Risk factors for TB in Australia and their association with delayed treatment completion.

BACKGROUND: Australia has a low incidence of TB and has committed to eliminating the disease. Identification of risk factors associated with TB is critical to achieving this goal.METHODS: We undertook a prospective cohort study involving persons receiving TB treatment in four Australian jurisdictions. Risk factors and their association with delayed treatment completion (treatment delayed by at least 1 month) were analysed using univariate analyses and multivariate logistic regression.RESULTS: Baseline surveys were completed for 402 persons with TB. Most (86.1%) were born overseas. Exposure to a person with TB was reported by 19.4%. Diabetes mellitus (10.2%), homelessness (9.2%), cigarette smoking (8.7%), excess alcohol consumption (6.0%) and mental illness (6.2%) were other common risk factors. At follow-up, 24.8% of patients had delayed treatment completion, which was associated with adverse events (34.1%, aOR 6.67, 95% CI 3.36-13.27), excess alcohol consumption (6.0%, aOR 21.94, 95% CI 6.03-79.85) and HIV co-infection (2.7%, aOR 8.10, 95% CI 1.16-56.60).CONCLUSIONS: We identified risk factors for TB and their association with delayed treatment completion, not all of which are routinely collected for surveillance purposes. Recognition of these risk factors should facilitate patient-centred care and assist Australia in reaching TB elimination.

The impact of Recovery Colleges on mental health staff, services and society.

AIMS: Recovery Colleges are opening internationally. The evaluation focus has been on outcomes for Recovery College students who use mental health services. However, benefits may also arise for: staff who attend or co-deliver courses; the mental health and social care service hosting the Recovery College; and wider society. A theory-based change model characterising how Recovery Colleges impact at these higher levels is needed for formal evaluation of their impact, and to inform future Recovery College development. The aim of this study was to develop a stratified theory identifying candidate mechanisms of action and outcomes (impact) for Recovery Colleges at staff, services and societal levels. METHODS: Inductive thematic analysis of 44 publications identified in a systematised review was supplemented by collaborative analysis involving a lived experience advisory panel to develop a preliminary theoretical framework. This was refined through semi-structured interviews with 33 Recovery College stakeholders (service user students, peer/non-peer trainers, managers, community partners, clinicians) in three sites in England. RESULTS: Candidate mechanisms of action and outcomes were identified at staff, services and societal levels. At the staff level, experiencing new relationships may change attitudes and associated professional practice. Identified outcomes for staff included: experiencing and valuing co-production; changed perceptions of service users; and increased passion and job motivation. At the services level, Recovery Colleges often develop somewhat separately from their host system, reducing the reach of the college into the host organisation but allowing development of an alternative culture giving experiential learning opportunities to staff around co-production and the role of a peer workforce. At the societal level, partnering with community-based agencies gave other members of the public opportunities for learning alongside people with mental health problems and enabled community agencies to work with people they might not have otherwise. Recovery Colleges also gave opportunities to beneficially impact on community attitudes. CONCLUSIONS: This study is the first to characterise the mechanisms of action and impact of Recovery Colleges on mental health staff, mental health and social care services, and wider society. The findings suggest that a certain distance is needed in the relationship between the Recovery College and its host organisation if a genuine cultural alternative is to be created. Different strategies are needed depending on what level of impact is intended, and this study can inform decision-making about mechanisms to prioritise. Future research into Recovery Colleges should include contextual evaluation of these higher level impacts, and investigate effectiveness and harms.

Multidrug-resistant tuberculosis in Australia, 1998-2012.

OBJECTIVE: To describe the epidemiology and outcomes of multidrug-resistant tuberculosis (MDR-TB) diagnosed in Australia between 1998 and 2012. DESIGN: A retrospective review was undertaken involving all patients with laboratory-confirmed MDR-TB notified in Australia between 1998 and 2012 inclusive. Demographic, clinical and laboratory features are described. Clinical outcomes were defined according to World Health Organization definitions of treatment success (cure and treatment completion), treatment failure, death, loss to follow-up (including transfer out), or not evaluated at treatment completion. RESULTS: A total of 244 cases of MDR-TB were diagnosed in Australia during the study period, representing 1.4% of all TB cases notified. The majority were born outside Australia, including one third in Papua New Guinea. Of those with treatment outcome data available, treatment success was demonstrated in 81%. Treatment success was positively associated with use of a second-line injectable agent. Those born in Papua New Guinea were less likely to achieve treatment success. CONCLUSION: MDR-TB is uncommon in Australia. The large number of cases born in Papua New Guinea, and the poorer outcomes in this cohort, represent challenges with cross-border management of MDR-TB in the Torres Strait. Australia has an ongoing role in the prevention and management of MDR-TB locally and in the region.

Effects of mild cognitive impairment on emotional scene memory.

Young and older adults experience benefits in attention and memory for emotional compared to neutral information, but this memory benefit is greatly diminished in Alzheimer's disease (AD). Little is known about whether this impairment arises early or late in the time course between healthy aging and AD. This study compared memory for positive, negative, and neutral items with neutral backgrounds between patients with mild cognitive impairment (MCI) and healthy older adults. We also used a divided attention condition in older adults as a possible model for the deficits observed in MCI patients. Results showed a similar pattern of selective memory for emotional items while forgetting their backgrounds in older adults and MCI patients, but MCI patients had poorer memory overall. Dividing attention during encoding disproportionately reduced memory for backgrounds (versus items) relative to a full attention condition. Participants performing in the lower half on the divided attention task qualitatively and quantitatively mirrored the results in MCI patients. Exploratory analyses comparing lower- and higher-performing MCI patients showed that only higher-performing MCI patients had the characteristic scene memory pattern observed in healthy older adults. Together, these results suggest that the effects of emotion on memory are relatively well preserved for patients with MCI, although emotional memory patterns may start to be altered once memory deficits become more pronounced.

Epigenetic analysis of the IFNλ3 gene identifies a novel marker for response to therapy in HCV-infected subjects.

Chronic hepatitis C virus (HCV) infection is characterized by high interindividual variability in response to pegylated interferon and ribavirin. A genetic polymorphism on chromosome 19 (rs12979860) upstream of interferon-λ3 (IFNλ3) is associated with a twofold change in sustained virologic response rate after 48 weeks of treatment with pegylated interferon/ribavirin in HCV genotype 1 (GT1) treatment-naïve patients. We conducted epigenetic analysis on the IFNλ3 promoter to investigate whether DNA methylation is associated with response to HCV therapy. DNA samples from HCV GT1-infected subjects receiving an interferon-free paritaprevir-containing combination regimen (N=540) and from HCV-uninfected, healthy controls (N=124) were analysed for IFNλ3 methylation levels. Methylation was strongly associated with rs12979860 allele status whether adjusting for HCV status (r=65.0%, 95% CI: [60.2%, 69.5%]), or not (r=64.4%), both with P<2.2×10-16 . In HCV GT1-infected subjects, C/C genotypes had significantly lower methylation levels relative to C/T or T/T genotypes (P<1×10-14 ), with each T allele resulting in a nine-unit increase in mean methylation level. Methylation levels did not correlate with response in subjects treated for 12 or 24 weeks. However, non-C/C subjects with higher methylation levels were more likely to relapse when treatment duration was 8 weeks. This analysis suggests that methylation status of the IFNλ3 promoter region may be a useful parameter that identifies patients more likely to relapse following HCV therapy; however, continuing therapy for a sufficient duration can overcome this difference. These findings may provide mechanistic insight into the role of IFNλ3 genetic variants in HCV treatment response.

Serum miR-122 may serve as a biomarker for response to direct acting antivirals: effect of paritaprevir/R with dasabuvir or ombitasvir on miR-122 in HCV-infected subjects.

Circulating microRNAs (miRNA) have been intensely investigated as biomarkers in disease and therapy. Several studies have identified miR-122 as an important regulator of HCV replication. The effect of new therapies that directly target the HCV replication life cycle on circulating microRNA levels has not been elucidated. We performed expression profiling of circulating miRNA in serum in subjects treated with HCV direct-acting antiviral agents (DAAs). Serum miRNA levels were evaluated from two studies in HCV GT1-infected treatment-naïve subjects and prior nonresponders to pegylated interferon (pegIFN) and ribavirin (RBV) who received paritaprevir/ritonavir + dasabuvir + RBV for 12 weeks, and in treatment-naïve genotype (GT)1-3-infected subjects who received paritaprevir/ritonavir + ombitasvir ± RBV for 12 weeks. Over 100 different miRNA species were detected in serum. Of these, levels of miR-122 showed the most consistent change in response to treatment across all HCV genotypes. In all subjects, miR-122 showed an average four-fold reduction between baseline and week 2, and remained below baseline through post-treatment week 12 in subjects who achieved sustained virological response. In contrast, in subjects who did not achieve SVR, miR-122 levels began to return to baseline levels after the second week of treatment. The change in miR-122 levels was similar across genotypes, and was comparable with or without RBV. This is the first report comparing expression levels of circulating miRNA in HCV GT1-3 subjects treated with IFN-free combinations of DAAs. The results suggest that serum levels of miR-122 are reduced following treatment in subjects who achieve SVR, and correlate with HCV RNA levels across genotypes.

Impact of 5-HTTLPR on hippocampal subregional activation in older adults.

Studies have shown that a functional polymorphism of the serotonin transporter gene (5-HTTLPR) impacts performance on memory-related tasks and the hippocampal structures that subserve these tasks. The short (s) allele of 5-HTTLPR has been linked to greater susceptibility for impaired memory and smaller hippocampal volume compared to the long allele (l). However, previous studies have not examined the associations between 5-HTTLPR allele and activation in subregions of the hippocampus. In this study, we used functional magnetic resonance imaging (fMRI) to measure activation in hippocampal and temporal lobe subregions in 36 elderly non-clinical participants performing a face-name encoding and recognition task. Although there were no significant differences in task performance between s allele carriers and l homozygotes, right CA1 and right parahippocampal activation during recognition errors was significantly greater in individuals bearing the s allele. In an exploratory analysis, we determined that these effects were more pronounced in s allele carriers with the apolipoprotein ɛ4 allele. Our results suggest that older individuals with the s allele inefficiently allocate neural resources while making errors in recognizing face-name associations, which could negatively impact memory performance during more challenging tasks.

Circulating mycobacterial-reactive CD4+ T cells with an immunosuppressive phenotype are higher in active tuberculosis than latent tuberculosis infection.

BACKGROUND: Previous studies suggest that control of Mycobacterium tuberculosis infection is compromised by the activity of regulatory T cells, including those that express CD39, an ectonucleotidase with immunosuppressive properties. Here, we examine the role of CD39 on CD4+ T cells reacting to M. tuberculosis antigens. METHODS: Cryopreserved PBMC from patients with active TB (n = 31) or individuals with LTBI (n = 30) were cultured with PPD, ESAT-6 or CFP-10 and antigen-reactive CD4+ T cells assessed by: A) intracellular expression of interferon-gamma (IFN-γ), tumour necrosis factor alpha (TNF-α) and interleukin (IL)-2, B) co-expression of CD25 and CD134 with or without CD39, and C) production of IFN-γ, TNF-α and IL-10 in culture supernatants. RESULTS: Active TB patients were not differentiated from individuals with LTBI by intracellular expression of IFN-γ, TNF-α or IL-2 (alone or together), nor by co-expression of CD25 and CD134. However, active TB patients exhibited higher proportions of CD25+, CD134+, CD4+ T cells expressing CD39 in response to all antigens (p ≤ 0.022). Furthermore, in response to PPD, CD39 expression on CD25+, CD134+, CD4+ T cells correlated with IL-10 production (r = 0.41, p = 0.005) and inhibition of CD39 decreased IL-10 production. CONCLUSIONS: Antigen-reactive CD4+ T cells expressing CD39 are more abundant in active TB than LTBI and are associated with production of the immunosuppressive cytokine IL-10. Modulating the effects of CD39 might enhance cellular immune responses against M. tuberculosis.

Efficacy of laparoscopic pyloroplasty for the treatment of gastroparesis.

BACKGROUND: The modest results of nonoperative modalities for the treatment of gastroparesis necessitate greater consideration of surgical therapies. However, the role of surgery is not well defined. The aim of this study is to present our experience with laparoscopic pyloroplasty as early treatment for gastroparesis. STUDY DESIGN: Fifty patients with refractory gastroparesis underwent laparoscopic pyloroplasty (hand-sewn Heineke-Mikulicz configuration) from 2006 to 2013 at our institution. Preoperative and postoperative symptom data, gastric emptying scintigraphy, and technical outcomes of the procedure were reviewed. A single-factor ANOVA was performed for the comparison of continuous variables. Results are reported as mean ± SD or median absolute deviation. RESULTS: Thirty-four of 50 (68%) patients had previous foregut procedures and/or cholecystectomy. Thirty-two of 50 (64%) patients underwent concomitant procedures (ie, paraesophageal hernia repair and gastrostomy takedown) along with the pyloroplasty. Operative time, including combined procedures, blood loss, and length of stay were 175 ± 56 minutes, 64 ± 50 mL, 2.5 ± 2.7 days, respectively. There were no conversions to open technique or intraoperative complications. There were no suture-line leaks. The readmission rate was 14%. All patients had symptom follow-up and 33 (66%) had postoperative gastric emptying scintigraphy. Postoperative symptom improvement was reported by 82% of the patients (p < 0.001). Median preoperative T1/2 was 180 ± 73 minutes and postoperative T1/2 was 60 ± 23 minutes (p < 0.001). Five patients (10%), who had normalized postoperative T1/2 times, required other gastric emptying procedures; distal gastrectomy (n = 2), duodenojejunostomy (n = 2), and gastric stimulator placement (n = 1). CONCLUSIONS: Laparoscopic pyloroplasty is an effective early-treatment modality for selected cases of gastroparesis, with substantial improvement in objective gastric emptying times and low morbidity. The laparoscopic approach does not preclude subsequent procedures when necessary.

Making lifestyle changes after colorectal cancer: insights for program development.

BACKGROUND: Healthy lifestyle behaviours may improve outcomes for people with colorectal cancer (crc), but the intention to take action and to change those behaviours may vary with time and resource availability. We aimed to estimate the prevalence of current lifestyle behaviours in people with and without crc in our community, and to identify their desire to change and their resource preferences. METHODS: A mixed-methods survey was completed by people diagnosed with crc who were pre-treatment (n = 54), undergoing treatment (n = 62), or done with treatment for less than 6 months (n = 67) or for more than 6 months (n = 178), and by people without cancer (n = 83). RESULTS: Current lifestyle behaviours were similar in all groups, with the exception of vigorous physical activity levels, which were significantly lower in the pre-treatment and ongoing treatment respondents than in cancer-free respondents. Significantly more crc respondents than respondents without cancer had made lifestyle changes. Among the crc respondents, dietary change was the change most frequently made (39.3%), and increased physical activity was the change most frequently desired (39.1%). Respondents wanted to use complementary and alternative medicine (cam), reading materials, self-efficacy, and group activities to make future changes. CONCLUSIONS: Resources for lifestyle change should be made available for people diagnosed with crc, and should be tailored to address physical activity, cam, and diet. Lifestyle programs offered throughout the cancer trajectory and beyond treatment completion might be well received by people with crc.

The structure of the small animal consultation.

OBJECTIVES: To analyse the structure of small animal consultations in order to increase understanding of the consultation processes, locate decision-making in the wider practice context and stimulate further research. METHODS: Analysis of 48 video-recorded consultations from first opinion small animal practices. These consultations were time and thematically coded in order to enable analysis. RESULTS: The mean length of the recorded consultations was 11 minutes and 45 seconds with a range of 4-28 minutes. Analysis indicates that both the clinical tasks and communication taking place in the consultation are often performed in an iterative and interactive fashion in contrast to the sequential methods frequently being taught. CLINICAL SIGNIFICANCE: This study shows that the consultation is a complex process that is often performed in an iterative and interactive fashion and that may be difficult to complete within the 10 minutes frequently allocated. This warrants further research.

Incidence of delayed gastric emptying associated with revisional laparoscopic paraesophageal hernia repair.

BACKGROUND: Over the past 15 years, laparoscopic repair of primary paraesophageal hernias (PEH) has become the preferred operative approach. Today, more surgeons are approaching recurrent PEHs laparoscopically, though few studies exist on the long-term results of these revisional operations, particularly regarding the incidence of postoperative delayed gastric emptying (DGE). METHODS: A retrospective review was conducted of all laparoscopic repairs for recurrent PEH done by three surgeons at a single institution from 2003 to 2011. Data collected included age, sex, weight, BMI, pre- and postoperative symptoms, and operative data, but our primary focus was on those patients with pre- and postoperative delayed gastric emptying ultimately requiring operative intervention. RESULTS: Of 284 patients who underwent laparoscopic PEH repair, 91 (32 %) were performed for recurrent PEH. A sleeve gastrectomy was performed in ten of these patients (11 %) for concomitant morbid obesity which were excluded from our study group, leaving 81 study patients. The mean age was 56 years, and mean BMI was 30. All cases were completed laparoscopically; in 45 (56 %) either a partial or complete fundoplication was performed, and in 68 (84 %) a percutaneous gastrostomy tube (PEG) was placed at the time of revision. Sixty-eight patients underwent repair of a first recurrence, of which 8 (12 %) ultimately required a gastric emptying procedure to alleviate symptoms of DGE. There were nine patients who had a second recurrence repaired, and six (66 %) progressed to a gastric emptying procedure. Finally, of the four patients who had a third recurrence repaired, three (75 %) eventually needed a gastric emptying procedure. CONCLUSION: While the incidence of DGE associated with initial PEH repair is low, DGE is a significantly more common finding in patients requiring reoperation for recurrent PEH. This risk increases significantly with repair of each subsequent recurrence. Our data suggest that DGE should be anticipated and patients counseled of the ramifications of this problem preoperatively. Surgeons performing revisional PEH surgery should preemptively develop protocols for the postoperative management of DGE from the time of operation.

Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation.

The cellular inhibitor of apoptosis 1 and 2 (cIAP1 and cIAP2) proteins have been implicated in the activation of NF-kappaB by TNFalpha; however, genetic deletion of either cIAP1 or 2 did not support a physiologically relevant role, perhaps because of functional redundancy. To address this, we used combined genetic and siRNA knockdown approaches and report that cIAP1 and 2 are indeed critical, yet redundant, regulators of NF-kappaB activation upon TNFalpha treatment. Whereas NF-kappaB was properly activated by TNFalpha in cultured and primary cells deficient in either cIAP1 or 2, removal of both cIAPs severely blunted its activation. After treatment with TNFalpha, cIAP1 and 2 were rapidly recruited to the TNF receptor 1, along with the adapter protein TNF receptor associated factor 2. Importantly, either cIAP1 or 2 was required for proper TNF receptor 1 signalosome function. In their combined absence, polyubiquitination of receptor interacting protein 1, an upstream event necessary for NF-kappaB signaling, was attenuated. As a result, phosphorylation of the inhibitor of kappaB kinase beta was diminished, and signal transduction was severely blunted. Consequently, cells missing both cIAP1 and 2 were sensitized to TNFalpha-mediated apoptosis. Collectively, these data demonstrate that either cIAP1 or 2 is required for proper Rip1 polyubiquitination and NF-kappaB activation upon TNFalpha treatment.

Safety and complexity: inter-departmental relationships as a threat to patient safety in the operating department.

PURPOSE: Current thinking about "patient safety" emphasises the causal relationship between the work environment and the delivery of clinical care. This research draws on the theory of normal accidents to extend this analysis and better understand the "organisational factors" that threaten safety. DESIGN/METHODOLOGY/APPROACH: Ethnographic research methods were used, with observations of the operating department setting for 18 month and interviews with 80 members of hospital staff. The setting for the study was the Operating Department of a large teaching hospital in the North-West of England. FINDINGS: The work of the operating department is determined by inter-dependant, "tightly coupled" organisational relationships between hospital departments based upon the timely exchange of information, services and resources required for the delivery of care. Failures within these processes, manifest as "breakdowns" within inter-departmental relationships lead to situations of constraint, rapid change and uncertainty in the work of the operating department that require staff to break with established routines and work with increased time and emotional pressures. This means that staff focus on working quickly, as opposed to working safely. ORIGINALITY VALUE: Analysis of safety needs to move beyond a focus on the immediate work environment and individual practice, to consider the more complex and deeply structured organisational systems of hospital activity. For departmental managers the scope for service planning to control for safety may be limited as the structured "real world" situation of service delivery is shaped by inter-department and organisational factors that are perhaps beyond the scope of departmental management.

Rules and guidelines in clinical practice: a qualitative study in operating theatres of doctors' and nurses' views.

BACKGROUND: The current orthodoxy within patient safety research and policy is characterised by a faith in rules based systems which limit the capacity for individual discretion, and hence fallibility. However, guidelines have been seen as stifling innovation and eroding trust. Our objectives were to explore the attitudes towards guidelines of doctors and nurses working together in surgical teams and to examine the extent to which trusting relationships are maintained in a context governed by explicit rules. METHODS: Fourteen consultant grade surgeons of mixed specialty, 12 consultant anaesthetists, and 15 nurses were selected to reflect a range of roles. Participant observation was combined with semi-structured interviews. RESULTS: Doctors' views about the contribution of guidelines to safety and to clinical practice differed from those of nurses. Doctors rejected written rules, instead adhering to the unwritten rules of what constitutes acceptable behaviour for members of the medical profession. In contrast, nurses viewed guideline adherence as synonymous with professionalism and criticised doctors for failing to comply with guidelines. CONCLUSIONS: While the creation of a "safety culture" requires a shared set of beliefs, attitudes and norms in relation to what is seen as safe clinical practice, differences of opinion on these issues exist which cannot be easily reconciled since they reflect deeply ingrained beliefs about what constitutes professional conduct. While advocates of standardisation (such as nurses) view doctors as rule breakers, doctors may not necessarily regard guidelines as legitimate or identify with the rules written for them by members of other social groups. Future safety research and policy should attempt to understand the unwritten rules which govern clinical behaviour and examine the ways in which such rules are produced, maintained, and accepted as legitimate.

Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes.

Investigations into Drosophila mutants with impaired vision due to mutations in the transient receptor potential gene (trp) initiated a systematic search for TRP homologs in other species, finally leading to the discovery of a whole new family of plasma membrane cation channels involved in multiple physiological processes. Among the recently discovered TRP cation channels two homologous proteins, TRPM6 and TRPM7, display unique domain compositions and biophysical properties. These remarkable genes are vital for Mg(2+) homeostasis in vertebrates and, if disrupted, lead to cell death or human disease.

The role of EUS for evaluation of mediastinal adenopathy.

This is one of a series of statements discussing the utilization of GI endoscopy in common clinical situations. The Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy prepared this text. In preparing this guideline, a MEDLINE literature search was performed, and additional references were obtained from the bibliographies of the identified articles and from recommendations of expert consultants. When little or no data exist from well-designed prospective trials, emphasis is given to results from large series and reports from recognized experts. Guidelines for appropriate utilization of endoscopy are based on a critical review of the available data and expert consensus. Further controlled clinical studies are needed to clarify aspects of this statement, and revision may be necessary as new data appear. Clinical consideration may justify a course of action at variance to these recommendations.