Benjamin Tang

Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis

BACKGROUND Whether calcium supplementation can reduce osteoporotic fractures is uncertain. We did a meta-analysis to include all the randomised trials in which calcium, or calcium in combination with vitamin D, was used to prevent fracture and osteoporotic bone loss. METHODS We identified 29 randomised trials (n=63 897) using electronic databases, supplemented by a hand-search of reference lists, review articles, and conference abstracts. All randomised trials that recruited people aged 50 years or older were eligible. The main outcomes were fractures of all types and percentage change of bone-mineral density from baseline. Data were pooled by use of a random-effect model. FINDINGS In trials that reported fracture as an outcome (17 trials, n=52 625), treatment was associated with a 12% risk reduction in fractures of all types (risk ratio 0.88, 95% CI 0.83-0.95; p=0.0004). In trials that reported bone-mineral density as an outcome (23 trials, n=41 419), the treatment was associated with a reduced rate of bone loss of 0.54% (0.35-0.73; p<0.0001) at the hip and 1.19% (0.76-1.61%; p<0.0001) in the spine. The fracture risk reduction was significantly greater (24%) in trials in which the compliance rate was high (p<0.0001). The treatment effect was better with calcium doses of 1200 mg or more than with doses less than 1200 mg (0.80 vs 0.94; p=0.006), and with vitamin D doses of 800 IU or more than with doses less than 800 IU (0.84 vs 0.87; p=0.03). INTERPRETATION Evidence supports the use of calcium, or calcium in combination with vitamin D supplementation, in the preventive treatment of osteoporosis in people aged 50 years or older. For best therapeutic effect, we recommend minimum doses of 1200 mg of calcium, and 800 IU of vitamin D (for combined calcium plus vitamin D supplementation).

Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis*

Objective:Controversy remains as to whether low-dose corticosteroids can reduce the mortality and morbidity of acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS) without increasing the risk of adverse reactions. We aimed to evaluate all studies investigating prolonged corticosteroids in low-to-moderate dose in ALI or ARDS. Data Sources:MEDLINE, EMBASE, Current Content, and Cochrane Central Register of Controlled Trials, and bibliographies of retrieved articles. Study Selection:Randomized controlled trials (RCTs) and observational studies reported in any language that used 0.5–2.5 mg·kg−1·d−1 of methylprednisolone or equivalent to treat ALI/ARDS. Data Extraction:Data were extracted independently by two reviewers and included study design, patient characteristics, interventions, and mortality and morbidity outcomes. Data Synthesis:Both cohort studies (five studies, n = 307) and RCTs (four trials, n = 341) showed a similar trend toward mortality reduction (RCTs relative risk 0.51, 95% CI 0.24–1.09; p = 0.08; cohort studies relative risk 0.66, 95% CI 0.43–1.02; p = 0.06). The overall relative risk was 0.62 (95% CI 0.43–0.91; p = 0.01). There was also improvement in length of ventilation-free days, length of intensive care unit stay, Multiple Organ Dysfunction Syndrome Score, Lung Injury Scores, and improvement in Pao2/Fio2. There was no increase in infection, neuromyopathy, or any major complications. There was significant heterogeneity in the pooled studies. Subgroup and meta-regression analyses showed that heterogeneity had minimal effect on treatment efficacy; however, these findings were limited by the small number of studies used in the analyses. Conclusion:The use of low-dose corticosteroids was associated with improved mortality and morbidity outcomes without increased adverse reactions. The consistency of results in both study designs and all outcomes suggests that they are an effective treatment for ALI or ARDS. The mortality benefits in early ARDS should be confirmed by an adequately powered randomized trial.

The confounding effects of age, gender, serum creatinine, and electrolyte concentrations on plasma B-type natriuretic peptide concentrations in critically ill patients.

ObjectiveTo investigate the confounding effects of age, gender, serum creatinine, and electrolyte concentrations on plasma B-type natriuretic peptide (BNP) concentrations in critically ill patients. DesignA prospective cross-sectional study. SettingA 20-bed general intensive care unit of a tertiary referral hospital. PatientsPatients were 121 patients admitted to the intensive care unit over a period of 9 wks. InterventionsIntravenous blood was collected for BNP measurements, and cardiac investigations including echocardiography were carried out for every patient on admission. Measurements and Main ResultsThe mean BNP concentration was 201 ± 317 pg/mL (n = 121). Thirty-five patients (28.9%), identified to have cardiac abnormalities, exhibited higher BNP concentrations than those without cardiac abnormalities (518 ± 394 vs. 60 ± 98 pg/mL, p < .001). The females exhibited higher concentrations of BNP than males in the noncardiac abnormality group (96 ± 132 pg/mL, n = 39 vs. 31 ± 38 pg/mL, n = 47, p = .016). BNP correlated significantly with age (r2 = .19) and creatinine (r2 = .084). The latter correlation became insignificant when patients with cardiac abnormality were excluded. No correlation was found between serum Na+ and K+ concentrations with BNP. Multivariate analyses demonstrated that the presence of cardiac abnormalities accounted for nearly 50% of the BNP variation. Addition of age and gender improved R2 to 60%. The contribution of creatinine was found to be insignificant. There was no association between BNP concentrations and serum Na+ and K+ concentrations. Logistic analysis confirmed that BNP is the strongest predictor for cardiac abnormalities in the critically ill patients. ConclusionThe current study demonstrated that plasma BNP concentrations increased with age and were higher in females than in males. Although the presence of cardiac disease was the most important determinant for BNP variations, age and gender also contributed significantly. The results suggest that age and gender need to be taken into account in the interpretation of BNP concentrations in critically ill patients.

Gene-expression profiling of peripheral blood mononuclear cells in sepsis.

Objectives:It has been shown that gene-expression profiling of circulating neutrophils could identify signature genes of sepsis. However, whether similar transcriptional changes occurred in peripheral blood mononuclear cells (PBMC) was not known. Using microarray technology, we performed gene-expression profiling of PBMC to identify signature genes that distinguish sepsis from noninfectious causes of systemic inflammatory response syndrome (SIRS), between Gram-positive and Gram-negative sepsis. Design:A cross-sectional, observational study. Setting:A 20-bed general intensive care unit of a tertiary referral hospital. Patients:Seventy critically ill patients (46 sepsis and 24 SIRS). Interventions:Intravenous blood was collected for leukocyte separation and RNA extraction. Gene-expression profiling was performed on PBMC using Affymetrix GeneChip microarrays with 54,675 transcripts. Data were divided into a training set (n = 35) and a validation set (n = 35). A molecular signature was developed in the training set using support vector machine and was then validated in the validation set. Measurements and Main Results:We identified a molecular signature of 138 genes that could differentiate between sepsis and SIRS patients with 91% and 80% accuracy in the training and validation sets, respectively. There were no signature genes that could differentiate between Gram-positive and Gram-negative sepsis. The expression of genes involved in inflammatory response and immune function was significantly reduced in septic patients when compared with those with SIRS. Genes involved in apoptosis, on the other hand, were more highly expressed in septic patients. Conclusion:There was evidence of sepsis-related immunosuppression and reduced inflammatory response in mononuclear cells on a transcriptome level. These characteristic transcriptional changes can be used to aid the diagnosis of sepsis.

Genome-wide transcription profiling of human sepsis: a systematic review

IntroductionSepsis is thought to be an abnormal inflammatory response to infection. However, most clinical trials of drugs that modulate the inflammatory response of sepsis have been unsuccessful. Emerging genomic evidence shows that the host response in sepsis does not conform to a simple hyper-inflammatory/hypo-inflammatory model. We, therefore, synthesized current genomic studies that examined the host response of circulating leukocytes to human sepsis.MethodsElectronic searches were performed in Medline and Embase (1987 to October 2010), supplemented by additional searches in multiple microarray data repositories. We included studies that (1) used microarray, (2) were performed in humans and (3) investigated the host response mediated by circulating leukocytes.ResultsWe identified 12 cohorts consisting of 784 individuals providing genome-wide expression data in early and late sepsis. Sepsis elicited an immediate activation of pathogen recognition receptors, accompanied by an increase in the activities of signal transduction cascades. These changes were consistent across most cohorts. However, changes in inflammation related genes were highly variable. Established inflammatory markers, such as tumour necrosis factor-α (TNF-α), interleukin (IL)-1 or interleukin-10, did not show any consistent pattern in their gene-expression across cohorts. The finding remains the same even after the cohorts were stratified by timing (early vs. late sepsis), patient groups (paediatric vs. adult patients) or settings (clinical sepsis vs. endotoxemia model). Neither a distinctive pro/anti-inflammatory phase nor a clear transition from a pro-inflammatory to anti-inflammatory phase could be observed during sepsis.ConclusionsSepsis related inflammatory changes are highly variable on a transcriptional level. We did not find strong genomic evidence that supports the classic two phase model of sepsis.

Development and validation of a novel molecular biomarker diagnostic test for the early detection of sepsis

IntroductionSepsis is a complex immunological response to infection characterized by early hyper-inflammation followed by severe and protracted immunosuppression, suggesting that a multi-marker approach has the greatest clinical utility for early detection, within a clinical environment focused on Systemic Inflammatory Response Syndrome (SIRS) differentiation. Pre-clinical research using an equine sepsis model identified a panel of gene expression biomarkers that define the early aberrant immune activation. Thus, the primary objective was to apply these gene expression biomarkers to distinguish patients with sepsis from those who had undergone major open surgery and had clinical outcomes consistent with systemic inflammation due to physical trauma and wound healing.MethodsThis was a multi-centre, prospective clinical trial conducted across four tertiary critical care settings in Australia. Sepsis patients were recruited if they met the 1992 Consensus Statement criteria and had clinical evidence of systemic infection based on microbiology diagnoses (n = 27). Participants in the post-surgical (PS) group were recruited pre-operatively and blood samples collected within 24 hours following surgery (n = 38). Healthy controls (HC) included hospital staff with no known concurrent illnesses (n = 20). Each participant had minimally 5 ml of PAXgene blood collected for leucocyte RNA isolation and gene expression analyses. Affymetrix array and multiplex tandem (MT)-PCR studies were conducted to evaluate transcriptional profiles in circulating white blood cells applying a set of 42 molecular markers that had been identified a priori. A LogitBoost algorithm was used to create a machine learning diagnostic rule to predict sepsis outcomes.ResultsBased on preliminary microarray analyses comparing HC and sepsis groups, a panel of 42-gene expression markers were identified that represented key innate and adaptive immune function, cell cycling, WBC differentiation, extracellular remodelling and immune modulation pathways. Comparisons against GEO data confirmed the definitive separation of the sepsis cohort. Quantitative PCR results suggest the capacity for this test to differentiate severe systemic inflammation from HC is 92%. The area under the curve (AUC) receiver operator characteristics (ROC) curve findings demonstrated sepsis prediction within a mixed inflammatory population, was between 86 and 92%.ConclusionsThis novel molecular biomarker test has a clinically relevant sensitivity and specificity profile, and has the capacity for early detection of sepsis via the monitoring of critical care patients.

Gene-expression profiling of gram-positive and gram-negative sepsis in critically ill patients.

Objective:It is unclear whether the host response of Gram-positive sepsis differs from Gram-negative sepsis at a transcriptome level. Using microarray technology, we compared the gene-expression profiles of Gram-positive sepsis and Gram-negative sepsis in critically ill patients. Design:A prospective cross-sectional study. Setting:A 20-bed general intensive care unit of a tertiary referral hospital. Patients:Seventy-two patients admitted to the intensive care unit. Interventions:Intravenous blood was collected for leukocyte separation and RNA extraction. Microarray experiments were then performed examining the expression level of 18,664 genes in each sample. Measurements and Main Results:There was no difference in the expression profile between Gram-positive and Gram-negative sepsis. The finding remained unchanged even when genes with lower expression level were included or after statistical stringency was lowered. There were, however, 94 genes differentially expressed between sepsis and control patients. These genes included those involved in immune regulation, inflammation, and mitochondrial function. Hierarchical cluster analysis confirmed that the difference in gene expression profile existed between sepsis and control patients but not between Gram-positive and Gram-negative patients. Conclusions:Gram-positive sepsis and Gram-negative sepsis share a common host response at a transcriptome level. These findings support the hypothesis that the septic response is nonspecific and is designed to provide a more general response that can be elicited by a wide range of different microorganisms.

A comparison of external and endoscopic endonasal dacryocystorhinostomy for acquired nasolacrimal duct obstruction

Purpose To compare success rates of external dacryocystorhinostomy (DCR) and endoscopic endonasal DCR for acquired nasolacrimal duct obstruction (NLDO). Design Historical cohort study. Participants 100 patients who underwent external DCR and 105 patients who underwent endoscopic endonasal DCR. Methods A retrospective review of medical records of patients with acquired NLDO who underwent DCR from 2004–2010 was performed. Data regarding the lacrimal drainage system, eye examination, surgical outcomes, patient symptom control, and postoperative care were analyzed. Main outcome measures Surgical success was defined by patient’s resolution of symptoms with patency on irrigation. Surgical failure was defined as no symptomatic reduction in epiphora and/or an inability to irrigate the lacrimal system postoperatively. Results A total of 205 patients underwent surgeries for acquired NLDO. The average age was 69 years, and 62.4% of subjects were female. Pooled results showed that both surgical approaches had similar success rates (endoscopic endonasal DCR 82.4% versus external DCR 81.6%; P = 0.895). Complication rates were low in both types of surgery. This included three patients with postoperative hemorrhage (two who had endonasal DCR surgery and one having external DCR surgery). This resolved with conservative treatment. Postoperative problems with lacrimal patency (including canalicular obstruction) occurred to 6.8% of endoscopic patients and 9% of those with the external DCR surgery. Of the 14 patients who had their silicone tubes fall out before the 2-month assessment, 10 were classified as failures (71%), in contrast to only a failure rate of 13.9% of those whose tubes were present for the recommended time. This difference was statistically significant (P < 0.01). Conclusion The success rate of DCR for acquired NLDO in our group of patients was high overall with a low complication rate between the two types of surgery. There was no statistically significant difference between endoscopic and external DCR. Endoscopic surgery may have a benefit of preserving the lacrimal pump system and leaving no surgical scar. Patient preference and availability of each service should direct management. Hence endoscopic endonasal DCR surgery should be considered for primary treatment of nasolacrimal duct obstruction.

A distinct influenza infection signature in the blood transcriptome of patients with severe community-acquired pneumonia

IntroductionDiagnosis of severe influenza pneumonia remains challenging because of a lack of correlation between the presence of influenza virus and clinical status. We conducted gene-expression profiling in the whole blood of critically ill patients to identify a gene signature that would allow clinicians to distinguish influenza infection from other causes of severe respiratory failure, such as bacterial pneumonia, and noninfective systemic inflammatory response syndrome.MethodsWhole-blood samples were collected from critically ill individuals and assayed on Illumina HT-12 gene-expression beadarrays. Differentially expressed genes were determined by linear mixed-model analysis and overrepresented biological pathways determined by using GeneGo MetaCore.ResultsThe gene-expression profile of H1N1 influenza A pneumonia was distinctly different from those of bacterial pneumonia and systemic inflammatory response syndrome. The influenza gene-expression profile is characterized by upregulation of genes from cell-cycle regulation, apoptosis, and DNA-damage-response pathways. In contrast, no distinctive gene-expression signature was found in patients with bacterial pneumonia or systemic inflammatory response syndrome. The gene-expression profile of influenza infection persisted through 5 days of follow-up. Furthermore, in patients with primary H1N1 influenza A infection in whom bacterial co-infection subsequently developed, the influenza gene-expression signature remained unaltered, despite the presence of a superimposed bacterial infection.ConclusionsThe whole-blood expression-profiling data indicate that the host response to influenza pneumonia is distinctly different from that caused by bacterial pathogens. This information may speed the identification of the cause of infection in patients presenting with severe respiratory failure, allowing appropriate patient care to be undertaken more rapidly.

Aberrant cell cycle and apoptotic changes characterise severe influenza A infection--a meta-analysis of genomic signatures in circulating leukocytes.

Influenza A infection is a global disease that has been responsible for four pandemics over the last one hundred years. However, it remains poorly understood as to why some infected individuals succumb to life threatening complications whilst others recover and are relatively unaffected. Using gene-expression analysis of circulating leukocytes, here we show that the progression towards severe influenza A infection is characterised by an abnormal transcriptional reprogramming of cell cycle and apoptosis pathways. In severely infected humans, leukocyte gene-expression profiles display opposing cell cycle activities; an increased aberrant DNA replication in the G1/S phase yet delayed progression in the G2/M phase. In mild infection, cell cycle perturbations are fewer and are integrated with an efficient apoptotic program. Importantly, the loss of integration between cell cycle perturbations and apoptosis marks the transition from a mild viral illness to a severe, life threatening infection. Our findings suggest that circulating immune cells may play a significant role in the evolution of the host response. Further study may reveal alternative host response factors previously unrecognized in the current disease model of influenza.