Search

COVID-19 continues to rampage around the world. Non-critical care trained physicians may be deployed into the intensive care unit to manage these complex patients. While COVID-19 is primarily a respiratory disease, it is also associated significant pathology in the brain, heart, vasculature, lungs, gastrointestinal tract and kidneys. This chapter provides an overview of COVID-19 using an organ-based, systematic approach.

Introduction: Evidence-based grading of the impact of intracranial surgery on rat’s well-being is important for ethical and legal reasons. We assessed the severity of complex and repeated intracranial surgery in a 6-hydroxydopamine (6-OHDA) Parkinson’s rat model with subsequent intracranial electrode implantation and in an intracranial tumor model with subsequent resection. Methods: Stereotactic surgery was performed in adult male rats with the same general anesthesia and perioperative pain management. In Parkinson’s model, Sprague Dawley rats received unilateral injection of 6-OHDA (n = 11) or vehicle (n = 7) into the medial forebrain bundle as first operation (1st OP). After four weeks, neural electrodes were implanted in all rats as second operation (2nd OP). For tumor formation, BDIX/UlmHanZtm rats (n = 8) received frontocortical injection of BT4Ca cells as 1st OP, followed by tumor resection as 2nd OP after one week. Multiple measures severity assessment was done two days before and four days after surgery in all rats, comprising clinical scoring, body weight, and detailed behavioral screening. To include a condition with a known burden, rats with intracranial tumors were additionally assessed up to a predefined humane endpoint that has previously been classified as “moderate”. Results: After the 1st OP, only 6-OHDA injection resulted in transient elevated clinical scores, a mild long-lasting weight reduction, and motor disturbances. After the second surgery, body weight was transiently reduced in all groups. All other parameters showed variable results. Principal component analysis showed a separation from the preoperative state driven by motor-related parameters after 6-OHDA injection, while separation after electrode implantation and more clearly after tumor resection was driven by pain-related parameters, although not reaching the level of the humane endpoint of our tumor model. Conclusion: Overall, cranial surgery of different complexity only transiently and rather mildly affects rat’s well-being. Multiple measures assessment allows the differentiation of model-related motor disturbances in Parkinson’s model from potentially pain-related conditions after tumor resection and electrode implantation.

Optical sinc-shaped Nyquist pulses are promising in photonic signal processing and high-speed optical data transmission due to their orthogonality and inter-symbol interference (ISI) free characteristics. Nonetheless, the presence of non-idealities results in a deteriorated system performance, especially for the metrological assessment of sampling precision. In this work, we explore the impact of the optical filter roll-off factor on Nyquist pulses for a three-line comb with a frequency spacing of 8.4 GHz using a wideband on-chip silicon Mach-Zehnder modulator. Furthermore, we characterize the integrated modulator and compare the sinc-shaped Nyquist pulse quality with the recently reported works.

BACKGROUND AND OBJECTIVES Viloxazine extended-release (viloxazine ER) capsules (QelbreeTM) is a novel nonstimulant recently approved as a treatment for attention-deficit/hyperactivity disorder in children and adolescents. Here, we determined whether the pharmacokinetics of viloxazine are impacted by consuming the capsule contents sprinkled on applesauce rather than an intact capsule, and the effect of a high-fat meal on the pharmacokinetics of viloxazine ER. METHODS This was a randomized, open-label, crossover, three-treatment, three-period study in healthy adults using orally administered single-dose viloxazine ER 200 mg capsules. Subjects consumed: (1) an intact capsule after a 10-h fast (control condition); (2) the capsule contents sprinkled on one tablespoon of applesauce; and (3) an intact capsule with a standard high-fat meal. Blood samples were collected for 48 h post-dosing. Relative bioavailability analyses were performed to assess the impact of each test condition against the control condition (intact capsule, fasting). The absence of an impact was indicated if the 90% confidence interval (CI) for the least-squares geometric mean ratio (LSGMR) of maximal concentration (Cmax), the area under the concentration-time curve from time 0 to the last measurable concentration time (AUClast), and the area under the concentration-time curve from time 0 to infinity (AUCinf) were within the predetermined no-difference limits of 80-125%. RESULTS Out of 27 enrolled subjects, 25 were included in the pharmacokinetic analysis. The LSGMR (90% CI) for viloxazine ER sprinkled vs. intact were 90.10% (83.35-97.40) for Cmax, 93.71% (89.09-98.57) for AUClast, and 95.37% (89.80-101.28) for AUCinf. The LSGMR (90% CI) for viloxazine ER consumed in the fed state vs. fasting state were 90.86% (84.05-98.21) for Cmax, 89.68% (85.26-94.33) for AUClast, and 92.35% (86.96-98.07) for AUCinf. The 90% CIs of the LSGMRs were within the predetermined no-difference limits of 80-125%. Viloxazine ER was well tolerated, with most adverse events reported as mild. CONCLUSIONS These data suggest that viloxazine ER can be consumed sprinkled on applesauce or as intact capsules with or without meals without significantly changing its pharmacokinetics.

Blockchain technologies enable new forms of data sharing in platforms. This raises questions around how they are jointly developed and managed in blockchain consortia and what role public agencies play in those efforts. Based on an analysis of prior work on data sharing in public-private partnerships and other blockchain projects, we analyze the case of the Cardossier. The Cardossier project and (later) association develops a platform to link the public and private actors in the Swiss car ecosystem. The participating car registration authority has the roles of an actor in interorganizational processes, supplier of data, source of trust, guarantor of data quality, user of data, and incentive for making goods public. We conclude that the public agencies have a very important role in blockchain consortia and propose that they should use this role actively as part of their efforts to create public value.

Chemotherapy is a standard treatment for pediatric acute lymphoblastic leukemia (ALL), which sometimes relapses with chemoresistant features. However, whether acquired drug-resistance mutations in relapsed ALL pre-exist or are induced by treatment remains unknown. Here we provide direct evidence of a specific mechanism by which chemotherapy induces drug-resistance-associated mutations leading to relapse. Using genomic and functional analysis of relapsed ALL we show that thiopurine treatment in mismatch repair (MMR)-deficient leukemias induces hotspot TP53 R248Q mutations through a specific mutational signature (thio-dMMR). Clonal evolution analysis reveals sequential MMR inactivation followed by TP53 mutation in some patients with ALL. Acquired TP53 R248Q mutations are associated with on-treatment relapse, poor treatment response and resistance to multiple chemotherapeutic agents, which could be reversed by pharmacological p53 reactivation. Our findings indicate that TP53 R248Q in relapsed ALL originates through synergistic mutagenesis from thiopurine treatment and MMR deficiency and suggest strategies to prevent or treat TP53-mutant relapse. Zhou and colleagues demonstrate that thiopurine chemotherapy in mismatch repair-deficient ALL cells leads to R248Q TP53 mutations and clonal selection that favors on-treatment ALL relapse and chemoresistance.

Against the backdrop of recent social and technological developments, the relationship between the educational system and the employment system has also changed. The “lifelong learning” paradigm is now firmly established within the field of educational research. In this article, we argue that empirical researchers have shifted using certificates to capture educational attainment, focusing instead on competence and performance. We define “performance” as the ability to react adequately and flexibly to new situations within job-related contexts. This paper thus aims to describe the shifting research paradigm in the context of political agenda-setting and presents some examples from different disciplinary perspectives to illustrate the potential of interdisciplinary research. Interdisciplinary, collaborative research, we suggest, shows great potential for providing empirical evidence to measure the consequences—intended and unintended—of political reforms in higher education. Even though our arguments and implications are formulated from the perspective of the German education and science system, their essence can also be applied to other national contexts.

Aims The direct anterior approach (DAA) for total hip arthroplasty (THA) has potential advantages over other approaches and is most commonly performed with the patient in the supine position. We describe a technique for DAA THA with the patient in the lateral decubitus position and report the early clinical and radiological outcomes, the characteristics of the learning curve, and perioperative complications. Methods All primary DAA THAs performed in the lateral position by a single surgeon over a four-year period from the surgeon’s first case using the technique were identified from a prospectively collected database. Modified Harris Hip Scores (mHHS) were collected to assess clinical outcome, and routine radiological analysis was performed. Retrospective review of the medical records identified perioperative complications, the characteristics of the learning curve, and revisions. Results A total of 257 patients were included in the study. Their mean age was 60 years (SD 9.0). A total of 164 (64%) were female. The mean mHHS improved significantly from 52.1 (SD 16.2) preoperatively to 94.4 (SD 11) at a follow-up of one year (p < 0.001), with 212 of 225 patients (94%) achieving a minimal clinically important difference (MCID) (> 8 points). Radiological evaluation showed a mean leg length discrepancy of 2.6 mm (SD 5.9) and a mean difference in femoral offset of 0.2 mm (SD 4.9). A total of 234/243 acetabular components (96.3%) were positioned within Lewinnek’s safe zone. Analysis of operating time, blood loss, the position of the components, and complications did not identify a learning curve. A total of 14 patients (5.4%) had a major perioperative complication and three (1.2%) required revision THA. There were no major neurovascular complications and no dislocations. Conclusion We have described and analyzed a surgical technique for undertaking DAA THA in the familiar lateral decubitus position using a routine operating table, positioning devices, and instrumentation, and shown that it can be performed safely and effectively under these circumstances. Cite this article: Bone Joint J 2021;103-B(7 Supple B):53–58.

Aims The purpose of this study was to determine the access to and ability to use telemedicine technology in adult patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA), and to determine associations with the socioeconomic characteristics of the patients, including age, sex, race, and education. We also sought to understand the patients’ perceived benefits, risks, and preferences when dealing with telemedicine. Methods We performed a cross-sectional survey involving patients awaiting primary THA and TKA by one of six surgeons at a single academic institution. Patients were included and called for a telephone-administered survey if their surgery was scheduled to be between 23 March and 2 June 2020, and were aged > 18 years. Results The response rate was 52% (189 of 363 patients). A total of 170 patients (90.4%) reported using the internet, 177 (94.1%) reported owning a device capable of videoconferencing, and 143 (76.1%) had participated in a video call in the past year. When asked for their preferred method for a consultation, 155 (82.8%) and 26 (13.9%) ranked in-person and a videoconference as their first choice, respectively. The perceived benefits of telemedicine consultations included reduced travel to appointments (165 (88.2%) agreed) and reduced cost of attending appointments (123 (65.8%) agreed). However, patients were concerned that they would not establish the same patient-physician connection (100 (53.8%) agreed), and would not receive the same level of care (52 (33.2%) agreed) using telemedicine consultations compared with in-person consultations. Conclusion Most patients undergoing arthroplasty have access to and are capable of using the technology required for telemedicine consultations. However, they still prefer in-person consultations due to concerns that they will not establish the same patient-physician connection and will not receive the same level of care, despite the benefits of reducing the time spent in travelling and the cost of attending appointments, and the appointments being easier to attend. Cite this article: Bone Joint J 2021;103-B(7 Supple B):98–102.

This study explores the barriers faced by white shrimp farmers in Vietnam in linking directly with food processing companies. The shrimp sector in Vietnam is still characterised by highly informal structures, weak implementation of food safety regulations and a lack of expertise among farmers to comply with international standards. The Vietnamese government anticipates modernising shrimp production and enabling farmers to achieve the quality standards of international retailers. While international food processing companies have established locations in Vietnam to serve international markets, farmers often lack the resources and expertise to comply with their requirements. The main challenges are related to infrastructure for transport and payment transfers, risk management and overcoming established production routines which are mostly based on tacit knowledge and experience. Hence, efforts are needed to improve infrastructures, establish risk management tools for farmers and promote successful cases which can act as guiding examples for adapting white shrimp production.

Zusammenfassung. Hintergrund: Notfälle in Pflegeheimen führen zu einer hohen Anzahl von Rettungsdiensteinsätzen und Krankenhauszuweisungen. Eine umfassende interprofessionelle Perspektive auf Notfälle in Pflegeheimen ist bislang wenig untersucht. Ziel: Charakterisierung, Identifizierung und Priorisierung von Notfallszenarien nach Relevanz und Häufigkeit in Pflegeheimen. Methoden: Zwei multimethodale berufsgruppenübergreifende Gruppendiskussionen wurden mit insgesamt 18 Teilnehmenden aus Pflege, Medizin und Wissenschaft im Januar und Februar 2020 durchgeführt. Die Gruppendiskussionen wurden aufgezeichnet, transkribiert und qualitativ-inhaltsanalytisch nach Mayring ausgewertet. Ergebnisse: Notfallszenarien in Pflegeheimen entstehen aus einem Zusammenspiel von personenbezogenen Anlässen und Kontextbedingungen. Als wesentliche personenbezogene Anlässe wurden genannt: Sturz, entgleiste Vitalwerte, auffälliges Verhalten, neurologische Symptome und Leblosigkeit. Kontextbedingungen gliedern sich in organisatorisch-strukturelle, politisch-rechtliche und ethische Aspekte. Als besonders relevant stellten sich unzureichende Kommunikation zwischen den Akteuren, Unsicherheiten beim Personal, fehlende Patientenverfügungen und Arbeitsverdichtung in der Pflege heraus. Schlussfolgerungen: Notfälle in Pflegeheimen stellen sich als komplexe Notfallszenarien dar. Kontextbedingungen sind bedeutsam für den Umgang mit Notfallszenarien in Pflegeheimen. Handlungsempfehlungen sollten sich an der Perspektive der in der Notfallversorgung beteiligten Akteure orientieren und die Kontextbedingungen stärker berücksichtigen.

An optoelectronic millimeter-wave (mm-wave) radar transmitter (TX) integrated circuit (IC) for multiple-input–multiple-output (MIMO) imaging radar in silicon photonics technology is presented. The MIMO radar system architecture in which the ICs shall be used features an optical local oscillator (LO) distributed over fiber to coherently operate mm-wave transceiver frontends. Optical LO distribution enables larger apertures and hence higher angular resolution for MIMO imaging radars. The optoelectronic TX frontend IC integrates all electronic and photonic components needed to receive the optical LO signal and to generate a transmit signal at mm-wave. It operates on both 1310- and 1550-nm LO wavelengths. The chip was designed in a pre-production photonic SiGe BiCMOS technology from IHP. Measured output power is 13 dBm at 67 GHz and 5 dBm at 77 GHz from −5-dBm optical modulation amplitude (OMA). The IC dissipates 900 mW from a single 3.6-V supply voltage.

Viloxazine has a long history of clinical use in Europe as an antidepressant, and has recently been repurposed into an extended-release form for the treatment of attention-deficit/hyperactivity disorder in the USA. An immediate-release formulation was approved for the treatment of depression in the UK in 1974, and was subsequently marketed there and in several European countries for 30 years with no major safety concerns. In contrast to first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), viloxazine was associated with a relatively low risk for cardiotoxicity. Gastrointestinal symptoms were the most commonly reported side effects. The therapeutic effects of viloxazine are thought to be primarily the result of its action as a norepinephrine reuptake inhibitor, although in vitro and preclinical in vivo animal data suggest that viloxazine may also impact the serotoninergic system. This review summarizes the evolving knowledge of viloxazine based on information from previously published preclinical and clinical investigations, and acquired unpublished historical study reports from both open-label and blinded controlled clinical trials. We review the chemical properties, mechanism of action, safety, and tolerability across these studies, and discuss the contemporary rationale for the development of this agent as an extended-release oral formulation for the treatment of attention-deficit/hyperactivity disorder.

Supplemental digital content is available in the text., Purpose This phase 3 clinical trial evaluated the efficacy and safety of viloxazine extended-release capsules (VLX-ER) as a monotherapy for attention-deficit/hyperactivity disorder (ADHD) in adolescents (12–17 years). Methods Eligible subjects (n = 310) were randomized to receive once-daily 200 and 400 mg VLX-ER, or placebo for 6 weeks. The primary efficacy end point was change from baseline (CFB) at the end of study (EOS) in ADHD Rating Scale-5 Total score. Key secondary end points were Clinical Global Impression—Improvement score at EOS, CFB at EOS in Conners 3—Parent Short Form Composite T-score, and CFB at EOS in Weiss Functional Impairment Rating Scale—Parent Total average score. Results In the 200-mg/d and 400-mg/d VLX-ER treatment groups, a significant improvement was found in the CFB at EOS in ADHD Rating Scale-5 Total (P = 0.0232, P = 0.0091) and Inattention (P = 0.0424, P = 0.0390) and Hyperactivity/Impulsivity (P = 0.0069, P = 0.0005) subscale scores versus placebo. The Clinical Global Impression—Improvement score was significantly improved at EOS in the 200-mg/d and 400-mg/d VLX-ER groups versus placebo (P = 0.0042, P = 0.0003). The Conners 3—Parent Short Form composite T-score and Weiss Functional Impairment Rating Scale—Parent Total average score exhibited improvement in both VLX-ER groups; however, the difference versus placebo was not statistically significant. The most common treatment-related adverse events were somnolence, headache, decreased appetite, nausea, and fatigue. The adverse event–related discontinuation rates were

SPN‐812 (viloxazine extended‐release) is a novel nonstimulant recently approved as a treatment for attention‐deficit/hyperactivity disorder in children and adolescents. Given that SPN‐812 is metabolized by CYP2D6 and may be coadministered with CYP2D6 inhibitors, this trial investigated the pharmacokinetics and safety of SPN‐812 coadministered with the potent CYP2D6 inhibitor paroxetine. In this single‐sequence, 3‐treatment period study in healthy volunteers, subjects received a single oral dose of 700 mg SPN‐812 alone (period 1), 20 mg daily paroxetine (10 days, period 2), followed by concurrent administration of SPN‐812 and paroxetine (period 3). Blood samples were collected for 72 hours post‐SPN‐812 dosing and analyzed for viloxazine and its primary metabolite, 5‐HVLX‐gluc. Twenty‐two healthy adults were enrolled; all completed the trial. The potential for drug interaction between SPN‐812 and paroxetine was assessed using analysis of variance on the log‐transformed pharmacokinetic parameters Cmax, AUC0‐t, and AUCinf. The least‐squares geometric mean ratios for viloxazine were (reported as the ratio of combination/SPN‐812 alone) Cmax, 116.04%; 90%CI, 109.49%‐122.99%; AUC0‐t, 134.65%; 90%CI, 127.65‐142.03; and AUCinf, 134.80%; 90%CI, 127.94%‐142.03%. CYP2D6 inhibition resulted in a modest change (

Background This Phase I, two-part, first-in-human study assessed safety/tolerability and pharmacokinetics/pharmacodynamics of single-ascending doses (SAD) and multiple doses (MD) of the oral toll-like receptor-7 agonist, JNJ-64794964 (JNJ-4964) in healthy adults. Methods In the SAD phase, participants received JNJ-4964 0.2 ( N = 6), 0.6 ( N = 6), 1.25 ( N = 8) or 1.8 mg ( N = 6) or placebo ( N = 2/dose cohort) in a fasted state. Food effect was evaluated for the 1.25 mg cohort following ≥6 weeks washout. In the MD phase, participants received JNJ-4964 1.25 mg ( N = 6) or placebo ( N = 2) weekly (fasted) for 4 weeks. Participants were followed-up for 4 weeks. Results No serious adverse events (AEs) occurred. 10/34 (SAD) and 5/8 (MD) participants reported mild-to-moderate (≤Grade 2), transient, reversible AEs possibly related to JNJ-4964. Five (SAD) participants had fever/flu-like AEs, coinciding with interferon-α serum levels ≥100 pg/mL and lymphopenia (9/L), between 24–48 h after dosing and resolving approximately 96 h after dosing. One participant (MD) had an asymptomatic Grade 1 AE of retinal exudates (cotton wool spots) during follow-up, resolving 6 weeks after observation. JNJ-4964 exhibited dose-proportional pharmacokinetics, with rapid absorption (tmax 0.5–0.75 h) and distribution, and a long terminal half-life (150–591 h). Overall, no significant differences in JNJ-4964 pharmacokinetic parameters were observed in the fed versus fasted state. JNJ-4964 dose-dependently and transiently induced cytokines with potential anti-HBV activity, including interferon-α, IP-10, IL-1 RA, and/or MCP-1, and interferon-stimulated genes (ISG15, MX1, and OAS1) in serum. Conclusions In healthy adults, JNJ-4964 was generally well-tolerated, exhibited dose-proportional pharmacokinetics and induced cytokines/ISGs, with possible anti-HBV activity.

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection1,2, but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19. The lungs from individuals with COVID-19 were highly inflamed, with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but had impaired T cell responses. Monocyte/macrophage-derived interleukin-1β and epithelial cell-derived interleukin-6 were unique features of SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. Alveolar type 2 cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type 1 cells, resulting in impaired lung regeneration. Furthermore, we identified expansion of recently described CTHRC1+ pathological fibroblasts3 contributing to rapidly ensuing pulmonary fibrosis in COVID-19. Inference of protein activity and ligand–receptor interactions identified putative drug targets to disrupt deleterious circuits. This atlas enables the dissection of lethal COVID-19, may inform our understanding of long-term complications of COVID-19 survivors, and provides an important resource for therapeutic development. Lung samples collected soon after death from COVID-19 are used to provide a single-cell atlas of SARS-CoV-2 infection and the ensuing molecular changes.

Vietnam is the world’s third largest exporter of shrimp products. Small-scale farmers are the main actors in producing shrimp but they depend on middlemen to market their products. This study aims ...

Deep brain stimulation (DBS) of the bed nucleus of the stria terminalis/anterior limb of the internal capsule (BNST/ALIC) is successfully used for treatment of patients with obsessive-compulsive disorder (OCD). Clinical and experimental studies have suggested that enhanced network synchronization in the theta band is correlated with severity of symptoms. The mechanisms of action of DBS remain unclear in OCD. We here investigate the effect of acute stimulation of the BNCT/ALIC on oscillatory neuronal activity in patients with OCD implanted with DBS electrodes. We recorded the oscillatory activity of local field potentials (LFPs) from DBS electrodes (contact + 0/− 3; bipolar configuration; both hemispheres) from the BNST/ALIC parallel with frontal cortical electroencephalogram (EEG) one day after DBS surgery in four patients with OCD. BNST/ALIC and frontal EEG oscillatory activities were analysed before stimulation as baseline, and after three periods of stimulation with different voltage amplitudes (1 V, 2 V and 3.5 V) at 130 Hz. Overall, acute high frequency DBS reduced oscillatory theta band (4-8 Hz; p

Background Obsessive compulsive disorder (OCD) is a severe disabling disease, and around 10% of patients are considered to be treatment-resistant (tr) in spite of guideline-based therapy. Deep brain stimulation (DBS) has been proposed as a promising treatment for patients with trOCD. However, the optimal site for stimulation is still a matter of debate, and clinical long-term follow-up observations including data on quality of life are sparse. We here present six trOCD patients who underwent DBS with electrodes placed in the bed nucleus of the stria terminalis/anterior limb of the internal capsule (BNST/ALIC), followed for four to eight years after lead implantation. Materials and methods In this prospective observational study, six patients (four men, two women) aged 32-51 years and suffering from severe to extreme trOCD underwent DBS of the BNST/ALIC. Symptom severity was assessed using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), and quality of life using the World Health Organization Quality of Life assessment scale (WHO-QoL BREF). Follow-up was obtained at least for four years in all patients. Results With chronic DBS for four to eight years, four of the six patients had sustained improvement. Two patients remitted and two patients responded (defined as >35% symptom reduction), while the other two patients were considered nonresponders on long-term. Quality of life markedly improved in remitters and responders. We did not observe peri-interventional side effects or adverse effects of chronic stimulation. Conclusions Chronic DBS of ALIC provides long-term benefit up to four to eight years in trOCD, although not all patients take profit. Targeting the BNST was not particularly relevant since no patient appeared to benefit from direct stimulation of the BNST. Quality of life improved in DBS responders, documented by improved QoL scores and, even more important, by regaining of autonomy and improving psychosocial functioning.

Plasmodium falciparum sporozoite (PfSPZ) Vaccine (radiation-attenuated, aseptic, purified, cryopreserved PfSPZ) and PfSPZ-CVac (infectious, aseptic, purified, cryopreserved PfSPZ administered to subjects taking weekly chloroquine chemoprophylaxis) have shown vaccine efficacies (VEs) of 100% against homologous controlled human malaria infection (CHMI) in nonimmune adults. Plasmodium falciparum sporozoite-CVac has never been assessed against CHMI in African vaccinees. We assessed the safety, immunogenicity, and VE against homologous CHMI of three doses of 2.7 × 106 PfSPZ of PfSPZ Vaccine at 8-week intervals and three doses of 1.0 × 105 PfSPZ of PfSPZ-CVac at 4-week intervals with each arm randomized, double-blind, placebo-controlled, and conducted in parallel. There were no differences in solicited adverse events between vaccinees and normal saline controls, or between PfSPZ Vaccine and PfSPZ-CVac recipients during the 6 days after administration of investigational product. However, from days 7–13, PfSPZ-CVac recipients had significantly more AEs, probably because of Pf parasitemia. Antibody responses were 2.9 times higher in PfSPZ Vaccine recipients than PfSPZ-CVac recipients at time of CHMI. Vaccine efficacy at a median of 14 weeks after last PfSPZ-CVac dose was 55% (8 of 13, P = 0.051) and at a median of 15 weeks after last PfSPZ Vaccine dose was 27% (5 of 15, P = 0.32). The higher VE in PfSPZ-CVac recipients of 55% with a 27-fold lower dose was likely a result of later stage parasite maturation in the liver, leading to induction of cellular immunity against a greater quantity and broader array of antigens.

This paper presents the Knowledge Graph Usage framework, which allows the introduction of Knowledge Graph features to support Trust, Privacy, Transparency and Accountability concerns regarding the use of its contents by applications. A real-world example is presented and used to illustrate how the framework can be used. This article also shows how knowledge graphs can be linked to the elements of legal governance. Thus, it is an invitation to dialogue for legal and Law & Society scholars who might be interested in how the evolution of the web of data and computational sciences intersects with their own discipline.

Background Frailty is a common characteristic of patients undergoing transcatheter mitral valve repair (TMVR). It is unclear whether the physical vulnerability of frail patients translates into increased procedural health care utilization. Methods and results Frailty was assessed using the Fried criteria in 229 patients undergoing TMVR using the MitraClip system at our institution and associations with total costs and costs by cost centers within the hospital incurred during periprocedural hospitalization were examined. Frail patients (n = 107, 47%) compared to non-frail patients showed significantly higher total costs [median/interquartile range, excluding implant costs: 7,337 € (5,911–9,814) vs 6,238 € (5,584–7,499), p = 0.001], with a difference in means of 2,317 €. Frailty was the only clinical baseline characteristic with significant association with total costs. Higher total costs in frail patients were attributable primarily to longer stay on intermediate/intensive care unit (3.8 ± 5.7 days in frail vs 2.1 ± 1.7 days in non-frail, p = 0.003), but also to costs of clinical chemistry and physiotherapy. The prolonged stay on intermediate/intensive care unit in frail patients was attributable to postprocedural complications such as bleeding, kidney injury, infections and cardiovascular instability. Conclusion Frailty is associated with a mean 32% increase of hospital costs in patients undergoing TMVR, which is primarily the result of a prolonged recovery and increased vulnerability to complications. These findings are valuable for a hospital’s total cost calculation and resource allocation planning. Since frailty is regarded a potentially reversible health state, preventive interventions may help reduce costs in frail patients. Graphic abstract

Citizen projects for electric carsharing are a relatively recent phenomenon in Germany which can contribute to the sustainable transition of existing mobility regimes. This article aims to outline the status quo of electric carsharing cooperatives in Germany, explore the niche-conditions in which such projects can develop and analyze intermediate mechanisms which promote their geographical dissemination. Success of cooperative e-carsharing projects depends on a dedicated volunteer group for project management as well as local and extra-local linkages to policy makers, other cooperatives and potential users. Different, mutually exclusive structures of disseminating cooperative e-carsharing projects are being established. This article argues, that intermediate structures of citizen projects not only act as facilitators of project-related knowledge but can also evolve as integrated systems for the provision of service portfolios.

Introduction Aeromedical transport of patients with highly-infectious diseases, particularly over long distances with extended transport times, is a logistical, medical and organizational challenge. Following the 2014-2016 Ebola Crisis, sophisticated transport solutions have been developed, mostly utilizing large civilian and military airframes and the patient treated in a large isolation chamber. In the present COVID-19 pandemic, however, many services offer aeromedical transport of patients with highly-infectious diseases in much smaller portable medical isolation units (PMIU), with the medical team on the outside, delivering care through portholes. Methods We conducted a retrospective review of all transports of patients with proven or suspected COVID-19 disease, transported by Jetcall, Idstein, Germany, between April 1 and August 1, 2020, using a PMIU (EpiShuttle, EpiGuard AS, Oslo, Norway). Demographics and medical data were analyzed using the services' standardized transport protocols. Transport-associated challenges and optimization strategies were identified by interviewing and debriefing all transport teams after each transport. Results Thirteen patients with COVID-19 have been transported in a PMIU over distances up to 7,400 kilometers (km), with flight times ranging from 02:15 hours to 11:10 hours. We identified the main limitations of PMIU transports as limited access to the patient and reduced manual dexterity when delivering care through the porthole gloves and disconnection of lines and tubes during loading and unloading procedures. Technical solutions such as bluetooth-enabled stethoscopes, cordless ultrasound scanners and communication devices, meticulous preparation of the PMIU and the patient following standardized protocols and scenario-based training of crew members can reduce some of the risks. Discussion Transporting a patient with COVID-19 or any other highly infectious disease in a PMIU is a feasible option even over long distances, but adding a significant layer of additional risk, thus requiring a careful and individualized risk-benefit analysis for each patient prior to transport.

Background Pharmacokinetics and safety of JNJ-64530440, a hepatitis B virus capsid assembly modulator producing normal empty capsids (CAM-N), in healthy volunteers were evaluated. Methods This Phase I study (NCT03439488) was a double-blind, randomised, placebo-controlled study. Adults ( n = 10/cohort, five Asian/five non-Asian), randomised 4:1, received single-ascending doses of oral JNJ-64530440 (first- and second-generation formulations) or placebo under fasted (50, 150, 300 and 900 mg) or fed (300, 750, 1,000, 2000 and 4000 mg) conditions. Multiple-ascending doses of 750 or 2000 mg once daily and 750 mg twice daily JNJ-64530440 (second-generation formulation) for 7 days were evaluated. Pharmacokinetic parameters were estimated from plasma concentrations. Safety was assessed throughout. Results Less than dose-proportional increases in maximum plasma concentrations (Cmax) and area under the plasma concentration–time curves (AUCs) were observed across the doses. Mean plasma half-lives ranged from 9.3 to 14.5 h. Cmax and AUC were ∼two fold higher under fed versus fasting conditions and slightly higher in Asians versus Caucasians. JNJ-64530440 doses ≥750 mg achieved plasma levels higher than protein-binding adjusted concentrations demonstrating in vitro antiviral activity. No serious adverse events (AEs), treatment discontinuations or dose-limiting toxicities were seen. AE frequency/severity did not increase with dose. Conclusions Single (up to 4000 mg) and multiple doses (up to 2000 mg for 7 days) of JNJ-64530440 were well tolerated in healthy volunteers. Multiple doses ≥750 mg/day achieved plasma concentrations expected to have antiviral activity that may lower hepatitis B surface antigen. No clinically relevant differences in tolerability or pharmacokinetic parameters were seen between Asians versus Caucasians.

The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide–MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design. Questions have arisen as to whether patients with severe COVID-19 disease can generate a T cell response against SARS-CoV-2. Tao Dong and colleagues report that convalescent patients with COVID-19 harbor functional memory CD4+ and CD8+ T cells that recognize multiple epitopes that span the viral proteome. CD4+ T cells predominated the memory response in patients with severe disease, whereas higher proportions of CD8+ T cells were found in patients with mild disease.

Purpose By increasing the digitalization of commercial services citizens' expect more from public services. First of all, this study will strive to identify which problems citizens encounter when they use a complex public service: preparation of an application for a building permit. In the light of the popularity of omnichannel approaches, the study then explores how omni-channel could help to address the problems which have been identified. Design/methodology/approach We implement the first phases of an action design science research project. We collect data both from citizens and public agencies and frame them as transparency problems. These abstract problems are then addressed by an omnichannel service provision as an abstract solution. The abstract solution is then instantiated in a design in the form of a user scenario developed in collaboration with current and future public officials. Findings The analysis uncovers multiple transparency issues: it distinguishes between process, case, language, cross-channel and cost transparency. One root cause of the transparency issues observed is the lack of service transparency which defines the purpose and scope of a ser-vice. We therefore recommend defining a service-strategy before informational and technical aspects of an omnichannel approach can be implemented. Following this strategy, omnichannel offers public administrations unique opportunities to excel in citizens' service provision. Originality/value The study provides insights into how citizens view complex public services. For researchers, this study offers the conceptualization as transparency issues. Practitioners from the public administrations can also benefit from the concept and vision of omnichannel public services.

Modern information technology promises to improve service encounters through automated documentation or better decision traceability. At the same time, research suggests a negative impact of technology on human-to-human advisory services: including the possibility that computers might degrade the quality of interpersonal communication and reinforce unpleasant behaviors. Consequently, despite obvious improvements, information technology might have a negative impact on how the participants perceive the service. This might imply serious consequences for the service provider: dissatisfied clients, ineffective information exchange, and/or lack of transparency. This scenario slows down the diffusion of computers into advisory services in banks and insurance companies, and so designing systems for use in interpersonal services remains a challenge. This article provides evidence that LivePaper, a system designed alongside the material practices of a financial advisory encounter, helps to improve important service quality dimensions, making the services not only more pleasant for the participants, but also improving key marketing and business metrics of the service. In experimental advisory services, the sessions supported with LivePaper outperformed conventional services with regard to overall bank service quality and satisfaction, salesperson listening and interaction rating scores, as well as information transparency. This shows that a carefully designed system not only preserves the perceived quality of a service, but might improve it objectively, and has implications for the marketing and business value of the service.

Subjective tinnitus is the conscious perception of sound in the absence of any acoustic source. The literature suggests various tinnitus mechanisms, most of which invoke changes in spontaneous firing rates of central auditory neurons resulting from modification of neural gain. Here, we present an alternative model based on evidence that tinnitus is: (1) rare in people who are congenitally deaf, (2) common in people with acquired deafness, and (3) potentially suppressed by active cochlear implants used for hearing restoration. We propose that tinnitus can only develop after fast auditory fiber activity has stimulated the synapse formation between fast-spiking parvalbumin positive (PV1) interneurons and projecting neurons in the ascending auditory path and coactivated frontostriatal networks after hearing onset. Thereafter, fast auditory fiber activity promotes feedforward and feedback inhibition mediated by PV1 interneuron activity in auditory-specific circuits. This inhibitory network enables enhanced stimulus resolution, attention-driven contrast improvement, and augmentation of auditory responses in central auditory pathways (neural gain) after damage of slow auditory fibers. When fast auditory fiber activity is lost, tonic PV1 interneuron activity is diminished, resulting in the prolonged response latencies, sudden hyperexcitability, enhanced cortical synchrony, elevated spontaneous c oscillations, and impaired attention/stress-control that have been described in previous tinnitus models. Moreover, because fast processing is gained through sensory experience, tinnitus would not exist in congenital deafness. Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies.

Purpose We conducted exposure-response modeling and simulations to compare the predicted efficacy of extended-release oxcarbazepine (OXC-XR), an oral once-daily (qd) antiepileptic drug, with that of immediate-release (IR) OXC twice-daily (bid) when the agents are used as monotherapy or adjunctive therapy in patients with epilepsy characterized by partial-onset seizures (POS). Methods Modeling assessed percent change from baseline 28-day seizure frequency (PCH) as a function of minimum concentration (Cmin) of monohydroxy derivative (MHD), the clinically relevant metabolite of OXC. For OXC-IR, the model used historical data; values for OXC-XR were derived from observed data. The model was simulated (N=100) to predict PCH at MHD Cmin concentrations achieved with 1200 and 2400 mg/day in adults and children receiving OXC-XR qd or OXC-IR bid. Mean PCH and 95% confidence intervals (CIs) were generated and compared. Results Predicted efficacy was not different (ie, 95% CI of mean PCH overlapped) for OXC-XR qd vs OXC-IR bid at mean MHD Cmin concentrations achieved with 1200 and 2400 mg/day adjunctive OXC-XR (47.4 and 76.4 µmol/L) and at target MHD Cmin concentrations for OXC-IR monotherapy (59.1 and 112 µmol/L) in adults. Predicted efficacy in adults vs children was not different between formulations. Depending on MHD Cmin, the predicted mean PCH in adults ranged from -51.4% to -73.4% with OXC-XR qd and -53.2% to -78.5% with OXC-IR bid. In children, the predicted mean PCH ranged from -48.4% to -58.1% (OXC-XR qd) and -32.5% to -70.4% (OXC-IR bid). Conclusion This model-based analysis predicted comparable efficacy for OXC-XR qd vs OXC-IR bid at MHD Cmin concentrations corresponding to 1200 and 2400 mg/day as monotherapy or adjunctive therapy. Based on this analysis, the US Food & Drug Administration approved OXC-XR for use as monotherapy in adults and children ≥6 years of age with POS.

Time-dependent estimation of playing instruments in music recordings is an important preprocessing for several music signal processing algorithms. In this approach, instrument recognition is realized by neural networks with a two-dimensional input of short-time Fourier transform (STFT) magnitudes and a time-frequency representation based on phase information. The modified group delay (MODGD) function and the product spectrum (PS), which is based on MODGD, are analysed as phase representations. Training and evaluation processes are executed based on the MusicNet dataset. By the incorporation of PS in the input, instrument recognition can be improved about 2% in F1-score.

Background Viloxazine was historically described as a norepinephrine reuptake inhibitor (NRI). Since NRIs have previously demonstrated efficacy in attention deficit/hyperactivity disorder (ADHD), viloxazine underwent contemporary investigation in the treatment of ADHD. Its clinical and safety profile, however, was found to be distinct from other ADHD medications targeting norepinephrine reuptake. Considering the complexity of neuropsychiatric disorders, understanding the mechanism of action (MoA) is an important differentiating point between viloxazine and other ADHD medications and provides pharmacology-based rationale for physicians prescribing appropriate therapy. Methods Viloxazine was evaluated in a series of in vitro binding and functional assays. Its effect on neurotransmitter levels in the brain was evaluated using microdialysis in freely moving rats. Results We report the effects of viloxazine on serotoninergic (5-HT) system. In vitro, viloxazine demonstrated antagonistic activity at 5-HT2B and agonistic activity at 5-HT2C receptors, along with predicted high receptor occupancy at clinical doses. In vivo, viloxazine increased extracellular 5-HT levels in the prefrontal cortex (PFC), a brain area implicated in ADHD. Viloxazine also exhibited moderate inhibitory effects on the norepinephrine transporter (NET) in vitro and in vivo, and elicited moderate activity at noradrenergic and dopaminergic systems. Conclusion Viloxazine's ability to increase 5-HT levels in the PFC and its agonistic and antagonistic effects on certain 5-HT receptor subtypes, which were previously shown to suppress hyperlocomotion in animals, indicate that 5-HT modulating activity of viloxazine is an important (if not the predominant) component of its MoA, complemented by moderate NET inhibition. Supported by clinical data, these findings suggest the updated psychopharmacological profile of viloxazine can be best explained by its action as a serotonin norepinephrine modulating agent (SNMA).

Background Postcardiotomy extracorporeal membrane oxygenation (PC-ECMO) represents a unique subset of critically ill patients, with a paucity of data regarding long-term survival and correlated characteristics. We present a retrospective cohort of PC-ECMO patients, with outcomes at 1 and 3 years. Methods Data were collected retrospectively for all patients requiring ECMO within 72 hours of an index cardiac operation (excluding assist devices and transplants). Primary outcomes were the ability to wean from ECMO, hospital survival, and long-term survival. Results Thirty-one patients required PC-ECMO, representing a total of 172 days of ECMO support. Overall survival data were the ability to wean 58%, hospital survival 52%, 1-month survival 42%. The estimated 12- and 36-month survival for all PC-ECMO patients was 35% and 29%, respectively. Twelve and 36-month survival for all hospital survivors was 62% and 56%. Operative times, the Society of Thoracic Surgeons risk scores, type of operation, open chest status, hemorrhage, and cannulation location, and timing were all compared. Centrally cannulated patients were more likely to wean from ECMO (83% vs 44%; P = .03), and survive hospitalization (75% vs 36%; P = .04) and trended toward long-term survival benefit (67% vs 33%; P = .06). Otherwise, no statistically significant relationships were observed. Conclusions Central cannulation may provide benefits in the postcardiotomy patient, compared to peripheral strategies. Twelve and 36-month survival for all PC-ECMO patients was 35% and 29%. For hospital survivors, 12 and 36-month survival 62% 56% at 36. These data support PC-ECMO as a reasonable salvage strategy, with midterm survival comparable to other surgically treated diseases.

Physical examination, laboratory tests, ultrasound, conventional radiography, multislice computed tomography (MSCT), and diagnostic laparoscopy are used for diagnosing blunt abdominal trauma. In this article, we investigate and evaluate the usefulness and limitations of various diagnostic modalities on the basis of a comprehensive review of the literature. We searched commonly used databases in order to obtain information about the aforementioned diagnostic modalities. Relevant articles were included in the literature review. On the basis of the results of our comprehensive analysis of the literature and a current case, we offer a diagnostic algorithm. A total of 86 studies were included in the review. Ecchymosis of the abdominal wall (seat belt sign) is a clinical sign that has a high predictive value. Laboratory values such as those for haematocrit, haemoglobin, base excess or deficit, and international normalised ratio (INR) are prognostic parameters that are useful in guiding therapy. Extended focused assessment with sonography for trauma (eFAST) has become a well established component of the trauma room algorithm but is of limited usefulness in the diagnosis of blunt abdominal trauma. Compared with all other diagnostic modalities, MSCT has the highest sensitivity and specificity. Diagnostic laparoscopy is an invasive technique that may also serve as a therapeutic tool and is particularly suited for haemodynamically stable patients with suspected hollow viscus injuries. MSCT is the gold standard diagnostic modality for blunt abdominal trauma because of its high sensitivity and specificity in detecting relevant intra-abdominal injuries. In many cases, however, clinical, laboratory and imaging findings must be interpreted jointly for an adequate evaluation of a patient’s injuries and for treatment planning since these data supplement and complement one another. Patients with blunt abdominal trauma should be admitted for clinical observation over a minimum period of 24 h since there is no investigation that can reliably rule out intra-abdominal injuries.

Over the past decades, the automotive sector in China has been characterized by the obligation of foreign manufacturers to enter joint ventures, transfer technologies, and localize production. Still, the Chinese automotive industry has remained dependent on foreign brands, capital, and technology. The advent of markets and supply chains for electric vehicles, however, changes the framework conditions for established foreign automotive firms in terms of competitive landscape and access to core technology components. This is mainly the result of political initiatives: Established automotive manufacturers are exposed to direct and indirect restrictions that influence their production of electric vehicles, their choice of suppliers, and their potential market shares in the future. This paper outlines multilevel bargaining processes of Chinese and foreign actors as they aim to maximize value capture in a fundamentally transitioning automotive sector. In contrast to the lead firm-centric focus of recent global production networks (GPN)-discussions, this paper argues that the determinants of how production networks evolve is first and foremost a question of the institutional environment. Focusing on power balances between state and firm actors in multilevel bargaining processes offers a way of explaining GPN-evolution in institutional contexts in which power concentrates in executive bodies and decision-making processes are often informal.

Case and knowledge management systems are spread at the frontline across public agencies. However, such systems are dedicated for the collaboration within the agency rather than for the face-to-face interaction with the clients. If used as a collaborative resource at the frontline, case and knowledge management systems might disturb the service provision by displaying unfiltered internal information, disclosing private data of other clients, or revealing the limits of frontline employees’ competence (if they cannot explain something) or their authority (if they cannot override something). Observation in the German Public Employment Agency shows that employment consultants make use of various coping strategies during face-to-face consultations to extend existing boundaries set by the case and knowledge management systems and by the rules considering their usage. The analysis of these coping strategies unveils the forces that shape the conduct of employment consultants during their contacts with clients: the consultants’ own understanding of work, the actual and the perceived needs of the clients, and the political mission as well as the internal rules of the employment agency. The findings form a twofold contribution: First, they contribute to the discourse on work in employment agencies by illustrating how the complexities of social welfare apparatus demonstrate themselves in singular behavioural patterns. Second, they contribute to the discourse on screen-level bureaucracy by depicting the consultants as active and conscious mediators rather than passive interfaces between the system and the client.

Nonalcoholic fatty liver disease is the most prevalent liver disease worldwide, affecting 20%-25% of the adult population. In 25% of patients, nonalcoholic fatty liver disease progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of cirrhosis, liver failure, and hepatocellular carcinoma. In patients with NASH, liver fibrosis is the main determinant of mortality. Here, we review how interactions between different liver cells culminate in fibrosis development in NASH, focusing on triggers and consequences of hepatocyte-macrophage-hepatic stellate cell (HSC) crosstalk. We discuss pathways through which stressed and dead hepatocytes instigate the profibrogenic crosstalk with HSC and macrophages, including the reactivation of developmental pathways such as TAZ, Notch, and hedgehog; how clearance of dead cells in NASH via efferocytosis may affect inflammation and fibrogenesis; and insights into HSC and macrophage heterogeneity revealed by single-cell RNA sequencing. Finally, we summarize options to therapeutically interrupt this profibrogenic hepatocyte-macrophage-HSC network in NASH.

This study explores how technical services for automotive applications organize their value-added activities. It does so from the background of a market transition towards electric vehicles and vehicle connectivity. Conceptually, the article combines the literature stream of global value chains and global production networks (GVC–GPN) and knowledge-intensive business services (KIBS). This paper puts a specific focus on the temporality of client–vendor relationships and argues that interfirm relationships often last longer than their project-based mode suggests they would. Despite ongoing fundamental transitions of industry structures towards electric vehicles and vehicle connectivity, the relationships of incumbent OEMs and technical service firms continues to be hierarchical. Analyzing these dynamics on the level of value-added inputs, the concepts of GVC–GPN and KIBS meaningfully complement each other for outlining the mutual dependencies of market dynamics, the characteristics of a service input and the organizational outcome of the client–vendor relationship.

Blockchain comes with the promise of being a disruptive technology with the potential for novel ways of interaction in a wide range of applications. Following broader application, scholarly interest in the technology is growing, though an extensive analysis of blockchain applications from a governance perspective is lacking to date. This research pays special attention to the governance of blockchain systems and illustrates decision problems in 14 blockchain systems from four application domains. Based on academic literature, semi-structured interviews with representatives from those organizations, and content analysis of grey literature, common problems in blockchain governance have been singled out and contextualized. Studying their enactment revealed their relevance to major organizational theories in what we labelled “Patrolling the borders,” “External Legitimation,” “Reduction of Discretionality,” and “Temporal Management.” The identification of these problems enriches the scarce body of knowledge on the governance of blockchain systems, resulting in a better understanding of how blockchain governance links to existing concepts and how it is enacted in practice.

Activating mutations in cytosolic 5′-nucleotidase II (NT5C2) are considered to drive relapse formation in acute lymphoblastic leukemia (ALL) by conferring purine analog resistance. To examine the clinical effects of NT5C2 mutations in relapsed ALL, we analyzed NT5C2 in 455 relapsed B-cell precursor ALL patients treated within the ALL-REZ BFM 2002 relapse trial using sequencing and sensitive allele-specific real-time polymerase chain reaction. We detected 110 NT5C2 mutations in 75 (16.5%) of 455 B-cell precursor ALL relapses. Two-thirds of relapses harbored subclonal mutations and only one-third harbored clonal mutations. Event-free survival after relapse was inferior in patients with relapses with clonal and subclonal NT5C2 mutations compared with those without (19% and 25% vs 53%, P < .001). However, subclonal, but not clonal, NT5C2 mutations were associated with reduced event-free survival in multivariable analysis (hazard ratio, 1.89; 95% confidence interval, 1.28-2.69; P = .001) and with an increased rate of nonresponse to relapse treatment (subclonal 32%, clonal 12%, wild type 9%, P < .001). Nevertheless, 27 (82%) of 33 subclonal NT5C2 mutations became undetectable at the time of nonresponse or second relapse, and in 10 (71%) of 14 patients subclonal NT5C2 mutations were undetectable already after relapse induction treatment. These results show that subclonal NT5C2 mutations define relapses associated with high risk of treatment failure in patients and at the same time emphasize that their role in outcome is complex and goes beyond mutant NT5C2 acting as a targetable driver during relapse progression. Sensitive, prospective identification of NT5C2 mutations is warranted to improve the understanding and treatment of this aggressive ALL relapse subtype.

For the first time in decades, the automotive industry is undergoing a technological paradigm shift, as the combustion engine technology is gradually being replaced by electric engines. This transition will make parts of the existing automotive supply chain redundant. Risks of this market shift are particularly pronounced in the automotive supply sector in Germany. Numerous studies examine the risks and opportunities of automotive market transitions on a macro-level. However, empirical evidence is missing on the aspect of how “traditional” German automotive suppliers actually respond to the expected market uptake of electric vehicles. This study aims to contribute to the understanding of strategic options and choices of automotive suppliers from the forging and foundry industries as well as system suppliers by presenting evidence from qualitative interviews. It argues that existing patterns of supplier-buyer relationships make upgrading strategies within given value chains a more attractive strategic option than sector diversification. In order to evaluate the individual circumstances on the company-level and the implications of firm strategies on their organizational environment, conceptual aspects from the theories of global production networks and global value chains are applied.

In recent years, an increasing number of blockchain consortia have emerged. However, little is known about how these consortia are developed and what tensions emerge in such collaborations. We describe the evolution of the cardossier blockchain consortium in Switzerland, which is building a system for managing car data and seeking to improve collaboration between players in the car-related ecosystem. From our involvement with the cardossier project, we have gained insights that will be valuable for enterprises considering whether to join a blockchain consortium.

Children with cerebral palsy (CP) will be cared for at some point by all pediatricians and many pediatric subspecialists due to this condition being the most common motor disability of childhood. Comprehensive care of the child with CP requires individuals with specialized training, and these children benefit from an interdisciplinary team approach to care. CP is heterogeneous due to varied causes, which necessitates individualized treatment plans. The CP specialist must be prepared to support the needs of the child with CP holistically and must dialogue regularly with members of the team and involve the family in decision-making.