Burnout among public health workers in Canada: a cross-sectional study.

BACKGROUND: This study presents the prevalence of burnout among the Canadian public health workforce after three years of the COVID-19 pandemic and its association with work-related factors. METHODS: Data were collected using an online survey distributed through Canadian public health associations and professional networks between November 2022 and January 2023. Burnout was measured using a modified version of the Oldenburg Burnout Inventory (OLBI). Logistic regressions were used to model the relationship between burnout and work-related factors including years of work experience, redeployment to pandemic response, workplace safety and supports, and harassment. Burnout and the intention to leave or retire as a result of the COVID-19 pandemic was explored using multinomial logistic regressions. RESULTS: In 2,079 participants who completed the OLBI, the prevalence of burnout was 78.7%. Additionally, 49.1% of participants reported being harassed because of their work during the pandemic. Burnout was positively associated with years of work experience, redeployment to the pandemic response, being harassed during the pandemic, feeling unsafe in the workplace and not being offered workplace supports. Furthermore, burnout was associated with greater odds of intending to leave public health or retire earlier than anticipated. CONCLUSION: The high levels of burnout among our large sample of Canadian public health workers and its association with work-related factors suggest that public health organizations should consider interventions that mitigate burnout and promote recovery.

A rapid review of current engagement strategies with people who use drugs in monitoring and reporting on substance use-related harms.

BACKGROUND: The Canadian drug supply has significantly increased in toxicity over the past few years, resulting in the worsening of the overdose crisis. A key initiative implemented during this crisis has been data monitoring and reporting of substance use-related harms (SRH). This literature review aims to: (1) identify strategies used for the meaningful engagement of people who use drugs (PWUD) in local, provincial, and national SRH data system planning, reporting, and action and (2) describe data monitoring and reporting strategies and common indicators of SRH within those systems. METHODS: We searched three academic and five gray literature databases for relevant literature published between 2012 and 2022. Team members who identify as PWUD and a librarian at Public Health Ontario developed search strings collaboratively. Two reviewers screened all search results and applied the eligibility criteria. We used Microsoft Excel for data management. RESULTS: Twenty-two articles met our eligibility criteria (peer-reviewed n = 10 and gray literature reports n = 12); most used qualitative methods and focused on the Canadian context (n = 20). There were few examples of PWUD engaged as authors of reports on SRH monitoring. Among information systems involving PWUD, we found two main strategies: (1) community-based strategies (e.g., word of mouth, through drug sellers, and through satellite workers) and (2) public health-based data monitoring and communication strategies (e.g., communicating drug quality and alerts to PWUD). Substance use-related mortality, hospitalizations, and emergency department visits were the indicators most commonly used in systems of SRH reporting that engaged PWUD. CONCLUSION: This review demonstrates limited engagement of PWUD and silos of activity in existing SRH data monitoring and reporting strategies. Future work is needed to better engage PWUD in these processes in an equitable manner. Building SRH monitoring systems in partnership with PWUD may increase the potential impact of these systems to reduce harms in the community.

Is local review of positron emission tomography scans sufficient in diffuse large B-cell lymphoma clinical trials? A CALGB 50303 analysis.

BACKGROUND: Quantitative methods of Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) interpretation, including the percent change in FDG uptake from baseline (ΔSUV), are under investigation in lymphoma to overcome challenges associated with visual scoring systems (VSS) such as the Deauville 5-point scale (5-PS). METHODS: In CALGB 50303, patients with DLBCL received frontline R-CHOP or DA-EPOCH-R, and although there were no significant associations between interim PET responses assessed centrally after cycle 2 (iPET) using 5-PS with progression-free survival (PFS) or overall survival (OS), there were significant associations between central determinations of iPET ∆SUV with PFS/OS. In this patient cohort, we retrospectively compared local vs central iPET readings and evaluated associations between local imaging data and survival outcomes. RESULTS: Agreement between local and central review was moderate (kappa = 0.53) for VSS and high (kappa = 0.81) for ∆SUV categories (<66% vs. ≥66%). ∆SUV ≥66% at iPET was significantly associated with PFS (p = 0.03) and OS (p = 0.002), but VSS was not. Associations with PFS/OS when applying local review vs central review were comparable. CONCLUSIONS: These data suggest that local PET interpretation for response determination may be acceptable in clinical trials. Our findings also highlight limitations of VSS and call for incorporation of more objective measures of response assessment in clinical trials.

Ambulatory Heart Function and Transplant Patients' Perceptions of Drug-Drug Interactions: A Qualitative Study.

Background: Drug-drug interactions (DDIs) can cause adverse drug events, leading to hospitalizations and an increase in the risk of morbidity and mortality. Until now, patients' perceptions of DDIs have represented an understudied area of research. Objectives: To explore patients' perceptions of DDIs and identify factors important to patients' understanding of their medications. Methods: Participants were recruited from 2 ambulatory clinics (heart function and transplant) in Vancouver, British Columbia. Participants engaged in key informant interviews and were asked to provide their demographic information, rate their understanding of their own medications, and define a DDI. Afterward, participants were interviewed to gather their perceptions of DDIs and factors important to their understanding of their medications. Results: A total of 7 patients were recruited. Participants struggled to define a DDI and were unsure if they had ever experienced a DDI. There was a reliance on health care professionals to help manage DDIs. Participants did not identify barriers preventing them from accessing medication information from health care professionals; however, they independently sought medication information found on the internet. Conclusions: Patients in this study had an incomplete understanding of DDIs and had difficulties differentiating DDIs from side effects of medications. As a result of their limited understanding of DDIs, patients relied on health care professionals to inform and manage their DDIs. Although patients did not identify barriers to accessing medication information, their pervasive use of the internet suggests that there are unidentified barriers preventing patients from speaking directly to their health care professionals regarding their medication therapy.

Contexte: Les interactions médicamenteuses (IM) peuvent provoquer des événements indésirables, entraínant des hospitalisations et une augmentation du risque de morbidité et de mortalité. Jusqu'à présent, les perceptions des patients concernant les IM représentaient un domaine de recherche sous-étudié. Objectifs: Explorer les perceptions des patients à l'égard des IM et recenser les facteurs importants pour qu'ils comprennent leurs médicaments. Méthodes: Les participants ont été recrutés dans deux cliniques ambulatoires (de la fonction cardiaque et de transplantation) à Vancouver, en Colombie-Britannique. Ils ont participé à des entretiens à titre d'informateurs clés et ont été invités à fournir leurs informations démographiques, à évaluer leur niveau de compréhension de leurs médicaments et à définir ce qu'on entend par « IM ¼. Par la suite, les participants ont été interrogés pour savoir comment ils percevaient les IM et pour recenser des facteurs importants leur permettant de comprendre leurs médicaments. Résultats: Au total, 7 patients ont été recrutés. Les patients avaient du mal à définir une IM et ne savaient pas s'ils avaient déjà vécu une IM. Ils comptaient ainsi sur les professionnels de la santé pour les aider à les gérer. Les patients n'ont identifié aucun obstacle les empêchant d'accéder aux informations sur les médicaments fournis par les professionnels de la santé; cependant, ils ont, de manière indépendante, cherché des informations sur les médicaments sur Internet. Conclusions: Les patients de cette étude avaient une compréhension limitée des IM et avaient des difficultés à faire la différence entre les IM et les effets secondaires des médicaments. En raison de cette compréhension limitée, les patients comptaient sur les professionnels de la santé pour les informer et gérer leurs IM. Bien que les patients n'aient pas signalé d'obstacles les empêchant d'accéder aux informations sur les médicaments, leur utilisation systématique d'Internet suggère que des obstacles non identifiés les empêchaient de parler directement à leurs professionnels de la santé au sujet de leur traitement médicamenteux.

AlbuCORE: an albumin-based molecular scaffold for multivalent biologics design.

As biologics have become a mainstay in the development of novel therapies, protein engineering tools to expand on their structural advantages, namely specificity, affinity, and valency are of interest. Antibodies have dominated this field as the preferred scaffold for biologics development while there has been limited exploration into the use of albumin with its unique physiological characteristics as a platform for biologics design. There has been a great deal of interest to create bispecific and more complex multivalent molecules to build on the advantages offered by protein-based therapeutics relative to small molecules. Here, we explore the use of human serum albumin (HSA) as a scaffold for the design of multispecific biologics. In particular, we describe a structure-guided approach to the design of split HSA molecules we refer to as AlbuCORE, that effectively and spontaneously forms a native albumin-like molecule, but in a heterodimeric state upon co-expression. We show that the split AlbuCORE designs allow the creation of novel fusion entities with unique alternate geometries. We also show that, apart from these AlbuCORE fusion entities, there is an opportunity to explore their albumin-like small hydrophobic molecule carrying capacity as a drug conjugate in these designs.

Protection from wintertime rainfall reduces nutrient losses and greenhouse gas emissions during the decomposition of poultry and horse manure-based amendments.

Manure-based soil amendments (herein "amendments") are important fertility sources, but differences among amendment types and management can significantly affect their nutrient value and environmental impacts. A 6-month in situ decomposition experiment was conducted to determine how protection from wintertime rainfall affected nutrient losses and greenhouse gas (GHG) emissions in poultry (broiler chicken and turkey) and horse amendments. Changes in total nutrient concentration were measured every 3 months, changes in ammonium (NH4+) and nitrate (NO3-) concentrations every month, and GHG emissions of carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) every 7-14 days. Poultry amendments maintained higher nutrient concentrations (except for K), higher emissions of CO2 and N2O, and lower CH4 emissions than horse amendments. Exposing amendments to rainfall increased total N and NH4+ losses in poultry amendments, P losses in turkey and horse amendments, and K losses and cumulative N2O emissions for all amendments. However, it did not affect CO2 or CH4 emissions. Overall, rainfall exposure would decrease total N inputs by 37% (horse), 59% (broiler chicken), or 74% (turkey) for a given application rate (wet weight basis) after 6 months of decomposition, with similar losses for NH4+ (69-96%), P (41-73%), and K (91-97%). This study confirms the benefits of facilities protected from rainfall to reduce nutrient losses and GHG emissions during amendment decomposition. IMPLICATIONS: The impact of rainfall protection on nutrient losses and GHG emissions was monitored during the decomposition of broiler chicken, turkey, and horse manure-based soil amendments. Amendments exposed to rainfall had large ammonium and potassium losses, resulting in a 37-74% decrease in N inputs when compared with amendments protected from rainfall. Nitrous oxide emissions were also higher with rainfall exposure, although it had no effect on carbon dioxide and methane emissions. Overall, this work highlights the benefits of rainfall protection during amendment decomposition to reduce nutrient losses and GHG emissions.

Lack of Evidence for Vasoactive and Inflammatory Mediators in the Promotion of Macular Edema Associated with Epiretinal Membranes.

The development of symptoms in patients with epiretinal membranes (ERMs) often corresponds with the accumulation of interstitial fluid in the retina [i.e., the development of macular edema, (ME)]. To explore the potential value of pharmacologic therapeutic options to treat ME in patients with ERMs, we examine here the expression of vasoactive and inflammatory mediators in the vitreous of patients with idiopathic ERMs. We observed that vitreous concentrations of classic vasoactive factors (e.g., vascular endothelial growth factor) were similar in ERM patients with ME compared to controls. Using an array assessing the expression of 102 inflammatory cytokines we similarly did not observe a marked difference in cytokine expression in the vitreous of most ERM patients with ME compared to control patients. While the array data did implicate a group of inflammatory cytokines that were elevated in a subset of ERM patients who had severe ME (central subfield thickness ≥450 µm on spectral domain optical coherence tomography), expression of 3 of these inflammatory cytokines, all previously implicated in the promotion of ME in ischemic retinal disease, were not elevated by quantitative enzyme-linked immunosorbent assay. We conclude that therapies modulating vasoactive mediators or inflammatory cytokines may not affect ME in ERM patients.

Impairment of decision making and disruption of synchrony between basolateral amygdala and anterior cingulate cortex in the maternally separated rat.

There is considerable evidence to suggest early life experiences, such as maternal separation (MS), play a role in the prevalence of emotional dysregulation and cognitive impairment. At the same time, optimal decision making requires functional integrity between the amygdala and anterior cingulate cortex (ACC), and any dysfunction of this system is believed to induce decision-making deficits. However, the impact of MS on decision-making behavior and the underlying neurophysiological mechanisms have not been thoroughly studied. As such, we consider the impact of MS on the emotional and cognitive functions of rats by employing the open-field test, elevated plus-maze test, and rat gambling task (RGT). Using multi-channel recordings from freely behaving rats, we assessed the effects of MS on the large scale synchrony between the basolateral amygdala (BLA) and the ACC; while also characterizing the relationship between neural spiking activity and the ongoing oscillations in theta frequency band across the BLA and ACC. The results indicated that the MS rats demonstrated anxiety-like behavior. While the RGT showed a decrease in the percentage of good decision-makers, and an increase in the percentage of poor decision-makers. Electrophysiological data revealed an increase in the total power in the theta band of the LFP in the BLA and a decrease in theta power in the ACC in MS rats. MS was also found to disrupt the spike-field coherence of the ACC single unit spiking activity to the ongoing theta oscillations in the BLA and interrupt the synchrony in the BLA-ACC pathway. We provide specific evidence that MS leads to decision-making deficits that are accompanied by alteration of the theta band LFP in the BLA-ACC circuitries and disruption of the neural network integrity. These observations may help revise fundamental notions regarding neurophysiological biomarkers to treat cognitive impairment induced by early life stress.

Impairment of decision making associated with disruption of phase-locking in the anterior cingulate cortex in viscerally hypersensitive rats.

Visceral hypersensitivity (VH) is a key factor of irritable bowel syndrome (IBS). Previous studies have identified an enhanced response of anterior cingulate cortex (ACC) to colorectal distension in VH rats, which can be observed up to 7weeks following colonic anaphylaxis, independent of colonic inflammation. The induction of VH produces a change in the ability to induce subsequent synaptic plasticity at the ACC circuitry. In clinical practice, a positive link between IBS and cognitive impairments has been noted for years, but no animal model has been reported. Decision-making is a valuable model for monitoring higher-order cognitive functions in animals, which depends on the integrated function of several sub-regions of the ACC and amygdala. Using rat gambling task (RGT) in the present study, we observed an impairment of decision-making behavior in VH rats. Electrophysiological study showed a reduction of long-term potentiation in the basolateral amygdala (BLA)-ACC synapses in VH rats. Multiple-electrode array recordings of local field potential (LFP) in both BLA and ACC were also performed in freely behaving rats. Spike-field coherence (SFC) analysis revealed chronic visceral pain led to disruption of ACC spike timing and BLA local theta oscillation. Finally, cross-correlation analysis revealed that VH was associated with suppressed synchronization of theta oscillation between the BLA and ACC, indicating reduced neuronal communications between these two regions under the VH state. The present results demonstrate that functional disturbances in BLA-ACC neural circuitry may be relevant causes for the deficits in decision-making in chronic pain state.

Pro-permeability Factors in Diabetic Macular Edema; the Diabetic Macular Edema Treated With Ozurdex Trial.

PURPOSE: The Diabetic Macular Edema Treated with Ozurdex (DMEO) Trial measured aqueous pro-permeability factors (PPFs) in diabetic macular edema (DME) patients before and after injection of dexamethasone implant or vascular endothelial growth factor (VEGF)-neutralizing protein and correlated changes in levels with changes in excess foveal thickness (EFT) to identify potential PPFs contributing to DME. DESIGN: Prospective, randomized crossover clinical trial. METHODS: Twenty DME patients randomized to dexamethasone implant or VEGF-neutralizing protein had aqueous taps and spectral-domain optical coherence tomography (SDOCT) at baseline and every 4 weeks for 28 weeks. Aqueous levels of 55 vasoactive proteins were measured with protein array. Crossover at week 16 provided changes in protein levels after each intervention in all 20 patients. RESULTS: After dexamethasone implant there was significant correlation between changes in levels of 13 vasoactive proteins with changes in EFT, including 3 known PPFs: angiopoietin-2 (r = 0.40, P = .001), hepatocyte growth factor (HGF; r = 0.31, P = .02), and endocrine gland-VEGF (EG-VEGF, r = 0.43, P < .001). Reduction of prolactin, insulin-like growth factor binding protein-3, and matrix metalloproteinase-9 correlated with edema reduction after injection of a VEGF-neutralizing protein as well as dexamethasone implant, suggesting their modulation is likely secondary to changes in edema rather than causative. CONCLUSIONS: Correlation of edema reduction with reduction in the PPFs angiopoietin-2, HGF, and EG-VEGF provides potential insight into the multifactorial molecular mechanism by which dexamethasone implants reduce edema and suggest that additional study is needed to investigate the contributions of these 3 factors to chronic DME.

The Herpes Simplex Virus Virion Host Shutoff Protein Enhances Translation of Viral True Late mRNAs Independently of Suppressing Protein Kinase R and Stress Granule Formation.

UNLABELLED: The herpes simplex virus (HSV) virion host shutoff (vhs) RNase destabilizes cellular and viral mRNAs, suppresses host protein synthesis, dampens antiviral responses, and stimulates translation of viral mRNAs. vhs mutants display a host range phenotype: translation of viral true late mRNAs is severely impaired and stress granules accumulate in HeLa cells, while translation proceeds normally in Vero cells. We found that vhs-deficient virus activates the double-stranded RNA-activated protein kinase R (PKR) much more strongly than the wild-type virus does in HeLa cells, while PKR is not activated in Vero cells, raising the possibility that PKR might play roles in stress granule induction and/or inhibiting translation in restrictive cells. We tested this possibility by evaluating the effects of inactivating PKR. Eliminating PKR in HeLa cells abolished stress granule formation but had only minor effects on viral true late protein levels. These results document an essential role for PKR in stress granule formation by a nuclear DNA virus, indicate that induction of stress granules is the consequence rather than the cause of the translational defect, and are consistent with our previous suggestion that vhs promotes translation of viral true late mRNAs by preventing mRNA overload rather than by suppressing eIF2α phosphorylation. IMPORTANCE: The herpes simplex virus vhs RNase plays multiple roles during infection, including suppressing PKR activation, inhibiting the formation of stress granules, and promoting translation of viral late mRNAs. A key question is the extent to which these activities are mechanistically connected. Our results demonstrate that PKR is essential for stress granule formation in the absence of vhs, but at best, it plays a secondary role in suppressing translation of viral mRNAs. Thus, the ability of vhs to promote translation of viral mRNAs can be largely uncoupled from PKR suppression, demonstrating that this viral RNase modulates at least two distinct aspects of RNA metabolism.

Changes in Retinal Nonperfusion Associated with Suppression of Vascular Endothelial Growth Factor in Retinal Vein Occlusion.

PURPOSE: To assess changes in retinal nonperfusion (RNP) in patients with retinal vein occlusion (RVO) treated with ranibizumab. DESIGN: Secondary outcome measure in randomized double-masked controlled clinical trial. PARTICIPANTS: Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO). METHODS: Subjects were randomized to 0.5 or 2.0 mg ranibizumab every month for 6 months and then were re-randomized to pro re nata (PRN) groups receiving either ranibizumab plus scatter laser photocoagulation or ranibizumab alone for an additional 30 months. MAIN OUTCOME MEASURES: Comparison of percentage of patients with increased or decreased area of RNP in patients with RVO treated with 0.5 versus 2.0 mg ranibizumab, during monthly injections versus ranibizumab PRN, and in patients treated with ranibizumab PRN versus ranibizumab PRN plus laser. RESULTS: In RVO patients given monthly injections of 0.5 or 2.0 mg ranibizumab for 6 months, there was no significant difference in the percentage who showed reduction or increase in the area of RNP. However, regardless of dose, during the 6-month period of monthly injections, a higher percentage of patients showed a reduction in area of RNP and a lower percentage showed an increase in area of RNP compared with subsequent periods of ranibizumab PRN treatment. After the 6-month period of monthly injections, BRVO patients, but not CRVO patients, randomized to ranibizumab PRN plus laser showed significantly less progression of RNP compared with patients treated with ranibizumab PRN. CONCLUSIONS: Regardless of dose (0.5 or 2.0 mg), monthly ranibizumab injections promote improvement and reduce progression of RNP compared with PRN injections. The addition of scatter photocoagulation to ranibizumab PRN may reduce progression of RNP in patients with BRVO, but a statistically significant reduction was not seen in patients with CRVO.

PKR deficiency alters E. coli-induced sickness behaviors but does not exacerbate neuroimmune responses or bacterial load.

BACKGROUND: Systemic inflammation induces neuroimmune activation, ultimately leading to sickness (e.g., fever, anorexia, motor impairments, exploratory deficits, and social withdrawal). In this study, we evaluated the role of protein kinase R (PKR), a serine-threonine kinase that can control systemic inflammation, on neuroimmune responses and sickness. METHODS: Wild-type (WT) PKR+/+ mice and PKR-/- mice were subcutaneously injected with live Escherichia coli (E. coli) or vehicle. Food consumption, rotarod test performance, burrowing, open field activity, object investigation, and social interaction were monitored. Plasma TNF-α and corticosterone were measured by ELISA. The percentage of neutrophils in blood was deduced from blood smears. Inflammatory gene expression (IL-1ß, TNF-α, IL-6, cyclooxygenase (COX)-2, iNOS) in the liver and the brain (hypothalamus and hippocampus) were quantified by real-time PCR. Blood and lavage fluid (injection site) were collected for microbiological plate count and for real-time PCR of bacterial 16S ribosomal DNA (rDNA). Corticotrophin-releasing hormone (CRH) expression in the hypothalamus was also determined by real-time PCR. RESULTS: Deficiency of PKR diminished peripheral inflammatory responses following E. coli challenge. However, while the core components of sickness (anorexia and motor impairments) were similar between both strains of mice, the behavioral components of sickness (reduced burrowing, exploratory activity deficits, and social withdrawal) were only observable in PKR-/- mice but not in WT mice. Such alteration of behavioral components was unlikely to be caused by exaggerated neuroimmune activation, by an impaired host defense to the infection, or due to a dysregulated corticosterone response, because both strains of mice displayed similar neuroimmune responses, bacterial titers, and plasma corticosterone profiles throughout the course of infection. Nevertheless, the induction of hypothalamic corticotrophin-releasing hormone (CRH) by E. coli was delayed in PKR-/- mice relative to WT mice, suggesting that PKR deficiency may postpone the CRH response during systemic inflammation. CONCLUSIONS: Taken together, our findings show that (1) loss of PKR could alter E. coli-induced sickness behaviors and (2) this was unlikely to be due to exacerbated neuroimmune activation, (3) elevated bacterial load, or (4) dysregulation in the corticosterone response. Further studies can address the role of PKR in the CRH response together with its consequence on sickness.

Sickness: From the focus on cytokines, prostaglandins, and complement factors to the perspectives of neurons.

Systemic inflammation leads to a variety of physiological (e.g. fever) and behavioral (e.g. anorexia, immobility, social withdrawal, depressed mood, disturbed sleep) responses that are collectively known as sickness. While these phenomena have been studied for the past few decades, the neurobiological mechanisms by which sickness occurs remain unclear. In this review, we first revisit how the body senses and responds to infections and injuries by eliciting systemic inflammation. Next, we focus on how peripheral inflammatory molecules such as cytokines, prostaglandins, and activated complement factors communicate with the brain to trigger neuroinflammation and sickness. Since depression also involves inflammation, we further elaborate on the interrelationship between sickness and depression. Finally, we discuss how immune activation can modulate neurons in the brain, and suggest future perspectives to help unravel how changes in neuronal functions relate to sickness responses.

Putative corneal neuralgia responding to vitamin d supplementation.

A patient with putative corneal neuralgia was incidentally discovered to have hypovitaminosis D. Supplementation of vitamin D appears to have led to a resolution of the patient's pain, whereas other efforts to treat the patient were unsuccessful.

Improving biophysical properties of a bispecific antibody scaffold to aid developability: quality by molecular design.

While the concept of Quality-by-Design is addressed at the upstream and downstream process development stages, we questioned whether there are advantages to addressing the issues of biologics quality early in the design of the molecule based on fundamental biophysical characterization, and thereby reduce complexities in the product development stages. Although limited number of bispecific therapeutics are in clinic, these developments have been plagued with difficulty in producing materials of sufficient quality and quantity for both preclinical and clinical studies. The engineered heterodimeric Fc is an industry-wide favorite scaffold for the design of bispecific protein therapeutics because of its structural, and potentially pharmacokinetic, similarity to the natural antibody. Development of molecules based on this concept, however, is challenged by the presence of potential homodimer contamination and stability loss relative to the natural Fc. We engineered a heterodimeric Fc with high heterodimeric specificity that also retains natural Fc-like biophysical properties, and demonstrate here that use of engineered Fc domains that mirror the natural system translates into an efficient and robust upstream stable cell line selection process as a first step toward a more developable therapeutic.

Cytokines: how important are they in mediating sickness?

Sickness refers to a set of coordinated physiological and behavioral changes in response to systemic inflammation. It is characterized by fever, malaise, social withdrawal, fatigue, and anorexia. While these responses collectively represent a protective mechanism against infection and injury, increasing lines of evidence indicate that over-exaggerated or persistent sickness can damage the brain, and could possibly raise the risk to developing delirium. Therefore, a clear understanding in sickness will be beneficial. It has long been believed that sickness results from increased systemic cytokines occurring during systemic inflammation. However, in recent years more and more conflicting data have suggested that development of sickness following peripheral immune challenge could be independent of cytokines. Hence, it is confusing as to whether cytokines really do act as primary mediators of sickness, or if they are secondary to alternative inducing factor(s). In this review, we will (1) introduce the relationships between systemic inflammation, cytokines, sickness, and delirium, and (2) attempt to interpret the recent controversies.