Background
Tigecycline is a third‐line therapy for severe Clostridium difficile infection (CDI) in Australasian guidelines. Differences in strain types make it difficult to extrapolate international ...tigecycline efficacy data with combination or monotherapy to Australian practice, where experience is limited.
Aim
To evaluate the efficacy and adverse effects associated with tigecycline combination therapy for severe and severe‐complicated CDI in an Australian healthcare setting.
Methods
This was a retrospective observational study at a metropolitan university‐affiliated hospital. All patients between February 2013 and October 2016 treated with adjunctive intravenous tigecycline for >48 h for severe or severe‐complicated CDI were included. Tigecycline was given in addition to oral vancomycin ± intravenous metronidazole. The primary outcome was all‐cause mortality at 30 days from start of tigecycline combination therapy. Secondary outcomes included clinical cure, colectomy, adverse events and recurrence rates.
Results
Thirteen patients with median age of 61 years had severe (n = 9) or severe‐complicated (n = 4) CDI at tigecycline commencement. In 92% of patients, tigecycline started within 48 h after in‐hospital CDI treatment, for median duration of 9 days. All‐cause mortality at 30 days was 8% with no mortality in severe CDI and 25% (1/4) in patients with severe‐complicated fulminant CDI, comparing favourably with historical rates of 9–38% and 30–80% in similar respective groups. Clinical cure was achieved in 77% of cases. There were no colectomies and one attributable tigecycline adverse reaction.
Conclusions
Tigecycline appears safe and effective as a part of combination therapy in severe CDI, and may be given earlier and for shorter durations than in current guidelines.
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•Dendritic cells (DC) treated with 1,25-dihydroxyvitamin D (1,25D) alone show a tolerogenic DC phenotype.•1,25D-treated DC show altered oxidative phosphorylation and electron ...transport.•1,25D-treated DC show altered glycolysis and TCA cycle metabolism.•TCA effects of 1,25D enhance fatty acid synthesis by DC.•Fatty acid synthesis appears to be essential for DC tolerogenic effects of 1,25D.
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is a potent regulator of immune function, promoting anti-inflammatory, tolerogenic T cell responses by modulating antigen presentation by dendritic cells (DC). Transcriptomic analyses indicate that DC responses to 1,25D involve changes in glycolysis, oxidative phosphorylation, electron transport and the TCA cycle. To determine the functional impact of 1,25D-mediated metabolic remodelling, human monocyte-derived DC were differentiated to immature (+vehicle, iDC), mature (+LPS, mDC), and immature tolerogenic DC (+1,25D, itolDC) and characterised for metabolic function. In contrast to mDC which showed no change in respiration, itolDC showed increased basal and ATP-linked respiration relative to iDC. Tracer metabolite analyses using 13C -labeled glucose showed increased lactate and TCA cycle metabolites. Analysis of lipophilic metabolites of 13C-glucose revealed significant incorporation of label in palmitate and palmitoleate, indicating that 1,25D promotes metabolic fatty acid synthesis in itolDC. Inhibition of fatty acid synthesis in itolDC altered itolDC morphology and suppressed expression of CD14 and IL-10 by these cells. These data indicate that the ability of 1,25D to induce tolerogenic DC involves metabolic remodelling leading to synthesis of fatty acids.
BackgroundSome strains of non–multidrug-resistant, methicillin-resistant Staphylococcus aureus (nmMRSA) in Australia are likely to have emerged from strains of methicillin-susceptible S. aureus ...(MSSA) in remote Aboriginal communities ObjectiveTo describe the clinical epidemiology of infection due to community-associated MRSA strains in an Australian tropical hospital setting with a significant Aboriginal population and to compare infections caused by community-associated strains of MRSA, health-care–associated strains of MRSA, and MSSA strains with respect to demographic risk factors and clinical outcomes MethodsWe queried the microbiology database for the Top End of the Northern Territory, Australia, to determine population incidences for S. aureus infection and conducted a prospective matched case-control study to compare infection due to nmMRSA, MSSA, or multidrug-resistant MRSA at the Royal Darwin Hospital ResultsThe annual incidence of S. aureus bacteremia was 65 cases per 100,000 population, but in the Aboriginal population the incidence was 172 cases per 100,000 population (odds ratio OR compared with non-Aboriginal population, 5.8 95% confidence interval {CI}, 3.8–8.9). Female sex (adjusted OR aOR, 1.5 95% CI, 1.1–2.0) and remote residence (aOR, 1.8 95% CI, 1.2–2.5) were associated with the isolation of nmMRSA rather than MSSA, but disease spectrum and outcomes were similar. Among those from whom nmMRSA was isolated, Aboriginal patients were younger (aOR for each additional year, 0.94 95% CI, 0.92–0.96), more likely to be female (aOR, 3.8 95% CI, 1.7–8.5), and more likely to reside in a remote community (aOR, 29 95% CI, 8.9–94) than non-Aboriginal patients. The presence of Panton-Valentine leukocidin in nmMRSA was associated with double the odds of sepsis (aOR, 2.2 95% CI, 1.1–4.6) ConclusionsThe association of nmMRSA infection with female sex and remote residence supports the hypothesis that nmMRSA arose from MSSA strains in remote Aboriginal communities where staphylococcal disease is highly prevalent. The similar clinical spectrum and outcomes for nmMRSA infection and MSSA infection suggest that virulence is not correlated with resistance phenotype
Background. Regional differences in the prevalence of Panton-Valentine leukocidin (PVL) and PVL isoform- harboring strains as well as in the local population structure of Staphylococcus aureus may ...influence the clinical spectrum of S. aureus infections. Methods. Using a prospective collection of S. aureus isolates from northern Australia, we determined differences between infections caused by (1) PVL+ and PVL− isolates, (2) PVL histidine (H) isoform- and PVL arginine (R) isoform-harboring isolates, and (3) different lineages, including the genetically divergent clonal complex (CC) 75 and the PVL+ CC93. Results. PVL+ isolates comprised 54% (128/239) of community-associated methicillin-resistant isolates and 40% (95/239) of methicillin-susceptible S. aureus (MSSA) isolates. There were 113 H isoform- and 110 R isoform-harboring isolates. PVL was associated with truly community-acquired disease, younger age, and presentation with sepsis. We found no differences in infections due to H isoform-harboring isolates, compared with R isoform-harboring isolates. CC93 was the most prevalent lineage. The genetically divergent CC75 caused clinical disease similar to that of other S. aureus clones. Conclusions. PVL+ and PVL− infections are clearly distinct. MSSA contributes a large but underrecognized burden of PVL+ disease. Compared with elsewhere in the world, there is a relative abundance of the clade that contains CC93 and CC121 in both northern Australia and Asia.
Buruli ulcer (BU), caused by Mycobacterium ulcerans, is increasing in incidence in Victoria, Australia. To improve understanding of disease transmission, we aimed to map the location of BU lesions on ...the human body.
Using notification data and clinical records review, we conducted a retrospective observational study of patients diagnosed with BU in Victoria from 1998-2015. We created electronic density maps of lesion locations using spatial analysis software and compared lesion distribution by age, gender, presence of multiple lesions and month of infection.
We examined 579 patients with 649 lesions; 32 (5.5%) patients had multiple lesions. Lesions were predominantly located on lower (70.0%) and upper (27.1%) limbs, and showed a non-random distribution with strong predilection for the ankles, elbows and calves. When stratified by gender, upper limb lesions were more common (OR 1·97, 95% CI 1·38-2·82, p<0·001) while lower limb lesions were less common in men than in women (OR 0·48, 95% CI 0·34-0·68, p<0·001). Patients aged ≥ 65 years (OR 3·13, 95% CI 1·52-6·43, p = 0·001) and those with a lesion on the ankle (OR 2·49, 95% CI 1·14-5·43, p = 0·02) were more likely to have multiple lesions. Most infections (71.3%) were likely acquired in the warmer 6 months of the year.
Comparison with published work in Cameroon, Africa, showed similar lesion distribution and suggests the mode of M. ulcerans transmission may be the same across the globe. Our findings also aid clinical diagnosis and provide quantitative background information for further research investigating disease transmission.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Clostridioides difficile infection (CDI) remains a significant clinical challenge both in the management of severe and severe-complicated disease and the prevention of recurrence. Guidelines ...released by the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America (IDSA/SHEA) and ESCMID had some consensus as well as some discrepancies in disease severity classification and treatment recommendations. We review and compare the key clinical strategies from updated IDSA/SHEA, ESCMID and current Australasian guidelines for CDI management in adults and discuss relevant issues for clinicians, particularly in the management of severe-complicated infection.
Updated IDSA/SHEA and ESCMID guidelines now reflect the increased efficacy of fidaxomicin in preventing recurrence and have both promoted fidaxomicin to first-line therapy with an initial CDI episode in both non-severe and severe disease and endorsed the role of bezlotoxumab in the prevention of recurrent infection. Vancomycin remains acceptable therapy and metronidazole is not preferred. For severe-complicated infection the IDSA/SHEA recommends high-dose oral ± rectal vancomycin and IV metronidazole, whilst in an important development, ESCMID has endorsed fidaxomicin and tigecycline as part of combination anti-CDI therapy, for the first time. The role of faecal microbiota transplantation (FMT) in second CDI recurrence is now clearer, but timing and mode of FMT in severe-complicated refractory disease still requires further study.
Cigarette smoking is a risk factor for several diseases such as cancer, cardiovascular disease (CVD), and chronic obstructive pulmonary diseases (COPD), however, the underlying mechanisms are not ...fully understood. Alternative nicotine products with reduced risk potential (RRPs) including tobacco heating products (THPs), and e-cigarettes have recently emerged as viable alternatives to cigarettes that may contribute to the overall strategy of tobacco harm reduction due to the significantly lower levels of toxicants in these products’ emissions as compared to cigarette smoke. Assessing the effects of RRPs on biological responses is important to demonstrate the potential value of RRPs towards tobacco harm reduction. Here, we evaluated the inflammatory and signaling responses of human lung epithelial cells to aqueous aerosol extracts (AqE) generated from the 1R6F reference cigarette, the glo™ THP, and the Vype ePen 3.0 e-cigarette using multiplex analysis of 37 inflammatory and phosphoprotein markers. Cellular exposure to the different RRPs and 1R6F AqEs resulted in distinct response profiles with 1R6F being the most biologically active followed by glo™ and ePen 3.0. 1R6F activated stress-related and pro-survival markers c-JUN, CREB1, p38 MAPK and MEK1 and led to the release of IL-1α. glo™ activated MEK1 and decreased IL-1β levels, whilst ePen 3.0 affected IL-1β levels but had no effect on the signaling activity compared to untreated cells. Our results demonstrated the reduced biological effect of RRPs and suggest that targeted analysis of inflammatory and cell signaling mediators is a valuable tool for the routine assessment of RRPs.
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•Cigarette, heated tobacco product (HTP) and electronic cigarette toxicity were assessed.•Inflammatory and signalling responses in lung cells were evaluated.•Reference cigarette was significantly more active than the other products tested.•Approach can be used as part of weight of evidence evaluation of product risk.
Worldwide, musculoskeletal injuries remain a major problem for the Thoroughbred racing industry. There is a strong interest in developing training and management strategies to reduce the impact of ...musculoskeletal injuries, however, progress has been limited by studies reporting conflicting findings, and a limited understanding of the role of different training methods in preventing injury. There is little data on patterns of rest periods and exercise data and how these vary between trainers. This prospective study of two-year-old racehorses was conducted in Queensland, Australia and involved weekly personal structured interviews with 26 trainers over 56 weeks. Detailed daily exercise data for 535 horses providing 1258 training preparations and 7512 weeks at risk were collected. Trainers were categorised into three groups by the mean number of two-year-old horses that they had in work each week over the study duration: (1) Small stables with five or less, (2) Medium stables with 6 to 15 and (3) Large stables with greater than 15 horses in training. Differences between trainers with small, medium and large stable sizes were evaluated using linear regression, Kruskal-Wallis equality-of-populations rank test if linear models were mis-specified or Chi-squared tests for categorical variables. Significant differences were observed between trainers, with horses from larger stables accumulating a greater high-speed exercise volume (
< 0.001), attaining training milestones more frequently (
= 0.01) and taking less time to reach their training milestones (
= 0.001). This study provides detailed data to which training practices from other locations can be compared. Presenting actual training data rather than trainers' estimation of a typical program provides a more accurate assessment of training practices. Understanding how training practices vary between regions improves comparability of studies investigating risk factors and is an important step towards reducing the impact of musculoskeletal injuries.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Musculoskeletal injuries remain a global problem for the Thoroughbred racing industry and there is conflicting evidence regarding the effect of age on the incidence of injuries. The ideal time to ...commence race training is strongly debated, with limited supporting literature. There is also conflicting evidence regarding the effect of high-speed exercise on musculoskeletal injuries. There is a strong interest in developing training and management strategies to reduce the frequency of injuries. The types of musculoskeletal injuries vary between 2-year-old and older horses, with dorsal metacarpal disease the most common injury in 2-year-old horses. It is likely that risk factors for injury in 2-year-old horses are different than those for older horses. It is also likely that the risk factors may vary between types of injury. This study aimed to determine the risk factors for musculoskeletal injuries and dorsal metacarpal disease. We report the findings of a large scale, prospective observational study of 2-year-old horses in Queensland, Australia. Data were collected weekly for 56-weeks, from 26 trainers, involving 535 2-year-old Thoroughbred racehorses, 1, 258 training preparations and 7, 512-weeks of exercise data. A causal approach was used to develop our statistical models, to build on the existing literature surrounding injury risk, by incorporating the previously established causal links into our analyses. Where previous data were not available, industry experts were consulted. Survival analyses were performed using Cox proportional hazards or Weibull regression models. Analysis of musculoskeletal injuries overall revealed the hazard was reduced with increased exposure to high-speed exercise Hazard ratio (HR) 0.89, 95% Confidence Interval (CI) 0.84, 0.94,
p
< 0.001, increased number of training preparations (HR 0.58, 95% CI 0.50, 0.67,
p
< 0.001), increased rest before the training preparation (HR 0.89, 95% CI 0.83, 0.96,
p
= 0.003) and increased dam parity (HR 0.86, 95% CI 0.77, 0.97,
p
= 0.01). The hazard of injury was increased with increasing age that training commenced (HR 1.13, 95% CI 1.06, 1.19,
p
< 0.001). Analyses were then repeated with the outcome of interest dorsal metacarpal disease. Factors that were protective against dorsal metacarpal disease and musculoskeletal injuries overall included: increased total cumulative distance (HR 0.89, 95% CI 0.82, 0.97,
p
= 0.001) and total cumulative days exercised as a gallop (HR 0.96, 95% CI 0.92, 0.99,
p
= 0.03), the number of the training preparations (HR 0.43, 95% CI 0.30, 0.61,
p
< 0.001). The age that training commenced was harmful for both dorsal metacarpal disease (HR 1.17, 95% CI 1.07, 1.28,
p
< 0.001 and overall musculoskeletal injuries.). The use of non-ridden training modalities was protective for dorsal metacarpal disease (HR 0.89, 95% CI 0.81, 0.97,
p
= 0.008), but not musculoskeletal injuries overall. The male sex increased the hazard of DMD compared to females (HR 2.58, 95% CI 1.20, 5.56,
p
= 0.02), but not MSI overall. In summary, the hazard of musculoskeletal injury is greatest for 2-year-old horses that are born from uniparous mares, commence training at a later age, are in their first training preparation, have undertaken little high-speed exercise or had limited rest before their training preparation. The hazard of dorsal metacarpal disease is greatest for 2-year-old horses that are males, commence training at a later age, are in their first training preparation, have undertaken little high-speed exercise or had limited use of non-ridden training modalities. Close monitoring of these high-risk horses during their training program could substantially reduce the impact of MSI. Furthermore, an understanding of how training methodologies affect the hazard of MSI facilitates modification of training programs to mitigate the risk impact of injury. The strengths of this study include a large sample size, a well-defined study protocol and direct trainer interviews. The main limitation is the inherent susceptibility to survival bias.
•CD8+ T-cell function and mitochondrial mass decline in the bone marrow in MM and are lower than in matched peripheral blood.•These changes are linked to uptake of long-chain fatty acids, and T-cell ...function can be rescued by blockade of the lipid transporter FATP1.
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T cells demonstrate impaired function in multiple myeloma (MM) but suppressive mechanisms in the bone marrow microenvironment remain poorly defined. We observe that bone marrow CD8+ T-cell function is decreased in MM compared with controls, and is also consistently lower within bone marrow samples than in matched peripheral blood samples. These changes are accompanied by decreased mitochondrial mass and markedly elevated long-chain fatty acid uptake. In vitro modeling confirmed that uptake of bone marrow lipids suppresses CD8+ T function, which is impaired in autologous bone marrow plasma but rescued by lipid removal. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8+ T cells in MM, and FATP1 blockade also rescued CD8+ T-cell function, thereby identifying this as a novel target to augment T-cell activity in MM. Finally, analysis of samples from cohorts of patients who had received treatment identified that CD8+ T-cell metabolic dysfunction resolves in patients with MM who are responsive to treatment but not in patients with relapsed MM, and is associated with substantial T-cell functional restoration.
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