bluuebunny/crossref_metadata_2025 huggingface dataset:
TROPiCS-04: Study of sacituzumab govitecan (SG) in patients (pts) with locally advanced (LA) unresectable or metastatic urothelial cancer (mUC) that has progressed after prior platinum (PLT) and checkpoint inhibitor (CPI) therapy.
Authors: Vulsteke Christof , Grivas Petros , Tagawa Scott T. , Bellmunt Joaquim , De Santis Maria , Duran Ignacio , Goebell Peter-Juergen , Necchi Andrea , Sridhar Srikala S. , Sternberg Cora N. , Sierecki Mitchell Robert , Aziz Usman , Goswami Trishna , Loriot Yohann
Published: February 2022

TPS582

Background: Treatment options are limited for pts with LA unresectable or mUC who progress after prior PLT-based and CPI therapies. SG is an antibody-drug conjugate (ADC) composed of an anti-trophopblast cell surface antigen 2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) via a proprietary hydrolyzable linker. In the phase 2 registrational study TROPHY-U-01 (NCT03547973), SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.9 months in pts with mUC who progressed after prior PLT-based and CPI therapies (n = 113; median, 3 prior lines of therapy; 84% with ≥1 Bellmunt risk factors; Tagawa et al, J Clin Oncol. 2021). These results compared favorably with historic data for single-agent chemotherapy (ORR, ̃18%; OS, 9 months; Powles et al. J Clin Oncol. 2021) and led to accelerated approval of SG by the US Food and Drug Administration for pts with LA or mUC who previously received a PLT-containing chemotherapy and CPI. The phase 3 TROPiCS-04 trial has been initiated to confirm these findings. Methods: TROPiCS-04 (NCT04527991) is a global, multicenter, open-label, randomized, controlled trial in pts with LA unresectable or mUC who progressed after prior PLT-based and CPI therapies. Key eligibility requirements include Eastern Cooperative Oncology Group performance status 0-1; no prior CPI or ADC therapy within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; and adequate hematologic, hepatic, and renal function. Pts will be randomly assigned 1:1 to receive SG 10 mg/kg intravenously (IV) on days 1 and 8 of 21-day cycles or single-agent treatment of physician’s choice (paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2 IV on day 1 of 21-day cycles) until progressive disease, unacceptable toxicity, or withdrawal of consent. Treatment beyond progressive disease may be permitted in pts deemed to be receiving clinical benefit per investigator assessment. Approximately 600 pts will be enrolled across ̃280 sites in 3 regions (North America, Europe, and Asia-Pacific) to provide 90% power on the primary endpoint of OS. Secondary endpoints include progression-free survival, ORR, clinical benefit rate, duration of response (all per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review and investigator assessment), safety, and quality of life. Study enrollment started in January 2021 and is ongoing with pts currently enrolled at 30 sites across all 3 regions. Clinical trial information: NCT04527991.
SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations—Urothelial cancer cohort (trial in progress).
Authors: Galsky Matt D. , Ramos Jorge , Tan Qianwen , Yu Evan Y.
Published: February 2022

TPS586

Background: Tucatinib, a highly selective HER2-directed tyrosine kinase inhibitor approved in multiple regions for HER2+ metastatic breast cancer, is being investigated as a novel therapy for metastatic colorectal cancer, gastric cancer, and other GI tumors. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with tucatinib and trastuzumab showed superior activity to either alone (Kulukian 2020; Peterson 2020 ). Despite development of several new therapies for metastatic urothelial cancer, most patients do not respond to subsequent therapies, and majority of patients succumb to the disease, highlighting the need for additional therapeutic approaches. Given 20%-30% of metastatic urothelial cancers have molecular alterations of the ErbB family, tucatinib + trastuzumab warrants further evaluation. SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, international Phase 2 study evaluating tucatinib + trastuzumab in patients with previously treated solid tumors displaying HER2+ or HER2-mutated solid tumors, including a cohort with locally advanced or metastatic urothelial cancer (UC). Methods: Eligible patients must have HER2+ or HER2-mutated locally advanced or metastatic solid tumors, with progression on or after the last systemic therapy for advanced disease. Additionally, patients must have an ECOG PS ≤1, adequate hepatic, hematologic, renal, and cardiac function, and no prior exposure to HER2-directed therapy in the UC cohort. For eligibility, HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH, or by HER2 amplification/mutation in prior or pre-screening NGS assay of ctDNA or prior tissue NGS assay. The HER2 overexpression/amplification UC cohort will enroll 12 response-evaluable patients per RECIST 1.1. If ≥2 responses are observed, the cohort will be expanded to 30. Patients with HER2-mutated UC will be enrolled into a cohort of 30 patients with HER2-mutated solid tumors (except breast and non-squamous non-small cell lung cancers). The primary objective is antitumor activity, with confirmed ORR as the primary endpoint, and disease control rate, duration of response, PFS, and OS as secondary efficacy endpoints. Patients will receive tucatinib 300 mg orally twice daily and trastuzumab 8 mg/kg intravenous on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. Trough concentrations of tucatinib will be evaluated in Cycles 2-6, with a peak concentration sampled in Cycle 3. Quality of life will be evaluated q2 cycle using EQ-5D-5L. Sites are currently enrolling within the US, EU, and Asia Pacific. Clinical trial information: NCT04579380.
Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR2/3 genetic alterations (GAs).
Authors: Jain Rohit K. , Kim Youngchul , Rembisz Jennifer , Piekarz Richard , Synold Timothy W. , Zhang Jingsong , Sonpavde Guru P.
Published: February 2022

TPS595

Background: Erdafitinib and enfortumab vedotin are available treatment options in mUC patients with somatic FGFR2/3 GAs after progression on platinum-based chemotherapy and PD-1/L1 inhibitors. However, due to decline in their clinical condition, the sequential delivery of these agents is challenging. Tubulin antagonists induce a G2-M cell-cycle block, while FGFR inhibitors cause a G1 block, with studies suggesting that their combination may be additive or synergistic. Retrospective studies suggest that the activity of EV is not compromised by somatic FGFR2/3 GAs. Hence, there is rationale to evaluate the feasibility of the combination of EV and E, to overcome the difficulties of resistance and sequencing these agents in mUC patients with FGFR2/3 GAs. Methods: This is a phase Ib, single arm, multicenter study in patients with mUC harboring somatic FGFR2/3 GAs who have progressed after platinum and PD-1/L1 inhibitor therapies with enrollment of up to 30 patients. Pts are required to have predominant urothelial component, ECOG-PS 0-2, neuropathy ≤ grade 1 and no ophthalmologic conditions precluding treatment with E. FGFR2/3 GAs may be identified by tumor tissue or circulating tumor (ct)-DNA profiling. The primary objective is feasibility and establishing a recommended phase-2 dose (RP2D). Secondary objectives include objective response rate, duration of response, progression-free survival and overall survival. The dose-escalation component will enroll up to 18 pts with 3+3 design (dosing cohorts in table), followed by dose-expansion component of 12 pts. The dose limiting toxicities (DLTs) will be evaluated using a sequential Bayesian toxicity monitoring that allows a maximum DLT rate of 0.33 during the dose-expansion phase. Exploratory biomarker analyses will be performed including 1) tumor PD-L1, Nectin-4 assessment by immunohistochemistry and association with response 2) ct-DNA evaluation at baseline and progression to evaluate resistance pathways 3) pharmacokinetic studies will assess plasma levels of E and free monomethyl auristatin-E (MMAE). This is led by North American Star Consortium as part of Experimental Therapeutics. Clinical trial information: NCT04963153. [Table: see text]
Randomized phase 2 umbrella study of various neoadjuvant therapies for patients with muscle-invasive urothelial carcinoma of the bladder (MIBC) who are cisplatin-ineligible or refuse cisplatin therapy and undergoing radical cystectomy (Optimus).
Authors: Necchi Andrea , Zakharia Yousef , Ghali Nadeem , Smith Michael , Hamer-Maansson J. E. , Lindley Anouk , Loriot Yohann , Meeks Joshua J
Published: February 2022

TPS599

Background: A growing body of data support that the key to generating anti-tumor immune responses triggered by administration of immuno-oncology (IO) agents, is the activation and invasion of T lymphocytes. Checkpoint inhibitors (CPIs) are being actively explored in the neoadjuvant setting of MIBC. CPIs documented 30-40% pathologic complete response-rates (ypT0N0) in previous trials. Increasingly, novel IO agents are being developed in combinations with anti PD(L)-1 therapies. Understanding the changes in the tumor microenvironment that occur with the addition of novel immunomodulating agents to PD(L)-1 inhibitors can help inform whether a compound is viable for further development. The OPTIMUS trial is a window of opportunity, neoadjuvant platform design study in MIBC patients that are cisplatin-ineligible. The study investigates the addition of the indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor epacadostat to the PD-1 inhibitor retifanlimab. The platform design allows for investigation of other novel immune-modulating combinations. Methods: This is an open-label, randomized, Phase 2, multi-treatment group, window-of-opportunity, platform study for participants with MIBC undergoing radical cystectomy who refuse or are not eligible for cisplatin-based neoadjuvant chemotherapy (NCT04586244). Participants are randomized based on tumor tissue PD-L1 CPS ≥ 10 or PD-L1 CPS < 10 to one of the following treatment groups: Treatment Group A (epacadostat + retifanlimab); Treatment Group B (retifanlimab monotherapy); Treatment Group C (epacadostat monotherapy). 18 patients will be enrolled in each of Treatment Groups A and B. 9 patients will be enrolled into Treatment Group C. Total treatment duration is a maximum of 10 weeks. The platform study design allows for addition of future treatment groups. Pre-treatment biopsy is obtained through transurethral resection of bladder tumor (TURBT), followed by neoadjuvant treatment, followed by radical cystectomy. In all treatment groups, tissue from the surgical specimen(s) is collected and compared with the initial pre-treatment samples. The primary endpoint is the change from baseline in CD8+ lymphocytes within resected tumor. Secondary endpoints include safety and tolerability, rates of ypT0N0 response, and major pathologic response. Exploratory analyses include tumoral changes in gene cell expression profile, immune-cell protein and metabolic marker levels, and spatial relationships between cell types. Plasma is also collected and will be investigated for changes in cytokines and other inflammatory or metabolic markers. Clinical trial information: NCT04586244.
Rugotaxis: Droplet motion without external energy supply
Authors: Theodorakis Panagiotis E. , Egorov Sergei A. , Milchev Andrey
Published: February 2022

Nano-patterned substrates offer possibilities for controlling the motion of fluids without external energy supply in novel technologies in microfluidics, coatings, etc. Here, we report on the rugotaxial motion of droplets on wrinkled substrates with gradient in the wavelength of the wrinkles by exploring a broad range of parameters, such as amplitude of the wrinkles, substrate wettability, droplet size and wavelength gradient. Adopting a theoretical and molecular dynamics approach, we determine the Cassie-Baxter and Wenzel states of the droplets, investigate the efficiency of rugotaxis as a function of different parameters, and discuss additional effects, such as pinning. We find that shallow wrinkles characterised by small wavelength gradients, and moderate adhesion of the droplet to the substrate favour the rugotaxis motion with growing droplet size, when pinning is avoided. We also find that the driving force in rugotaxis is the gain in interfacial energy between the droplet and the substrate as the droplet enters regions of denser wrinkles (smaller wavelengths of the wrinkles).
Adipose Mitochondrial Complex I Deficiency Modulates Inflammation and Glucose Homeostasis in a Sex-Dependent Manner
Authors: Choi Kyung-Mi , Ryan Karen K , Yoon John C
Published: February 2022

Mitochondrial dysfunction in adipose tissue has been associated with type 2 diabetes, but it is unclear whether it is a cause or the consequence. Mitochondrial complex I is a major site of reactive oxygen species generation and a therapeutic target. Here we report that genetic deletion of the complex I subunit Ndufs4 specifically in adipose tissue results in an increased propensity to develop diet-induced weight gain, glucose intolerance, and elevated levels of fat inflammatory genes. This outcome is apparent in young males but not in young females, suggesting that females are relatively protected from the adverse consequences of adipose mitochondrial dysfunction for metabolic health. Mutant mice of both sexes exhibit defects in brown adipose tissue thermogenesis. Fibroblast growth factor 21 (FGF21) signaling in adipose tissue is selectively blunted in male mutant mice relative to wild-type littermates, consistent with sex-dependent regulation of its autocrine/paracrine action in adipocytes. Together, these findings support that adipocyte-specific mitochondrial dysfunction is sufficient to induce tissue inflammation and can cause systemic glucose abnormalities in male mice.
The Prediction Model Using Thyroid-stimulating Immunoglobulin Bioassay For Relapse of Graves’ Disease
Authors: Baek Han-Sang , Lee Jaejun , Jeong Chai-Ho , Lee Jeongmin , Ha Jeonghoon , Jo Kwanhoon , Kim Min-Hee , Cho Jae Hyoung , Kang Moo Il , Lim Dong-Jun
Published: February 2022

Objective

Thyroid-stimulating immunoglobulin (TSI) bioassay has a better ability to predict the relapse rate of Graves’ disease (GD) than the thyroid-stimulating hormone (TSH)-binding inhibitory immunoglobulin method in terms of measuring the TSH receptor antibody. However, the optimal TSI bioassay cutoff for predicting relapse after antithyroid drug (ATD) withdrawal is not well evaluated.

Methods

This retrospective study enrolled GD patients who had been treated with ATD and obtained their TSI bioassay <140% from January 2010 to December 2019 in a referral hospital.

Results

Among 219 study subjects, 86 patients (39.3%) experienced relapse. The TSI bioassay value of 66.5% significantly predicted the relapse of GD (P = 0.049). The group with a TSI bioassay value > 66.5% were expected to show a 23.8% relapse rate at 2 from ATD withdrawal, and the group with a TSI < 66.5% had a 12.7% relapse rate based on Kaplan-Meier curves analysis. The TSI bioassay showed a good ability to predict relapse GD in the female group (P = 0.041) but did not in the male group (P = 0.573). The risk scoring based on the nomogram with risk factors for GD relapse, which was constructed to overcome the limitation, increased the predictive ability of GD relapse by 11.5% compared to the use of the TSI bioassay alone.

Conclusions

The cutoff value of the TSI bioassay to predict GD relapse should be lower than that for diagnosing GD. However, as the single use of the TSI bioassay has limitations, a nomogram with multiple risk factors including TSI bioassay could be helpful to predict GD relapse.
A Decision Tree Approach to Airway Management Pathways in the 2022 Difficult Airway Algorithm of the American Society of Anesthesiologists
Authors: Rosenblatt William H. , Yanez N. David
Published: February 2022

The American Society of Anesthesiologists’ (ASA) Task Force on Management of the Difficult Airway has developed a decision tree tool that uses inductive assessments to guide the anesthesiologist’s choice of pathway in the ASA’s Difficult Airway Algorithm. The tool prompts the anesthesiologist to consider the risk of difficulty with laryngoscopy (direct or indirect) and tracheal intubation, facemask or supraglottic ventilation, gastric contents aspiration, and rapid oxyhemoglobin desaturation. For every airway management event, the approach integrates the anesthesiologist’s unique combination of experience, expertise, patient anatomy and disease, equipment availability, and other contextual conditions into the decision process. Entry into the awake intubation pathway is encouraged when the patient is judged at risk of difficult tracheal intubation and one or more of the following: difficult ventilation, significant aspiration risk, and/or rapid oxyhemoglobin desaturation. The decision tree tool is anticipated to improve communication between anesthesiologists and others by clearly identifying those factors of concern and how decision-making is affected by those concerns.
The Association Between Angiotensin II and Renin Kinetics in Patients After Cardiac Surgery
Authors: Meersch Melanie , Weiss Raphael , Massoth Christina , Küllmar Mira , Saadat-Gilani Khaschayar , Busen Manuel , Chawla Lakhmir , Landoni Giovanni , Bellomo Rinaldo , Gerss Joachim , Zarbock Alexander
Published: February 2022

BACKGROUND:

Hyperreninemia after cardiac surgery is associated with cardiovascular instability. Angiotensin II (AT-II) could potentially attenuate hyperreninemia while maintaining target blood pressure. This study assesses the association between AT-II usage and renin levels in cardiac surgery patients with postoperative hyperreninemia and vasoplegia.

METHODS:

Between September 2020 and March 2021, we retrospectively identified 40 cardiac surgery patients with high Δ-renin levels (4 hours after cardiopulmonary bypass [CPB] minus preoperative levels) (defined as higher than 3.7 µU/mL) and vasopressor use who received a vasopressor therapy with either AT-II or continued norepinephrine alone. The primary outcome was the renin plasma level at 12 hours after surgery, adjusted by the renin plasma level at 4 hours after surgery.

RESULTS:

Overall, the median renin plasma concentration increased from a baseline with median of 44.3 µU/mL (Q1–Q3, 14.6–155.5) to 188.6 µU/mL (Q1–Q3, 29.8–379.0) 4 hours after CPB. High Δ-renin (difference between postoperation and preoperation) patients (higher than 3.7 µU/mL) were then treated with norepinephrine alone (median dose of 3.25 mg [Q1–Q3, 1.00–4.75]) or with additional AT-II (norepinephrine dose: 1.33 mg [Q1–Q3, 0.78–2.04]; AT-II dose: 0.34 mg [Q1–Q3, 0.29–0.78]). At 12 hours after surgery, AT-II patients had lower renin levels than standard of care patients (71.7 µU/mL [Q1–Q3, 21.9–211.4] vs 130.6 µU/mL [Q1–Q3, 62.9–317.0]; P = .034 adjusting for the renin plasma level at 4 hours after surgery).

CONCLUSIONS:

In cardiac surgery patients with hypotonia and postoperative high Δ-renin levels, AT-II was associated with reduced renin plasma levels for at 12 hours and significantly decreased norepinephrine use, while norepinephrine alone was associated with increased renin levels. Further studies of AT-II in cardiac surgery appear justified.
Dreadful Desires
Authors: Zhang Charlie Yi
Published: February 2022

In Dreadful Desires Charlie Yi Zhang examines how the Chinese state deploys affective notions of love to regulate the population and secure China’s place in the global economy. Zhang shows how the state frames love as a set of desires that encompass heteronormative intimacy, familial and communal attachment, upward mobility, and private property ownership. These desires—as circulated in performance in the nationalistic ceremony, same-sex romantic fan fiction, the wildly popular reality television dating show If You Are the One, and the cult of patriarchal personality around Xi Jinping—are explicitly based in oppressive systems of gender, class, and sexuality. Zhang contends that such desires connect love to economic survival and gender normativity in ways that underwrite Chinese neoliberalism at the expense of individual flourishing. By outlining how state-framed forms of love create desires that cannot be fulfilled, Zhang places China at the forefront of using affective attachments to nation, leader, and family in the global shifts toward exploitation and authoritarianism.
Engineering Vulnerability
Authors: Vaughn Sarah E.
Published: February 2022

In Engineering Vulnerability Sarah E. Vaughn examines climate adaptation against the backdrop of ongoing processes of settler colonialism and the global climate change initiatives that seek to intervene in the lives of the world’s most vulnerable. Her case study is Guyana in the aftermath of the 2005 catastrophic flooding that ravaged the country’s Atlantic coastal plain. The country’s ensuing engineering projects reveal the contingencies of climate adaptation and the capacity of flooding to shape Guyanese expectations about racial (in)equality. Analyzing the coproduction of race and vulnerability, Vaughn details why climate adaptation has implications for how we understand the past and the continued human settlement of a place. Such understandings become particularly apparent not only through experts’ and ordinary citizens’ disputes over resources but in their attention to the ethical practice of technoscience over time. Approaching climate adaptation this way, Vaughn exposes the generative openings as well as gaps in racial thinking for theorizing climate action, environmental justice, and, more broadly, future life on a warming planet.

Duke University Press Scholars of Color First Book Award recipient
Synthesis and Reactivity of Heterobimetallic Co-PAlP Pincer Complexes
Authors: Semba Kazuhiko , Shimoura Fumiya , Nakao Yoshiaki
Published: February 2022

A cobalt complex ligated with a PAlP pincer ligand was synthesized. The Lewis acidity of the aluminum atom on the cobalt complex was confirmed by coordination with 4-dimethylaminopyridine (DMAP). Reactions of the cobalt complex with H2O, EtOH, i-PrOH, and t-BuOH efficiently afforded the corresponding cobalt hydride complexes.
Biphasic split-bolus injection protocol for routine contrast-enhanced chest CT: comparison with conventional early-phase single bolus technique
Authors: Kul Melahat , Kuru Öz Diğdem , Gürsoy Coruh Ayşegül , Özalp Ateş Funda , Gülpınar Başak , Uzun Çağlar , Atasoy K.Çetin
Published: February 2022

Objectives:

To present a routine contrast-enhanced chest CT protocol with a split-bolus injection technique achieving combined early- and delayed phase images with a single aquisition, and to compare this technique with a conventional early-phase single-bolus chest CT protocol we formerly used at our institution, in terms of attenuation of great thoracic vessels, pleura, included hepatic and portal venous enhancement, contrast-related artifacts, and image quality.

Methods:

A total of 202 patients, who underwent routine contrast-enhanced chest CT examination aquired with either conventional early-phase single-bolus technique (group A,n = 102) or biphasic split-bolus protocol (group B,n = 100), were retrospectively included. Attenuation measurements were made by two radiologists independently on mediastinal window settings using a circular ROI at the following sites: main pulmonary artery (PA) at its bifurcation level, thoracal aorta (TA) at the level of MPA bifurcation,portal vein (PV) at porta hepatis, left and right hepatic lobe, and if present, thickened pleura (>2 mm) at the level with the most intense enhancement. Respective normalized enhancement values were also calculated. Contrast-related artifacts were graded and qualitative evaluation of mediastinal lymph nodes was performed by both reviewers independently. Background noise was measured and contrast-to-noise ratios (CNRs) of the liver and TA were calculated.

Results:

While enhancement of thoracic vessels and normalised MPA enhancement did not differ significantly between both groups (p > 0.05), enhancement and normalised enhancement of pleura, liver parenchyma and PV was significantly greater in group B (p < 0.001). Perivenous artifacts limiting evaluation were less frequent in group B than in A and mediastinal lymph nodes were judged to be evaluated worse in group A than in group B with an excellent agreement between both observers. No significant difference was detected in CNRTA (p = 0.633), whereas CNR liver was higher in group B (p < 0.001).

Conclusion:

Our split-bolus chest CT injection protocol enables simultaneous enhancement for both vascular structures and soft tissues, and thus, might raise diagnostic confidence without the need of multiple acquisitions.

Advances in knowledge:

We think that this CT protocol might also be a promising alternative in lung cancer staging, where combined contrast-enhanced CT of the chest and abdomen is indicated. We therefore suggest to further evaluate its diagnostic utility in this setting, in particular in comparison with a late delayed chest-upper abdominal CT imaging protocol.
Digital twins for well-being: an overview
Authors: Ferdousi Rahatara , Laamarti Fedwa , Hossain M. Anwar , Yang Chunsheng , El Saddik Abdulmotaleb
Published: February 2022

Digital twin (DT) has gained success in various industries, and it is now getting attention in the healthcare industry in the form of well-being digital twin (WDT). In this paper, we present an overview of WDT to understand its potential scope, architecture and impact. We then discuss the definition  and the benefits of WDT. After that, we present the evolution of DT frameworks. Subsequently we discuss the challenges, the different types, the drawbacks, and potential application areas of WDT. Finally we present the requirements for a WDT framework extracted from the literature.
Brain death debates: from bioethics to epistemology
Authors: Molina Pérez Alberto
Published: February 2022

50 years after its introduction, brain death remains controversial among scholars. The debates focus on one question: is brain death a good criterion for determining death? This question has been answered from various perspectives: medical, metaphysical, ethical, and legal or political. Most authors either defend the criterion as it is, propose some minor or major revisions, or advocate abandoning it and finding better solutions to the problems that brain death was intended to solve when it was introduced. In short, debates about brain death have been characterized by partisanship, for or against. Here I plead for a non-partisan approach that has been overlooked in the literature: the epistemological or philosophy of science approach. Some scholars claim that human death is a matter of fact, a biological phenomenon whose occurrence can be determined empirically, based on science. We should take this claim seriously, whether we agree with it or not. The question is: how do we know that human death is a scientific matter of fact? Taking the epistemological approach means, among other things, examining how the determination of human death became an object of scientific inquiry, exploring the nature of the brain death criterion itself, and analysing the meaning of its core concepts such as “irreversibility” and “functions”.
Treatment profiles and trajectories surrounding the diagnosis of major depressive disorder: a research protocol for a Danish register-based study.
Authors: Herold Jeberg Pernille , Overgaard Nielsen Anne Marije Christina , Osler Merete , Kim Wirum-Andersen Marie , Jacobsen Ramune , Almarsdóttir Anna Birna , Jarlov Jensen Kristoffer , Petersen Janne
Published: February 2022

Background: Major depressive disorder (MDD) is a prevalent illness that causes significant suffering and expenses at the personal and societal levels. The disorder is subject to heterogeneity reflected by diverse clinical phenotypes and assorted responses to treatment. Research on MDD treatments have focused on one treatment at a time, however many patients receive several different treatments. Considering the number of available treatment options, we hypothesize that it is possible to identify clinically meaningful groups of patients based on their psychiatric treatment. The objective of this study is therefore to identify psychiatric treatment profiles and trajectories of patients with major depressive disorder and, for the identified profiles and trajectories, to assess clinical and sociodemographic factors.

Method: The study will be a population-based register study of patients with major depressive disorder in the Danish National Patient Register between 2011 and 2015. Using latent class analyses, we will identify homogenous groups of patients based on their psychiatric treatment patterns. These patterns constitute psychiatric treatment profiles which will be identified at six time-intervals, from 1.5 years before to 3 years after diagnosis of major depressive disorder. By cross-tabulating the identified treatment profiles, we will establish psychiatric treatment trajectories. Patients sharing profiles and trajectories will be characterized.

Discussion: Identification of psychiatric treatment profiles and trajectories based on an unsupervised learning algorithm have the potential to reveal hidden patterns of psychiatric treatment. This will potentially pave the way for future studies of treatment combinations and a larger insight into the different courses of treatment. Furthermore, the assessment of clinical and sociodemographic factors may indicate different patient characteristics across treatment profiles and trajectories.
A protocol for a longitudinal, observational cohort study of infection and exposure to zoonotic and vector-borne diseases across a land-use gradient in Sabah, Malaysian Borneo: a socio-ecological systems approach
Authors: Fornace Kimberly , Manin Benny Obrain , Matthiopoulos Jason , Ferguson Heather M. , Drakeley Chris , Ahmed Kamruddin , Khoon Koay Teng , Ewers Robert M. , Daim Sylvia , Chua Tock Hing
Published: February 2022

Introduction.Landscape changes disrupt environmental, social and biological systems, altering pathogen spillover and transmission risks. This study aims to quantify the impact of specific land management practices on spillover and transmission rates of zoonotic and vector-borne diseases within Malaysian Borneo. This protocol describes a cohort study with integrated ecological sampling to assess how deforestation and agricultural practices impact pathogen flow from wildlife and vector populations to human infection and detection by health facilities. This will focus on malaria, dengue and emerging arboviruses (Chikungunya and Zika), vector-borne diseases with varying contributions of simian reservoirs within this setting.

Methods.A prospective longitudinal observational cohort study will be established in communities residing or working within the vicinity of the Stability of Altered Forest Ecosystems (SAFE) Project, a landscape gradient within Malaysian Borneo encompassing different plantation and forest types. The primary outcome of this study will be transmission intensity of selected zoonotic and vector-borne diseases, as quantified by changes in pathogen-specific antibody levels. Exposure will be measured using paired population-based serological surveys conducted at the beginning and end of the two-year cohort study. Secondary outcomes will include the distribution and infection rates ofAedesandAnophelesmosquito vectors, human risk behaviours and clinical cases reported to health facilities. Longitudinal data on human behaviour, contact with wildlife and GPS tracking of mobility patterns will be collected throughout the study period. This will be integrated with entomological surveillance to monitor densities and pathogen infection rates ofAedesandAnophelesmosquitoes relative to land cover. Within surrounding health clinics, continuous health facility surveillance will be used to monitor reported infections and febrile illnesses. Models will be developed to assess spillover and transmission rates relative to specific land management practices and evaluate abilities of surveillance systems to capture these risks.
Broadband optical network design for the future aircraft cabin
Authors: Saadaoui Hamza , Bacou Alexandre , Rebiere Yoann , Fracasso Bruno , Morvan Michel
Published: February 2022

Bringing an optical network infrastructure into civil aircraft cabins is one of the major technological evolutions of the aeronautic industry. During the last decade, copper networks installed in aircraft cabins have proven to be unable to support new technologies and services throughout the life of the aircraft. With severe constraints and high maintenance costs in the aeronautical field, there is also a significant increase in aircraft weight and hence fuel consumption with the current cabin infrastructure. In order to overcome these problems while offering the best trade-off in terms of heterogeneous service transport, we propose therein various optical network architectures for future civil aircraft cabins combining point to multi-point time division multiplexing transport over passive optical networks with wavelength division multiplexing technology. These architectures offer promising solutions for commercial aircraft with capacities up to about 500 seats, while allowing for a significant decrease in operating costs and maintenance/installation time, thus facilitating the intervention on the aircraft.
Abnormal optical response of PAMAM dendrimer-based silver nanocomposite metamaterials
Authors: Wu Xianfeng , Li Zhenchun , Zhao Yuan , Yang Chaoshun , Zhao Wei , Zhao Xiaopeng
Published: February 2022

Optical metamaterials present opportunities and challenges for manipulation of light. However, metamaterials with visible and near infrared responses are still particularly challenging to fabricate due to the complex preparation process and high loss. Here, a visible light poly(amidoamine) (PAMAM)-Ag metamaterial is prepared with the assistance of fifth-generation PAMAM (5G PAMAM), based on the dendritic structure. The large area of metamaterials, where Ag nanoparticles are spherical with diameters of

∼
9
  
nm

and distributed in a multilevel netlike sphere, results in broadband resonance. The negative Goos–Hänchen shift and anomalous spin Hall effect of light generated by 5G PAMAM-Ag in visible broadband are observed, and a strong slab focusing effect at 750–1050 nm is demonstrated. In addition, the simulation shows possible application of the dendritic structure in topological photonics. The results offer advances in the preparation of large-scale visible light metamaterials, showing the potential for subwavelength super-resolution imaging and quantum optical information fields.
Implementation of an interactive mobile application to pilot a rapid assay to detect HIV drug resistance mutations in Kenya
Authors: Vrana Justin D. , Panpradist Nuttada , Higa Nikki , Ko Daisy , Ruth Parker , Kanthula Ruth , Lai James J. , Yang Yaoyu , Sakr Samar R. , Chohan Bhavna , Chung Michael H. , Frenkel Lisa M. , Lutz Barry R. , Klavins Eric , Beck Ingrid A.
Published: February 2022

Usability is an overlooked aspect of implementing lab-based assays, particularly novel assays in low-resource-settings. Esoteric instructions can lead to irreproducible test results and patient harm. To address these issues, we developed a software application based on “Aquarium”, a laboratory-operating system run on a computer tablet that provides step-by-step digital interactive instructions, protocol management, and sample tracking. Aquarium was paired with a near point-of-care HIV drug resistance test, “OLA-Simple”, that detects mutations associated with virologic failure. In this observational study we evaluated the performance of Aquarium in guiding untrained users through the multi-step laboratory protocol with little supervision. To evaluate the training by Aquarium software we conducted a feasibility study in a laboratory at Coptic Hope Center in Nairobi, Kenya. Twelve volunteers who were unfamiliar with the kit performed the test on blinded samples (2 blood specimens; 5 codons/sample). Steps guided by Aquarium included: CD4+ T-Cell separation, PCR, ligation, detection, and interpretation of test results. Participants filled out a short survey regarding their demographics and experience with the software and kit. None of the laboratory technicians had prior experience performing CD4+ separation and 7/12 had no experience performing laboratory-based molecular assays. 12/12 isolated CD4+ T cells from whole blood with yields comparable to isolations performed by trained personnel. The OLA-Simple workflow was completed by all, with genotyping results interpreted correctly by unaided-eye in 108/120 (90%) and by software in 116/120 (97%) of codons analyzed. In the surveys, participants favorably assessed the use of software guidance. The Aquarium digital instructions enabled first-time users in Kenya to complete the OLA-simple kit workflow with minimal training. Aquarium could increase the accessibility of laboratory assays in low-resource-settings and potentially standardize implementation of clinical laboratory tests.
Zika virus disrupts gene expression in human myoblasts and myotubes: Relationship with susceptibility to infection
Authors: Riederer Ingo , Mendes-da-Cruz Daniella Arêas , da Fonseca Guilherme Cordenonsi , González Mariela Natacha , Brustolini Otavio , Rocha Cássia , Loss Guilherme , de Carvalho Joseane Biso , Menezes Mariane Talon , Raphael Lidiane Menezes Souza , Gerber Alexandra , Bonaldo Myrna Cristina , Butler-Browne Gillian , Mouly Vincent , Cotta-de-Almeida Vinicius , Savino Wilson , Ribeiro de Vasconcelos Ana Tereza
Published: February 2022

The tropism of Zika virus (ZIKV) has been described in the nervous system, blood, placenta, thymus, and skeletal muscle. We investigated the mechanisms of skeletal muscle susceptibility to ZIKV using an in vitro model of human skeletal muscle myogenesis, in which myoblasts differentiate into myotubes. Myoblasts were permissive to ZIKV infection, generating productive viral particles, while myotubes controlled ZIKV replication. To investigate the underlying mechanisms, we used gene expression profiling. First, we assessed gene changes in myotubes compared with myoblasts in the model without infection. As expected, we observed an increase in genes and pathways related to the contractile muscle system in the myotubes, a reduction in processes linked to proliferation, migration and cytokine production, among others, confirming the myogenic capacity of our system in vitro. A comparison between non-infected and infected myoblasts revealed more than 500 differentially expressed genes (DEGs). In contrast, infected myotubes showed almost 2,000 DEGs, among which we detected genes and pathways highly or exclusively expressed in myotubes, including those related to antiviral and innate immune responses. Such gene modulation could explain our findings showing that ZIKV also invades myotubes but does not replicate in these differentiated cells. In conclusion, we showed that ZIKV largely (but differentially) disrupts gene expression in human myoblasts and myotubes. Identifying genes involved in myotube resistance can shed light on potential antiviral mechanisms against ZIKV infection.
One Health, One Hive: A scoping review of honey bees, climate change, pollutants, and antimicrobial resistance
Authors: de Jongh Etienne J. , Harper Sherilee L. , Yamamoto Shelby S. , Wright Carlee J. , Wilkinson Craig W. , Ghosh Soumyaditya , Otto Simon J. G.
Published: February 2022

Anthropogenic climate change and increasing antimicrobial resistance (AMR) together threaten the last 50 years of public health gains. Honey bees are a model One Health organism to investigate interactions between climate change and AMR. The objective of this scoping review was to examine the range, extent, and nature of published literature on the relationship between AMR and honey bees in the context of climate change and environmental pollutants. The review followed systematic search methods and reporting guidelines. A protocol was developed a priori in consultation with a research librarian. Resulting Boolean search strings were used to search Embase® via Ovid®, MEDLINE®, Scopus®, AGRICOLA™ and Web of Science™ databases. Two independent reviewers conducted two-stage screening on retrieved articles. To be included, the article had to examine honey bees, AMR, and either climate change or environmental pollution. Data, in accordance with Joanna Briggs Institute guidelines, were extracted from relevant articles and descriptively synthesized in tables, figures, and narrative form. A total of 22 articles met the inclusion criteria, with half of all articles being published in the last five years (n = 11/22). These articles predominantly investigated hive immunocompetence and multi-drug resistance transporter downregulation (n = 11/22), susceptibility to pests (n = 16/22), especially American foulbrood (n = 9/22), and hive product augmentation (n = 3/22). This review identified key themes and gaps in the literature, including the need for future interdisciplinary research to explore the link between AMR and environmental change evidence streams in honey bees. We identified three potential linkages between pollutive and climatic factors and risk of AMR. These interconnections reaffirm the necessity of a One Health framework to tackle global threats and investigate complex issues that extend beyond honey bee research into the public health sector. It is integral that we view these “wicked” problems through an interdisciplinary lens to explore long-term strategies for change.
Developing a multiplex loop-mediated isothermal amplification assay (LAMP) to determine severe fever with thrombocytopenia syndrome (SFTS) and scrub typhus
Authors: Jang Woong Sik , Lim Da Hye , Choe Young Lan , Nam Jeonghun , Moon Kyung Chul , Kim Chaewon , Choi Minkyeong , Park Insu , Park Dae Won , Lim Chae Seung
Published: February 2022

Severe fever with thrombocytopenia syndrome (SFTS) and scrub typhus are endemic zoonotic diseases that pose significant public health threats in East Asia. As these two diseases share common clinical features, as well as overlapping disease regions, it is difficult to differentiate between SFTS and scrub typhus. A multiplex reverse-transcription loop‑mediated isothermal amplification (RT-LAMP) assay was developed to detect large segments and GroES genes for SFTS virus (SFTSV) andOrientia tsutsugamushi(OT). The performance of the RT-LAMP assay was compared and evaluated with those of commercial PowerChek™SFTSV real-time PCR and LiliF™TSUTSU nested PCR for 23 SFTS and 12 scrub typhus clinical samples, respectively. The multiplex SFTSV/OT/Internal control (IC) RT-LAMP assay showed comparable sensitivity (91.3%) with that of commercial PowerChek™SFTSV Real-time PCR (95.6%) and higher sensitivity (91.6%) than that of LiliF™TSUTSU nested PCR (75%). In addition, the multiplex SFTSV/OT RT-LAMP assay showed 100% specificity and no cross-reactivity for blood from uninfected healthy patients and samples from patients infected with other fever viruses. Thus, the multiplex SFTSV/OT/IC RT-LAMP assay could serve as a useful point-of-care molecular diagnostic test for SFTS and scrub typhus.
Secondary attack rates in primary and secondary school bubbles following a confirmed case: Active, prospective national surveillance, November to December 2020, England
Authors: Powell Annabel A. , Ireland Georgina , Baawuah Frances , Beckmann Joanne , Okike Ifeanyichukwu O. , Ahmad Shazaad , Garstang Joanna , Brent Andrew J. , Brent Bernadette , Aiano Felicity , Hargreaves James , Langan Sinéad M. , Mangtani Punam , Nguipdop-Djomo Patrick , Sturgess Joanna , Oswald William , Halliday Katherine , Rourke Emma , Dawe Fiona , Amin-Chowdhury Zahin , Kall Meaghan , Zambon Maria , Poh John , Ijaz Samreen , Lackenby Angie , Elli Joanna , Brown Kevin E. , Diamond Sir Ian , Ramsay Mary E. , Ladhani Shamez N.
Published: February 2022

Background

Following the full re-opening of schools in England and emergence of the SARS-CoV-2 Alpha variant, we investigated the risk of SARS-CoV-2 infection in students and staff who were contacts of a confirmed case in a school bubble (school groupings with limited interactions), along with their household members.

Methods

Primary and secondary school bubbles were recruited into sKIDsBUBBLE after being sent home to self-isolate following a confirmed case of COVID-19 in the bubble. Bubble participants and their household members were sent home-testing kits comprising nasal swabs for RT-PCR testing and whole genome sequencing, and oral fluid swabs for SARS-CoV-2 antibodies.

Results

During November-December 2020, 14 bubbles were recruited from 7 schools, including 269 bubble contacts (248 students, 21 staff) and 823 household contacts (524 adults, 299 children). The secondary attack rate was 10.0% (6/60) in primary and 3.9% (4/102) in secondary school students, compared to 6.3% (1/16) and 0% (0/1) among staff, respectively. The incidence rate for household contacts of primary school students was 6.6% (12/183) and 3.7% (1/27) for household contacts of primary school staff. In secondary schools, this was 3.5% (11/317) and 0% (0/1), respectively. Household contacts were more likely to test positive if their bubble contact tested positive although there were new infections among household contacts of uninfected bubble contacts.

Interpretation

Compared to other institutional settings, the overall risk of secondary infection in school bubbles and their household contacts was low. Our findings are important for developing evidence-based infection prevention guidelines for educational settings.
Self-reported non-adherence to P2Y12 inhibitors in patients undergoing percutaneous coronary intervention: Application of the medication non-adherence academic research consortium classification
Authors: Ueki Yasushi , Zanchin Thomas , Losdat Sylvain , Karagiannis Alexios , Otsuka Tatsuhiko , Siontis George C. M. , Häner Jonas , Stortecky Stefan , Pilgrim Thomas , Valgimigli Marco , Windecker Stephan , Räber Lorenz
Published: February 2022

Aims

The Non-adherence Academic Research Consortium (NARC) has recently developed a consensus-based standardized classification for medication non-adherence in cardiovascular clinical trials. We aimed to assess the prevalence of NARC-defined self-reported non-adherence to P2Y12 inhibitors and its impact on clinical outcomes in patients undergoing percutaneous coronary intervention (PCI).

Methods and results

Using a standardized questionnaire administered at 1 year after PCI, we assessed the 4 NARC-defined non-adherence levels including type, decision-maker, reasons, and timing within the Bern PCI registry. The primary endpoint was the patient-oriented composite endpoint (POCE) defined as a composite of death, myocardial infarction, stroke, and any revascularization at 1 year. The recommended P2Y12 inhibitor duration was 12 months. Among 3,896 patients, P2Y12 inhibitor non-adherence was observed in 647 (17%) patients. Discontinuation was permanent in the majority of patients (84%). The decision was mainly driven by a physician (94%), and rarely by patients (6%). The most frequent reason was risk profile change (43%), followed by unlisted reasons (25%), surgery (17%), and adverse events (14%). Non-adherence occurred early (<30 days) in 21%, late (30–180 days) in 45%, and very late (>180 days) in 33%. The majority of POCE events (n = 421/502, 84%) occurred during adherence to the prescribed P2Y12 inhibitor. Permanent discontinuation, doctor-driven non-adherence, and risk profile change emerged as independent predictors for POCE.

Conclusions

In real-world PCI population treated with 1-year DAPT, non-adherence was observed in nearly one-fifth of patients. Non-adherence to P2Y12 inhibitors was associated with worse clinical outcomes, while the risk was related to underlying contexts.

ClinicalTrials.gov identifier

NCT02241291.