Outbreak of multidrug-resistant Salmonella infections in people linked to pig ear pet treats, United States, 2015-2019: results of a multistate investigation.

Background: International distribution of contaminated foods can be a source of Salmonella infections in people and can contribute to the spread of antimicrobial-resistant bacteria across countries. We report an investigation led by the United States Centers for Disease Control and Prevention, the Food and Drug Administration (FDA), and state governmental officials into a multistate outbreak of salmonellosis linked to pig ear pet treats. Methods: Pig ear treats and companion dogs were tested for Salmonella by state officials and the FDA. Products were traced back to the country of origin when possible. Cases were defined as outbreak illnesses in people associated with one of seven Salmonella serotypes genetically related to samples from pig ear pet treats, with isolation dates from June 2015 to September 2019. Whole genome sequencing (WGS) of isolates was used to predict antimicrobial resistance. Findings: The outbreak included 154 human cases in 34 states. Of these, 107 of 122 (88%) patients reported dog contact, and 65 of 97 (67%) reported contact with pig ear pet treats. Salmonella was isolated from 137 pig ear treats, including some imported from Argentina, Brazil, and Colombia, and from four dogs. WGS predicted 77% (105/137) of human and 43% (58/135) of pig ear treat isolates were resistant to ≥3 antimicrobial classes. Interpretation: This was the first documented United States multistate outbreak of Salmonella infections linked to pig ear pet treats. This multidrug-resistant outbreak highlights the interconnectedness of human health and companion animal ownership and the need for zoonotic pathogen surveillance to prevent human illness resulting from internationally transported pet food products. Funding: Animal Feed Regulatory Program Standards award. Animal and product testing conducted by FDA Vet-LIRN was funded by Vet-LIRN infrastructure grants (PAR-22-063).

Leadership in ophthalmology training : Opportunities and risks of medical specialist education.

Medical specialist training requires constant improvement and adaptation of the contents to the current situation. Nowadays, young physicians have the opportunity to select among the most renowned institutions and can choose the one most qualified for their training. Hospitals on the other hand still have the desire to recruit highly qualified physicians for their resident programs, which requires a good, well-rounded and reliable offer by the department under good leadership. Thus, among other issues a modern and multilingual homepage is already an important instrument for successfully addressing applicants and winning them over for the department. In addition to a well-planned and structured training plan (e.g., the "Homburg Curriculum") and a so-called "resident guide", many other additional offers are nowadays part of a successful training, such as structured internal and external specialist training courses, well thought out research concepts available to all interested parties, wet labs for practical exercises on pig's eyes and as the latest most innovative addition, a virtual reality simulator. Due to a structured curriculum with regular continuous education during the daily early morning meetings and an exchange program with another university eye hospital, not only the residents can benefit but ultimately also the department itself. In addition, future specialists are involved in the respective organization (so-called "service teams") from the very beginning. This conveys a great deal of knowledge and expertise but also organizational skills and thus improves the quality of training. In any case, standardized residency training with a view beyond the horizon, which is transparently organized and reliably carried out, improves the quality of training in order to become a certified ophthalmologist and increases the satisfaction of the residents. A department which is committed and can offer a wide range of services will benefit from motivated and satisfied employees in a good interpersonal climate, which in the end benefits not only the team but also the patients.

[Comparison of the Effect of Autologous Serum on Therapy Resistant Corneal Erosions and Ulcers on the Corneal Graft vs. the Patient's Own Cornea]. / Die Wirkung von autologen Serumaugentropfen bei therapieresistenten Erosiones und Ulcera der Kornea bei eigenem im Vergleich zu transplantiertem Gewebe.

PURPOSE: The aim of this study is to compare the healing of corneal epithelial defects or ulcers on the corneal graft in comparison with the patient's own cornea after treatment with 100%, undiluted autologous serum eye drops. METHODS: In a retrospective study over 7 years, we analysed 263 treatments with autologous serum eye drops of persistent corneal epithelial defects (erosions [88%] vs. ulcers [12%]). We compared the epithelial healing tendency of patients with defects on their own cornea (51.9%) vs. patients who had previously undergone penetrating keratoplasty (48.1%). Complete epithelial healing during the 28 days of treatment was considered as therapeutic success. In addition, the recurrence rate of the epithelial defects after finishing the therapy was analysed. RESULTS: 88.2% of the epithelial defects healed during 28 days of therapy. The recurrence rate during follow-up was 5.1%. There was no significant difference with respect to success rate between corneal defects on the patient's own cornea (87.8%) and on the graft (88.6%; p = 0.137). There was a significantly lower success rate for corneal ulcers (74.2%) than for erosions (90.3%; p < 0.001). The recurrence rate of erosions was 4.4%, vs. 4.3% in ulcers during follow-up. CONCLUSION: The results of our study suggest that autologous serum eye drops are a non-invasive and safe alternative treatment for persistent corneal epithelial defects - with no significant difference in patients with a defect on their own cornea vs. defects on the corneal graft. The success rate, but not the recurrence rate, is significantly worse in ulcers than in erosions.

Descemet's membrane endothelial keratoplasty is the predominant keratoplasty procedure in Germany since 2016: a report of the DOG-section cornea and its keratoplasty registry.

BACKGROUND/AIMS: This retrospective multicentric panel study provides absolute numbers, types of and indications for corneal transplantation in Germany from 2011 to 2021 and sets them into the international context. METHODS: A questionnaire was sent to the 104 German ophthalmologic surgery departments and 93 (89%) provided their data. RESULTS: The number of reported keratoplasties more than doubled from 2011 (n=4474) to 2021 (n=8998). Lamellar keratoplasties (49% posterior (n=2883), 4% anterior (n=231)) surpassed penetrating keratoplasty (PKP, 47%, n=2721) for the first time in 2014. Since 2016, Descemet's membrane endothelial keratoplasty (DMEK) has become the predominant keratoplasty procedure in Germany. Its number increased by 1.5-fold from 3850 (2016) to 5812 (2021). Main indications in 2021 were Fuchs' endothelial corneal dystrophy (FECD, 43%), pseudophakic corneal decompensation (12%), repeated keratoplasty (11%), infections (7%), keratoconus (6%) and corneal scarring (4%, others: 9%). The PKP percentage decreased from 70.2% in 2011 (n=3141) to 31.7% in 2021 (n=2853). Descemet's stripping (automated) endothelial keratoplasties (DSAEKs) decreased to 1% in 2021 (n=74). 98.6% of all posterior lamellar keratoplasties were DMEKs in Germany in 2021. The number of deep anterior lamellar keratoplasties (DALKs) remained comparable from 2011 (n=269) to 2021 (n=251, 2.8%). CONCLUSION: Main indications for corneal transplantation in Germany (2021) were FECD and pseudophakic corneal decompensation. DMEK is by far the predominant corneal transplantation procedure since 2016 followed by PKP, whose absolute number decreased only slightly during the decade from 2011 to 2021. DALK proportions remain low, but stable, whereas DSAEK decreased annually and plays a minor role in Germany. TRIAL REGISTRATION NUMBER: NCT03381794.

[Leadership in ophthalmology training : Opportunities and risks of medical specialist education]. / Führung in der augenärztlichen Ausbildung : Chancen und Risiken der Facharztweiterbildung.

Medical specialist training requires constant improvement and adaptation of the contents to the current situation. Nowadays, young physicians have the opportunity to select among the most renowned institutions and can choose the best qualified for their training. Hospitals on the other hand still have the desire to recruit highly qualified physicians for continuing education, which requires a good, well-rounded and reliable offer by the department under good leadership. Thus, among other issues a modern and multilingual homepage is already an important instrument for successfully addressing applicants and winning them over for the department. In addition to a well-planned and structured training plan (e.g., the Homburg curriculum) and a so-called resident guide, many other additional offers are nowadays part of a successful training, such as structured internal and external continuing education, well thought out research concepts available to all interested parties, wet labs for practical exercises on pig's eyes and as the latest most innovative addition, a virtual reality simulator. Due to a structured curriculum with regular continuous education during the daily early morning meetings and an exchange program with another university eye hospital, not only the residents can benefit but ultimately also the department itself. In addition, future specialists are involved in the respective organization (so-called service teams) from the very beginning. This conveys a great deal of knowledge and expertise but also organizational skills and thus improves the quality of training. In any case, standardized residency training with a view beyond the horizon, which is transparently organized and reliably carried out, improves the quality of training in order to become a certified ophthalmologist and increases the satisfaction of the residents. A department which is committed and can offer a wide range of services will benefit from motivated and satisfied employees in a good interpersonal climate, which in the end benefits not only the team but also the patients.

The antidiabetic drug metformin acts on the bone microenvironment to promote myeloma cell adhesion to preosteoblasts and increase myeloma tumour burden in vivo.

Multiple myeloma is a haematological malignancy that is dependent upon interactions within the bone microenvironment to drive tumour growth and osteolytic bone disease. Metformin is an anti-diabetic drug that has attracted attention due to its direct antitumor effects, including anti-myeloma properties. However, the impact of the bone microenvironment on the response to metformin in myeloma is unknown. We have employed in vitro and in vivo models to dissect out the direct effects of metformin in bone and the subsequent indirect myeloma response. We demonstrate how metformin treatment of preosteoblasts increases myeloma cell attachment. Metformin-treated preosteoblasts increased osteopontin (OPN) expression that upon silencing, reduced subsequent myeloma cell adherence. Proliferation markers were reduced in myeloma cells cocultured with metformin-treated preosteoblasts. In vivo, mice were treated with metformin for 4 weeks prior to inoculation of 5TGM1 myeloma cells. Metformin-pretreated mice had an increase in tumour burden, associated with an increase in osteolytic bone lesions and elevated OPN expression in the bone marrow. Collectively, we show that metformin increases OPN expression in preosteoblasts, increasing myeloma cell adherence. In vivo, this translates to an unexpected indirect pro-tumourigenic effect of metformin, highlighting the importance of the interdependence between myeloma cells and cells of the bone microenvironment.

Draft Genome Sequence of a Dictyoglomus sp. from an Enrichment Culture of a New Zealand Geothermal Spring.

A draft genome of a novel Dictyoglomus sp., NZ13-RE01, was obtained from a New Zealand hot spring enrichment culture. The 1,927,012-bp genome is similar in both size and G+C content to other Dictyoglomus spp. Like its relatives, Dictyoglomus sp. NZ13-RE01 encodes many genes involved in complex carbohydrate metabolism.

The Role of the Microenvironment in Prostate Cancer-Associated Bone Disease.

The bone is a common site for metastasis in patients with advanced prostate carcinoma, and provides a 'fertile' milieu which stimulates tumour growth and associated bone disease. For years, the concept of treatment strategies has remained targeting the tumour itself; however, the occurrence of chemoresistance remains a challenge now more than ever. The attraction of targeting the bone microenvironment in order to disrupt tumour localisation and proliferation stems from the idea that stromal cells are superiorly stable at a genetic level, thus decreasing the risk of resistance manifestation. In this review, we will discuss recent findings with regards to the pathogenesis of prostate cancer-induced bone disease and recent therapeutic strategies in an aim to evaluate the ever increasing role of the microenvironment in disease progression.

The role of interleukin-8 (IL-8) and IL-8 receptors in platinum response in high grade serous ovarian carcinoma.

Platinum based drugs are the cornerstone of chemotherapy for ovarian cancer, however the development of chemoresistance hinders its success. IL-8 is involved in regulating several pro-survival pathways in cancer. We studied the expression of IL-8 and IL-8 receptors in platinum sensitive and resistant cell lines. Using qRT-PCR and immunohistochemistry, both platinum sensitive (PEA1, PEO14) and resistant (PEA2, PEO23) show increased expression of IL-8 and IL-8 receptors. IL-8RA shows nuclear and cytoplasmic expression, whilst IL-8RB is present solely in the cytoplasm. Knockdown of IL-8 increased sensitivity to cisplatin in platinum sensitive and reversed platinum resistance in resistant cell lines, decreased the expression of anti-apoptotic Bcl-2 and decreased inhibitory phosphorylation of pro-apoptotic Bad. IL-8 receptor antagonist treatment also enhanced platinum sensitivity. Nuclear localisation of IL-8RA was only detected in platinum resistant tumours. Inhibition of IL-8 signalling can enhance response in platinum sensitive and resistant disease. Nuclear IL-8RA may have potential as a biomarker of resistant disease.

Prevalence of sexually transmitted co-infections in people living with HIV/AIDS: systematic review with implications for using HIV treatments for prevention.

Sexually transmitted co-infections increase HIV infectiousness through local inflammatory processes. The prevalence of STI among people living with HIV/AIDS has implications for containing the spread of HIV in general and the effectiveness of HIV treatments for prevention in particular. Here we report a systematic review of STI co-infections in people living with HIV/AIDS. We focus on STI contracted after becoming HIV infected. Electronic database and manual searches located 37 clinical and epidemiological studies of STI that increase HIV infectiousness. Studies of adults living with HIV/AIDS from developed and developing countries reported STI rates for 46 different samples (33 samples had clinical/laboratory confirmed STI). The overall mean point-prevalence for confirmed STI was 16.3% (SD=16.4), and median 12.4% STI prevalence in people living with HIV/AIDS. The most common STI studied were Syphilis with median 9.5% prevalence, Gonorrhea 9.5%, Chlamydia 5%, and Trichamoniasis 18.8% prevalence. STI prevalence was greatest at the time of HIV diagnosis, reflecting the role of STI in HIV transmission. Prevalence of STI among individuals receiving HIV treatment was not appreciably different from untreated persons. The prevalence of STI in people infected with HIV suggests that STI co-infections could undermine efforts to use HIV treatments for prevention by increasing genital secretion infectiousness.

Parathyroid hormone inhibits renal phosphate transport by phosphorylation of serine 77 of sodium-hydrogen exchanger regulatory factor-1.

Parathyroid hormone (PTH), via activation of PKC and/or protein kinase A, inhibits renal proximal tubular phosphate reabsorption by facilitating the internalization of the major sodium-dependent phosphate transporter, Npt2a. Herein, we explore the hypothesis that the effect of PTH is mediated by phosphorylation of serine 77 (S77) of the first PDZ domain of the Npt2a-binding protein sodium-hydrogen exchanger regulatory factor-1 (NHERF-1). Using recombinant polypeptides representing PDZ I, S77 of NHERF-1 is phosphorylated by PKC but not PKA. When expressed in primate kidney epithelial cells (BSC-1 cells), however, activation of either protein kinase phosphorylates S77, suggesting that the phosphorylation of PDZ I by PKC and PKA proceeds by different biochemical pathways. PTH and other activators of PKC and PKA dissociate NHERF-1/Npt2a complexes, as assayed using quantitative coimmunoprecipitation, confocal microscopy, and sucrose density gradient ultracentrifugation in mice. Murine NHERF-1-/- renal proximal tubule cells infected with adenovirus-GFP-NHERF-1 containing an S77A mutation showed significantly increased phosphate transport compared with a phosphomimetic S77D mutation and were resistant to the inhibitory effect of PTH compared with cells infected with wild-type NHERF-1. These results indicate that PTH-mediated inhibition of renal phosphate transport involves phosphorylation of S77 of the NHERF-1 PDZ I domain and the dissociation of NHERF-1/Npt2a complexes.

Selective cleavage of human IgG by the matrix metalloproteinases, matrilysin and stromelysin.

We have shown that two of the matrix metalloproteinases (MMPs), matrilysin and stromelysin-1, are capable of cleaving all of the human IgG subclasses. The cleavage occurs at a conserved site in the CH(2) domain of the heavy chain of IgG, releasing a single chain Fc-like fragment. We have not been able to demonstrate cleavage of IgA, IgD, IgM or IgE classes, which lack the cleavage site, nor could we show cleavage of IgG by collagenase, gelatinase, macrophage metalloelastase or membrane-type (MT)-MMP. This cleavage of IgG, by separating the antigen-binding (Fabprime prime or minute)(2) from the Fc portion, will remove much of the immunoglobulins' functionality, e.g. complement fixation, Fc receptor binding. In the context of a tumour producing matrilysin or stromelysin, this may represent a way in which the tumour protects itself from ADCC. In inflamed or damaged tissues where plasma protein leakage occurs, degradation by MMPs may be a mechanism for clearance of IgG.