How to predict relapse in leukemia using time series data: A comparative in silico study.

Risk stratification and treatment decisions for leukemia patients are regularly based on clinical markers determined at diagnosis, while measurements on system dynamics are often neglected. However, there is increasing evidence that linking quantitative time-course information to disease outcomes can improve the predictions for patient-specific treatment responses. We designed a synthetic experiment simulating response kinetics of 5,000 patients to compare different computational methods with respect to their ability to accurately predict relapse for chronic and acute myeloid leukemia treatment. Technically, we used clinical reference data to first fit a model and then generate de novo model simulations of individual patients' time courses for which we can systematically tune data quality (i.e. measurement error) and quantity (i.e. number of measurements). Based hereon, we compared the prediction accuracy of three different computational methods, namely mechanistic models, generalized linear models, and deep neural networks that have been fitted to the reference data. Reaching prediction accuracies between 60 and close to 100%, our results indicate that data quality has a higher impact on prediction accuracy than the specific choice of the particular method. We further show that adapted treatment and measurement schemes can considerably improve the prediction accuracy by 10 to 20%. Our proof-of-principle study highlights how computational methods and optimized data acquisition strategies can improve risk assessment and treatment of leukemia patients.

Contribution of Adventitia-Derived Stem and Progenitor Cells to New Vessel Formation in Tumors.

Blocking tumor vascularization has not yet come to fruition to the extent it was hoped for, as angiogenesis inhibitors have shown only partial success in the clinic. We hypothesized that under-appreciated vascular wall-resident stem and progenitor cells (VW-SPCs) might be involved in tumor vascularization and influence effectiveness of anti-angiogenic therapy. Indeed, in patient samples, we observed that vascular adventitia-resident CD34+ VW-SPCs are recruited to tumors in situ from co-opted vessels. To elucidate this in detail, we established an ex vivo model using concomitant embedding of multi-cellular tumor spheroids (MCTS) and mouse aortic rings (ARs) into collagen gels, similar to the so-called aortic ring assay (ARA). Moreover, ARA was modified by removing the ARs' adventitia that harbors VW-SPCs. Thus, this model enabled distinguishing the contribution of VW-SPCs from that of mature endothelial cells (ECs) to new vessel formation. Our results show that the formation of capillary-like sprouts is considerably delayed, and their number and network formation were significantly reduced by removing the adventitia. Substituting iPSC-derived neural spheroids for MCTS resulted in distinct sprouting patterns that were also strongly influenced by the presence or absence of VW-SPCs, also underlying the involvement of these cells in non-pathological vascularization. Our data suggest that more comprehensive approaches are needed in order to block all of the mechanisms contributing to tumor vascularization.

Use of sedating medications around nursing home admission in Denmark.

PURPOSE: To examine use of sedating medications around the time of nursing home admission in Denmark. METHODS: We conducted a register-based drug utilization study, describing patterns of commonly used medications with sedative effects leading up to and after nursing home admission using data from 94 Danish nursing homes between 2015 and 2017. RESULTS: We identified 5179 residents (median age 84 years, 63% female) and described monthly incidence and total use of benzodiazepines (BZDs), Z drugs, mirtazapine/mianserin, quetiapine, promethazine, and melatonin. The proportion of unique users of sedating medications was similar before and after admission (42% before vs. 40% after) despite an increase in total use after admission. The overall incidence of sedating medications peaked in the 6 months before and 6 months after admission (peaking at 4.6 per 100 person-months 1 month after admission). The most commonly initiated medications were mirtazapine/mianserin, followed by BZDs and Z drugs. Total use of sedating medications increased leading up to admission (peaking at 1001 defined daily doses per 100 residents per month 1 month after admission) and decreased gradually after admission. CONCLUSIONS: Sedative medication initiation increases sharply leading up to admission in Danish nursing homes. Mirtazapine/mianserin is a commonly used agent in nursing homes, despite limited evidence on benefits and harms. Efforts to promote rational use of these medications in nursing homes remain warranted.

Use of medication among nursing home residents: a Danish drug utilisation study.

BACKGROUND: Data on drug utilisation patterns in nursing home populations is scarce. We aimed to describe drug use patterns in Danish nursing home residents. METHODS: We established a cohort of 5,179 individuals (63% women; median age of 84 years) admitted into 94 nursing homes across Denmark during 2015-2017. Data on prescription drug use and other census data were obtained from the nationwide Danish health registries. RESULTS: The total number of drug classes filled increased from a median of 6 drugs (interquartile range [IQR] 3-9) at 18-24 months before nursing home admission to a median of 8 drugs (IQR 6-11) just after admission, with the most common drug classes comprising paracetamol (61%), platelet inhibitors (41%), proton pump inhibitors (34%), statins (33%) and potassium supplements (31%). The incidence rate of new drug treatments increased from 21 new treatments/100 residents/month at 12-24 months before admission to a peak of 71 new treatments/100 residents/month in the month prior to admission, while it levelled off to about 34 new treatments/100 residents/month after 6-9 months. The drug classes primarily responsible for this peak were laxatives, antibiotics and analgesics. The largest absolute increases were seen for laxatives (53%), paracetamol (43%) and antidepressants (36%), all showing a marked increase up to and following admission. A high proportion of residents remained on therapy in the 3-year period following admission, with users of antidepressants and antidementia drugs being most persistent. CONCLUSION: Nursing home admission is associated with an increase in use of both predominantly preventive and non-preventive drug classes.

Morbidity and mortality among older people admitted to nursing home.

BACKGROUND: the increasing number of multimorbid older people places high demands on future health care systems. To inform the discussion on how to structure future care strategies, we aimed to describe the temporal relationship between admission, and morbidity and mortality in nursing home residents. METHODS: data on 5,179 older individuals admitted to 94 Danish nursing homes in 12 municipalities during 2015-2017 were linked to the nationwide Danish health registries to retrieve information on the temporal relation between nursing home admission and morbidity and mortality. RESULTS: at the time of nursing home admission, the majority were women (63%). Male residents were younger than women (median 82 vs 85 years) and had a higher prevalence of comorbidities (median Charlson score 2 vs 1 among women). The median survival after nursing home admission was 25.8 months, with the 3-year survival being 37%. Three-year survival was lower among men (29 vs 43% among women) and among the oldest residents (23% among those aged ≥90 years vs 64% among individuals ≤65 years). In addition to age and sex, predictors of mortality included hospitalisations prior to nursing home admission and a high burden of comorbidity. The rate of hospitalisations, primarily for reasons related to frailty, increased substantially during the 9 months prior to nursing home admission. CONCLUSION: we provide detailed information on differences in morbidity and mortality across age span and sex at the time of nursing home admission, thereby contributing to the ongoing discussion of how to structure the future health care system.

Dating glacier ice of the last millennium by quantum technology.

Radiometric dating with 39Ar covers a unique time span and offers key advances in interpreting environmental archives of the last millennium. Although this tracer has been acknowledged for decades, studies so far have been limited by the low abundance and radioactivity, thus requiring huge sample sizes. Atom trap trace analysis, an application of techniques from quantum physics such as laser cooling and trapping, allows us to reduce the sample volume by several orders of magnitude compared with conventional techniques. Here we show that the adaptation of this method to 39Ar is now available for glaciological applications, by demonstrating the entire process chain for dating of alpine glacier ice by argon trap trace analysis (ArTTA). Ice blocks as small as a few kilograms are sufficient and have been obtained at two artificial glacier caves. Importantly, both sites offer direct access to the stratigraphy at the glacier base and validation against existing age constraints. The ice blocks obtained at Chli Titlis glacier at 3,030 m asl (Swiss Alps) have been dated by state-of-the-art microradiocarbon analysis in a previous study. The unique finding of a bark fragment and a larch needle within the ice of Schaufelferner glacier at 2,870 m asl (Stubai Alps, Austria) allows for conventional radiocarbon dating. At both sites the existing age information based on radiocarbon dating and visual stratigraphy corroborates the 39Ar ages. With our results, we establish argon trap trace analysis as the key to decipher so far untapped glacier archives of the last millennium.

LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy.

The potential of altering the tumor ECM to improve drug response remains fairly unexplored. To identify targets for modification of the ECM aiming to improve drug response and overcome resistance, we analyzed expression data sets from pre-treatment patient cohorts. Cross-evaluation identified a subset of chemoresistant tumors characterized by increased expression of collagens and collagen-stabilizing enzymes. We demonstrate that strong collagen expression and stabilization sets off a vicious circle of self-propagating hypoxia, malignant signaling, and aberrant angiogenesis that can be broken by an appropriate auxiliary intervention: Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models, even in metastatic disease. Inhibition of collagen stabilization by itself can reduce or enhance tumor growth depending on the tumor type. The mechanistical basis for this behavior is the dependence of the individual tumor on nutritional supply on one hand and on high tissue stiffness for FAK signaling on the other.

The Role of Historical Context in Understanding Past Climate, Pollution and Health Data in Trans-disciplinary Studies: Reply to Comments on More et al., 2017.

Understanding the context from which evidence emerges is of paramount importance in reaching robust conclusions in scientific inquiries. This is as true of the present as it is of the past. In a trans-disciplinary study such as More et al. (2017, https://doi.org/10.1002/2017GH000064) and many others appearing in this and similar journals, a proper analysis of context demands the use of historical evidence. This includes demographic, epidemiological, and socio-economic data-common in many studies of the impact of anthropogenic pollution on human health-and, as in this specific case, also geoarchaeological evidence. These records anchor climate and pollution data in the geographic and human circumstances of history, without which we lose a fundamental understanding of the data itself. This article addresses Hinkley (2018, https://doi.org/10.1002/2017GH000105) by highlighting the importance of context, focusing on the historical and archaeological evidence, and then discussing atmospheric deposition and circulation in the specific region of our study. Since many of the assertions in Bindler (2018, https://doi.org/10.1002/2018GH000135) are congruent with our findings and directly contradict Hinkley (2018), this reply refers to Bindler (2018), whenever appropriate, and indicates where our evidence diverges.

Next-generation ice core technology reveals true minimum natural levels of lead (Pb) in the atmosphere: Insights from the Black Death.

Contrary to widespread assumptions, next-generation high (annual to multiannual) and ultra-high (subannual) resolution analyses of an Alpine glacier reveal that true historical minimum natural levels of lead in the atmosphere occurred only once in the last ~2000 years. During the Black Death pandemic, demographic and economic collapse interrupted metal production and atmospheric lead dropped to undetectable levels. This finding challenges current government and industry understanding of preindustrial lead pollution and its potential implications for human health of children and adults worldwide. Available technology and geographic location have limited previous ice core investigations. We provide new high- (discrete, inductively coupled plasma mass spectrometry, ICP-MS) and ultra-high resolution (laser ablation inductively coupled plasma mass spectrometry, LA-ICP-MS) records of atmospheric lead deposition extracted from the high Alpine glacier Colle Gnifetti, in the Swiss-Italian Alps. We show that contrary to the conventional wisdom, low levels at or approaching natural background occurred only in a single 4 year period in ~2000 years documented in the new ice core, during the Black Death (~1349-1353 C.E.), the most devastating pandemic in Eurasian history. Ultra-high chronological resolution allows for the first time detailed and decisive comparison of the new glaciochemical data with historical records. Historical evidence shows that mining activity ceased upwind of the core site from ~1349 to 1353, while concurrently on the glacier lead (Pb) concentrations-dated by layer counting confirmed by radiocarbon dating-dropped to levels below detection, an order of magnitude beneath figures deemed low in earlier studies. Previous assumptions about preindustrial "natural" background lead levels in the atmosphere-and potential impacts on humans-have been misleading, with significant implications for current environmental, industrial, and public health policy, as well as for the history of human lead exposure. Trans-disciplinary application of this new technology opens the door to new approaches to the study of the anthropogenic impact on past and present human health.

Reprint of "Modeling the intracellular replication of influenza A virus in the presence of defective interfering RNAs.

Like many other viral pathogens, influenza A viruses can form defective interfering particles (DIPs). These particles carry a large internal deletion in at least one of their genome segments. Thus, their replication depends on the co-infection of cells by standard viruses (STVs), which supply the viral protein(s) encoded by the defective segment. However, DIPs also interfere with STV replication at the molecular level and, despite considerable research efforts, the mechanism of this interference remains largely elusive. Here, we present a mechanistic mathematical model for the intracellular replication of DIPs. In this model, we account for the common hypothesis that defective interfering RNAs (DI RNAs) possess a replication advantage over full-length (FL) RNAs due to their reduced length. By this means, the model captures experimental data from yield reduction assays and from studies testing different co-infection timings. In addition, our model predicts that one important aspect of interference is the competition for viral proteins, namely the heterotrimeric viral RNA-dependent RNA polymerase (RdRp) and the viral nucleoprotein (NP), which are needed for encapsidation of naked viral RNA. Moreover, we find that there may be an optimum for both the DI RNA synthesis rate and the time point of successive co-infection of a cell by DIPs and STVs. Comparing simulations for the growth of DIPs with a deletion in different genome segments suggests that DI RNAs derived from segments which encode for the polymerase subunits are more competitive than others. Overall, our model, thus, helps to elucidate the interference mechanism of DI RNAs and provides a novel hypothesis why DI RNAs derived from the polymerase-encoding segments are more abundant in DIP preparations.

Modeling the intracellular replication of influenza A virus in the presence of defective interfering RNAs.

Like many other viral pathogens, influenza A viruses can form defective interfering particles (DIPs). These particles carry a large internal deletion in at least one of their genome segments. Thus, their replication depends on the co-infection of cells by standard viruses (STVs), which supply the viral protein(s) encoded by the defective segment. However, DIPs also interfere with STV replication at the molecular level and, despite considerable research efforts, the mechanism of this interference remains largely elusive. Here, we present a mechanistic mathematical model for the intracellular replication of DIPs. In this model, we account for the common hypothesis that defective interfering RNAs (DI RNAs) possess a replication advantage over full-length (FL) RNAs due to their reduced length. By this means, the model captures experimental data from yield reduction assays and from studies testing different co-infection timings. In addition, our model predicts that one important aspect of interference is the competition for viral proteins, namely the heterotrimeric viral RNA-dependent RNA polymerase (RdRp) and the viral nucleoprotein (NP), which are needed for encapsidation of naked viral RNA. Moreover, we find that there may be an optimum for both the DI RNA synthesis rate and the time point of successive co-infection of a cell by DIPs and STVs. Comparing simulations for the growth of DIPs with a deletion in different genome segments suggests that DI RNAs derived from segments which encode for the polymerase subunits are more competitive than others. Overall, our model, thus, helps to elucidate the interference mechanism of DI RNAs and provides a novel hypothesis why DI RNAs derived from the polymerase-encoding segments are more abundant in DIP preparations.

Electrophysiological study with prophylactic pacing and survival in adults with myotonic dystrophy and conduction system disease.

CONTEXT: Up to one-third of patients with myotonic dystrophy type 1 die suddenly. Thus far, no intervention has effectively prevented sudden death. OBJECTIVE: To determine whether an invasive strategy based on systematic electrophysiological studies and prophylactic permanent pacing is associated with longer survival in patients presenting with myotonic dystrophy type 1 and major infranodal conduction delays than a noninvasive strategy. DESIGN, SETTING, AND PATIENTS: A retrospective study, the DM1 Heart Registry included 914 consecutive patients older than 18 years with genetically confirmed myotonic dystrophy type 1 who were admitted to the Neurological Unit of the Myology Institute of Pitié-Salpêtrière Hospital, a teaching medical center in Paris, France, between January 2000 and December 2009. INTERVENTIONS: Among 486 patients whose electrocardiogram showed a PR interval greater than 200 milliseconds, a QRS duration greater than 100 milliseconds, or both, the outcome of 341 (70.2%) who underwent an invasive strategy was compared with 145 (29.8%) who underwent a noninvasive strategy. A propensity score risk adjustment and propensity-based matching analysis was used to account for selection biases. MAIN OUTCOME MEASURES: Rates of overall survival (main outcome measure) and sudden death, respiratory death, and other deaths (secondary outcome measures). RESULTS: Over a median follow-up of 7.4 years (range, 0-9.9 years), 50 patients died in the invasive strategy group and 30 died in the noninvasive strategy group (hazard ratio [HR], 0.74 [95 CI, 0.47-1.16]; P = .19), corresponding to an overall 9-year survival of 74.4% (95% CI, 69.2%-79.9%). Regardless of the technique used to adjust for between-group differences in baseline characteristics, the invasive strategy was associated with a longer survival, with adjusted HRs ranging from 0.47 (95% CI, 0.26-0.84; P = .01) for a covariate-adjusted analysis of propensity-matched data to 0.61 (95% CI, 0.38-0.99; P = .047) for an analysis adjusted for propensity score quintiles. The survival difference was largely attributable to a lower incidence of sudden death, which occurred in 10 patients in the invasive strategy group and in 16 patients in the noninvasive strategy group, with HRs ranging from 0.24 (95% CI, 0.10-0.56; P = .001) for an analysis adjusted for propensity score quintiles and covariates to 0.28 (95% CI, 0.13-0.61; P = .001) for an unadjusted analysis of propensity-matched data. CONCLUSION: Among patients with myotonic dystrophy type 1, an invasive strategy was associated with a higher rate of 9-year survival than a noninvasive strategy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01136330.