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The most amount of withdrawn freshwater in the world is used for agriculture activities to extract essential products for human survival. Smart Farming can manage and optimize the water amount given to crop fields in various crop development stages, weather, and soil condition. Sensors installed in several monitoring spots can gather soil moisture of the crop field to indicate the level of water retained in it. However, due to connectivity or sensor failure problems, the smart farming system can not receive the soil moisture data given by the irrigation management. Deep learning techniques can predict soil moisture data using other irrigation management types as data from weather, crop, and irrigation systems. The Fog Computing paradigm also tackles the connectivity problem in the farms since it extends the traditional cloud computing architecture to the edge of the network, providing edge nodes with computational resources to process and analyze sensor requests. In this context, we propose different deep neural network architectures to build prediction models of soil moisture. We also handle the problem of missing data for the dataset features. For this purpose, we use KNN data imputation, which requires filling the values of unknown (or missing) features with values that ensure a desired degree of reliability. Finally, we also embedded the prediction models on a small single-board computer, often used as a fog node, to evaluate the performance of the prediction models according to CPU and RAM usage. This evaluation showed a maximum consumption increase of 10% CPU and 1% RAM. Therefore, the models are viable to fog architectures in the Internet of Things context. Our results indicate that the predictive models achieve a satisfactory efficiency to improve irrigation water saving.

European spine journal 31(4), 1013-1021 (2021). doi:10.1007/s00586-021-07035-4, Published by Springer, Berlin ; Heidelberg ; New York

In this article, we provide the first comprehensive study of user-chosen four- and six-digit PINs ( n =1705) collected on smartphones with participants being explicitly primed for device unlocking. We find that against a throttled attacker (with 10, 30, or 100 guesses, matching the smartphone unlock setting), using six-digit PINs instead of four-digit PINs provides little to no increase in security and surprisingly may even decrease security. We also study the effects of blocklists, where a set of “easy to guess” PINs is disallowed during selection. Two such blocklists are in use today by iOS, for four digits (274 PINs) as well as six digits (2,910 PINs). We extracted both blocklists and compared them with six other blocklists, three for each PIN length. In each case, we had a small (four-digit: 27 PINs; six-digit: 29 PINs), a large (four-digit: 2,740 PINs; six-digit: 291,000 PINs), and a placebo blocklist that always excluded the first-choice PIN. For four-digit PINs, we find that the relatively small blocklist in use today by iOS offers little to no benefit against a throttled guessing attack. Security gains are only observed when the blocklist is much larger. In the six-digit case, we were able to reach a similar security level with a smaller blocklist. As the user frustration increases with the blocklists size, developers should employ a blocklist that is as small as possible while ensuring the desired security. Based on our analysis, we recommend that for four-digit PINs a blocklist should contain the 1,000 most popular PINs to provide the best balance between usability and security and for six-digit PINs the 2,000 most popular PINs should be blocked.

Introduction The coronavirus-19 (COVID-19) pandemic has forced radical changes in management of healthcare in military treatment facilities (MTFs). Military treatment facilities serve unique patients that have a service connection; thus, research and data on this population are relatively sparse. The purpose of this study was to provide descriptive data on characteristics and outcomes of MTF patients with COVID-19 who are treated with heated high-flow nasal cannula (HHFNC). Materials and Methods We performed a single-center retrospective cohort study at the Wright-Patterson Medical Center, a 52-bed hospital in an urban setting. We received approval from our Institutional Review Board. The cohort included patients admitted from June 1, 2020, through May 15, 2021 with severe or life-threatening COVID-19 from a positive severe acute respiratory syndrome–related coronavirus 2 reverse transcription polymerase chain reaction test who were placed on HHFNC during their hospital stay. Severe disease was defined as dyspnea, respiratory rate ≥30/min, blood oxygen saturation ≤93% without supplemental oxygen, partial pressure of arterial oxygen to fraction of inspired oxygen ratio 50% of lung fields within 24-48 hours. Life-threatening disease was defined as having septic shock or multiple organ dysfunction or requiring intubation. Patients meeting these criteria were retrieved from a quality improvement cohort that represents a consecutive group of patients with COVID-19 admitted to the Wright-Patterson Medical Center. Results Our MTF managed 70 cases of severe or life-threatening COVID-19 from June 1, 2020, to May 15, 2021. Of the 70 cases, 19 (27%) were placed on HHFNC. After initiation of HHFNC, median SpO2/FiO2 was 281.8 and at 24 hours 145.4. Median respiratory rate oxygenation at these times were 10.7 and 9.4, respectively. Fifty percent required mechanical ventilation during hospitalization. Median intensive care unit length of stay was 11 days, with a maximum stay of 39 days. Median hospital length of stay was 12 days, with a maximum of 39 days. Conclusion Our retrospective cohort study characterized and analyzed outcomes observed in a MTF population, with severe or life-threatening COVID-19, who were treated with HHFNC. While the study did not have the power to make concrete conclusions on the optimal form of respiratory support for COVID-19 patients, our data support HHFNC as a reasonable treatment modality despite some notable differences between our cohort and prior studied patient populations.

In the present work, different types of acoustic emission (AE) sources are identified by means of computational intelligence. The goal is to characterize the type of AE source and to successfully differentiate between sources that are related to an internal damage, such as a fracture initiation, or an external load represented by an elastic impact. A Hsu-Nielsen source (pencil-lead break) and two steel ball impacts of different diameters are selected for the excitation of an aluminum plate equipped with four piezoelectric transducers to record the acoustic emissions. Furthermore, 25 different areas for the AE sources are defined to collect a large database. Three different machine learning architectures are considered, which can predict the type of the AE source. Time domain signals of the acoustic emissions are used for the training of an artificial neural network and a 1D convolutional neural network. Additionally, the wavelet transformation is performed on the captured signals to generate RGB images of the sensor responses and to train a 2D convolutional neural network in combination with deep transfer learning. An error evaluation of each machine learning model is performed to discuss the classification results. The proposed methodology demonstrates that computational intelligence can be applied to accurately identify the type of AE source based on the captured acoustic emission signals.

Deficiency or mutation of von Willebrand factor (VWF) leads to a coagulation disorder (von Willebrand disease; VWD) which requires a lifelong therapy. For avoiding maternal complications treatment may be necessary also in pregnancy, but placental transfer to the fetus might impact its coagulation system and evoke undesired side effects. As VWF is a very large molecule it may be assumed that it does not pass the placental barrier. To prove this hypothesis the materno-fetal transfer of recombinant VWF (rVWF) has been analyzed ex vivo in a total of 21 valid dual side placenta perfusions. Three groups of five placentas each have been perfused with physiological and up to ten-fold increased concentrations of rVWF for 2 h. Six placentas have been used for control perfusions. A series of different control parameters has been assessed for documentation of intactness and functionality of the placenta and the perfusion system. In not a single analysis, independent of time and concentration, rVWF was detected in the fetal circuit. In the maternal circuit VWF concentration decreased slightly during perfusion. These results demonstrate that recombinant VWF does not pass the human placenta.

Determination of treatment response to immunotherapy in glioblastoma multiforme (GBM) is a process which can take months. Detection of CD8+ T cell recruitment to the tumor with a noninvasive imaging modality such as positron emission tomography (PET) may allow for tumor characterization and early evaluation of therapeutic response to immunotherapy. In this study, we utilized 89Zr-labeled anti-CD8 cys-diabody-PET to provide proof-of-concept to detect CD8+ T cell immune response to oncolytic herpes simplex virus (oHSV) M002 immunotherapy in a syngeneic GBM model. Immunocompetent mice (n = 16) were implanted intracranially with GSC005 GBM tumors, and treated with intratumoral injection of oHSV M002 or saline control. An additional non-tumor bearing cohort (n = 4) receiving oHSV M002 treatment was also evaluated. Mice were injected with 89Zr-labeled anti-CD8 cys-diabody seven days post oHSV administration and imaged with a preclinical PET scanner. Standardized uptake value (SUV) was quantified. Ex vivo tissue analyses included autoradiography and immunohistochemistry. PET imaging showed significantly higher SUV in tumors which had been treated with M002 compared to those without M002 treatment (p = 0.0207) and the non-tumor bearing M002 treated group (p = 0.0021). Accumulation in target areas, especially the spleen, was significantly reduced by blocking with the non-labeled diabody (p + cell trafficking patterns after oHSV treatment. This PET imaging strategy could aid in distinguishing responders from non-responders during immunotherapy of GBM.

A 30-year-old woman with idiopathic intracranial hypertension experienced worsening headaches and decreasing vision in her left eye. She underwent an uncomplicated ventriculoperitoneal shunt procedure but the following day was found to have cerebral venous sinus thrombosis. Treatment included venous sinus thrombectomy and anticoagulation. She had a favourable clinical outcome. Extensive evaluation including testing for thrombophilia was unremarkable. Potential causes for this rare association are discussed.

Introduction Safe and effective vaccines against severe acute respiratory syndrome-associated coronavirus 2 are essential tools in the fight against the coronavirus disease 2019 (COVID-19) pandemic. However, hesitancy to vaccination is a major barrier to achieving herd immunity, particularly among a population working on a military base. To better understand the perceptions and concerns of these individuals, a voluntary survey was conducted. Materials and Methods An interactive, online survey was constructed and disseminated to individuals associated with Wright-Patterson Air Force Base (WPAFB) in Dayton, OH. Survey participation was voluntary with responses collected over the initial weeks in which WPAFB began to distribute COVID-19 vaccines in a series of phases. Although initially designed to collect demographic data and identify reasons for potential vaccine hesitancy among WPAFB 88th Medical Group personnel, the study population was expanded to include all WPAFB-affiliated personnel at the direction of base leadership. The chi-squared test was used to examine the relationships between categorical variables, while multivariable logistic regression was used to assess age and occupation as independent risk factors for vaccine hesitancy. Results A total of 816 individuals completed the survey, of whom 22.7% (n = 185) self-identified as vaccine hesitant (VH). The VH group had a lower mean age than the not vaccine hesitant (NVH) group (39.3 ± 14.2 vs. 45.9 ± 13.4, P Conclusions Younger age and medical occupation were independent risk factors for vaccine hesitancy and these individuals were less likely to recommend vaccination to a friend or family member. We also identified several key concerns related to vaccination hesitancy, in particular those related to short- and long-term side effects, and the spread of misinformation. Among military personnel, these findings carry important implications that may negatively impact mission readiness, a matter that merits further investigation. Our COVID-19 vaccination hesitancy findings can be used to guide targeted interventions at future vaccination campaigns in a military population.

Vancomycin plus piperacillin–tazobactam (VPT) is a commonly used antimicrobial regimen for septic patients. VPT is more nephrotoxic than other regimens such as vancomycin plus cefepime (VC) when given over several days. This risk of nephrotoxicity is less clear when VPT is given for initial empiric therapy in sepsis and de-escalated quickly based on evolving clinical information. The objective of this study was to assess nephrotoxicity among septic patients empirically treated with either VPT or VC at initial clinical presentation. We conducted a retrospective study of septic patients who received VPT or VC within 12 h of presentation to the emergency department. The primary outcomes were acute kidney injury (AKI) and renal recovery 72 h after presentation. For the total of 418 patients, 306 received VPT and 112 received VC. Rates of AKI at 72 h were 15.2% for VPT patients and 11.0% for VC patients [p = 0.44]. Among patients with AKI at presentation, 16.3% of VPT patients had AKI at 72 h compared to 8.9% of VC patients [p = 0.19]. Among those without AKI at presentation, 14.2% VPT patients and 16.7% VC patients had AKI at 72 h [p = 0.71]. Renal recovery rates for patients with AKI at presentation were 42.3% for VPT patients versus 40.3% for VC patients [p = 0.78]. In-hospital renal replacement therapy occurred in 6.2% VPT patients and 0.9% VC patients [p = 0.024]. Therefore, initial empiric therapy with VPT in sepsis may not confer increased risk of AKI when de-escalated appropriately.

Satellite remote sensing plays an important role in mapping the location and extent of surface water. A variety of approaches are available for mapping surface water, but deep learning approaches are not commonplace as they are ‘data hungry’ and require large amounts of computational resources. However, with the availability of various satellite sensors and rapid development in cloud computing, the remote sensing scientific community is adapting modern deep learning approaches. The new integration of cloud-based Google AI platform and Google Earth Engine enables users to deploy calculations at scale. In this paper, we investigate two methods of automatic data labeling: 1. the Joint Research Centre (JRC) surface water maps; 2. an Edge-Otsu dynamic threshold approach. We deployed a U-Net convolutional neural network to map surface water from Sentinel-1 Synthetic Aperture Radar (SAR) data and tested the model performance using different hyperparameter tuning combinations to identify the optimal learning rate and loss function. The performance was then evaluated using an independent validation data set. We tested 12 models overall and found that the models utilizing the JRC data labels showed a better model performance, with F1-scores ranging from 0.972 to 0.986 for the training test and validation efforts. Additionally, an independently sampled high-resolution data set was used to further evaluate model performance. From this independent validation effort we observed models leveraging JRC data labels produced F1-Scores ranging from 0.9130.922. A pairwise comparison of models, through varying input data, learning rates, and loss functions constituents, revealed the JRC Adjusted Binary Cross Entropy Dice model to be statistically different than the 66 other model combinations and displayed the highest relative evaluations metrics including accuracy, precision score, Cohen Kappa coefficient, and F1-score. These results are in the same range as many of the conventional methods. We observed that the integration of Google AI Platform into Google Earth Engine can be a powerful tool to deploy deep-learning algorithms at scale and that automatic data labeling can be an effective strategy in the development of deep-learning models, however independent data validation remains an important step in model evaluation.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first identified in 2019 in Wuhan, China, and has rapidly spread across the world. As of April 2021, SARS-CoV-2 has infected more than 140,000,000 and caused more than 3,000,000 deaths globally. In November 2020, the monoclonal antibody bamlanivimab was approved by the FDA for non-hospitalized patients with SARS-CoV-2 (COVID-19) who possessed risk factors for progression to severe COVID-19. This provided a treatment option that may help prevent hospitalization. Methods Patients who regularly received ambulatory care at a military treatment facility and who were diagnosed with mild-to-moderate COVID-19 and possessed risk factors for progression to severe COVID-19 were treated with a single, intravenous infusion (700 mg) of the virus-neutralizing monoclonal antibody bamlanivimab. The primary outcome was improvement of self-reported symptoms within 24 to 72 hours of receiving the infusion. The secondary outcome was prevention of disease progression requiring emergency department (ED) utilization or hospitalization related to COVID-19 within 30 days of infusion. Bamlanivimab was administered in accordance with the FDA’s approval and Defense Health Agency’s guidance, including follow-up within 72 hours of administration. Institutional Review Board (IRB) approval was obtained. Results Of the COVID-19 patients who were given the option of a bamlanivimab infusion, 40 accepted and 6 did not (40/46, 86.9%). Thirty-six of 40 patients in the treatment group were contacted within 72 hours. ED/hospitalization information was available for all 46 patients. In the treatment group, 94.4% (34/36) reported global improvement. Three of 40 (7.5%) patients in the treatment group required inpatient admission, and 2 of 40 patients (5%) required ED evaluation within 30 days of infusion. Therefore, 5 of 40 (12.5%) patients required evaluation shortly after infusion, while 2 of 6 (33.3%) patients who declined treatment required hospital evaluation or admission related to COVID-19 within 30 days of infusion (P = .15). Conclusions Global improvement of symptoms within 24 to 72 hours of infusion was reported by 94.4% of patients receiving bamlanivimab; however, statistical significance could not be determined due to the small sample size and lack of placebo group due to study design. Furthermore, ED visits and hospital admissions were analyzed, but with only six patients in the comparison group, the relative risk was not statistically significant and could not be precisely estimated. In the future, this study can be replicated with both larger control/treatment arms to validate the initial results of this small, retrospective, cohort study.

Zusammenfassung Ziel der Studie Der Einfluss des sozialen Status auf die Gesundheit ist gut belegt. Für den Bereich der Rehabilitation geben wenige Studien erste Hinweise auf sozial ungleiche Versorgung. Die Studie untersucht anhand einer Risikokohorte der Deutschen Rentenversicherung Bund die Rolle sozialer Ungleichheiten beim Zugang und in der Inanspruchnahme von Leistungen zur medizinischen Rehabilitation. Methodik Die Datengrundlage bilden Fragebogendaten der ersten beiden Wellen des Dritten Sozialmedizinischen Panels für Erwerbspersonen (SPE III) sowie administrative Daten der Teilnehmenden (2013–2016). Diese Risikokohorte umfasst 40- bis 54-jährige Erwerbspersonen mit Krankengeldbezug im Jahr 2012. Mittels logistischer Regressionsmodelle wurden Antragstellung, Bewilligung und Ablehnung, Bewilligung nach Widerspruch und Inanspruchnahme von Rehabilitationsleistungen analysiert. Der soziale Status wurde sowohl als sozioökonomischer Status (Index) als auch in der Einzeldimension Bildung als Prädiktor herangezogen. Die Analysen erfolgten getrennt nach Geschlecht. Alter, Erwerbsstatus sowie der subjektive Gesundheitszustand wurden als Kontrollvariablen berücksichtigt. Ergebnisse Insgesamt wurden 2376 Versicherte, davon 1284 Frauen, in die Analysen eingeschlossen. 639 (26,9%) stellten mindestens einen Antrag auf Leistungen zur medizinischen Rehabilitation. Die Chance auf Antragstellung war bei Männern mit niedrigem sozioökonomischen Status (OR=1,8; 95%-KI=1,3–2,5) bzw. niedriger (OR=1,9; 95%-KI=1,3–2,8) und mittlerer Bildung (OR=1,5; 95%-KI=1,1–2,2) im Vergleich zur hohen Status- bzw. Bildungsgruppe erhöht. Bei den Frauen zeigte sich bei der Antragstellung ein signifikanter Unterschied zugunsten niedriger Bildung (OR=1,6; 95%-KI=1,1–2,5). Nach Adjustierung des Gesundheitszustandes und der aktuellen Erwerbstätigkeit verschwanden die Unterschiede. Hinsichtlich Bewilligung und Inanspruchnahme zeigten sich keine signifikanten Unterschiede nach sozialem Status, jedoch erfolgte bei Frauen mit mittlerer Bildung signifikant häufiger eine Bewilligung auf Grundlage eines Widerspruchverfahrens (OR=3,0; 95%-KI=1,1–8,2) als bei Frauen mit hoher Bildung. Schlussfolgerung Die Analysen gaben keine Hinweise auf einen sozial ungleichen Zugang oder eine sozial ungleiche Inanspruchnahme von Leistungen zur medizinischen Rehabilitation. Allerdings beantragten Versicherte mit niedrigem sozialen Status insbesondere aufgrund einer schlechteren subjektiven Gesundheit häufiger Leistungen zur medizinischen Rehabilitation. Weitere Untersuchungen sind nötig, um zu überprüfen, ob dies dem objektiven Bedarf dieser Statusgruppe gerecht wird.

Objective This article analyzes the changes in downloads and activity of users of select popular mental health mobile applications (mHealth apps) during coronavirus disease 2019 (COVID-19). Background The outbreak of the COVID-19 crisis has shown a negative impact on public mental health. Mobile health has the potential to help address the psychological needs of existing and new patients during the pandemic and beyond. Method Downloads data of 16 widely used apps were analyzed. The quality of apps was reviewed using the Mobile Application Rating Scale (MARS) framework. Correlation analysis was conducted to investigate the relationship between app quality and app popularity. Results Among the 16 apps, 10 were meditational in nature, 13 showed increased downloads, with 11 apps showing above 10% increase in the downloads after the pandemic started. The popular apps were satisfactory in terms of functionality and esthetics but lacked clinical grounding and evidence base. There exists a gap between app quality and app popularity. Conclusion This study provided evidence for increased downloads of mental mHealth apps (primarily meditation apps) during the COVID-19 pandemic but revealed several gaps and opportunities to address deficiencies in evidence-based design, usability and effective assessment, and integration into current workflows. Application The COVID-19 pandemic is a potential turning point for mHealth applications for mental health care. Whereas the evidence suggests a need for alternative delivery of care, human factors and ergonomics methods should be utilized to ensure these tools are user-centered, easy to use, evidence-based, well-integrated with professional care, and used sustainably.

Properly planned single isocenter volumetric modulated arc therapy (VMAT) radiosurgery plans exhibit high quality and efficiency. We report here the largest clinical experience to date, to our knowledge, comparing manual planning with a new automated platform designed to standardize and simplify radiosurgery planning and delivery processes.We treated 693 patients with single isocenter VMAT radiosurgical plans generated by either our conventional manual (mVMAT) or a recently implemented automated (HyperArcThe median Radiation Therapy Oncology Group (RTOG) conformity index was 1.14 and was not different between the 2 techniques. The median Paddick gradient index was 5.42 for HyperArc versus 7.09 for mVMAT (P.001). The median mean brain doses were 4.6% and 5.1% for HyperArc and mVMAT, respectively (P = .04). The PSQA for both techniques met clinical criteria, but 97% of the HyperArc plans satisfied the gamma tolerance limit recommended by the American Association of Physicists in Medicine Task Group No. 218, compared with 94% of the mVMAT plans (P = .02). The median treatment-planning times were not significantly different. The median treatment times were 10.5 and 11.4 minutes for HyperArc and mVMAT, respectively (P.001). The Kaplan-Meier estimate of local control was 90.1% at 1 year.HyperArc produces high-quality radiosurgical plans that are at least as good as mVMAT plans created by an expert manual planner with easier planning and more efficient delivery workflow. A less experienced planner can produce very high-quality radiosurgical plans even for patients with more than 10 targets. The use of a single-isocenter technique for multiple targets with no PTV margin did not compromise clinical outcomes, and 1-year local control for treated targets remained congruent with historical series.

Purpose Several roles are attributed to the myometrium including sperm and embryo transport, menstrual discharge, control of uterine blood flow, and labor. Although being a target of diabetes complications, the influence of high glucose on this compartment has been poorly investigated. Both miRNAs and IGF1R are associated with diabetic complications in different tissues. Herein, we examined the effects of high glucose on the expression of miRNAs and IGF1R signaling pathway in the human myometrium. Methods Human myometrial explants were cultivated for 48 h under either high or low glucose conditions. Thereafter, the conditioned medium was collected for biochemical analyses and the myometrial samples were processed for histological examination as well as miRNA and mRNA expression profiling by qPCR. Results Myometrial structure and morphology were well preserved after 48 h of cultivation in both high and low glucose conditions. Levels of lactate, creatinine, LDH and estrogen in the supernatant were similar between groups. An explorative screening by qPCR arrays revealed that 6 out of 754 investigated miRNAs were differentially expressed in the high glucose group. Data validation by single qPCR assays confirmed diminished expression of miR-215-5p and miR-296-5p, and also revealed reduced miR-497-3p levels. Accordingly, mRNA levels of IGF1R and its downstream mediators FOXO3 and PDCD4, which are potentially targeted by miR-497-3p, were elevated under high glucose conditions. In contrast, mRNA expression of IGF1, PTEN, and GLUT1 was unchanged. Conclusions The human myometrium responds to short-term exposure (48 h) to high glucose concentrations by regulating the expression of miRNAs, IGF1R and its downstream targets.

OBJECTIVES The amount of colorectal cancer (CRC) screening using the noninvasive fecal immunochemical test (FIT) at a federally qualified health center, Five Rivers Health Clinic (Dayton, Ohio), has been low historically. Our quality improvement (QI) project aimed to improve CRC screening adherence in eligible patients who opted for FIT. METHODS Three hundred ninety-two patients with FIT orders for CRC were screened during an 11-month period. The preintervention group (pre-I) was enrolled from December 1, 2018 to May 31, 2019, and the postintervention group (post-I) from June 1, 2019 to October 31, 2019. Three interventions were used: resident physicians trained during clinic meetings regarding FIT education for patients, posters displayed in patient rooms outlining the benefits of CRC screening, and standardized US mail reminder letters sent to FIT patients. Patient demographics and clinical variables were collected along with return rate. RESULTS The return rate for post-I was twice that of pre-I (74.4%, 95% confidence interval 64.6-82.3 vs 31.1, 95% confidence interval 26.2-36.6; P < 0.001). The pre-I/post-I groups did not differ on demographic and clinical characteristics, and, except for race, none of these variables was associated with returning the FIT screening card. CONCLUSIONS The compliance rate for FIT completion and return more than doubled among our clinic patients after using a three-component QI intervention. Except for a difference in race, the lack of association between demographic and clinical characteristics with either pre-I/post-I group or return/no return of the FIT card leads us to conclude that our QI program for increasing FIT compliance is effective. Other settings where CRC screening is a prominent component of preventive care may benefit from adopting a similar QI intervention.

OBJECTIVEDespite significant recent efforts applied toward the development of efficacious therapies for glioblastoma (GBM) through exploration of GBM’s genome and transcriptome, curative therapeutic strategies remain highly elusive. As such, novel and effective therapeutics are urgently required. In this study, the authors sought to explore the kinomic landscape of GBM from a previously underutilized approach (i.e., spatial heterogeneity), followed by validation of Bruton’s tyrosine kinase (BTK) targeting according to this stepwise kinomic-based novel approach.METHODSTwelve GBM tumor samples were obtained and characterized histopathologically from 2 patients with GBM. PamStation peptide-array analysis of these tissues was performed to measure the kinomic activity of each sample. The Ivy GBM database was then utilized to determine the intratumoral spatial localization of BTK activity by investigating the expression of BTK-related transcription factors (TFs) within tumors. Genetic inhibition of BTK family members through lentiviral short hairpin RNA (shRNA) knockdown was performed to determine their function in the core-like and edge-like GBM neurosphere models. Finally, the small-molecule inhibitor of BTK, ONO/GS-4059, which is currently under clinical investigation in nonbrain cancers, was applied for pharmacological inhibition of regionally specified newly established GBM edge and core neurosphere models.RESULTSKinomic investigation identified two major subclusters of GBM tissues from both patients exhibiting distinct profiles of kinase activity. Comparatively, in these spatially defined subgroups, BTK was the centric kinase differentially expressed. According to the Ivy GBM database, BTK-related TFs were highly expressed in the tumor core, but not in edge counterparts. Short hairpin RNA–mediated gene silencing of BTK in previously established edge- and core-like GBM neurospheres demonstrated increased apoptotic activity with predominance of the sub-G1 phase of core-like neurospheres compared to edge-like neurospheres. Lastly, pharmacological inhibition of BTK by ONO/GS-4059 resulted in growth inhibition of regionally derived GBM core cells and, to a lesser extent, their edge counterparts.CONCLUSIONSThis study identifies significant heterogeneity in kinase activity both within and across distinct GBM tumors. The study findings indicate that BTK activity is elevated in the classically therapy-resistant GBM tumor core. Given these findings, targeting GBM’s resistant core through BTK may potentially provide therapeutic benefit for patients with GBM.

Understanding the spatial and temporal distribution of hydrologic variables, such as streamflow, is important for sustainable development, especially with global population growth and climate variations. Typical monitoring of streamflow is conducted using in situ gauging stations; however, stations are costly to setup and maintain, leading to data gaps in regions that cannot afford gauges. Satellite data, including altimetry data, are used to supplement in situ observations and in some cases supply information where they are lacking. This study introduces an open-source web application to access and explore altimetry datasets for use in water level monitoring, named the Altimetry Explorer (AltEx). This web application, along with its relevant REST API, facilitates access to altimetry data for analysis, visualization, and impact. The data provided through AltEx is validated using thirteen gauges in the Amazon Basin from 2008 to 2018 with an average Nash-Sutcliffe Coefficient and root mean square error of 0.78 and 1.2 m, respectively. Access to global water level data should be particularly helpful for water resource practitioners and researchers seeking to understand the long-term trends and dynamics of global water level and availability. This work provides an initial framework for a more robust and comprehensive platform to access future altimetry datasets and support research related to global water resources.

Introduction Current electroencephalography (EEG) practice relies on interpretation by expert neurologists, which introduces diagnostic and therapeutic delays that can impact patients’ clinical outcomes. As EEG practice expands, these experts are becoming increasingly limited resources. A highly sensitive and specific automated seizure detection system would streamline practice and expedite appropriate management for patients with possible nonconvulsive seizures. We aimed to test the performance of a recently FDA-cleared machine learning method (Claritγ, Ceribell Inc.) that measures the burden of seizure activity in real time and generates bedside alerts for possible status epilepticus (SE). Methods We retrospectively identified adult patients (n = 353) who underwent evaluation of possible seizures with Rapid Response EEG system (Rapid-EEG, Ceribell Inc.). Automated detection of seizure activity and seizure burden throughout a recording (calculated as the percentage of ten-second epochs with seizure activity in any 5-min EEG segment) was performed with Claritγ, and various thresholds of seizure burden were tested (≥ 10% indicating ≥ 30 s of seizure activity in the last 5 min, ≥ 50% indicating ≥ 2.5 min of seizure activity, and ≥ 90% indicating ≥ 4.5 min of seizure activity and triggering a SE alert). The sensitivity and specificity of Claritγ’s real-time seizure burden measurements and SE alerts were compared to the majority consensus of at least two expert neurologists. Results Majority consensus of neurologists labeled the 353 EEGs as normal or slow activity (n = 249), highly epileptiform patterns (HEP, n = 87), or seizures [n = 17, nine longer than 5 min (e.g., SE), and eight shorter than 5 min]. The algorithm generated a SE alert (≥ 90% seizure burden) with 100% sensitivity and 93% specificity. The sensitivity and specificity of various thresholds for seizure burden during EEG recordings for detecting patients with seizures were 100% and 82% for ≥ 50% seizure burden and 88% and 60% for ≥ 10% seizure burden. Of the 179 EEG recordings in which the algorithm detected no seizures, seizures were identified by the expert reviewers in only two cases, indicating a negative predictive value of 99%. Discussion Claritγ detected SE events with high sensitivity and specificity, and it demonstrated a high negative predictive value for distinguishing nonepileptiform activity from seizure and highly epileptiform activity. Conclusions Ruling out seizures accurately in a large proportion of cases can help prevent unnecessary or aggressive over-treatment in critical care settings, where empiric treatment with antiseizure medications is currently prevalent. Claritγ’s high sensitivity for SE and high negative predictive value for cases without epileptiform activity make it a useful tool for triaging treatment and the need for urgent neurological consultation.

Brain tumors represent the most common pediatric solid neoplasms and leading cause of childhood cancer-related morbidity and mortality. Although most adult brain tumors are supratentorial and arise in the cerebrum, the majority of pediatric brain tumors are infratentorial and arise in the posterior fossa, specifically the cerebellum. Outcomes from malignant cerebellar tumors are unacceptable despite aggressive treatments (surgery, radiation, and/or chemotherapy) that are harmful to the developing brain. Novel treatments/approaches such as oncolytic virotherapy are urgently needed. Preclinical and prior clinical studies suggest that genetically engineered oncolytic herpes simplex virus (HSV-1) G207 can safely target cerebellar malignancies and has potential to induce an antitumor immune response at local and distant sites of disease, including spinal metastases and leptomeningeal disease. Herein, we outline the rationale, design, and significance of a first-in-human immunotherapy Phase 1 clinical trial targeting recurrent cerebellar malignancies with HSV G207 combined with a single low-dose of radiation (5 Gy), designed to enhance virus replication and innate and adaptive immune responses. We discuss the unique challenges of inoculating virus through intratumoral catheters into cerebellar tumors. The trial utilizes a single arm open-label traditional 3 + 3 design with four dose cohorts. The primary objective is to assess safety and tolerability of G207 with radiation in recurrent/progressive malignant pediatric cerebellar tumors. After biopsy to prove recurrence/progression, one to four intratumoral catheters will be placed followed by a controlled-rate infusion of G207 for 6 h followed by the removal of catheters at the bedside. Radiation will be given within 24 h of virus inoculation. Patients will be monitored closely for toxicity and virus shedding. Efficacy will be assessed by measuring radiographic response, performance score, progression-free and overall survival, and quality of life. The data obtained will be invaluable in our efforts to produce more effective and less toxic therapies for children with high-grade brain tumors.

Annual Meeting of the German Society of Biomedical Engineering, Leipzig, Germany, 29 Sep 2020 - 1 Oct 2020; Current directions in biomedical engineering 6(3), 200-204 (2020). doi:10.1515/cdbme-2020-3051 special issue: "Proceedings of the 2020 Annual Meeting of the German Society of Biomedical Engineering (29 September – 1 October 2020, Leipzig)", Published by De Gruyter, Berlin

Doxorubicin (DOX) is one of the most commonly used drugs for the treatment of childhood cancers, including leukemia and lymphomas. Despite the high survival rate, female leukemia survivors are at higher risk of ovarian failure and infertility later in life. Treatment with chemotherapeutic drugs like DOX is associated with damage in ovarian follicles, but the affectation grade of granulosa cells remains unclear. To assess and avoid the possible side-effects of DOX, early biomarkers of ovarian injury and chemotherapy-induced ovarian toxicity should be identified. MicroRNAs (miRNAs) have emerged in recent years as a promising new class of biomarkers for drug-induced tissue toxicity. In this study, the effects of DOX on cell viability, steroidogenesis, and miRNA expression were studied in primary granulosa cells (GCs) and in two cellular models (COV434 and KGN cells). We report that compared to other chemotherapeutic drugs, DOX treatment is more detrimental to granulosa cells as observed by decrease of cell viability. Treatment with DOX changes the expression of the aromatase gene (CYP19A1) and the secretion of 17β-estradiol (E2) in a cell-specific manner. miR-132-3p is dose-dependently increased by DOX in all cellular models. In absence of DOX, miR-132-3p overexpression in COV434 cells has no effect on E2 secretion or CYP19A1 expression. Altogether, these findings contribute to understanding the hormonal disbalance caused by DOX in human ovarian cells and suggest miR-132 as a putative sensor to predict DOX-induced ovarian toxicity.

The aviation industry faces the challenge of offering aircraft that are lighter, more economical, and safer. One of the solutions is to increase the use of composites. For these materials, adhesive bonding has proven to be the appropriate joining technology. To check these adhesive joints, costly and time-consuming maintenance measures are carried out. An intelligent Structural Health Monitoring (SHM) system can extend these intervals and allow the use of a predictive maintenance system. This paper describes the method of Ultrasonic Lamb Waves for monitoring a adhesively bonded Carbon Fiber Reinforced Polymer (CFRP) aircraft fuselage. Prior to this, the production of a segment of a fuselage and the characterization of the materials (CFRP and adhesive) is shown. Afterwards the method of Ultrasonic Lamb Waves with the use of piezoelectric transducers and signal processing based on the Reconstruction Algorithm for Probabilistic Inspection of Damage (RAPID) algorithm are explained. At the end, the experimental evaluation of an undamaged and a damaged fuselage structure is done. The results have shown the possibility of RAPID algorithm for damage detection on adhesive. An outlook on future work is given.

Distress in oncology patients (pts) has a negative impact on quality of life, survival, and healthcare satisfaction. Higher distress leads to lower compliance with treatment and follow-up [1–8]. The 2012 American College of Surgeons Commission on Cancer (CoC) standard of care for oncology pts included an assessment for distress [1]. A screening process for distress allows the healthcare team to address these issues early and refer to appropriate resources [2–9]. This project was initiated to meet National Comprehensive Cancer Network (NCCN) and CoC standard of care, identify distress in veterans with cancer, and address these concerns. Patients who attended the Tuesday oncology clinic at the Dayton VAMC were given the NCCN Distress Thermometer (DT) during triage. The treating physician addressed problems identified. The Wilcoxon signed rank test and the Friedman test were used. DTs were completed by 296 pts from March to December 2016. Mean age was 68, 93% male, 83% white, 55% married, and 93% without PTSD. The distress level was not different from T1 through T3. Number of problems decreased over three time periods. Referrals to nutrition, mental health, and social work services increased over time. Although over time periods we found no decrease in distress scores, there was a decline in number of problems. The mean distress score at all but time 4 was

Key Points 3D organoid T-cell differentiation from a few hundred peripheral blood CD34+ cells was successfully achieved. 3D organoid T-cell differentiation could help physicians distinguish intrinsic from extrinsic defects underlying a clinical SCID phenotype.

OBJECTIVE Recent studies have shown an increase of C-reactive-protein (CRP) after exposure to zinc- and copper-containing welding fumes. The objective of this study was to determine the effects of exposure to zinc- and copper-containing welding fumes on leukocytes, their subtypes, and myeloperoxidase (MPO). METHODS Serum samples of male volunteers were examined after exposures to welding fumes in two settings: repeated exposure on 4 consecutive days for 6 hours and single exposures for different times (3, 4, 5 hours). RESULTS Neutrophil granulocyte and MPO levels showed increases 24 hours after single and repeated exposures for 6 hours similar to CRP increases reported in literature. Overall leukocyte levels and levels of monocytes and lymphocytes were not significantly affected. CONCLUSIONS This study indicates the involvement of neutrophil granulocytes in welding fume fever additional to mediator related effects.

The Colloid Cyst Risk Score (CCRS) was devised to identify patients with symptomatic colloid cyst and stratify risk of hydrocephalus. The CCRS considers patient age, presence of headache, colloid cyst diameter, fluid-attenuated inversion recovery hyperintensity, and location within the third ventricle.The purpose of this study was to independently evaluate the validity of the CCRS.Patients with a colloid cyst of the third ventricle were identified retrospectively from institutional billing records and radiology report archives. Patients without a confirmed diagnosis of colloid cyst of the third ventricle or magnetic resonance imaging of the brain were excluded. Data were collected via retrospective chart review.One hundred and fifty-six patients met inclusion and exclusion criteria. In our cohort, the CCRS stratified symptomatic patients and patients with hydrocephalus across all scores (P0.001). From CCRS 2 to 5, the percentage of symptomatic patients increased from 13% to 100%, whereas the percentage of patients with hydrocephalus increased from 8% to 83%. Simple logistic regression showed that total CCRS, headache, axial diameter, fluid-attenuated inversion recovery hyperintensity, and risk zone were all highly predictive of symptomatic status and hydrocephalus (P0.001). Logistic regression with receiver operating curves for the CCRS showed an area under the curve of 0.914 for symptomatic colloid cysts and an area under the curve of 0.892 for colloid cysts with hydrocephalus.Our data analysis validates the predictive value of the CCRS for both symptomatic status and hydrocephalus and supports the use of the CCRS in risk stratification and clinical decision making.

Background In critical care settings, electroencephalography (EEG) with reduced number of electrodes (reduced montage EEG, rm-EEG) might be a timely alternative to the conventional full montage EEG (fm-EEG). However, past studies have reported variable accuracies for detecting seizures using rm-EEG. We hypothesized that the past studies did not distinguish between differences in sensitivity from differences in classification of EEG patterns by different readers. The goal of the present study was to revisit the diagnostic value of rm-EEG when confounding issues are accounted for. Methods We retrospectively collected 212 adult EEGs recorded at Massachusetts General Hospital and reviewed by two epileptologists with access to clinical, trending, and video information. In Phase I of the study, we re-configured the first 4 h of the EEGs in lateral circumferential montage with ten electrodes and asked new readers to interpret the EEGs without access to any other ancillary information. We compared their rating to the reading of hospital clinicians with access to ancillary information. In Phase II, we measured the accuracy of the same raters reading representative samples of the discordant EEGs in full and reduced configurations presented randomly by comparing their performance to majority consensus as the gold standard. Results Of the 95 EEGs without seizures in the selected fm-EEG, readers of rm-EEG identified 92 cases (97%) as having no seizure activity. Of 117 EEGs with “seizures” identified in the selected fm-EEG, none of the cases was labeled as normal on rm-EEG. Readers of rm-EEG reported pathological activity in 100% of cases, but labeled them as seizures (N = 77), rhythmic or periodic patterns (N = 24), epileptiform spikes (N = 7), or burst suppression (N = 6). When the same raters read representative epochs of the discordant EEG cases (N = 43) in both fm-EEG and rm-EEG configurations, we found high concordance (95%) and intra-rater agreement (93%) between fm-EEG and rm-EEG diagnoses. Conclusions Reduced EEG with ten electrodes in circumferential configuration preserves key features of the traditional EEG system. Discrepancies between rm-EEG and fm-EEG as reported in some of the past studies can be in part due to methodological factors such as choice of gold standard diagnosis, asymmetric access to ancillary clinical information, and inter-rater variability rather than detection failure of rm-EEG as a result of electrode reduction per se.

Currently, stem cell donor registries include more than 35 million potential donors worldwide to provide HLA‐matched stem cell products for patients in need of an unrelated donor transplant. DKMS is a leading stem cell donor registry with more than 9 million donors from Germany, Poland, the United States, the United Kingdom, India and Chile. DKMS donors have donated hematopoietic stem cells more than 80,000 times. Many aspects of donor registry work are closely related to topics from immunogenetics or population genetics. In this two‐part review article, we describe, analyse and discuss these areas of donor registry work by using the example of DKMS. Part 1 of the review gives a general overview on DKMS and includes typical donor registry activities with special focus on the HLA system: high‐throughput HLA typing of potential stem cell donors, HLA haplotype frequencies and resulting matching probabilities, and donor file optimization with regard to HLA diversity.

Purpose: Surgery is often used for large or symptomatic brain metastases but is associated with risk of developing leptomeningeal dissemination. Emerging data suggest that fractionated stereotactic radiation therapy (FSRT) is an effective management strategy in large brain metastases. We sought to retrospectively compare leptomeningeal disease (LMD) and local control (LC) rates for patients treated with surgical resection followed by radiosurgery (S + SRS) versus FSRT alone. Methods and Materials: We identified all patients with a brain metastasis ≥3 cm in diameter treated from 2004 to 2017 with S + SRS or FSRT alone (25 or 30 Gy in 5 fractions) who had follow-up imaging. LMD was defined as focal or diffuse leptomeningeal enhancement that was >5 mm from the index metastasis. Categorical baseline characteristics were compared with the χ2 test. LMD and LC rates were evaluated by the Kaplan-Meier (KM) method, with the log-rank test used to compare subgroups. Results: A total of 125 patients were identified, including 82 and 43 in the S + SRS and FSRT alone groups, respectively. Median pretreatment Graded Prognostic Assessment in the S + SRS and FSRT groups was 2.5 and 1.5, respectively (P

Effects of varying types of short duration workouts in high-intensity functional training (HIFT) on inflammatory biomarkers have not been adequately characterized. Objectives: The purpose of this descriptive study was to examine the acute effects of HIFT workouts on biomarkers of inflammation, over time, in two HIFT bouts. Materials and Methods: Ten apparently healthy males (28.1 ± 5 yrs) completed two HIFT sessions (“short bout:” sub-5-minute vs. “long bout:” 15-minute) in a randomized crossover design. Blood was drawn pre and post-exercise, and 1 hour, 3 hours, and 6 hours post-exercise, centrifuged, and plasma frozen for analysis. Inflammation was assessed through plasma interleukin-6 (IL-6), interleukin-10 (IL-10), and tumour necrosis factor alpha (TNF-α). Results: Repeated measures ANOVA revealed a single trial-dependent difference (IL-6, p≤ 0.05), and while statistically significant, this difference may not be biologically significant. The biomarkers IL-6, IL-10, and TNF-α all follow a similar pattern of peaking post-exercise and returning to baseline within 6 hours in both trials. Conclusions: Both temporal responses and concentrations were similar in the short and long bout. A practical implication is that both bouts of a HIFT elicit certain specific physiologic inflammatory responses.

Purpose: Interest and application of stereotactic radiosurgery for multiple brain metastases continue to increase. Various planning systems are available for linear accelerator (linac)–based single-isocenter multiple metastasis radiosurgery. Two of the most advanced systems are BrainLAB Multiple Metastases Elements (MME), a dynamic conformal arc (DCA) approach, and Varian RapidArc (RA), a volumetric modulated arc therapy (VMAT) approach. In this work, we systematically compared plan quality between the 2 techniques. Methods and Materials: Thirty patients with 4 to 10 metastases (217 total; median 7.5; Vmin = 0.014 cm3; Vmax = 17.73 cm3) were planned with both Varian RA and MME at 2 different institutions with extensive experience in each respective technique. All plans had a single isocenter and used Varian linac equipped with high-definition multileaf collimator. RA plans used 2 to 4 noncoplanar VMAT arcs with 10 MV flattening filter-free beam. MME plans used 4 to 9 noncoplanar DCAs and 6 MV flattening filter-free beam, (minimum planning target volume [PTVmin] = 0.49 cm3; PTVmax = 27.32 cm3; PTVmedian = 7.05 cm3). Prescriptions were 14 to 24 Gy in a single fraction. Target coverage goal was 99% of volume receiving prescription dose (D99% ≥ 100%). Plans were evaluated by Radiation Therapy Oncology Group/Paddick conformity index (CI) score, 12 Gy volume (V12Gy), V8Gy, V5Gy, mean brain dose (Dmean), and beam-on time. Results: Conformity was favorable among RA plans (median: MME CIRTOG = 1.38; RA CIRTOG = 1.21; P < .0001). V12Gy and V8Gy were lower for RA plans (median: MME V12 = 23.7 cm3; RA V12 = 19.2 cm3; P = .0001; median: MME V8Gy = 53.6 cm3; RA V8Gy = 44.1 cm3; P = .024). V5Gy was lower for MME plans (median: MME V5Gy = 141.4 cm3; RA V5Gy = 142.8 cm3; P = .009). Mean brain was lower for MME plans (median: MME Dmean = 2.57 Gy; RA Dmean = 2.76 Gy; P < .0001). Conclusions: For linac-based multiple metastasis stereotactic radiosurgery, RapidArc VMAT facilitates favorable conformity and V12Gy/V8Gy volume compared with the MME DCA plan. MME planning facilitates reduced dose spill at levels ≤V5Gy.

Background Currently, the evidence for exercise in maintaining health, well-being, and physical functioning is overwhelming. Despite these benefits, more than 50% of the population fails to meet the recommended exercise requirements for age and health status. In our study, we sought to provide a method to increase exercise adherence that was both effective and time-efficient for physicians and their patients. Methods The primary objective of this research study was to evaluate the effectiveness of a graded exercise protocol and biweekly monitoring on increasing the duration of aerobic exercise to 150 min per week in a population of elderly individuals with chronic disease. Secondarily, we evaluated for improvement in resting heart rate, blood pressure, body mass index (BMI), and cardiorespiratory fitness. The overall study design was a randomized, prospective cohort study with assessor blinding. Forty-five patients aged ≥60 years with multiple comorbidities were recruited from the Internal Medicine Clinic at Wright-Patterson AFB. Participants were randomized into a treatment or control arm and observed over a period of 34 weeks. Those in the treatment arm were given a graded walking protocol and received biweekly phone calls to evaluate compliance. Those in the control arm did not receive an intervention or biweekly monitoring. Measurements of heart rate, blood pressure, and BMI were taken quarterly in both groups. At the beginning and conclusion of the study, each participant completed a modified Balke treadmill test and Physical Activity Scale for the Elderly (PASE). Continuous variables were evaluated with the independent samples t-test, whereas categorical variables were evaluated with the chi-squared test. Results A greater percentage of the treatment group achieved the primary outcome (41.6% vs. 0%; p = 0.003). Those in the treatment group also had favorable improvements in heart rate response (− 2.4 beats/min vs. + 5.3 beats/min; p = 0.038) and PASE (+ 66 vs.-20; p Conclusion Guided, independent exercise and surveillance can be an effective tool in primary care practice to help patients reach the recommended levels of exercise for both age and health status.

The unpredictable occurrences of a pandemic and trade conflicts have recently demonstrated the fragility of global, industrial value chains. Local value creation structures have the potential to mitigate these issues by increasing resilience and meeting present ecological, economic and social challenges. However, the idea of localizing manufacturing encompasses various concepts of value creation that are often used without clearly differentiating them. This paper presents a meta-synthesis which evaluates study results on the topic of local manufacturing aiming to outline Distributed Manufacturing (DM), Re-Distributed Manufacturing (RDM) and Urban Manufacturing (UM). Key attributes are identified and used to characterize the concepts, also highlighting overlaps and differences between them. This allows for a better understanding of local manufacturing and consolidates multiple descriptions of these concepts, thus enabling a more universal and unambiguous communication when referring to DM, RDM or UM.

Chemotherapeutic drugs such as the alkylating agent Temozolomide (TMZ), in addition to reducing tumor mass, can also sensitize tumors to immune recognition by transient upregulation of multiple stress induced NKG2D ligands (NKG2DL). However, the potential for an effective response by innate lymphocyte effectors such as NK and γδ T cells that recognize NKG2DL is limited by the drug’s concomitant lymphodepleting effects. We have previously shown that modification of γδ T cells with a methylguanine DNA methyltransferase (MGMT) transgene confers TMZ resistance via production of O6-alkylguanine DNA alkyltransferase (AGT) thereby enabling γδ T cell function in therapeutic concentrations of TMZ. In this study, we tested this strategy which we have termed Drug Resistant Immunotherapy (DRI) to examine whether combination therapy of TMZ and MGMT-modified γδ T cells could improve survival outcomes in four human/mouse xenograft models of primary and refractory GBM. Our results confirm that DRI leverages the innate response of γδ T cells to chemotherapy-induced stress associated antigen expression and achieves synergies that are significantly greater than either individual approach.

Introduction: The Department of Defense has been training primary care providers in battlefield acupuncture (BFA), a subtype of auricular acupuncture, as an adjunct therapy for pain management. Methods: The objective of this study was to evaluate the effectiveness and safety of BFA for pain management in an outpatient Internal Medicine clinic staffed by resident physicians. The target population for this single-center prospective cohort study were military beneficiaries at a medical treatment facility located at the Wright-Patterson Air Force Base. Participants who met inclusion criteria were treated with BFA in addition to routine standard care for pain (n = 69). The control group was composed of participants who received routine standard care only without BFA (n = 27). Pain was assessed by a self-reported pain scale (0–10) at the time of encounter, immediately after BFA (for the intervention group), then at 24 and 48 h afterwards. Results: Mean pain for the intervention group decreased from 5.45 before BFA to 3.29 immediately following BFA to 2.21 at 24 h and to 2.10 at 48 h (p Conclusion: BFA provided by Internal Medicine residents appears to be a safe and effective adjunct therapy for pain management in an outpatient setting, but requires further validation by randomized controlled trials.

Today, medical technology manufacturers enter the service market through the development of digital service innovations. In the field of audiology, these developments increasingly shift the service capacities from audiologists to manufacturers and technical systems. However, the technology-driven developments of manufacturers lack acceptance of hearing device users and undermine the important role of audiologists within the service provision. By following a user-centered design approach in order to deal with the technological and social challenges of disruptive services, we aim to develop service innovations on an integrated service platform in the field of tele-audiology. To ensure the acceptance of technology-driven service innovations among hearing device users and audiologists, we systematically integrated these actors in a participatory innovation process. With qualitative and quantitative data we identified several requirements and preferences for different service innovations in the field of tele-audiology. According to the preferences of the different actors, we proposed a service platform approach based on a connected hearing device in three pillars of application: 1) one-to-one (1:1) service innovations based on a remote fitting concept directly improve the availability of services offered by audiologists without being physically present. Based on this, 2) one-to-many (1:N) service innovations allow the use of the connected hearing device as an indirect data source for training a machine learning algorithm that empowers users through the automation of service processes. A centralized server system collects the data and performs the training of this algorithm. The optimized algorithm is provided to the connected hearing devices to perform automatic acoustic scene classification. This in turn allows optimization of the hearing devices within each acoustic scene. After the user-centered development of the different service innovations which are designed to converge on an integrated service platform, we experimentally evaluated the functionality and applicability of the system as well as the associated role models between the technical system, the hearing device users and audiologists. As a future outlook, we show potentials to use the connected hearing device for 3) cross-industry (N:M) service innovations in contexts outside the healthcare domain and give practical implications for the market launch of successful service innovations in the field of tele-audiology.

This opinion paper briefly presents arguments that support the unlikelihood of an impact on female fertility from current covid-19 vaccines.

Tobacco smoking is an important public health issue recognized by the world health organization as one of the most serious, preventable risk factors for developing a series of pregnancy pathologies. Maternal smoking is positively associated with intrauterine growth restriction (IUGR) and gestational diabetes (GDM), but negatively associated with preeclampsia (PE). In this review, we examine epidemiological, clinical and laboratory studies of smoking effects on immunoregulation during pregnancy, trophoblast function, and placental vasculature development and metabolism. We aim to identify effects of tobacco smoke components on specific placental compartments or cells, which may contribute to the understanding of the influences of maternal smoking on placenta function in normal and pathological pregnancies. Data corroborates that in any trimester, smoking is unsafe for pregnancy and that its detrimental effects outweigh questionable benefits. The effects of maternal smoking on the maternal immune regulation throughout pregnancy and the impact of different tobacco products on fetal growth have not yet been fully understood. Smoking cessation rather than treatment with replacement therapies is recommended for future mothers because also single components of tobacco and its smoke may have detrimental effects on placental function.

Charged-particle spectra at midrapidity are measured in Pb-Pb collisions at the centre-of-mass energy per nucleon-nucleon pair $\sqrt{s_{\rm NN}}$ = 5.02 TeV and presented in centrality classes ranging from most central (0-5%) to most peripheral (95-100%) collisions. Possible medium effects are quantified using the nuclear modification factor ($R_{\rm AA}$) by comparing the measured spectra with those from proton-proton collisions, scaled by the number of independent nucleon-nucleon collisions obtained from a Glauber model. At large transverse momenta ($8, Comment: 24 pages, 7 captioned figures, 2 tables, authors from page 18, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/4437

People, livelihoods, and infrastructure in Myanmar suffer from devastating monsoonal flooding on a frequent basis. Quick and effective management of flood risk relies on planning and preparedness to ensure the availability of supplies, shelters and emergency response personnel. The mandated government agency Department of Disaster Management (DDM) as well as local and international organizations play roles in producing, disseminating, and using accurate and timely information on flood risk. Currently, systematic flood risk maps are lacking, which leaves DDM to rely on inconsistent historic reports and local knowledge to inform their emergency planning. Although these types of knowledge are critical, they can be complemented to reduce bias and human error to planning processes and decisions. As such, the present situation has led to ineffective distribution of emergency response resources prior to flooding, leaving vulnerable populations less-than-prepared for inevitable flood events. Given these issues, we have developed a flood risk decision-support tool in collaboration with DDM. The tool uses surface water maps developed by the Joint Research Center (JRC), which were derived from more than 30 years of Landsat imagery. We have also incorporated population data, land cover data, and other information on flood exposure and vulnerability to create the first scalable and replicable Flood Risk Index (FRI) for flood risk reduction in Myanmar.

Significance In this manuscript, we report a rare case of a patient with localized seizures originating from the right anterior and dorsal posteromedial cortex (PMC). We mapped the electrophysiological and neuroimaging connectivity of the ictal onset site and replicated seizure auras by stimulating the homotopical PMC site in the left hemisphere. Our findings provide a causal link between PMC and the sense of self and provide unique clues about the pathophysiology of self-dissociation in neuropsychiatric conditions., The posteromedial cortex (PMC) is known to be a core node of the default mode network. Given its anatomical location and blood supply pattern, the effects of targeted disruption of this part of the brain are largely unknown. Here, we report a rare case of a patient (S19_137) with confirmed seizures originating within the PMC. Intracranial recordings confirmed the onset of seizures in the right dorsal posterior cingulate cortex, adjacent to the marginal sulcus, likely corresponding to Brodmann area 31. Upon the onset of seizures, the patient reported a reproducible sense of self-dissociation—a condition he described as a distorted awareness of the position of his body in space and feeling as if he had temporarily become an outside observer to his own thoughts, his “me” having become a separate entity that was listening to different parts of his brain speak to each other. Importantly, 50-Hz electrical stimulation of the seizure zone and a homotopical region within the contralateral PMC induced a subjectively similar state, reproducibly. We supplement our clinical findings with the definition of the patient’s network anatomy at sites of interest using cortico-cortical–evoked potentials, experimental and resting-state electrophysiological connectivity, and individual-level functional imaging. This rare case of patient S19_137 highlights the potential causal importance of the PMC for integrating self-referential information and provides clues for future mechanistic studies of self-dissociation in neuropsychiatric populations.

Highlights • Rare, high grade neuroendocrine-like pediatric tumor has TYRO3 and ALK mutations. • Crizotinib downregulates STAT3 and ERK1/2 signaling in tumor. • In vivo analysis demonstrated crizotinib resistance. • Crizotinib resistant cells have upregulation of PDGFRß signaling. • PDGFRß inhibition overrides resistance., Patient-derived xenografts provide significant advantages over long-term passage cell lines when investigating efficacy of treatments for solid tumors. Our laboratory encountered a high-grade, metastatic, neuroendocrine-like tumor from a pediatric patient that presented with a unique genetic profile. In particular, mutations in TYRO3 and ALK were identified. We established a human patient-derived xenoline (PDX) of this tumor for use in the current study. We investigated the effect of crizotinib, a chemotherapeutic known to effectively target both TYRO3 and ALK mutations. Crizotinib effectively decreased viability, proliferation, growth, and the metastatic properties of the PDX tumor through downregulation of STAT3 signaling, but expression of PDGFRß was increased. Sunitinib is a small molecule inhibitor of PDGFRß and was studied in this PDX independently and in combination with crizotinib. Sunitinib alone decreased viability, proliferation, and growth in vitro and decreased tumor growth in vivo. In combination, sunitinib was able to overcome potential crizotinib-induced resistance through downregulation of ERK 1/2 activity and PDGFRß receptor expression; consequently, tumor growth was significantly decreased both in vitro and in vivo. Through the use of the PDX, it was possible to identify crizotinib as a less effective therapeutic for this tumor and suggest that targeting PDGFRß would be more effective. These findings may translate to other solid tumors that present with the same genetic mutations.

Background:Central line-associated bloodstream infection (CLABSI) is a preventable medical condition that results in increased patient morbidity and mortality. We describe the impact of various quality improvement interventions on the incidence of CLABSI in an 848-bed community teaching hospital from 1 January 2013 to 31 December 2017.Aim:To reduce CLABSI rates after implementation of a comprehensive central line insertion and maintenance bundle.Methods:A comprehensive bundle of interventions was implemented incorporating the standard US Centers for Disease Control and Prevention bundle with additional measures such as root-cause analysis of all CLABSI cases, use of passive disinfection caps on vascular access ports, standardisation of weekly central venous catheter (CVC) site dressing changes, and use of antithrombotic and antimicrobial-coated CVCs with fewer lumens. A retrospective study evaluated CLABSI rates and time of CLABSI onset after CVC placement in both intensive care unit (ICU) and non-ICU settings.Results:The annual number of CLABSI cases declined 68% (34 to 11 patients) from 2013 to 2017. There was a 30% decline in CVC days from years 2014 to 2017. Over the same period, CLABSI cases per 1000 CVC days decreased from 0.624 to 0.362: a 42% decline.Conclusion:Following the implementation of a comprehensive bundle of interventions for CVC insertion and maintenance, we found a reduction in rates of CLABSI.

Pregnant women have been carefully observed during the COVID-19 pandemic, as the pregnancy-specific immune adaptation is known to increase the risk for infections. Recent evidence indicates that even though most pregnant have a mild or asymptomatic course, a severe course of COVID-19 and a higher risk of progression to diseases have also been described, along with a heightened risk for pregnancy complications. Yet, vertical transmission of the virus is rare and the possibility of placental SARS-CoV-2 infection as a prerequisite for vertical transmission requires further studies. We here assessed the severity of COVID-19 and onset of neonatal infections in an observational study of women infected with SARS-CoV-2 during pregnancy. Our placental analyses showed a paucity of SARS-CoV-2 viral expression ex vivo in term placentae under acute infection. No viral placental expression was detectable in convalescent pregnant women. Inoculation of placental explants generated from placentas of non-infected women at birth with SARS-CoV-2 in vitro revealed inefficient SARS-CoV-2 replication in different types of placental tissues, which provides a rationale for the low ex vivo viral expression. We further detected specific SARS-CoV-2 T cell responses in pregnant women within a few days upon infection, which was undetectable in cord blood. Our present findings confirm that vertical transmission of SARS-CoV-2 is rare, likely due to the inefficient virus replication in placental tissues. Despite the predominantly benign course of infection in most mothers and negligible risk of vertical transmission, continuous vigilance on the consequences of COVID-19 during pregnancy is required, since the maternal immune activation in response to the SARS-CoV2 infection may have long-term consequences for children’s health.