The effectiveness and safety of rescue treatments in 108 patients with steroid-refractory ulcerative colitis with sequential rescue therapies in a subgroup of patients.

BACKGROUND: Among patients with steroid-refractory ulcerative colitis (UC) in whom a first rescue therapy has failed, a second line salvage treatment can be considered to avoid colectomy. AIM: To evaluate the efficacy and safety of second or third line rescue therapy over a one-year period. METHODS: Response to single or sequential rescue treatments with infliximab (5mg/kg intravenously (iv) at week 0, 2, 6 and then every 8weeks), ciclosporin (iv 2mg/kg/daily and then oral 5mg/kg/daily) or tacrolimus (0.05mg/kg divided in 2 doses) in steroid-refractory moderate to severe UC patients from 7 Swiss and 1 Serbian tertiary IBD centers was retrospectively studied. The primary endpoint was the one year colectomy rate. RESULTS: 60% of patients responded to the first rescue therapy, 10% went to colectomy and 30% non-responders were switched to a 2(nd) line rescue treatment. 66% of patients responded to the 2(nd) line treatment whereas 34% failed, of which 15% went to colectomy and 19% received a 3(rd) line rescue treatment. Among those, 50% patients went to colectomy. Overall colectomy rate of the whole cohort was 18%. Steroid-free remission rate was 39%. The adverse event rates were 33%, 37.5% and 30% for the first, second and third line treatment respectively. CONCLUSION: Our data show that medical intervention even with 2(nd) and 3(rd) rescue treatments decreased colectomy frequency within one year of follow up. A longer follow-up will be necessary to investigate whether sequential therapy will only postpone colectomy and what percentage of patients will remain in long-term remission.

Prevalence and risk factors for gastro-esophageal reflux disease in the North-Eastern part of Bangladesh.

Despite a common disorder population-based data on gastro-esophageal reflux disease (GERD) in Bangladesh is lacking. This epidemiological study was designed to determine the prevalence of GERD and its association with lifestyle factors. This population-based cross-sectional study was done by door to door interview of randomly selected persons in both urban and rural areas of North Eastern part of Bangladesh by using a validated questionnaire. A cutoff point 3 was chosen as a valid and reliable scale to confirm GERD. Statistical analysis was done by SPSS-12 version and the level of significance was set at P < or = 0.05. A total of 2000 persons with an age range of 15 to 85 years were interviewed; 1000 subjects from urban area and 1000 from rural area. Among the study subjects 1064 were male and 936 were female. A total of 110 persons (5.5%) were found to have GERD symptoms and among them 47 were men and 67 were women. The monthly, weekly and daily prevalence of heart-burn and or acid regurgitation was 5.5%, 5.25% and 2.5% respectively. Female sex, increased age and lower level of education were significantly associated with GERD symptoms. Prevalence was found more among city dwellers (approximately 6.0% versus 4.8%), married (6.23%, n = 86), widowed/widowers (16.83%, n = 17) and day labourer (8.78%). Level of education inversely influenced the prevalence. No significant association of GERD was found with body mass index (BMI) and smoking. Prevalence of GERD in North-Eastern part of Bangladesh was lower than that of western world. Prevalence was found higher in urban population, women, married, widowed/widowers and in poor an dilliterate persons. BMI and smoking had no significant association with GERD.

VeriStrat(®) has a prognostic value for patients with advanced non-small cell lung cancer treated with erlotinib and bevacizumab in the first line: Pooled analysis of SAKK19/05 and NTR528.

BACKGROUND: VeriStrat(®) is a serum proteomic test used to determine whether patients with advanced non-small cell lung cancer (NSCLC) who have already received chemotherapy are likely to have good or poor outcomes from treatment with gefitinib or erlotinib. The main objective of our retrospective study was to evaluate the role of VS as a marker of overall survival (OS) in patients treated with erlotinib and bevacizumab in the first line. PATIENTS AND METHODS: Patients were pooled from two phase II trials (SAKK19/05 and NTR528). For survival analyses, a log-rank test was used to determine if there was a statistically significant difference between groups. The hazard ratio (HR) of any separation was assessed using Cox proportional hazards models. RESULTS: 117 patients were analyzed. VeriStrat classified patients into two groups which had a statistically significant difference in duration of OS (p=0.0027, HR=0.480, 95% confidence interval: 0.294-0.784). CONCLUSION: VeriStrat has a prognostic role in patients with advanced, nonsquamous NSCLC treated with erlotinib and bevacizumab in the first line. Further work is needed to study the predictive role of VeriStrat for erlotinib and bevacizumab in chemotherapy-untreated patients.

Clinical characteristics and outcome of patients admitted to a medico- surgical ICU requiring non invasive ventilation (NIV) for hypercapnic respiratory failure

Introduction Because it decreases intubation rate and mortality, NIV has become first-line treatment in case of hypercapnic acute respiratory failure (HARF). Whether this approach is equally successful for all categories of HARF patients is however debated. We assessed if any clinical characteristics of HARF patients were associated with NIV intensity, success, and outcome, in order to identify prognostic factors. Methods Retrospective analysis of the clinical database (clinical information system and MDSi) of patients consecutively admitted to our medico-surgical ICU, presenting with HARF (defined as PaCO2 > 50 mmHg), and receiving NIV between May 2008 and December 2010. Demographic data, medical diagnoses (including documented chronic lung disease), reason for ICU hospitalization, recent surgical interventions, SAPS II and McCabe scores were extracted from the database. Total duration of NIV and the need for tracheal intubation during the 5 days following the first hypercapnia documentation, as well as ICU, hospital and one year mortality were recorded. Results are reported as median [IQR]. Comparisons were carried out with Chi2 or Kruskal-Wallis tests, p<0.05 (*). Results Two hundred and twenty patients were included. NIV successful patients received 16 [9-31] hours of NIV for up to 5 days. Fifty patients (22.7%) were intubated 11 [2-34] hours after HARF occurence, after having receiving 10 [5-21] hours of NIV. Intubation was correlated with increased ICU (18% vs. 6%, p<0.05) and hospital (42% vs. 31%, p>0.05) mortality. SAPS II score was related to increasing ICU (51 [29-74] vs. 23 [12-41]%, p<0.05), hospital (37% [20-59] vs 20% [12-37], p<0.05) and one year mortality (35% vs 20%, p<0.05). Surgical patients were less frequent among hospital fatalities (28.8% vs. 46.3%, p<0.05, RR 0.8 [0-6-0.9]). Nineteen patients (8.6%) died in the ICU, 73 (33.2%) during their hospital stay and 108 (49.1%) were dead one year after HARF. Conclusion The practice to start NIV in all suitable patients suffering from HARF is appropriate. NIV can safely and appropriately be used in patients suffering from HARF from an origin different from COPD exacerbation. Beside usual predictors of severity such as severity score (SAPS II) appear to be associated with increased mortality. Although ICU mortality was low in our patients, hospital and one year mortality were substantial. Surgical patients, although undergoing a similar ICU course, had a better hospital and one year outcome.

Prospective assessment of CYP2D6 by genotyping, phenotyping and measurement of tamoxifen, PD 05-09 4-hydroxy-tamoxifen and endoxifen in breast cancer patients treated with tamoxifen.

Tamoxifen (tam) is a widely used endocrine therapy in the treatment of early and advanced stage breast cancer in women and men. It is a pro-drug having weak affinity with the estrogen receptor and needs to be converted to its main metabolite, endoxifen (endox), to have full anticancer activity. Cytochrome 2D6 (CYP2D6) plays a major role in the metabolism of tamoxifen to endoxifen. It is genetically highly polymorphic and its activity influences profoundly the synthesis of endoxifen and potentially the efficacy of tamoxifen treatment. Genotyping is currently the most widely used approach in studies and also in clinical practice to categorize patients as poor- (PM), intermediate- (IM), extensive- (EM) and ultra rapid-metabolizers (UM). Some clinicians already use genotyping in order to tailor the endocrine therapy of their patients. Owing to the large inter-individual variations in concentrations of the active moitey due to genetic and non-genetic influences renders the predictive value of the test uncertain for an individual patient. A significant number of patients classified as EM or IM by genotyping have indeed relatively low endoxifen levels similar to PMs1. This suggests that genotyping is probably not the opti ma l meth o d f or predi cti ng end oxif en l evels.

Energy-nitrogen balances and protein turnover in small and appropriate for gestational age low birthweight infants.

The aim of the present study was to compare, under the same nursing conditions, the energy-nitrogen balance and the protein turnover in small for gestational age (SGA) and appropriate for gestational age (AGA) low birthweight infants. We compared 8 SGA's (mean +/- s.d.: gestational age 35 +/- 2 weeks, birthweight 1520 +/- 330 g) to 11 AGA premature infants (32 +/- 2 weeks, birthweight 1560 +/- 240 g). When their rate of weight gain was above 15 g/kg/d (17.6 +/- 3.0 and 18.2 +/- 2.6 g/kg/d, mean postnatal age 18 +/- 10 and 20 +/- 9 d respectively) they were studied with respect to their metabolizable energy intake, their energy expenditure, their energy and protein gain and their protein turnover. Energy balance was assessed by the difference between metabolizable energy and energy expenditure as measured by indirect calorimetry. Protein gain was calculated from the amount of retained nitrogen. Protein turnover was estimated by a stable isotope enrichment technique using repeated nasogastric administration of 15N-glycine for 72 h. Although there was no difference in their metabolizable energy intakes (110 +/- 12 versus 108 +/- 11 kcal/kg/d), SGA's had a higher rate of resting energy expenditure (64 +/- 8 versus 57 +/- 8 kcal/kg/d, P less than 0.05). Protein gain and composition of weight gain was very similar in both groups (2.0 +/- 0.4 versus 2.1 +/- 0.4 g protein/kg/d; 3.5 +/- 1.1 versus 3.3 +/- 1.4 g fat/kg/d in SGA's and AGA's respectively). However, the rate of protein synthesis was significantly lower in SGA's (7.7 +/- 1.6 g/kg/d) as compared to AGA's (9.7 +/- 2.8 g/kg/d; P less than 0.05). It is concluded that SGA's have a more efficient protein gain/protein synthesis ratio since for the same weight and protein gains, SGA's show a 20 per cent slower protein turnover. They might therefore tolerate slightly higher protein intakes. Postconceptional age seems to be an important factor in the regulation of protein turnover.

Renin inhibition by aliskiren prevents atherosclerosis progression: comparison with irbesartan, atenolol, and amlodipine.

Hypertension is associated with increased risk of cardiovascular diseases. Antihypertensive treatment, particularly blockade of the renin-angiotensin system, contributes to prevent atherosclerosis-mediated cardiovascular events. Direct comparison of different antihypertensive treatments on atherosclerosis and particularly plaque stabilization is sparse. ApoE(-/-) mice with vulnerable (2-kidney, 1-clip renovascular hypertension model) or stable (1-kidney, 1-clip renovascular hypertension model) atherosclerotic plaques were used. Mice were treated with aliskiren (renin inhibitor), irbesartan (angiotensin-receptor blocker), atenolol (beta-blocker), or amlodipine (calcium channel blocker). Atherosclerosis characteristics were assessed. Hemodynamic and hormonal parameters were measured. Aliskiren and irbesartan significantly prevented atherosclerosis progression in 2-kidney, 1-clip mice. Indeed, compared with untreated animals, plaques showed thinner fibrous cap (P&lt;0.05); smaller lipid core (P&lt;0.05); decreased media degeneration, layering, and macrophage content (P&lt;0.05); and increased smooth muscle cell content (P&lt;0.05). Interestingly, aliskiren significantly increased the smooth muscle cell compared with irbesartan. Despite similar blood pressure lowering, only partial plaque stabilization was attained by atenolol and amlodipine. Amlodipine increased plaque smooth muscle cell content (P&lt;0.05), whereas atenolol decreased plaque inflammation (P&lt;0.05). This divergent effect was also observed in 1-kidney, 1-clip mice. Normalizing blood pressure by irbesartan increased the plasma renin concentration (5932+/-1512 ng/mL per hour) more than normalizing it by aliskiren (16085+/-5628 ng/mL per hour). Specific renin-angiotensin system blockade prevents atherosclerosis progression. First, evidence is provided that direct renin inhibition mediates atherosclerotic plaque stabilization. In contrast, beta-blocker and calcium channel blocker treatment only partially stabilize plaques differently influencing atherogenesis. Angiotensin II decisively mediates plaque vulnerability. The plasma renin concentration measurement by an indirect method did not confirm the excessive increase of plasma renin concentration reported in the literature during aliskiren compared with irbesartan or amlodipine treatment.

A novel technique using echocardiography to evaluate venous cannula performance perioperatively in CPB cardiac surgery.

OBJECTIVE: Transthoracic echocardiography (TTE) has been used clinically to disobstruct venous drainage cannula and to optimise placement of venous cannulae in the vena cava but it has never been used to evaluate performance capabilities. Also, little progress has been made in venous cannula design in order to optimise venous return to the heart lung machine. We designed a self-expandable Smartcanula (SC) and analysed its performance capability using echocardiography. METHODS: An epicardial echocardiography probe was placed over the SC or control cannula (CTRL) and a Doppler image was obtained. Mean (V(m)) and maximum (V(max)) velocities, flow and diameter were obtained. Also, pressure drop (DeltaP(CPB)) was obtained between the central venous pressure and inlet to venous reservoir. LDH and Free Hb were also compared in 30 patients. Comparison was made between the two groups using the student's t-test with statistical significance established when p<0.05. RESULTS: Age for the SC and CC groups were 61.6+/-17.6 years and 64.6+/-13.1 years, respectively. Weight was 70.3+/-11.6 kg and 72.8+/-14.4 kg, respectively. BSA was 1.80+/-0.2 m(2) and 1.82+/-0.2 m(2), respectively. CPB times were 114+/-53 min and 108+/-44 min, respectively. Cross-clamp time was 59+/-15 min and 76+/-29 min, respectively (p=NS). Free-Hb was 568+/-142 U/l versus 549+/-271 U/l post-CPB for the SC and CC, respectively (p=NS). LDH was 335+/-73 mg/l versus 354+/-116 mg/l for the SC and CC, respectively (p=NS). V(m) was 89+/-10 cm/s (SC) versus 63+/-3 cm/s (CC), V(max) was 139+/-23 cm/s (SC) versus 93+/-11 cm/s (CC) (both p<0.01). DeltaP(CPB) was 30+/-10 mmHg (SC) versus 43+/-13 mmHg (CC) (p<0.05). A Bland-Altman test showed good agreement between the two devices used concerning flow rate calculations between CPB and TTE (bias 300 ml+/-700 ml standard deviation). CONCLUSIONS: This novel Smartcanula design, due to its self-expanding principle, provides superior flow characteristics compared to classic two stage venous cannula used for adult CPB surgery. No detrimental effects were observed concerning blood damage. Echocardiography was effective in analysing venous cannula performance and velocity patterns.

Considerations on the ASTM Standards 1789-04 and 1422-05 on the Forensic Examination of Ink

The ASTM standards on Writing Ink Identification (ASTM 1789-04) and on Writing Ink Comparison (ASTM 1422-05) are the most up-to-date guidelines that have been published on the forensic analysis of ink. The aim of these documents is to cover most aspects of the forensic analysis of ink evidence, from the analysis of ink samples, the comparison of the analytical profile of these samples (with the aim to differentiate them or not), through to the interpretation of the result of the examination of these samples in a forensic context. Significant evolutions in the technology available to forensic scientists, in the quality assurance requirements brought onto them, and in the understanding of frameworks to interpret forensic evidence have been made in recent years. This article reviews the two standards in the light of these evolutions and proposes some practical improvements in terms of the standardization of the analyses, the comparison of ink samples, and the interpretation of ink examination. Some of these suggestions have already been included in a DHS funded project aimed at creating a digital ink library for the United States Secret Service.

Cytogenetic response to imatinib in chronic myeloid leukaemia patients: concentration dependency and associated influences under field-conditions

Introduction: Imatinib, a first-line drug for chronic myeloid leukaemia (CML), has been increasingly proposed for therapeutic drug monitoring (TDM), as trough concentrations >=1000 ng/ml (Cmin) have been associated with improved molecular and complete cytogenetic response (CCyR). The pharmacological monitoring project of EUTOS (European Treatment and Outcome Study) was launched to validate retrospectively the correlation between Cmin and response in a large population of patients followed by central TDM in Bordeaux.¦Methods: 1898 CML patients with first TDM 0-9 years after imatinib initiation, providing cytogenetic data along with demographic and comedication (37%) information, were included. Individual Cmin, estimated by non-linear regression (NONMEM), was adjusted to initial standard dose (400 mg/day) and stratified at 1000 ng/ml. Kaplan-Meier estimates of overall cumulative CCyR rates (stratified by sex, age, comedication and Cmin) were compared using asymptotic logrank k-sample test for interval-censored data. Differences in Cmin were assessed by Wilcoxon test.¦Results: There were no significant differences in overall cumulative CCyR rates between Cmin strata, sex and comedication with P-glycoprotein inhibitors/inducers or CYP3A4 inhibitors (p >0.05). Lower rates were observed in 113 young patients <30 years (p = 0.037; 1-year rates: 43% vs 60% in older patients), as well as in 29 patients with CYP3A4 inducers (p = 0.001, 1-year rates: 40% vs 66% without). Higher rates were observed in 108 patients on organic-cation-transporter-1 (hOCT-1) inhibitors (p = 0.034, 1-year rates: 83% vs 56% without). Considering 1-year CCyR rates, a trend towards better response for Cmin above 1000 ng/ml was observed: 64% (95%CI: 60-69%) vs 59% (95%CI: 56-61%). Median Cmin (400 mg/day) was significantly reduced in male patients (732 vs 899ng/ml, p <0.001), young patients <30 years (734 vs 802 ng/ml, p = 0.037) and under CYP3A4 inducers (758 vs 859 ng/ml, p = 0.022). Under hOCT-1 inhibitors, Cmin was increased (939 vs 827 ng/ml, p = 0.038).¦Conclusion: Based on observational TDM data, the impact of imatinib Cmin >1000 ng/ml on CCyR was not salient. Young CML patients (<30 years) and patients taking CYP3A4 inducers probably need close monitoring and possibly higher imatinib doses, due to lower Cmin along with lower CCyR rates. Patients taking hOCT-1 inhibitors seem in contrast to have improved CCyR response rates. The precise role for imatinib TDM remains to be established prospectively.

Respiratory effects of an exposure to grain dust among grain workers in the Vaud region (Switzerland)

Introduction: Bioaerosols such as grain dust (GD) elicit direct immunological reactions within the human respiratory system. Workplace-dependent exposure to GD may induce asthma, chronic bronchitis, and hypersensitivity pneumonitis. Aims: To assess the clinical impact of occupational exposure to GD and to determine quantitative biological markers of bioaerosol exposure in grain workers. Methods: This longitudinal study has been conducted from summer 2012 to summer 2013, comprising 6 groups of 30 active workers with different GD exposure patterns (4 groups of grain workers, 2 control groups). Two evaluations at high- and low-exposing seasons take place, during which an occupational and a medical history are questionnaire-assessed, lung function is evaluated by spirometry, airway inflammation is measured by exhaled nitric oxide (eNO) and specific blood IgG and IgE are titrated. Results: The preliminary results are those of 2 of the 4 exposed groups, (harvesters and mill workers), compared to the control groups, at first assessment (n=100). Mean age is 38.4 [years]; 98% are male. Exposed groups differ from controls (p<0.05) in daily contact with animals (57% vs. 40%) and active smoking (39% vs. 11%). Grain workers have more respiratory (50%), nasal (57%), ocular (45%) and dermatologic (36%) occupational symptoms than controls (6.4%, 19%, 16%, 6.4% respectively, p<0.05). Lower mean peak-expiratory-flow (PEF) values (96.1 ± 18.9 vs. 108.2 ± 17.4 [% of predicted], p<0.05) and eNO values (13.9 ± 9.6 vs. 20.5 ± 14.7 [ppm], p<0.05) are observed in the exposed groups. Conclusion: Preliminary results show a higher prevalence of clinical symptoms and a lower mean PEF value in the groups exposed to GD.

Application of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versus amphotericin B for therapy of invasive aspergillosis: a collaborative study of the Mycoses Study Group (MSG 05) and the European Organization for Research and Treatment of Cancer Infectious Diseases Group.

BACKGROUND: Strict definition of invasive aspergillosis (IA) cases is required to allow precise conclusions about the efficacy of antifungal therapy. The Global Comparative Aspergillus Study (GCAS) compared voriconazole to amphotericin B (AmB) deoxycholate for the primary therapy of IA. Because predefined definitions used for this trial were substantially different from the consensus definitions proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group in 2008, we recategorized the 379 episodes of the GCAS according to the later definitions. METHODS: The objectives were to assess the impact of the current definitions on the classification of the episodes and to provide comparative efficacy for probable/proven and possible IA in patients treated with either voriconazole or AmB. In addition to original data, we integrated the results of baseline galactomannan serum levels obtained from 249 (65.7%) frozen samples. The original response assessment was accepted unchanged. RESULTS: Recategorization allowed 59 proven, 178 probable, and 106 possible IA cases to be identified. A higher favorable 12-week response rate was obtained with voriconazole (54.7%) than with AmB (29.9%) (P < .0001). Survival was higher for voriconazole for mycologically documented (probable/proven) IA (70.2%) than with AmB (54.9%) (P = .010). Higher response rates were obtained in possible IA treated with voriconazole vs AmB with the same magnitude of difference (26.2%; 95% confidence interval [CI], 7.2%-45.3%) as in mycologically documented episodes (24.3%; 95% CI, 11.9%-36.7%), suggesting that possible cases are true IA. CONCLUSIONS: Recategorization resulted in a better identification of the episodes and confirmed the higher efficacy of voriconazole over AmB deoxycholate in mycologically documented IA.

Characterization of the staphylococcal cassette chromosome mec insertion site in 108 isolates lacking the mecA gene and identified as methicillin-resistant Staphylococcus aureus by the Xpert MRSA assay.

During a 3-year period, 848 patients were detected as carriers of methicillin-resistant Staphylococcus aureus (MRSA) by the Xpert MRSA assay (Cepheid). Among them, 108 patients (12.7 %) were colonized with strains showing methicillin-susceptible phenotypes and absence of the mecA gene, despite being positive with the rapid polymerase chain reaction (PCR) assay. DNA sequences of the staphylococcal cassette chromosome mec (SCCmec) insertion site of these "false-positive" strains was determined by direct sequencing of the genomic DNA. More than half (53.7 %) of the strains had DNA sequences unrelated to either SCC or SCCmec and one-third had DNA sequences related to non-mec SCC. Only 10.2 % of the strains carried sequences related to SCCmec, suggesting that a sequence containing the mecA gene was lost from an SCCmec. These findings differ from the general idea that all methicillin-susceptible S. aureus having positive Xpert MRSA assay results are essentially MRSA that lost the mecA gene.

Respiratory effects of an exposure to grain dust among grain workers in the Vaud region (Switzerland)

Introduction: Bioaerosols such as grain dust, via biologically active agents, elicit local inflammation and direct immunological reactions within the human respiratory system. Workplace-dependent exposure to grain dust (GD) may thus induce asthma, chronic bronchitis, and hypersensitivity pneumonitis. The aim of this study is to assess the clinical impact of occupational exposure to GD and to determine quantitative biological markers of bioaerosol exposure in grain workers. Methods: This longitudinal study has been conducted from summer 2012, to summer 2013, comprising 6 groups of 30 active workers with different GD exposure patterns (4 groups of grain workers, 2 control groups). After obtaining informed consent, two evaluations at high- and low-exposing seasons take place, during which an occupational history and a detailed medical history are questionnaire-assessed, lung function is evaluated by spirometry, airway inflammation is measured by exhaled nitric oxide (eNO), and specific blood IgG and IgE are titrated. The preliminary results presented hereafter are those of two of the four exposed groups, namely harvesters and mill workers, compared to the control groups, at first assessment (n=100). Results: Mean age is 38.4 [years]; 98% are male. Exposed groups differ from controls (p<0.05) in daily contact with animals (57% vs. 40%) and active smoking (39% vs. 11%). Grain workers have more respiratory (50%), nasal (57%), ocular (45%), dermatologic (36%) and systemic (20%) occupational symptoms than controls (6.4%, 19%, 16%, 6.4%, 1.6% respectively, p<0.05). Lower mean peak-expiratory-flow (PEF) values (96.1 ± 18.9 vs. 108.2 ± 17.4 [% of predicted], p<0.05) and eNO values (13.9 ± 9.6 vs. 20.5 ± 14.7 [ppm], p<0.05) are observed in the exposed groups. Conclusion: Preliminary results show a higher prevalence of clinical symptoms and a lower mean PEF value in the exposed groups. Detailed supplementary analyses are pending.