Vaccine-Preventable Disease Outbreaks among Healthcare Workers: A Scoping Review.

BACKGROUND: Outbreaks of vaccine preventable diseases (VPDs) in health care workers (HCWs) can result in morbidity and mortality and cause significant disruptions to health care services, patients and visitors as well as an added burden on the health system. This scoping review is aimed to describe the epidemiology of VPD outbreaks in HCW, caused by diseases which are prevented by the ten vaccines recommended by World Health Organization (WHO) for HCWs. METHODS: In April 2022 CINAHL, MEDLINE, Global Health and EMBASE were searched for all articles reporting on VPD outbreaks in HCWs since the year 2000. Articles were included regardless of language and study type. Clinical and epidemiological characteristics of VPD outbreaks were described. RESULTS: Our search found 9363 articles, of which 216 met inclusion criteria. Studies describing six of the ten VPDs were found: influenza, measles, varicella, tuberculosis, pertussis and rubella. Most articles (93%) were from high- and upper middle-income countries. While most outbreaks occurred in hospitals, several influenza outbreaks were reported in long term care facilities. Based on available data, vaccination rates amongst HCWs were rarely reported. CONCLUSION: We describe several VPD outbreaks in HCWs from 2000 to April 2022. The review emphasises the need to understand the factors influencing outbreaks in HCWs and highlight importance of vaccination amongst HCWs.

Disease-modifying interactions between chronic kidney disease and osteoarthritis: a new comorbid mouse model.

OBJECTIVE: The prevalence of comorbid chronic kidney disease (CKD) and osteoarthritis (OA) is increasing globally. While sharing common risk factors, the mechanism and consequences of concurrent CKD-OA are unclear. The aims of the study were to develop a preclinical comorbid model, and to investigate the disease-modifying interactions. METHODS: Seventy (70) male 8-10 week-old C57BL/6 mice were subjected to 5/6 nephrectomy (5/6Nx)±destabilisation of medial meniscus (DMM) or sham surgery. OA pathology and CKD were assessed 12 weeks postinduction by blinded histology scoring, micro-CT, immunohistochemistry for osteoclast and matrix metalloproteinase (MMP)-13 activity, and serum analysis of bone metabolic markers. RESULTS: The 5/6Nx model recapitulated characteristic features of CKD, with renal fibrosis and deranged serum alkaline phosphatase, calcium and phosphate. There was no histological evidence of cartilage pathology induced by 5/6Nx alone, however, synovial MMP-13 expression and subchondral bone osteoclastic activity were increased (p<0.05), with accompanying reductions (p<0.05) in subchondral trabecular bone, bone volume and mineral density. DMM significantly (p<0.05) increased tibiofemoral cartilage damage, subchondral bone sclerosis, marginal osteophytes and synovitis, in association with increased cartilage and synovial MMP-13. DMM alone induced (p<0.05) renal fibrosis, proteinuria and increased (p<0.05) 5/6Nx-induced serum urea. However, DMM in 5/6Nx-mice resulted in significantly reduced (p<0.05) cartilage pathology and marginal osteophyte development, in association with reduced subchondral bone volume and density, and inhibition of 5/6Nx-induced subchondral bone osteoclast activation. CONCLUSION: This study assessed a world-first preclinical comorbid CKD-OA model. Our findings demonstrate significant bidirectional disease-modifying interaction between CKD and OA.

Murine models of orthopedic infection featuring Staphylococcus aureus biofilm.

Introduction: Osteomyelitis remains a major clinical challenge. Many published rodent fracture infection models are costly compared with murine models for rapid screening and proof-of-concept studies. We aimed to develop a dependable and cost-effective murine bone infection model that mimics bacterial bone infections associated with biofilm and metal implants. Methods: Tibial drilled hole (TDH) and needle insertion surgery (NIS) infection models were compared in C57BL/6 mice (female, N = 150 ). Metal pins were inserted selectively into the medullary canal adjacent to the defect sites on the metaphysis. Free Staphylococcus aureus (ATCC 12600) or biofilm suspension (ATCC 25923) was locally inoculated. Animals were monitored for physiological or radiographic evidence of infection without prophylactic antibiotics for up to 14 d. At the end point, bone swabs, soft-tissue biopsies, and metal pins were taken for cultures. X-ray and micro-CT scans were performed along with histology analysis. Results: TDH and NIS both achieved a 100 % infection rate in tibiae when a metal implant was present with injection of free bacteria. In the absence of an implant, inoculation with a bacterial biofilm still induced a 40 %-50 % infection rate. In contrast, freely suspended bacteria and no implant consistently showed lower or negligible infection rates. Micro-CT analysis confirmed that biofilm infection caused local bone loss even without a metal implant as a nidus. Although a metal surface permissive for biofilm formation is impermeable to create progressive bone infections in animal models, the metal implant can be dismissed if a bacterial biofilm is used. Conclusion: These models have a high potential utility for modeling surgery-related osteomyelitis, with NIS being simpler to perform than TDH.

Modeling anabolic and antiresorptive therapies for fracture healing in a mouse model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a genetic bone fragility disorder that features frequent fractures. Bone healing outcomes are contingent on a proper balance between bone formation and resorption, and drugs such as bone morphogenetic proteins (BMPs) and bisphosphonates (BPs) have shown to have utility in modulating fracture repair. While BPs are used for OI to increase BMD and reduce pain and fracture rates, there is little evidence for using BMPs as local agents for fracture healing (alone or with BPs). In this study, we examined wild-type and OI mice (Col1a2+/G610C ) in a murine tibial open fracture model with (i) surgery only/no treatment, (ii) local BMP-2 (10 µg), or (iii) local BMP-2 and postoperative zoledronic acid (ZA; 0.1 mg/kg total dose). Microcomputed tomography reconstructions of healing fractures indicated BMP-2 was less effective in an OI setting, however, BMP-2 +ZA led to considerable increases in bone volume (+193% WT, p < 0.001; +154% OI, p < 0.001) and polar moment of inertia (+125% WT, p < 0.01; +248% OI, p < 0.05). Tissue histology revealed a thinning of the neocortex of the callus in BMP-2 treated OI bone, but considerable retention of woven bone in the healing callus with BMP + ZA specimens. These data suggest a cautious approach may be warranted with the sole application of BMP-2 in an OI surgical setting as a bone graft substitute. However, this may be overcome by off-label BP administration.

Preventing osteolytic lesions and osteomyelitis in multiple myeloma.

Multiple myeloma is a hematological malignancy affecting the plasma cells. It is the second most common hematologic cancer in adults. Over 90% of patients develop local osteolytic lesions and skeletal-related events at some point during the progression of the disease. Bone lesions can induce severe pain and immobility and can also increase the risk of fractures and osteomyelitis. Skeletal complications are associated with poor clinical outcomes, affecting quality of life and mortality. Current standards of care for myeloma, e.g., autologous stem-cell transplantation (ASCT) and chemotherapy, do not lessen the risk of adverse events in bone. Once bone lesions are present, bone-targeted interventions are limited, with bone antiresorptive drugs being a mainstay of treatment. This review highlights the growing literature surrounding osteolytic lesions and bone infections associated with multiple myeloma and assesses current and emerging treatments. Emerging evidence from clinical trials suggests that denosumab can reduce skeletal-related events, and the potential application of bortezomib/1D11 can reduce bone destruction and pathological fractures in MM patients. Once established, bone lesions are prone to develop osteomyelitis - especially in immunocompromised individuals. Antibiotics and surgical interventions have been used to manage bone infections in most reported cases. As the bone infection risk associated with MM bone lesions become more evident, there is scope to improve patient management by mitigating this risk with prophylactic antimicrobial therapy.

What's New in Cryptococcus gattii: From Bench to Bedside and Beyond.

Cryptococcus species are a major cause of life-threatening infections in immunocompromised and immunocompetent hosts. While most disease is caused by Cryptococcus neoformans, Cryptococcus gattii, a genotypically and phenotypically distinct species, is responsible for 11-33% of global cases of cryptococcosis. Despite best treatment, C. gattii infections are associated with early mortality rates of 10-25%. The World Health Organization's recently released Fungal Priority Pathogen List classified C. gattii as a medium-priority pathogen due to the lack of effective therapies and robust clinical and epidemiological data. This narrative review summarizes the latest research on the taxonomy, epidemiology, pathogenesis, laboratory testing, and management of C. gattii infections.

Synthesis and Characterization of Bone Binding Antibiotic-1 (BBA-1), a Novel Antimicrobial for Orthopedic Applications.

Osteomyelitis and orthopedic infections are major clinical problems, limited by a lack of antibiotics specialized for such applications. In this paper, we describe the design and synthesis of a novel bone-binding antibiotic (BBA-1) and its subsequent structural and functional characterization. The synthesis of BBA-1 was the result of a two-step chemical conjugation of cationic selective antimicrobial-90 (CSA-90) and the bisphosphonate alendronate (ALN) via a heterobifunctional linker. This was analytically confirmed by HPLC, FT-IR, MS and NMR spectroscopy. BBA-1 showed rapid binding and high affinity to bone mineral in an in vitro hydroxyapatite binding assay. Kirby-Baur assays confirmed that BBA-1 shows a potent antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus comparable to CSA-90. Differentiation of cultured osteoblasts in media supplemented with BBA-1 led to increased alkaline phosphatase expression, which is consistent with the pro-osteogenic activity of CSA-90. Bisphosphonates, such as ALN, are inhibitors of protein prenylation, however, the amine conjugation of ALN to CSA-90 disrupted this activity in an in vitro protein prenylation assay. Overall, these findings support the antimicrobial, bone-binding, and pro-osteogenic activities of BBA-1. The compound and related agents have the potential to ensure lasting activity against osteomyelitis after systemic delivery.

Personalized Baghdadite scaffolds: stereolithography, mechanics and in vivo testing.

An ongoing challenge in the field of orthopedics is to produce a clinically relevant synthetic ceramic scaffold for the treatment of 'critical-sized' bone defects, which cannot heal without intervention. We had developed a bioactive ceramic (baghdadite, Ca3ZrSi2O9) and demonstrated its outstanding bioactivity using traditional manufacturing techniques. Here, we report on the development of a versatile stereolithography printing technology that enabled fabrication of anatomically-shaped and -sized Baghdadite scaffolds. We assessed the in vivo bioactivity of these scaffolds in co-delivering of bone morphogenetic protein-2 (BMP2) and zoledronic acid (ZA) through bioresorbable coatings to induce bone formation and increase retention in a rat model of heterotopic ossification. Micro-computed tomography, histology, mechanical tests pre- and post-implantation, and mechanical modelling were used to assess bone ingrowth and its effects on the mechanics of the scaffolds. Bone ingrowth and the consequent mechanical properties of the scaffolds improved with increasing BMP2 dose. Co-delivery of ZA with BMP2 further improved this outcome. The significant bone formation within the scaffolds functionalized with 10 µg BMP2 and 2 µg ZA made them 2.3 × stiffer and 2.7 × stronger post-implantation and turned these inherently brittle scaffolds into a tough and deformable material. The effects of bone ingrowth on the mechanical properties of scaffolds were captured in a mechanical model that can be used in future clinical studies for non-destructive evaluation of scaffold's stiffness and strength as new bone forms. These results support the practical utilization of our versatile stereolithographic printing methods and BMP2/ZA functionalization to create fit-for-purpose personalized implants for clinical trials. STATEMENT OF SIGNIFICANCE: In this study, we addressed a long-standing challenge of developing a ceramic printing technology that enables fabrication of customizable anatomically-shaped and -sized bioceramic scaffolds with precise internal architectures using an inexpensive desktop printer. We also addressed another challenge related to delivery of pharmaceuticals. BMP2, currently available as a bone-inducing bioactive protein, is clinically administered in a collagen scaffold that has limited moldability and poor mechanical properties. The comparably stiffer and stronger 3D printed personalized Baghdadite scaffolds developed here can be readily functionalized with bioresorbable coatings containing BMP2 ± ZA. These innovations considerably improve on the prior art and are scalable for use in human surgery.

The application of ceragenins to orthopedic surgery and medicine.

Osteomyelitis and infections associated with orthopedic implants represent a significant burden of disease worldwide. Ceragenins (CSAs) are a relatively new class of small-molecule antimicrobials that target a broad range of Gram-positive and Gram-negative bacteria as well as fungi, viruses, and parasites. This review sets the context of the need for new antimicrobial strategies by cataloging the common pathogens associated with orthopedic infection and highlighting the increasing challenges of managing antibiotic-resistant bacterial strains. It then comparatively describes the antimicrobial properties of CSAs with a focus on the CSA-13 family. More recently developed members of this family such as CSA-90 and CSA-131 may have a particular advantage in an orthopedic setting as they possess secondary pro-osteogenic properties. In this context, we consider several new preclinical studies that demonstrate the utility of CSAs in orthopedic models. Emerging evidence suggests that CSAs are effective against antibiotic-resistant Staphylococcus aureus strains and can prevent the formation of biofilms. There remains considerable scope for developing CSA-based treatments, either as coatings for orthopedic implants or as local or systemic antibiotics to prevent bone infection.

MLST-Based Population Genetic Analysis in a Global Context Reveals Clonality amongst Cryptococcus neoformans var. grubii VNI Isolates from HIV Patients in Southeastern Brazil.

Cryptococcosis is an important fungal infection in immunocompromised individuals, especially those infected with HIV. In Brazil, despite the free availability of antiretroviral therapy (ART) in the public health system, the mortality rate due to Cryptococcus neoformans meningitis is still high. To obtain a more detailed picture of the population genetic structure of this species in southeast Brazil, we studied 108 clinical isolates from 101 patients and 35 environmental isolates. Among the patients, 59% had a fatal outcome mainly in HIV-positive male patients. All the isolates were found to be C. neoformans var. grubii major molecular type VNI and mating type locus alpha. Twelve were identified as diploid by flow cytometry, being homozygous (AαAα) for the mating type and by PCR screening of the STE20, GPA1, and PAK1 genes. Using the ISHAM consensus multilocus sequence typing (MLST) scheme, 13 sequence types (ST) were identified, with one being newly described. ST93 was identified from 81 (75%) of the clinical isolates, while ST77 and ST93 were identified from 19 (54%) and 10 (29%) environmental isolates, respectively. The southeastern Brazilian isolates had an overwhelming clonal population structure. When compared with populations from different continents based on data extracted from the ISHAM-MLST database (mlst.mycologylab.org) they showed less genetic variability. Two main clusters within C. neoformans var. grubii VNI were identified that diverged from VNB around 0.58 to 4.8 million years ago.