Abstract
We introduce a machine-learning approach to predict the complex non-Markovian dynamics of supercooled liquids from static averaged quantities. Compared to techniques based on particle ...propensity, our method is built upon a theoretical framework that uses as input and output system-averaged quantities, thus being easier to apply in an experimental context where particle resolved information is not available. In this work, we train a deep neural network to predict the self intermediate scattering function of binary mixtures using their static structure factor as input. While its performance is excellent for the temperature range of the training data, the model also retains some transferability in making decent predictions at temperatures lower than the ones it was trained for, or when we use it for similar systems. We also develop an evolutionary strategy that is able to construct a realistic memory function underlying the observed non-Markovian dynamics. This method lets us conclude that the memory function of supercooled liquids can be effectively parameterized as the sum of two stretched exponentials, which physically corresponds to two dominant relaxation modes.
Due to processes of financialisation, financial parties increasingly penetrate the healthcare domain and determine under which conditions care is delivered. Their influence becomes especially visible ...when healthcare organisations face financial distress. By zooming‐in on two of such cases, we come to know more about the considerations, motives and actions of financial parties in healthcare. In this research, we were able to examine the social dynamics between healthcare executives, banks and health insurers involved in a Dutch hospital and mental healthcare organisation on the verge of bankruptcy. Informed by interviews, document analysis and translation theory, we reconstructed the motives and strategies of executives, banks and health insurers and show how they play a crucial role in decision‐making processes surrounding the survival or downfall of healthcare organisations. While parties are bound by legislation and company procedures, the outcome of financial distress can still be influenced. Much depends on how executives are perceived by financial stakeholders and how they deal with threats of destabilisation of the network. We further draw attention to the consequences of financialisation processes on the practices of healthcare organisations in financial distress.
Parkinson's disease (PD) has a long, heterogeneous, pre-diagnostic phase, during which pathology insidiously accumulates. Increasing evidence suggests that environmental and lifestyle factors in ...early life contribute to disease risk and progression. Thanks to the extensive study of this pre-diagnostic phase, the first prevention trials of PD are being designed. However, the highly heterogenous evolution of the disease across the life course is not yet sufficiently taken into account. This could hamper clinical trial success in the advent of biological disease definitions. In an interdisciplinary patient-clinician study group, we discussed how an approach that incorporates the lifetime evolution of PD may benefit the design of disease-modifying trials by impacting population, target and outcome selection. We argue that the timepoint of exposure to risk and protective factors plays a critical role in PD subtypes, influencing population selection. In addition, recent developments in differential disease mechanisms, aided by biological disease definitions, could impact optimal treatment targets. Finally, multimodal biomarker panels using this lifetime approach will likely be most sensitive as progression markers for more personalized trials. We believe that the lifetime evolution of PD should be considered in the design of clinical trials, and that such initiatives could benefit from more patient-clinician partnerships.
Recurrent laryngeal nerve (RLN) injury caused by esophagectomy may lead to postoperative morbidity, however data on long-term recovery are scarce. The aim of this study was to evaluate the ...consequences of RLN palsy (RLNP) in terms of pulmonary morbidity and long-term functional recovery.
Patients who underwent a 3-stage transthoracic (McKeown) or a transhiatal esophagectomy for esophageal carcinoma in the University Medical Center Utrecht (UMCU) between January 2004 and March 2016 were included from a prospective database. Multivariable analyses were conducted to assess the association between RLNP and pulmonary complications and hospital stay. Data regarding long-term recovery were summarized using descriptive statistics.
Out of the 451 included patients, 47 (10%) were diagnosed with RLNP. Of the patients with RLNP, 34 (7%) had a unilateral lesion, 8 (2%) had a bilateral lesion, and in 5 (1%) the location of the lesion was unknown. The incidence of RLNP was 3/127 (2%) in the transhiatal group, and 44/324 (14%) in the McKeown group. RLNP after McKeown esophagectomy was associated with a higher incidence of pulmonary complications (OR 2.391; 95% CI 1.222-4.679; P=0.011), as well as a longer hospital stay (+4 days) (P=0.001). Of the RLNP patients with more than 6 months follow up almost half recovered fully {median follow-up of 17.5 7-135 months}. Of the remainder, six required a surgical intervention and the others had residual symptoms.
RLNP after McKeown esophagectomy is associated with an increased pulmonary complication rate, longer hospital stay, and a moderate long-term recovery. Further studies are necessary that examine technologies, which may reduce RLNP incidence and contribute to the early detection and treatment of RLNP.
The objective of the study was to explore the effect of breed on the composition and coagulation properties (rennet coagulation time (min), curd firming rate (min), and curd firmness (mm)) of milk ...from cows milked once a day or twice a day in the morning and afternoon, using a Formagraph. Thirty cows (11 Holstein-Friesian, 8 Holstein-Friesian × Jersey cross, and 11 Jersey) from a once-a-day milking herd and thirty cows (16 Holstein-Friesian, 10 Holstein-Friesian × Jersey cross, and 4 Jersey) from a twice-a-day milking herd were sampled in late lactation. The milk composition and coagulation properties were analysed for each milk sample. Jersey cows had better milk coagulation properties at each milking frequency-milking time compared to Holstein-Friesian cows. Curd firmness 30 min after the addition of rennet was positively (p < 0.05) correlated with the protein concentration. However, the correlations were inconsistent between milking frequencies and milking times, resulting in poor prediction of the changes in cheese-making potential. This study indicated that milk composition and coagulation properties were affected by breed and milking frequency. The effect of the breed could be due to the variation in the composition of the milk, but firm recommendations were hampered by a low number of samples. Further research with larger cow numbers is justified.
In patients with phenylketonuria, stability of blood phenylalanine and tyrosine concentrations might influence brain chemistry and therefore patient outcome. This study prospectively investigated the ...effects of tetrahydrobiopterin (BH4), as a chaperone of phenylalanine hydroxylase on diurnal and day-to-day variations of blood phenylalanine and tyrosine concentrations.
Blood phenylalanine and tyrosine were measured in dried blood spots (DBS) four times daily for 2 days (fasting, before lunch, before dinner, evening) and once daily (fasting) for 6 days in a randomized cross-over design with a period with BH4 and a period without BH4. The sequence was randomized. Eleven proven BH4 responsive PKU patients participated, 5 of them used protein substitutes during BH4 treatment. Natural protein intake and protein substitute dosing was adjusted during the period without BH4 in order to keep DBS phenylalanine levels within target range. Patients filled out a 3-day food diary during both study periods. Variations of DBS phenylalanine and Tyr were expressed in standard deviations (SD) and coefficient of variation (CV).
BH4 treatment did not significantly influence day-to-day phenylalanine and tyrosine variations nor diurnal phenylalanine variations, but decreased diurnal tyrosine variations (median SD 17.6 μmol/l, median CV 21.3%, p = 0.01) compared to diet only (median SD 34.2 μmol/l, median CV 43.2%). Consequently, during BH4 treatment diurnal phenylalanine/tyrosine ratio variation was smaller, while fasting tyrosine levels tended to be higher.
BH4 did not impact phenylalanine variation but decreased diurnal tyrosine and phenylalanine/tyrosine ratio variations, possibly explained by less use of protein substitute and increased tyrosine synthesis.
Conflicting results have been reported on the influence of carbohydrates in breast cancer.
To determine the influence of pre-operative per-oral carbohydrate load on proliferation in breast tumors.
...Randomized controlled trial.
University hospital with primary and secondary care functions in South-West Norway.
Sixty-one patients with operable breast cancer from a population-based cohort.
Per-oral carbohydrate load (preOp™) 18 and 2-4 h before surgery (n = 26) or standard pre-operative fasting with free consumption of tap water (n = 35).
The primary outcome was post-operative tumor proliferation measured by the mitotic activity index (MAI). The secondary outcomes were changes in the levels of serum insulin, insulin-c-peptide, glucose, IGF-1, and IGFBP3; patients' well-being, and clinical outcome over a median follow-up of 88 months (range 33-97 months).
In the estrogen receptor (ER) positive subgroup (n = 50), high proliferation (MAI ≥ 10) occurred more often in the carbohydrate group (CH) than in the fasting group (p = 0.038). The CH group was more frequently progesterone receptor (PR) negative (p = 0.014). The CH group had a significant increase in insulin (+ 24.31 mIE/L, 95% CI 15.34 mIE/L to 33.27 mIE/L) and insulin c-peptide (+ 1.39 nM, 95% CI 1.03 nM to 1.77 nM), but reduced IGFBP3 levels (- 0.26 nM; 95% CI - 0.46 nM to - 0.051 nM) compared to the fasting group. CH-intervention ER-positive patients had poorer relapse-free survival (73%) than the fasting group (100%; p = 0.012; HR = 9.3, 95% CI, 1.1 to 77.7). In the ER-positive patients, only tumor size (p = 0.021; HR = 6.07, 95% CI 1.31 to 28.03) and the CH/fasting subgrouping (p = 0.040; HR = 9.30, 95% CI 1.11 to 77.82) had independent prognostic value. The adverse clinical outcome of carbohydrate loading occurred only in T2 patients with relapse-free survival of 100% in the fasting group vs. 33% in the CH group (p = 0.015; HR = inf). The CH group reported less pain on days 5 and 6 than the control group (p < 0.001) but otherwise exhibited no factors related to well-being.
Only applicable to T2 tumors in patients with ER-positive breast cancer.
Pre-operative carbohydrate load increases proliferation and PR-negativity in ER-positive patients and worsens clinical outcome in ER-positive T2 patients.
CliniTrials.gov; NCT03886389. Retrospectively registered March 22, 2019.
The spatial scales of relativistic radio jets, probed by relativistic magneto-hydrodynamic (RMHD) jet launching simulations and by most very long baseline interferometry (VLBI) observations differ by ...an order of magnitude. Bridging the gap between these RMHD simulations and VLBI observations requires selecting nearby active galactic nuclei (AGN), the parsec-scale region of which can be resolved. The radio source 3C 84 is a nearby bright AGN fulfilling the necessary requirements: it is launching a powerful, relativistic jet powered by a central supermassive black hole, while also being very bright. Using 22 GHz globe-spanning VLBI measurements of 3C 84 we studied its sub-parsec region in both total intensity and linear polarisation to explore the properties of this jet, with a linear resolution of ∼0.1 parsec. We tested different simulation set-ups by altering the bulk Lorentz factor Γ of the jet, as well as the magnetic field configuration (toroidal, poloidal, helical). We confirm the persistence of a limb brightened structure, which reaches deep into the sub-parsec region. The corresponding electric vector position angles (EVPAs) follow the bulk jet flow inside but tend to be orthogonal to it near the edges. Our state-of-the-art RMHD simulations show that this geometry is consistent with a spine-sheath model, associated with a mildly relativistic flow and a toroidal magnetic field configuration.
The overall survival rate is good for lymph-node-negative breast cancer patients, but they still suffer from serious over- and some undertreatments. Prognostic and predictive gene signatures for ...node-negative breast cancer have a high number of genes related to proliferation. The prognostic value of gene sets from commercial gene-expression assays were compared with proliferation markers.
Illumina WG6 mRNA microarray analysis was used to examine 94 fresh-frozen tumour samples from node-negative breast cancer patients. The patients were divided into low- and high-risk groups for distant metastasis based on the MammaPrint-related genes, and into low-, intermediate- and high-risk groups based on the recurrence score algorithm with genes included in Oncotype DX. These data were then compared to proliferation status, as measured by the mitotic activity index, the expressions of phosphohistone H3 (PPH3), and Ki67.
Kaplan-Meier survival analysis for distant-metastasis-free survival revealed that patients with weak and strong PPH3 expressions had 14-year survival rates of 87% (n=45), and 65% (n=49, p=0.014), respectively. Analysis of the MammaPrint classification resulted in 14-year survival rates of 80% (n=45) and 71% (n=49, p=0.287) for patients with low and high risks of recurrence, respectively. The Oncotype DX categorization yielded 14-year survival rates of 83% (n=18), 79% (n=42) and 68% (n=34) for those in the low-, intermediate- and high-risk groups, respectively (p=0.52). Supervised hierarchical cluster analysis for distant-metastasis-free survival in the subgroup of patients with strong PPH3 expression revealed that the genes involved in Notch signalling and cell adhesion were expressed at higher levels in those patients with distant metastasis.
This pilot study indicates that proliferation has greater prognostic value than the expressions of either MammaPrint- or Oncotype-DX-related genes. Furthermore, in the subgroup of patients with high proliferation, Notch signalling pathway genes appear to be expressed at higher levels in patients who develop distant metastasis.
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