Sex Differences in Spontaneous Behavior and Cognition in Mice Using an Automated Behavior Monitoring System.

Isolation of sex differences as a key characteristic underlying neurobehavioral differentiation is an essential component of studies in neuroscience. The current study sought to address this concern by observing behavioral differences using an automated home cage system for neurobehavioral assessment, a method rapidly increasing in use due to advances in technology and advantages such as reduced handling stress and cross-lab variability. Sex differences in C57BL/6 mice arose for motor activity and circadian-linked behavior, with females being more active compared to males, and males having a stronger anticipatory increase in activity leading up to the onset of the light phase compared to females. These activity differences were observed not only across the lifespan, but also in different genetic background mouse strains across different testing sites showing the generalizability and robustness of these observed effects. Activity differences were also observed in performance on a spatial learning and reversal task with females making more responses and receiving a corresponding elevation in reward pellets. Notably, there were no sex differences in learning nor achieved accuracy, suggesting these observed effects were predominantly in activity. The outcomes of this study align with previous reports showcasing differences in activity between males and females. The comparison across strains and testing sites showed robust and reproducible differences in behavior between female and male mice that are relevant to consider when designing behavioral studies. Furthermore, the observed sex differences in performance on the learning and reversal procedure raise concern for interpretation of behavior differences between sexes due to the attribution of these differences to motor activity rather than cognition.

Resting state MRI reveals spontaneous physiological fluctuations in the kidney and tracks diabetic nephropathy in rats.

The kidneys maintain fluid-electrolyte balance and excrete waste in the presence of constant fluctuations in plasma volume and systemic blood pressure. The kidneys perform these functions to control capillary perfusion and glomerular filtration by modulating the mechanisms of autoregulation. An effect of these modulations are spontaneous, natural fluctuations in nephron perfusion. Numerous other mechanisms can lead to fluctuations in perfusion and flow. The ability to monitor these spontaneous physiological fluctuations in vivo could facilitate the early detection of kidney disease. The goal of this work was to investigate the use of resting- state magnetic resonance imaging (rsMRI) to detect spontaneous physiological fluctuations in the kidney. We performed rsMRI of rat kidneys in vivo over 10 minutes, applying motion correction to resolve time series in each voxel. We observed spatially variable, spontaneous fluctuations in rsMRI signal between 0-0.3 Hz, in frequency bands also associated with autoregulatory mechanisms. We further applied rsMRI to investigate changes in these fluctuations in a rat model of diabetic nephropathy. Spectral analysis was performed on time series of rsMRI signal in kidney cortex and medulla. Power from spectra in specific frequency bands from kidney cortex correlated with severity of glomerular pathology caused by diabetic nephropathy. Finally, we investigated the feasibility of using rsMRI of the human kidney in two participants, observing the presence of similar, spatially variable fluctuations. This approach may enable a range of preclinical and clinical investigations of kidney function, and facilitate the development of new therapies to improve outcomes in patients with kidney disease.

Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles.

The axon-initial-segment (AIS) of mature neurons contains microtubule (MT) fascicles (linear bundles) implicated as retrograde diffusion barriers in the retention of MT-associated protein (MAP) tau inside axons. Tau dysfunction and leakage outside of the axon is associated with neurodegeneration. We report on the structure of steady-state MT bundles in varying concentrations of Mg2+ or Ca2+ divalent cations in mixtures containing αß-tubulin, full-length tau, and GTP at 37 °C in a physiological buffer. A concentration-time kinetic phase diagram generated by synchrotron SAXS reveals a wide-spacing MT bundle phase (Bws), a transient intermediate MT bundle phase (Bint), and a tubulin ring phase. SAXS with TEM of plastic-embedded samples provides evidence of a viscoelastic intervening network (IN) of complexes of tubulin oligomers and tau stabilizing MT bundles. In this model, αß-tubulin oligomers in the IN are crosslinked by tau's MT binding repeats, which also link αß-tubulin oligomers to αß-tubulin within the MT lattice. The model challenges whether the cross-bridging of MTs is attributed entirely to MAPs. Tubulin-tau complexes in the IN or bound to isolated MTs are potential sites for enzymatic modification of tau, promoting nucleation and growth of tau fibrils in tauopathies.

Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility.

BACKGROUND: Ventricular arrhythmias (VAs) demonstrate a prominent day-night rhythm, commonly presenting in the morning. Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the underlying mechanisms are not understood. We investigated the recruitment of transcription factors that underpins transcriptional rhythms in ion channels and assessed whether this mechanism was pertinent to the heart's intrinsic diurnal susceptibility to VA. METHODS AND RESULTS: Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte nuclei at the beginning of the animals' inactive (ZT0) and active (ZT12) periods revealed differentially accessible chromatin sites annotating to rhythmically transcribed ion channels and distinct transcription factor binding motifs in these regions. Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) in open chromatin profiles at ZT12 was observed, in line with the well-recognized ZT12 peak in circulating corticosteroids. Molecular, electrophysiological, and in silico biophysically-detailed modeling approaches demonstrated GR-mediated transcriptional control of ion channels (including Scn5a underlying the cardiac Na+ current, Kcnh2 underlying the rapid delayed rectifier K+ current, and Gja1 responsible for electrical coupling) and their contribution to the day-night rhythm in the vulnerability to VA. Strikingly, both pharmacological block of GR and cardiomyocyte-specific genetic knockout of GR blunted or abolished ion channel expression rhythms and abolished the ZT12 susceptibility to pacing-induced VA in isolated hearts. CONCLUSIONS: Our study registers a day-night rhythm in chromatin accessibility that accompanies diurnal cycles in ventricular myocytes. Our approaches directly implicate the cardiac GR in the myocyte excitability rhythm and mechanistically link the ZT12 surge in glucocorticoids to intrinsic VA propensity at this time.

FiPhA: an open-source platform for fiber photometry analysis.

Significance: Fiber photometry (FP) is a widely used technique in modern behavioral neuroscience, employing genetically encoded fluorescent sensors to monitor neural activity and neurotransmitter release in awake-behaving animals. However, analyzing photometry data can be both laborious and time-consuming. Aim: We propose the fiber photometry analysis (FiPhA) app, which is a general-purpose FP analysis application. The goal is to develop a pipeline suitable for a wide range of photometry approaches, including spectrally resolved, camera-based, and lock-in demodulation. Approach: FiPhA was developed using the R Shiny framework and offers interactive visualization, quality control, and batch processing functionalities in a user-friendly interface. Results: This application simplifies and streamlines the analysis process, thereby reducing labor and time requirements. It offers interactive visualizations, event-triggered average processing, powerful tools for filtering behavioral events, and quality control features. Conclusions: FiPhA is a valuable tool for behavioral neuroscientists working with discrete, event-based FP data. It addresses the challenges associated with analyzing and investigating such data, offering a robust and user-friendly solution without the complexity of having to hand-design custom analysis pipelines. This application thus helps standardize an approach to FP analysis.

Partial or Complete Loss of Norepinephrine Differentially Alters Contextual Fear and Catecholamine Release Dynamics in Hippocampal CA1.

Background: Contextual fear learning is heavily dependent on the hippocampus. Despite evidence that catecholamines contribute to contextual encoding and memory retrieval, the precise temporal dynamics of their release in the hippocampus during behavior is unknown. In addition, new animal models are required to probe the effects of altered catecholamine synthesis on release dynamics and contextual learning. Methods: We generated 2 new mouse models of altered locus coeruleus-norepinephrine (NE) synthesis and utilized them together with GRABNE and GRABDA sensors and in vivo fiber photometry to investigate NE and dopamine (DA) release dynamics in the dorsal hippocampal CA1 during contextual fear conditioning. Results: Aversive foot shock increased both NE and DA release in the dorsal CA1, while freezing behavior associated with recall of fear memory was accompanied by decreased release. Moreover, we found that freezing at the recent time point was sensitive to both partial and complete loss of locus coeruleus-NE synthesis throughout prenatal and postnatal development, similar to previous observations of mice with global loss of NE synthesis beginning postnatally. In contrast, freezing at the remote time point was compromised only by complete loss of locus coeruleus-NE synthesis beginning prenatally. Conclusions: Overall, these findings provide novel insights into the role of NE in contextual fear and the precise temporal dynamics of both NE and DA during freezing behavior and highlight complex relationships between genotype, sex, and NE signaling.

Preferences for risks and benefits of treatment outcomes for chronic low back pain: Choice-based conjoint measure development and discrete choice experiment.

INTRODUCTION: Understanding individual patient preferences for chronic low back pain (cLBP) outcomes is essential for targeting available therapeutic options; yet tools to elicit patient outcome preferences are limited. OBJECTIVE: To develop and test a choice-based conjoint (CBC) measure, commonly used in behavioral economics research, to elicit what outcomes patients with cLBP want to achieve and avoid. DESIGN: We developed a survey-based CBC measure to allow patients to make risk/benefit trade-off choices between possible treatment outcomes. After extensive literature, clinician, and patient input, our measure included seven attributes: fatigue, anxiety/depression, difficulty thinking/making decisions, pain intensity, physical abilities, change in pain, and ability to enjoy life despite pain. Random-parameters logit models were used to estimate strength of preferences, and latent class analysis was used to identify patient characteristics associated with distinct preference. SETTING: Online study using the Sawtooth web-based platform. PARTICIPANTS: Two hundred eleven individuals with cLBP recruited from online advertising as well as at clinical sites across multiple academic and private institutions. INTERVENTIONS: Not applicable. RESULTS: The most valued outcome was the highest level of physical activity (ß = 1.6-1.98; p < .001), followed by avoiding cognitive difficulties (ß = -1.48; p < .001). Avoidance of severe pain was comparable to avoiding constant fatigue and near-constant depression/anxiety (ß = -0.99, -1.02); p < .001). There was an association between preferences and current pain/disability status; patients with higher pain had a stronger preference to avoid severe pain, whereas those with higher disability have stronger preferences for achieving physical activity. The latent class analysis identified two distinct groups: (1) more risk-seeking and willing to accept worse outcomes (56%); and (2) more risk-averse with a stronger preference for achieving maximum benefits (44%). CONCLUSIONS: Our study illuminated cLBP patient preferences for treatment outcomes and heterogeneity in these preferences. Patients stressed the importance of reaching high physical activity and avoiding cognitive declines, even over a desire to avoid pain. More work is needed to understand patient preferences to aid informed, shared decisions.

Entorhinal cortical delta oscillations drive memory consolidation.

Long-term memories are formed by creating stable memory representations via memory consolidation, which mainly occurs during sleep following the encoding of labile memories in the hippocampus during waking. The entorhinal cortex (EC) has intricate connections with the hippocampus, but its role in memory consolidation is largely unknown. Using cell-type- and input-specific in vivo neural activity recordings, here we show that the temporoammonic pathway neurons in the EC, which directly innervate the output area of the hippocampus, exhibit potent oscillatory activities during anesthesia and sleep. Using in vivo individual and populational neuronal activity recordings, we demonstrate that a subpopulation of the temporoammonic pathway neurons, which we termed sleep cells, generate delta oscillations via hyperpolarization-activated cyclic-nucleotide-gated channels during sleep. The blockade of these oscillations significantly impaired the consolidation of hippocampus-dependent memory. Together, our findings uncover a key driver of delta oscillations and memory consolidation that are found in the EC.

Patient Preference Trade-offs for Next-Generation Kidney Replacement Therapies.

BACKGROUND: Next-generation implantable and wearable KRTs may revolutionize the lives of patients undergoing dialysis by providing more frequent and/or prolonged therapy along with greater mobility compared with in-center hemodialysis. Medical device innovators would benefit from patient input to inform product design and development. Our objective was to determine key risk/benefit considerations for patients with kidney failure and test how these trade-offs could drive patient treatment choices. METHODS: We developed a choice-based conjoint discrete choice instrument and surveyed 498 patients with kidney failure. The choice-based conjoint instrument consisted of nine attributes of risk and benefit pertinent across KRT modalities. Attributes were derived from literature reviews, patient/clinician interviews, and pilot testing. The risk attributes were serious infection, death within 5 years, permanent device failure, surgical requirements, and follow-up requirements. The benefit attributes were fewer diet restrictions, improved mobility, pill burden, and fatigue. We created a random, full-profile, balanced overlap design with 14 choice pairs plus five fixed tasks to test validity. We used a mixed-effects regression model with attribute levels as independent predictor variables and choice decisions as dependent variables. RESULTS: All variables were significantly important to patient choice preferences, except follow-up requirements. For each 1% higher risk of death within 5 years, preference utility was lower by 2.22 ( ß =-2.22; 95% confidence interval [CI], -2.52 to -1.91), while for each 1% higher risk of serious infection, utility was lower by 1.38 ( ß =-1.46; 95% CI, -1.77 to -1.00) according to comparisons of the ß coefficients. Patients were willing to trade a 1% infection risk and 0.5% risk of death to gain complete mobility and freedom from in-center hemodialysis ( ß =1.46; 95% CI, 1.27 to 1.64). CONCLUSIONS: Despite an aversion to even a 1% higher risk of death within 5 years, serious infection, and permanent device rejection, patients with kidney failure suggested that they would trade these risks for the benefit of complete mobility.

FiPhA: An Open-Source Platform for Fiber Photometry Analysis.

Significance: Fiber photometry is a widely used technique in modern behavioral neuroscience, employing genetically encoded fluorescent sensors to monitor neural activity and neurotransmitter release in awake-behaving animals, However, analyzing photometry data can be both laborious and time-consuming. Aim: We propose the FiPhA (Fiber Photometry Analysis) app, which is a general-purpose fiber photometry analysis application. The goal is to develop a pipeline suitable for a wide range of photometry approaches, including spectrally resolved, camera-based, and lock-in demodulation. Approach: FiPhA was developed using the R Shiny framework and offers interactive visualization, quality control, and batch processing functionalities in a user-friendly interface. Results: This application simplifies and streamlines the analysis process, thereby reducing labor and time requirements. It offers interactive visualizations, event-triggered average processing, powerful tools for filtering behavioral events and quality control features. Conclusions: FiPhA is a valuable tool for behavioral neuroscientists working with discrete, event-based fiber photometry data. It addresses the challenges associated with analyzing and investigating such data, offering a robust and user-friendly solution without the complexity of having to hand-design custom analysis pipelines. This application thus helps standardize an approach to fiber photometry analysis.

Systemic Administration of Acazicolcept, a Dual CD28 and Inducible T cell Costimulator Inhibitor, Ameliorates Experimental Autoimmune Uveitis.

Purpose: Combined inhibition of CD28 and inducible T cell costimulator (ICOS) pathways with acazicolcept (ALPN-101) represents a potential new treatment for uveitis. Here, we evaluate preclinical efficacy using experimental autoimmune uveitis (EAU) in Lewis rats. Methods: Efficacy was tested in 57 Lewis rats treated with either systemic (subcutaneous) or local (intravitreal) administration of acazicolcept and compared to treatment with a matched Fc-only control or corticosteroid. Impact of treatment on uveitis was assessed using clinical scoring, optical coherence tomography (OCT), and histology. Ocular effector T cell populations were determined using flow cytometry, and multiplex ELISA used to measure aqueous cytokine concentrations. Results: When compared to Fc control treatment, systemic acazicolcept led to statistically significant decreases in clinical score (P < 0.01), histologic score (P < 0.05), and number of ocular CD45+ cells (P < 0.01). Number of ocular CD4+ and CD8+ T cells expressing IL-17A+ and IFNγ+ were also decreased with statistical significance (P < 0.01). Similar results were achieved with corticosteroids. Intravitreal acazicolcept decreased inflammation scores when compared to untreated fellow eyes and to Fc control treated eyes, although not statistically significant. Systemic toxicity, measured by weight loss, occurred in the corticosteroid-treated, but not in the acazicolcept-treated animals. Conclusions: Systemic treatment with acazicolcept statistically significantly suppressed EAU. Acazicolcept was well-tolerated without the weight loss associated with corticosteroids. Acazicolcept may be an effective alternative to corticosteroids for use in treating autoimmune uveitis. Additional studies are needed to clarify the optimal dose and route for use in humans. Translational Relevance: We show that T cell costimulatory blockade could be an effective mechanism for treating uveitis.

CAPER: patient preferences to inform nonsurgical treatment of chronic low back pain: a discrete-choice experiment.

OBJECTIVE: We developed and used a discrete-choice measure to study patient preferences with regard to the risks and benefits of nonsurgical treatments when they are making treatment selections for chronic low back pain. METHODS: "CAPER TREATMENT" (Leslie Wilson) was developed with standard choice-based conjoint procedures (discrete-choice methodology that mimics an individual's decision-making process). After expert input and pilot testing, our final measure had 7 attributes (chance of pain relief, duration of relief, physical activity changes, treatment method, treatment type, treatment time burden, and risks of treatment) with 3-4 levels each. Using Sawtooth software (Sawtooth Software, Inc., Provo, UT, USA), we created a random, full-profile, balanced-overlap experimental design. Respondents (n = 211) were recruited via an emailed online link and completed 14 choice-based conjoint choice pairs; 2 fixed questions; and demographic, clinical, and quality-of-life questions. Analysis was performed with random-parameters multinomial logit with 1000 Halton draws. RESULTS: Patients cared most about the chance of pain relief, followed closely by improving physical activity, even more than duration of pain relief. There was comparatively less concern about time commitment and risks. Gender and socioeconomic status influenced preferences, especially with relation to strength of expectations for outcomes. Patients experiencing a low level of pain (Pain, Enjoyment, and General Activity Scale [PEG], question 1, numeric rating scale score<4) had a stronger desire for maximally improved physical activity, whereas those in a high level of pain (PEG, question 1, numeric rating scale score>6) preferred both maximum and more limited activity. Highly disabled patients (Oswestry Disability Index score>40) demonstrated distinctly different preferences, placing more weight on achieving pain control and less on improving physical activity. CONCLUSIONS: Individuals with chronic low back pain were willing to trade risks and inconveniences for better pain control and physical activity. Additionally, different preference phenotypes exist, which suggests a need for clinicians to target treatments to particular patients.

Prosthesis preferences for those with upper limb loss: Discrete choice study of PULLTY® for use in regulatory decisions.

Introduction: The patient's voice in shared decision-making has progressed from physician's office to regulatory decision-making for medical devices with FDA's Patient Preference Initiative. A discrete-choice preference measure for upper limb prosthetic devices was developed to investigate patient's risk/benefit preference choices for regulatory decision making. Methods: Rapid ethnographic procedures were used to design a discrete-choice measure describing risk and benefits of osseointegration with myoelectric control and test in a pilot preference study in adults with upper limb loss. Primary outcome is utility of each choice based conjoint (CBC) attribute using mixed-effects regression. Utilities with and without video, and between genders were compared. Results: Strongest negative preference was for avoiding infection risk (B = -1.77, p < 0.001) and chance of daily pain (B = -1.22, p, 0.001). Strongest positive preference was for attaining complete independence when cooking dinner (B = 1.62, p < 0.001) and smooth grip patterns at all levels (B = 1.62, B = 1.28, B = 1.26, p < 0.001). Trade-offs showed a 1% increase in risk of serious/treatable infection resulted in a 1.77 decrease in relative preference. There were gender differences, and where video was used, preferences were stronger. Conclusions: Strongest preferences were for attributes of functionality and independence versus connectedness and sensation but showed willingness to make risk-benefit trade-offs. Findings provide valuable information for regulatory benefit-risk decisions for prosthetic device innovations. Trial Registration: This study is not a clinical trial reporting results of a health care intervention so is not registered.

Cost-effectiveness analysis of primary treatments for localised prostate cancer: A population-based Markov analysis using real-world evidence.

OBJECTIVE: We evaluate cost-effectiveness of primary treatments for localised prostate cancer by uniquely combining prospectively collected real-world outcomes and costs from UCSF Cancer of Prostate Strategic Urologic Research Endeavor (CaPSURE™). METHODS: Markov models assessed cost-effectiveness of radical prostatectomy (RP), brachytherapy, electron beam radiation therapy (EBRT) and brachytherapy with EBRT by risk from US payers perspective over 8 years. Treatment costs included office visits, hospitalisation, procedures, medication and long-term care. Patients' surveyed HRQoL were mapped into utilities. Incremental cost-effectiveness ratios (ICERs) used cost per quality-adjusted life years (QALYs) and willingness-to-pay of $150,000/QALY. RESULTS: Cost-effectiveness analysis (CEA) showed for low-risk prostate cancer, EBRT dominated the lowest cost brachytherapy, but RPns and brachytherapy plus EBRT were cost-effective compared to brachytherapy with ICERs of $18,926 and $41,662 per QALY. In medium-risk patients, RP, EBRT and brachytherapy plus EBRT all were cost-effective compared with brachytherapy, with ICERs of $30,604, $22,588 and $21,627/QALY. In high-risk, brachytherapy dominated all treatments. Procedure cost and utility are driving ICER, but probabilistic sensitivity analysis showed the model was robust across variables. CONCLUSION: This first CEA combining prospective real-world evidence for HRQOL outcomes with costs shows cost-effectiveness of treatments vary by risk groups, providing new evidence for treatment decisions.

MPCVD-Grown Nanodiamond Microelectrodes with Oxygen Plasma Activation for Neurochemical Applications.

Nanodiamonds (NDs) are a carbon nanomaterial that has a diamond core with heteroatoms and defects at the surface. The large surface area, defect sites, and functional groups on NDs make them a promising material for electrochemical sensing. Previously, we dip-coated ND onto carbon-fiber microelectrodes (CFMEs) and found increases in sensitivity, but the coating was sparse. Here, we directly grew thin films of ND on niobium wires using microwave plasma chemical vapor deposition (MP-CVD) to provide full surface coverage. ND microelectrodes show a reliable performance in neurotransmitter detection with good antifouling properties. To improve sensitivity, we oxygen plasma etched ND films to activate the surface and intentionally add defects and oxygen surface functional groups. For fast-scan cyclic voltammetry detection of dopamine, oxygen plasma-etching increases the sensitivity from 21 nA/µM to 90 nA/µM after treatment. Fouling was tested by repeated injections of serotonin or tyramine, and both ND and plasma oxidized nanodiamond (NDO) microelectrodes maintain their currents better compared to CFMEs and therefore are more antifouling. A biofouling test in brain slices shows that ND microelectrodes barely have any current drop, while the more hydrophilic NDO microelectrodes decrease more, but still not as much as CFMEs. Overall, grown ND microelectrodes are promising in neurotransmitter detection with excellent fouling resistance, whereas oxygen plasma etching slightly lowers the fouling resistance but dramatically increases sensitivity.

Natural locus coeruleus dynamics during feeding.

Recent data demonstrate that noradrenergic neurons of the locus coeruleus (LC-NE) are required for fear-induced suppression of feeding, but the role of endogenous LC-NE activity in natural, homeostatic feeding remains unclear. Here, we found that LC-NE activity was suppressed during food consumption, and the magnitude of this neural response was attenuated as mice consumed more pellets throughout the session, suggesting that LC responses to food are modulated by satiety state. Visual-evoked LC-NE activity was also attenuated in sated mice, suggesting that satiety state modulates LC-NE encoding of multiple behavioral states. We also found that food intake could be attenuated by brief or longer durations of LC-NE activation. Last, we found that activation of the LC to the lateral hypothalamus pathway suppresses feeding and enhances avoidance and anxiety-like responding. Our findings suggest that LC-NE neurons modulate feeding by integrating both external cues (e.g., anxiogenic environmental cues) and internal drives (e.g., satiety).

Systemic prime exacerbates the ocular immune response to heat-killed Mycobacterium tuberculosis.

Post-infectious uveitis describes the condition of chronic immune mediated ocular inflammation associated with pathogens such as Mycobacterium tuberculosis (Mtb). Mtb associated post-infectious uveitis can be modeled in mice by intravitreal injection of heat-killed Mtb (HKMtb). To better understand how prior systemic exposure to the pathogen alters the local immune response to Mtb, we used flow cytometry and multiplex ELISAs to compare ocular responses to intravitreal HKMtb in the presence or absence of a systemic "prime" of HKMtb. Priming resulted in exacerbation of local inflammation with significantly increased clinical and histologic inflammation scores and increased vitreous cytokines concentrations one day after intravitreal injection of HKMtb. Seven days after injection, uveitis in unprimed animals had largely resolved. In contrast in primed animals, clinical signs of chronic inflammation were associated with a significant increase in the number of ocular T cells, NK cells, and Ly6Chi macrophages and increasing vitreous concentrations of IL-17, VEGF, MIG(CXCL9), IP-10(CXCL10), IL-12p40 and MIP-1α(CCL3). In mice lacking mature T and B cells (RAG2 deficient), the impact of priming on the ocular immune response was ameliorated with significantly lower vitreous cytokine concentrations and spontaneous resolution of uveitis. Altogether these results suggest that the ocular response to Mtb is exacerbated by prior systemic Mtb infection and chronic post-infectious uveitis is mediated by local production of cytokines and chemokines that amplify Th17 and Th1 responses. This mouse model of chronic Mtb associated uveitis will help elucidate mechanisms of disease in patients with post-infectious uveitis.

Preferences for Risks and Benefits of Islet Cell Transplantation for Persons With Type 1 Diabetes With History of Episodes of Severe Hypoglycemia: A Discrete-Choice Experiment to Inform Regulatory Decisions.

BACKGROUND: The advisory panel for US Food and Drug Administration (FDA) recently endorsed pancreatic islet cell transplantation (ICT) therapy for suboptimally controlled type 1 diabetes (T1D), and FDA approval is under consideration. An important part of regulatory approval includes the patient perspective, through discrete choice. We developed a discrete-choice instrument and used it to determine how 90 people with T1D weigh the risks and benefits of ICT to inform regulatory decisions. METHODS: Sawtooth software created a random, full-profile, balanced-overlap experimental design for a measure with 8 attributes of ICT risks/benefits, each with 3 to 5 levels. We asked 18 random task pairs, sociodemographics, diabetes management, and hypoglycemia questions. Analysis was performed using random parameters logistic regression technique. RESULTS: The strongest preference was for avoiding the highest chance (15%) of serious procedure-related complications (ß = -2.03, P < 0.001). The strongest positive preference was for gaining 5-y insulin independence (ß = 1.75, P < 0.001). The desire for 5-y HbA1C-defined clinical treatment success was also strong (ß = 1.39, P < 0.001). Subgroup analysis suggested strong gender differences with women showing much higher preferences for all benefits (68% higher for 5-y insulin independence), and men were generally more risk averse than women. Those with high versus low diabetes distress showed 3 times stronger preference for 5-y insulin independence but also twice preference to avoid risks of serious complications. CONCLUSIONS: Despite showing the most preference for avoiding serious ICT complications, people with T1D had a strong preference for achieving ICT benefits, especially insulin independence. We identified important attributes of ICT and demonstrated that patients are willing to make these trade-offs, showing support for the introduction of ICT.

Analyzing excipient-related adverse events in antiseizure drug formulations.

There have been several reports that switching formulations of antiseizure medications (ASMs) has been associated with a deterioration of seizure control, seizure relapse or increased adverse effects. Considering recent findings that excipients, namely purported inactive ingredients, may nevertheless exert biological effects, it is possible that the variation in adverse event profile of antiseizure drugs may be related to differences in excipients. To test our hypothesis, we constructed a new research tool to connect FDA-compiled adverse event reports to the excipient in the medicine. Analysis of adverse events to formulations of five different second-generation antiseizure drugs - gabapentin, lamotrigine, levetiracetam, oxcarbazepine, and topiramate - showed several significant associations between specific excipient in the formulations and an adverse event when compared to the same medicine formulated with other excipients. Epilepsy and seizure adverse events were associated with multiple excipients across gabapentin, lamotrigine, and levetiracetam formulations. A different group of excipients were associated with reports of hypersensitivity reactions including urticaria, rash, erythema, and Stevens-Johnson syndrome. Our study provides a novel approach to analyzing post-market surveillance reports by including excipients. It may be useful to clinicians when evaluating select patient groups that may be refractory to pharmacological treatment or experience worsening adverse events when switching formulations of the same antiseizure medicine.

Cost-Effectiveness Analysis of Atezolizumab Versus Durvalumab as First-Line Treatment of Extensive-Stage Small-Cell Lung Cancer in the USA.

BACKGROUND AND OBJECTIVES: Durvalumab and atezolizumab are approved as first-line therapy in extensive-stage small-cell lung cancer. Although cost-effectiveness analyses compared these immunotherapy drugs with standard chemotherapy-alone regimens, no head-to-head cost-effectiveness comparisons for these treatments exist. The aim of the present analysis is to determine the cost-effectiveness of durvalumab and atezolizumab as first-line therapy for extensive-stage small-cell lung cancer from the US payers' perspective. METHODS: This study is based on two placebo-controlled, phase 3 clinical trials: CASPIAN and IMpower133. A Markov model was developed to simulate the three health states: progression-free survival, progressed disease, and death in patients with extensive-stage small-cell lung cancer. Transition probabilities were estimated from the clinical trial survival curves and extended with life-time modelling. Health utilities and direct costs of adverse event treatment were included. Main outcome was the incremental cost-effectiveness ratio (ICER) using quality-adjusted life-years saved (QALYS). Sensitivity analysis was performed to assess the impact of variables on the ICER. RESULTS: Durvalumab group has a cost of $187,503 with an effectiveness of 1.08 while atezolizumab has a cost of $160,219 and an effectiveness of 0.932. Durvalumab is not cost-effective compared to atezolizumab with an ICER of $165,182 QALYS, which is over the willingness-to-pay threshold of $150,000. The model was most sensitive to durvalumab cost and the cost of treating durvalumab adverse effects. CONCLUSIONS: With the ICER of durvalumab treatment group being very close to $150,000, setting a higher willingness-to-pay threshold or decreasing the drug cost through contract pricing can increase the cost-effectiveness of durvalumab compared to atezolizumab.