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Diabetes is a well-recognised risk factor for the development of heart failure, with a prevalence higher than 30% in patients with diabetes aged over 60 years. Heart failure often emerges as the primary cardiovascular manifestation in patients with type 2 diabetes and appears to be even more prevalent in type 1 diabetes. In Switzerland, there are approximately 500,000 individuals with diabetes, and the number of affected people has been steadily rising in recent years. Therefore, the consequences of heart failure will affect an increasing number of patients, further straining the Swiss healthcare system. Early lifestyle modification and initiation of appropriate treatment can prevent or at least significantly delay the onset of symptomatic heart failure by several years. These facts underscore the urgent need for early detection of individuals with subclinical heart failure, which often remains undiagnosed until the first episode of acute heart failure requiring hospital admission occurs. To address this issue, the European Society of Cardiology, the American Diabetes Association (ADA) and other international professional societies have published recommendations on heart failure screening, diagnosis and management. To address this issue in Switzerland, experts from the Swiss Society of Endocrinology and Diabetology, the Swiss Society of Cardiology and the General Internal Medicine specialty met and prepared a consensus report including a simple diagnostic algorithm for use in everyday practice.

Abstract Rural regions in Europe are often structurally weaker than urban areas and are subject to strong socio-economic development. At the same time, they offer opportunities for a high quality of life and sustainability. The key question of this article is how quality of life in high-income countries can be achieved more sustainably. Little is known about the perception of the rural population itself on the reconciling of high quality of life with sustainability. Thus, based on a concept of sustainable quality of life, qualitative interviews with 90 rural residents were conducted to ask them which factors benefit sustainable quality of life. In the perception of the interview participants, a change in attitudes and values would be a starting point for shaping many other areas to enhance sustainable quality of life; social and legal norms should provide reference points for individuals and economic actors; infrastructure should support individuals in their ecological behaviour; and the economy should serve the common good. We derive four strands of recommendations for decision-makers from these results: the enhancement of education on applicable environmental behaviours, equal access to renewable energies and local productions and services.

Biosphere reserves and nature parks are protected areas that aim to combine nature conservation with human-development goals. These areas provide ideal environments for promoting and testing sustainable ways of living. The goal of this study was to determine how park management can best contribute to the quality of life of residents. The article presents the results of a survey in Switzerland of 2,409 residents of a biosphere reserve and two regional nature parks on the provision of quality of life. The results indicate that the quality of life in the parks is generally high. The identified dimensions that constitute this quality of life, their perceived importance, and the needs expressed by residents suggest that park management can help to increase and safeguard extant conditions by offering activities that improve health, social relations, and sustainable mobility. Awareness of how park management can contribute to the quality of life of park residents sustainably enables the setting of new priorities that have joint outputs that can be positive for both nature and people.

AimsThere is a considerable challenge in treating bone infections and orthopaedic device-associated infection (ODAI), partly due to impaired penetration of systemically administrated antibiotics at the site of infection. This may be circumvented by local drug administration. Knowledge of the release kinetics from any carrier material is essential for proper application. Ceftriaxone shows a particular constant release from calcium sulphate (CaSO4) in vitro, and is particularly effective against streptococci and a large portion of Gram-negative bacteria. We present the clinical release kinetics of ceftriaxone-loaded CaSO4 applied locally to treat ODAI.MethodsA total of 30 operations with ceftriaxone-loaded CaSO4 had been performed in 28 patients. Ceftriaxone was applied as a single local antibiotic in 21 operations and combined with vancomycin in eight operations, and in an additional operation with vancomycin and amphotericin B. Sampling of wound fluid was performed from drains or aspirations. Ceftriaxone concentrations were measured by liquid chromatography with tandem mass spectrometry (LC-MS/MS).ResultsA total of 37 wound fluid concentrations from 16 operations performed in 14 patients were collected. The ceftriaxone concentrations remained approximately within a range of 100 to 200 mg/l up to three weeks. The median concentration was 108.9 mg/l (interquartile range 98.8 to 142.5) within the first ten days. No systemic adverse reactions were observed.ConclusionOur study highlights new clinical data of locally administered ceftriaxone with CaSO4 as carrier material. The near-constant release of ceftriaxone from CaSO4 observed in vitro could be confirmed in vivo. The concentrations remained below known local toxicity thresholds.Cite this article: Bone Joint Res 2022;11(11):835–842.

Abstract Soluble αKlotho (sKl) is a disease-specific biomarker that is elevated in patients with acromegaly and declines after surgery for pituitary adenoma. Approximately 25% of patients do not achieve remission after surgery, therefore a risk stratification for patients early in the course of their disease may allow for the identification of patients requiring adjuvant treatment. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have been assessed as biomarker for disease activity, however the value of sKl as a predictive biomarker of surgical success has not been evaluated yet. In this study, we measured serum biomarkers before and after transsphenoidal pituitary surgery in 55 treatment-naïve patients. Based on biochemical findings at follow-up (7–16 years), we divided patients into three groups: (A) long-term cure (defined by normal IGF-1 and random low GH (

As a first step, the authors emphasise lifestyle changes (increased physical activity, stopping smoking), blood pressure control, and lowering cholesterol). The initial medical treatment should always be a combination treatment with metformin and a sodium-glucose transporter 2 (SGLT-2) inhibitor or a glucagon-like 1 peptide (GLP-1) receptor agonist. Metformin is given first and up-titrated, followed by SGLT-2 inhibitors or GLP-1 receptor agonists. In persons with type 2 diabetes, if the initial double combination is not sufficient, a triple combination (SGLT-2 inhibitor, GLP-1 receptor agonist, and metformin) is recommended. This triple combination has not been officially tested in cardiovascular outcome trials, but there is more and more real-world experience in Europe and in the USA that proves that the triple combination with metformin, SGLT-2 inhibitor, and GLP-1 receptor agonist is the best treatment to reduce 3-point MACE, total mortality, and heart failure as compared to other combinations. The treatment with sulfonylurea is no longer recommended because of its side effects and higher mortality compared to the modern treatment with SGLT-2 inhibitors and GLP-1 receptor agonists. If the triple combination is not sufficient to reduce the HbA1c to the desired target, insulin treatment is necessary. A quarter of all patients with type 2 diabetes (sometimes misdiagnosed) require insulin treatment. If insulin deficiency is the predominant factor at the outset of type 2 diabetes, the order of medications has to be reversed: insulin first and then cardio-renal protective medications (SGLT-2 inhibitors, GLP-1 receptor agonists).

Aims: In orthopaedic and trauma surgery, implant-associated infections are increasingly treated with local application of antibiotics, which allows a high local drug concentration to be reached without eliciting systematic adverse effects. While ceftriaxone is a widely used antibiotic agent that has been shown to be effective against musculoskeletal infections, high local concentrations may harm the surrounding tissue. This study investigates the acute and subacute cytotoxicity of increasing ceftriaxone concentrations as well as their influence on the osteogenic differentiation of human bone progenitor cells. Methods: Human preosteoblasts were cultured in presence of different concentrations of ceftriaxone for up to 28 days and potential cytotoxic effects, cell death, metabolic activity, cell proliferation, and osteogenic differentiation were studied. Results: Ceftriaxone showed a cytotoxic effect on human bone progenitor cells at 24 h and 48 h at concentrations above 15,000 mg/l. With a longer incubation time of ten days, subtoxic effects could be observed at concentrations above 500 mg/l. Gene and protein expression of collagen, as well as mineralization levels of human bone progenitor cells, showed a continuous decrease with increasing ceftriaxone concentrations by days 14 and 28, respectively. Notably, mineralization was negatively affected already at concentrations above 250 mg/l. Conclusion: This study demonstrates a concentration-dependent influence of ceftriaxone on the viability and mineralization potential of primary human bone progenitor cells. While local application of ceftriaxone is highly established in orthopaedic and trauma surgery, a therapeutic threshold of 250 mg/l or lower should diminish the risk of reduced osseointegration of prosthetic implants. Cite this article: Bone Joint Res 2021;10(3):218–225.

Background: Neuropsychiatric symptoms (NPS) and mild cognitive impairment (MCI) are common in Parkinson disease (PD) and have a negative impact on the patient’s quality of life (QoL). We aim to describe the effect of NPS and MCI on each other and on QoL. Methods: Sixteen MCI and 37 non-MCI PD patients completed different self-assessment questionnaires including the Parkinson’s Disease Questionnaire (PDQ-39), the Beck Depression Inventory (BD), the Beck Anxiety Inventory (BAI), and the Self-Report Manic Inventory (SRMI). Linear regression with stepwise elimination was used to select the significant predictors of QoL and to control for confounding factors. Results: The significant linear regression model (R2 = 0.68, p ≤ 0.01) revealed significant effects of MCI (p = 0.03), BDI (p ≤ 0.01), BAI (p ≤ 0.01), age (p = 0.03), a trend of SRMI (p = 0.06), and disease duration (p = 0.08) on QoL. Conclusions: MCI, anxiety, depression, and age decrease QoL in patients with PD. NPS has the main influence in the prediction of QoL in patients with PD, whereas MCI is only of minor importance.

Abstract Introduction Somatostatin‐secreting neuroendocrine tumours may present with diabetes, cholelithiasis and steatorrhoea. In addition, hypoglycaemia has been associated with somatostatinomas. However, the mechanism of hypoglycaemia in patients with somatostatinomas has not been well characterized. Methods We describe two patients with recurrent neuroglycopenic episodes caused by somatostatin‐secreting neuroendocrine tumours in the liver, detected by abdominal CTs and whole‐body octreotide scintigraphy scans and confirmed by biopsy. Results Pancreatic islet hyperplasia and co‐secretion of insulin (in addition to somatostatin) from tumour cells, respectively, have been characterized as completely distinct mechanisms of hypoglycaemia at both the functional and morphological levels in these two patients. Conclusions Hypoglycaemia may be caused by different mechanisms in patients with somatostatinomas.

Conjugate vaccines belong to the most efficient preventive measures against life-threatening bacterial infections. Functional expression of N-oligosaccharyltransferase (N-OST) PglB of Campylobacter jejuni in Escherichia coli enables a simplified production of glycoconjugate vaccines in prokaryotic cells. Polysaccharide antigens of pathogenic bacteria can be covalently coupled to immunogenic acceptor proteins bearing engineered glycosylation sites. Transfer efficiency of PglBCj is low for certain heterologous polysaccharide substrates. In this study, we increased glycosylation rates for Salmonella enterica sv. Typhimurium LT2 O antigen (which lacks N-acetyl sugars) and Staphylococcus aureus CP5 polysaccharides by structure-guided engineering of PglB. A three-dimensional homology model of membrane-associated PglBCj, docked to the natural C. jejuni N-glycan attached to the acceptor peptide, was used to identify potential sugar-interacting residues as targets for mutagenesis. Saturation mutagenesis of an active site residue yielded the enhancing mutation N311V, which facilitated fivefold to 11-fold increased in vivo glycosylation rates as determined by glycoprotein-specific ELISA. Further rounds of in vitro evolution led to a triple mutant S80R-Q287P-N311V enabling a yield improvement of S. enterica LT2 glycoconjugates by a factor of 16. Our results demonstrate that bacterial N-OST can be tailored to specific polysaccharide substrates by structure-guided protein engineering.

The treatment of critical size peripheral nerve defects represents one of the most serious problems in neurosurgery. If the gap size exceeds a certain limit, healing can't be achieved. Connection mismatching may further reduce the clinical success. The present study investigates how far specific surface structures support neurite outgrowth and by that may represent one possibility to push distance limits that can be bridged. For this purpose, growth cone displacement of fluorescent embryonic chicken spinal cord neurons was monitored using time-lapse video. In a first series of experiments, parallel patterns of polyimide ridges of different geometry were created on planar silicon oxide surfaces. These channel-like structures were evaluated with and without amorphous hydrogenated carbon (a-C:H) coating. In a next step, structured and unstructured textile fibers were investigated. All planar surface materials (polyimide, silicon oxide and a-C:H) proved to be biocompatible, i.e. had no adverse effect on nerve cultures and supported neurite outgrowth. Mean growth cone migration velocity measured on 5 minute base was marginally affected by surface structuring. However, surface structure variability, i.e. ridge height, width and inter-ridge spacing, significantly enhanced the resulting net velocity by guiding the growth cone movement. Ridge height and inter-ridge distance affected the frequency of neurites crossing over ridges. Of the evaluated dimensions ridge height, width, and inter-ridge distance of respectively 3, 10, and 10 µm maximally supported net axon growth. Comparable artificial grooves, fabricated onto the surface of PET fibers by using an excimer laser, showed similar positive effects. Our data may help to further optimize surface characteristics of artificial nerve conduits and bioelectronic interfaces.

Biosphere reserves and nature parks are protected areas that aim to combine nature conservation with human-development goals. These areas provide ideal environments for promoting and testing sustainable ways of living. The goal of this study was to determine how park management can best contribute to the quality of life of residents. The article presents the results of a survey in Switzerland of 2,409 residents of a biosphere reserve and two regional nature parks on the provision of quality of life. The results indicate that the quality of life in the parks is generally high. The identified dimensions that constitute this quality of life, their perceived importance, and the needs expressed by residents suggest that park management can help to increase and safeguard extant conditions by offering activities that improve health, social relations, and sustainable mobility. Awareness of how park management can contribute to the quality of life of park residents sustainably enables the setting of new priorities that have joint outputs that can be positive for both nature and people. [ABSTRACT FROM AUTHOR]

Abstract Background Protein glycosylation is of fundamental importance in many biological systems. The discovery of N-glycosylation in bacteria and the functional expression of the N-oligosaccharyltransferase PglB of Campylobacter jejuni in Escherichia coli enabled the production of engineered glycoproteins and the study of the underlying molecular mechanisms. A particularly promising application for protein glycosylation in recombinant bacteria is the production of potent conjugate vaccines where polysaccharide antigens of pathogenic bacteria are covalently bound to immunogenic carrier proteins. Results In this study capsular polysaccharides of the clinically relevant pathogen Staphylococcus aureus serotype 5 (CP5) were expressed in Escherichia coli and linked in vivo to a detoxified version of Pseudomonas aeruginosa exotoxin (EPA). We investigated which amino acids of the periplasmic domain of PglB are crucial for the glycosylation reaction using a newly established 96-well screening system enabling the relative quantification of glycoproteins by enzyme-linked immunosorbent assay. A random mutant library was generated by error-prone PCR and screened for inactivating amino acid substitutions. In addition to 15 inactive variants with amino acid changes within the previously known, strictly conserved WWDYG motif of N-oligosaccharyltransferases, 8 inactivating mutations mapped to a flexible loop in close vicinity of the amide nitrogen atom of the acceptor asparagine as revealed in the crystal structure of the homologous enzyme C. lari PglB. The importance of the conserved loop residue H479 for glycosylation was confirmed by site directed mutagenesis, while a change to alanine of the adjacent, non-conserved L480 had no effect. In addition, we investigated functional requirements in the so-called MIV motif of bacterial N-oligosaccharyltransferases. Amino acid residues I571 and V575, which had been postulated to interact with the acceptor peptide, were subjected to cassette saturation mutagenesis. With the exception of I571C only hydrophobic residues were found in active variants. Variant I571V performed equally well as the wild type, cysteine at the same position reduced glycoprotein yield slightly, while a change to phenylalanine reduced activity by a factor of three. Conclusions This study provides novel structure-function relationships for the periplasmic domain of the Campylobacter jejuni N-oligosaccharyltransferase PglB and describes procedures for generating and screening oligosaccharyltransferase mutant libraries in an engineered E. coli system.

Abstract Objective GH excess in acromegaly leads to lower fat mass and insulin resistance; both reverse following pituitary surgery. Soluble delta like-1 homolog (sDlk1) inhibits adipocyte differentiation and may mediate the antiadipogenic effects of GH. It is released into the circulation by ectodomain shedding through 'A Disintegrin And Metalloproteinase domain 17' (ADAM17), which also sheds soluble α-Klotho (sKlotho). Klotho is a transmembrane protein, which influences life span. sKlotho inhibits insulin signalling, and is markedly elevated in acromegaly and decreases after surgery. Therefore, we examined if sDlk1 parallels the course of sKlotho, which could explain the well-known changes in fat mass in patients with acromegaly after surgery. Design We measured serum levels of GH, IGF-1, sDlk1 and sKlotho (both by ELISA) in 42 treatment-naïve acromegaly patients (20 females/22 males) before and 1–3 months after transsphenoidal surgery. Data are presented as median(interquartile range). Results GH decreased in all patients postoperatively (in 32/42 to <1 ng/ml during oral glucose tolerance testing). Likewise, IGF-1 and sKlotho decreased in all patients, from 587 (432–708) to 195 (133–270) ng/ml, and from 4.0 (2.7–5.9) to 0.7 (0.6–1.2) ng/ml, respectively; sDlk1 fell in 40/42 subjects, from 10.7 (5.8–13.4) to 7.1 (3.7–10.4) ng/ml following pituitary surgery. P < 0.0001 for all parameters. Conclusions sDlk1 declined after pituitary surgery in our patients with acromegaly, but to a lesser extent than sKlotho. It remains to be seen whether this may contribute to the well-known postoperative changes in body composition. Our findings may extend beyond the scope of acromegaly, and thus further elucidate mechanisms in the fields of obesity and anti-ageing. Highlights • Growth hormone excess in acromegaly reduces fat mass and insulin sensitivity. • IGF-1 and soluble (s)Klotho decrease after pituitary surgery for acromegaly. • Soluble (s)Dlk-1 decreases after surgery in untreated patients with acromegaly. • Antiadipogenic effects of sDlk-1 may explain increasing fat mass after surgery. [ABSTRACT FROM AUTHOR]

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