Incorrect diagnoses in patients with neutralizing anti-interferon-gamma-autoantibodies.

OBJECTIVES: Early diagnosis of adult-onset immunodeficiency associated with neutralizing anti-interferon-gamma autoantibodies (anti-IFNγ Abs) remains difficult given the lack of a distinctive phenotype and a routine test. This study aimed to investigate the determinants of incorrect tentative diagnoses and useful clues for early disease recognition. METHODS: This study enrolled adult patients who had unexplained opportunistic infections diagnosed at six hospitals and identified those having neutralizing anti-IFNγ Abs (cases). Demographics, medical history, initial presentations and laboratory data, causative pathogens, tentative diagnoses, and treatment were analysed and compared among individuals having neutralizing anti-IFNγ Abs (cases) and those without (controls). RESULTS: Among the 154 patients enrolled, neutralizing anti-IFN-γ Abs were detected in 50 (71%) of 70 patients with disseminated non-tuberculous mycobacterial infection (dNTM) but not in 84 patients without dNTM. The median time from disease onset to the recognition of dNTM associated with neutralizing anti-IFNγ Abs was 1.6 years (range, 0.25-19 years). Incorrect tentative diagnoses resulted in the administration of anti-tuberculosis regimens (60%, 30/50), immunosuppressants (48%, 24/50), and systemic chemotherapy (2%, 10/50) to the 50 cases. Multivariate analysis revealed that case patients were more likely than controls to present with multiple bone lesions (adjusted odds ratio (OR), 27.16; 95% confidence interval (CI), 1.21-609.59) and leukocytosis (adjusted OR, 1.48; 95% CI, 1.12-1.95); however, the controls had a higher rate of mycobacterial bloodstream infection (adjusted OR, 0.05; 95% CI 0.00-0.66). CONCLUSIONS: The high rate of incorrect tentative diagnoses led to frequent inappropriate management in patients with neutralizing anti-IFNγ Abs, and highlighted the need for increased awareness among clinicians.

Endodontic considerations of survival rate for autotransplanted third molars: a nationwide population-based study.

AIM: To investigate whether the timing of root canal treatment (primary aim) or other endodontic parameters (secondary aim) is associated with the survival probability of autotransplanted third molars, using a nationwide population-based database. METHODOLOGY: A total of 1811 third molars autotransplanted between 2000 and 2013 met the inclusion criteria and were followed until the end of 2016. The teeth were classified into three groups on the basis of timing between root canal treatment and the autotransplantation: preoperative, extraoral and postoperative treatment groups. Univariate and multivariate Cox proportional hazards models were used to estimate the association between the timing of root canal treatment and the risk of tooth extraction after autotransplantation. RESULTS: Of the 1811 autotransplanted third molars, 462 were extracted, yielding a 17-year survival probability of 0.578. The survival probability of autotransplanted teeth that received postoperative root fillings after 17 years was 0.583, which was significantly higher than the 0.434 and 0.566 for teeth that received preoperative and extraoral root fillings, respectively (P = 0.0013). After adjustment for potential confounding factors, teeth that received postoperative root fillings were associated with a significantly lower tooth extraction hazard ratio (HR) compared with those that received extraoral root fillings (adjusted HR, 1.43; 95% confidence interval [CI], 1.14-1.78) and those that received preoperative root fillings (adjusted HR, 2.13; 95% CI, 1.19-3.82). Furthermore, the use of a rubber dam during postoperative root filling was associated with a significantly lower extraction rate after autotransplantation (adjusted HR, 0.54; 95% CI, 0.43-0.69). CONCLUSIONS: Postoperative root canal treatment resulted in a significantly lower extraction rate than did preoperative or extraoral root canal treatment amongst autotransplanted third molars during a mean follow-up period of 8.33 years. Rubber dam use is recommended during postoperative root canal treatment to improve the outcomes of autotransplantation.

Association of depression and diabetes complications and mortality: a population-based cohort study.

AIMS: Several studies suggested that depression might worsen the clinical outcome of diabetes mellitus; however, such association was confounded by duration of illness and baseline complications. This study aimed to assess whether depression increases the risk of diabetes complications and mortality among incident patients with diabetes. METHODS: This was a population-based matched cohort study using Taiwan's National Health Insurance Research Database. A total of 38 537 incident patients with diabetes who had depressive disorders and 154 148 incident diabetes patients without depression who were matched by age, sex and cohort entry year were randomly selected. The study endpoint was the development of macrovascular and microvascular complications, all-cause mortality and cause-specific mortality. RESULTS: Among participants, the mean (±SD) age was 52.61 (±12.45) years, and 39.63% were male. The average duration of follow-up for mortality was 5.5 years, ranging from 0 to 14 years. The adjusted hazard ratios were 1.35 (95% confidence interval [CI], 1.32-1.37) for macrovascular complications and 1.08 (95% CI, 1.04-1.12) for all-cause mortality. However, there was no association of depression with microvascular complications, mortality due to cardiovascular diseases or mortality due to diabetes mellitus. The effect of depression on diabetes complications and mortality was more prominent among young adults than among middle-aged and older adults. CONCLUSIONS: Depression was associated with macrovascular complications and all-cause mortality in our patient cohort. However, the magnitude of association was less than that in previous studies. Further research should focus on the benefits and risks of treatment for depression on diabetes outcome.

Directly Placed Restorative Materials: Review and Network Meta-analysis.

For restoring cavitated dental lesions, whether carious or not, a large number of material combinations are available. We aimed to systematically review and synthesize data of comparative dental restorative trials. A systematic review was performed. Randomized controlled trials published between 2005 and 2015 were included that compared the survival of ≥2 restorative and/or adhesive materials (i.e., no need for restorative reintervention). Pairwise and Bayesian network meta-analyses were performed, with separate evaluations for cervical cavitated lesions and load-bearing posterior cavitated lesions in permanent and primary teeth. A total of 11,070 restorations (5,330 cervical, 5,740 load bearing) had been placed in 3,633 patients in the included trials. Thirty-six trials investigated restoration of cervical lesions (all in permanent teeth) and 36 of load-bearing lesions (8 in primary and 28 in permanent teeth). Resin-modified glass ionomer cements had the highest chance of survival in cervical cavitated lesions; composites or compomers placed via 2-step self-etch and 3-step etch-and-rinse adhesives were ranked next. Restorations placed with 2-step etch-and-rinse or 1-step self-etch adhesives performed worst. For load-bearing restorations, conventional composites had the highest probability of survival, while siloranes were found least suitable. Ambiguity remains regarding which adhesive strategy to use in load-bearing cavitated lesions. Most studies showed high risk of bias, and several comparisons were prone for publication bias. If prioritized for survival, resin-modified glass ionomer cements might be recommended to restore cervical lesions. For load-bearing ones, conventional or bulk fill composites seem most suitable. The available evidence is quantitatively and qualitatively insufficient for further recommendations, especially with regard to adhesive strategies in posterior load-bearing situations. Moreover, different material classifications might yield different findings on the same materials. Future trials should aim for sufficient power, longer follow-up times, and high internal validity to prove or refute differences between certain material combinations. An agreed material classification for future syntheses is desirable.

Epidemiology of invasive fungal diseases among patients with haematological disorders in the Asia-Pacific: a prospective observational study.

We conducted a 2-year multicentre prospective observational study to determine the epidemiology of and mortality associated with invasive fungal diseases (IFDs) among patients with haematological disorders in Asia. Eleven institutions from 8 countries/regions participated, with 412 subjects (28.2% possible, 38.3% probable and 33.5% proven IFDs) recruited. The epidemiology of IFDs in participating institutions was similar to Western centres, with Aspergillus spp. (65.9%) or Candida spp. (26.7%) causing the majority of probable and proven IFDs. The overall 30-day mortality was 22.1%. Progressive haematological disorder (odds ratio [OR] 5.192), invasive candidiasis (OR 3.679), and chronic renal disease (OR 6.677) were independently associated with mortality.

Treating pit-and-fissure caries: a systematic review and network meta-analysis.

For shallow or moderately deep pit-and-fissure lesions, various treatment options are available: (1) noninvasive treatments (e.g., fluoride application, antibacterial treatments, oral hygiene advice) avoid any dental hard tissue removal; (2) microinvasive treatments (e.g., sealing) remove only a few micrometers of hard tissues by etching; and minimally invasive methods (e.g., "preventive" resin/sealant restoration) remove carious dentin but avoid sacrificing sound tissues. We aimed at systematically reviewing and comparing these strategies for treating pit-and-fissure lesions in permanent teeth using network meta-analysis. Randomized or nonrandomized clinical trials investigating shallow or moderately deep primary caries lesions in fissured or pitted surfaces were included. We compared the risk of requiring invasive treatments or any retreatments in noninvasive, microinvasive, and minimally invasive treated lesions; untreated lesions were used as controls. Five electronic databases were systematically screened up to September 2013 and cross-referencing performed. Pairwise and network meta-analyses were performed and odds ratios and 95% confidence intervals (CI) calculated. Certainty of estimates was evaluated via GRADE criteria. From a total of 2,214 identified records, 14 studies representing 1,440 patients with 3,551 treated lesions were included. Pairwise meta-analysis found microinvasive and minimally invasive treated lesions to require less invasive retreatments than control lesions (odds ratios [95% confidence intervals]: 0.13 [0.07 to 0.26], 0.13 [0.03 to 0.50], respectively), whereas the estimate for noninvasively treated lesions remained nonsignificant (0.64 [0.39 to 1.06]). These findings were reflected in the strategy ranking stemming from network meta-analysis (first, minimally invasive; second, microinvasive; third, noninvasive). However, microinvasive treatment required significantly more total retreatments (including resealing) than minimally or noninvasive treatments. Due to limited study quality, the evidence was graded as low or very low. Clinical treatment decisions should consider the long-term sequelae and costs stemming from different therapies as well as their subjective impact on the patient. Available treatment options seem suitable for treating shallow or moderately deep pit-and-fissure lesions in permanent teeth; further conclusions are not possible.

Rapidly growing mycobacteria in Singapore, 2006-2011.

Nontuberculous mycobacteria infection is a growing global concern, but data from Asia are limited. This study aimed to describe the distribution and antibiotic susceptibility profiles of rapidly growing mycobacterium (RGM) isolates in Singapore. Clinical RGM isolates with antibiotic susceptibility tests performed between 2006 and 2011 were identified using microbiology laboratory databases and minimum inhibitory concentrations of amikacin, cefoxitin, clarithromycin, ciprofloxacin, doxycycline, imipenem, linezolid, moxifloxacin, sulfamethoxazole or trimethoprim-sulfamethoxazole, tigecycline and tobramycin were recorded. Regression analysis was performed to detect changes in antibiotic susceptibility patterns over time. A total of 427 isolates were included. Of these, 277 (65%) were from respiratory specimens, 42 (10%) were related to skin and soft tissue infections and 36 (8%) were recovered from blood specimens. The two most common species identified were Mycobacterium abscessus (73%) and Mycobacterium fortuitum group (22%), with amikacin and clarithromycin being most active against the former, and quinolones and trimethoprim-sulfamethoxazole against the latter. Decreases in susceptibility of M. abscessus to linezolid by 8.8% per year (p 0.001), M. fortuitum group to imipenem by 9.5% per year (p 0.023) and clarithromycin by 4.7% per year (p 0.033) were observed. M. abscessus in respiratory specimens is the most common RGM identified in Singapore. Antibiotic options for treatment of RGM infections are increasingly limited.

Use of independent component analysis to improve signal-to-noise ratio in multi-probe fluorescence microscopy.

In conventional multi-probe fluorescence microscopy, narrow bandwidth filters on detectors are used to avoid bleed-through artefacts between probes. The limited bandwidth reduces the signal-to-noise ratio of the detection, often severely compromising one or more channels. Herein, we describe a process of using independent component analysis to discriminate the position of different probes using only a dichroic mirror to differentiate the signals directed to the detectors. Independent component analysis was particularly effective in samples where the spatial overlap between the probes is minimal, a very common case in cellular microscopy. This imaging scheme collects nearly all of the emitted light, significantly improving the image signal-to-noise ratio. In this study, we focused on the detection of two fluorescence probes used in vivo, NAD(P)H and ANEPPS. The optimal dichroic mirror cutoff frequency was determined with simulations using the probes spectral emissions. A quality factor, defined as the cross-channel contrast-to-noise ratio, was optimized to maximize signals while maintaining spatial discrimination between the probes after independent component analysis post-processing. Simulations indicate that a ∼3 fold increase in signal-to-noise ratio using the independent component analysis approach can be achieved over the conventional narrow-band filtering approach without loss of spatial discrimination. We confirmed this predicted performance from experimental imaging of NAD(P)H and ANEPPS in mouse skeletal muscle, in vivo. For many multi-probe studies, the increased sensitivity of this 'full bandwidth' approach will lead to improved image quality and/or reduced excitation power requirements.

Sustained meticillin-resistant Staphylococcus aureus control in a hyper-endemic tertiary acute care hospital with infrastructure challenges in Singapore.

BACKGROUND: Meticillin-resistant Staphylococcus aureus (MRSA) has been entrenched in Singapore hospitals since the 1980s, with an excess of 600 non-duplicate cases of infections (120 bacteraemia episodes) each year in our 995-bed university hospital. Approximately 5% of our hospital beds are used as isolation facilities. AIM: To study the impact of an MRSA control bundle that was implemented via gradual geographic extension across hospital wards. METHODS: The bundle included active surveillance on admission and transfer/discharge to identify ward-based acquisition of MRSA, isolation and cohorting of MRSA-infected patients, enhanced hand hygiene initiatives, and publicly displayed feedback of MRSA acquisition and hand hygiene compliance rates. Implementation was between October 2006 and June 2010 in order to provide lead-time for the incremental development of infrastructural capacity, and to develop an ethic of infection prevention among staff. Results were analysed via interrupted time-series analysis. FINDINGS: MRSA infections fell midway through the implementation, with MRSA bacteraemia declining from 0.26 [95% confidence interval (CI): 0.18-0.34] cases per 1000 inpatient-days in the first quarter of 2004 to 0.11 (95% CI: 0.07-0.19) cases per 1000 inpatient-days in the first quarter of 2012. MRSA acquisition rates fell a year after the programme had been fully implemented, whereas hand hygiene compliance rose significantly from 47% (95% CI: 44-49) in the first quarter of 2009 to 69% (95% CI: 68-71) in the first quarter of 2012. CONCLUSION: Successful staged implementation of an MRSA bundle in a hyper-endemic setting is sustainable and represents a model that may be adapted for similar settings.

ST22 and ST239 MRSA duopoly in Singaporean hospitals: 2006-2010.

Surveillance is integral for the monitoring and control of infectious diseases. We conducted prospective laboratory surveillance of methicillin-resistant Staphylococcus aureus (MRSA) in five Singaporean public-sector hospitals from 2006 to 2010, using WHONET 5.6 for data compilation and analysis. Molecular profiling using multilocus variable-number tandem-repeat analysis, staphylococcal cassette chromosome mec classification and multilocus sequence typing was performed for a random selection of isolates. Our results showed overall stable rates of infection and bacteraemia, although there was significant variance among the individual hospitals, with MRSA rates increasing in two smaller hospitals and showing a trend towards decreasing in the two largest hospitals. The proportion of blood isolates that are EMRSA-15 (ST22-IV) continued to increase over time, slowly replacing the multi-resistant ST239-III. A new MRSA clone - ST45-IV - is now responsible for a small subset of hospital infections locally. More effort is required in Singaporean hospitals in order to reduce the rates of MRSA infection significantly.

Prospective audit and feedback on antibiotic prescription in an adult hematology-oncology unit in Singapore.

We evaluated the impact of a prospective audit and feedback antimicrobial stewardship program (ASP) on antibiotic prescription and resistance trends in a hematology-oncology unit in a university hospital (National University Cancer Institute, Singapore [NCIS]). A prospective interrupted time-series study comprising 11-month pre-intervention (PIP) and intervention evaluation phases (IEP) flanking a one-month implementation phase was carried out. Outcome measures included defined daily dose per 100 (DDD/100) inpatient-days of ASP-audited and all antibiotics (encompassing audited and non-audited antibiotics), and the incidence-density of antibiotic-resistant microorganisms at the NCIS. Internal and external controls were DDD/100 inpatient-days of paracetamol at the NCIS and DDD/100 inpatient-days of antibiotics prescribed in the rest of the hospital. There were 580 ASP recommendations from 1,276 audits, with a mean monthly compliance of 86.9%. Significant reversal of prescription trends towards reduced prescription of audited (coefficient = -2.621; 95% confidence interval [CI]: -4.923, -0.319; p = 0.026) and all evaluated antibiotics (coefficient = -4.069; 95% CI: -8.075, -0.063; p = 0.046) was observed. No changes were seen for both internal and external controls, except for the reversal of prescription trends for cephalosporins hospital-wide. Antimicrobial resistance did not change over the time period of the study. Adverse outcomes-the majority unavoidable-occurred following 5.5% of accepted ASP recommendations. Safe and effective ASPs can be implemented in the complex setting of hematology-oncology inpatients.

The impact of multidrug resistance in healthcare-associated and nosocomial Gram-negative bacteraemia on mortality and length of stay: cohort study.

Multidrug-resistant Gram-negative bacteria (MDR-GNB) are an emerging public health threat. Accurate estimates of their clinical impact are vital for justifying interventions directed towards preventing or managing infections caused by these pathogens. A retrospective observational cohort study was conducted between 1 January 2007 and 31 July 2009, involving subjects with healthcare-associated and nosocomial Gram-negative bacteraemia at two large Singaporean hospitals. Outcomes studied were mortality and length of stay post-onset of bacteraemia in survivors (LOS). There were 675 subjects (301 with MDR-GNB) matching study inclusion criteria. On multivariate analysis, multidrug resistance was not associated with 30-day mortality, but it was independently associated with longer LOS in survivors (coefficient, 0.34; 95% CI, 0.21-0.48; p < 0.001). The excess LOS attributable to multidrug resistance after adjustment for confounders was 6.1 days. Other independent risk factors for higher mortality included male gender, higher APACHE II score, higher Charlson comorbidity index, intensive care unit stay and presence of concomitant pneumonia. Concomitant urinary tract infection and admission to a surgical discipline were associated with lower risk of mortality. Appropriate empirical antibiotic therapy was neither associated with 30-day mortality nor LOS, although the study was not powered to assess this covariate adequately. Our study adds to existing evidence that multidrug resistance per se is not associated with higher mortality when effective antibiotics are used for definitive therapy. However, its association with longer hospitalization justifies the use of control efforts.

Acinetobacter calcoaceticus-Acinetobacter baumannii complex species in clinical specimens in Singapore.

This study was performed to determine the prevalence, distribution of specimen sources, and antimicrobial susceptibility of the Acinetobacter calcoaceticus-Acinetobacter baumannii (Acb) species complex in Singapore. One hundred and ninety-three non-replicate Acb species complex clinical isolates were collected from six hospitals over a 1-month period in 2006. Of these, 152 (78·7%) were identified as A. baumannii, 18 (9·3%) as 'Acinetobacter pittii' [genomic species (gen. sp.) 3], and 23 (11·9%) as 'Acinetobacter nosocomialis' (gen. sp. 13TU). Carbapenem resistance was highest in A. baumannii (72·4%), followed by A. pittii (38·9%), and A. nosocomialis (34·8%). Most carbapenem-resistant A. baumannii and A. nosocomialis possessed the bla(OXA-23-like) gene whereas carbapenem-resistant A. pittii possessed the bla(OXA-58-like) gene. Two imipenem-resistant strains (A. baumannii and A. pittii) had the bla(IMP-like) gene. Representatives of carbapenem-resistant A. baumannii were related to European clones I and II.

Hand hygiene and infection control survey pre- and peri-H1N1-2009 pandemic: knowledge and perceptions of final year medical students in Singapore.

INTRODUCTION: Infection control and hand hygiene are taught at different points in the undergraduate medical curriculum. We conducted a survey on fifth year medical (M5) students pre- and peri-influenza A (H1N1-2009) pandemic, attempting to ascertain whether the pandemic had affected their knowledge, perception and practice of hand hygiene and other aspects of infection control. METHODS: A self-administered anonymous survey of M5 students was performed between August 2008 and February 2010, corresponding to two successive classes: M5-2008 (Class of 2004/09) and M5-2009 (Class of 2005/10). Completed survey forms were collated and analysed centrally. RESULTS: There were 191 and 123 respondents for M5-2008 and M5-2009, respectively, corresponding to 74.9% and 47.3% of the respective classes. More M5-2009 respondents recognised alcohol hand rub as the preferred mode of hand hygiene practice and felt that there were insufficient isolation facilities in hospitals. Otherwise, survey responses were consistent. The majority felt that few doctors practiced hand hygiene appropriately, with the major obstructing factor being lack of time during ward rounds. The most important factor for improving hand hygiene compliance among junior doctors and students was for senior clinicians to lead by example. A significant minority believed that it was necessary to isolate patients with chikungunya, malaria or HIV. CONCLUSION: The 2009 H1N1 pandemic made little impact on medical students' knowledge and practice of infection control. Nonetheless, their responses have suggested avenues for improving infection control practice, including persuading senior clinicians to lead by example in hand hygiene practice and addressing gaps in knowledge on patient isolation policies.