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Chronic opioid consumption is associated with addiction, physical dependence, and tolerance. Tolerance results in dose escalation to maintain the desired opioid effect. Intake of high-dose or potent opioids may cause life-threatening respiratory depression, an effect that may be reduced by tolerance. We performed a pharmacokinetic-pharmacodynamic analysis of the respiratory effects of fentanyl in chronic opioid users and opioid-naïve subjects to quantify tolerance to respiratory depression. Fourteen opioid-naïve individuals and eight chronic opioid users received escalating doses of intravenous fentanyl (opioid-naïve subjects: 75-350 µg/70 kg; chronic users: 250-700 µg/70 kg). Isohypercapnic ventilation was measured and the fentanyl plasma concentration-ventilation data were analyzed using nonlinear mixed-effects modeling. Apneic events occurred in opioid-naïve subjects after a cumulative fentanyl dose (per 70 kg) of 225 (n = 3) and 475 µg (n = 6), and in 7 chronic opioid users after a cumulative dose of 600 (n = 2), 1,100 (n = 2), and 1,800 µg (n = 3). The time course of fentanyl's respiratory depressant effect was characterized using a biophase equilibration model in combination with an inhibitory maximum effect (E max ) model. Differences in tolerance between populations were successfully modeled. The effect-site concentration causing 50% ventilatory depression, was 0.42 ± 0.07 ng/mL in opioid-naïve subjects and 1.82 ± 0.39 ng/mL in chronic opioid users, indicative of a 4.3-fold sensitivity difference. Despite higher tolerance to fentanyl-induced respiratory depression, apnea still occurred in the opioid-tolerant population indicative of the potential danger of high-dose opioids in causing life-threatening respiratory depression in all individuals, opioid-naïve and opioid-tolerant., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumour and a rare variant of thyroid cancer with different aetiology, presentation and treatment to differentiated thyroid cancer. Currently available thyroid cancer-specific quality of life (QoL) tools focus on issues and treatments more relevant to patients with differentiated thyroid cancer and therefore may not address issues specific to a MTC diagnosis and cancer journey., Method: This prospective multicentre randomised study involved 204 MTC patients completing four quality of life questionnaires (QOLQ) and stating their most and least preferred. The questionnaires were a general instrument, the EORTC QLQ-C30, two disease-specific tools, the MD Anderson Symptom Inventory (MDASI) thyroid module and the City of Hope Quality of Life Scale/THYROID (amended) and the neuroendocrine questionnaire, EORTC QLQ-GINET21. Patients were randomised to complete the four questionnaires in one of 24 possible orders and then answered questions about which tool they preferred. The primary outcome measure was patients' preferred QoL instrument for describing their concerns and for facilitating communication with their healthcare professional. Secondary analyses looked at differences between preferred QOLQs amongst patient subgroups (WHO performance status [0 and 1+], disease stage: early [T1-3, N0 or N1A], metastatic [T4, any T N1b] and advanced [any T any N M1], and type of MTC [sporadic and inherited]), identification of MTC patients' least preferred questionnaire and clinicians' views on the QoL tools in terms of their ability to highlight problems not otherwise ascertained by a standard clinical review., Results: No evidence of a difference was observed for most preferred QOLQ ( p = 0.650). There was however evidence of a difference in least preferred questionnaire in the cohort of 128 patients who stated their least preferred questionnaire ( p = 0.042), with 36% (46/128) of patients choosing the EORTC QLQ-GI.NET21 questionnaire. Subgroup analyses showed that there was no evidence of a difference in patients' most preferred questionnaire in sporadic MTC patients ( p = 0.637), patients with WHO PS 0 or 1+ ( p = 0.844 and p = 0.423) nor when comparing patients with early, advanced local or metastatic disease ( p = 0.132, p = 0.463 and p = 0.506, respectively). Similarly, subgroup analyses on patients' least preferred questionnaires showed no evidence of differences in sporadic MTC patients ( p = 0.092), patients with WHO PS 0 or 1+ ( p = 0.423 and p = 0.276), nor in early or metastatic disease patients ( p = 0.682 and p = 0.345, respectively). There was however some evidence to suggest a difference in least preferred questionnaire in patients with advanced local stage disease ( p = 0.059), with 43% (16/37) of these patients choosing the EORTC QLQ-GI.NET21 questionnaire., Conclusions: MTC patients regardless of their performance status, disease aetiology and disease burden did not express a preference for any one particular questionnaire suggesting any of the tools studied could be utilized in this patient cohort. The least preferred questionnaire being a gastrointestinal NET specific tool suggests that diarrhoea was not a significant symptom and concern for the population studied., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 by European Thyroid Association Published by S. Karger AG, Basel.)

The presence of anti-citrullinated protein/peptide antibodies (ACPA) and epitope spreading across the target autoantigens is a unique feature of rheumatoid arthritis (RA). ACPA are present in the peripheral blood for several years prior to the onset of arthritis and clinical classification of RA. ACPA recognize multiple citrullinated proteins, including histone H3 (H3). Intracellular citrullination of H3 in neutrophils and T cells is known to regulate immune cell function by promoting neutrophil extracellular trap formation and citrullinated autoantigen release as well as regulating the Th2/Th17 T cell phenotypic balance. However, the roles of H3 citrullination in other immune cells are not fully elucidated. We aimed to explore H3 citrullination and cytokine/metabolomic signatures in peripheral blood immune cells from subjects prior to and after the onset of RA, at baseline and in response to ex vivo toll-like receptor (TLR) stimulation. Here, we analyzed 13 ACPA (+) subjects without arthritis but at-risk for future development of RA, 14 early RA patients, and 13 healthy controls. We found significantly elevated H3 citrullination in CD14 hi monocytes, as well as CD1c + dendritic cells and CD66 + granulocytes. Unsupervised analysis identified two distinct subsets in CD14 hi monocytes characterized by H3 modification and unique cytokine/metabolomic signatures. CD14 hi monocytes with elevated TLR-stimulated H3 citrullination were significantly increased in ACPA (+) at-risk subjects. These cells were skewed to produce TNFα, MIP1β, IFNα, and partially IL-12. Additionally, they demonstrate peptidyl arginine deiminase 4 (PAD4) mediated upregulation of the glycolytic enzyme PFKFB3. These CD14 hi monocytes with elevated H3 citrullination morphologically formed monocyte extracellular traps (METs). Taken together, dysregulated PAD4-driven cytokine production as well as MET formation in CD14 hi monocytes in ACPA (+) at-risk subjects likely plays an important role in the development of RA via promoting and perpetuating inflammation and generation of citrullinated autoantigens., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Recent advances in the understanding of depression have led to increasing interest in ketamine and the role that N -methyl-d-aspartate (NMDA) receptor inhibition plays in depression. l-4-Chlorokynurenine (4-Cl-KYN, AV-101), a prodrug, has shown promise as an antidepressant in preclinical studies, but this promise has not been realized in recent clinical trials. We sought to determine if transporters in the CNS could be playing a role in this clinical response. We used radiolabeled uptake assays and microdialysis studies to determine how 4-Cl-KYN and its active metabolite, 7-chlorokynurenic acid (7-Cl-KYNA), cross the blood-brain barrier (BBB) to access the brain and its extracellular fluid compartment. Our data indicates that 4-Cl-KYN crosses the blood-brain barrier via the amino acid transporter LAT1 ( SLC 7 A 5) after which the 7-Cl-KYNA metabolite leaves the brain extracellular fluid via probenecid-sensitive organic anion transporters OAT1/3 ( SLC 22 A 6 and SLC 22 A 8) and MRP4 ( ABCC 4). Microdialysis studies further validated our in vitro data, indicating that probenecid may be used to boost the bioavailability of 7-Cl-KYNA. Indeed, we found that coadministration of 4-Cl-KYN with probenecid caused a dose-dependent increase by as much as an 885-fold increase in 7-Cl-KYNA concentration in the prefrontal cortex. In summary, our data show that 4-Cl-KYN crosses the BBB using LAT1, while its active metabolite, 7-Cl-KYNA, is rapidly transported out of the brain via OAT1/3 and MRP4. We also identify a hitherto unreported mechanism by which the brain extracellular concentration of 7-Cl-KYNA may be increased to produce significant boosting of the drug concentration at its site of action that could potentially lead to an increased therapeutic effect.

The relationship between optimal cerebral perfusion pressure (CPPopt) and patient characteristics has yet to be defined but could have significant implications for future guidelines recommending cerebral perfusion pressure (CPP) targets.Data from 36 traumatic brain injured patients admitted to neurological intensive care were analysed retrospectively. Linear mixed effects (LME) analysis was performed using an unadjusted-adjusted approach.Clinical characteristics with p < 0.10 were included in the adjusted model. A second adjusted model which included all variables of interest was created. Model fit was assessed using the root-mean-square error (RMSE).The adjusted model included time from initiation of intracranial pressure (ICP) monitoring (estimate = 0.00292, p < 0.001), age (estimate = -0.211, p = 0.0750) and the presence of diffuse axonal injury (DAI) (estimate = -35.5, p < 0.001). The RMSE of this model was 8.11 mmHg. The RMSE of the model containing all variables was 8.09 mmHg.Time, age and the presence of DAI may be important predictors of CPPopt. The models were too inaccurate at predicting CPPopt for employment in clinical practice but warrant further investigation. CPPopt is a dynamic measurement influenced by many factors, supporting the utility of investigating the feasibility of CPPopt-guided therapy.

Intracranial pressure monitoring and brain tissue oxygen monitoring are commonly used in head injury for goal-directed therapies, but there may be more indications for its use. Moyamoya disease involves progressive stenosis of the arterial circulation and formation of collateral vessels that are at risk of hemorrhage. The risk of ischemic events during revascularization surgery and postoperatively is high. Impaired cerebral autoregulation may be one of the factors that are implicated. We present our experience with monitoring of cerebral oxygenation and autoregulation in the pathological hemisphere during the perioperative period in four patients with moyamoya disease.

Telemetric intracranial pressure (ICP) monitors are useful tools in the management of complex hydrocephalus and idiopathic intracranial hypertension (IIH). Clinicians may use them as a "snapshot" screening tool to assess shunt function or ICP. We compared "snapshot" telemetric ICP recordings with extended, in-patient periods of monitoring to determine whether this practice is safe and useful for clinical decision making.

Challenges inherent in clinical guideline development include a long time lag between the key results and incorporation into best practice and the qualitative nature of adherence measurement, meaning it will have no directly measurable impact. To address these issues, a framework has been developed to automatically measure adherence by clinicians in neurological intensive care units to the Brain Trauma Foundation's intracranial pressure (ICP)-monitoring guidelines for severe traumatic brain injury (TBI).The framework processes physiological and treatment data taken from the bedside, standardises the data as a set of process models, then compares these models against similar process models constructed from published guidelines. A similarity metric (i.e. adherence measure) between the two models is calculated, composed of duration and scale of non-adherence.In a pilot clinical validation test, the framework was applied to physiological/treatment data from three TBI patients exhibiting ICP secondary insults at a local neuro-centre where clinical experts coded key clinical interventions/decisions about patient management.The framework identified non-adherence with respect to drug administration in one patient, with a spike in non-adherence due to an inappropriately high dosage; a second patient showed a high severity of guideline non-adherence; and a third patient showed non-adherence due to a low number of associated events and treatment annotations.

Clozapine is a second-generation antipsychotic with a superior efficacy for the management of treatment-resistant schizophrenia but underutilized because of potential side effects. A 59-year-old Caucasian male veteran was transferred from the long-term care unit to the acute psychiatry unit because of suicidality. He was noted as having a long-standing history of psychosis with significant referential and paranoid delusions. He had experienced two previous trials of clozapine; although he had significant response in the past, both trials ended in neutropenia and an absolute neutrophil count <500 cells per microliter, despite the second trial also including supplemental "as-needed" doses of pegfilgrastim to manage decline in neutrophil counts. This particular strategy of filgrastim use was determined to be a weakness of the second trial. A PubMed search identified recent literature that discussed preemptive dosing of filgrastim to prevent neutropenia. Thus, a protocol was established to administer 300 μg filgrastim subcutaneously, three times weekly, concurrently with clozapine initiation. This plan was discussed on local and national levels to achieve consensus before its initiation. Using a revised, patient-specific protocol led to successful initiation of clozapine and the ability to maintain the regimen for over 24 months without interruption or any further suicidal ideation., Competing Interests: The authors report no financial relationships with commercial interests., (Copyright © 2021 by the American Psychiatric Association.)

Intracranial pressure (ICP) monitoring is a key clinical tool in the assessment and treatment of patients in a neuro-intensive care unit (neuro-ICU). As such, a deeper understanding of how an individual patient's ICP can be influenced by therapeutic interventions could improve clinical decision-making. A pilot application of a time-varying dynamic linear model was conducted using the BrainIT dataset, a multi-centre European dataset containing temporaneous treatment and vital-sign recordings. The study included 106 patients with a minimum of 27 h of ICP monitoring. The model was trained on the first 24 h of each patient's ICU stay, and then the next 2 h of ICP was forecast. The algorithm enabled switching between three interventional states: analgesia, osmotic therapy and paralysis, with the inclusion of arterial blood pressure, age and gender as exogenous regressors. The overall median absolute error was 2.98 (2.41-5.24) mmHg calculated using all 106 2-h forecasts. This is a novel technique which shows some promise for forecasting ICP with an adequate accuracy of approximately 3 mmHg. Further optimisation is required for the algorithm to become a usable clinical tool.

Objective: To examine serum autoantibodies to malondialdehyde-acetaldehyde (MAA) prior to rheumatoid arthritis (RA) diagnosis., Methods: Concentrations of anti-MAA antibody isotypes, anti-cyclic citrullinated peptide 2 (anti-CCP-2), and IgM rheumatoid factor (IgM-RF) were evaluated before and after RA diagnosis in samples from cases (n = 214) and controls (n = 210). The timing of elevations in autoantibody concentrations relative to RA diagnosis was explored using separate mixed models for each antibody and/or isotype. Associations between prediagnosis autoantibody concentrations in RA patients were examined using mixed effects linear regression models., Results: Concentrations of IgG (log 2 difference 0.34) and IgA (log 2 difference 0.43) anti-MAA antibodies in RA patients diverged from controls at 3.0 years and 2.3 years prior to diagnosis, respectively (P < 0.05 for both). There was no evidence of case-control divergence for IgM anti-MAA antibody concentration. Anti-CCP-2 and IgM-RF concentrations diverged between RA patients and controls beginning at 17.6 years and 7.2 years prior to RA diagnosis, respectively. All 3 anti-MAA antibody isotypes (IgA, IgM, and IgG) were significantly associated with anti-CCP-2 antibody and RF concentrations prior to diagnosis (β = 0.22-0.27 for IgM-RF; β = 0.44-0.93 for anti-CCP-2) (P < 0.001)., Conclusion: IgG and IgA anti-MAA autoantibodies are elevated prior to RA diagnosis but appear later in the preclinical course than anti-CCP-2 or RF. These findings suggest that MAA formation and anti-MAA immune responses could play a role in the transition from subclinical autoimmunity to clinically apparent arthritis., (© 2020, American College of Rheumatology.)

We report the isolation of Equid herpesvirus 8 from a rescued donkey that suffered severe postcastration complications. Despite intensive treatment, the donkey deteriorated and was euthanized. Postmortem virologic analysis revealed the isolation of a herpesvirus that is closely related to herpesviruses reported from donkeys and horses in Australia, China, and Ireland, causing respiratory disease in donkeys and abortion in mares. To our knowledge, this is the first report of this equid herpesvirus in Israel. The potential significance of this herpesvirus to the equid population in Israel needs further investigation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: RA develops slowly over years. We tested for metabolic changes prior to RA onset using a large non-targeted metabolomics platform to identify novel pathways and advance understanding of RA development., Methods: Two hundred and fifty-four incident RA cases with plasma samples drawn pre-RA onset in the Nurses' Health Study (NHS) cohorts were matched 1:2 to 501 controls on age, race, menopause/post-menopausal hormone use and blood collection features. Relative abundances of 360 unique, known metabolites were measured. Conditional logistic regression analyses assessed associations between metabolites and incidence of RA, adjusted for age, smoking and BMI, accounting for multiple comparisons. Subgroup analyses investigated seropositive (sero+) RA and RA within 5 years of sample collection. Significant metabolites were then tested in a female military pre-RA case-control study (n = 290)., Results: In the NHS, metabolites associated with RA and sero+RA in multivariable models included 4-acetamidobutanoate (odds ratio (OR) = 0.80/S.d., 95% CI: 0.66, 0.95), N-acetylputrescine (OR = 0.82, 95% CI: 0.69, 0.96), C5 carnitine (OR = 0.84, 95% CI: 0.71, 0.99) and C5:1 carnitine (OR = 0.81, 95% CI: 0.68, 0.95). These were involved primarily in polyamine and leucine, isoleucine and valine metabolism. Several metabolites associated with sero+RA within 5 years of diagnosis were replicated in the independent military cohort: C5 carnitine (OR = 0.55, 95% CI: 0.33, 0.92), C5:1 carnitine (OR = 0.62, 95% CI: 0.39, 0.99) and C3 carnitine (OR = 0.57, 95% CI: 0.36, 0.91)., Conclusion: Several metabolites were inversely associated with incidence of RA among women. Three short-chain acylcarnitines replicated in a smaller dataset and may reflect inflammation in the 5-year period prior to sero+RA diagnosis., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

What criteria are most suitable to identify endocrine disrupting substances (EDSs) for regulatory purposes in the EU? The results of the European Commission's public consultation, as part of the process to establish identification criteria for EDSs, show that different regulatory options are supported. Some respondents prefer an option including hazard characterization considerations, whereas others prefer an option that avoids these considerations and introduces several hazard-identification based weight-of-evidence categories. In this study, the argumentation underlying the different preferences for identification criteria are analyzed and compared using pragma-dialectical argumentation theory (PDAT). All responses of non-anonymous, national governments that submitted a response in English (n = 17) were included. Responses of other stakeholder organizations were included if a Google News search returned an opinionated presence in the media on the subject (n = 9). Five topical themes and 21 underlying issues were identified. The themes are 1) mechanistic understanding of EDSs, 2) regulatory considerations related to the identification of EDSs, 3) consistency with existing regulatory frameworks, and 4) evaluations of specific issues related to a category approach and 5) related to including potency. We argue that two overarching (implicit) 'advocacy coalitions' can be discerned, that adopted contrasting positions towards the identified themes and issues. Among these 'coalitions', there appears to be consensus about the necessity of having 'science-based' criteria, though different perspectives exist as to what the most accurate mechanistic understanding of EDSs entails. To move the discussion forward, we argue that a societal dialogue would be beneficial, where EDS science and regulation are discussed as interrelated themes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: International guidelines on the treatment of differentiated thyroid cancers (DTC) promote the use of low iodine diets (LID) prior to radioactive iodine remnant ablation (RIA), as high iodine status may interfere with radioiodine uptake. Most UK treatment centres adhere to these guidelines and advise people to consume a LID. There is limited research as to how people cope with the LID or its impact on daily life and wellbeing, and no studies have been conducted in the UK. This study explored peoples' views and experiences in relation to consuming a LID during treatment for DTC with RIA., Methods: Twenty-eight semi-structured interviews were conducted with people from across three treatment centres where differing advice had been delivered regarding a LID. Interviews were recorded, transcribed verbatim and key themes were developed through inductive thematic analyses., Results: Individuals advised to consume a LID believed that adhering to the diet would help their treatment. Most restricted their diets beyond what was recommended and there was confusion surrounding what they could eat as part of the diet. Food selection and preparation were important which included substitution of foods and ingredient checking. Being on the diet was considered to have both a physical and psychological impact., Conclusions: The findings of this study provide a qualitative insight into the lived experiences of people with DTC in relation to consuming a LID. The results have relevance for professionals providing dietary guidance at oncology centres treating patients with RIA therapy in the UK., Competing Interests: Declaration of Competing Interest IHS is the lead and LM is a member of the UK Low Iodine Diet Working Group., (Copyright © 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Fractalkine (CX3CL1; FKN) is a chemokine expressed by neurons that mediates communication between neurons and microglia. By regulating microglial activity, CX3CL1 can mitigate the damaging effects of chronic microglial inflammation within the brain, a state that plays a major role in aging and neurodegeneration. CX3CL1 is present in two forms, a full-length membrane-bound form and a soluble cleaved form (sFKN), generated by a disintegrin and metalloproteinase (ADAM) 10 or 17. Levels of sFKN decrease with aging, which could lead to enhanced inflammation, deficits in synaptic remodeling, and subsequent declines in cognition. Recently, the idea that these two forms of CX3CL1 may display differential activities within the CNS has garnered increased attention, but remains unresolved., Methods: Here, we assessed the consequences of CX3CL1 knockout (CX3CL1 -/- ) on cognitive behavior as well as the functional rescue with the two different forms of CX3CL1 in mice. CX3CL1 -/- mice were treated with adeno-associated virus (AAV) expressing either green fluorescent protein (GFP), sFKN, or an obligate membrane-bound form of CX3CL1 (mFKN) and then subjected to behavioral testing to assess cognition and motor function. Following behavioral analysis, brains were collected and analyzed for markers of neurogenesis, or prepared for electrophysiology to measure long-term potentiation (LTP) in hippocampal slices., Results: CX3CL1 -/- mice showed significant deficits in cognitive tasks for long-term memory and spatial learning and memory in addition to demonstrating enhanced basal motor performance. These alterations correlated with deficits in both hippocampal neurogenesis and LTP. Treatment of CX3CL1 -/- mice with AAV-sFKN partially corrected changes in both cognitive and motor function and restored neurogenesis and LTP to levels similar to wild-type animals. Treatment with AAV-mFKN partially restored spatial learning and memory in CX3CL1 -/- mice, but did not rescue long-term memory, or neurogenesis., Conclusions: These results are the first to demonstrate that CX3CL1 knockout causes significant cognitive deficits that can be rescued by treatment with sFKN and only partially rescued with mFKN. This suggests that treatments that restore signaling of soluble forms of CX3CL1 may be a viable therapeutic option for aging and disease.

Background: Guidelines suggest that a low iodine diet (LID) is advised prior to radioiodine ablation (RIA) for thyroid cancer. We aim to describe current practice regarding LID advice in the UK, determine uptake of the 2016 UK LID Working Group diet sheet and discover whether there are differences in practice., Methods: We used an online survey distributed between November 2018 and April 2019 to centres in the UK that administer 131 I. We asked questions on whether a LID is advised, for how long, how advice is presented, whether and how compliance is measured and whether treatment is delayed if LID advice is not followed., Results: Fifty-six clinicians from 47 centres that carry out RIA for thyroid cancer responded. Forty-four centres (94%) advise a LID prior to RIA, the majority for 14 days (82%). Two-thirds of the centres use the UK LID Working Group diet sheet. Patients are told to resume normal eating when 131 I is administered at 17 centres (39%), with 18 (41%) advising waiting for 24-48 h after administration. Most centres (95%) use only a simple question or do not assess compliance. Only 2 (5%) indicate that RIA would be delayed if someone said they had not followed LID advice., Conclusions: UK practice regarding LID prior to RIA for thyroid cancer is consistent with current guidelines, but non-adherence does not usually delay RIA. The UK Low Iodine Diet Working Group diet sheet is widely recognised and used. Practice could be improved by centres working to harmonise advice on when to restart a normal diet., Competing Interests: L.M. and I.H.-S. are members of the UK Low Iodine Diet Working Group. The remaining authors report no conflict of interest., (Copyright © 2019 by S. Karger AG, Basel.)

Purpose: Venous thromboembolism (VTE) in injured children is rare, but sequelae can be morbid and life-threatening. Recent trauma society guidelines suggesting that all children over 15 years old should receive thromboprophylaxis may result in overtreatment. We sought to evaluate the efficacy of a previously published VTE prediction algorithm and compare it to current recommendations., Methods: Two institutional trauma registries were queried for all pediatric (age < 18 years) patients admitted from 2007 to 2018. Clinical data were applied to the algorithm and the area under the receiver operating characteristic (AUROC) curve was calculated to test algorithm efficacy., Results: A retrospective review identified 8271 patients with 30 episodes of VTE (0.36%). The VTE prediction algorithm classified 51 (0.6%) as high risk (> 5% risk), 322 (3.9%) as moderate risk (1-5% risk) and 7898 (95.5%) as low risk (< 1% risk). AUROC was 0.93 (95% CI 0.89-0.97). In our population, prophylaxis of the 'moderate-' and 'high-risk' cohorts would outperform the sensitivity (60% vs. 53%) and specificity (96% vs. 77%) of current guidelines while anticoagulating substantially fewer patients (373 vs. 1935, p < 0.001)., Conclusion: A VTE prediction algorithm using clinical variables can identify injured children at risk for venous thromboembolic disease with more discrimination than current guidelines. Prospective studies are needed to investigate the validity of this model., Level of Evidence: III-Clinical decision rule evaluated in a single population.

In this work, the bioconcentration capacity of heavy metals Cd, Cu, Pb and Zn in the moss Leskea angustata Tayl., exposed under laboratory conditions was evaluated, and subsequently the usefulness of moss for the heavy metals' biomonitoring associated with suspended particulate matter in air of the Toluca Valley Metropolitan Area was determined by means of the moss bag technique. To achieve the aims, bioassays were carried out in the laboratory with the moss, the exposure for a period of 6 months of the moss bags in the sites of the Automatic Atmospheric Monitoring Network of the Government of the State of Mexico and their subsequent analysis through of elemental and structural characterization techniques. The results of the bioassays on the moss L. angustata , demonstrate that this moss has adequate bioconcentration capabilities to be used as a biomonitor of heavy metals in polluted areas. The structural characterization of the moss L. angustata , shows that this moss has good adsorption characteristics (presence of functional groups, surface area of 19.87 m2 g−1, average pore diameter equal to 2.86 nm and a total pore volume of 0.014218 cm3 g−1). The significant correlations between Cd–Zn–Pb and between Pb and Zn with PM 2.5 , as well as a strong correlation between Pb and Zn with PM 10 , allow us to establish that these three metals have their main origin in the domestic combustion of wood and liquid petroleum gas (LP gas), as well as emissions from agricultural burning in the study area. Cu has a different origin than other metals and PM 10 and PM 2.5. The findings demonstrate a strong association between anthropogenic activities - such as domestic wood and LP gas combustion, agricultural burning emissions, vehicular emissions, tire wear, and industrial activities - and the detection, entrapment, and accumulation of several heavy metals by L. angustata moss. [Display omitted] • Native moss proved to have great qualities for atmospheric biomonitoring. • Significant correlations between metals in moss and particulate matter. • Strong association between anthropogenic activities and heavy metals in moss. • Forest vegetation appears to act as a barrier to retain airborne particulate matter. [ABSTRACT FROM AUTHOR]

Extraordinary advances in medicine and public health have contributed to increasing life expectancy worldwide. However, health span-"healthy aging"-has paradoxically lagged to parallel this increase. Consequently, aging-associated illnesses, such as Alzheimer's disease and aging frailty, are having a growing impact on patients, their families, and entire health-care systems. Typically, such disorders have been treated as isolated disease entities. However, the inextricable links between aging-associated disorders and the aging process itself have become increasingly recognized, leading to formation of the field of geroscience. The geroscience concept is that treating the aging process itself should lead to treatment and prevention of aging-related disorders. However, the aging process is complex, dictated by highly interrelated pleiotropic processes. As such, therapeutics with pleiotropic mechanisms of action (either alone, or as part of combinatorial strategies) will be required for preventing and treating both aging and related disorders. Mesenchymal stem cells (MSCs) have multiple mechanisms of action that make these highly promising geroscience therapeutic candidates. These cells have a high safety profile for clinical use, are amenable to allogeneic use since tissue-type matching is not required, and can have sustained activity after transplantation. Herein, we review preclinical and clinical data supporting the utility of allogeneic MSCs as a geroscience therapeutic candidate., Competing Interests: CONFLICTS OF INTEREST All authors are affiliated with Longeveron LLC, either as full-time employees or consultants. Dr. Hare reported having a patent for cardiac cell-based therapy. He holds equity in Vestion Inc. and maintains a professional relationship with Vestion Inc. as a consultant and member of the Board of Directors and Scientific Advisory Board. Dr. Joshua Hare is the Chief Scientific Officer, a compensated consultant and advisory board member for Longeveron and holds equity in Longeveron. He is also the co-inventor of intellectual property licensed to Longeveron.

Objectives: Financial toxicity is increasingly recognized as an adverse outcome of cancer treatment. Our objective was to measure financial toxicity among gynecologic oncology patients and its association with demographic and disease-related characteristics; self-reported overall health; and cost-coping strategies., Methods: Follow-up patients at a gynecologic oncology practice completed a survey including the COmprehensive Score for Financial Toxicity (COST) tool and a self-reported overall health assessment, the EQ-VAS. We abstracted disease and treatment characteristics from medical records. We dichotomized COST scores into low and high financial toxicity and assessed the correlation (r) between COST scores and self-reported health. We calculated risk ratios (RR) and 95% confidence intervals (CI) for the associations of demographic and disease-related characteristics with high financial toxicity, as well as the associations between high financial toxicity and cost-coping strategies., Results: Among 240 respondents, median COST score was 29. Greater financial toxicity was correlated with worse self-reported health (r = 0.47; p < 0.001). In the crude analysis, Black or Hispanic race/ethnicity, government-sponsored health insurance, lower income, unemployment, cervical cancer and treatment with chemotherapy were associated with high financial toxicity. In the multivariable analysis, only government-sponsored health insurance, lower income, and treatment with chemotherapy were significantly associated with high financial toxicity. High financial toxicity was significantly associated with all cost-coping strategies, including delaying or avoiding care (RR: 7.3; 95% CI: 2.8-19.1)., Conclusions: Among highly-insured gynecologic oncology patients, many respondents reported high levels of financial toxicity. High financial toxicity was significantly associated with worse self-reported overall health and cost-coping strategies, including delaying or avoiding care., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Thyroid cancer is the most common endocrine malignancy. Some advanced disease is, or becomes, resistant to radioactive iodine therapy (refractory disease); this holds poor prognosis of 10% 10-year overall survival. Whilst Sorafenib and Lenvatinib are now licenced for the treatment of progressive iodine refractory thyroid cancer, these treatments require continuing treatment and can be associated with significant toxicity. Evidence from a pilot study has demonstrated feasibility of Selumetinib to allow the reintroduction of I-131 therapy; this larger, multicentre study is required to demonstrate the broader clinical impact of this approach before progression to a confirmatory trial., Methods: SEL-I-METRY is a UK, single-arm, multi-centre, two-stage phase II trial. Participants with locally advanced or metastatic differentiated thyroid cancer with at least one measureable lesion and iodine refractory disease will be recruited from eight NHS Hospitals and treated with four-weeks of oral Selumetinib and assessed for sufficient I-123 uptake (defined as any uptake in a lesion with no previous uptake or 30% or greater increase in uptake). Those with sufficient uptake will be treated with I-131 and followed for clinical outcomes. Radiation absorbed doses will be predicted from I-123 SPECT/CT and verified from scans following the therapy. Sixty patients will be recruited to assess the primary objective of whether the treatment schedule leads to increased progression-free survival compared to historical control data., Discussion: The SEL-I-METRY trial will investigate the effect of Selumetinib followed by I-131 therapy on progression-free survival in radioiodine refractory patients with differentiated thyroid cancer showing increased radioiodine uptake following initial treatment with Selumetinib. In addition, information on toxicity and dosimetry will be collected. This study presents an unprecedented opportunity to investigate the role of lesional dosimetry in molecular radiotherapy, leading to greater personalisation of therapy. To date this has been a neglected area of research. The findings of this trial will be useful to healthcare professionals and patients alike to determine whether further study of this agent is warranted. It is hoped that the development of the infrastructure to deliver a multicentre trial involving molecular radiotherapy dosimetry will lead to further trials in this field., Trial Registration: SEL-I-METRY is registered under ISRCTN17468602 , 02/12/2015.

Background: As the clinical and financial environments of total joint arthroplasty (TJA) have evolved over the last several decades so has the role of the surgeon in providing this care to patients. Our objective was to examine current practices and influential factors among fellowship-trained arthroplasty surgeons., Methods: An electronic survey was sent to all surgeons who had completed one of the three high-volume adult reconstruction fellowships from the years 2007-2016. The survey consisted of 34 questions regarding current practice characteristics, case volumes for primary and revision total hip arthroplasty (THA) and total knee arthroplasty (TKA), use of advanced technologies, choice of surgical approach and implant design, factors influencing their choices, and their involvement in implant selection and contract negotiations., Results: Questionnaires were sent to 53 surgeons; 52 were completed. Sixty percent of respondents performed at least 100 TKAs and 84% performed at least 50 THAs annually. Ninety-four percent use a single company's implant for more than 90% of primary TKA and THA. Fellowship or residency experience was the most significant influence on TKA and THA implant selection for 62% and 45% of surgeons, respectively, while contracts of their current institution were the primary influence for 17% and 12%, respectively. Fifty-five percent of surgeons used some advanced technology of which 16% said this influenced their implant choice. Eighty-six percent perform the majority of cases at centers performing at least 200 TJAs per year, and 39% participate in implant contract negotiations., Conclusion: Despite changes in the economic environment of TJA, this study demonstrates that experience with a specific implant during training, particularly fellowship, is the most influential factor for implant selection among fellowship-trained arthroplasty surgeons., (Copyright © 2019. Published by Elsevier Inc.)

Importance: Hypertrophic cardiomyopathy causes limiting symptoms in patients, mediated partly through inefficient myocardial energy use. There is conflicting evidence for therapy with inhibitors of myocardial fatty acid metabolism in patients with nonobstructive hypertrophic cardiomyopathy., Objective: To determine the effect of oral therapy with trimetazidine, a direct inhibitor of fatty acid β-oxidation, on exercise capacity in patients with symptomatic nonobstructive hypertrophic cardiomyopathy., Design, Setting, and Participants: This randomized, placebo-controlled, double-blind clinical trial at The Heart Hospital, University College London Hospitals, London, United Kingdom was performed between May 31, 2012, and September 8, 2014. The trial included 51 drug-refractory symptomatic (New York Heart Association class ≥2) patients aged 24 to 74 years with a maximum left ventricular outflow tract gradient 50 mm Hg or lower and a peak oxygen consumption during exercise of 80% or less predicted value for age and sex. Statistical analysis was performed from March 1, 2016 through July 4, 2018., Interventions: Participants were randomly assigned to trimetazidine, 20 mg, 3 times daily (n = 27) or placebo (n = 24) for 3 months., Main Outcomes and Measures: The primary end point was peak oxygen consumption during upright bicycle ergometry. Secondary end points were 6-minute walk distance, quality of life (Minnesota Living with Heart Failure questionnaire), frequency of ventricular ectopic beats, diastolic function, serum N-terminal pro-brain natriuretic peptide level, and troponin T level., Results: Of 49 participants who received trimetazidine (n = 26) or placebo (n = 23) and completed the study, 34 (70%) were male; the mean (SD) age was 50 (13) years. Trimetazidine therapy did not improve exercise capacity, with patients in the trimetazidine group walking 38.4 m (95% CI, 5.13 to 71.70 m) less than patients in the placebo group at 3 months after adjustment for their baseline walking distance measurements. After adjustment for baseline values, peak oxygen consumption was 1.35 mL/kg per minute lower (95% CI, -2.58 to -0.11 mL/kg per minute; P = .03) in the intervention group after 3 months., Conclusions and Relevance: In symptomatic patients with nonobstructive hypertrophic cardiomyopathy, trimetazidine therapy does not improve exercise capacity. Pharmacologic therapy for this disease remains limited., Trial Registration: ClinicalTrials.gov identifier: NCT01696370.

The incidence of neurodegenerative disorders and cognitive impairment is increasing. Rising prevalence of age-related medical conditions is associated with a dramatic economic burden; therefore, developing strategies to manage these health concerns is of great public health interest. Nutritionally based interventions have shown promise in treatment of these age-associated conditions. Astaxanthin is a carotenoid with reputed neuroprotective properties in the context of disease and injury, while emerging evidence suggests that astaxanthin may also have additional biological activities relating to neurogenesis and synaptic plasticity. Here, we investigate the potential for astaxanthin to modulate cognitive function and neural plasticity in young and aged mice. We show that feeding astaxanthin to aged mice for 1 month improves performance on several hippocampal-dependent cognitive tasks and increases long-term potentiation. However, we did not observe an alteration in neurogenesis, nor did we observe a change in microglial-associated IBA1 immunostaining. This demonstrates the potential for astaxanthin to modulate neural plasticity and cognitive function in aging.

Background: Medullary thyroid cancer (MTC) is a rare form of cancer that affects patients' health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq ® ; Ipsen, Paris, France) and vandetanib (Caprelsa ® ; Sanofi Genzyme, Cambridge, MA, USA) are currently the treatment modality of choice for treating unresectable progressive and symptomatic MTC., Objectives: (1) To evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. (2) To estimate the incremental cost-effectiveness of cabozantinib and vandetanib versus each other and best supportive care. (3) To identify key areas for primary research. (4) To estimate the overall cost of these treatments in England., Data Sources: Peer-reviewed publications (searched from inception to November 2016), European Public Assessment Reports and manufacturers' submissions., Review Methods: A systematic review [including a network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. The economic analysis included a review of existing analyses and the development of a de novo model., Results: The systematic review identified two placebo-controlled trials. The Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial evaluated the efficacy and safety of cabozantinib in patients with unresectable locally advanced, metastatic and progressive MTC. The ZETA trial evaluated the efficacy and safety of vandetanib in patients with unresectable locally advanced or metastatic MTC. Both drugs significantly improved progression-free survival (PFS) more than the placebo ( p  < 0.001). The NMA suggested that, within the symptomatic and progressive MTC population, the effects on PFS were similar (vandetanib vs. cabozantinib: hazard ratio 1.14, 95% credible interval 0.41 to 3.09). Neither trial demonstrated a significant overall survival benefit for cabozantinib or vandetanib versus placebo, although data from ZETA were subject to potential confounding. Both cabozantinib and vandetanib demonstrated significantly better objective response rates and calcitonin (CTN) and carcinoembryonic antigen (CEA) response rates than placebo. Both cabozantinib and vandetanib produced frequent adverse events, often leading to dose interruption or reduction. The assessment group model indicates that, within the EU-label population (symptomatic and progressive MTC), the incremental cost-effectiveness ratios (ICERs) for cabozantinib and vandetanib are > £138,000 per quality-adjusted life-year (QALY) gained. Within the restricted EU-label population (symptomatic and progressive MTC with CEA/CTN doubling times of ≤ 24 months), the ICER for vandetanib is expected to be > £66,000 per QALY gained. The maximum annual budget impact within the symptomatic and progressive population is estimated to be ≈£2.35M for cabozantinib and ≈£5.53M for vandetanib. The costs of vandetanib in the restricted EU-label population are expected to be lower., Limitations: The intention-to-treat populations of the EXAM and ZETA trials are notably different. The analyses of ZETA subgroups may be subject to confounding as a result of differences in baseline characteristics and open-label vandetanib use. Attempts to statistically adjust for treatment switching were unsuccessful. No HRQoL evidence was identified for the MTC population., Conclusions: The identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs for cabozantinib and vandetanib are > £138,000 per QALY gained. Within the restricted EU-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained., Future Research Priorities: (1) Primary research assessing the long-term effectiveness of cabozantinib and vandetanib within relevant subgroups. (2) Reanalyses of the ZETA trial to investigate the impact of adjusting for open-label vandetanib use using appropriate statistical methods. (3) Studies assessing the impact of MTC on HRQoL., Study Registration: This study is registered as PROSPERO CRD42016050403., Funding: The National Institute for Health Research Health Technology Assessment programme., Competing Interests: Jonathan Wadsley has received personal fees from Sanofi Genzyme (Cambridge, MA, USA), Ipsen (Paris, France), Bayer AG (Leverkusen, Germany), Baxalta (Shire Pharmaceuticals, London, UK), Eisai Co. Ltd (Tokyo, Japan) and Eli Lilly and Company (Basingstoke, UK), grants and personal fees from AstraZeneca plc (Cambridge, UK), non-financial support from Swedish Orphan Biovitrum AB (Stockholm, Sweden), and personal fees and non-financial support from Novartis International AG (Basel, Switzerland) and Celgene Corporation (Summit, NJ, USA) outside the submitted work.

Background: Traumatic brain injury (TBI) poses a significant challenge to healthcare providers, necessitating meticulous management of hemodynamic parameters to optimize patient outcomes. This article delves into the critical task of defining and meeting continuous arterial blood pressure (ABP) and cerebral perfusion pressure (CPP) targets in the context of severe TBI in neurocritical care settings., Methods: We narratively reviewed existing literature, clinical guidelines, and emerging technologies to propose a comprehensive approach that integrates real-time monitoring, individualized cerebral perfusion target setting, and dynamic interventions., Results: Our findings emphasize the need for personalized hemodynamic management, considering the heterogeneity of patients with TBI and the evolving nature of their condition. We describe the latest advancements in monitoring technologies, such as autoregulation-guided ABP/CPP treatment, which enable a more nuanced understanding of cerebral perfusion dynamics. By incorporating these tools into a proactive monitoring strategy, clinicians can tailor interventions to optimize ABP/CPP and mitigate secondary brain injury., Discussion: Challenges in this field include the lack of standardized protocols for interpreting multimodal neuromonitoring data, potential variability in clinical decision-making, understanding the role of cardiac output, and the need for specialized expertise and customized software to have individualized ABP/CPP targets regularly available. The patient outcome benefit of monitoring-guided ABP/CPP target definitions still needs to be proven in patients with TBI., Conclusions: We recommend that the TBI community take proactive steps to translate the potential benefits of personalized ABP/CPP targets, which have been implemented in certain centers, into a standardized and clinically validated reality through randomized controlled trials., (© 2024. The Author(s).)

Background: Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are prevalent and frequently comorbid. Approximately 42-48% of patients with PTSD also meet diagnostic criteria for MDD. Maintenance electroconvulsive therapy (mECT) has been found to be efficacious for the prevention of recurrence of MDD. This study investigated the efficacy of mECT in the treatment of MDD with and without comorbid syndromal PTSD., Methods: This retrospective study includes 36 patients, 26 with MDD and 10 with comorbid MDD & PTSD receiving monthly mECT for a mean of 1.5 years. The mean age was 52 ± 14 years and 25% were female. The change in PTSD and MDD symptoms in response to mECT was assessed using Clinical Global Impression - Severity Scale (CGI-S). Heart rate variability (HRV), 12-month hospitalization rate, suicide rate and all-cause mortality in response to mECT were assessed and compared between groups using repeated generalized linear regression (GLM) analysis., Results: At mECT baseline, there were no statistically significant differences in CGI-S scores, HRV between patients with MDD alone and those with comorbid MDD and PTSD (P > 0.05). After 12-months of mECT, a significant increase in HRV (mean difference: 10.9 95%CI 4.8-20.3, p = 0.001) and decrease in CGI-S overall (mean difference: 3.5, 95% CI 3.3-3.6, p = 0.001)], PTSD (mean difference: 3.4, 95% CI 3.2-3.6, p = 0.001)], and MDD (mean difference: 3.8, 95% CI 3.5-3.9, p = 0.001)] symptoms in both groups were noted (p < 0.05). No psychiatric hospitalization or suicide occurred in any of the patients., Conclusions: Maintenance ECT is associated with improved HRV, reduction of both major depression and PTSD symptoms, and a favorable clinical outcome., (Copyright © 2018 Elsevier Ltd. All rights reserved.)