Suicide and the COVID-19 pandemic: A qualitative study of discourse on an online pro-choice for suicide discussion forum.

The COVID-19 pandemic had a widespread impact on millions of individuals. Many turned to social media as an outlet for sharing personal experiences, such as the impact of the pandemic on suicidality. The purpose of this study was to understand the pandemic's impact on individuals who discuss their suicidality on social media. Keywords were used to search for discussion threads (N = 118) related to the pandemic on an online pro-choice for suicide forum. Using reflexive thematic analysis, six themes related to the pandemic's impact on mental health, suicidality, living conditions, and optimism were identified. Examination of the content from pro-choice for suicide forums may yield authentic information on the impact of the pandemic on those considering suicide. This study contributes to our understanding of the nuances of factors impacting mental health and suicidality during the pandemic, including unique risk and protective factors.

Quantitative systems pharmacology model of the amyloid pathway in Alzheimer's disease: Insights into the therapeutic mechanisms of clinical candidates.

Despite considerable investment into potential therapeutic approaches for Alzheimer's disease (AD), currently approved treatment options are limited. Predictive modeling using quantitative systems pharmacology (QSP) can be used to guide the design of clinical trials in AD. This study developed a QSP model representing amyloid beta (Aß) pathophysiology in AD. The model included mechanisms of Aß monomer production and aggregation to form insoluble fibrils and plaques; the transport of soluble species between the compartments of brain, cerebrospinal fluid (CSF), and plasma; and the pharmacokinetics, transport, and binding of monoclonal antibodies to targets in the three compartments. Ordinary differential equations were used to describe these processes quantitatively. The model components were calibrated to data from the literature and internal studies, including quantitative data supporting the underlying AD biology and clinical data from clinical trials for anti-Aß monoclonal antibodies (mAbs) aducanumab, crenezumab, gantenerumab, and solanezumab. The model was developed for an apolipoprotein E (APOE) ɛ4 allele carrier and tested for an APOE ɛ4 noncarrier. Results indicate that the model is consistent with data on clinical Aß accumulation in untreated individuals and those treated with monoclonal antibodies, capturing increases in Aß load accurately. This model may be used to investigate additional AD mechanisms and their impact on biomarkers, as well as predict Aß load at different dose levels for mAbs with known targets and binding affinities. This model may facilitate the design of scientifically enriched and efficient clinical trials by enabling a priori prediction of biomarker dynamics in the brain and CSF.

Adaptation of Human iPSC-Derived Cardiomyocytes to Tyrosine Kinase Inhibitors Reduces Acute Cardiotoxicity via Metabolic Reprogramming.

Tyrosine kinase inhibitors (TKIs) are widely used to treat solid tumors but can be cardiotoxic. The molecular basis for this toxicity and its relationship to therapeutic mechanisms remain unclear; we therefore undertook a systems-level analysis of human cardiomyocytes (CMs) exposed to four TKIs. CMs differentiated from human induced pluripotent stem cells (hiPSCs) were exposed to sunitinib, sorafenib, lapatinib, or erlotinib, and responses were assessed by functional assays, microscopy, RNA sequencing, and mass spectrometry (GEO: GSE114686; PRIDE: PXD012043). TKIs have diverse effects on hiPSC-CMs distinct from inhibition of tyrosine-kinase-mediated signal transduction; cardiac metabolism is particularly sensitive. Following sorafenib treatment, oxidative phosphorylation is downregulated, resulting in a profound defect in mitochondrial energetics. Cells adapt by upregulating aerobic glycolysis. Adaptation makes cells less acutely sensitive to sorafenib but may have long-term negative consequences. Thus, CMs exhibit adaptive responses to anti-cancer drugs conceptually similar to those previously shown in tumors to mediate drug resistance.

Data transmission at 1300 nm using optical interposer comprising hybrid integrated silicon waveguide and dilute nitride electroabsorption modulator.

High speed back-to-back transmission of NRZ data at 12.5 Gbit/s was achieved over a repeaterless optical network without the use of forward error correction or optical clock recovery using a hybrid integrated silicon photonics optical interconnect. The interconnect comprises an electroabsorption modulator based on dilute nitride multiple quantum well material on GaAs substrate optically coupled to large core silicon waveguide using passive alignment and flip-chip bonding.

BioNetGen 2.2: advances in rule-based modeling.

: BioNetGen is an open-source software package for rule-based modeling of complex biochemical systems. Version 2.2 of the software introduces numerous new features for both model specification and simulation. Here, we report on these additions, discussing how they facilitate the construction, simulation and analysis of larger and more complex models than previously possible. AVAILABILITY AND IMPLEMENTATION: Stable BioNetGen releases (Linux, Mac OS/X and Windows), with documentation, are available at http://bionetgen.org Source code is available at http://github.com/RuleWorld/bionetgen CONTACT: bionetgen.help@gmail.comSupplementary information: Supplementary data are available at Bioinformatics online.

A Neutrophil Phenotype Model for Extracorporeal Treatment of Sepsis.

Neutrophils play a central role in eliminating bacterial pathogens, but may also contribute to end-organ damage in sepsis. Interleukin-8 (IL-8), a key modulator of neutrophil function, signals through neutrophil specific surface receptors CXCR-1 and CXCR-2. In this study a mechanistic computational model was used to evaluate and deploy an extracorporeal sepsis treatment which modulates CXCR-1/2 levels. First, a simplified mechanistic computational model of IL-8 mediated activation of CXCR-1/2 receptors was developed, containing 16 ODEs and 43 parameters. Receptor level dynamics and systemic parameters were coupled with multiple neutrophil phenotypes to generate dynamic populations of activated neutrophils which reduce pathogen load, and/or primed neutrophils which cause adverse tissue damage when misdirected. The mathematical model was calibrated using experimental data from baboons administered a two-hour infusion of E coli and followed for a maximum of 28 days. Ensembles of parameters were generated using a Bayesian parallel tempering approach to produce model fits that could recreate experimental outcomes. Stepwise logistic regression identified seven model parameters as key determinants of mortality. Sensitivity analysis showed that parameters controlling the level of killer cell neutrophils affected the overall systemic damage of individuals. To evaluate rescue strategies and provide probabilistic predictions of their impact on mortality, time of onset, duration, and capture efficacy of an extracorporeal device that modulated neutrophil phenotype were explored. Our findings suggest that interventions aiming to modulate phenotypic composition are time sensitive. When introduced between 3-6 hours of infection for a 72 hour duration, the survivor population increased from 31% to 40-80%. Treatment efficacy quickly diminishes if not introduced within 15 hours of infection. Significant harm is possible with treatment durations ranging from 5-24 hours, which may reduce survival to 13%. In severe sepsis, an extracorporeal treatment which modulates CXCR-1/2 levels has therapeutic potential, but also potential for harm. Further development of the computational model will help guide optimal device development and determine which patient populations should be targeted by treatment.

Cutting Edge: Differential Regulation of PTEN by TCR, Akt, and FoxO1 Controls CD4+ T Cell Fate Decisions.

Signaling via the Akt/mammalian target of rapamycin pathway influences CD4(+) T cell differentiation; low levels favor regulatory T cell induction and high levels favor Th induction. Although the lipid phosphatase phosphatase and tensin homolog (PTEN) suppresses Akt activity, the control of PTEN activity is poorly studied in T cells. In this study, we identify multiple mechanisms that regulate PTEN expression. During Th induction, PTEN function is suppressed via lower mRNA levels, lower protein levels, and an increase in C-terminal phosphorylation. Conversely, during regulatory T cell induction, PTEN function is maintained through the stabilization of PTEN mRNA transcription and sustained protein levels. We demonstrate that differential Akt/mammalian target of rapamycin signaling regulates PTEN transcription via the FoxO1 transcription factor. A mathematical model that includes multiple modes of PTEN regulation recapitulates our experimental findings and demonstrates how several feedback loops determine differentiation outcomes. Collectively, this work provides novel mechanistic insights into how differential regulation of PTEN controls alternate CD4(+) T cell fate outcomes.

Using the Internet to recruit patients for epilepsy trials: results of a New Zealand pilot study.

PURPOSE: We created a database that could be accessed via the Internet by any neurologist or pediatric neurologist in New Zealand. The database was designed to facilitate recruitment of patients for investigator-driven drug trials. METHODS: We established an epilepsy database, and invited neurologists and pediatric neurologists throughout New Zealand to register patients via the Internet when they were uncertain of the optimal management. Details regarding seizure type and frequency, epilepsy syndrome, etiology, drug history, and investigations were collected. We produced an algorithm to select patients who had failed to respond to a single antiepileptic drug (AED). These patients were randomized immediately via the Internet to receive a different drug. Participants were not reimbursed. RESULTS: The pilot study recruited patients from mid-June to December 2007. Sixteen neurologists participated; neurologists were based in eight different cities. One hundred thirty-seven patients were registered, of whom 113 were considered suitable for drug trials. Thirty-five patients who had used a single antiepileptic drug AED were enrolled, and 14 of these were successfully randomized online to a different drug. Follow-up information was entered via the Internet for all 108 patients who were seen again during the following year. DISCUSSION: We have demonstrated that patients can be recruited for trials and randomized from routine clinics via the Internet. Trials could compare AEDs or look at other aspects of epilepsy management. An international pilot study is planned. Neurologists are invited to enroll patients with epilepsy, who would be suitable for randomized controlled trials, into a Web-based register.