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1.  A Field Evaluation of the Hardy TB MODS Kit™ for the Rapid Phenotypic Diagnosis of Tuberculosis and Multi-Drug Resistant Tuberculosis 
PLoS ONE  2014;9(9):e107258.
Even though the WHO-endorsed, non-commercial MODS assay offers rapid, reliable TB liquid culture and phenotypic drug susceptibility testing (DST) at lower cost than any other diagnostic, uptake has been patchy. In part this reflects misperceptions about in-house assay quality assurance, but user convenience of one-stop procurement is also important. A commercial MODS kit was developed by Hardy Diagnostics (Santa Maria, CA, USA) with PATH (Seattle, WA, USA) to facilitate procurement, simplify procedures through readymade media, and enhance safety with a sealing silicone plate lid. Here we report the results from a large-scale field evaluation of the MODS kit in a government service laboratory.
Methods & Findings
2446 sputum samples were cultured in parallel in Lowenstein-Jensen (LJ), conventional MODS and in the MODS kit. MODS kit DST was compared with conventional MODS (direct) DST and proportion method (indirect) DST. 778 samples (31.8%) were Mycobacterium tuberculosis culture-positive. Compared to conventional MODS the sensitivity, specificity, positive, and negative predictive values (95% confidence intervals) of the MODS Kit were 99.3% (98.3–99.8%), 98.3% (97.5–98.8%), 95.8% (94.0–97.1%), and 99.7% (99.3–99.9%). Median (interquartile ranges) time to culture-positivity (and rifampicin and isoniazid DST) was 10 (9–13) days for conventional MODS and 8.5 (7–11) for MODS Kit (p<0.01). Direct rifampicin and isoniazid DST in MODS kit was almost universally concordant with conventional MODS (97.9% agreement, 665/679 evaluable samples) and reference indirect DST (97.9% agreement, 687/702 evaluable samples).
MODS kit delivers performance indistinguishable from conventional MODS and offers a convenient, affordable alternative with enhanced safety from the sealing silicone lid. The availability in the marketplace of this platform, which conforms to European standards (CE-marked), readily repurposed for second-line DST in the near future, provides a fresh opportunity for improving equity of access to TB diagnosis and first and second-line DST in settings where the need is greatest.
PMCID: PMC4167337  PMID: 25225802
2.  Diagnostic value of maximal-outer-diameter and maximal-mural-thickness in use of ultrasound for acute appendicitis in children 
AIM: To evaluate the maximal-outer-diameter (MOD) and the maximal-mural-thickness (MMT) of the appendix in children with acute appendicitis and to determine their optimal cut-off values to diagnose acute appendicitis.
METHODS: In total, 164 appendixes from 160 children between 1 and 17 years old (84 males, 76 females; mean age, 7.38 years) were examined by high-resolution abdominal ultrasound for acute abdominal pain and the suspicion of acute appendicitis. We measured the MOD and the MMT at the thickest point of the appendix. Patients were categorized into two groups according to their medical records: patients who had surgery (surgical appendix group) and patients who did not have surgery (non-surgical appendix group). Data were analyzed by MedCalc v.9.3. The rank sum test (Mann-Whitney test) was used to evaluate the difference in the MOD and the MMT between the two groups. ROC curve analysis was used to determine the optimal cut-off value of the MOD and the MMT on diagnosis of acute appendicitis.
RESULTS: There were 121 appendixes (73.8%) in the non-surgical appendix group and 43 appendixes (26.2%) in the surgical appendix group. The median MOD differed significantly between the two groups (0.37 cm vs 0.76 cm, P < 0.0001), and the median MMT also differed (0.15 cm vs 0.33 cm, P < 0.0001). The optimal cut-off value of the MOD and the MMT for diagnosis of acute appendicitis in children was > 0.57 cm (sensitivity 95.4%, specificity 93.4%) and > 0.22 cm (sensitivity 90.7%, specificity 79.3%), respectively.
CONCLUSION: The MOD and the MMT are reliable criteria to diagnose acute appendicitis in children. An MOD > 0.57 cm and an MMT > 0.22 cm are the optimal criteria.
PMCID: PMC2699009  PMID: 19533813
Appendicitis; Ultrasonography; Pediatrics; Diagnosis; ROC curve
3.  Diagnosis of Pulmonary Tuberculosis in HIV-Positive Patients by Microscopic Observation Drug Susceptibility Assay ▿  
Journal of Clinical Microbiology  2010;48(12):4573-4579.
The microscopic observation drug susceptibility assay (MODS) is a novel and promising test for the early diagnosis of tuberculosis (TB). We evaluated the MODS assay for the early diagnosis of TB in HIV-positive patients presenting to Pham Ngoc Thach Hospital for Tuberculosis and Lung Diseases in southern Vietnam. A total of 738 consecutive sputum samples collected from 307 HIV-positive individuals suspected of TB were tested by smear, MODS, and the mycobacteria growth indicator tube method (MGIT). The diagnostic sensitivity and specificity of MODS compared to the microbiological gold standard (either smear or MGIT) were 87 and 93%, respectively. The sensitivities of smear, MODS, and MGIT were 57, 71, and 75%, respectively, against clinical gold standard (MODS versus smear, P < 0.001; MODS versus MGIT, P = 0.03). The clinical gold standard was defined as patients who had a clinical examination and treatment consistent with TB, with or without microbiological confirmation. For the diagnosis of smear-negative patients, the sensitivities of MODS and MGIT were 38 and 45%, respectively (P = 0.08). The median times to detection using MODS and MGIT were 8 and 11 days, respectively, and they were 11 and 17 days, respectively, for smear-negative samples. The original bacterial/fungal contamination rate of MODS was 1.1%, while it was 2.6% for MGIT. The cross-contamination rate of MODS was 4.7%. In conclusion, MODS is a sensitive, specific, and rapid test that is appropriate for the detection of HIV-associated TB; its cost and ease of use make it particularly useful in resource-limited settings.
PMCID: PMC3008451  PMID: 20926704
4.  Using Parametric Multipoint Lods and Mods for Linkage Analysis Requires a Shift in Statistical Thinking 
Human Heredity  2011;72(4):264-275.
Multipoint (MP) linkage analysis represents a valuable tool for whole-genome studies but suffers from the disadvantage that its probability distribution is unknown and varies as a function of marker information and density, genetic model, number and structure of pedigrees, and the affection status distribution [Xing and Elston: Genet Epidemiol 2006;30:447–458; Hodge et al.: Genet Epidemiol 2008;32:800–815]. This implies that the MP significance criterion can differ for each marker and each dataset, and this fact makes planning and evaluation of MP linkage studies difficult. One way to circumvent this difficulty is to use simulations or permutation testing. Another approach is to use an alternative statistical paradigm to assess the statistical evidence for linkage, one that does not require computation of a p value. Here we show how to use the evidential statistical paradigm for planning, conducting, and interpreting MP linkage studies when the disease model is known (lod analysis) or unknown (mod analysis). As a key feature, the evidential paradigm decouples uncertainty (i.e. error probabilities) from statistical evidence. In the planning stage, the user calculates error probabilities, as functions of one's design choices (sample size, choice of alternative hypothesis, choice of likelihood ratio (LR) criterion k) in order to ensure a reliable study design. In the data analysis stage one no longer pays attention to those error probabilities. In this stage, one calculates the LR for two simple hypotheses (i.e. trait locus is unlinked vs. trait locus is located at a particular position) as a function of the parameter of interest (position). The LR directly measures the strength of evidence for linkage in a given data set and remains completely divorced from the error probabilities calculated in the planning stage. An important consequence of this procedure is that one can use the same criterion k for all analyses. This contrasts with the situation described above, in which the value one uses to conclude significance may differ for each marker and each dataset in order to accommodate a fixed test size, α. In this study we accomplish two goals that lead to a general algorithm for conducting evidential MP linkage studies. (1) We provide two theoretical results that translate into guidelines for investigators conducting evidential MP linkage: (a) Comparing mods to lods, error rates (including probabilities of weak evidence) are generally higher for mods when the null hypothesis is true, but lower for mods in the presence of true linkage. Royall [J Am Stat Assoc 2000;95:760–780] has shown that errors based on lods are bounded and generally small. Therefore when the true disease model is unknown and one chooses to use mods, one needs to control misleading evidence rates only under the null hypothesis; (b) for any given pair of contiguous marker loci, error rates under the null are greatest at the midpoint between the markers spaced furthest apart, which provides an obvious simple alternative hypothesis to specify for planning MP linkage studies. (2) We demonstrate through extensive simulation that this evidential approach can yield low error rates under the null and alternative hypotheses for both lods and mods, despite the fact that mod scores are not true LRs. Using these results we provide a coherent approach to implement a MP linkage study using the evidential paradigm.
PMCID: PMC3267993  PMID: 22189469
Evidential paradigm; Likelihood; Parametric linkage; Complex disease
5.  Validation of microscopic observation drug susceptibility testing for rapid, direct rifampicin and isoniazid drug susceptibility testing in patients receiving tuberculosis treatment 
Drug susceptibility testing (DST) is often needed in patients clinically failing tuberculosis (TB) therapy. Most studies of phenotypic direct drug susceptibility tests, such as microscopic observation drug susceptibility (MODS) tests, have been performed in patients not receiving TB treatment. The effect of ongoing TB treatment on the performance of MODS direct DST has not been previously explored, but patients failing such therapy constitute an important target group. The aim of this study was to determine the performance of MODS direct rifampicin and isoniazid DST in patients clinically failing first-line TB treatment, and to compare MODS direct DST with indirect proportion method DST. Sputa from 264 TB patients were cultured in parallel in Lowenstein–Jensen (LJ) and MODS assays; strains were tested for rifampicin and isoniazid susceptibility by the proportion method at the national reference laboratory. Ninety-three samples were culture-positive by LJ and MODS (concordance of 96%; kappa 0.92). With conventional MODS plate DST reading (performed on the same day as the sample is classified as culture-positive), the isoniazid DST concordance was 96.8% (kappa 0.89), and the concordance for rifampicin susceptibility testing was 92.6% (kappa 0.80). Reading of MODS DST plates 1 week after cultures had been determined to be culture-positive improved overall performance marginally—the isoniazid DST concordance was 95.7% (kappa 0.85); and the rifampicin DST concordance was 96.8% (kappa 0.91). Sensitivity for detection of multidrug-resistant TB was 95.8%. MODS testing provided reliable rifampicin and isoniazid DST results for samples obtained from patients receiving TB therapy. A modified DST reading schedule for such samples, with a final reading 1 week after a MODS culture turns positive, marginally improves the concordance with reference DST.
PMCID: PMC4302318  PMID: 24107197
Drug susceptibility test; MODS; treatment failure; tuberculosis
6.  Microscopic-Observation Drug-Susceptibility Assay for the Diagnosis of Drug-Resistant Tuberculosis in Harare, Zimbabwe 
PLoS ONE  2013;8(2):e55872.
Limited data exist on use of the microscopic-observation drug-susceptibility (MODS) assay among persons suspected of MDR-TB living in high HIV-prevalence settings.
We retrospectively reviewed available clinical and drug susceptibility data for drug-resistant TB suspects referred for culture and drug-susceptibility testing between April 1, 2011 and March 1, 2012. The diagnostic accuracy of MODS was estimated against a reference standard including Löwenstein-Jensen (LJ) media and manual liquid (BACTEC MGIT) culture. The accuracy of MODS drug-susceptibility testing (DST) was assessed against a reference standard absolute concentration method.
One hundred thirty-eight sputum samples were collected from 99 drug-resistant TB suspects; in addition, six previously cultured MDR isolates were included for assessment of DST accuracy. Among persons with known HIV infection status, 39/59 (66%) were HIV-infected. Eighty-six percent of patients had a history of prior TB treatment, and 80% of individuals were on antituberculous treatment at the time of sample collection. M. tuberculosis was identified by reference standard culture among 34/98 (35%) MDR-TB suspects. Overall MODS sensitivity for M. tuberculosis detection was 85% (95% CI, 69–95%) and specificity was 93% (95% CI, 84–98%); diagnostic accuracy did not significantly differ by HIV infection status. Median time to positivity was significantly shorter for MODS (7 days; IQR 7–15 days) than MGIT (12 days; IQR 6–16 days) or LJ (28 days; IQR 21–35 days; p<0.001). Of 33 specimens with concurrent DST results, sensitivity of the MODS assay for detection of resistance to isoniazid, rifampin, and MDR-TB was 88% (95% CI, 68–97%), 96% (95% CI, 79–100%), and 91% (95% CI, 72–99%), respectively; specificity was 89% (95% CI, 52–100%), 89% (95% CI, 52–100%), and 90% (95% CI, 56–100%), respectively.
In a high HIV-prevalence setting, MODS diagnosed TB and drug-resistant TB with high sensitivity and shorter turnaround time compared with standard culture and DST methods.
PMCID: PMC3569460  PMID: 23409072
7.  Microscopic Observation Drug Susceptibility Assay (MODS) for Early Diagnosis of Tuberculosis in Children 
PLoS ONE  2009;4(12):e8341.
MODS is a novel liquid culture based technique that has been shown to be effective and rapid for early diagnosis of tuberculosis (TB). We evaluated the MODS assay for diagnosis of TB in children in Viet Nam. 217 consecutive samples including sputum (n = 132), gastric fluid (n = 50), CSF (n = 32) and pleural fluid (n = 3) collected from 96 children with suspected TB, were tested by smear, MODS and MGIT. When test results were aggregated by patient, the sensitivity and specificity of smear, MGIT and MODS against “clinical diagnosis” (confirmed and probable groups) as the gold standard were 28.2% and 100%, 42.3% and 100%, 39.7% and 94.4%, respectively. The sensitivity of MGIT and MODS was not significantly different in this analysis (P = 0.5), but MGIT was more sensitive than MODS when analysed on the sample level using a marginal model (P = 0.03). The median time to detection of MODS and MGIT were 8 days and 13 days, respectively, and the time to detection was significantly shorter for MODS in samples where both tests were positive (P<0.001). An analysis of time-dependent sensitivity showed that the detection rates were significantly higher for MODS than for MGIT by day 7 or day 14 (P<0.001 and P = 0.04), respectively. MODS is a rapid and sensitive alternative method for the isolation of M.tuberculosis from children.
PMCID: PMC2791864  PMID: 20020056
8.  Evaluation of microscopic observation drug susceptibility assay for diagnosis of multidrug-resistant Tuberculosis in Viet Nam 
Early diagnosis of tuberculosis (TB) and multidrug resistant tuberculosis (MDR TB) is important for the elimination of TB. We evaluated the microscopic observation drug susceptibility (MODS) assay as a direct rapid drug susceptibility testing (DST) method for MDR-TB screening in sputum samples
All adult TB suspects, who were newly presenting to Pham Ngoc Thach Hospital from August to November 2008 were enrolled into the study. Processed sputum samples were used for DST by MODS (DST-MODS) (Rifampicin (RIF) 1 μg/ml and Isoniazid (INH) 0.4 μg/ml), MGIT culture (Mycobacterial Growth Indicator Tube) and Lowenstein Jensen (LJ) culture. Cultures positive by either MGIT or LJ were used for proportional DST (DST-LJ) (RIF 40 μg/ml and INH 0.2 μg/ml). DST profiles on MODS and LJ were compared. Discrepant results were resolved by multiplex allele specific PCR (MAS-PCR).
Seven hundred and nine TB suspects/samples were enrolled into the study, of which 300 samples with DST profiles available from both MODS and DST-LJ were analyzed. Cording in MODS was unable to correctly identify 3 Mycobacteria Other Than Tuberculosis (MOTT) isolates, resulting in 3 false positive TB diagnoses. None of these isolates were identified as MDR-TB by MODS. The sensitivity and specificity of MODS were 72.6% (95%CI: 59.8, 83.1) and 97.9% (95%CI: 95.2, 99.3), respectively for detection of INH resistant isolates, 72.7% (95%CI: 30.9, 93.7) and 99.7% (95%CI: 98.1, 99.9), respectively for detecting RIF resistant isolates and 77.8% (95%CI: 39.9, 97.1) and 99.7% (95%CI: 98.1, 99.9), respectively for detecting MDR isolates. The positive and negative predictive values (PPV and NPV) of DST-MODS were 87.5% (95%CI: 47.3, 99.6) and 99.3% (95%CI: 97.5, 99.9) for detection of MDR isolates; and the agreement between MODS and DST-LJ was 99.0% (kappa: 0.8, P < 0.001) for MDR diagnosis. The low sensitivity of MODS for drug resistance detection was probably due to low bacterial load samples and the high INH concentration (0.4 μg/ml). The low PPV of DST-MODS may be due to the low MDR-TB rate in the study population (3.8%). The turnaround time of DST-MODS was 9 days and 53 days for DST-LJ.
The DST-MODS technique is rapid with low contamination rates. However, the sensitivity of DST-MODS for detection of INH and RIF resistance in this study was lower than reported from other settings.
PMCID: PMC3347990  PMID: 22375832
MDR-TB; Tuberculosis; MODS; Diagnosis
9.  Modified Pediatric ASPECTS Correlates with Infarct Volume in Childhood Arterial Ischemic Stroke 
Background and Purpose: Larger infarct volume as a percent of supratentorial brain volume (SBV) predicts poor outcome and hemorrhagic transformation in childhood arterial ischemic stroke (AIS). In perinatal AIS, higher scores on a modified pediatric version of the Alberta Stroke Program Early CT Score using acute MRI (modASPECTS) predict later seizure occurrence. The objectives were to establish the relationship of modASPECTS to infarct volume in perinatal and childhood AIS and to establish the interrater reliability of the score. Methods: We performed a cross sectional study of 31 neonates and 40 children identified from a tertiary care center stroke registry with supratentorial AIS and acute MRI with diffusion weighted imaging (DWI) and T2 axial sequences. Infarct volume was expressed as a percent of SBV using computer-assisted manual segmentation tracings. ModASPECTS was performed on DWI by three independent raters. The modASPECTS were compared among raters and to infarct volume as a percent of SBV. Results: ModASPECTS correlated well with infarct volume. Spearman rank correlation coefficients (ρ) for the perinatal and childhood groups were 0.76, p < 0.001 and 0.69, p < 0.001, respectively. Excluding one perinatal and two childhood subjects with multifocal punctate ischemia without large or medium sized vessel stroke, ρ for the perinatal and childhood groups were 0.87, p < 0.001 and 0.80, p < 0.001, respectively. The intraclass correlation coefficients for the three raters for the neonates and children were 0.93 [95% confidence interval (CI) 0.89–0.97, p < 0.001] and 0.94 (95% CI 0.91–0.97, p < 0.001), respectively. Conclusion: The modified pediatric ASPECTS on acute MRI can be used to estimate infarct volume as a percent of SBV with a high degree of validity and interrater reliability.
PMCID: PMC3449492  PMID: 23015799
modified pediatric ASPECTS; arterial ischemic stroke; MRI; infarct volume; childhood; perinatal
10.  Prospective evaluation of simply modified MODS assay: an effective tool for TB diagnosis and detection of MDR-TB 
Background and setting
Thailand is one of the highest tuberculosis (TB)-burdened countries. Chiang Rai, the northernmost province of Thailand has high tuberculosis and human immunodeficiency virus (HIV) prevalence and the laboratory workload for TB culture and drug susceptibility testing is increasing.
To evaluate the simply modified microscopic-observation drug-susceptibility assay (MODS) in the setting of a developing country.
In this cross-sectional diagnostic study, a total of 202 sputum samples of clinically diagnosed TB patients were used to test the performance of MODS assay in reference to gold standard BACTEC™ MGIT™ 960 liquid culture system and Ogawa solid culture. Sputum samples were collected from clinically diagnosed TB patients. Culture growth rate and time to culture positivity were compared among three methods. Performance of modified MODS assay was evaluated for detection of mycobacterium drug resistance in reference to MGIT antimicrobial susceptibility test (AST).
Median time to culture positivity by MODS, solid, and liquid culture were 12, 30, and 6 days respectively. Compared to the drug susceptibility test (DST) result of reference liquid culture, the sensitivity and specificity of MODS for detection of multidrug-resistant tuberculosis (MDR-TB) was 85.7% and 97.5% respectively. MODS assay has a positive predicative value of 80% and negative predictive value of 96.5% for isoniazid resistance, 70% and 100% for rifampicin resistance, and 66.7% and 99.1% for MDR-TB.
MODS is a highly effective screening test for detection of MDR-TB.
PMCID: PMC3358813  PMID: 22629112
tuberculosis; drug resistance; MODS assay; Chiang Rai; Thailand
11.  Influence of hypothermia on right atrial cardiomyocyte apoptosis in patients undergoing aortic valve replacement 
There is increasing evidence that programmed cell death can be triggered during cardiopulmonary bypass (CPB) and may be involved in postoperative complications. The purpose of this study was to investigate whether apoptosis occurs during aortic valve surgery and whether modifying temperature during CPB has any influence on cardiomyocyte apoptotic death rate.
20 patients undergoing elective aortic valve replacement for aortic stenosis were randomly assigned to either moderate hypothermic (ModHT group, n = 10, 28°C) or mild hypothermic (MiHT group, n = 10, 34°C) CPB. Myocardial samples were obtained from the right atrium before and after weaning from CPB. Specimens were examined for apoptosis by flow cytometry analysis of annexin V-propidium iodide (PI) and Fas death receptor staining.
In the ModHT group, non apoptotic non necrotic cells (annexin negative, PI negative) decreased after CPB, while early apoptotic (annexin positive, PI negative) and late apoptotic or necrotic (PI positive) cells increased. In contrast, no change in the different cell populations was observed over time in the MiHT group. Fas expression rose after reperfusion in the ModHT group but not in MiHT patients, in which there was even a trend for a lower Fas staining after CPB (p = 0.08). In ModHT patients, a prolonged ischemic time tended to induce a higher increase of Fas (p = 0.061).
Our data suggest that apoptosis signal cascade is activated at early stages during aortic valve replacement under ModHT CPB. This apoptosis induction can effectively be attenuated by a more normothermic procedure.
PMCID: PMC1783850  PMID: 17241480
12.  Comparision of modified and conventional delta-shaped gastroduodenostomy in totally laparoscopic surgery 
World Journal of Gastroenterology : WJG  2014;20(30):10478-10485.
AIM: To evaluate the safety and feasibility of a modified delta-shaped gastroduodenostomy (DSG) in totally laparoscopic distal gastrectomy (TLDG).
METHODS: We performed a case-control study enrolling 63 patients with distal gastric cancer (GC) undergoing TLDG with a DSG from January 2013 to June 2013. Twenty-two patients underwent a conventional DSG (Con-Group), whereas the other 41 patients underwent a modified version of the DSG (Mod-Group). The modified procedure required only the instruments of the surgeon and assistant to complete the involution of the common stab incision and to completely resect the duodenal cutting edge, resulting in an anastomosis with an inverted T-shaped appearance. The clinicopathological characteristics, surgical outcomes, anastomosis time and complications of the two groups were retrospectively analyzed using a prospectively maintained comprehensive database.
RESULTS: DSG procedures were successfully completed in all of the patients with histologically complete (R0) resections, and none of these patients required conversion to open surgery. The clinicopathological characteristics of the two groups were similar. There were no significant differences between the groups in the operative time, intraoperative blood loss, extension of the lymph node (LN) dissection and number of dissected LNs (150.8 ± 21.6 min vs 143.4 ± 23.4 min, P = 0.225 for the operative time; 26.8 ± 11.3 min vs 30.6 ± 14.8 mL, P = 0.157 for the intraoperative blood loss; 4/18 vs 3/38, P = 0.375 for the extension of the LN dissection; and 43.9 ± 13.4 vs 39.5 ± 11.5 per case, P = 0.151 for the number of dissected LNs). The anastomosis time, however, was significantly shorter in the Mod-Group than in the Con-Group (13.9 ± 2.8 min vs 23.9 ± 5.6 min, P = 0.000). The postoperative outcomes, including the times to out-of-bed activities, first flatus, resumption of soft diet and postoperative hospital stay, as well as the anastomosis size, did not differ significantly (1.9 ± 0.6 d vs 2.3 ± 1.5 d, P = 0.228 for the time to out-of-bed activities; 3.2 ± 0.9 d vs 3.5 ± 1.3 d, P = 0.295 for the first flatus time; 7.5 ± 0.8 d vs 8.1 ± 4.3 d, P = 0.489 for the resumption of a soft diet time; 14.3 ± 10.6 d vs 11.5 ± 4.9 d, P = 0.148 for the postoperative hospital stay; and 30.5 ± 3.6 mm vs 30.1 ± 4.0 mm, P = 0.730 for the anastomosis size). One patient with minor anastomotic leakage in the Con-Group was managed conservatively; no other patients experienced any complications around the anastomosis. The operative complication rates were similar in the Con- and Mod-Groups (9.1% vs 7.3%, P = 1.000).
CONCLUSION: The modified DSG, an alternative reconstruction in TLDG for GC, is technically safe and feasible, with a simpler process that reduces the anastomosis time.
PMCID: PMC4130856  PMID: 25132765
Stomach neoplasms; Totally laparoscopic surgery; Digestive tract reconstruction; Modified anastomosis; Treatment outcome
13.  HumMod: A Modeling Environment for the Simulation of Integrative Human Physiology 
Mathematical models and simulations are important tools in discovering key causal relationships governing physiological processes. Simulations guide and improve outcomes of medical interventions involving complex physiology. We developed HumMod, a Windows-based model of integrative human physiology. HumMod consists of 5000 variables describing cardiovascular, respiratory, renal, neural, endocrine, skeletal muscle, and metabolic physiology. The model is constructed from empirical data obtained from peer-reviewed physiological literature. All model details, including variables, parameters, and quantitative relationships, are described in Extensible Markup Language (XML) files. The executable (HumMod.exe) parses the XML and displays the results of the physiological simulations. The XML description of physiology in HumMod's modeling environment allows investigators to add detailed descriptions of human physiology to test new concepts. Additional or revised XML content is parsed and incorporated into the model. The model accurately predicts both qualitative and quantitative changes in clinical and experimental responses. The model is useful in understanding proposed physiological mechanisms and physiological interactions that are not evident, allowing one to observe higher level emergent properties of the complex physiological systems. HumMod has many uses, for instance, analysis of renal control of blood pressure, central role of the liver in creating and maintaining insulin resistance, and mechanisms causing orthostatic hypotension in astronauts. Users simulate different physiological and pathophysiological situations by interactively altering numerical parameters and viewing time-dependent responses. HumMod provides a modeling environment to understand the complex interactions of integrative physiology. HumMod can be downloaded at
PMCID: PMC3082131  PMID: 21647209
integrative physiology; HumMod; physiome; model
14.  Meta-analysis to compare the accuracy of GeneXpert, MODS and the WHO 2007 algorithm for diagnosis of smear-negative pulmonary tuberculosis 
BMC Infectious Diseases  2013;13:507.
Smear-negative pulmonary tuberculosis (SN-PTB), which is common in HIV-infected patients, is difficult to diagnose using smear microscopy alone. In 2007, the WHO developed an algorithm to improve the diagnosis and management of smear-negative tuberculosis in HIV prevalent and resource constrained settings. Implementation of the algorithm required individuals with presumptive TB to be initially evaluated using two sputum microscopy examinations followed by clinical diagnosis that may include chest X-ray and antibiotic treatment in smear-negative individuals. Since that time, the WHO has endorsed several new tests for diagnosis of tuberculosis. However, it is unclear how the new tests perform when compared to the WHO 2007 algorithm in diagnosis of SN-PTB. Using meta-analysis study design, we summarized and compared the accuracy of Xpert® MTB/Rif assay (GeneXpert) and Microscopic Observation Drug Susceptibility assay (MODS), with the WHO 2007 algorithm in the diagnosis of SN-PTB.
A systematic review and meta-analysis of publications on GeneXpert, or MODS, or the WHO 2007 algorithm for diagnosis of SN-PTB, using culture as reference test was performed. Meta-Disc software was used to obtain pooled sensitivity and specificity of the diagnostic methods. Heterogeneity in the accuracy estimates was tested by reviewing the generated forest plots, sROC curves and the Spearman correlation coefficient of the logit of true positive rate versus the logit of false positive rate.
Twenty-four publications on all three diagnostic methods were meta-analyzed. The pooled sensitivity and specificity for detection of smear-negative pulmonary tuberculosis were 67% and 98% for GeneXpert, 73% and 91% for MODS, and 61% and 69% for WHO 2007 algorithm, respectively. The sensitivity of GeneXpert reduced from 67% to 54% when sub-group analysis of studies with patient HIV prevalence ≥30% was performed.
The GeneXpert, MODS, and the WHO algorithm have moderate to high accuracy for the diagnosis of SN-PTB. However, the accuracy of the tests is extremely variable. The setting and context under which the tests are conducted in addition to several other factors could explain this variability. There is therefore need to investigate these factors further. The information from these studies would inform the adoption and placement of these new tests.
PMCID: PMC3833313  PMID: 24172543
Smear negative; Pulmonary TB; GeneXpert; MODS; WHO TB algorithm
15.  Rapid, Efficient Detection and Drug Susceptibility Testing of Mycobacterium tuberculosis in Sputum by Microscopic Observation of Broth Cultures 
Journal of Clinical Microbiology  2000;38(3):1203-1208.
Inexpensive, rapid, and reliable methods of detecting infection by and drug susceptibility of Mycobacterium tuberculosis (MTB) are crucial to the control of tuberculosis. The novel microscopic observation broth-drug susceptibility assay (MODS) detects early growth of MTB in liquid medium, allowing more timely diagnosis and drug susceptibility testing. Sputum samples from hospitalized patients in Peru were analyzed by using stains, culture, and PCR. Sensitivity of MODS (92%) compared favorably with the most sensitive of the other culture methods (93%). Sputum samples positive for tuberculosis were tested for susceptibility to isoniazid and rifampin with the microwell alamar blue assay (MABA) and MODS. In 89% of cases, there was concordance between MODS and MABA. Of the diagnostic and susceptibility testing methods used, MODS yielded results most rapidly (median, 9.0 and 9.5 days, respectively). MODS is a rapid, inexpensive, sensitive, and specific method for MTB detection and susceptibility testing; it is particularly appropriate for use in developing countries burdened by significant infection rates and increasing numbers of multiple-drug-resistant cases.
PMCID: PMC86377  PMID: 10699023
16.  Genetic analysis of the modABCD (molybdate transport) operon of Escherichia coli. 
Journal of Bacteriology  1995;177(17):4851-4856.
DNA sequence analysis of the modABCD operon of Escherichia coli revealed the presence of four open reading frames. The first gene, modA, codes for a 257-amino-acid periplasmic binding protein enunciated by the presence of a signal peptide-like sequence. The second gene (modB) encodes a 229-amino-acid protein with a potential membrane location, while the 352-amino-acid ModC protein (modC product) contains a nucleotide-binding motif. On the basis of sequence similarities with proteins from other transport systems and molybdate transport proteins from other organisms, these three proteins are proposed to constitute the molybdate transport system. The fourth open reading frame (modD) encodes a 231-amino-acid protein of unknown function. Plasmids containing different mod genes were used to map several molybdate-suppressible chlorate-resistant mutants; interestingly, none of the 40 mutants tested had a mutation in the modD gene. About 35% of these chlorate-resistant mutants were not complemented by mod operon DNA. These mutants, designated mol, contained mutations at unknown chromosomal location(s) and produced formate hydrogenlyase activity only when cultured in molybdate-supplemented glucose-minimal medium, not in L broth. This group of mol mutants constitutes a new class of molybdate utilization mutants distinct from other known mutants in molybdate metabolism. These results show that molybdate, after transport into cells by the ModABC proteins, is metabolized (activated?) by the products of the mol gene(s).
PMCID: PMC177257  PMID: 7665460
17.  Early Blood Product and Crystalloid Volume Resuscitation: Risk Association with Multiple Organ Dysfunction after Severe Blunt Traumatic Injury 
The Journal of trauma  2011;71(2):299-305.
Elements of volume resuscitation from hemorrhagic shock, such as amount of blood product and crystalloid administration, have been shown to be associated with Multiple Organ Dysfunction (MOD). However, it is unknown whether these are causative factors or merely markers of an underlying requirement for large-volume resuscitation. We sought to further delineate the relevance of the major individual components of early volume resuscitation to onset of MOD after severe blunt traumatic injury.
We performed a secondary analysis of a large, multi-center prospective observational cohort of severely injured blunt trauma patients, the NIGMS Trauma Glue Grant, to assess the relevance of individual components of resuscitation administered in the first 12 hours of resuscitation including packed red blood cells (PRBC), fresh frozen plasma (FFP) and isotonic crystalloid, to the onset of MOD within the first 28 days after injury. Deaths within 48 hours of injury were excluded. We utilized a two-tiered, exhaustive logistic regression model search technique to adjust for potential confounders from clinically relevant MOD covariates, including indicators of shock severity, injury severity, comorbidities, age and gender.
The study cohort consisted of 1,366 severely injured blunt trauma patients (median NISS=34). Incidence of 28-day Marshall MOD was 19.6%. Transfusion of ≥10 Units of PRBC in the first 12 hrs (OR 2.06, 95% CI 1.44 - 2.94), but not FFP (≥8 U) or large volume crystalloid administration (≥12L), was independently associated with onset of 28-day Marshall MOD. PRBC:FFP ratio in the first 12 hours was not significantly associated with MOD.
When controlling for all major components of acute volume resuscitation, massive-transfusion volumes of PRBC’s within the first 12 hours of resuscitation are modestly associated with MOD, while FFP and large volume crystalloid administration are not independently associated with MOD. Previous reported associations of blood products and large-volume crystalloid with MOD may be reflecting overall resuscitation requirements and burden of injury rather than independent causation.
PMCID: PMC3716363  PMID: 21825930
Multiple Organ Dysfunction; Blood; Trauma; Injury
18.  The change and effect of endothelial progenitor cells in pig with multiple organ dysfunction syndromes 
Critical Care  2009;13(4):R118.
The dysfunction and decrease of endothelial progenitor cells (EPCs) may play a very important role in the initiation of organ dysfunction caused by trauma or severe sepsis. We aim to measure the number and function of EPCs in the progression of multiple organ dysfunction syndromes (MODS) caused by severe sepsis, which may help to understand the pathogenesis of MODS by the changing of EPCs.
A total of 40 pigs were randomly divided into two groups, which were subjected to hemorrhagic shock, resuscitation and endotoxemia (experimental group, n = 20) or acted as a control (control group, n = 20). The number and function of EPCs including adhesive, migratory and angiogenesis capacities were analyzed at different times in both groups.
All the animals in the experimental group developed MODS (100%) and 17 of 20 animals (85%) died due to MODS; the incidence of MODS and death of the animals in the control group were 0% (P < 0.01). The number, migratory and adhesive capacities of EPCs decreased sharply in the animals of the experimental group corresponding to the increasing severities of MODS, but the angiogenesis function increased gradually until death. The decrease in function of EPCs preceded the decrease in number of EPCs. The decrease in number and function of EPCs occurred prior to the occurrence of MODS.
For the first time, it was observed that the number and function of EPCs decreased sharply in the progression of MODS and that it was prior to the occurrence of MODS. The decrease in number and function of EPCs may be one of the main pathogenic factors of MODS.
PMCID: PMC2750166  PMID: 19604356
19.  Evaluation of Xpert MTB/RIF and MODS assay for the diagnosis of pediatric tuberculosis 
Tuberculosis (TB) in children is rarely confirmed due to the lack of effective diagnostic tools; only 10 to 15% of pediatric TB is smear positive due to paucibacillary samples and the difficulty of obtaining high-quality specimens from children. We evaluate here the accuracy of Xpert MTB/RIF in comparison with the Micoroscopic observation drug susceptibility (MODS) assay for diagnosis of TB in children using samples stored during a previously reported evaluation of the MODS assay.
Ninety-six eligible children presenting with suspected TB were recruited consecutively at Pham Ngoc Thach Hospital in Ho Chi Minh City Viet Nam between May to December 2008 and tested by Ziehl-Neelsen smear, MODS and Mycobacterial growth Indicator (MGIT, Becton Dickinson) culture. All samples sent by the treating clinician for testing were included in the analysis. An aliquot of processed sample deposit was stored at −20°C and tested in the present study by Xpert MTB/RIF test. 183 samples from 73 children were available for analysis by Xpert. Accuracy measures of MODS and Xpert were summarized.
The sensitivity (%) in detecting children with a clinical diagnosis of TB for smear, MODS and Xpert were 37.9 [95% CI 25.5; 51.6], 51.7 [38.2; 65.0] and 50.0 [36.6; 63.4], respectively (per patient analysis). Xpert was significantly more sensitive than smear (P=0.046). Testing of additional samples did not increase case detection for MODS while testing of a second sputum sample by Xpert detected only two additional cases. The positive and negative predictive values (%) of Xpert were 100.0 [88.0; 100.0] and 34.1 [20.5; 49.9], respectively, while those of MODS were 96.8 [83.3; 99.9] and 33.3 [19.6; 49.5].
MODS culture and Xpert MTB/RIF test have similar sensitivities for the detection of pediatric TB. Xpert MTB RIF is able to detect tuberculosis and rifampicin resistance within two hours. MODS allows isolation of cultures for further drug susceptibility testing but requires approximately one week to become positive. Testing of multiple samples by xpert detected only two additional cases and the benefits must be considered against costs in each setting. Further research is required to evaluate the optimal integration of Xpert into pediatric testing algorithms.
PMCID: PMC3562258  PMID: 23343418
Tuberculosis; GeneXpert MTB/RIF; MODS; Pediatric; Childhood
20.  Changing Impact of Modifiable Risk Factors on the Incidence of Major Outcomes of Type 1 Diabetes 
Diabetes Care  2013;36(12):3999-4006.
The incidence of type 1 diabetes complications appears to be decreasing, but relative contributions of risk factors are unclear. We thus estimated the effect of modifiable risk factors on the incidence of a composite end point, major outcomes of diabetes (MOD).
The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study was used to derive two cohorts based on diabetes diagnosis year (1960–1969 and 1970–1980). Baseline exam data in the current analysis for the 1960s group were collected in 1986–1988 and for the 1970s in 1996–1998. Each group was followed for 8 years for MOD incidence (diabetes-related death, myocardial infarction, revascularization procedure/blockage ≥50%, stroke, end-stage renal disease, blindness, and amputation). Assessed risk factors include the following: HbA1c, hypertension, microalbuminuria, BMI, hypercholesterolemia, and smoking. Accelerated failure time models were used to estimate the acceleration factor.
MOD incidence decreased in the 1970s cohort (15.8% [95% CI 11.6–21.4]) compared with the 1960s (22.6% [17.0–29.1]) over the 8-year follow-up (P = 0.06). Hypertension and microalbuminuria were associated with significantly accelerated MOD incidence in both cohorts (P < 0.01 for both). High HbA1c (P = 0.0005), hypercholesterolemia (P = 0.01), and current smoking (P = 0.003) significantly accelerated the incidence of MOD in the 1960s but not 1970s cohort. BMI was not associated with MOD in either cohort.
These results suggest that hypertension and microalbuminuria remain important predictors of complications that are not being adequately addressed.
PMCID: PMC3836155  PMID: 24170748
21.  Objective assessment, repeatability, and agreement of shoulder ROM with a 3D gyroscope 
Assessment of shoulder mobility is essential for diagnosis and clinical follow-up of shoulder diseases. Only a few highly sophisticated instruments for objective measurements of shoulder mobility are available. The recently introduced DynaPort MiniMod TriGyro ShoulderTest-System (DP) was validated earlier in laboratory trials. We aimed to assess the precision (repeatability) and agreement of this instrument in human subjects, as compared to the conventional goniometer.
The DP is a small, light-weight, three-dimensional gyroscope that can be fixed on the distal upper arm, recording shoulder abduction, flexion, and rotation. Twenty-one subjects (42 shoulders) were included for analysis. Two subsequent assessments of the same subject with a 30-minute delay in testing of each shoulder were performed with the DP in two directions (flexion and abduction), and simultaneously correlated with the measurements of a conventional goniometer. All assessments were performed by one observer. Repeatability for each method was determined and compared as the statistical variance between two repeated measurements. Agreement was illustrated by Bland-Altman-Plots with 95% limits of agreement. Statistical analysis was performed with a linear mixed regression model. Variance for repeated measurements by the same method was also estimated and compared with the likelihood-ratio test.
Evaluation of abduction showed significantly better repeatability for the DP compared to the conventional goniometer (error variance: DP = 0.89, goniometer = 8.58, p = 0.025). No significant differences were found for flexion (DP = 1.52, goniometer = 5.94, p = 0.09). Agreement assessment was performed for flexion for mean differences of 0.27° with 95% limit of agreement ranging from −7.97° to 8.51°. For abduction, the mean differences were 1.19° with a 95% limit of agreement ranging from −9.07° to 11.46°.
In summary, DP demonstrated a high precision even higher than the conventional goniometer. Agreement between both methods is acceptable, with possible deviations of up to greater than 10°. Therefore, static measurements with DP are more precise than conventional goniometer measurements. These results are promising for routine clinical use of the DP.
PMCID: PMC3614536  PMID: 23442604
Repeatability; Precision; Shoulder motion; Objective assessment; Dynaport; Gyroscope
22.  Reinstatement of methamphetamine seeking in male and female rats treated with modafinil and allopregnanolone 
Drug and alcohol dependence  2011;120(1-3):233-237.
Sex differences in methamphetamine (METH) use (females>males) have been demonstrated in clinical and preclinical studies. This experiment investigated the effect of sex on the reinstatement of METH-seeking behavior in rats and to determine whether pharmacological interventions for METH-seeking behavior vary by sex. Treatment drugs were modafinil (MOD), an analeptic, and allopregnanolone (ALLO), a neuroactive steroid and progesterone metabolite.
Male and female rats were trained to self-administer i.v. infusions of METH (0.05mg/kg/infusion). Next, rats self-administered METH for a 10-day maintenance period. METH was then replaced with saline, and rats extinguished lever-pressing behavior over 18 days. A multi-component reinstatement procedure followed where priming injections of METH (1 mg/kg) were administered at the start of each daily session, preceded 30 min by MOD (128 mg/kg, i.p.), ALLO (15 mg/kg, s.c.), or vehicle treatment. MOD was also administered at the onset of the session to determine if it would induce the reinstatement of METH-seeking behavior.
Female rats had greater METH-induced reinstatement responding compared to male rats following control treatment injections. MOD (compared to the DMSO control) attenuated METH-seeking behavior in male and female rats; however, ALLO only reduced METH-primed responding in females. MOD alone did not induce the reinstatement of METH-seeking behavior.
These results support previous findings that females are more susceptible to stimulant abuse compared to males and ALLO effectively reduced METH-primed reinstatement in females. Further, they illustrate the utility of MOD as a potential agent for prevention of relapse to METH use in both males and females.
PMCID: PMC3213316  PMID: 21820819
Allopregnanolone; Methamphetamine; Modafinil; Rats; Reinstatement; Sex differences
23.  Mixed venous versus central venous oxygen saturation in patients undergoing on pump beating coronary artery bypass grafting 
Saudi Journal of Anaesthesia  2010;4(2):63-67.
To examine the validity of central venous oxygen saturation (ScvO2) as a numerical substitution of mixed venous oxygen saturation (SvO2) in adult patients undergoing normothermic on pump beating coronary artery bypass grafting (CABG).
Materials and Methods:
Prospective clinical observational study was done at King Khalid University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia. Thirty four adult patients scheduled for coronary artery surgery were included. Patients were monitored by a pulmonary artery catheter (PAC) as a part of our routine intraoperative monitoring. SvO2 and ScvO2 were simultaneously measured 15 minutes (T1) and 30 minutes (T2) after induction of anesthesia, 15 and 30 minutes after initiation of cardiopulmonary bypass (T3 and T4), and 15 and 30 minutes after admission to intensive care unit (T5 and T6).
ScvO2 showed higher reading than SvO2 all through our study. Our results showed perfect positive statistically significant correlation between SvO2 and ScvO2 at all data points. Individual mean of difference (MOD) between both the readings at study time showed MOD of 1.34 and 1.44 at T1 and T2 simultaneously. This MOD was statistically insignificant, but after on pump beating normothermic bypass was initiated; MOD was 5.2 and 4.4 at T3 and T4 with high statistical significance. In ICU, MOD continues to have high statistical significance, MOD was 6.3 at T5 and at T6 it was 4.6.
In on pump beating CABG patients; ScvO2 and SvO2 are not interchangeable numerically. ScvO2 is useful in the meaning of trend; our data suggest that ScvO2 is equivalent to SvO2 , only in the course of clinical decisions as long as absolute values are not required.
PMCID: PMC2945516  PMID: 20927264
Coronary artery bypass grafting; mixed venous oxygen saturation; coronary artery bypass grafting; mixed venous oxygen saturation; central venous oxygen saturation
24.  Diagnostic Accuracy of Microscopic Observation Drug Susceptibility (MODS) Assay for Pediatric Tuberculosis in Hanoi, Vietnam 
PLoS ONE  2013;8(9):e72100.
icroscopic Observation Drug Susceptibility (MODS) has been shown to be an effective and rapid technique for early diagnosis of tuberculosis (TB). Thus far only a limited number of studies evaluating MODS have been performed in children and in extra-pulmonary tuberculosis. This study aims to assess relative accuracy and time to positive culture of MODS for TB diagnosis in children admitted to a general pediatric hospital in Vietnam.
Methods/Principal Findings
Specimens from children with suspected TB were tested by smear, MODS and Lowenstein-Jensen agar (LJ). 1129 samples from 705 children were analyzed, including sputum (n = 59), gastric aspirate (n = 775), CSF (n = 148), pleural fluid (n = 33), BAL (n = 41), tracheal fluid (n = 45), other (n = 28). 113 TB cases were defined based on the “clinical diagnosis” (confirmed and probable groups) as the reference standard, in which 26% (n = 30) were diagnosed as extra-pulmonary TB. Analysis by patient shows that the overall sensitivity and specificity of smear, LJ and MODS against “clinical diagnosis” was 8.8% and 100%, 38.9% and 100%, 46% and 99.5% respectively with MODS significantly more sensitive than LJ culture (P = 0.02). When analyzed by sample type, the sensitivity of MODS was significantly higher than LJ for gastric aspirates (P = 0.004). The time to detection was also significantly shorter for MODS than LJ (7 days versus 32 days, P<0.001).
ODS is a sensitive and rapid culture technique for detecting TB in children. As MODS culture can be performed at a BSL2 facility and is inexpensive, it can therefore be recommended as a routine test for children with symptoms suggestive of TB in resource-limited settings.
PMCID: PMC3762843  PMID: 24023726
25.  Preoperative Mild-to-Moderate Coronary Artery Disease Does Not Affect Long-Term Outcomes of Lung Transplantation 
Transplantation  2014;97(10):1079-1085.
Coronary artery disease has a high prevalence among lung transplant recipients and has historically been a contraindication to transplant at many institutions. In patients with mild-to-moderate coronary artery disease (Mod-CAD) undergoing lung transplant, outcomes are not well defined.
All patients who underwent pulmonary transplantation from January 1996 through November 2010 with pretransplant coronary angiogram were included in our study. Recipients of multivisceral, redo, and lobar lung transplants and those who underwent pretransplant coronary revascularization were excluded. Patients were grouped into Mod-CAD or no-coronary artery disease group (No-CAD). Primary end point was overall survival. Secondary end points were 30-day events and the need for posttransplant coronary revascularization.
Approximately 539 patients were included in the study: 362 in the No-CAD, 177 in the Mod-CAD group. Patients with Mod-CAD were predominantly male, older, and had a higher body mass index. No difference in either perioperative morbidity and mortality (Mod-CAD, 4.2% vs. No-CAD 3.3%, P=0.705) or late overall mortality was shown between groups. Mod-CAD patients had a shorter hospitalization (median: 12 days vs. 14 days, P=0.009) and required a higher rate of late coronary revascularization procedures (PCI: Mod-CAD vs. No-CAD, 0.3% vs. 4.0%, P=0.0035; CABG: Mod-CAD vs. No-CAD, 0.3% vs. 2.3%, P=0.0411).
Mod-CAD does not appear to be associated with increased perioperative morbidity or decreased survival after transplant. Coronary artery disease may worsen and require coronary revascularization in patients with risk factors for disease progression. In these patients, close follow-up and screening for progression of coronary artery disease may help prevent late cardiac morbidity.
PMCID: PMC4336175  PMID: 24646771
Lung transplant; Coronary artery disease; Coronary artery bypass; Percutaneous coronary intervention

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