Clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation (CASSETTE)-an open-labelled pilot randomized controlled trial.

BACKGROUND: Combination antibiotic therapy with an antitoxin agent, such as clindamycin, is included in some guidelines for severe, toxin-mediated Staphylococcus aureus infections. The evidence to support this practice is currently limited to in vitro, animal and observational human case-series data, with no previous randomized controlled trials (RCTs). OBJECTIVES: This pilot RCT aimed to determine the feasibility of conducting a clinical trial to examine if adjunctive clindamycin with standard therapy has greater efficacy than standard therapy alone for S. aureus infections. METHODS: We performed an investigator-initiated, open-label, multicentre, pilot RCT (ACTRN12617001416381p) in adults and children with severe S. aureus infections, randomized to standard antibiotic therapy with or without clindamycin for 7 days. RESULTS: Over 28 months, across nine sites, 127 individuals were screened and 34 randomized, including 11 children (32%). The primary outcome-number of days alive and free of systemic inflammatory response syndrome ≤14 days-was similar between groups: clindamycin (3 days [IQR 1-6]) versus standard therapy (4 days [IQR 0-8]). The 90 day mortality was 0% (0/17) in the clindamycin group versus 24% (4/17) in the standard therapy group. Secondary outcomes-microbiological relapse, treatment failure or diarrhoea-were similar between groups. CONCLUSIONS: As the first clinical trial assessing adjunctive clindamycin for S. aureus infections, this study indicates feasibility and that adults and children can be incorporated into one trial using harmonized endpoints, and there were no safety concerns. The CASSETTE trial will inform the definitive S. aureus Network Adaptive Platform (SNAP) trial, which includes an adjunctive clindamycin domain and participants with non-severe disease.

Hospitalisation for lower respiratory tract infection is associated with an increased incidence of acute myocardial infarction and stroke in tropical Northern Australia.

Acute respiratory infections appear to precipitate vascular events. Acute myocardial infarction (AMI) and stroke are the leading cause of death and disability globally. This study was based on a cohort of patients admitted to Townsville University Hospital between January 2006 and December 2016. Using a self-controlled case series design, we investigated the risk of AMI or ischaemic stroke after an episode of pneumonia. We defined the 'risk interval' as the first 14 days after hospitalisation for pneumonia and the 'control interval' as one year before and one year after the risk interval. Among a population (N = 4557) with a median age of over 70, a total of 128 AMI and 27 stroke cases were identified within 1 year of an episode of pneumonia in this study. Ten and two admissions occurred during the risk interval, while 118 and 25 admissions occurred during the control period. The relative incidence ratios (RIR) of AMI increased after an episode of pneumonia (RIR=4.85, 95% confidence interval (CI) 2.44-9.67). The risk for stroke after the exposure period of 14 days was 4.94 (95% CI 1.12-21.78) considering only the first stroke incidence. The RIR results for AMI and stroke were not altered by adjusting for age, sex or Indigenous status. The risk of AMI and stroke were significantly higher two weeks after an episode of pneumonia.

IgM in human immunity to Plasmodium falciparum malaria.

Most studies on human immunity to malaria have focused on the roles of immunoglobulin G (IgG), whereas the roles of IgM remain undefined. Analyzing multiple human cohorts to assess the dynamics of malaria-specific IgM during experimentally induced and naturally acquired malaria, we identified IgM activity against blood-stage parasites. We found that merozoite-specific IgM appears rapidly in Plasmodium falciparum infection and is prominent during malaria in children and adults with lifetime exposure, together with IgG. Unexpectedly, IgM persisted for extended periods of time; we found no difference in decay of merozoite-specific IgM over time compared to that of IgG. IgM blocked merozoite invasion of red blood cells in a complement-dependent manner. IgM was also associated with significantly reduced risk of clinical malaria in a longitudinal cohort of children. These findings suggest that merozoite-specific IgM is an important functional and long-lived antibody response targeting blood-stage malaria parasites that contributes to malaria immunity.

Hidradenitis suppurativa: a review with a focus on treatment data.

Hidradenitis suppurativa (HS) is a chronic disease of the follicular unit that often leads to marked impairment of quality of life and usually affects the axillary, perineum and inframammary regions resulting in tender subcutaneous nodules, abscesses, fibrosis and sinus tract formation. New updates on HS underscores the role of various genes as well as the innate and adaptive immune response in its pathogenesis. Although every patient requires an individualized approach to treatment, topical therapy and antibiotics are mainly used for mild to moderate disease, whereas various systemic immune modulators and/or surgical approaches play a pivotal role in moderate to severe disease. New treatments using various immune modulators, laser modalities and other novel agents provide clinicians with better ways of managing HS.

Electrobrasion vs. manual dermabrasion: a randomized, double-blind, comparative effectiveness trial.

BACKGROUND: Electrobrasion, like dermabrasion, is a method of surgical planing that is purported to improve postoperative scarring. Data regarding its benefits and harms relative to dermabrasion are absent. OBJECTIVE: To compare the efficacy and potential harms of electrobrasion and dermabrasion. METHODS: This was a pragmatic, randomized, double-blind, split-scar intervention in patients with suboptimal surgical outcomes. Half of the wound was randomized to treatment with dermabrasion and half to electrobrasion. At 3-month follow-up, both the patient and a blinded investigator evaluated the wound. RESULTS: Electrobrasion and dermabrasion reduced the mean scores of the Manchester Scar Scale 1·6 and 1·3 points from baseline, respectively (P = 0·0003). The difference between treatments was not significant (P = 0·08). Global cosmetic improvement by physician and patient assessment indicated clinical improvement for both procedures but did not demonstrate statistical significance between treatments (P = 0·57, P = 0·32 for physician and patient, respectively). CONCLUSIONS: Both dermabrasion and electrobrasion improved scars, but there was no significant difference between the outcomes of the two procedures on several measures. Procedure time and bleeding time were significantly lower for electrobrasion.

If there is an evolutionary selection pressure for the high frequency of MBL2 polymorphisms, what is it?

Either immune selection or stochastic processes may have influenced the frequency of highly polymorphic genes such as mannose-binding lectin 2 (MBL2). This pattern recognition receptor of the innate immune system recognizes and binds to pathogenic microorganisms and apoptotic cells leading to lectin pathway complement killing or clearance. In almost all of a large number of studies in different ethnic groups worldwide there is 20-25% carriage of low MBL2 haplotypes, with 8-10% of each population having no MBL detectable in the blood. The source of this high variability of MBL2 remains cryptic. It arises from six main snps in the prompter and exon regions of the gene that assort into seven common haplotypes under linkage disequilibrium. While global studies of MBL2 show that it is not under immune selection pressure, these results are not the same when the same population genetic tools are used on large national studies. Other analyses point to the silenced MBL1 pseudogene and development of promoter polymorphisms in humans as evidence of selection pressure favouring low-producing haplotypes. While these analyses cannot be reconciled readily, there are two processes by which MBL heterozygosity could have been advantageous in an evolutionary sense; protection against adverse effects of various infectious diseases and lethal manifestations of atherosclerosis - a disease that now seems to have a more ancient history than assumed previously. Ultimately, consideration of the context for possible future therapeutic manipulation of MBL means that this can proceed independently of resolution of the evolutionary forces that have shaped MBL2 polymorphism.

Aspergillus arachnoiditis post intrathecal baclofen pump insertion.

This report describes an unusual fungal infection of an intrathecal baclofen pump which, to our knowledge, has not been reported previously. We describe a 39-year-old man with severe lower limb spasticity due to secondary progressive multiple sclerosis that was managed with insertion of an intrathecal baclofen pump. He subsequently presented with distinct neurological decline secondary to an intrathecal baclofen pump infection with Aspergillus terreus.

Computer-assisted analysis of abrasive transepithelial brush biopsies increases the effectiveness of esophageal screening: a multicenter prospective clinical trial by the EndoCDx Collaborative Group.

BACKGROUND: The sensitivity of screening for Barrett's esophagus (BE) and esophageal dysplasia (ED) is hampered by the limited amount of tissue that can be sampled by forceps biopsy (FB). AIM: The aim of this study was to evaluate computer assisted analysis of an abrasive, transepithelial brush biopsy as an adjunct to FB to increase detection of BE and ED. METHODS: This was a multicenter prospective trial of patients being screened for BE and ED. Each patient had two brush biopsies (BB) and then random four-quadrant FB every 1-2 cm of the esophagus. All BB were examined with computer assistance by pathologists at CDx Laboratories (Suffern, NY), and all FB were examined by the investigators' local pathologists. RESULTS: Of 1,266 patients enrolled, 363 were diagnosed with BE by FB alone and 146 additional cases of BE were identified by adding BB. The addition of BB to FB increased the overall detection of BE by 39.8% (95% CI 32-48%). This added detection of BE in 11.5% of all patients tested with the BB (146/1266) resulted in a number of patients needed to test (NNT) to obtain each additional positive finding of Barrett's esophagus of 8.7. Among a subset of 848 patients with gastroesophageal reflux disease and no prior history of BE, the addition of BB to FB identified an additional 105 patients with BE increasing the overall detection of BE by 70.5% (95% CI 54-90%). Dysplasia was diagnosed in 16 patients by FB alone, with an additional 14 cases detected by adding BB. The addition of BB to FB thus increased the detection of ED by 87.5%. CONCLUSION: These results suggest that adjunctive computer-assisted analysis of an abrasive brush biopsy has the potential to substantially improve the detection of Barrett's esophagus and dysplasia in screening populations.

Portable video media for presenting informed consent and wound care instructions for skin biopsies: a randomized controlled trial.

BACKGROUND: In fast-paced dermatology clinics, the process of obtaining informed consents for biopsies and providing postprocedure instructions may be incomplete and inconsistent. OBJECTIVES: To compare effectiveness of video-based education with that of verbal education for giving informed consent and providing postprocedure wound care instructions in patients undergoing skin biopsies. METHODS: In this randomized controlled trial, participants were randomized to receive either video education on portable video devices or conventional verbal instructions regarding skin biopsies. Participants completed a skin-biopsy knowledge assessment, patient satisfaction assessment and evaluation of educational medium. Main outcome measures were differences in the changes in the prestudy and poststudy knowledge assessment scores, patient satisfaction and evaluation of the educational medium. RESULTS: Eight-four patients undergoing skin biopsies at the University of California Davis dermatology clinic participated in the study. Participants in the control group had a nonstatistically significant increase in knowledge score (mean ± SD 1·12 ± 1·74), whereas those in the video group had a statistically significant increase in knowledge score (mean ± SD 1·55 ± 1·71). The difference in knowledge scores between the video and verbal groups was not statistically significant. Participants in both groups were highly satisfied with the biopsy education. On a 10-point scale, the mean ± SD usefulness and appeal of the videos were 9·01 ± 1·5 and 9·01 ± 1·66, respectively. CONCLUSIONS: Our study demonstrated a significant increase in knowledge score following video education, but not following oral education. Although between-group comparisons did not achieve statistical significance, portable video media for presenting informed consent and wound care instructions for skin biopsies appear to be more effective and result in higher satisfaction than traditional oral education.

Mannose-binding lectin and susceptibility to tuberculosis: a meta-analysis.

It has been proposed that mannose-binding lectin (MBL) levels may impact upon host susceptibility to tuberculosis (TB) infection; however, evidence to date has been conflicting. We performed a literature review and meta-analysis of 17 human trials considering the effect of MBL2 genotype and/or MBL levels and TB infection. No significant association was demonstrated between MBL2 genotype and pulmonary TB infection. However, the majority of studies did not report MBL2 haplotype inclusive of promoter polymorphisms. Serum MBL levels were shown to be consistently elevated in the setting of TB infection. While this may indicate that high MBL levels protect against infection with TB, the increase was also of a degree consistent with the acute-phase reaction. This analysis suggests that the relatively poorly characterized MBL2 genotypes reported are not associated significantly with susceptibility to pulmonary TB infection, but high MBL serum levels may be.

Association between severe pandemic 2009 influenza A (H1N1) virus infection and immunoglobulin G(2) subclass deficiency.

BACKGROUND: . Severe pandemic 2009 influenza A virus (H1N1) infection is associated with risk factors that include pregnancy, obesity, and immunosuppression. After identification of immunoglobulin G(2) (IgG(2)) deficiency in 1 severe case, we assessed IgG subclass levels in a cohort of patients with H1N1 infection. METHODS: Patient features, including levels of serum IgG and IgG subclasses, were assessed in patients with acute severe H1N1 infection (defined as infection requiring respiratory support in an intensive care unit), patients with moderate H1N1 infection (defined as inpatients not hospitalized in an intensive care unit), and a random sample of healthy pregnant women. RESULTS: Among the 39 patients with H1N1 infection (19 with severe infection, 7 of whom were pregnant; 20 with moderate infection, 2 of whom were pregnant), hypoabuminemia (P < .001), anemia (P < .001), and low levels of total IgG (P= .01), IgG(1) (P= .022), and IgG(2) (15 of 19 vs 5 of 20; P= .001; mean value +/- standard deviation [SD], 1.8 +/- 1.7 g/L vs 3.4 +/- 1.4 g/L; P= .003) were all statistically significantly associated with severe H1N1 infection, but only hypoalbuminemia (P= .02) and low mean IgG(2) levels (P= .043) remained significant after multivariate analysis. Follow-up of 15 (79%) surviving IgG(2)-deficient patients at a mean (+/- SD) of 90 +/- 23 days (R, 38-126) after the initial acute specimen was obtained found that hypoalbuminemia had resolved in most cases, but 11 (73%) of 15 patients remained IgG(2) deficient. Among 17 healthy pregnant control subjects, mildly low IgG(1) and/or IgG(2) levels were noted in 10, but pregnant patients with H1N1 infection had significantly lower levels of IgG(2) (P= .001). CONCLUSIONS: Severe H1N1 infection is associated with IgG(2) deficiency, which appears to persist in a majority of patients. Pregnancy-related reductions in IgG(2) level may explain the increased severity of H1N1 infection in some but not all pregnant patients. The role of IgG(2) deficiency in the pathogenesis of H1N1 infection requires further investigation, because it may have therapeutic implications.

Leptotrichia endocarditis: report of two cases from the International Collaboration on Endocarditis (ICE) database and review of previous cases.

Leptotrichia species typically colonize the oral cavity and genitourinary tract. We report the first two cases of endocarditis secondary to L. goodfellowii sp. nov. Both cases were identified using 16S rRNA gene sequencing. Review of the English literature revealed only two other cases of Leptotrichia sp. endocarditis.

Low mannose-binding lectin complement activation function is associated with predisposition to Legionnaires' disease.

Innate immune system deficiency may predispose to severe infections such as Legionnaires' disease. We have investigated the role of mannose-binding lectin (MBL) deficiency in the Melbourne Aquarium Legionnaires' disease outbreak. Serum samples from patients and controls that were exposed but shown to be uninfected from the Melbourne Aquarium Legionnaires' disease outbreak were tested for MBL function (C4 deposition) and level (mannan-binding). MBL function was lower in Legionnaires' disease cases than in age- and sex-matched uninfected, exposed controls. The frequency of MBL deficiency with C4 deposition < 0.2 U/microl was significantly higher in Legionnaires' disease cases than in controls. This also applied to Legionnaires' disease cases requiring hospital care. There was no difference in MBL mannan-binding levels between Legionnaires' disease patients and controls. There was no significant interval change in MBL function or level after a mean of 46 days. MBL complement activation functional deficiency appears to predispose to Legionnaires' disease.

Number V Oral lichen planus: clinical features and management.

Oral lichen planus (OLP) is a relatively common chronic inflammatory disorder affecting stratified squamous epithelia. Whereas in the majority of instances, cutaneous lesions of lichen planus (LP) are self-limiting and cause itching, oral lesions in OLP are chronic, rarely undergo spontaneous remission, are potentially premalignant and are often a source of morbidity. Current data suggest that OLP is a T cell-mediated autoimmune disease in which auto-cytotoxic CD8+ T cells trigger apoptosis of oral epithelial cells. The characteristic clinical aspects of OLP may be sufficient to make a correct diagnosis if there are classic skin lesions present. An oral biopsy with histopathologic study is recommended to confirm the clinical diagnosis and mainly to exclude dysplasia and malignancy. The most commonly employed and useful agents for the treatment of lichen planus (LP) are topical corticosteroids but other newer agents are available.

Mannose binding lectin acute phase activity in patients with severe infection.

Mannose Binding Lectin (MBL) is a liver derived, circulating plasma protein that plays a pivotal role in innate immunity. MBL functions as a pathogen recognition molecule, opsonising organisms and initiating the complement cascade. MBL deficiency arising from mutations and promoter polymorphisms in the MBL2 gene is common and has been associated with risk, severity, and frequency of infection in a number of clinical settings. With MBL therapy on the horizon, the usefulness of replacement MBL therapy has been challenged by the notion, that as an acute phase protein, MBL levels may rise under stress to sufficient levels, in individuals who are usually deficient. This report demonstrates that in patients with sepsis and septic shock, the majority of patients do not display an MBL acute phase response: 41.4% of individuals maintained consistent MBL levels throughout hospital stay, 31.3% of individuals demonstrated a positive acute phase response, and a negative acute phase response was observed in 27.3% of individuals studied. Importantly, a positive acute phase response was generally observed in individuals with wild-type MBL2 genes. When a positive acute phase response was observed in individuals with coding mutation, these individuals demonstrated a normal MBL level on admission to hospital. Furthermore, no individual, regardless of genotype who was MBL deficient at admission was able to demonstrate a positive acute phase response into the normal MBL range. These findings indicate MBL demonstrates a variable acute phase response in the clinical setting of sepsis and septic shock.