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The cell surface molecule CD40 is a member of the tumor necrosis factor receptor superfamily and is broadly expressed by immune cells including B cells, dendritic cells, and monocytes, as well as other normal cells and some malignant cells. CD40 is constitutively expressed on antigen-presenting cells, and ligation promotes functional maturation, leading to an increase in antigen presentation and cytokine production, and a subsequent increase in the activation of antigen-specific T cells. It is postulated that CD40 agonists can mediate both T cell-dependent and T cell-independent immune mechanisms of tumor regression in mice and patients. In addition, it is believed that CD40 activation also promotes apoptotic death of tumor cells and that the presence of the molecule on the surface of cancer cells is an important factor in the generation of tumor-specific T cell responses that contribute to tumor cell elimination. Notably, CD40 agonistic therapies were evaluated in patients with solid tumors and hematologic malignancies with reported success as a single agent. Preclinical studies have shown that subcutaneous administration of CD40 agonistic antibodies reduces systemic toxicity and elicits a stronger and localized pharmacodynamic response. Two independent studies in cynomolgus macaque (Macaca fascicularis) were performed to further evaluate potentially immunotoxicological effects associated with drug-induced adverse events seen in human subjects. Studies conducted in monkeys showed that when selicrelumab is administered at doses currently used in clinical trial patients, via subcutaneous injection, it is safe and effective at stimulating a systemic immune response.

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Across a broad set of applications, system outcomes may be summarized as probabilities in confusion or contingency tables. In settings with more than two outcomes (e.g., stages of cancer), these outcomes represent multinomial experiments. Measures to summarize system performance have been presented as linear combinations of the resulting multinomial probabilities. Statistical inference on the linear combination of multinomial probabilities has been focused on large-sample and parametric settings and not small-sample settings. Such inference is valuable, however, especially in settings such as those resulting from pilot or low-cost studies. To address this gap, we leverage the fiducial approach to derive confidence intervals around the linear combination of multinomial parameters with desirable frequentist properties. One of the original arguments against the fiducial approach was its inability to extend to multiparameter settings. Therefore, the great novelty of this work is both the derived interval and the logical framework for applying the fiducial approach in multiparameter settings. Through simulation, we demonstrate that the proposed method maintains a minimum coverage of 1 - α $1 - \alpha$ , unlike the bootstrap and large-sample methods, at comparable interval lengths. Finally, we illustrate its use in a medical problem of selecting classifiers for diagnosing chronic allograph nephropathy in postkidney transplant patients.

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Transcranial alternating current stimulation (tACS) modulates oscillations in a frequency- and location-specific manner and affects cognitive and motor functions. This effect appears during stimulation as well as "offline," following stimulation, presumably reflecting neuroplasticity. Whether tACS produces long-lasting aftereffects that are physiologically meaningful, is still of current debate. Thus, for tACS to serve as a reliable method for modulating activity within neural networks, it is important to first establish whether "offline" aftereffects are robust and reliable. In this study, we employed a novel machine-learning approach to detect signatures of neuroplasticity following 10-Hz tACS to two critical nodes of the motor network: left motor cortex (lMC) and right cerebellum (rCB). To this end, we trained a classifier to distinguish between signals following lMC-tACS, rCB-tACS, and sham. Our results demonstrate better classification of electroencephalography (EEG) signals in both theta (θ, 4-8 Hz) and alpha (α, 8-13 Hz) frequency bands to lMC-tACS compared with rCB-tACS/sham, at lMC-tACS stimulation location. Source reconstruction allocated these effects to premotor cortex. Stronger correlation between classification accuracies in θ and α in lMC-tACS suggested an association between θ and α efffects. Together these results suggest that EEG signals over premotor cortex contains unique signatures of neuroplasticity following 10-Hz motor cortex tACS.

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Alpha oscillations (8-13 Hz) have been suggested to play an important role in dynamic neural processes underlying learning and memory. The goal of this study was to scrutinize the role of alpha oscillations in communication within a cortico-cerebellar network implicated in motor sequence learning. To this end, we conducted two EEG experiments using a serial reaction time task. In the first experiment, we explored changes in alpha power and cross-channel alpha coherence as subjects learned a motor sequence. We found a gradual decrease in spectral alpha power over left premotor cortex (PMC) and sensorimotor cortex (SM1) during learning blocks. In addition, alpha coherence between left PMC/SM1 and left cerebellar crus I was specifically decreased during sequence learning, possibly reflecting a functional decoupling in the broader motor learning network. In the second experiment in a different cohort, we applied 10Hz transcranial alternating current stimulation (tACS), a method shown to entrain local oscillatory activity, to left M1 (lM1) and right cerebellum (rCB) during sequence learning. We observed a tendency for diminished learning following rCB tACS compared to sham, but not following lM1 tACS. Learning-related alpha power following rCB tACS was increased in left PMC, possibly reflecting increase in local inhibitory neural activity. Importantly, learning-specific alpha coherence between left PMC and right cerebellar lobule VIIb was enhanced following rCB tACS. These findings provide strong evidence for a causal role of alpha oscillations in controlling information transfer in a premotor-cerebellar loop during motor sequence learning. Our findings are consistent with a model in which sequence learning may be impaired by enhancing premotor cortical alpha oscillation via external modulation of cerebellar oscillations.

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Although matrix metalloproteinase 9 (MMP9) has been found associated with various psychiatric disorders and with threat memories in humans, its role in post-traumatic stress disorder (PTSD) and related animal models is understudied. Thus, we analyzed MMP9 mRNA expression kinetics during two different stress experiments, i.e., the Trier Social Stress Test and the dexamethasone suppression test (DST), in whole blood of two independent cohorts of PTSD patients vs. non-traumatized healthy controls (HC) and, moreover, in a mouse model of PTSD and in dexamethasone-treated mice. Besides MMP9, we quantified mRNA levels of four of its regulators, i.e., interleukin (IL)-1 receptor 1 and 2 (IL1R1, IL1R2), IL-6 receptor and tumor necrosis factor receptor 1 (TNFR1) in 10 patients exposed to the DST before vs. after successful PTSD psychotherapy vs. 13 HC and, except from Il6r, also in different brain regions of the PTSD mouse model. We are the first to show that blood MMP9 mRNA concentrations were elevated after acute dexamethasone in PTSD patients, improved upon partial remission of PTSD and were, furthermore, also elevated, together with its regulator Tnfr1, in the prefrontal cortex of PTSD-like mice. In contrast, blood TNFR1 and IL1R2 were markedly underexpressed in PTSD patients. In conclusion, we found translational evidence supporting that, I, TNFR1 and MMP9 mRNA expression might be involved in PTSD pathobiology, II, might constitute potential diagnostic blood biomarkers for PTSD and, importantly, III, post-dexamethasone blood MMP9 hyperexpression, which speculatively results from post-dexamethasone underexpression of IL1R2, might serve also as potential treatment monitoring biomarker for PTSD.

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This study aimed to identify yet unavailable blood biomarkers for the responsive and the hyporesponsive hypothalamic-pituitary-adrenal (HPA) axis subtypes of posttraumatic stress disorder (PTSD). As, I, we recently discovered the intranasal neuropeptide oxytocin to reduce experimentally provoked PTSD symptoms, II, expression of its receptor (OXTR) has hitherto not been assessed in PTSD patients, and III, oxytocin and OXTR have previously been related to the HPA axis, we considered both as suitable candidates. During a Trier Social Stress Test (TSST), we compared serum oxytocin and blood OXTR mRNA concentrations between female PTSD patients, their HPA axis reactivity subtypes and sex and age-matched healthy controls (HC). At baseline, both candidates differentiated the hyporesponsive HPA axis subtype from HC, however, only baseline OXTR mRNA discriminated also between subtypes. Furthermore, in the hyporesponsive HPA axis subgroup, OXTR mRNA levels correlated with PTSD symptoms and changed markedly during the TSST. To assess the influence of (traumatic) stress on the cerebral expression of oxytocin and its receptor and to test their suitability as biomarkers for the mouse PTSD-like syndrome, we then analyzed oxytocin, its mRNA (Oxt) and Oxtr mRNA in three relevant brain regions and Oxt in blood of a PTSD mouse model. To further explore the HPA axis reactivity subtype dependency of OXTR, we compared cerebral OXTR protein expression between mice exhibiting two different HPA axis reactivity traits, i.e., FK506 binding protein 51 knockout vs. wildtype mice. In summary, blood OXTR mRNA emerged as a potential biomarker of the hyporesponsive HPA axis PTSD subtype and prefrontal cortical Oxtr and Oxt of the mouse PTSD-like syndrome. Moreover, we found first translational evidence for a HPA axis responsivity trait-dependent regulation of OXTR expression. The lack of a cohort of the (relatively rare) hyporesponsive HPA axis subtype of HC is a limitation of our study.

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Internalizing symptoms are prevalent in students as they enter and complete college. Considering research suggesting mental health benefits of pet ownership, this study explores the relationship between pet ownership, social support (SS), and internalizing symptoms (IS) in a cohort of students across their 4-year college experience. With no differences at college entry, students growing up with pets had greater IS through the fourth year, and greater SS through the third year, than those without pets. Currently living with a pet, gender, SS and personality predicted IS in the fourth year. Females experiencing higher IS in their first year are more likely to live with pets in their fourth year, and fourth year females living with pets or greatly missing absent pets have higher IS than females without pets or missing pets less. Findings suggest a unique relationship between IS in female students and their pet relationships not seen in males.

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Posttraumatic growth (PTG) may play a role in the treatment of posttraumatic stress disorder (PTSD) as it is supposed to have either beneficial or dysfunctional effects on treatment-related PTS symptom (PTSS) changes. This study examined whether cognitive behavioral therapy (CBT) for PTSD patients can foster PTG assessed by self-reports and reports from significant others. Forty-eight PTSD patients participating in trauma-focused CBT were assessed twice: at the beginning of therapy (T1) and after 3 months of therapy (T2, N = 34). We used the Clinician Administered PTSD Scale and the Posttraumatic Growth Inventory (PTGI), and constructed a significant other version of the PTGI (PTGI-SOA). The PTSS severity declined during the course of treatment, whereas PTG levels remained stable. Both the PTGI and PTGI-SOA were associated with higher PTSS reduction at T2. The results suggest that PTG is associated with greater improvement in PTSS during trauma-focused CBT, even though treatment could not directly enhance PTG. Significant other assessments seem to be a promising approach to improve PTG measurement.

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Cost and burden of diagnostic testing may be reduced if fewer tests can be applied. Sequential testing involves selecting a sequence of tests, but only administering subsequent tests dependent on results of previous tests. This research provides guidance to choosing between single tests or the believe the positive (BP) and believe the negative (BN) sequential testing strategies, using accuracy (as measured by the Youden Index) as the primary determinant. Approximately 75% of the parameter combinations examined resulted in either BP or BN being recommended based on a higher accuracy at the optimal point. In about half of the scenarios BP was preferred, and the other half, BN, with the choice often a function of the value of the ratio of standard deviations of those without and with disease (b). Large values of b for the first test of the sequence tended to be associated with preference for BN as opposed to BP, while small values of b appear to favor BP. When there was no preference between sequences and/or single tests based on the Youden Index, cost of the sequence was considered. In this case, disease prevalence plays a large role in the selection of strategies, with lower values favoring BN and sometimes higher values favoring BP. The cost threshold for the sequential strategy to be preferred over a single, more accurate test, was often quite high. It appears that while sequential strategies most often increase diagnostic accuracy over a single test, sequential strategies are not always preferred.

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Critically ill patients are at risk for developing pressure injuries during operative and other invasive procedures. The purpose of this secondary analysis was to explore the relationship of OR time to sacral pressure injuries in critically ill patients using high frequency ultrasound as a method of assessment. The 41 participants examined in this study had both time in the OR and up to eight days of pressure injury data. The multivariable model containing OR bed time, body mass index, and Braden Scale score produced the best prediction of pressure injury (area under the curve = 0.859). A higher body mass index (P = .09), shorter OR bed time (P = .01), and lower Braden Scale score (P = .05) were associated with a greater chance of pressure injury. These results suggest that use of high frequency ultrasound may identify tissue changes before observable skin changes, leading to earlier pressure injury prevention strategies.

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Although key to development of tailored drugs for augmentation treatment of psychotherapy for posttraumatic stress disorder (PTSD), the biological correlates of PTSD remission are still unknown, probably because pre-post treatment studies searching for them are rare. Not even the feedback sensitivity of the otherwise well-studied hypothalamic-pituitary-adrenal (HPA) axis nor arterial blood pressure (BP), which was previously reported to be elevated in PTSD patients, have so far been analyzed during PTSD treatment. To narrow this knowledge gap, we first performed an overnight dexamethasone suppression test (DST) in a mixed-sex cohort of 25 patients with severe PTSD vs. 20 non-traumatized healthy controls (nt-HC). In addition to hormones, BP and heart rate (HR) were measured at each of the four assessment points (APs). Second, the same parameters were assessed again in 16 of these patients after 12 sessions of integrative trauma-focused cognitive behavioral therapy (iTF-CBT). In relation to nt-HC, PTSD patients showed a significant elevation in HR and diastolic BP while their systolic BP, DST outcomes and basal serum cortisol levels (BSCL) were not significantly altered. In response to iTF-CBT, PTSD symptoms and dysfunctional stress coping strategies improved significantly in PTSD patients. Most important, also their systolic and diastolic BP levels ameliorated at distinct APs while their DST outcomes and BSCL remained unchanged. To our knowledge, this is the first pre-post treatment study assessing the stability of the DST outcome and BP levels during PTSD treatment. Our results provide first evidence for a non-involvement of HPA axis feedback sensitivity in PTSD symptom improvement and, furthermore, suggest a possible role for BP-regulating pathways such as the sympathetic nervous system in PTSD remission. Limitations arise from the small sample size, the lack of an untreated patient group and drug treatment of patients.

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BACKGROUND: Although higher backrest elevation may be a theoretical risk for integrity of sacral tissues, few data support use of high backrest elevation. OBJECTIVE: To describe the effect of backrest elevation on the integrity of sacral tissue in critically ill adults receiving mechanical ventilation. METHODS: Patients from 3 critical care units (surgical trauma, medical respiratory, and neuroscience) who were expected to have mechanical ventilation for at least 24 hours were intubated and mechanical ventilation was started. Participants were enrolled in the study within 24 hours of intubation. Backrest elevation was continuously measured by using mechanical system- based accelerometers. Integrity of sacral tissue was evaluated by using high-frequency sonography. RESULTS: Data for 84 patients who had measurements of both backrest elevation and skin integrity were available for analysis. General linear models indicated no significant difference among the proportions of time spent at less than 20° (P values: .57 the first 24 hours, .17 the first 48 hours, .81 the first 72 hours), 20° to 30° (P values: .25 the first 24 hours, .08 the first 48 hours, .25 the first 72 hours), or greater than 30° (P values: .62 the first 24 hours, .28 the first 48 hours, .68 the first 72 hours) among participants with no injury, no change in injury, improvement in injury, or injury that worsened. CONCLUSIONS: Level of backrest elevation is not associated with changes in tissue integrity. Body positioning in critically ill patients receiving mechanical ventilation may not be as important or as effective as once thought.

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Objective: High-frequency ultrasound (HFUS) images are being researched for use in the prevention, detection, and monitoring of pressure injuries in patients at risk. This seminal longitudinal study in mechanically ventilated adults describes image quality, the incidence of image artifacts, and their effect on image quality in critically ill subjects. Approach: Mechanically ventilated subjects from three adult intensive care units were enrolled, and multiple sacral images from each subject were obtained daily. Using a subset of best image per patient per day, artifacts were grouped, and their effect on image quality was statistically evaluated. Results: Of a total of 1761 images collected from 137 subjects, 8% were rated as poor. In the subset, 70% had good quality ratings. Four groups of artifacts were identified as follows: "bubbles," "texture problems," "layer nondifferentiation," and "reduced area for evaluation." Artifacts from at least one group were found in 83% of images. Bubbles were most frequently seen, but artifacts with adverse effect on image quality were "layer nondifferentiation," "texture problems," and "reduced area for evaluation." Innovation: HFUS image evaluation is still in the development phase with respect to tissue injury use. Artifacts are generally omnipresent. Quickly recognizing artifacts that most significantly affect image quality during scanning will result in higher quality images for research and clinical applications. Conclusion: Good quality images were achievable in study units; although frequent artifacts were present in images, in general, they did not interfere with evaluation. Artifacts related to "layer nondifferentiation" was the greatest predictor of poor image quality, prompting operators to immediately rescan the area.

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OBJECTIVES: The purpose of this study was to describe selected sacral tissue characteristics in a convenience sample of healthy volunteer subjects. DESIGN: Descriptive. SAMPLE AND SETTING: Fifty healthy volunteers in a clinical learning center in a school of nursing. METHODS: Sacral scans were obtained using a 20-MHz ultrasound scanning system in 3 positions: prone and 60° and 90° side-lying from the back. The images were analyzed by software in the ultrasound program using quantitative parameters of dermal thickness and density (dermal median intensity and derived number of low-echogenic pixels to total pixels [LEP:TP] ratio). RESULTS: In general, average values were as follows: dermal thickness between 2.32 and 2.65 mm; median pixel intensity between 102 and 112; and the LEP:TP ratio between 0.39 and 0.56. There were significant differences in sacral tissue characteristics between measures of thickness and dermal density (median intensity and LEP:TP ratio) by subject side-lying position (60° and 90°) versus prone position, with all P values less than .0001. CONCLUSIONS: Overall, the ranges were consistent across measures of thickness and dermal density except for systematic differences between side-lying and prone positions. When comparing thickness, median intensity, or LEP:TP ratio, it is important to report subject position. To best recognize tissue inflammation indicative of pressure injuries before surface changes are seen, it is useful to understand healthy high-frequency ultrasound sacral tissue characteristics. It is anticipated that quantitative assessment of dermal thickness, density, and LEP:TP ratio could help identify individuals with incipient pressure injury.

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Gantenerumab is intended for the treatment of Alzheimer's disease. It is a fully human recombinant monoclonal IgG1 which binds aggregated forms of amyloid beta such as Aß oligomers, fibrils and neuritic amyloid plaques. A full package of developmental and reproductive toxicity (DART) studies was performed in the PS2APP double-transgenic mouse model of Alzheimer's disease. A combined fertility and embryo fetal development study and a pre-and post-natal development study were performed. The PS2APP mouse model allowed a more complete DART evaluation than would have been possible in conventional species or strains which do not express the target antigen of gantenerumab. No developmental or reproductive hazards were identified.

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With the emergence of novel biotherapeutic formats and immunostimulatory biotherapeutics in cancer immunotherapy, an understanding of immune-complex (IC) mediated hypersensitivity reactions in toxicology studies - and their differentiation from pharmacology - remains key to the preclinical evaluation of these drugs. In this review we provide an in-depth evaluation and comparison of case examples where IC-mediated hypersensitivity reactions were observed in cynomolgus monkeys. We provide details of the parameters evaluated in each study to substantiate and guide the interpretation of these findings. Five study cases (1 therapeutic protein, 4 monoclonal antibodies) are discussed for which effects ranged from minor to fatal. Common characteristics are the high incidence of clinical signs, detectable antidrug antibodies, and accelerated drug clearance up to virtual loss of exposure. In our experience, measurement of cytokine levels in vivo and detection of complement (split products) were supportive markers in situations where coagulopathy was suspected to play a role in the observed effects. Recommendations are outlined to prepare for root-cause analysis of suspected hypersensitivity reactions. Overall, a thorough analysis of the findings has helped to start clinical trials despite major findings. The hypersensitivity reactions with our human(ized) immunoglobulins have not proven to be predictive for humans.

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PURPOSE: High frequency ultrasound (HFUS) systems may identify tissue injury. We compared HFUS tissue characteristics (dermal thickness and dermal density) with visual image examination. METHODS: Longitudinal study in critically ill mechanically ventilated adults, from three ICUs (Surgical Trauma, Medical Respiratory, Neuroscience) enrolled within 24hours of airway intubation. Sacral HFUS images were obtained daily for up to seven days. Expert evaluation of the best image per day was completed and compared to HFUS generated tissue characteristics (dermal thickness and dermal density). RESULTS: Of the113 subjects with 1614 comparisons analysed, 73.2% to 84% were normal, and 6.3% to 11.8% of the comparisons had injury present but no change was noted in the injury observed. There were no significant differences in one-day comparisons among type of injury and mean dermal thickness (p=0.6645) or dermal median intensity (adjusted p=0.06-0.17). All other day-to-day comparisons were similarly non-significant. CONCLUSIONS: We found no association among dermal density, dermal thickness and visual examination of changes in sacral HFUS images for any day-to-day comparison. The use of sacral HFUS as a screening tool for the development of tissue injury is in its infancy. Additional comparative studies should be conducted to identify its future clinical usefulness.

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OBJECTIVE: To describe tissue interface pressure, time spent above critical pressure levels and the effect on skin integrity at seven anatomical locations. DESIGN, SETTING, PATIENTS: Descriptive, longitudinal study in critically ill mechanically ventilated adults, from Surgical Trauma ICU-STICU; Medical Respiratory ICU-MRICU; Neuroscience ICU-NSICU in a Mid-Atlantic urban university medical centre. Subjects were enroled in the study within 24hours of intubation. MEASUREMENTS: Tissue interface pressure was measured continuously using the XSENSOR pressure mapping system (XSENSOR Technology Corporation, Calgary, Canada). Skin integrity was observed at all sites, twice daily, using the National Pressure Ulcer Advisory Panel staging system, for the first seven ICU days and at day 10 and 14. RESULTS: Of the 132 subjects, 90.9% had no observed changes in skin integrity. Maximum interface pressure was above 32mmHg virtually 100% of the time for the sacrum, left and right trochanter. At the 45mmHg level, the left and right trochanter had the greatest amount of time above this level (greater than 95% of the time), followed by the sacrum, left and right scapula, and the left and right heels. Similarly, at levels above 60mmHg, the same site order applied. For those six subjects with sacral skin integrity changes, maximum pressures were greater than 32mmHg 100% of the time. Four of the six sacral changes were associated with greater amounts of time above both 45mmHg and 60mmHg than the entire sample. CONCLUSIONS: Maximum tissue interface pressure was above critical levels for the majority of the documented periods, especially in the sacrum, although few changes in skin integrity were documented. Time spent above critical levels for mean pressures were considerably less compared to maximum pressures. Maximum pressures may have reflected pressure spikes, but the large amount of time above the critical pressure levels remains substantial.

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BACKGROUND: Backrest elevations less than 30° are recommended to reduce pressure ulcers, but positions greater than 30° are recommended during mechanical ventilation to reduce risk for ventilator-associated pneumonia. Interface pressure may vary with level of backrest elevation and anatomical location (eg, sacrum, heels). OBJECTIVE: To describe backrest elevation and anatomical location and intensity of skin pressure across the body in patients receiving mechanical ventilation. METHODS: In a longitudinal study, patients from 3 adult intensive care units in a single institution receiving mechanical ventilation were enrolled within 24 hours of intubation from February 2010 through May 2012. Backrest elevation (by inclinometer) and pressure (by a pressure-mapping system) were measured continuously for 72 hours. Mean tissue interface pressure was determined for 7 anatomical areas: left and right scapula, left and right trochanter, sacrum, and left and right heel. RESULTS: Data on 133 patients were analyzed. For each 1° increase in backrest elevation, mean interface pressure decreased 0.09 to 0.42 mm Hg. For each unit increase in body mass index, mean trochanter pressure increased 0.22 to 0.24 mm Hg. Knee angle (lower extremity bent at the knee) and mobility were time-varying covariates in models of the relationship between backrest elevation and tissue interface pressure. CONCLUSIONS: Individual factors such as patient movement and body mass index may be important elements related to risk for pressure ulcers and ventilator-associated pneumonia, and a more nuanced approach in which positioning decisions are tailored to optimize outcomes for individual patients appears warranted.

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