The use of HBV model for flash flood forecasting

International audienceThe standard conceptual HBV model was originally developed with daily data and is normally operated on daily time step. But many floods in Slovenia are usually flash floods as result of intense frontal precipitation combined with orographic enhancement. Peak discharges are maintained only for hours or even minutes. To use the HBV model for flash flood forecasting, the version of HBV-96 has been applied on the catchment with complex topography with the time step of one hour. The recording raingauges giving hourly values of precipitation have been taken in calibration of the model. The uncertainty of simulated runoff is mainly the result of precipitation uncertainty associated with the mean areal precipitation and is higher for mountainous catchments. Therefore the influence of number of raingauges used to derive the areal precipitation by the method of Thiessen polygons was investigated. The quantification of hydrological uncertainty has been performed by analysis of sensitivity of the HBV model to error in precipitation input. The results show that an error of 10% in the amount of precipitation causes an error of 17% in the peak of flood wave. The polynomial equations showing the relationship between the errors in rainfall amounts and peak discharges were derived for two water stations on the Savinja catchment. Simulated discharges of half-yearly runs demonstrate the applicability of the HBV model for flash flood forecasting using the mesoscale meteorological forecasts of ALADIN/SI model as input precipitation data

Precipitation forecasts and their uncertainty as input into hydrological models

International audienceTorrential streams and fast runoff are characteristic of most Slovenian rivers and extensive damage is caused almost every year by rainstorms affecting different regions of Slovenia. Rainfall-runoff models which are tools for runoff calculation can be used for flood forecasting. In Slovenia, the lag time between rainfall and runoff is only a few hours and on-line data are used only for now-casting. Predicted precipitation is necessary in flood forecasting some days ahead. The ECMWF (European Centre for Medium-Range Weather Forecasts) model gives general forecasts several days ahead while more detailed precipitation data with the ALADIN/SI model are available for two days ahead. Combining the weather forecasts with the information on catchment conditions and a hydrological forecasting model can give advance warning of potential flooding notwithstanding a certain degree of uncertainty in using precipitation forecasts based on meteorological models. Analysis of the sensitivity of the hydrological model to the rainfall error has shown that the deviation in runoff is much larger than the rainfall deviation. Therefore, verification of predicted precipitation for large precipitation events was performed with the ECMWF model. Measured precipitation data were interpolated on a regular grid and compared with the results from the ECMWF model. The deviation in predicted precipitation from interpolated measurements is shown with the model bias resulting from the inability of the model to predict the precipitation correctly and a bias for horizontal resolution of the model and natural variability of precipitation

Epidemiology of thyroid disorders in the Lifelines Cohort Study (the Netherlands)

Background Thyroid hormone plays a pivotal role in human metabolism. In epidemiologic studies, adequate registration of thyroid disorders is warranted. We examined the prevalence of thyroid disorders, reported thyroid medication use, thyroid hormone levels, and validity of thyroid data obtained from questionnaires in the Lifelines Cohort Study. Methods We evaluated baseline data of all 152180 subjects (aged 18-93 years) of the Lifelines Cohort Study. At baseline, participants were asked about previous thyroid surgery and current and previous thyroid hormone use. At follow-up (n = 136776, after median 43 months), incident thyroid disorders could be reported in an open, non-structured question. Data on baseline thyroid hormone measurements (TSH, FT4 and FT3) were available in a subset of 39935 participants. Results Of the 152180 participants, mean (+/- SD) age was 44.6 +/- 13.1 years and 58.5% were female. Thyroid medication was used by 4790 participants (3.1%); the majority (98.2%) used levothyroxine, and 88% were females. 59.3% of levothyroxine users had normal TSH levels. The prevalence of abnormal TSH levels in those not using thyroid medication was 10.8%; 9.4% had a mildly elevated (4.01-10.0 mIU/L), 0.7% had suppressed (10.0 mIU/L) TSH levels. Over 98% of subjects with TSH between 4 and 10 mIU/L had normal FT4. Open text questions allowing to report previous thyroid surgery and incident thyroid disorders proved not to be reliable and severely underestimated the true incidence and prevalence of thyroid disorders. Conclusions Undetected thyroid disorders were prevalent in the general population, whereas the prevalence of thyroid medication use was 3.1%. Less than 60% of individuals using levothyroxine had a normal TSH level. The large group of individuals with subclinical hypothyroidism (9.4%) offers an excellent possibility to prospectively follow the natural course of this disorder. Both structured questions as well as linking to G.P.'s and pharmacists' data are necessary to improve the completeness and reliability of Lifelines' data on thyroid disorders

Estimating blood pressure trends and the nocturnal dip from photoplethysmography

Objective: Evaluate a method for the estimation of the nocturnal systolic blood pressure dip from 24-hour blood pressure trends using a wrist-worn Photoplethysmography (PPG) sensor and a deep neural network in free-living individuals, comparing the deep neural network to traditional machine learning and non-machine learning baselines. Approach: A wrist-worn PPG sensor was worn by 106 healthy individuals for 226 days during which 5111 reference values for blood pressure were obtained with a 24-hour ambulatory blood pressure monitor as ground truth and matched with the PPG sensor data. Features based on heart rate variability and pulse morphology were extracted from the PPG waveforms. Machine learning models (linear regression, random forests, dense neural networks and long- and short-term memory neural networks) were then trained and evaluated in their capability of tracking trends in systolic and diastolic blood pressure, as well as the estimation of the nocturnal systolic blood pressure dip. Main results Best performance was obtained with a deep long- and shortterm memory neural network with a Root Mean Squared Error (RMSE) of 3.12±2.20 ∆mmHg and a correlation of 0.69 (p = 3 ∗ 10−5) with the ground truth Systolic Blood Pressure (SBP) dip. This dip was derived from trend estimates of blood pressure which had an RMSE of 8.22±1.49 mmHg for systolic and 6.55±1.39 mmHg for diastolic blood pressure. The random forest model showed slightly lower average error magnitude for SBP trends (7.86±1.57 mmHg), however Bland-Altmann analysis revealed systematic problems in its predictions that were less present in the long- and short-term memory model. Significance The work provides first evidence for the unobtrusive estimation of the nocturnal blood pressure dip, a highly prognostic clinical parameter. It is also the first to evaluate unobtrusive blood pressure measurement in a large data set of unconstrained 24-hour measurements in free-living individuals and provides evidence for the utility of long- and short-term models in this domain

A Manually Curated Database on Clinical Studies Involving Cell Products Derived from Human Pluripotent Stem Cells

The last 5 years have witnessed a significant increase in the number of clinical studies based on human pluripotent stem cells (hPSCs). In parallel, concern is increasing about the proliferation of unregulated stem cell treatments worldwide. Regulated clinical testing is a de facto standard to establish the safety and efficacy of new cell therapies, yet reliable information on clinical studies involving hPSCs is scattered. Our analysis of a multitude of resources found 54 clinical studies involving several types of hPSCs, which are performed in ten countries. While the majority of those studies is based on human embryonic stem cells (hESCs), clinical studies involving human induced pluripotent stem cells increased more strongly in the past 2 years than the number of hESC-based studies. A publicly accessible database was created using the human pluripotent stem cell registry (https://hpscreg.eu) platform, providing a steadily updated comprehensive overview on hPSC-based clinical studies performed worldwide

Onset of hypothyroidism after total laryngectomy:Effects of thyroid gland surgery and preoperative and postoperative radiotherapy

Background: To determine time of onset and risk of hypothyroidism after total laryngectomy (TL) with and without (hemi)thyroidectomy in relation to treatment regimen, that is, preoperative radiotherapy (RT-TL), postoperative radiotherapy (TL-RT), and postoperative re-irradiation (RT-TL-RT). Methods: Retrospective review of 128 patients treated by RT-TL (51 patients), TL-RT (55 patients), and RT-TL-RT (22 patients). Risk of hypothyroidism was determined by multivariable Cox regression analysis and euthyroid survival was calculated using Kaplan-Meier method. Results: Hypothyroidism developed in 69 (54%) patients. The median onset of hypothyroidism was later (P <.01) and the risk of hypothyroidism was lower (hazard ratio 0.49; P =.014) in the TL-RT group compared to both other treatment regimens. Euthyroid survival did not differ between the treatment regimens. Two years euthyroid survival was 24% with and 61% without (hemi)thyroidectomy (P <.001). Conclusions: Patients treated with TL-RT have later onset of hypothyroidism. Higher risk for hypothyroidism is associated with salvage TL after radiotherapy and (hemi)thyroidectomy

NK cells armed with chimeric antigen receptors (CAR): roadblocks to successful development

In recent years, cell-based immunotherapies have demonstrated promising results in the treatment of cancer. Chimeric antigen receptors (CARs) arm effector cells with a weapon for targeting tumor antigens, licensing engineered cells to recognize and kill cancer cells. The quality of the CAR-antigen interaction strongly depends on the selected tumor antigen and its expression density on cancer cells. CD19 CAR-engineered T cells approved by the Food and Drug Administration have been most frequently applied in the treatment of hematological malignancies. Clinical challenges in their application primarily include cytokine release syndrome, neurological symptoms, severe inflammatory responses, and/or other off-target effects most likely mediated by cytotoxic T cells. As a consequence, there remains a significant medical need for more potent technology platforms leveraging cell-based approaches with enhanced safety profiles. A promising population that has been advanced is the natural killer (NK) cell, which can also be engineered with CARs. NK cells which belong to the innate arm of the immune system recognize and kill virally infected cells as well as (stressed) cancer cells in a major histocompatibility complex I independent manner. NK cells play an important role in the host’s immune defense against cancer due to their specialized lytic mechanisms which include death receptor (i.e., Fas)/death receptor ligand (i.e., Fas ligand) and granzyme B/perforin-mediated apoptosis, and antibody-dependent cellular cytotoxicity, as well as their immunoregulatory potential via cytokine/chemokine release. To develop and implement a highly effective CAR NK cell-based therapy with low side effects, the following three principles which are specifically addressed in this review have to be considered: unique target selection, well-designed CAR, and optimized gene delivery

Mediators of Obesity Do Not Influence SARS-CoV-2 Infection or Activation of Primary Human Lung Microvascular Endothelial Cells In Vitro

Clinical observations have shown that obesity is associated with the severe outcome of SARS-CoV-2 infection hallmarked by microvascular dysfunction in the lungs and other organs. Excess visceral fat and high systemic levels of adipose tissue (AT) derived mediators such as leptin and other adipokines have also been linked to endothelial dysfunction. Consequently, we hypothesized that AT-derived mediators may exacerbate microvascular dysfunction during of SARS-CoV-2 infection and tested this in a primary human lung microvascular endothelial (HLMVEC) cell model. Our results indicate that HLMVEC are not susceptible to SARS-CoV-2 infection since no expression of viral proteins and no newly produced virus was detected. In addition, exposure to the virus did not induce endothelial activation as evidenced by a lack of adhesion molecule, E-selectin, VCAM-1, ICAM-1, and inflammatory cytokine IL-6 induction. Incubation of endothelial cells with the pro-inflammatory AT-derived mediator, leptin, prior to virus inoculation, did not alter the expression of endothelial SARS-CoV-2 entry receptors and did not alter their susceptibility to infection. Furthermore, it did not induce inflammatory activation of endothelial cells. To verify if the lack of activated phenotype in the presence of adipokines was not leptin-specific, we exposed endothelial cells to plasma obtained from critically ill obese COVID-19 patients. Plasma exposure did not result in E-selectin, VCAM-1, ICAM-1, or IL-6 induction. Together our results strongly suggest that aberrant inflammatory endothelial responses are not mounted by direct SARS-CoV-2 infection of endothelial cells, even in the presence of leptin and other mediators of obesity. Instead, endothelial activation associated with COVID-19 is likely a result of inflammatory responses initiated by other cells. Further studies are required to investigate the mechanisms regulating endothelial behavior in COVID-19 and the mechanisms driving severe disease in obese individuals

Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel

PURPOSE This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS Peripheral blood mononuclear cells were isolated before and 30~days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. RESULTS Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0~months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0~months (p = 0.011), respectively. CONCLUSIONS Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC