Planning for healthcare services during the COVID-19 pandemic in the Southeast of England: a system dynamics modelling approach.

OBJECTIVES: To develop, test, validate and implement a system dynamics model to simulate the pandemic progress and the impact of various interventions on viral spread, healthcare utilisation and demand in secondary care. DESIGN: We adopted the system dynamics model incorporating susceptible, exposed, infection and recovery framework to simulate the progress of the pandemic and how the interventions for the COVID-19 response influence the outcomes with a focus on secondary care. SETTING: This study was carried out covering all the local health systems in Southeast of England with a catchment population of six million with a specific focus on Kent and Medway system. PARTICIPANTS: Six local health systems in Southeast of England using Kent and Medway as a case study. INTERVENTIONS: Short to medium 'what if' scenarios incorporating human behaviour, non-pharmaceutical interventions and medical interventions were tested using the model with regular and continuous feedback of the model results to the local health system leaders for monitoring, planning and rapid response as needed. MAIN OUTCOME MEASURES: Daily output from the model which included number infected in the population, hospital admissions needing COVID-19 care, occupied general beds, continuous positive airway pressure beds, intensive care beds, hospital discharge pathways and deaths. RESULTS: We successfully implemented a regional series of models based on the local population needs which were used in healthcare planning as part of the pandemic response. CONCLUSIONS: In this study, we have demonstrated the utility of system dynamics modelling incorporating local intelligence and collaborative working during the pandemic to respond rapidly and take decisions to protect the population. This led to strengthened cooperation among partners and ensured that the local population healthcare needs were met.

A comparison of neuroelectrophysiology databases.

As data sharing has become more prevalent, three pillars - archives, standards, and analysis tools - have emerged as critical components in facilitating effective data sharing and collaboration. This paper compares four freely available intracranial neuroelectrophysiology data repositories: Data Archive for the BRAIN Initiative (DABI), Distributed Archives for Neurophysiology Data Integration (DANDI), OpenNeuro, and Brain-CODE. The aim of this review is to describe archives that provide researchers with tools to store, share, and reanalyze both human and non-human neurophysiology data based on criteria that are of interest to the neuroscientific community. The Brain Imaging Data Structure (BIDS) and Neurodata Without Borders (NWB) are utilized by these archives to make data more accessible to researchers by implementing a common standard. As the necessity for integrating large-scale analysis into data repository platforms continues to grow within the neuroscientific community, this article will highlight the various analytical and customizable tools developed within the chosen archives that may advance the field of neuroinformatics.

A Comparison of Neuroelectrophysiology Databases.

As data sharing has become more prevalent, three pillars - archives, standards, and analysis tools - have emerged as critical components in facilitating effective data sharing and collaboration. This paper compares four freely available intracranial neuroelectrophysiology data repositories: Data Archive for the BRAIN Initiative (DABI), Distributed Archives for Neurophysiology Data Integration (DANDI), OpenNeuro, and Brain-CODE. The aim of this review is to describe archives that provide researchers with tools to store, share, and reanalyze both human and non-human neurophysiology data based on criteria that are of interest to the neuroscientific community. The Brain Imaging Data Structure (BIDS) and Neurodata Without Borders (NWB) are utilized by these archives to make data more accessible to researchers by implementing a common standard. As the necessity for integrating large-scale analysis into data repository platforms continues to grow within the neuroscientific community, this article will highlight the various analytical and customizable tools developed within the chosen archives that may advance the field of neuroinformatics.

Factors Associated With Discontinuation of Tuberculosis Preventive Treatment: Post Hoc Analysis of 2 Randomized, Controlled Trials.

BACKGROUND: Adherence to tuberculosis preventive treatment (TPT) is an important determinant of clinical benefit. We assessed the association of participant behaviors early in TPT with subsequent discontinuation. METHODS: We used data from a phase 3 randomized trial and the preceding phase 2 trial to compare 4 months of rifampin to 9 months of isoniazid for TPT. We excluded participants whose providers discontinued TPT due to adverse events or tuberculosis disease. We analyzed 4 outcomes: discontinuing TPT within the first month of treatment, discontinuing TPT between the first and second month, discontinuing TPT after the second month, and completing treatment but not per protocol. We analyzed the association of outcomes with regimen and participant characteristics and 4 behavioral predictors of discontinuation recorded at the month 1 and month 2 follow-up visits: reporting symptoms of intolerance, missing >20% of doses, rescheduling appointments, and not bringing their medication bottle. RESULTS: Overall, 6656 participants were included (phase 3, 5848; phase 2, 808), of whom 4318 (64.9%) completed treatment per protocol. Participant characteristics were inconsistently associated with discontinuation. Phase 3 trial participants with 1, 2, or 3-4 behavioral predictors at the month 1 follow-up had 5.0 (95% confidence interval, 3.6-6.7), 18.6 (13.3-26.1), and 79.4 (38.2-165.0), respectively, higher odds of discontinuing before the second month. The corresponding number of predictors at the month 2 follow-up had 1.8 (1.4-2.2), 4.7 (3.6-6.2), and 7.4 (4.6-11.9) higher odds of discontinuing before completing treatment; phase 2 findings were similar. CONCLUSIONS: Four behavioral predictors recorded early in therapy were more strongly associated with subsequent discontinuation than participant characteristics, particularly when more than 1 behavioral predictor was recorded. Clinical Trials Registration. NCT00170209; NCT00931736.

Nanomedicine: controlling nanoparticle clearance for translational success.

Achieving complete nanoparticle (NP) clearance is a key consideration in the design of safe and translatable nanomedicines. Renal-clearable nano formulations must encompass the beneficial nanoscale functionalities whilst exhibiting clearance profiles like those of small-molecule therapeutics. Recent developments in the field have enabled the growth of novel renal-clearable NPs with transformable sizes that take advantage of alternative clearance mechanisms to achieve controlled and efficient renal excretion to improve potential clinical translation.

Caspase cleavage and nuclear retention of the energy sensor AMPK-α1 during apoptosis.

AMP-activated protein kinase (AMPK) coordinates energy homeostasis during metabolic and energy stress. We report that the catalytic subunit isoform AMPK-α1 (but not α2) is cleaved by caspase-3 at an early stage during induction of apoptosis. AMPK-α1 cleavage occurs following Asp529, generating an ∼58-kDa N-terminal fragment (cl-AMPK-α1) and leading to the precise excision of the nuclear export sequence (NES) from the C-terminal end. This cleavage does not affect (1) the stability of pre-formed heterotrimeric complexes, (2) the ability of cl-AMPK-α1 to become phosphorylated and activated by the upstream kinases LKB1 or CaMKK2, or (3) allosteric activation by AMP or A-769662. Importantly, cl-AMPK-α1 is only detectable in the nucleus, consistent with removal of the NES, and ectopic expression of cleavage-resistant D529A-mutant AMPK-α1 promotes cell death induced by cytotoxic agents. Thus, we have elucidated a non-canonical mechanism of AMPK activation within the nucleus, which protects cells against death induced by DNA damage.

Building a High-Dose-Rate Prostate Brachytherapy Program With Real-Time Ultrasound-Based Planning: Initial Safety, Quality, and Outcome Results.

PURPOSE: Growing evidence supports the efficacy and safety of high-dose-rate (HDR) brachytherapy as a boost or monotherapy in prostate cancer treatment. We initiated a new HDR prostate brachytherapy practice in April 2014. Here, we report the learning experiences, short-term safety, quality, and outcome. METHODS AND MATERIALS: From April 2014 to December 2017, 164 men were treated with HDR brachytherapy with curative intent. Twenty-eight men (17.1%) underwent HDR brachytherapy as monotherapy, receiving 25 to 27 Gy in 2 fractions. Men treated with HDR brachytherapy as a boost received 19 to 21 Gy in 2 fractions. Fifty-two men (31.7%) had high-risk disease. HDR procedure times, dosimetry, and response were recorded and analyzed. Genitourinary (GU) and gastrointestinal (GI) toxicities were recorded according to the toxicity criteria of the Radiation Therapy Oncology Group. RESULTS: Mean HDR procedure times decreased yearly from 179 minutes in 2014 to 115 minutes in 2017. Median follow-up was 18.6 months (range, 3-55 months). At last review, 79% of patients reported returning to baseline GU status, and 100% of patients noted no change in GI status from their baseline. Four patients experienced acute urinary retention. Treatment planning target volume (PTV) was defined as prostate with margins. Dosimetrically, 97.5% of all HDR implants had PTV D90 ≥100%, 81.5% had PTV V100 ≥95%, 73.6% had maximal urethral doses ≤120%, and 77.5% had rectal 1 mL dose ≤70% (all but one ≤10.8 Gy). The estimated 3-year overall survival was 98.7% (95% confidence interval, 91.4%-99.8%), and disease-free survival was 96.2% (95% confidence interval, 89.5%-98.7%). CONCLUSIONS: The low incidence of GU and GI complications in our cohort demonstrates that a HDR brachytherapy program can be successfully developed as a treatment option for patients with localized prostate cancer.

The bottom-up approach to defining life: deciphering the functional organization of biological cells via multi-objective representation of biological complexity from molecules to cells.

In silico representation of cellular systems needs to represent the adaptive dynamics of biological cells, recognizing a cell's multi-objective topology formed by temporally cohesive intracellular structures. The design of these models needs to address the hierarchical and concurrent nature of cellular functions and incorporate the ability to self-organize in response to transitions between healthy and pathological phases, and adapt accordingly. The functions of biological systems are constantly progressing, due to the ever changing demands of their environment. Biological systems meet these demands by pursuing objectives, aided by their constituents, giving rise to biological functions. A biological cell is organized into an objective/task hierarchy. These objective hierarchy corresponds to the nested nature of temporally cohesive structures and representing them will facilitate in studying pleiotropy and polygeny by modeling causalities propagating across multiple interconnected intracellular processes. Although biological adaptations occur in physiological, developmental and reproductive timescales, the paper is focused on adaptations that occur within physiological timescales, where the biomolecular activities contributing to functional organization, play a key role in cellular physiology. The paper proposes a multi-scale and multi-objective modeling approach from the bottom-up by representing temporally cohesive structures for multi-tasking of intracellular processes. Further the paper characterizes the properties and constraints that are consequential to the adaptive dynamics in biological cells.

Providing confusion: the need for education not information in chronic care.

Patient information is one aspect of meeting the needs of health service users; it is meant to empower patients and their carers in making informed decisions and managing their health needs. Mary Dixon-Woods described two types of discourse in patient education: the first is more concerned with making patients comply with their doctors orders and the second is about empowering patients and rejecting direction. This article looks at the aims of the two and shows that neither is capable of supporting highly successful best practice within medicine. Instead, a hybrid set of strategic aims are proposed for patient education created by merging the two discourses in the same way that John Dewey merged the child-centred and child-led schools of thought in education. These hybrid strategic aims for patient education are then used to develop requirements for an information system to support patient education, using a mixture of system centric and user centric approaches.

Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4)P2 in regulating insulin sensitivity defined by knock-in analysis.

Insulin sensitivity is critically dependent on the activity of PI3K (phosphoinositide 3-kinase) and generation of the PtdIns(3,4,5)P(3) second messenger. PtdIns(3,4,5)P(3) can be broken down to PtdIns(3,4)P(2) through the action of the SHIPs (Src-homology-2-domain-containing inositol phosphatases). As PtdIns(3,4)P(2) levels peak after those of PtdIns(3,4,5)P(3), it has been proposed that PtdIns(3,4)P(2) controls a negative-feedback loop that down-regulates the insulin and PI3K network. Previously, we identified two related adaptor proteins termed TAPP [tandem PH (pleckstrin homology)-domain-containing protein] 1 and TAPP2 that specifically bind to PtdIns(3,4)P(2) through their C-terminal PH domain. To determine whether TAPP1 and TAPP2 play a role in regulating insulin sensitivity, we generated knock-in mice that express normal endogenous levels of mutant TAPP1 and TAPP2 that are incapable of binding PtdIns(3,4)P(2). These homozygous TAPP1(R211L/R211L) TAPP2(R218L/R218L) double knock-in mice are viable and exhibit significantly enhanced activation of Akt, a key downstream mediator of insulin signalling. Consistent with increased PI3K and Akt activity, the double knock-in mice display enhanced whole body insulin sensitivity and disposal of glucose uptake into muscle tissues. We also generated wild-type and double TAPP1(R211L/R211L) TAPP2(R218L/R218L) knock-in embryonic fibroblasts and found that insulin triggered enhanced production of PtdIns(3,4,5)P(3) and Akt activity in the double knock-in fibroblasts. These observations provide the first genetic evidence to support the notion that binding of TAPP1 and TAPP2 adap-tors to PtdIns(3,4)P(2) function as negative regulators of the insulin and PI3K signalling pathways.

Onset of dyskinesia with adjunct ropinirole prolonged-release or additional levodopa in early Parkinson's disease.

Levodopa-induced dyskinesia can result in significant functional disability and reduced quality of life in patients with Parkinson's disease (PD). The goal of this study was to determine if the addition of once-daily ropinirole 24-hour prolonged-release (n = 104) in PD patients not optimally controlled with levodopa after up to 3 years of therapy with less than 600 mg/d delays the onset of dyskinesia compared with increasing doses of levodopa (n = 104). During the study, 3% of the ropinirole prolonged-release group (mean dose 10 mg/d) and 17% of the levodopa group (mean additional dose 284 mg/d) developed dyskinesia (P < 0.001). There were no significant differences in change in Unified Parkinson's Disease Rating Scale activities of daily living or motor scores, suggesting comparable efficacy between the two treatments. Adverse events were comparable in the two groups with nausea, dizziness, insomnia, back pain, arthralgia, somnolence, fatigue, and pain most commonly reported. Ropinirole prolonged-release delayed the onset of dyskinesia with comparable efficacy to increased doses of levodopa in early PD patients not optimally controlled with levodopa.

Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR).

mTOR (mammalian target of rapamycin) stimulates cell growth by phosphorylating and promoting activation of AGC (protein kinase A/protein kinase G/protein kinase C) family kinases such as Akt (protein kinase B), S6K (p70 ribosomal S6 kinase) and SGK (serum and glucocorticoid protein kinase). mTORC1 (mTOR complex-1) phosphorylates the hydrophobic motif of S6K, whereas mTORC2 phosphorylates the hydrophobic motif of Akt and SGK. In the present paper we describe the small molecule Ku-0063794, which inhibits both mTORC1 and mTORC2 with an IC50 of approximately 10 nM, but does not suppress the activity of 76 other protein kinases or seven lipid kinases, including Class 1 PI3Ks (phosphoinositide 3-kinases) at 1000-fold higher concentrations. Ku-0063794 is cell permeant, suppresses activation and hydrophobic motif phosphorylation of Akt, S6K and SGK, but not RSK (ribosomal S6 kinase), an AGC kinase not regulated by mTOR. Ku-0063794 also inhibited phosphorylation of the T-loop Thr308 residue of Akt phosphorylated by PDK1 (3-phosphoinositide-dependent protein kinase-1). We interpret this as implying phosphorylation of Ser473 promotes phosphorylation of Thr308 and/or induces a conformational change that protects Thr308 from dephosphorylation. In contrast, Ku-0063794 does not affect Thr308 phosphorylation in fibroblasts lacking essential mTORC2 subunits, suggesting that signalling processes have adapted to enable Thr308 phosphorylation to occur in the absence of Ser473 phosphorylation. We found that Ku-0063794 induced a much greater dephosphorylation of the mTORC1 substrate 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1) than rapamycin, even in mTORC2-deficient cells, suggesting a form of mTOR distinct from mTORC1, or mTORC2 phosphorylates 4E-BP1. Ku-0063794 also suppressed cell growth and induced a G1-cell-cycle arrest. Our results indicate that Ku-0063794 will be useful in delineating the physiological roles of mTOR and may have utility in treatment of cancers in which this pathway is inappropriately activated.

Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking.

Phosphatidylinositol-3-OH kinase (PI(3)K) and the nutrient sensor mTOR are evolutionarily conserved regulators of cell metabolism. Here we show that PI(3)K and mTOR determined the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. The key lymph node-homing receptors CD62L (L-selectin) and CCR7 were highly expressed on naive T lymphocytes but were downregulated after immune activation. CD62L downregulation occurred through ectodomain proteolysis and suppression of gene transcription. The p110delta subunit of PI(3)K controlled CD62L proteolysis through mitogen-activated protein kinases, whereas control of CD62L transcription by p110delta was mediated by mTOR through regulation of the transcription factor KLF2. PI(3)K-mTOR nutrient-sensing pathways also determined expression of the chemokine receptor CCR7 and regulated lymphocyte trafficking in vivo. Hence, lymphocytes use PI(3)K and mTOR to match metabolism and trafficking.

The control of phosphatidylinositol 3,4-bisphosphate concentrations by activation of the Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2, SHIP2.

Activation of class Ia PI3K (phosphoinositide 3-kinase) produces PtdInsP3, a vital intracellular mediator whose degradation generates additional lipid signals. In the present study vanadate analogues that inhibit PTPs (protein tyrosine phosphatases) were used to probe the mechanisms which regulate the concentrations of these molecules allowing their independent or integrated function. In 1321N1 cells, which lack PtdInsP3 3-phosphatase activity, sodium vanadate or a cell permeable derivative, bpV(phen) [potassium bisperoxo(1,10-phenanthroline)oxovanadate (V)], increased the recruitment into anti-phosphotyrosine immunoprecipitates of PI3K activity and of the p85 and p110a subunits of class Ia PI3K and enhanced the recruitment of PI3K activity stimulated by PDGF (platelet-derived growth factor). However, neither inhibitor much increased cellular PtdInsP3 concentrations, but both diminished dramatically the accumulation of PtdInsP3 stimulated by PDGF or insulin and markedly increased the control and stimulated concentrations of PtdIns(3,4)P2. These actions were accounted for by the ability of PTP inhibitors to stimulate the activity of endogenous PtdInsP3 5-phosphatase(s), particularly SHIP2 (Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2) and to inhibit types I and II PtdIns(3,4)P2 4-phosphatases. Thus bpV(phen) promoted the translocation of SHIP2 from the cytosol to a Triton X-100-insoluble fraction and induced a marked (5-10-fold) increase in SHIP2 specific activity mediated by enhanced tyrosine phosphorylation. The net effect of these inhibitors was, therefore, to switch the signal output of class I PI3K from PtdInsP3 to PtdIns(3,4)P2. A key component controlling this shift in the balance of lipid signals is the activation of SHIP2 by increased tyrosine phosphorylation, an effect observed in HeLa cells in response to both PTP inhibitors and epidermal growth factor.

Localization of agonist-sensitive PtdIns(3,4,5)P3 reveals a nuclear pool that is insensitive to PTEN expression.

Phosphatidylinositol (3,4,5) trisphosphate [PtdIns(3,4,5)P3] is a lipid second messenger, produced by Type I phosphoinositide 3-kinases (PI 3-kinases), which mediates intracellular responses to many growth factors. Although PI 3-kinases are implicated in events at both the plasma membrane and intracellular sites, including the nucleus, direct evidence for the occurrence of PtdIns(3,4,5)P3 at non-plasma membrane locations is limited. We made use of the pleckstrin homology (PH) domain of general receptor for phosphoinositides (Grp1) to detect PtdIns(3,4,5)P3 in an on-section labeling approach by quantitative immunogold electron microscopy. Swiss 3T3 cells contained low levels of PtdIns(3,4,5)P3 that increased up to 15-fold upon stimulation with platelet-derived growth factor (PDGF). The signal was sensitive to PI 3-kinase inhibitors and present mainly at plasma membranes, including lamellipodia, and in a surprisingly large pool within the nuclear matrix. Comparatively little labeling was observed in endomembranes. A similar distribution of PtdIns(3,4,5)P3 was observed in U87MG cells, which lack the PtdIns(3,4,5)P3 phosphatase, PTEN. Re-expression of PTEN into U87MG cells ablated plasma membrane PtdIns(3,4,5)P3, but not the nuclear pool of this lipid even when PTEN was targeted to nuclei. These data have important implications for the versatility of PI 3-kinase signaling and for the proposed functions of PTEN in the nucleus.

Personalizing web information for patients: linking patient medical data with the web via a patient personal knowledge base.

This paper describes ongoing study that examines problems with existing patient health information sources and investigates an approach for linking (i.e. integrating) data from a patient's medical record(s) with relevant health information on the web. The aim is to provide patients with simplified, customized and controlled access to web information. Data from patient medical records are extracted and linked with relevant health information on the web through a web search service. These are made available to patients through a web portal that we refer to as the patient knowledge base (PatientKB). Our integration approach utilizes term semantics (i.e. meaning) to enrich the web search and simplify medical terms for patients. In the current implementation, patients have guided, secure and relatively customized access to basic and relevant web information on their diagnoses. Future implementation will attempt to achieve further customization, extensibility and safety features. This paper investigates how ideas presented in an earlier study can be implemented.

Primary care oncology: addressing the challenges.

The last decade has seen an emerging clinical discipline known as 'primary care oncology' that describes the involvement of general practitioners (GPs) in preventing, diagnosing, treating and following up patients with cancer. This paper reports the experience of our team in investigating the information required to develop a shared electronic care record system to link GPs and cancer specialists in Wales in order to facilitate information sharing between them in a timely and effective manner. It identifies a potential minimum dataset that can provide the basis for the development of a Welsh primary care cancer dataset. It also addresses the associated challenges to be overcome at implementation, namely information, technical, cultural/organisational and management challenges. This work is a collaboration between the Department of Computer Science at Cardiff University and Velindre NHS Trust, the South East Wales Cancer Centre.

Probing phosphoinositide functions in signaling and membrane trafficking.

The inositol phospholipids (PIs) comprise a family of eight species with different combinations of phosphate groups arranged around the inositol ring. PIs are among the most versatile signaling molecules known, with key roles in receptor-mediated signal transduction, actin remodeling and membrane trafficking. Recent studies have identified effector proteins and specific lipid-binding domains through which PIs signal. These lipid-binding domains can be used as probes to further our understanding of the spatial and temporal control of individual PI species. New layers of complexity revealed by the use of such probes include the occurrence of PIs at intracellular locations, the identification of phosphatidylinositol signaling hotspots and the presence of non-membrane pools of PIs in cell nuclei.

Peripheral kappa-opioid agonist, ICI 204448, evokes hypothermia in cold-exposed rats.

ICI 204448, a selective kappa-opioid agonist with limited CNS access, can be used to discriminate central and peripheral opioid actions on physiological systems such as pain and thermoregulation. Therefore, we investigated the effect of ICI 204448 (2.5, 5, and 10 mg/kg, s.c.) on male Sprague-Dawley rats exposed to ambient temperatures of 5, 20, or 32 degrees C. ICI 204448 did not alter the body temperature of rats maintained at 20 or 32 degrees C. However, 5 and 10 mg/kg of ICI 204448 evoked significant hypothermia in rats exposed to 5 degrees C. The i.c.v. administration of nor-BNI, a kappa-opioid antagonist, did not affect the hypothermia produced by the systemic injection of ICI 204448. Thus, an involvement of brain kappa-opioid receptors in ICI 204448-evoked hypothermia is unlikely. The present data demonstrate for the first time that ICI 204448 produces hypothermia in cold-exposed rats and suggest that the role of peripheral kappa-opioid receptors in thermoregulation becomes more significant at cold ambient temperatures.