CRPS improved. Though the authors noted nonsignificant changes in the edema, the peripheral changes were not clearly monitored objectively at follow-up, to be certain. Though the changes related to edema can affect the MEPs at both 110% and 130%, the variability in the MEPs is higher at intensities between 120% and 140% RMT and, as a result, the delta scores may be further falsely inflated.Evidence does exist for motor system reorganization in CRPS and I reference some of the current literature on the subject in this write-up. The efforts by the authors to find objective measures to corroborate improvements in motor function are commendable. However, interpretation of their findings as evidence for motor system reorganization is misguided in my opinion.Shabbir Hussain Merchant has no relevant conflict of interest to declare related to this publication.


Such concepts, then called human- or body-on-a-chip, claimed that microphysiological systems would become the relevant technology platform emulating the physiology and morphology of human organisms at the smallest biologically acceptable scale in vitro and, therefore, would enable the selection of personalized therapies for any patient at unprecedented precision. Meanwhile, the first human organoids—stem cell-derived complex three-dimensional organ models that expand and self-organize in vitro—have proven that in vitro self-assembly of minute premature human organ-like structures is feasible, once the respective stimuli of ontogenesis are provided to human stem cells. Such premature organoids can precisely reflect a number of distinct physiological and pathophysiological features of their respective counterparts in the human body. We now develop the human-on-a-chip concepts of the past into an organismoid theory. We describe the current concept and principles to create a series of organismoids—minute, mindless and emotion-free physiological in vitro equivalents of an individual's mature human body—by an artificially short process of morphogenetic self-assembly mimicking an individual's ontogenesis from egg cell to sexually mature organism. Subsequently, we provide the concept and principles to maintain such an individual's set of organismoids at a self-sustained functional healthy homeostasis over very long time frames in vitro. Principles how to perturb a subset of healthy organismoids by means of the natural or artificial induction of diseases are enrolled to emulate an individual's disease process. Finally, we discuss using such series of healthy and perturbed organismoids in predictively selecting, scheduling and dosing an individual patient's personalized therapy or medicine precisely. The potential impact of the organismoid theory on our healthcare system generally and the rapid adoption of disruptive personalized T-cell therapies particularly is highlighted.The first concepts for reproducing human systemic organismal biology  A human individual's lifespan is characterized by phases of development (ontogenesis) and functional maintenance (adulthood) of the physiology and morphology of the human body and a lifelong sociogenesis of an individual's soul and mind in a bidirectional person to population context , schematin vitro equivalents of an individual's human body, which we now call organismoids. Different terminologies, such as human-on-a-chip, body-on-a-chip, or universal physiological template, have been used in the past for organismoids, but it is common sense among the MPS community that the targeted organismal homeostasis can be achieved by combining the prime organ equivalents from at least the following 10 human systems: circulatory, endocrine, gastrointestinal, immune, integumentary, musculoskeletal, nervous, reproductive, respiratory and urinary. A chip-based system interconnecting these organ models will compose a minimal organismal equivalent and the MPS community forecasts at least another decade to establish such functional organismoids on chips  (induced pluripotent) stem cell-based formation of premature organoids of an individual body in vitro; (ii) physiology-based integration of the relevant type and ratio/numbers of such premature organoids into premature self-sustained organismoids through whole blood perfusion and innervation, applying on-chip MPS; and the (iii) completion of in vitro ontogenesis toward healthy mature organismoids (emulating the adult stage) by organoid on-chip cross talk and accelerated exposure to ontogenic stimuli.The organismoid theory is based on two chronologically interrelated concepts, each with three principles for implementation. The concept of Subsequently, the concept of emulating the process of disease and healing of an individual patient using his/her organismoids on chips follows the principles of (i) induction of a disease in organismoids by natural disease processes or the transmission of pathogens or diseased tissues derived from the patient; (ii) the mimicry of a human clinical trial with a large number of patients by a trial with the equivalent number of healthy and diseased organismoids of one single patient; and (iii) the precise selection of the right medicine or therapy and the most efficacious exposure regime for each individual patient.In this paper, we take you through the concepts and principles of organismoid theory, underpin the most important aspects with actual results and observations, describe its disruptive potential for our healthcare system and provide an outlook on possible approaches to a final proof of the theory.in vivo has fascinated scientists for over a century. Their studies were confined to classical cell culture and animal models for lack of more physiologically relevant test systems. These models have vastly enhanced our basic understanding of cellular function and disease mechanisms. However, translation of results to the human situation has become a major bottleneck. Recent advancements in the field of stem cell research and three-dimensional (3D) culture systems have led to the generation of a promising complex and completely human model system called organoids. These organoids are generated from either pluripotent stem cells (PSCs) (either induced PSCs [iPSCs] or embryonic stem cells), adult stem cells (ASCs) or adult tumor tissue by self-organization. Their use for drug discovery and personalized medicine has been reviewed . Other crucial lineages, such as vascular, neuronal or immune lineages, are mostly absent, therewith silencing paracrine signaling that might become relevant during further maturation.Allowing a finely orchestrated systemic interaction of premature organoids with other organ systems at physiologically relevant scales promotes an alignment of functionality and a higher spatial resolution of stimulation. Nature's organ building blocks—the smallest functional units described above—form, in their multiplicity, an entire human organ. The number of those repetitive subunits depends on the requirements signaled by the interacting organs. Therewith, organ sizes, medium flow rates and fluid residence times in organs and overall liquid to cell ratios self-adjust in a dynamic interplay of tissues.Several approaches enabling the systemic interaction of tissue models have been devised to date—the most prominent being patient-derived xenograft (PDX) models and MPS. In the former, immunodeficient or humanized mice serve as hosts, enabling the engraftment of primarily tumor models. The interplay of grafts with local and systemic environments, also through a vascularization of the models, eventually allows for a nutrition of cells and a propagation of models. However, species' differences between the host organism and the patient's tissue prevents a complete match of biology. A plethora of drawbacks have been described in using these methods, but the assets of having a systemic circulation supporting the models could be shown.Substantial efforts have been made over the past two decades to improve organ model culture conditions by introducing them into MPS. Dozens of human organ equivalents in MPS have been established using primary- and cell line-based models and have been reviewed in great detail –111. It Once the notion became clear that the autologous nature of such systems is essential, the MPS community started to establish stem cell-derived models on-chip. A huge variety of additional human tissue and organ models have been published. However, attempts at organismal on-chip homeostasis have so far failed to integrate the systemic components, such as whole blood supply through vascularized microvessels, a personalized (autologous) immune system and tissue innervation. Here, we have extended the theorization of creating MPS-based organismoids by integrating the premature organoids of each relevant organ system into a self-regulating vascularized and innervated systemic circulation.We hypothesized already in 2012 that “the lack of a dynamic interplay between organ-specific cell types, with their vascular and stromal tissue bed, and the absence of adult stem cell and progenitor niches for local regeneration, are responsible for the crucial missing capabilities of current ‘human-on-a-chip’ systems” . The vasThe organismoid theory hypothesizes that the generation and renewal of all crucial whole blood components—red blood cells, platelets, white blood cells and plasma components—is feasible and will lead to a self-sustained systemic organismoid. Therefore, a steady functional on-chip hematopoiesis is required. Several approaches to model the human bone marrow-based hematopoietic stem cell niche using MPS have been described , 139. AdThe academic MPS development landscape has provided a number of other indicators that particular elements of blood perfusion can be recapitulated using MPS. The capability of emulating platelet-induced blood coagulation has been demonstrated by Westein et al.  and numeAs soon as it comes to organismoid-based physiological whole blood provision to all on-chip organ equivalents, the assets of using stem cell-derived organoids of an autologous source becomes relevant to prevent foreign organ model rejection by the immune system. Multi-organ systems published previously were mostly composed of tissues from different donors, which made the rejection-free integration of an individual's immune system, as the major defense mechanisms of any human organism, impossible. The first steps toward an autologous co-culture of several cell types from one iPSC donor were reported as early as 2013 . The preSuch data support the organismoid theory's concept that once liver functionality matches the requirements of the systemic organismoid, a regular application of nutrients through the intestinal model and removal of waste substances through the kidney model will suffice to maintain functional homeostasis of the organismoid.The majority of plasma proteins in humans are produced by the liver with albumin at a concentration of about 40 g/L, plasma being by far the largest component. In addition, the liver is a gatekeeper for toxicants and xenobiotics arriving through the food. Finally, it keeps homeostatic conditions regarding protein, carbohydrate and amino acid metabolism throughout the circulation. A plethora of MPS literature has provided evidence that human liver equivalents on chips composed of primary or iPSC-derived hepatocytes are capable of continuously secreting albumin and other proteins into the circulation . AnotherA preliminary adjustment of the plasma composition by technical means is feasible by closely monitoring metabolic activities on-chip by online sensors and might lead to an advanced maturation of organ models in the long term. Here, the use of automated systems maintaining a close observation of on-chip cultures will become an essential component .Sensors can generally play a crucial role in the implementation of the organismoid theory, extending an individual's data generation beyond any currently available. On the one hand, the sensors can be inherent in the system. Analogous to pulse oximetry, for example, the oxygen saturation in the blood of an organismoid can be measured using different optical spectra of the various hemoglobin derivatives. In addition, pulse oximetry provides qualitative information about the pulsatile properties of the blood . The meaOn the other hand, the sensors can be embedded directly into the MPS. In parallel with the body area network technology for the health monitoring of the human body , the intin vitro models has so far been mostly neglected due to the complexity of achieving proper guidance and integration of neurons into non-neural tissue models. First steps have been taken to model both the synaptic junction between neural models and the neuroeffector junction formation between neural and non-neural tissue models both in static and MPS organoid cultures during the last decade. A major challenge in this field is the directed guidance of axon growth from the neuronal to the effector tissue. Consequently, the development of MPS that enable the assembly and cultivation of stem cell-derived myelinated motor neurons, as published by  with 3D skeletal muscle bundles in a patterned chip platform which enhanced the guided innervation of tissue constructs. Motor neurons in this setup were transduced with the light-sensitive channel rhodopsin-2, which enabled light-activated muscle contraction to show the formation of functional NMJs . AnotherProtocols have been developed to omit the complex guidance of axon growth to the respective non-neural tissue organoid; these allowed the simultaneous differentiation of neural and non-neural tissue in one organoid. This has been achieved for neuromuscular organoids that contain functional NMJs and myelinated axons in the presence of terminal Schwann cells and contractile activity of the muscle part, which stopped upon blockage of acetylcholine receptors . Such inin vitro tissue innervation will be to build a closed neuronal circuit model with a sensory  and effector  that are interconnected by a cortical model, and achieving the myelination of motor neurons axons by Schwann cells or oligodendrocytes  models have the potential to become an important cornerstone for studying the pharmacological effects of compounds on the NMJs. A first step in this direction was recently published by neurons, modeling of the peripheral nervous system is also of interest for the field of neurodegenerative diseases such as amyotrophic lateral sclerosis. ished by  on the MAnother critical aspect regarding organismal homeostasis is the interaction of autonomic innervation with the immune system. Looking at the digestive tract, for example, the gut immune system impacts on the local enteric nervous system, the extrinsic neurons of sympathetic and parasympathetic systems and, ultimately, on brain functions, such as mood, cognition and mental health. Conversely, the brain is able to modulate immune function in the intestine through the vagus nerve via the intestinal cholinergic anti-inflammatory pathway . InnervaAnother important aspect to emulate systemic organismal pathways on chips includes the integration of the relevant donor-specific microbiota to mimic a patient's interaction with the respective metabolites in general –169.It appears that innervation, vascularization, lymphatics, microbiota, and the emulation of a human-like enterohepatic circulation of bile products are indispensable prerequisites to bridge the gap between the simple physical combination of organoids in multi-organ MPS and real tissue interaction and homeostasis in an organismoid.The latter needs a biological combination of the prime organ equivalents from at least 10 human systems (as highlighted in the introduction) and their biological interconnection through vasculature, innervation and lymphatics. Two early attempts to establish MPS containing at least 10 technically interconnectable organ culture compartments have already been published. Those prime examples include the 13-organ culture compartment system of the Shuler Lab at Cornell University  and the in vitro, reduced in scale as far as possible. They are created by the systemic physiological integration of the functional units of the major human organs into an organismal, self-sustained template that reflects the systemic organization of the human body. The on-chip fast-track differentiation of stem cell derived organ equivalents originates from their cross talk and a physiological reliance on each other. The extreme reduction in scale is due to the goal of generating a large number of replicates of the organismoid of an individual. Large numbers of such identical, minute, mindless and emotion-free physiological in vitro equivalents of an individual's mature human body can be maintained at self-sustained functional healthy homeostasis over very lengthy time frames. They are open to perturbation leading to the natural or artificial induction of diseases. The diseased organismoids are hypothesized to emulate the pathophysiology of the respective patient's disease precisely. This, in turn, may enable the performance of predictive patient-specific organismoid studies to determine the most effective personalized therapy for the patient concerned. Similar to clinical studies on patient cohorts, statistically verified predictions can then be generated with the advantage that genetically identical replicates of the patient's organismoids can be compared under physiological and pathophysiological conditions. Two major usage scenarios can be derived from that. One is related to a cutting-edge improvement of an individual patient's personal treatment in the real world; the other has the potential to change the drug development paradigm on a clinical trial level, saving enormous amounts of time and capital expenditure.According to the organismoid theory, organismoids are biological replica of the living human body Regarding the first scenario, organismoids can be used in predictively selecting, scheduling and dosing an individual patient's personalized therapy or medicine accurately along their disease progression. This can significantly decrease the potential risk to each and every patient by the early detection of unsuccessful treatment schedules. Your lifespan might eventually include periods of life-threatening illness, for example, cancer growth (top: Blue-bordered arrow). A pluripotent stem cell bank is established from your healthy cells. Subsequently, a large number of identical healthy organismoids are generated within a few months (yellow triangle). Various options are currently available to treat cancer, therefore, relevant test groups are created, including placebo treatments, other treatment groups and healthy recovery controls (in the black-bordered arrow). In this hypothetical example, within a few weeks, the CAR-T cell therapy in combination with a checkpoint inhibitor turns out to be the fastest and most effective cure for you. Therefore, this therapy is immediately and successfully applied.According to the organismoid theory, an individual's stem cell bank can be created when healthy or from a healthy organ when illness occurs. Preventive stem cell banking  is already in use and will be the choice in the future as it takes time. The near-to-human element of the theory provides precise test results which animal tests in patient-derived xenograft models or human patient-derived organoids cannot achieve. Xenograft models are phylogenetically distant and, therefore, cannot provide sufficient tumor outgrowth. Additionally, they do not have a patient's immune background to fight cancer. Patient-derived organoids are also not embedded in the patient's immune system and lack systemic interaction with the organism.Regarding the second scenario, the average success rate of drug candidates entering clinical trials to become an approved drug has been below 20% for decades; no other industry can afford this inefficiency of translating any prototype into a marketed product. Poor predictivity of the preclinical safety and efficacy evaluation program of candidate drugs using laboratory animals is the prime reason for that inefficiency. Lengthy clinical trials averaging 13.5 years and bearing cumulative costs reaching as much as 2.5 billion USD to get a new medicine approved are the consequences . SimultaOrganismoids have the potential to break this cost spiral by bringing about a paradigm shift in drug development. The stakeholder report of the MPS community produced in 2016 already projected a decrease of the cumulative drug development costs by a factor of five and a halving of the drug development times once MPS-based clinical trial-like studies on organismoids have enabled the accurate prediction of efficacy, safety, dosing and scheduling for any new medicine or therapy prior to use in human and replacing animal testing and Phase 1 and 2 clinical trials . An advaIn order to achieve that, a set of healthy and diseased organismoids representing the patient's disease status and their healthy homeostasis would allow one to conduct organismoid-based preclinical serial testing of medicines and advanced therapies in a setting emulating clinical trials with large trial-specific patient cohorts. In contrast to trials with patient cohorts, organismoid-based trials offer a number of crucial advantages. Stem cell samples from four donors representing a relevant diabetes patient cohort are collected from a global stem cell bank pool according to criteria equivalent to those of a clinical trial recruitment. A relevant number of healthy organismoids are produced from each of these four donor vials. Blue, brown, yellow and green colors indicate each individual donor background. Subsequently, following the principles of the organismoid theory, diabetic organismoids are generated, for example, through a high glucose diet. In order to evaluate a new SGLT2 inhibitor treatment, a 3 months' trial comprising six arms is conducted with 12 organismoids per arm  and a daily oral-like administration of the respective medication. The control arms include the healthy recovery group (1) and the diseased untreated placebo group (2) which provide the readout for cure (green baseline) and for no change of disease status (red baseline), respectively. Furthermore, three doses of the new SGLT2 inhibitor are administered at 100,000-fold lower doses than expected in patients, due to the respective downscale of organismoid size in comparison to a human body. Readouts for arms (3), (4), and (5) illustrate the potential of the new monotherapy to change the disease status from baseline toward cure at doses corresponding to 25 mg (yellow squares), 15 mg (yellow triangles), and 5 mg (yellow circles), respectively, per day and patient. A standard monotherapy arm hypothetically treated with metformin (blue circles) provides current standard care reference data. Arm (2) generates the most favorable treatment results in this hypothetical example.The most prominent advantage is the fact that, for the first time in the history of drug development, organismoid-based trials on chips will include statistically relevant human autologous biological repeats of the patient's body and of the same individual's healthy body status. Due to the lack of any biological repeat for an individual patient and knowledge of their individual biological status at healthy homeostasis, clinical trials traditionally require large cohorts of patients. Therefore, the trials are divided into Phase 1, 2, and 3 and, unfortunately, can only approximate the pathobiology of an individual patient and their complete cure recovery status. Both aspects make the traditional clinical trial process a lengthy and incredibly costly and inefficient way of developing drugs and advanced therapies. “Clinical trials” on chips with healthy and diseased organismoids eliminate these two roadblocks. On the one hand, they allow the uniformity of inbred laboratory animal tests to be matched due to the genetic identity of each trial “participant” on an individual's organismoid level but with an entirely human background. On the other hand, the usage of organismoids of a variety of different individuals reflects the heterogeneity of patient cohorts in a clinical trial but with the advantage of statistically relevant biological repeats for each individual patient's organismoids.Another obvious advantage of the organismoid approach is the independence from patient recruitment and hospital usage to conduct such trials. Given the existence of large PSC banks reflecting the genetic predisposition, gender and other categories relevant for the trials, an organismoid-based trial can be conducted at any time, anywhere in the world. Regarding the hypothetical example above, donor selection by diabetic predisposition, comparison of genetic ancestry and equal gender distribution might be interesting stem cell vial selection strategies.The third advantage to mention is the flexibility regarding the trial size. The number of diseased organismoids (commonly referred to as “patients” on chips) which can be generated is theoretically unlimited. This allows the integration of pharmacokinetic aspects, finding of effective doses and combined safety and efficacy evaluation of a new chemical or biological entity in one and the same organismoid-based trial. Data which are currently generated in separate preclinical and clinical trials in laboratory animals, healthy volunteers and patients, such as the toxicity profile, the no-observed-adverse-effect-level, absorption and excretions rates, metabolite formation, the finding of effective doses, duration and scheduling of a new medication, can result from one organismoid-based trial. Our hypothetical case study to treat Type 2 diabetes could, for example, be easily extended to a larger dose range and a comparison of a single oral-like  daily administration with two doses a day. This would include a dose-dependent evaluation of efficacy while simultaneously observing the occurrence and severity of urinal or genital tract infections, well-known side effects of SGLT2 inhibitors. The definition of a therapeutic window for the use of the drug candidate in a respective patient cohort results from such an all-in-one trial, still at a preclinical candidate development stage.in silico approaches will further increase the predictive power for precise medications for large patient cohorts and reduce costs further.Regarding both usage scenarios, we envisage that organismoids will contribute significantly to medical real-world big data collection from an individual's databases. This is due to the ability to generate unique reproducible data on microenvironmental disruption at the defined location of a first disease hit  for each patient. The combination of organismoid and in vitro cell culture work is usually connected in people's minds with high costs. One might speculate that the generation and processing of thousands of organismoids in a trial involves an astronomical budget because currently available MPSs are expensive both in disposable chips and operations. Here, the nature of organismoids—reflecting a self-sustainable human body—and economy of scale effects come into play. In the real world, a human body at rest can be sustained with a daily supply of about 2,000 kcal in proteins, carbohydrates and fat. This can be achieved in some poorer areas of the world for a single digit US dollar bill per person. Consequently, the daily feeding of 100,000 organismoids could be achieved for the same costs. The price of the consumable chips hosting the organismoids will predictively go down to the single dollar range as well, a downscale factor which has already been experienced with computer chips and human genome sequencing costs.Sophisticated The socioeconomical dimension of the ability of organismoids to identify the best fitting medication for every individual patient and to radically cut costs and transform drug development is envisioned to be enormous. The same applies to the ethical dimension. Human MPS-based organismoids bear the potential to replace the majority of laboratory animal tests and Phase 1 and 2 clinical trials in human volunteers. They will reduce the number of Phase 3 clinical trial patients manifold. All of this will have a radically positive impact on both the patient's benefit and animal welfare on a global scale.TM and YescartaTM, have recently proven their potential to cure former treatment-resistant tumor patients  T cell therapies Kymriahpatients , 177. Inpatients . More thpatients .Inter alia, the emulation of the intravenous delivery of the T-cell infusion to the target site and its interaction with other major organ sites are missing crucial factors to emulate T-cell therapies and their efficacy profile in patient-derived organoids precisely. As outlined earlier, the organismoid theory here provides an alternative solution overcoming any remaining obstacles.This unprecedented efficacy in such areas of unmet medical need has spurred regulatory acceptance at the cost of standard safety testing procedures , which nAccording to organismoid theory, an organismoid cannot and should not emulate the empathy or consciousness  which are the major parts of the sociogenesis of a human individual. Consequently, it is not able to model a patient's psychiatric disorders. The dysfunction of a 300 g human heart muscle or hip fracture and its healing rely on biophysical properties, some of which cannot be represented on organismoids due to the mismatch of scale and the physics involved.in vitro culture) is prohibited in many parts of the world. The authors of the organismoid theory would like to emphasize that their ethical paradigms extend beyond this. One should not use the concepts and principles of the organismoid theory to create a human or hybrid embryo and further develop and differentiate human or hybrid tissue from that. Other methods should be used to circumvent this part of ontogenesis. The individual's consent to donate tissue to create organismoids could be a good tool to prevent misuse in the areas mentioned at an early stage.Ethical considerations are paramount for human society and are the basis for humanity. Organismoid theory, due to its nature, introduces a number of points which must be considered ethically. Development of the human embryo until a few centimeters in scale is one of the most crucial issues. Fertilization of a human egg and its subsequent embryonic development in an artificial environment  individual.The organismoid theory presented here claims the ability to artificially recapitulate the ontogenesis of an individual's body in vitro, which, in recent years, has proven to enable the emulation of distinct functions of single tissues and organs at a miniaturized scale. Leveraging on what has been learnt from organoids, human organismoids will add the systemic innervation and supply of whole blood generated on-chip via a miniaturized physiology-based vascular and blood capillary network to the functional units of each organ equivalent. The local separation of the organotypic microenvironments of each organ equivalent from the common bloodstream by the endothelial cell layer will enable the separate organ-specific, genetically encoded and microenvironment-driven self-assembly of exact copies of the functional units of the different human organs on-chip. That, in turn, will enable the physiological cross talk of mature organ equivalents, leading to organismal on-chip homeostasis. Once established, organismoids will only require daily feeding with equivalents of digested food to emulate long-term, so-called self-sustained, body functionality on a chip.Nature's principles of genetically and microenvironmentally encoded self-organization and maintenance of the smallest functional units of human organs and their integration into a cross talking and efficiently interacting system of blood perfusion and innervated organs are the blueprint for creating organismoids on chips. We envision them becoming the next level of emulation of human biology, providing the best possible approximation of the human counterpart. Organismoids will organically follow the organoid level of human biology in vitro culture technologies and human single-organ chips produced within the last 10 years have provided vast evidence for the concept of artificial in vitro ontogenesis of single organ equivalents. Furthermore, human iPSC-derived multi-organ chips have furnished first indications of an accelerated artificial organ ontogenesis on chips. Finally, an ever-growing scientific literature on human disease modeling and treatment testing on human tissue chips points toward the capability of such microphysiological platforms to precisely emulate the pathobiology of a disease and the mode of action of a medicine or therapy when organismoids can be fully functionally established on MPSs. Major challenges for the further development of organ-on-a-chip systems are nervous innervation and the implementation of capillarization of the organoids, which also allows the migration of cells, especially immune cells, into the tissue.We have illustrated that human organoid We have enrolled the two concepts underlying the organismoid theory and detailed the principles of how to generate and use organismoids for personalized precision medicine.The prime socioeconomic driver for challenging the organismoid theory is an urgently needed paradigm shift in advanced therapy and drug development for the much faster implementation of affordable advanced therapies and precision medicines into real-world healthcare to cure patients with unmet medical needs. The prime ethical driver is the replacement of the majority of laboratory animal tests and Phase 1 clinical trials on healthy volunteers in the drug development cycle and the shift from treating symptoms toward a curing paradigm for chronic diseases on a global healthcare level. Therefore, we have proposed accelerating the establishment of human organismoids by their first proof of concept studies in predicting the outcome, dosing and scheduling of advanced autologous T-cell therapies.The MPS community envisions the first proof-of-theory for organismoids to occur within a decade, tackling the radical improvements for the healthcare system described. However, major milestones, such as the interconnection of organ equivalents by a biological vasculature and lymphatics, organ innervation, integration of microbiota, an enterohepatic circulation and, finally, a human-relevant degree of hematopoiesis need to be achieved to accomplish this aim. Above and beyond healthcare, human organismoids, once established, will provide a unique tool for the next level of basic discoveries in the life science of humans. The stable long-term functionality on such a tiny scale and the arbitrary variability in gender, age and genetic background of individual body organismoids will enable previously unimagined insights into human biology. We foresee the use of organismoids for predicting optimized diets, including the adaptation of the microbiome, on an individual or subpopulation level. The development of optimized functional synthetic food to feed the global population beyond 2,100 can be effectively guided by organismoids. The latter will serve as sensitive personalized biological sensors for environmental pollution in air and drinking water and identify potential hypersensitivity risks for their donors. Finally, they bear the potential to become the prime tool for the personalized prediction of measures to ensure the longevity of their respective donors.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745596/.Publicly available datasets were analyzed in this study. This data can be found here: All authors listed have made a substantial, direct and intellectual contribution to the work, drafted the manuscript, revised it and approved it for publication. UM and RL developed the concept. RD, LK, and AW performed, analyzed and interpreted experiments relating to Part of this work was supported by the German Federal Ministry of Education and Research (GO-Bio 3B grant agreement No. 031B0062 and Alternativmethoden – Verbund grant agreement No. 031L0099A) and the European Union's Horizon 2020 research and innovation program (RESTORE grant agreement No. 820292).UM is a founder, shareholder, and the CSO of TissUse GmbH, an organ-on-a-chip company dealing with MPS-based biological models. RL is a shareholder of TissUse GmbH. APR, AW, EA, HE, LK, and E-MD are employed by TissUse. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The purpose of this study was to implement an occupational therapy intervention that could be used for telehealth services with an emphasis on participants learning ways to independently choose and sustain engagement in meaningful music activities, known as occupations. The researchers’ aim was to examine how music occupation interventions lower risks of occupational deprivation  that could occur due to the COVID-19 pandemic. Eight adults participated who were 65 years or older, lived in the community, and enjoyed music. The researchers used narrative qualitative methodology to analyze pre- and post-intervention focus group data. The participants completed seven intervention sessions designed to increase and sustain music engagement outside of the sessions. The pre-intervention focus group data resulted in an occupational pattern analysis and a single occupational narrative. Triangulation of data post-intervention included the two focus groups and their pattern analyses and narratives, field notes from each intervention session, and documents produced through group completion. The final analysis produced an occupational change pattern analysis and narrative. The focus of the change narrative was on the participant’s management or prevention of occupational deprivation. The researchers identified several common themes involving change in routines and habits to include regular engagement in meaningful music activities, skills for using occupational participation as an important method of coping with COVID-19, and developing new technological skills to access music to replace in-person participation of attending live concerts and shows when deemed unsafe because of potential for virus transmission.


Nutrients provides new insights on nutritional assessment and potential modifications of nutritional behaviours and supplements to prevent age-associated disorders and increase life expectancy in different populations of older subjects.Appropriate nutrition is a cornerstone of preventive gerontology. This Special Issue of This Special Issue includes five original articles and four systematic reviews. The first review discusses the synergistic action of selected antioxidant micronutrients  for inhibiting oxidative stress and DNA damage. Micronutrients are involved in every cellular/biochemical process. Seniors are prone to micronutrient deficiencies due to age-associated physiological changes and often poor diet. Moreover, the lack of micronutrients has an indirect impact on the genome. Their low levels reduce the activity of antioxidant enzymes and therefore inhibit the efficiency of defense against free radicals, which can lead to the formation of DNA lesions. The more DNA damage in the genetic material, the faster aging at the cellular level and the higher the risk of pathological processes . Targeted supplementation of crucial antioxidative micronutrients such as selenium, zinc, vitamin C, and vitamin E seems to have the potential to positively influence the condition of an ageing organism, including minimizing inflammation, enhancing antioxidative defense, and limiting the formation of DNA lesions. Consequently, it may lead to lowering the risk and incidence of age-related diseases such as cardiovascular diseases, neurodegenerative diseases, and malnutrition .The continuous increase in life expectancy results in a growing risk of cancer, which consequently increases the population of older adults with cancer. In the second review, problems associated with diet and nutrition in the elderly undergoing active cancer therapy have been presented. As epigenetics, an emerging element of the regulation of gene expression, is involved in both aging and cancer and the epigenetic profile can be modulated by the diet, it seems to be a candidate to assist with planning a nutritional intervention in elderly populations with cancer. Nutritional interventions modulating the epigenetic profile, including caloric restriction and basal diet with modifications , are discussed as the ways to improve the efficacy of cancer therapy and maintain the quality of life of older adults with cancer .Nutritional interventions have been shown to be especially effective for cardiometabolic risk. The Mediterranean diet, with olive oil as a vital component, has both health benefits and acceptable adherence. The third review provides an updated overview of current knowledge on the benefits of olive oil most relevant to menopause-associated metabolic syndrome, including an analysis of the components with the greatest health impact, their effect on basic mechanisms of disease, and the state of the art regarding their action on the main features of metabolic syndrome .Neurological diseases have steadily increasing significance for the health of aging populations. Citicoline is a chemical compound involved in the synthesis of cell membranes with a promising role in neurology. Citicoline is often used to enhance cognitive functions. In the fourth review, accessible databases were searched for articles regarding citicoline use in neurological diseases. The review found that citicoline has been proven to enhance cognitive functions among healthy individuals and improve prognosis after stroke. In an animal model of nerve damage and neuropathy, citicoline stimulated regeneration and lessened pain. Citicoline has a wide range of effects and could be an essential substance in the treatment of many neurological diseases .Depression is one of the diseases with increasing prevalence in the older population. The first original article analyzes the relationship between nutritional status and depression symptoms severity in 1975 older outpatients. Women with higher-severity depression symptoms had significantly lower nutritional status, shorter education time, smaller calf circumference, and higher waist to height ratio. Men with depression symptoms had lower nutritional status, shorter education, and smaller calf circumference. In the model of stepwise multiple regression, nutritional status and education years were the only independent variables predicting the severity of depression symptoms in both women and men. Results obtained in the study indicate a strong relationship between proper nutritional status and education level with severity of depression symptoms in older women and men [The second original article analyses the role of serotonin and other tryptophan (TRP) metabolites generated in the kynurenine pathway in the pathogenesis of depression. Ninety subjects in three groups, 30 subjects each, were enrolled in this study: controls  and older individuals without (group II) or with (group III) symptoms of mild and moderate depression. The average daily intake of TRP was significantly lower in group III than the remaining two groups, but group III was also characterised by higher urinary levels of L-kynurenine, kynurenic acid, xanthurenic acid, and quinolinic acid compared with younger adult individuals and older patients without mood disorders. Therefore, mild and moderate depression in the elderly may be associated with a lower intake of TRP and changes in its kynurenine metabolic pathway, which suggests a potential dietary TRP-based intervention in this group of patients .The last three original articles assess nutritional status in hospitalised older adults. The first one presents an optimal set of variables that are independently associated with the mortality risk of 433 older comorbid adults that have been discharged from the geriatric ward. Stepwise backward variable selection and the iterative Bayesian model averaging approaches to the Cox proportional hazards models were used. The results of the multivariable analysis identified seven explanatory variables that were independently associated with the length of survival. The mortality rate was higher in males than in females; it increased with the comorbidity level and C-reactive proteins plasma level but was negatively affected by a person’s mobility, geriatric nutritional risk index (GNRI), and lymphocyte count, as well as the vitamin D plasma level .The second study compares two widely recommended short nutrition assessment tools—Nutrition Risk Screening 2002 (NRS-2002) and Subjective Global Assessment Form (SGA)—with other Comprehensive Geriatric Assessment (CGA) measurements in 622 consecutively hospitalised older subjects. Both NRS-2002 and SGA were inversely related to anthropometric measurements, functional assessment tests, and Mini-Mental State Examination (MMSE) and positively associated with the Vulnerable Elders Survey-13 (VES-13) score. Comparison of well-nourished subjects and patients with suggested problems with nutrition according to NRS-2002 (0–2 vs. 3–7) and SGA (A vs. B + C) gave comparable results. Both nutritional scales at given cut-off points similarly discriminated anthropometric data and other CGA tools in the populations of well-nourished vs. malnourished hospitalised older subjects. In conclusion, the authors recommend using both NRS-2002 and SGA to detect malnutrition or risk of malnutrition in routine clinical practice of the geriatric department ward .The last original article emphasises the role of albumin as a useful marker of in-hospital malnutrition and frailty. The prevalence of preexisting hypoalbuminemia at the time of discharge from the hospital was investigated using a sample of 9428 patients. Analysis of albumin levels at admission and at discharge was conducted by classes of albuminemia and then stratified by age. At the time of admission, hypoalbuminemia was found to be present in more than half of the sample, with no sex differences. The serum albumin level tended to decrease with age. The condition of marked and mild hypoalbuminemia was more prevalent in patients over 65 years of age. The authors conclude that albumin levels should be integrated into the routine assessment of patients, especially when dealing with nutritionally fragile populations [In conclusion, the present Special Issue presents several aspects of assessment of nutritional status and prevention and treatment of nutritional deficiencies in different populations of older adults. Undoubtedly, future research will deepen our knowledge on this crucial public health issue.