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Bone healing complications such as delayed healing or non-union affect 5-10 % of patients with a long-bone fracture and lead to reduced quality of life and increased health-care costs. The gut microbiota and the metabolites they produce, mainly short-chain fatty acids (SCFAs), have been shown to impact nearly all organs of the human body including bone. SCFAs show broad activity in positively influencing bone healing outcomes either by acting directly on cell types involved in fracture healing, such as osteoblasts, osteoclasts, chondrocytes and fibroblasts, or indirectly, by shaping an appropriate anti-inflammatory and immune regulatory response. Due to the ability of SCFAs to influence osteoblast and osteoclast differentiation, SCFAs may also affect the integration of orthopaedic implants in bone. In addition, SCFA-derivatives have already been used in a variety of tissue engineering constructs to reduce inflammation and induce bone tissue production. The present review summarises the current knowledge on the role of the gut microbiota, in particular through the action of SCFAs, in the individual stages of bone healing and provides insights into how SCFAs may be utilised in a manner beneficial for fracture healing and surgical reconstruction.

The probiotic Bifidobacterium longum subsp. longum 35624® (B. longum 35624®), with its surface exopolysaccharide (EPS624), has previously been demonstrated to induce immunoregulatory responses in the host and may, therefore, be a novel approach to prevent bone loss in inflammatory conditions such as post-menopausal osteoporosis (PMO). The aim of this study was to investigate the effect of EPS624 on osteoclast and osteoblast differentiation and to assess the potential of B. longum 35624® to prevent bone loss in vivo. In vitro cell assays were used to assess the impact of EPS624 on osteoclast and osteoblast differentiation. The potential of two probiotic B. longum 35624® strains, including an EPS-deficient strain, for preventing ovariectomy (Ovx)-induced bone loss was assessed in a murine model. EPS624 prevented osteoclast formation from murine bone marrow precursors under both normal and TNFα-induced inflammatory conditions and modestly increased mineralized matrix deposition in osteogenic cell cultures. However, in the presence of an anti-TLR2 blocking antibody, or in MyD88−/− osteoclast precursors, the inhibitory effect of EPS624 on osteoclast formation was diminished or completely prevented, respectively. Moreover, EPS624 induced IL-10 production in osteoclast precursors in a TLR2-dependent manner, although IL-10 was dispensable in the EPS624-mediated inhibition of osteoclast formation. In addition, EPS624-producing B. longum 35624® partially prevented bone loss in Ovx mice when administered by oral gavage. This study introduced EPS624 as a potential anti-resorptive therapy, although optimal in vivo delivery of the probiotic strain for treating low-grade inflammatory diseases such as PMO remains to be determined.

Empirical research on environmental justice often simplifies normative implications, and ethical investigations in these fields often lack real-world complexity. A new working group bridges these gaps., GAIA - Ecological Perspectives for Science and Society, 30 (2), ISSN:0940-5550

The availability of attractive complementary products offered by a nearby company positively affects other companies in the value network of a winter sports destination. We aim to illustrate empirically the positive effects of the campaign of a local ski lift company in Switzerland on other companies in the same value network. For the first time in tourism research, the synthetic control method is used to investigate the impact of a new pricing strategy. In this case, the company’s practice of radically discounting the prices of its seasonal lift passes had a positive impact on accommodation businesses in the same winter sports destination. The impact amounts to about 35% additional overnight stays by domestic tourists per winter season that is a seasonal increase of 32,000 overnight stays. However, the ski lift company concluded that the campaign had been unsuccessful. We therefore discuss the difficulties of such a new pricing strategy and emphasize the importance of cooperation between independent companies in the wider destination area.

Evidence of observed negative impacts on natural and human systems from anthropogenic climate change is increasing. However, human systems in particular are dynamic and influenced by multiple drivers and hence identifying an anthropogenic climate signal is challenging. Here we analyze the case of lake Palcacocha in the Andes of Peru, which offers a representative model for other glacier lakes and related risks around the world because it features a dynamic evolution of flood risk driven by physical and socioeconomic factors and processes. Furthermore, it is the object of a prominent climate litigation case, wherein a local Peruvian citizen sued a large German energy producer over risk of flooding from lake Palcacocha. Adopting a conceptual model of cascading impacts and multiple drivers of risk, we first study climatic and other geophysical drivers of flood risk. We find that an anthropogenic signal from flood risk to greenhouse gas emissions is traceable. In parallel, flood risk has been strongly shaped (and increased) by interacting socioeconomic, institutional and cultural processes over the past few decades. The case raises important questions about the differentiation of responsibilities relating to flood risk of both global and local agents, which are, however, difficult to address in cases like Palcacocha, where we reveal a complex network of interlinked global, national and local drivers. Following from this, we outline a normative framework with a differentiated perspective on responsibility, implying that global emitters commit to support strengthening capacities in affected regions and localities and that local institutions and societies engage in local risk reduction measures and policies in collaboration with and driven by local communities.

Plasmodium spp., the causative agent of malaria, have a complex life cycle. The exponential growth of the parasites during the blood stage is responsible for almost all malaria-associated morbidity and mortality. Therefore, tight immune control of the intraerythrocytic replication of the parasite is essential to prevent clinical malaria. Despite evidence that the particular lymphocyte subset of γδ T cells contributes to protective immunity during the blood stage in naive hosts, their precise inhibitory mechanisms remain unclear. Using human PBMCs, we confirmed in this study that γδ T cells specifically and massively expanded upon activation with Plasmodium falciparum culture supernatant. We also demonstrate that these activated cells gain cytolytic potential by upregulating cytotoxic effector proteins and IFN-γ. The killer cells bound to infected RBCs and killed intracellular P. falciparum via the transfer of the granzymes, which was mediated by granulysin in a stage-specific manner. Several vital plasmodial proteins were efficiently destroyed by granzyme B, suggesting proteolytic degradation of these proteins as essential in the lymphocyte-mediated death pathway. Overall, these data establish a granzyme- and granulysin-mediated innate immune mechanism exerted by γδ T cells to kill late-stage blood-residing P. falciparum.

Background: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). Methods: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT–Elecsys) and 3 hs-cTnI assays (hs-cTnI–Architect, hs-cTnI–Access, hs-cTnI–Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. Results: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P P P TNNT2 , encoding cTnT (but none for TNNI3 , encoding cTnI) versus control subjects (n=16, P Wald R =0.59, P t-statistic R =0.26, P t-statistic =0.031). Conclusions: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03660969.

People with severe mental illness (SMI) are often in poor physical health, resulting in higher mortality and reduced life expectancy compared to the general population. Although eating habits are one of the main predictors of physical health, few studies assess the nutritional status and eating behavior of people with SMI. The aim of this study was to examine the nutritional status and risk of malnutrition in people with SMI who were in need of intensive psychiatric treatment. The cross-sectional study included 65 inpatients and 67 outpatients with psychotic or depressive disorders from the Psychiatric Hospital of the University of Zurich. Patients’ assessments at admission included anthropometric measurements, such as weight and height, and interview data including severity of symptoms and functioning (SCL-K-9, PHQ-D, CGI, m-GAF), personal and medical data, nutrition risk screening tools (adapted NRS, MNA-SF), and laboratory values. The results showed that 32% of the inpatients and 34% of the outpatients were at risk of malnutrition, which was associated with higher levels of psychiatric symptoms and lower levels of functioning. Regardless, the body mass index (BMI) was overweight in both groups (mean BMIinpatients = 25.3, mean BMIoutpatients = 27.9). These results indicate that a substantial proportion of psychiatric patients seems to be at risk of malnutrition, despite most being overweight, and hence they might benefit from nutritional support during their psychiatric treatment. Moreover, nutritional risk screening tools specifically developed for the mental healthcare setting are needed.