Infections with Clostridium difficile increasingly cause morbidity and mortality worldwide. Bacterial surface glycans including lipoteichoic acid (LTA) were identified as auspicious vaccine antigens to prevent colonization. Here, we report on the potential of synthetic LTA glycans as vaccine candidates. We identified LTA-specific antibodies in the blood of C. difficile patients. Therefore, we evaluated the immunogenicity of a semi-synthetic LTA-CRM glycoconjugate. The conjugate elicited LTA-specific antibodies in mice that recognized natural LTA epitopes on the surface of C. difficile bacteria and inhibited intestinal colonization of C. difficile in mice in vivo. Our findings underscore the promise of synthetic LTA glycans as C. difficile vaccine candidates.

Infections with Clostridioides difficile (formerly Clostridium difficile) have increased in incidence, morbidity, and mortality over the past decade. Preventing infections is becoming increasingly important, as frontline antibiotics become less effective and frequently induce recurrence by disrupting intestinal microbiota. The clinically most advanced vaccine approaches prevent symptoms once C. difficile infection is established by inducing immunity to secreted clostridial cytotoxins. However, they do not inhibit bacterial colonization and thereby favor asymptomatic carriage. Synthetic oligosaccharides resembling the C. difficile surface glycans PS-I, PS-II, and PS-III are immunogenic and serve as basis for colonization-preventing vaccines. Here, we demonstrate that glycoconjugate vaccine candidates based on synthetic oligosaccharides protected mice from infections with two different C. difficile strains. Four synthetic antigens, ranging in size from disaccharides to hexasaccharides, were conjugated to CRM197, which is a carrier protein used in commercial vaccines. The vaccine candidates induced glycan-specific antibodies in mice and substantially limited C. difficile colonization and colitis after experimental infection. The glycoconjugates ameliorated intestinal pathology more substantially than a toxin-targeting vaccine. Colonization of the gut by C. difficile was selectively inhibited while intestinal microbiota remained preserved. Passive transfer experiments with anti-PS-I serum revealed that protection is mediated by specific antiglycan antibodies; however, cell-mediated immunity likely also contributed to protection in vivo. Thus, glycoconjugate vaccines against C. difficile are a complementary approach to toxin-targeting strategies and are advancing through preclinical work.

The antifibrotic effect of atorvastatin has already been demonstrated in several organ systems. In the present study, a rat model was used to investigate the effect of atorvastatin on posttraumatic joint contracture. Forty-eight Sprague Dawley rats were equally randomized into an atorvastatin group and a control group. After initial joint trauma, knee joints were immobilized for intervals of 2 weeks (n = 16) or 4 weeks (n = 16) or immobilized for 4 weeks with subsequent remobilization for another 4 weeks (n = 16). Starting from the day of surgery, animals received either atorvastatin or placebo daily. After euthanasia at week 2, 4 or 8, joint contracture was determined, histological examinations were performed, and gene expression was assessed. The results suggest that the joint contracture was primarily arthrogenic. Atorvastatin failed to significantly affect contracture formation and showed a reduction in myofibroblast numbers to 98 ± 58 (control: 319 ± 113, p < 0.01) and a reduction in joint capsule collagen to 60 ± 8% (control: 73 ± 9%, p < 0.05) at week 2. Gene expression of α-smooth muscle actin (α-SMA), collagen type I, transforming growth factor β1 (TGF-β1) and interleukin-6 (IL-6) was not significantly affected by atorvastatin. Atorvastatin decreases myofibroblast number and collagen deposition but does not result in an improvement in joint mobility.

Purpose Personality traits, such as dispositional optimism and pessimism, have impact on a variety of health-related problems. Influence on outcome in total knee arthroplasty (TKA) could only be shown for other personality trait concepts, but not for dispositional optimism/pessimism. This study aims to examine the association of dispositional optimism/pessimism with pre-operative joint function and post-operative outcome in TKA. Methods Data were acquired in a multicentre, cross-sectoral, prospective study (the PROMISE Trial). Patients were followed for 12 months post-operatively. Dispositional optimism/pessimism was measured pre-operatively via the revised Life Orientation Test (LOT-R), pre- and post-operative function was measured via the 12 Item Knee-osteoarthritis outcome Scores (KOOS-12). Log-linear regression models considering known confounders and t-test were carried out to show the association of LOT-R scores with pre- and post-operative KOOS-12 scores. Results 740 patients were analyzed. Optimistic LOT-R was significantly positively associated to the mean scores of KOOS-12 pre- and post-operative, while pessimistic LOT-R was significantly associated negatively (pre-operative: optimistic p = 0.001, pessimistic p = 0.001; post-operative optimistic: 3M p = 0.001, 6M p = 0.001, 12M p = 0.001; post-operative pessimistic: 3M p = 0.01, 6M p = 0.004, 12M p = 0.001). Conclusion Optimism was positively associated with pre-operative joint function and, more importantly, post-operative functional outcome in TKA, while pessimism was associated with the opposite. Assessing patients’ general personality traits prior to surgery to identify pessimistic patients, hence being at risk for poor outcome in TKA, should be considered to react to the patients’ special needs and possible pessimistic expectations, i.e., through a cognitive–behavioral intervention, to potentially increase optimism and hereby post-operative outcome in TKA. Level of evidence Prognostic Level III.

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