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Sarah MacFarlane and colleagues share their lessons engaging in educational reform and faculty development with the Muhimbili University of Health and Allied Sciences in Tanzania and the University of California San Francisco.

Summary: Objective: While a role for vitamin K in maintaining joint tissue homeostasis has been proposed based on the presence of vitamin K dependent proteins in cartilage and bone, it is not clear if low vitamin K intake is causally linked to joint tissue degeneration. To address this gap, we manipulated vitamin K status in aging mice to test its effect on age-related changes in articular cartilage and sub-chondral bone. Methods: Eleven-month old male C57BL6 mice were randomly assigned to a low vitamin K diet containing 120 mcg phylloquinone/kg diet (n = 32) or a control diet containing 1.5 mg phylloquinone/kg diet (n = 30) for 6 months. Knees were evaluated histologically using Safranin O and H&E staining, as well as using micro-CT. Results: Eleven mice in the low vitamin K diet group and three mice in the control group died within the first 100 days of the experiment (p = 0.024). Mice fed the low vitamin K diet had higher Safranin-O scores, indicative of more proteoglycan loss, compared to mice fed the control diet (p ≤ 0.026). The articular cartilage structure scores did not differ between the two groups (p ≥ 0.190). The sub-chondral bone parameters measured using micro CT also did not differ between the two groups (all p ≥ 0.174). Conclusion: Our findings suggest low vitamin K status can promote joint tissue proteoglycan loss in older male mice. Future studies are needed to confirm our findings and obtain a better understanding of the molecular mechanisms underlying the role of vitamin K in joint tissue homeostasis.

Background: Mesothelin is expressed at very low levels by normal mesothelial cells but is overexpressed in several human cancers. This makes mesothelin a promising target for immunotherapy. Limited data exist about mesothelin expression in esophageal carcinoma. In a current clinical trial, the highly potent anti-mesothelin antibody anetumab ravtansine is used in patients with mesothelin-positive tumors. Response rates are correlated with mesothelin expression (using the Ventana antibody) in tumor cells. No data are available on expression levels using the Ventana antibody. Most data have been generated using the Novocastra antibody. As patients are selected for clinical trials based on antibody staining of tumor samples, a comparison of these two available antibodies is crucial. Methods: We analyzed 481 esophageal carcinomas [373 esophageal adenocarcinomas (EACs), 108 esophageal squamous cell carcinomas (ESCCs)] using two different monoclonal antibodies (Novocastra and Ventana) for mesothelin expression (low–mid and high-level expression, as used in one clinical trial). We also checked for the correlation of these results with clinical and molecular data. Results: We revealed different staining results for both antibodies in EACs: Ventana: 53.6% (low expression: 25.3%; high expression: 28.3%) and Novocastra: 35.7% (low expression: 21.2%; high expression 14.5%). In ESCC we found comparable staining results: Ventana: 13.3% (low expression: 9.5%; high expression: 3.8%) and Novocastra: 13% (low expression: 11.1%; high expression: 1.9%). ARID1a-deficient EAC patients demonstrated significantly higher rates of mesothelin-positive tumors than ARID1a intact EAC patients. No correlations were found with other molecular alterations ( TP53 mutation, ERBB2 amplification) or survival rates. Conclusion: To the best of our knowledge, this is the largest study analyzing the importance of mesothelin expression in esophageal carcinoma. This study revealed a significant number of mesothelin-positive esophageal carcinomas, especially adenocarcinomas. New therapeutic targets are urgently required to improve the outcome of patients with locally advanced or metastasized esophageal carcinoma. The inhibition of mesothelin can be a new attractive target.

Summary: Objective: To stimulate future research directions that seek solutions for osteoarthritis (OA) at the interface between diverse disciplines and address osteoarthritis (OA) as a serious disease with a complexity that has presented a barrier to finding safe effective solutions. Methods: Sessions were conducted at the 2019 meetings of the Orthopaedic Research Society (ORS) and Osteoarthritis Research Society International (OARSI) that included presentations and questions/comments submitted from leading OA researchers representing imaging, mechanics, biomarkers, phenotyping, clinical, epidemiology, inflammation and exercise. Results: Solutions for OA require a paradigm shift in research and clinical methods in which OA is contextualized as a complex whole-body/person disease. New OA definition(s)/phenotype(s) and OA markers/signals are needed to address the interplay between genetic and environmental factors of the disease as well as capture the mechanosensitivity of the disease. The term “Mechanokines” was proposed to highlight the importance of incorporating whole body mechanics as a marker of early OA. New interventions and apparent paradoxical observations/questions (e.g. exercise vs. load modification) were also discussed in the context of considering OA as a complex system. Conclusion: To advance new OA treatments that are safe and effective, OA should be considered as a “Whole Person” disease. This approach requires a concerted effort to bridge disciplines and include interactions across scales from the molecule to the whole body, including psychosocial aspects.

Background. Indoleamine 2,3-dioxygenase (IDO) is an interferon-inducible immune checkpoint expressed on tumor-infiltrating lymphocytes (TILs). IDO is known as a poor prognostic marker in esophageal squamous cell cancer, while a positive effect was shown for breast cancer. A comprehensive analysis of IDO expression in a well-defined cohort of esophageal adenocarcinoma (EAC) is missing. Methods. We analyzed 551 patients with EAC using single-protein and multiplex immunohistochemistry as well as mRNA in situ technology for the expression and distribution of IDO on subtypes of TILs (INF-γ mRNA and CD4- and CD8-positive T lymphocytes). Results. IDO expression on TILs was seen in up to 59.6% of tumors, and expression on tumor cells was seen in 9.2%. We found a strong positive correlation of IDO-positive TILs, CD3-positive T lymphocytes, and INF-γ mRNA-producing TILs in the tumor microenvironment of EACs showing significantly better overall survival (47.7 vs. 22.7 months, p

Due to the ongoing trend towards a decarbonisation of energy use, the power system is expected to become the backbone of all energy sectors and thus the fundamental critical infrastructure. High penetration with distributed energy resources demands the coordination of a large number of prosumers, partly controlled by home energy management systems (HEMS), to be designed in such a way that the power system’s operational limits are not violated. On the grid level, distribution management systems (DMS) seek to keep the power system in the normal operational state. On the prosumer level, distributed HEMS optimise the internal power flows by setpoint specification of batteries, photovoltaic generators, or flexible loads. The vision of the ODiS (Organic Distribution System) initiative is to develop an architecture to operate a distribution grid reliably, with high resiliency, and fully autonomously by developing “organic” HEMS and DMS which possess multiple self-x capabilities, collectively referred to as self-management. Thus, ODiS seeks answers to the following question: How can we create the most appropriate models, techniques, and algorithms to develop novel kinds of self-configuring, self-organising, self-healing, and self-optimising DMS that are integrally coupled with the distributed HEMS? In this concept paper, the vision of ODiS is presented in detail based on a thorough review of the state of the art.

Supervisor induction and continued professional development programmes constitute good practice and are enshrined in institutional policies and national codes of practice. However, there is little evidence about whether they have an impact on either supervisors' learning or day-to-day practice. Set in a discussion of previous literature, this article unpacks the concepts "impact" and "evaluation" and assesses the medium- and longer term impact of the University of South Australia's doctoral supervisor induction programme, "Supervising@UniSA." It suggests that the workshop leads to the acquisition of understanding and knowledge and, for the majority of attendees, also has an impact on supervisory practice.

Abstract Clinical research generally focuses on results involving a statistical mean with little attention in trial design to patients who respond considerably better or worse than average. Exploring the reasons underlying an “atypical response” will increase understanding of the mechanisms involved in cancer progression and treatment resistance, accelerate biomarker identification, and improve precision medicine by allowing clinicians to prospectively select optimal treatments. Based on our review, we suggest two ways to move this field forward. First, we suggest that clear categorization of “atypical responders” is needed. This encompasses three sub-categories of patients: “exceptional responders” (those with an unusually favorable treatment response), “rapid progressors” (patients demonstrating an unusually poor or no therapeutic response), and “exceptional survivors” (patients who have far outlived their initial prognosis). Such categorization may depend upon the clinical context and disease subtype. Second, we suggest that atypical responses may be due not only to somatic mutations in tumors, but also to inherited polymorphisms in non-tumor tissue, host and tumor environments, lifestyle factors, co-morbidities, use of complementary and integrative medicine, and the interaction among these components. Here, we summarize new research initiatives exploring atypical responses, the potential reasons for atypical responses, and a strategic call to action. Rigorous studies of normal and atypical responses to treatment will be needed to strengthen understanding of the role of non-tumor factors. Clinical trial design for targeted and other types of therapies should be enhanced to collect data in a standardized manner beyond tumor genetics, resulting in more thorough study of the whole patient.

Management of domesticated ungulates on grasslands has the potential to affect ecosystem function at landscape to global scales. In the southwestern United States, introduction of livestock in the 1800s corresponded with grassland degradation and dramatic shifts in vegetation, including the rapid spread of invasive plant species. In contemporary grasslands, however, evidence increasingly suggests that responsible grazing may enhance plant diversity in the region, though positive effects on diversity may or may not offer corresponding benefits to ecosystem function. Here, we examined the effects of grazing on land cover and functional composition of a semiarid grassland over a 20-year period. We found that high intensity grazing increased exposed soil and shifted community composition toward a greater proportion of annual and exotic species. This was particularly apparent following a severe drought event that initiated a significant loss of perennial plant cover, especially forbs, and was followed by a nearly 4-fold expansion of exotic species. Plots that were grazed at moderate levels consistently exhibited the lowest proportion of exotic species and were similar in functional group composition to exclosure plots. However, moderate grazing did increase soil exposure relative to exclosure plots. These findings suggest that moderate grazing could provide benefits to grassland ecosystem diversity and correlated ecosystem services like invasive species control and pollination services, while simultaneously increasing erosion, reducing water infiltration and altering nutrient cycling, due to increased soil exposure and disturbance. The potential for grazing to exert antagonistic effects on ecosystem services, depending on site conditions and grazing intensity, suggests that livestock management decisions should be tailored to individual management and conservation goals that address the inherent spatiotemporal variability of arid grasslands. Keywords: Plant functional groups, Climate change, Southwestern United States, Exotic species, Ecosystem services, Livestock management

Immune checkpoint modulation in cancer has been demonstrated as a high-value therapeutic strategy in many tumor entities. VISTA is an immune checkpoint receptor regulating T-cell function. To the best of our knowledge, nothing is known about the expression and prognostic impact of VISTA on tumor infiltrating lymphocytes (TILs) in the tumor microenvironment of esophageal adenocarcinoma (EAC). We analyzed in total 393 EACs within a test-cohort (n = 165) and a validation-cohort (n = 228) using a monoclonal antibody (clone D1L2G). These data were statistically correlated with clinical as well as molecular data. 22.2% of the tumor cohort presented with a VISTA expression on TILs. These patients demonstrated an improved median overall survival compared to patients without VISTA expression (202.2 months vs. 21.6 months; p

We show how optical free-electron lasers and enhanced incoherent Thomson scattering radiation sources can be realized with Traveling-Wave Thomson-Scattering (TWTS) today. Emphasis is put on the realization of optical free-electron lasers (OFELs) with existing state-of-the-art technology for laser systems and electron accelerators. The conceptual design of optical setups for the preparation of laser pulses suitable for TWTS OFELs and enhanced Thomson sources is presented. We further provide expressions to estimate the acceptable alignment tolerances of optical components for TWTS OFEL operation. Examples of TWTS OFELs radiating at 100 nm, 13.5 nm and 1.5 Å as well as an incoherent source producing 30 keV photons highlight the feasibility of the concept and detail the procedure to determine the optical components parameters of a TWTS setup.

The purpose of this study was to investigate the effect of age and oxidative stress on regulation of nuclear factor erythroid-2-related factor 2 (Nrf2) in young, old, and osteoarthritic (OA) human articular chondrocytes. Levels of Nrf2 in primary human chondrocytes isolated from young, old, and OA donors were measured by immunoblotting, qPCR, and immunohistochemistry. Effects on levels of Nrf2, antioxidant proteins regulated by Nrf2, as well as p65, and the anabolic response to insulin-like growth factor-1 (IGF-1) were evaluated after induction of oxidative stress with menadione, Nrf2 knockdown with siRNA, and/or Nrf2 activation with RTA-408. Nrf2 protein levels were significantly lower in older adult chondrocytes (∼0.59 fold; p = 0.034) and OA chondrocytes (∼0.50 fold; p = 0.016) compared to younger cells. Menadione significantly increased Nrf2 protein levels in young chondrocytes by just under four-fold without changes in old chondrocytes. Nrf2 knockdown and activation differentially regulated levels of anti-oxidant proteins including sulfiredoxin and NAD(P)H quinone dehydrogenase 1. Nrf2 activation with RTA-408 also decreased basal p65 phosphorylation, increased aggrecan and type II collagen gene expression, and increased production of proteoglycans in OA chondrocytes treated with IGF-1. Targeted therapeutic strategies aimed at maintaining Nrf2 activity could be useful in maintaining chondrocyte homeostasis through maintenance of intracellular antioxidant function and redox balance. [ABSTRACT FROM AUTHOR]

Abstract Background Intention-to-treat (ITT) analysis is commonly recommended for use, due to its benefits on external validity, in randomized, controlled trials (RCTs). No published reports describe how ITT analysis, as well as alternative approaches, are used in anti-infective RCTs. The purpose of this study is to describe the extent to which ITT analysis and alternative data approaches are used, the practices used to handle missing subject data, and whether non-inferiority trials present both ITT and per protocol (PP) analyses. Results of this analysis will help guide end users of infectious diseases primary drug literature. Methods A cross-sectional study of RCTs of anti-infectives published from January 1, 2013 through December 31, 2014 was conducted. A PubMed search identified relevant articles published in five specialty infectious diseases journals and four general medical journals. Each article was reviewed by two independent investigators with discrepancies resolved by consensus. Descriptive statistics were used to quantify results. Results One hundred four articles met study criteria. The most common medication classes represented in the RCTs were hepatitis C antivirals (26 %), antibacterials (25 %), and antiretrovirals (21 %). Thirty studies (29 %) were non-inferiority trials. Most studies (77 %) described use of ITT or modified ITT (mITT) in their methods. Of the ITT and mITT studies, most (73 %) did not describe practices used to handle missing data. Most (97 %) non-inferiority trials described use of ITT, mITT, or both; however, only 15 (50 %) also described use of PP. Conclusions RCTs of anti-infectives commonly employ ITT and mITT. Most do not describe how missing data were addressed. Non-inferiority trials of anti-infectives do not consistently employ both ITT and PP populations.

Introduction: Despite recent advances in critical care, sepsis remains a crucial cause of morbidity and mortality in intensive care units. Therefore, the identification of new therapeutic strategies is of great importance. Since ancient times, frankincense is used in traditional medicine for the treatment of chronic inflammatory disorders such as rheumatoid arthritis. Thus, the present study intends to evaluate if Casperome® (Casp), an orally bioavailable soy lecithin-based formulation of standardized frankincense extract, is able to ameliorate systemic effects and organ damages induced by severe systemic inflammation using a murine model of sepsis, i.e., intraperitoneal administration of lipopolysaccharides (LPS).Methods: Male 60-day-old mice were assigned to six treatment groups: (1) control, (2) LPS, (3) soy lecithin (blank lecithin without frankincense extract), (4) Casp, (5) soy lecithin plus LPS, or (6) Casp plus LPS. Soy lecithin and Casp were given 3 h prior to LPS treatment; 24 h after LPS administration, animals were sacrificed and health status and serum cytokine levels were evaluated. Additionally, parameters representing liver damage or liver function and indicating oxidative stress in different organs were determined. Furthermore, markers for apoptosis and immune cell redistribution were assessed by immunohistochemistry in liver and spleen.Results: LPS treatment caused a decrease in body temperature, blood glucose levels, liver glycogen content, and biotransformation capacity along with an increase in serum cytokine levels and oxidative stress in various organs. Additionally, apoptotic processes were increased in spleen besides a pronounced immune cell infiltration in both liver and spleen. Pretreatment with Casp significantly improved health status, blood glucose values, and body temperature of the animals, while serum levels of pro-inflammatory cytokines and oxidative stress in all organs tested were significantly diminished. Finally, apoptotic processes in spleen, liver glycogen loss, and immune cell infiltration in liver and spleen were distinctly reduced. Casp also appears to induce various cytochromeP450 isoforms, thus causing re-establishment of liver biotransformation capacity in LPS-treated mice.Conclusion: Casp displayed anti-inflammatory, anti-oxidative, and hepatoprotective effects. Thus, orally bioavailable frankincense extracts may serve as a new supportive treatment option in acute systemic inflammation and accompanied liver dysfunction.

We present picosecond Yb:YAG and Yb:CaF2 regenerative laser amplifiers with ultra-high repetition rates in the MHz range. A maximum pulse energy of 40 μJ was obtained at 20 kHz while we achieved around 1 μJ at 1 MHz. We demonstrated a pulse duration of 2.1 ps for Yb:YAG and 4.8 ps for Yb:CaF2 when seeded by a mode-locked Yb:KGW fs-oscillator without pulse stretching or phase compensation.

In captivity, positive human-animal interactions are often part of daily management procedures, which can enhance the welfare of animals and help caregivers with routine husbandry tasks. For example, the provisioning of food (produce or enrichment) can be an effective tool to reward animals for positive behavior. Another option is to use species-typical behavior to request an action on the part of the animal. In both captive and wild settings, chimpanzees (Pan troglodytes) use a variety of food vocalizations to announce the presence of different food sources. In this study, we examined how species-typical vocalizations (chimpanzee-based food calls, CBFCs) compared to human vocalizations (name-calling and encouragement, NCE) in relation to the shifting behavior of sanctuary chimpanzees at Chimp Haven, Inc., during routine husbandry tasks. Both CBFCs and NCE were associated with the provisioning of enrichment or produce, and observations were balanced for time of day. We found that CBFCs were slightly more effective in shifting of the chimpanzees when it was used along with the provisioning of enrichment (n = 22, p = 0.017). We also found that the chimpanzees were more likely to shift in the morning rather than in the afternoon (n = 34, p = 0.012). These results suggest that predictable schedules and the use of positive communication, whether it is in the form of a species-typical food call or the calling of a chimpanzee’s name and general positive encouragement, assisted in the daily management of chimpanzees housed in a sanctuary setting.