Further research effectively targeting the mediators of MBD, targeting both bone resorption and bone formation, is urgently needed. This should translate promptly to clinical trials of combination therapy comprising anti-resorptives and bone anabolic therapies to demonstrate efficacy and improved outcomes over BPs.

Animal models of multiple myeloma vary in terms of consistency of onset, degree of tumour burden and degree of myeloma bone disease. Here we describe five pre-clinical models of myeloma in NOD/SCID-GAMMA mice to specifically study the effects of therapeutic agents on myeloma bone disease. Groups of 7–8 week old female irradiated NOD/SCID-GAMMA mice were injected intravenously via the tail vein with either 1x106 JJN3, U266, XG-1 or OPM-2 human myeloma cell lines or patient-derived myeloma cells. At the first signs of morbidity in each tumour group all animals were sacrificed. Tumour load was measured by histological analysis, and bone disease was assessed by micro-CT and standard histomorphometric methods. Mice injected with JJN3, U266 or OPM-2 cells showed high tumour bone marrow infiltration of the long bones with low variability, resulting in osteolytic lesions. In contrast, mice injected with XG-1 or patient-derived myeloma cells showed lower tumour bone marrow infiltration and less bone disease with high variability. Injection of JJN3 cells into NOD/SCID-GAMMA mice resulted in an aggressive, short-term model of myeloma with mice exhibiting signs of morbidity 3 weeks later. Treating these mice with zoledronic acid at the time of tumour cell injection or once tumour was established prevented JJN3-induced bone disease but did not reduce tumour burden, whereas, carfilzomib treatment given once tumour was established significantly reduced tumour burden. Injection of U266, XG-1, OPM-2 and patient-derived myeloma cells resulted in less aggressive longer-term models of myeloma with mice exhibiting signs of morbidity 8 weeks later. Treating U266-induced disease with zoledronic acid prevented the formation of osteolytic lesions and trabecular bone loss as well as reducing tumour burden whereas, carfilzomib treatment only reduced tumour burden. In summary, JJN3, U266 or OPM-2 cells injected into NOD/SCID-GAMMA mice provide robust models to study anti-myeloma therapies, particularly those targeting myeloma bone disease.

BackgroundChronic otitis media with effusion (COME) is a prevalent upper airway infection resulting in hearing loss. The aim of this research was to determine risk factors for COME in preschool children.MethodsA case–control design was conducted in Auckland, New Zealand from May 2011 until November 2013. The cases were children aged 3 and 4 years referred for tympanostomy tube placement due to a diagnosis of COME (n = 178). The controls were a random sample of healthy children aged 3 and 4 years from primary care practices (n = 209). The children’s guardians completed an interviewer-administered questionnaire that covered topics including socio-demographic information, pregnancy and birth, infant feeding practices, home environment, and respiratory health. In addition, skin prick tests for atopy were performed. Odds ratios (OR) estimating the risk of COME independently associated with the exposures were calculated using a logistic regression model.ResultsChildren with COME frequently had nasal obstruction (OR: 4.38 [95% CI: 2.37–8.28]), always snored (OR: 3.64 [95% CI: 1.51–9.15]) or often snored (OR: 2.45 [95% CI: 1.04–5.96]), spent more hours per week in daycare (OR per hour/week: 1.03 [95% CI: 1.00–1.05]), had frequent colds (OR: 2.67 [95% CI: 1.59–4.53]), had siblings who had undergone tympanostomy tube placement (OR: 2.68 [95% CI: 1.22–6.02]), underwent long labour (OR: 2.59 [95% CI: 1.03–6.79]), and had early introduction of cow’s milk (OR: 1.76 [95% CI: 1.05–2.97]). Asian ethnicity (OR: 0.20 [95% CI: 0.07–0.53]) and having older siblings (OR: 0.54 [95% CI: 0.31–0.93]) were inversely associated with COME.ConclusionCOME in preschool children was associated with pathogen exposure, respiratory infection, and nasal obstruction. Strategies to prevent pathogen transmission warrant investigation. The novel findings of long labour and early cow’s milk introduction require replication in future studies.

Objectives Chronic otitis media with effusion (COME) in children can cause prolonged hearing loss, which is associated with an increased risk of learning delays and behavioural problems. Dispersal of bacterial pathogens from the nasal passages to the middle ear is implicated in COME. We sought to determine whether there is an association between nasal microbial composition and COME in children. Methods A case-control study of children aged 3 and 4 years was conducted. Cases undergoing placement of tympanostomy tubes for COME were compared to healthy controls. Nasal swabs were collected and a questionnaire was administered. The V1-3 region of the 16S rRNA gene was amplified, and sequenced on the Illumina MiSeq. Results 73 children with COME had a lower Shannon diversity index than 105 healthy controls (1.62 [.80] versus 1.88 [.84], respectively; P = .046). The nasal microbiota of cases and controls differed in composition using Bray-Curtis dissimilarity (p = 0.002). Children with COME had a higher abundance of otopathogens and lower abundance of commensals including alpha haemolytic Streptococci and Lactococcus . Cluster analysis revealed 4 distinct nasal microbial profiles. Profiles that were Corynebacterium -dominated (aOR 4.18 [95%CI, 1.68–10.39], Streptococcus -dominated (aOR 3.12 [95%CI, 1.08–9.06], or Moraxella -dominated (aOR 4.70 [95%CI, 1.73–12.80] were associated with COME, compared to a more mixed microbial profile when controlling for age, ethnicity, and recent antibiotics use. Conclusions Children with COME have a less diverse nasal microbial composition with a higher abundance of pathogens, compared to healthy children who have a more mixed bacterial profile with a higher abundance of commensals. Further research is required to determine how nasal microbiota may relate to the pathogenesis or maintenance of COME, and whether modification of the nasal microbiota can prevent or treat children at risk of COME.