Introduction. The aim of this study was to investigate the efficacy of herbal formula QiangGuYin (QGY) in postmenopausal women. Materials and Methods. A total of 240 participants from six clinical centers were randomly to receive alendronate 70 mg/week, QGY granules 20 g/day, and placebo. Primary end points were BMD changes over 6 and 12 months; secondary end points were bone turnover markers changes at 3, 6, 9, and 12 months. Safety was monitored by clinical adverse events reported during the follow-up. Results. Of 240 women recruited, 218 completed the study. Significant BMD increases from baseline were observed over 6 and 12 months at each observed part both in QGY and alendronate compared with placebo (p < 0.01). Alendronate-treated subjects had significant decreases in β-CTX compared to QGY-treated subjects at each time point assessed (p < 0.01). Reduction in t-P1NP was only observed in the QGY group at 3 and 6 months . No significant difference was observed in the overall incidence of clinical adverse events among the alendronate group and the QGY group . Conclusion. 1-Year treatment with QGY demonstrated a safe statistical increase in BMD and new balance may be rebuilt after 9 months. This trail is registered with ChiCTR-POC-16008026. Osteoporosis, a global public health problem, is considered to be a major health issue secondary to coronary heart disease by World Health Organization (WHO) . In ChinMajor therapeutic options including bisphosphonates, calcitonin, estrogen, Vitamin D analogs, selective estrogen receptor modulators , and recombinant human parathyroid hormone (PTH) 1–34 (teriparatide) are available to postmenopausal women for prevention and treatment of osteoporosis. The efficacy mechanisms, both the reversible inhibition in osteoclast-mediated bone resorption and the moderate acceleration in osteoblast-mediated bone formation, are well documented .Traditional Chinese medicine (TCM) gradually attracts the attention. According to Chinese special historical cultural environment and social background, TCM have long been widely used in clinical practice to prevent and treat osteoporosis and many other bone diseases. Due to the fewer side effects and being more suitable for long-term application compared with other chemically synthesized medicines, TCM have received extensive attention. TCM theories have extensive experience accumulated over thousands of years . The thePostmenopausal osteoporosis (type I osteoporosis) is the most common disease in women after menopause, which is linked to an estrogen deficiency. Based on over ten years of clinical practice, the guideline that TCM with qi-tonifying and meridian-warming effects have the potential effects on treating osteoporosis is summarized from experience . QiangGu Gentiana macrophylla 15 g, Radix Sileris 15 g, Nidus Vespae 20 g, cinnamon 10 g, Ligusticum wallichii 20 g, Astragalus membranaceus 30 g, Rhizoma Drynariae 20 g, Eucommia ulmoides 15 g, and Dipsacus asperoides 30 g, produced by Pharmaceutical Preparation Centre of the Second Affiliated Hospital of Heilongjiang University Of Chinese Medicine), or placebo (placebo group). Randomization was performed according to computer-generated randomization list and stratified to each hospital provided by the study center. All patients were instructed on the correct way to take the tablets, as per the manufacturer's doing instructions. Drug distribution was performed at each clinical center every 3 months. To be taking 800 mg of calcium daily in food and giving informed consent to participate are required in the study.This 12-month, multicenter, randomized, open-label, placebo-controlled study was conducted in Xinhua Hospital, Zhongshan Hospital, Rongjun Hospital, Bo'ai Hospital, Haiyan Hospital of Zhejiang Province, and the Second Affiliated Hospital of Heilongjiang University of Chinese Medicine from March 2013 to May 2015. After screening between September 2013 and March 2014, 240 participants were randomly assigned in a 1 : 1 ratio to receive either alendronate 70 mg/week  S.p.A., J20130085), TCM prescription QiangGuYin granules 20 g/day , secondary causes of osteoporosis , hypercalcemia or hypocalcemia, serious cardiovascular disease, or kidney failure. Women who were treated with drugs that were potentially able to alter bone metabolism or switched more than one osteoporosis drug differing from their initial therapy were excluded from the trial. Use of oral bisphosphonates, parathyroid hormone, sodium fluoride, strontium ranelate, calcitonin, testosterone, systemic glucocorticoids, or anabolic steroids and any investigational therapy except the study medication was prohibited throughout the trial .β-isomerized C-terminal telopeptide of type 1 collagen (β-CTX) during the same trial period [The primary end point was percent change from baseline in bone mineral density at the lumbar spine, total superior hip, femoral neck, and hip trochanter at 6 and 12 months. An increase of 1% in QGY group was the excepted response to express its efficacy. Secondary end points were changes in bone turnover markers (BTM) of total procollagen type 1 aminoterminal propeptide (t-P1NP) and the serum l period , 11.Every 3 months after each study drug administration, patients were evaluated for the following trial including vital signs, body weight, laboratory tests , and physical examinations and questioned for the occurrence of adverse events. Clinically relevant changes and possible spontaneous adverse events were documented as adverse or severe adverse events.BMD of the lumbar spine (L1–L4), total hip, trochanter, and femoral neck in the anteroposterior view was measured by dual-energy X-ray absorptiometry (DXA) using Osteocore 2  at baseline and months 6 and 12. Instruments' quality control includes standard deviation (0.0032), variability range (0.41%), age grouping (15–95 years old), weight (<150 kg), and bone mineral density range .β-CTX and t-P1NP) levels were measured by electrochemiluminescence immunoassay  using Roche commercial kits.For bone turnover markers, serum samples were collected at approximately the same time in the morning after an overnight fast and delivered to the central laboratory  for measurement at baseline and 3, 6, 9, and 12 months. Bone turnover markers (n) in each group was computed as [Sample size n=β = 90% power  to detect a 1% difference from baseline with respect to change in BMD over 12 months, assuming a measurement precision error of 1.7% and setting α at 0.05 (Uα = 1.96). Allowing for a drop-out rate of 15%, a sample of n = 80 in each group was therefore planned to be randomized.The trial was designed to give 1 − t-test. All statistical analyses were performed using the SPSS 19.0 program. A significance level of p < 0.05 was used for all comparisons. Primary efficacy results were analyzed in the modified intention-to-treat population (participants who underwent baseline and one or more postbaseline assessments of the primary efficacy variable). In the case of missing data on BTM and BMD at 12 months, the data were input with the use of the last-observation-carried-forward method. If a month 9 BTM was missing, it was assumed that there was no percent change at month 6. Incidence between the QGY and alendronate groups with regard to safety was descriptive and unadjusted for multiple comparisons; p values were based on Pearson's Chi-Square.Data are expressed as means ± standard deviation (SD) or standard error (SE). Baseline date was verified by one-way analysis of variance (ANOVA) with repeated measurements. The significance of percentage changes comparisons between the chosen double groups was determined by the unpaired In total, 331 patients were screened at six study sites in China and a total of 240 patients  received at least one stage of this study. After MITT (modified intention-to-treat), the completion rates for this 12-month trial in the three treatment groups  were similar .Baseline demographics and characteristics were balanced between the treatment groups. Patients' baseline information, BMD, and biochemical marker values are presented in p < 0.01, For primary end point, regarding BMD, significant increases from baseline were observed at 6 and 12 months both in QGY and alendronate compared with placebo (The standard difference (SD) at 12 months in alendronate was greater than QGY except in femoral neck . Similarly, at month 3, mean decreases were less in the QGY group than in the alendronate group . At month 9, subjects received the second dose of QGY; an increase in β-CTX was observed compared with month 6 . At month 12, the mean decreases in β-CTX were similar for both neighboring point data  but were still significantly less than that noted in the placebo-treated subjects . Alendronate-treated subjects had significantly greater decreases in serum concentrations of β-CTX than QGY-treated subjects at each time point assessed ; reduction in t-P1NP was only observed in the QGY group by month 3 and month 6  and was maintained in the alendronate group through month 12 (p < 0.01) and was significantly greater than that observed for month 6 .A rapid fall in the bone formation marker t-P1NP also was observed for both treatment groups during the first 3 months. At month 3, t-P1NP levels decreased from baseline to −23.81% in the QGY group and −58.14% in the alendronate group (month 12 . For thep = 0.513). None of the events were observed with respect to deaths or serious adverse events (p = 0.155), nausea , diarrhea  and fractures .No significant differences were observed in the overall incidence of clinical adverse events between the two groups , in comparison with the treatment of alendronate, a widely used antiresorptive therapy, and placebo in Chinese postmenopausal osteoporosis by the change of BMD, BTM, and adverse events. To our knowledge, traditional Chinese medicine products are widely used in China and have been a dispute for long; those clinical trials reported online stay in negligible quantity as a result.β-CTX concentrations to antiresorptive therapies has been assessed in clinical studies on postmenopausal women undergoing QGY therapy, as the response of t-P1NP to bone formation therapies accordingly. Researches show that reduction of bone turnover is the main mechanism of how drugs increase BMD and reduce the fracture risk [Bone, a highly mineralized connective tissue, is continuously broken down and reformed in a process of turnover known as bone remodeling, which occurs through the interaction and balance between bone forming cells called osteoblasts and bone resorbing cells called osteoclasts . The resure risk . But theure risk , 16. A nβ-CTX, respectively, compared with placebo. The therapeutic effect was testified by the increasing bone mass and the risk for fractures needs more treatment courses to be proven. To explore the mechanism, compared with the alendronate, the rangeability was wider and the onset time was earlier, but the more interesting finding is that the inhibiting was not continuous as treatment goes on. The new balance may be rebuilt after 9 months of QGY therapy namely. The specific mechanism and length of efficacy duration are the focus of next stage.Treatment with QGY resulted in significant increase in BMD at the lumbar spine (L1–L4), total hip, trochanter, and femoral neck, with increase in t-P1NP and decrease in β-CTX, 0.111 ± 0.019 ng/ml) remain BTM steady (p > 0.05) in 12 months but 1 case has increased BTM level. Through call visits, patients problems have been solved to different degrees but 3 of them have effective BMD change. Symptoms including knee pain, weakness, aversion to cold, and constipation have been treated actually. The quantity of cases was rare but can verify the efficacy of QGY in postmenopausal women with low bone metabolic rate.In the placebo group, BMD increases in lumbar and decreases in hip. To be honest, this result is common in clinical practice because of the hyperosteogeny of lumbar vertebrae. The total hip BMD may be more reliable in some researches. In the QGY group, 6 cases with bone turnover markers in low level attract attention that 5 of them  which affects the bone metabolism [Natural products have modulatory effects on transcription factors, OPG/RANKL system, and signaling pathways  and possess major effects on promoting osteoblasts proliferation and differentiation .The comptabolism , 21. SimBisphosphonates directly inhibit the bone resorption activity through osteoclast and have nothing to do with bone mineralization. Hypocalcemia prohibition and upper gastrointestinal tract stimulation are the major restriction . CompareThe clinical adverse profiles between the alendronate and QGY groups were similar; most reported adverse events were moderate and under control. TCM related research in clinical settings needs to continue.


The inter-relationships of atrial fibrillation (AF) to retinal vascular occlusions  or retinal venous occlusion (RVO)) remain unclear. It is unknown if a presentation of retinal artery or venous occlusions may indicate a new onset cardiac arrhythmia. To shed light on this association, we investigated the risk of new onset AF in patients with known RAO and RVO.Patients with retinal occlusions from 1997 to 2011 were identified through Danish nationwide registries and matched 1:5 according to sex and age. Cumulative incidence and unadjusted rates of AF according to retinal vascular occlusions (i.e. RAO or RVO) were determined. Hazard ratios (HR) of AF according to retinal vascular occlusion were adjusted for hypertension, diabetes, vascular disease and prior stroke/systemic thromboembolism/transient ischemic attack.p = 0.019) for any retinal vascular occlusion, 1.45  for RAO, and 1.02  for RVO.One thousand three hundred sixty-eight cases with retinal vascular occlusions were identified (median age 71.4 (inter quartile range (IQR); 61.2–79.8), 47.3% male). RAO constituted 706 cases (51.6%) and RVO 529 (38.7%). The rate of incident AF amongst all cases with retinal vascular occlusion was 1.74 per 100 person-years , 1.47–2.06) compared to 1.22  in the matched control group. The rate of AF in RAO was 2.01  and 1.52 (1.15–2.01) in RVO. HRs of incident AF adjusted for cardiovascular comorbidities were 1.26 (95% CI; 1.04–1.53, A new diagnosis of retinal vascular occlusion in patients without prior AF was associated with increased risk of incident AF, particularly amongst patients with RAO. Awareness of AF in patients with retinal vascular occlusions is advised. Retinal artery and vein occlusions (RAO and RVO) are common causes of retinal vascular disease. The pathogenesis of RVO is mainly considered to be thrombus formation, whereas embolisms result in RAO.  Atrial fIschemic stroke is an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction.  This def2DS2-VASc . [,. We have previously shown that retinal vascular occlusion independently increases the risk of ischemic stroke and thromboembolism in patients with AF. [Guidelines recommend treatment with anticoagulation to decrease the risk of ischemic stroke in patients with AF according to the CHA score). –26,. We with AF.  AccordinWe hypothesized that in patients without previously known AF, retinal vascular occlusions (i.e. RAO or RVO) overall would be associated with increased risk of incident AF. To explore these associations, we identified all new cases of retinal vascular occlusion in patients without prior AF in Denmark between 1997 and 2011 in a nationwide cohort study. Furthermore, independent subgroup analyses were performed for RAO and RVO.Data was collected from the following Danish nationwide registers: The Danish National Patient Register contains information regarding all hospital admissions since 1974 classified by diagnoses according to International Classification of Diseases (ICD). ICD-8 codes were used from 1974 to 1995, and ICD-10 codes from 1996 onwards.  In the RRAO was identified according to ICD-8 code 37702 and ICD-10 code H340, H341 and H342. RVO was identified according to ICD-8 37703 and ICD-10 H348. Unspecified retinal vascular occlusion was defined by ICD-10 code H34 without specification of RAO or RVO. AF was identified by ICD-8 code 42793,42794 and ICD-10 code I48.Other comorbidities established from discharge diagnosis were heart failure . Prior stroke, transitory ischemic attack or systemic thromboembolism  and vascular disease .Preceding use of anticoagulation was identified as redeemed prescriptions of warfarin (ATC: B01AA) prior to index date i.e. the date of the qualifying diagnosis of retinal vascular occlusions for cases. Index date for controls were the same date as for the corresponding cases. Medication at baseline was defined as redeemed prescriptions 180 days prior to admission. Prescriptions of any glucose-lowering drug (ATC: A10) defined diabetes mellitus. Specific drugs identified included; clopidogrel (ATC: B01AC04), dipyridamole (ATC: B01AC07), non-steroidal anti-inflammatory drugs (ATC: M01A except M01AX05), loop diuretics (ATC: C03C) and acetylsalicylic acid (ATC: B01AC06 and N02BA01). Notably, although acetylsalicylic acid can be sold over-the-counter, most use continues to be registered due to reimbursement policies.Hypertension was defined as concurrent treatment with two antihypertensive drugs of different classes: antiadrenergic , non-loop diuretics , vasodilators , beta blockers , calcium channel blockers , and renin angiotensin system inhibitors . This method has previously been validated. http://www.mayo.edu/research/documents/gmatchsas/doc-10027248). Controls were free from previous AF or prior use of warfarin. Patients were followed until incident of AF, death, or end of study period.All patients with discharge diagnosis of retinal vascular occlusions (i.e. RAO and RVO) from January 1st 1997 to December 31st 2011 were identified. Patients with previous AF or previous use of warfarin were excluded. Inclusion in the study happened on the day of discharge of retinal vascular occlusion. Each patient with retinal vascular occlusion was matched according to sex and age with five controls from the Danish National Patient Register using the Greedy Matching Macro (https://www.R-project.org).Rates of AF were calculated as new cases of AF per 100 person-years. Cumulative incidence was calculated taking into account the competing risk of death. Risk of AF according to retinal vascular occlusion was determined by Cox regression analysis and presented unadjusted and adjusted for hypertension, diabetes, vascular disease, and prior stroke/systemic thromboembolism/transitory ischemic attack. Independent subgroup analyses were performed for RAO, RVO, and unspecified occlusions, using the corresponding controls as reference. Fulfillment of all model assumptions including proportional hazards, goodness of fit chi-square test, and significance of interactions between all covariates adjusted for in the model were tested and found valid.. Data management and statistical analyses were performed using SAS 9.2  and R 3.0.2. (R Core Team (2013). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL Retrospective register based studies do not require ethical approval in Denmark and the study was approved by the Danish Data Protection Agency .Selection of the study population is depicted in Fig. The number of controls matched for sex and age was 6840. Baseline characteristics according to presence and type of retinal vascular occlusion are summarized in Table The rates of incident AF are shown in Table p = 0.029), while no significant difference was observed between patients with RVO and the control group (p = 0.66). Cumulative incidence of all-cause death was also significantly different between RAO and matched controls (p <  0.001) and RVO and matched controls (p = 0.018).Figures p = 0.019).Results from Cox regression analysis are shown in Fig. p = 0.015). For RVO the HRs of AF were non-significant  and  for unadjusted and adjusted analysis, respectively).In the subgroup analyses we calculated an unadjusted HR of AF amongst patients with RAO of 1.71  and adjusted HR of 1.45  and an adjusted HR of 1.32 .Patients with unspecified retinal vascular occlusion (including those diagnosed with coinciding artery and vein occlusions) had a rate of incident AF of 1.45 , unadjusted HR of 1.40  criteria.  Cardio-eIn stroke patients, guidelines recommend timely diagnosis of AF is prioritized to ensure prescription of oral anticoagulation to prevent future ischemic strokes. As AF in many cases is paroxysmal, detection rate of AF after ischemic stroke depends on the applied diagnostic method. Using a 7-day event-recorder, AF can be detected in 12.5–15% of stroke patients free of previous – known – AF. , 34 The The association of AF and RAO is not investigated to the same extent as the association of AF and ischemic stroke. Whereas one study found a similar detection rate of AF in RAO patients AF (12.5% of patients using 24-h ECG (at least)), other studies indicate that AF is more common in patients with ischemic stroke and find a higher number needed to screen in patients with RAO than in patients with ischemic stroke , 37, 38.No studies have however investigated the proportion of cardio-embolic strokes in RAO. –42 In ouWe have previously shown how retinal vascular occlusion (either RAO or RVO) is an independent and substantial risk factor for stroke and thromboembolism in patients with known AF. In this study of 87,000 patients with AF, HR of RAO and RVO was 1.39 (1.08–1.79) and 1.26 (1.02–1.54), respectively, after adjustment for cardiovascular comorbidities and medication. In contrast to results from the present study, findings from another study found an increased risk of AF in patients with RVO, which may be explained by difference between the study designs or ethnicity of the populations.  Because Since this is a registry-based cohort study, the results represent an association between the two conditions rather than a causal relation. The hypothesis that subclinical AF may be an underlying cause of RAO is supported by the significant increase in cumulative incidence of AF amongst RAO patients compared to controls. Comparably, no significant difference was found between RVO and controls. This observed difference is also relevant when addressing the issue of detection bias: Because this is an observational study, patients with retinal vascular occlusion conceivably receive greater medical attention after study inclusion compared with controls (i.e. surveillance bias), but the cumulative incidence of AF did not differ between RVO patients and controls, thereby countering the premise of surveillance bias. Thus, the observed results support a hypothesis of RAO, and not RVO, being caused by – undiagnosed – silent AF.As we did not have access to information about risk factors such as obesity, excessive use of alcohol, the increase in risk of incident AF in patients with RAO may reflect a higher frequency of unmeasured risk factors associated with cardiovascular disease compared to controls and patients with RVO. However, cumulative incidence of death was similar in RVO and RAO patients, thereby implying that the increased risk of AF in RAO – and not RVO – reflects a genuine association independent of differences in health status of cases and controls.2DS2-VASc point) to efficiently reduce risk of ischemic stroke. [This study substantiates the importance of a careful work-up required in patients with retinal vascular occlusion, which is in accordance with other studies. , 45 Dete stroke. , 47 FurtThe primary strength of the study is the substantial size of the cohort of patients diagnosed with retinal vascular occlusion in Denmark between 1997 and 2011, and the 1:5 matched population without retinal vascular occlusion.However, only retinal vascular occlusions diagnosed in hospitals were included, as we did not have access to data regarding patients treated outside of hospitals. As such, it is possible that the identified retinal vascular occlusions treated in hospitals are more severe compared to cases treated outside of hospitals. Consequently, if the association between retinal vascular occlusion and AF is more pronounced for more severe cases, our study may overestimate this association.In this nationwide cohort study of patients without previous AF or prior warfarin, we found that retinal vascular occlusions increased the risk of incident AF. In subgroup analyses, the risk was increased in patients with RAO but not in patients with RVO. As retinal vascular occlusions increases the risk of thromboembolism risk in patients with AF, vigilance for incident AF in patients with retinal vascular occlusions is recommended.


Does the Veterans Affairs Community Care Program, which allows veterans to receive care at non–Veterans Affairs sites, increase the accessibility and value of their elective coronary revascularization procedures?Among 13 237 elective percutaneous coronary interventions and 5818 elective coronary artery bypass graft procedures in this veteran cohort study, use of the Community Care Program reduced aggregate veteran travel distance for revascularization. Community Care Program hospitals had higher mortality and costs for percutaneous coronary intervention and had equivalent mortality and lower costs for coronary artery bypass graft surgery.In our veteran cohort, use of Community Care Program hospitals improved overall access for revascularization; Community Care Program hospitals provided lower-value percutaneous coronary intervention procedures but higher-value coronary artery bypass graft procedures. The Veterans Affairs (VA) Community Care (CC) Program supplements VA care with community-based medical services. However, access gains and value provided by CC have not been well described.To compare the access, cost, and quality of elective coronary revascularization procedures between VA and CC hospitals and to evaluate if procedural volume or publicly reported quality data can be used to identify high-value care.Observational cohort study of veterans younger than 65 years undergoing an elective coronary revascularization, controlling for differences in risk factors using propensity adjustment. The setting was VA and CC hospitals. Participants were veterans undergoing elective percutaneous coronary intervention (PCI) and veterans undergoing coronary artery bypass graft (CABG) procedures between October 1, 2008, and September 30, 2011. The analysis was conducted between July 2014 and July 2017.Receipt of an elective coronary revascularization at a VA vs CC facility.Access to care as measured by travel distance, 30-day mortality, and costs.P < .001) but was similar after CABG surgery . There were no differences in adjusted 30-day readmission rates for PCI  or CABG surgery . The mean adjusted PCI cost was higher in CC . The mean adjusted CABG cost was lower in CC . Neither procedural volume nor publicly reported mortality data identified hospitals that provided higher-value care with the exception that CABG mortality was lower in small-volume CC hospitals.In the 3 years ending on September 30, 2011, a total of 13 237 elective PCIs (79.1% at the VA) and 5818 elective CABG procedures (83.6% at the VA) were performed in VA or CC hospitals among veterans meeting study inclusion criteria. On average, use of CC was associated with reduced net travel by 53.6 miles for PCI and by 73.3 miles for CABG surgery compared with VA-only care. Adjusted 30-day mortality after PCI was higher in CC compared with VA (1.54% for CC vs 0.65% for VA, In this veteran cohort, PCIs performed in CC hospitals were associated with shorter travel distance but with higher mortality, higher costs, and minimal travel savings compared with VA hospitals. The CABG procedures performed in CC hospitals were associated with shorter travel distance, similar mortality, and lower costs. As the VA considers expansion of the CC program, ongoing assessments of value and access gains are essential to optimize veteran outcomes and VA spending. This veteran cohort study compares the access, cost, and quality of elective coronary revascularization procedures between Veterans Affairs and Community Care Program hospitals and evaluates if procedural volume or publicly reported quality data can be used to predict high-value care. The US Department of Veterans Affairs (VA) supplements its hospitals and clinics with care purchased from community providers. This initiative, known as the Community Care Program (CC), cost $5.6 billion in 2014, representing 10% of the VA health care budget.Elective coronary revascularization procedures, including percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) procedures, accounted for $170 million of CC costs in 2014 . Understanding the influence of the CC program on access, outcomes, and costs is critical to the future of US veterans’ health care. We addressed 4 questions. First, did CC improve veterans’ access to elective coronary revascularization procedures by reducing travel distance and cost? Second, was the quality of care at CC hospitals comparable to that at VA hospitals? Third, was the cost of care lower at CC hospitals than at VA hospitals? Fourth, could the value of care be improved by selecting hospitals using publicly available information on factors associated with the quality of care, including annual procedure volumes and publicly reported risk-adjusted mortality?In this veteran cohort study, we evaluated patients younger than 65 years who had an elective coronary revascularization (PCI or CABG) sponsored by the VA between October 1, 2008, and September 30, 2011. Analysis was conducted between July 2014 and July 2017. Patients 65 years or older were excluded because they frequently use Medicare benefits to obtain coronary revascularization.Outcomes of interest were evaluated. These included access to care (as measured by travel distance), 30-day all-cause mortality, 30-day readmission for a cardiac-related diagnosis, and cost.Access was measured as the additional travel distance required by the VA care arrangements: the distance traveled to the hospital that provided the procedure minus the distance to the nearest hospital offering that procedure (either VA or CC). Actual road distance and travel time between patient residence and hospital were calculated using a software program . Zip code centroid was used for 3.0% of the cohort members with an incomplete address. There was no residential address for 3.1% of the cohort, and they were excluded from the travel analysis. We estimated all travel costs as if they were fully reimbursed by the VA regardless of current VA reimbursement practices. Travel cost was estimated at 41.5 cents per mile,Date of death was determined from the VA Vital Status File. Hospital readmissions were considered cardiac related if they were stays in acute medical-surgical units that were assigned a principal diagnosis for heart disease, a specific procedural complication, cerebrovascular disease, renal failure, embolism or thrombosis of extremities, or other conditions plausibly related to complications or failure of coronary revascularization  and more likely to have multivessel procedures. The CC patients were more likely to have renal impairment  and an ejection fraction less than 30% .Veterans Affairs hospitals provided 10 474 (79.1%) of all PCIs in the study . The VA P < .001) (P < .001).The VA patients were much more likely to receive PCI from a hospital that did not meet the recommended volume threshold of 200 cases annually  . In contP < .001) (P < .001), type 1 diabetes , 3-vessel and 4-vessel procedures, or an ejection fraction less than 30% .The VA hospitals provided 4866 (83.6%) of all CABG procedures in the study cohort. Compared with CC patients, VA patients undergoing CABG surgery were more likely to have atrial fibrillation  . The CC P < .001) (P = .91).The VA patients were more likely to receive CABG surgery at a hospital that did not meet the recommended volume threshold of 125 cases annually  . There wP < .001) (P < .001). Patients who used CC for PCI traveled a net distance that was, on average, 53.6 miles less and incurred a mean of $153 less in travel expense.Relative to the nearest hospital offering PCI, the adjusted mean extra travel distance was 18.6 miles for CC patients and 72.2 miles for VA patients ( < .001) . The meaP < .001) (P < .001). Patients who used CC for CABG surgery traveled a net distance that was an average of 73.3 miles less and incurred an average of $690 less in travel expense.Relative to the nearest hospital offering CABG surgery, the adjusted mean extra travel distance was 27.7 miles for CC patients and 101.0 miles for VA patients ( < .001) . The cosP < .001). After propensity adjustment, 30-day mortality was higher for patients treated in CC hospitals compared with VA hospitals   .P = .57). After propensity adjustment, 30-day mortality was similar for patients treated in CC hospitals compared with VA hospitals   .P = .66) (P = .28).Unadjusted 30-day readmission rate after PCI was 7.14% for CC and 7.78% for VA (215 readmissions for CC and 748 readmissions for VA). Propensity-adjusted RR was 0.96  . UnadjusP < .001) (P < .001). The mean adjusted cost of the index CABG procedures was $55 526 in CC hospitals and $63 144 in VA hospitals (P < .01). Total costs were also significantly lower in CC hospitals .The mean adjusted cost of the index PCI procedure was $22 025 in CC hospitals and $15 683 in VA hospitals ( < .001) . Total cP < .001)  . Low-volP = .03)  . There wSelecting hospitals using proxy measures did not improve outcomes or reduce cost. Because there was no advantage to this strategy, we did not quantify how it would have increased the burden of patient travel.P < .001).Additional analyses tested if outcomes differed by the interaction between proxy measure and the type of hospital (VA or CC). The interaction was significant for CABG mortality for low-volume hospitals. Low-volume CC hospitals had significantly lower mortality after CABG surgery relative to standard-volume CC hospitals , low-volume VA hospitals , and standard-volume VA hospitals . The only other interaction that was significant was the cost of the index PCI care for low-volume hospitals. The mean adjusted cost of the index PCI was $22 257 at standard-volume CC hospitals, $15 702 at low-volume CC hospitals, $16 031 at low-volume VA hospitals, and $15 431 at standard-volume VA hospitals , similar readmission rates, and lower costs ($15 683 vs $22 025 for CC). For CABG surgery, VA hospitals had similar mortality, similar readmission rates, and higher cost ($63 144 vs $55 526 for CC).The higher mortality of CC-provided PCIs was not necessarily due to lower quality of care at CC hospitals. Other possible factors include delay in making care arrangements, incomplete coordination of care between VA and CC hospitals, or failure to refill medications prescribed by CC clinicians. These are obvious areas for future research and quality improvement efforts. New VA data on scheduling of care, including a database of CC approvals, will help the VA detect problems associated with treatment delay.We found that publicly available data on hospital volume and Medicare mortality did not reliably identify centers where veterans had better outcomes. The VA currently requires CC providers to have an active license and a lack of sanctions but does not set minimum quality thresholds or choose hospitals based on cost.Our findings also demonstrate that, on average, veterans seeking high-quality care, with low mortality and readmission rates, are well served by the VA. This outcome confirms the findings of prior studies finding that the quality of VA care is generally similar to that of non-VA hospitals,This study has several limitations. Mortality in our sample was a sufficiently rare event that the power to detect differences in the quality of care of VA and CC may have been limited. We only examined patients younger than 65 years, and our findings may not generalize to an older population. Our data only include procedures between 2008 and 2011, and patterns may have changed over time. We did not study the influence of waiting time on outcomes because we did not have information on when procedures were first recommended. We attempted to address this issue by limiting the study to elective procedures, which are not as time sensitive as emergent procedures.While VA and CC patients were similar in terms of coded comorbidities, it is possible that there was undetected referral bias such that patients referred to CC hospitals had elevated risk beyond that represented by the available covariates. Our comparison was limited by the lack of information on CC patients. We had information on the VA registry of patients undergoing PCI, but data for CC patients were not available because of the restrictions governing the national registry of patients undergoing PCI.Finally, we did not have the clinical detail needed to ascertain if procedures were appropriate. Such an evaluation will be needed for a complete assessment of the value of CC.In summary, our study found that almost 1 in 5 elective coronary revascularizations for VA patients was performed at CC sites. The VA hospitals had lower mortality and lower costs than CC hospitals for PCI and had similar mortality but higher costs for CABG surgery. To ensure that veterans receive care that is timely, accessible, and of the highest quality, policymakers should consider providing information to help veterans seek care from the highest-value hospitals and health care professionals regardless of whether the hospitals are VA or CC.


For early detection of cancer, we have previously developed the AminoIndex Cancer Screening (AICS) system, which quantifies 6 plasma-free amino acids (PFAAs) in blood samples. Herein, we examined the usefulness of the AICS in patients with colorectal cancer (CRC) by comparing the preoperative and postoperative PFAA profiles.Our study cohort consisted of 62 patients who had undergone curative resection for CRC at our cancer center, with no recurrence at the time of the study. Blood samples were collected from fasted patients within 1 week before the resection and at 0.5–6.5 years post-resection. Following plasmapheresis, the PFAA levels were measured via liquid chromatography/mass spectrometry, and the AICS values were computed . Risk was calculated from the AICS value and ranked as A, B, or C, with rank C representing the highest risk. All patients in our study were rank B + C.p < 0.001). The decline in both was stage-independent, even occurring in patients with right-sided tumors or poorly differentiated adenocarcinomas. For comparative purposes, the levels of 2 tumor markers (carbohydrate antigen 19–9 and carcinoembryonic antigen) were also examined; these were within the reference ranges in 70–80% of patients preoperatively and in 80–90% postoperatively.The postoperative AICS value was lower than the preoperative value in 57 of the 62 patients; the rank was also lower postoperatively  contains supplementary material, which is available to authorized users. Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the fourth leading cause of cancer-related death in the world. By 2030, its burden is expected to increase by 60% to more than 2.2 million new cases, with 1.1 million deaths  and metabolomics analysis  have been reported in the context of various diseases, including cancer. Plasma-free amino acid (PFAA) profiles have been shown to differ in healthy individuals and patients with cancer or other diseases, owing to complex metabolic changes , 10. BasAICS consists of a combination of 6 amino acids that are differentially expressed in different cancer types. It discriminates between changes in the levels of amino acids that are characteristic of a specific cancer type and those that are common among cancer types , 14, andAlthough tumor markers such as carbohydrate antigen 19–9 (CA19–9) and carcinoembryonic antigen (CEA) can be easily quantified in blood tests, their levels may not be increased in early-stage cancers . AICS deAlthough assessment of the clinical usefulness of AICS is ongoing, it remains unclear why the PFAA levels fluctuate  and whether such fluctuations trigger cancer. Further elucidation of the biological mechanisms underlying the changes in the PFAA levels might allow for the development of both static and dynamic models of carcinogenesis via system analysis. System analysis of cancer patients based on systemic amino acid metabolism provides information on the nature of the cancer and, by doing so, may not only facilitate early detection but also the formulation of treatment, prognostic, and relapse monitoring strategies.In this preliminary study, the preoperative and postoperative PFAA profiles, which are indicative of tumor-bearing status, were compared in patients with CRC via AICS.Our study cohort consisted of patients who underwent curative resection for primary stage 0–III CRC at the Department of Gastrointestinal Surgery, Kanagawa Cancer Center (KCC) between 2007 and 2014. Patients who already had undergone treatment for cancer, patients with a previous history of cancer, and patients with metastatic or recurrent cancer were excluded. Data from the amino acid research database of the KCC –15 were Among the 124 patients who fulfilled the above criteria and had both preoperative and postoperative PFAA concentration measurements, 62 had a preoperative AICS rank of B + C; these 62 patients were the target of the preoperative and postoperative comparative analysis.This study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the KCC Research Ethical Committee. The attending physician provided each participant with an explanatory document and written consent form approved by the committee before the study. The content of the study was fully explained in writing and verbally, and voluntary written consent was obtained from all patients. The samples and data in this study were used for research and analysis after undergoing linkable anonymization.Preoperative blood samples were collected from hospitalized patients the morning before the operation. Postoperative blood samples were collected at least 6 months after the operation, based on the in vivo amino acid metabolism timeframe. All patients fasted for 8 h before blood sampling; postoperative blood samples were obtained in the outpatient blood collection room.PFAA analysis was performed as described previously , 16. SpeThe 6 amino acids used to detect CRC via AICS were serine, proline, valine, methionine, isoleucine, and lysine , 14  and CA19–9 .We calculated the mGPS value using the C-reactive protein (CRP) and albumin (Alb) values from biochemical tests performed pre- and postoperatively. Subsequently, the mGPS was divided into 3 groups  according to previous research .2-test and t-test were used for comparative analyses of the patients’ demographics. The Wilcoxon signed-rank test was used to compare the preoperative and postoperative AICS values. GraphPad Prism 6  and R version 3.2.2  software were used for all statistical analyses. A p-value of < 0.05 was considered statistically significant.The χThe demographics of the 62 patients in our study are shown in Table p < 0.001)   Fig. . In the 01) Fig. . Among aThe AICS values declined significantly after resection for disease stages I–III  (Table n = 39), respectively. The postoperative reduction in the AICS value was significantly greater in patients with right-sided tumors  versus left-sided tumors   Table . By contAfter resection, the AICS values declined in some patients with tubular adenocarcinomas or moderately differentiated cancers Table . Howeverp = 0.015). The preoperative CA19–9 level was below the cutoff (≤37.0 U/ml) in 54 (87.1%) patients and above the cutoff value in 8 (12.9%) patients, whereas the postoperative CA19–9 level was above and below the cutoff value in 58 (93.5%) and 4 (6.5%) patients, respectively. Moreover, in the preoperative rank C group, the preoperative CEA and CA19–9 levels were below the cutoff value in approximately 90% of the patients; however, postoperatively, the differences were not significant. The accuracy of determination of these tumor markers was not high.Table Table p = 0.52; Additional file There was no significant correlation between the time of postoperative blood collection and the AICS value in the 62 patients analyzed  of various disease states has shown alterations in the PFAA profiles owing to collapsed regulatory mechanisms; these disease states include cancer, liver failure, kidney failure, Alzheimer’s disease, and psychiatric disorders. Via metabolomics analysis, AICS statistically compares PFAA profiles between patients with CRC and healthy individuals; consequently, it can determine whether an individual has CRC. Although clinical application of this screening method has widened recently, the biological mechanisms that control the PFAA levels remain unknown, as does the cause and effect relationship between the PFAA levels and cancer. Hence, whether fluctuations in the PFAA levels cause cancer or vice versa has yet to be determined.The present study showed a significant decline in the AICS values after surgical resection in patients with primary CRC and a preoperative rank of B + C. The decline was stage-independent, even occurring in patients with right-sided tumors or poorly differentiated adenocarcinomas, both of which are highly malignant . These results indicate that elimination of cancer cells restores the PFAA levels to precancer levels, as determined in vivo. Previous animal experiments have suggested that release of the nuclear protein HMGB1 into the blood, which affects the metabolism of distant organs, accounts in part for the altered PFAA levels in cancer patients . AlteratThe results of this study suggest that changes in the PFAA levels in patients with CRC strongly reflect CRC-bearing conditions; i.e., the cancer causes the changes in the PFAA levels. This point should be further clarified, as recurrence of CRC after resection is an important problem.Tumor markers are often used to monitor for relapse after CRC resection. However, in the present study, the sensitivities of CEA and CA19–9 for detecting CRC were low, similar to in a previous study of early-stage CRC . MoreoveAlthough previous studies have compared the preoperative and postoperative PFAA profiles in patients with breast, stomach, and thyroid cancers , 24, theRecent reports have indicated that right-sided CRCs are more malignant than left-sided CRCs and have a worse prognosis . The comOur study examined changes in the preoperative and postoperative PFAA profiles in patients with CRC via AICS, which is a cancer probability assessment test. We suggest that cancer cells alter the PFAA profiles, which is reflected in the AICS value. This premise has important clinical implications but requires verification.Several aspects of our study require discussion and further testing. First, in 5 patients, the AICS value did not decline after resection. All 5 patients were classified with left-sided CRC, and postoperative adjuvant chemotherapy was administered to 4 of these cases. The four cases of moderately differentiated cancers demonstrated a deeper invasion depth than the one case with highly differentiated cancer; many cases have been previously reported showing vascular invasion, lymph node metastasis, and peritoneal dissemination . In regaSecond, the present study excluded subjects classified as AICS rank A. These patients showed no postoperative changes in their PFAA profiles, which were within the AICS tolerance range for sensitivity, specificity, and positive predictive value . However, there was no significant correlation between the AICS value and the blood collection time . Axis: Area under the ROC curve discriminating between healthy people and patients with CRC for each amino acid. Abbreviations: Pre-op, preoperative; Post-op, postoperative; AICS, AminoIndex Cancer Screening. (PPTX 108 kb)Additional file 2:Figure S2. Correlation between the period of postoperative blood collection and the AICS value. Spearman rank correlation coefficient: r = − 0.083 (− 0.333~ 0.178), p = 0.52. Abbreviations: AICS, AminoIndex Cancer Screening. (PPTX 91 kb)Additional file 3:Figure S3. Recurrent cases after postoperative AICS  measurement. a: Pre-op rank B + C, b: Pre-op rank C. Wilcoxon signed rank test: p > 0.05. Abbreviations: Pre-op, preoperative; Post-op, postoperative; AICS, AminoIndex Cancer Screening; n.s., not significant. (PPTX 102 kb)Additional file 4:TableS1. Characteristics of rank A patients. (DOCX 21 kb)


Hyperlactataemia (HL) is a biomarker of disease severity that predicts mortality in patients with sepsis and malaria. Lactate clearance (LC) during resuscitation has been shown to be a prognostic factor of survival in critically ill adults, but little data exist for African children living in malaria-endemic areas.In a secondary data analysis of severely ill febrile children included in the Fluid Expansion as Supportive Therapy (FEAST) resuscitation trial, we assessed the association between lactate levels at admission and LC at 8 h with all-cause mortality at 72 h (d72). LC was defined as a relative lactate decline ≥ 40% and/or lactate normalisation (lactate < 2.5 mmol/L).Plasmodium falciparum malaria, 3008 (95%) had a baseline lactate measurement, 2127 (71%) had HL (lactate ≥ 2.5 mmol/L), and 1179 (39%) had severe HL (≥ 5 mmol/L). Within 72 h, 309 children (10.3%) died, of whom 284 (92%) had baseline HL. After adjustment for potential confounders, severe HL was strongly associated with mortality (Odds Ratio (OR) 6.96; 95% CI 3.52, 13.76, p < 0.001). This association was not modified by malaria status, despite children with malaria having a higher baseline lactate  and a lower mortality rate  compared to non-malarial cases. Sensitivity and specificity analysis identified a higher lactate on admission cut-off value predictive of d72 for children with malaria (5.2 mmol/L) than for those with other febrile illnesses (3.4 mmol/L).Of 3170 children in the FEAST trial, including 1719 children (57%) with p < 0.001). Absence of LC (< 10%) at 8 h was strongly associated with death at 72 h .At 8 h, 2748/3008 survivors (91%) had a lactate measured, 1906 (63%) of whom had HL on admission, of whom 1014 (53%) fulfilled pre-defined LC criteria. After adjustment for confounders, LC independently predicted survival after 8 h  contains supplementary material, which is available to authorized users. Infection is a leading cause of death in children under 5 years of age in resource-poor countries in Africa, mainly related to pneumonia, diarrhea, and malaria . IrrespeHyperlactataemia (HL) is a well-known biomarker of severe disease that strongly predicts death in paediatric and adult patients with bacterial sepsis and malaria –9. Its pIn recent years, several studies including two meta-analyses have demonstrated that early LC and lactate normalisation are powerful independent predictors of survival in critically ill adults –17. FurtThe main aim of the current study was to assess the prognostic value of LC at 8 h on all-cause mortality at 72 h (d72) in a large cohort of severely ill febrile children in a malaria-endemic area. Secondary aims were to confirm the association between HL and d72, assess if this was modified by type of severe febrile illness , and to determine the cut-off lactate level on admission that best predicts mortality in these children.The current study is a secondary analysis derived from the FEAST trial . The oveChildren were eligible for the FEAST trial if they were between 60 days and 12 years of age, had a history of fever and/or abnormal temperature (pyrexia [≥ 37.5 °C] or hypothermia [< 36 °C]), and were admitted to hospital with severe illness (respiratory distress and/or impaired consciousness) plus at least one of the following signs of impaired peripheral perfusion: capillary refill time > 2 s; lower limb temperature gradient (defined as a notable temperature change from cold [dorsum of foot] to warm [knee] when running the back of the hand from the toe to the knee); weak radial pulse; or severe tachycardia . Children were excluded from the trial if they presented with severe acute malnutrition, gastroenteritis, burns, or surgical conditions. Children were randomised to receive immediate boluses of 20–40 mL/kg of 5% human albumin solution or 0.9% saline solution over 1 h (intervention group) following by maintenance fluids, or maintenance intravenous fluids only at 4 mL/kg/h (control group) until able to drink. The primary endpoint was mortality at 48 h after randomisation.Standardised case report forms were completed at enrolment and at specific time points during the first 48 h. At enrolment, lactate, haemoglobin, and glucose point-of-care measurements were conducted, together with an HIV antibody test, malaria blood film, and a rapid diagnostic test for malaria. At 8 h and 24 h, lactate and haemoglobin measurements were repeated. Lactate was measured using a Lactate Pro®  hand-held analyser, which was calibrated daily, and each time a new box of Lactate Pro® Test Strips was used. The test results, available in 60 s, displayed ‘LO’ if the lactate level was below 0.8 mmol/L and ‘HI’ if the lactate level was above 23.3 mmol/L. Out-of-range results were repeated for verification. Haemoglobin was determined with the HemoCue® Hb 301 system, Angelholm, Sweden. Children were managed on general paediatric wards, with no facilities for ventilation other than short-term ‘bag-and-mask’ support. Training in triage, identification, and definitions of adverse events related to fluid management (including transfusion) was given prior to and throughout the trial and was included in the trial manual of operations that was given to every team member. The main outcome of the FEAST trial  × 100, for which lactate initial was the measurement at randomisation. Lactate normalisation was defined as a lactate decline to < 2.5 mmol/L at 8 h. The 8-h LC goal was defined by a relative lactate decrease of at least 40% from baseline and/or lactate normalisation.Baseline clinical characteristics by survival status were described, combining randomisation groups. Frequencies and percentages were used for categorical variables, and medians with their inter-quartile range (IQR) for non-normally distributed continuous data. Baseline clinical characteristics were compared across outcome categories using the chi-squared test or the Wilcoxon signed-rank test as appropriate. Descriptive analysis reported both missing and available data.a priori in both models due to their association with a wide range of health parameters. The effect of the trial intervention was included as a potential confounder and tested as an effect modifier of the association between LC and d72 with increased mortality in the FEAST trial. Likelihood ratio tests were used to assess for the model fit.The main exposure of interest was LC at 8 h. The primary outcome was all-cause in-hospital mortality at 72 h of randomisation (d72). As a first step in the LC analysis, the association between baseline HL and d72 was examined. For each of the exposures, HL and LC, the crude odds ratio (OR) with 95% confidence interval (CI) was calculated for the association with d72. To identify potential confounders, associations between patient characteristics and exposure and outcome variables were determined. Classic Mantel-Haenszel methods were used to explore for confounding and effect modification. A multivariable logistic regression model was fitted with a stepwise forward process selection to estimate the OR adjusted for several covariates simultaneously using all available data. Candidate variables were selected using previously defined risk factors of mortality and confounders identified in the univariate analysis. Age, sex, and study site were included Receiver operating characteristic (ROC) curve analysis was used to determine the cut-off value for lactate level at hospital admission that would best predict death at 72 h. As children with malaria had a higher prevalence of severe HL despite a lower mortality rate, ROC curves were also built separately for children with and without malaria to assess if the best prognostic cut-offs differed Fig. . A ROC cp < 0.001 and 13.13; 95% CI 6.62, 26; p < 0.001 respectively). Severe anaemia (Hb < 5 g/dL) was present in 958 children (33%) at admission. Plasmodium falciparum malaria was confirmed in 1719 children (57%) and HIV infection in 106 (4%) of the 2417 children tested. A blood culture was positive in 123 (12%) of the 1052 children in whom the test was performed.Of 3170 children randomised in the FEAST trial, 3008 (95%) had a lactate measurement on hospital admission and were included in the current analysis. In this group, there were 309 deaths (10.3%) in the first 72 h after randomisation, which accounted for 90% of the overall mortality by 28 days. The clinical and laboratory baseline characteristics of the children by primary outcome are summarised in Table SpO2 < 90% by pulse oximetry) (p < 0.001), coma (p < 0.001), severe anaemia (p < 0.001), or severe acidosis (p < 0.001). Children with malaria parasitaemia had higher mean baseline lactate  and prevalence of severe HL  than those with other febrile illnesses.At hospital admission 2127 children (71%) had a raised baseline lactate (≥ 2.5 mmol/L). Of these, 948 children (32%) had moderate HL (lactate 2.5 to < 5 mmol/L) and 1179 (39%) had severe HL (lactate ≥ 5 mmol/L). Children with severe HL had a higher prevalence of other clinical and laboratory markers of disease severity, including hypoxaemia (p < 0.001). Amongst those children who died, the median admission lactate was higher when death occurred in the first 8 h  than when it occurred between 8 and 72 h  or after 72 h  of the admission respectively.Of the 309 children who died in the first 72 h, 238 (77%) had severe HL on admission and 46 (15%) had moderate HL. The median admission lactate in children who died was significantly higher  than in those who survived the first 72 h  (p < 0.01), elevated blood urea nitrogen (BUN) (heterogeneity test p < 0.001), and presence of crackles on auscultation (heterogeneity test p = 0.025) , whilst moderate HL had a weaker effect on mortality . This association did not significantly vary amongst children with and without malaria, indicating that severe HL was equally prognostic for both conditions. Evidence for an effect modification, however, was found between HL and hyperglycaemia (glucose ≥ 8.3 mmol/L) , and elevated BUN and HIV infection were moderately strong independent risk factors of death identified in the model. Whilst a positive malaria test appeared to be more strongly associated with higher likelihood of survival, this cannot be interpreted as a protective effect of parasitaemia per se, since the model was controlling for other factors which are likely impacted by malaria and strongly associated with mortality.p < 0.01), although the effect of HL on the risk of mortality in the absence of hyperglycaemia  was slightly greater. Furthermore, logistic regression analysis accounting for the additional interactions identified demonstrated that the association of HL with d72 was considerably lower in the 427 children (21%) with high admitting BUN  and much higher in the 655 children (22%) with crackles on auscultation   and a higher relative LC  at 8 h. Median relative LC was significantly higher in children with severe HL  than in those with moderate HL  (p < 0.001). Children with malaria had a similar relative LC as those with other severe febrile illnesses .Of all children included in the analysis, 2748/3008 (91.4%) were alive and had a blood lactate level measured at 8 h of randomisation; 1906 (63.3%) of these had an elevated lactate level (≥ 2.5 mmol/L) on admission and contributed to the LC analysis. Table p < 0.001). Furthermore, achieving the combined LC pre-defined goal was the strongest prognostic factor of survival  compared to relative LC or lactate normalisation alone  had a relative LC < 10%, whereas a total of 1014 (53%) met the pre-defined LC criteria . After full adjustment for confounders, including the effects of lactate level on admission and the FEAST trial (fluid) intervention arm, failure to clear lactate (LC < 10%) at 8 h of treatment was strongly associated with death at 72 h . Of note, as previously demonstrated in the FEAST trial, fluid boluses were strongly associated with death at 72 h  in the full-adjusted logistic regression model.Persistent severe HL at 8 h remained a strong independent risk factor of death at 72 h  . The overall AUROC based on LC at 8 h was 0.58 (95% CI 0.53–0.64), and for the group of children with severe HL (> 5 mmol/L) on admission it was greater . Lastly, the AUROC for d72 based on a logistic regression model for LC at 8 h was even more predictive as 0.84 (95% CI 0.80–0.88)  for d72 based on lactate at admission was 0.77 (95% CI 0.74–0.80), with no statistically significant difference in AUROC amongst children with and without malaria (47) Fig. . The AURSensitivity and specificity analysis identified that for children without falciparum malaria a lactate level on admission of ≥ 3.4 mmol/L had a sensitivity to predict mortality at 72 h of 80% and a specificity of 61.6%, whereas for children with malaria a sensitivity of 80% corresponded with a lactate cut-off value of 5.2 mmol/L (specificity of 59.2%). For a baseline lactate level of ≥ 5 mmol/L, the sensitivity in children without malaria was 71.7% (specificity 75.53%), whereas in those with malaria it was 82.43% (specificity 57.7%). This indicates that in non-malaria cases, lower levels of HL have a similar effect on 72-h mortality.Our study confirms the association between HL on hospital admission and mortality, and it demonstrates that a failure to clear lactate (relative LC < 10%) within the first 8 h of treatment is a relevant prognostic factor of early death in severely ill febrile children in a malaria-endemic area irrespective of the underlying diagnosis . Importantly, this is the first paediatric study to demonstrate that a relative LC ≥ 40% and/or lactate normalisation within the first 8 h of treatment strongly predicts 72-h survival in this context.These results, derived from a very large multicentre randomised trial, are compelling and raise the question of whether LC could be a simple, valid and cost-effective risk-stratification tool, as well as a potential therapeutic target to guide resuscitation in children with severe febrile illnesses in resource-poor settings. Furthermore, it is not limited to children with specific diagnoses, but rather covers different presentation syndromes, which reflects the population of children presenting to hospital in the setting in which the trial was conducted. Lastly, for research studies the inclusion of lactate level could be used for inter-site or inter-centre comparisons of disease severity.et al. [et al. [Despite a paucity of paediatric data, our findings are supported by the literature. A recent meta-analysis  and a laet al.  found th [et al.  recentlyIt is therefore possible that failure to clear lactate within the first hours of therapy could serve as a simpler risk stratification tool in malaria-endemic areas, potentially more reliable than absolute lactate values alone and easier to apply than more complex clinical scores. However, to have an outcome benefit, a similar lack of LC effect should likely be shown at an interval shorter than 8 h that would allow a therapeutic intervention or the appropriate recruitment into clinical trials of those children with a higher chance to die.et al. in a large cohort of adult patients with malaria [ScvO2 alone [Moreover, to demonstrate an association between LC and survival in severely ill febrile children in a malaria-endemic area is relevant at least in two aspects. On one hand, LC could serve as a valid surrogate endpoint of clinical trials of malaria aiming to improve mortality, as recently demonstrated by Jeeyapant  malaria . Thus, oO2 alone , 19, andO2 alone .Unfortunately, the observational design of our study does not allow one to answer whether targeting resuscitation to achieve a specific relative LC or lactate normalisation improves outcomes in severely ill febrile children in this context. Interestingly, a recent study including 218 adult patients with severe infection at a regional referral hospital in Uganda  questionSome other limitations of our study should be taken into account. First, despite the optimal LC threshold or the LC rate not having been clearly defined, many studies on LC in sepsis have used a relative clearance rate of 10–20% in repeated samples measured at 2- to 3-h intervals during the first 6 h of resuscitation. Our definition of LC criteria was based on published data , 18, 19,Whilst lactate levels can falsely increase with haemolysis, frequent with difficult phlebotomies or with long time span from extraction to processing, blood samples in the FEAST trial were obtained from a free-flowing vein and immediately measured at the bedside. Arterial lactates are recommended over peripheral venous lactates in sepsis studies looking at absolute values and clearance rate, due to poor agreement between both parameters . Neverthp = 0.01); however, as it did not confound or modify the association between HL and d72, it was not included in the logistic regression model. Moreover, children septic with pneumonia (defined as crackles on auscultation and presence of hyperlactataemia) were more likely to suffer from hypoxaemia . Owing to the poor specificity of signs for pneumonia, WHO promotes the use of pulse oximeters to direct children with signs of pneumonia for oxygen therapy. Yet, pulse oximetry remains poorly implemented [Relevant to the FEAST Paediatric Emergency Triage (PET) clinical score , which ilemented . One exaLastly, our findings suggest that the predictive values of lactate on admission for mortality are lower in children without malaria (3.4 mmol/L) than for those with malaria 5.2 mmol/L). This is important, as a detailed pathogenesis of HL in septic shock and and in malaria is still imperfectly understood and may actually differ. Whereas in sepsis HL is mostly viewed as a result of anaerobic metabolism secondary to systemic hypoperfusion , HL in m mmol/L. In conclusion, severe HL, defined as a venous lactate level ≥ 5 mmol/L on hospital admission, is a strong risk factor for death within the first 72 h in children with severe febrile illnesses in east Africa, independently of the underlying diagnosis. Failure to clear lactate (relative LC ≤ 10%) within 8 h is also strongly prognostic of death, which could serve as a simple risk-stratification tool or a surrogate endpoint of mortality in clinical trials. Those children able to normalise or clear their lactate by at least 40% within 8 h have an improved chance of survival. An LC measured at an earlier time point may have yielded even more relevant results owing to the high mortality prior to 8 h that occurred in our cohort. Whether LC alone, or in combination with other clinical markers, can be used as a cost-effective therapeutic target to guide initial resuscitation and ultimately improve clinical outcomes of severely ill febrile children in malaria-endemic areas, where lack of basic patient monitoring and intensive therapies is standard, remains uncertain. Given severe infection is the most common cause of death in children under 5 years of age in these settings, and that early and aggressive initial resuscitation is key for survival, this question warrants further investigation. These data provide the rationale for a clinical trial of lactate clearance as an early therapeutic resuscitation goal in children with severe infection in malaria-endemic areas. We encourage the use of point-of-care lactate testing whenever possible in limited-resource settings to identify high-risk patients.Additional file 1:Multivariable analysis (logistic regression model) of clinical and laboratory factors associated with death at 72 h: fully adjusted OR . (DOCX 106 kb)Additional file 2:Plots of the relationship between haemoglobin and lactate and mortality estimated from the adjusted Cox regression model. Originally published in BMC Medicine 13:174 by George et al. . (PNG 80


Our results suggested that E. coli with the tetX.co-module driven by either the PJ23119 or PBAD promoters conferred resistance up to 50 μg/mL of tetracycline and degrades over 95% of tetracycline within 24 h. The detoxification ability of tetX was further verified in conditioned media by typical E. coli K-12 and B strains as well as Shewanella oneidensis. Our strategy demonstrated the feasibility of introducing genetic modules into model hosts to enable environmental functions, and this work will inspire more environmental innovations through synthetic biological devices.Synthetic biology enables infinite possibilities in biotechnology via employing genetic modules. However, not many researches have explored the potentials of synthetic biology in environmental bioprocesses. In this study, we introduced a genetic module harboring the codon-optimized tetracycline degrading gene,  Due to these achievements, metabolic engineering and synthetic biology have made tremendous progress in heterologous pathway integration5, genetic toolkit developments6, and physiological function discoveries8. However, this progress has mainly focused on the fields of biofuel and value-added chemical production, medicine discovery, and genetic diagnoses and therapies. Environmental biotechnology is one of the most important sectors of applied microbiology, but to our knowledge, not many examples exist of synthetic biology approaches applied for environmental biotechnology purposes.Advances in DNA reading and writing techniques, as well as developments in genetic circuits, have enabled synthetic biological designs in microorganisms for precise purposes11. Functional microbial consortia are the main participants in almost all bioprocesses, especially in wastewater treatment, such as activated sludge12, aerobic or anaerobic granules13, and biological electrosystems15. Despite of these mixed cultures, microbial strains with novel physiological functions have been defined, such as Nitrosomonas sp., Nitrosococcus sp., Nitrospira sp., and Dehalococcoides mccartyi20. The direct utilization of pure cultures with single strains of microbes harboring unique functions is, nevertheless, a significant challenge.Environmental biotechnology has been extensively utilized in water and wastewater treatment, soil remediation, and sludge disposal20, while model hosts, such as Escherichia coli and Saccharomyces cerevisiae, although amenable to genetic manipulation and easy to cultivate, lack desired functions21. Therefore, it would be a promising alternative if we transplant particular functions of environmental microorganisms into model hosts with well-established genetic information and toolkits.Most widely used microbial strains in environmental biotechnology have been identified because of their distinct and innate properties instead of being engineered from model strains with integrated genetic modules. Compared with the fields where synthetic biology and metabolic engineering have prospered, similar scenarios can be developed in environmental biotechnology. Microorganisms with unique and desirable functions usually experience native bottlenecks like low growth rate, harsh cultivation conditions, and limited genetic informationE. coli, to examine whether a model microbial host could be engineered to a whole-cell biodevice for environmental purposes. On behalf of environmental science, antibiotics are not only pollutants of particular concerns but also harbor antimicrobial effects, which severely impact the existing water and wastewater treatment bioprocesses24. As a proof of principle, we chose tetracycline, a typical antibiotic detected in nature and environmental facilities, as our target, and the tetX gene from Bacteroides fragilis26 was codon-optimized (denoted as tetX.co) and expressed in E. coli BW25113 strain (briefed as BW25113 hereafter). Unlike other tetracycline resistance genes used in molecular biology, tetX confers resistance against tetracycline via bioconversion and detoxification rather than blocking the antimicrobial machinery of tetracycline26. The resistance and degradation capability toward tetracycline plus the detoxification ability of tetX have been demonstrated and discussed.In this endeavor, we designed and introduced a genetic module capable of degrading antibiotics into tetX gene from the transposon Tn4351 in B. fragilis was codon optimized for better expression in BW25113 and the resulting tetX.co was fused to the pBAD backbone plasmids led by either a constitutive (PJ23119) or an inducible promoter (PBAD) with different strengths  and pTi (tetX.co led by PBAD) were then transformed into BW25113. The transformants with the designed plasmids together with the control strain (BW25113 with empty plasmid) were tested whether they could survive in different concentrations of tetracycline.To construct the genetic modules, the ths Fig. , resulti12/OD0 in the presence of 50 μg/mL  was able to grow in the same conditions, suggesting the requirement of pre-accumulated TetX for cells to survive in high levels of tetracycline. Then, we added L-arabinose during preculture of BW25113 harboring pTi, and identified the promising growth profile of this strain in the presence of 50 μg/mL tetracycline , and at 24 h, almost no absorbance at 365 nm was observed, indicating a complete conversion of tetracycline. These results suggested the conversion of tetracycline, and the strong expression of tetX.co, which regulated by the PBAD promoter, led to faster degradation under the same conditions. Then, the MS was employed to analyze the products in the culture of BW25113 with pTi. The peak at 443 m/z was clearly identified in M9 media with 50 μg/mL of tetracycline  of the tetracycline was converted and at 24 h over 95% (C/C0 0.023 ± 0.002) of tetracycline was degraded in M9 media. Meanwhile, only 20% (C/C0 0.801 ± 0.035) of the total tetracycline was removed from the media for the control strain, which might result from the adsorption. Similar trends were found in the LB media with some slight differences, and the E. coli cells in LB media degraded the tetracycline more completely at 24 h .The degradation kinetics of 2 or ethanol, it addresses the first and the most important step of tetracycline degradation, detoxification. Our engineered E. coli with tetX.co destroys the antimicrobial functions of tetracycline and facilitate the subsequent degradation. Therefore, the detoxification effects of TetX were analyzed to test the utility of our synthetic biological strategy. To do so, we selected the typical E. coli K-12 MG1655, B strain BL21 as well as Shewanella oneidensis29, to evaluate whether the conditioned media (CM) of our engineered strain, the supernatant from the culture of the control and our engineered strain with 50 μg/mL of tetracycline, were detoxified.Although TetX cannot fully degrade tetracycline into small molecules, such as COM9) and LB (CMLB) media, respectively. Both the E. coli MG1655 and BL21 grew well in the CMM9, indicating the tetracycline in the original M9 media has been detoxified, and the CMM9 allowed wild-type strains grow , the S. oneidensis did not grow in the CMM9. Then, we evaluated the effects of CMLB of our engineered strain on all three tested strains. First, we identified the growth of S. oneidensis in CMLB, indicating that the converted tetracycline lost most of the antimicrobial effects on S. oneidensis after conversion by BW25113 with pTi. Moreover, we tested the CMLB with the two E. coli strains. Glucose with the final concentration of 4 g/L was added into the CMLB before inoculation to supply nutrients, and both strains grew well in the CMLB of BW25113 with pTi, which in addition evidenced the promising detoxification capability of TetX in rich media. The slightly lower OD12/OD0 of E. coli BL21 and MG1655 might attribute to the depletion of substrates and the residue tetracycline (0.47 ± 0.15 μg/mL) in the CM.As shown in Fig. row Fig. . As S. o31. Most applied bioprocesses for environmental purposes prefer mixed cultures because of the resistance and tolerance toward toxic chemicals, varied operating conditions and other detrimental shocks. However, even mixed culture cannot thrive in some harsh conditions, such as wastewater with high concentrations of antimicrobial chemicals. As reported, traditional biological treatment processes could only remove 11.6% to 85.4% of the total tetracycline32, and our previous work demonstrated that 83.6% of the tetracycline at an initial concentration of 10 μg/mL could be removed by enriched mixed culture33. Nevertheless, the activity and function of the mixed culture were severely inhibited by tetracycline at this level34. In pharmaceutical industry, the concentration of tetracycline could reach up to 19–32 μg/mL (mg/L), which was a grand challenge to current treatment procedures36.Selection of proper microorganisms is the most important step in biotechnologytetX gene was selected to construct our genetic modules. The efficient conversion of tetracycline via hydroxylation, the degradation kinetics, as well as the detoxification of tetracycline by TetX have been evaluated in vivo. According to our results, the designed whole-cell biodevice was able to grow in the presence of 50 μg/mL tetracycline and it degraded over 95–99% of the total tetracycline in 24 h, indicating a much higher capability of resistance and degradation than those of the mixed culture. Therefore, we achieved the targeted degradation of tetracycline via a synthetic biology approach, and, as the tetracycline was successfully detoxified, our whole-cell device can be utilized as a pretreatment module coupled with traditional biological processes for the treatment of wastewater with high concentrations of tetracycline. Unlike tetracycline, to which only TetX has been reported to confer resistance by detoxification, aminoglycoside, amphenicol, and β-lactam antibiotics are mainly defended by enzymatic deactivation37. Therefore, our proposed whole-cell biodevice can be easily adopted and generalized for the degradation of various types of antibiotics.Synthetic biology and metabolic engineering provide an alternative approach to overcome the limitations inherent in traditional strategies via introducing genetic modules into model microorganisms. This can be easily cultivated and manipulated at various levels. To prove this concept and propose a prototype to bridge synthetic biology and environmental bioprocess, we chose the typical antibiotic, tetracycline, as our environmental target, and the 23. To this end, the CRISPR system provides a powerful tool to control the introduced gene programmably38, and we will discuss another prototypal strain with combined functional modules and a genetic regulation circuit soon.Originated from model host, our designed biodevice can be easily cultivated, genetically manipulated and further engineered for additional functions. Moreover, this strategy can be generalized for other environmental benefits through general methodology, including codon-optimization, gene synthesis, and expression regulation using platform toolkits in model hosts. One of the concerns of synthetic routines, however, might be the introduction of heterologous and synthetic DNAs and the leaking risks of antibiotics resistance genesE. coli DH5α  was used for molecular cloning and maintaining the plasmids with antibiotic markers. E. coli BW25113 (CGSC#7636) was used as the model host to test whether our strategy worked. E. coli MG1655 (CGSC#6300) and E. coli BL21 (CGSC#12504) were employed for the detoxification assay. S. oneidensis MR-1 was a generous gift from Professor Han-Qing Yu . Luria-Bertani (LB) medium was used for all overnight cultures and most experiments unless otherwise noted. LB medium consisted of 10 g tryptone , 5 g yeast extract , and 10 g NaCl per liter of H2O. M9 medium contained 12.8 g/L of Na2HPO4, 3 g/L of KH2PO4, 0.5 g/L of NaCl, 1 g/L of NH4Cl, 0.24 g/L of MgSO4, 0.01 g/L of CaCl2 and 4 g/L glucose. To maintain plasmids with ampicillin resistance, 100 µg/mL of ampicillin was added to the media when necessary. L-arabinose was added to induce PBAD promoters in both overnight culture and experimental cultures and to overcome the repression effects of glucose on PBAD promoters via pre-accumulation of TetX, when presented in specific tests. Tetracycline  was added at different concentrations  to evaluate the resistance and degradation capability of TetX. All the experiments were conducted in a biosafety level 1 (BSL-1) laboratory.tetX gene from B. fragilis was codon-optimized via JCat (http://www.jcat.de) for better expression in E. coli. Then, the tetX.co gene was synthesized  and fused to the pBAD backbones with PJ23119 and PBAD promoters, generating pTc and pTi, respectively. The plasmids were constructed via Gibson assembly according to the manufacturer’s protocols , and the transformation and selection of E. coli with designed plasmids were carried out following the standard protocols. The plasmids pcrRNA.con (Addgene 61285) and pcrRNA.ind (Addgene 61284) were used as the templates to provide backbones39. The sequence of tetX.co and all primers used in this study were summarized in Table SI.The 0) and those at 12 h (OD12) were recorded with a UV-2000 spectrophotometer . The growth properties of E. coli were represented by OD12/OD0.To evaluate the antimicrobial effects of tetracycline, cells were first cultivated in LB medium overnight at 37 °C and 200 rpm, and then were inoculated into fresh LB medium with different concentrations of tetracycline. The initial optical densities at 600 nm (OD33.The conversion of tetracycline was characterized via UV-Vis spectrophotometric scanning and mass spectrometric (MS) analysis. The BW25113 with pTc and pTi, respectively, and BW25113 with an empty plasmid were cultured overnight and inoculated into M9 medium with 50 μg/mL of tetracycline. Samples were taken at different time intervals and filtered for UV-Vis analysis. The UV-Vis scanning ranged from 240 nm to 480 nm and the absorbance was recorded every 0.5 nm. After 24 h, the final culture was harvested and filtered for MS analysis. The MS with a LCQ Fleet  was used, and ESI (electron spray ionization) was employed with a spray voltage set at 4,000 V. The sheath gas flow was 30 arb, aux gas flow was 10 arb, and the capillary temperature was 320 °C. The MS was obtained from 100 Da to 500 Da in the negative ion mode, and the results were shown in relative abundance of negative ions from 400 to 500 m/z (ratio of mass to charge). The concentrations of tetracycline were measured using HPLC  coupled with a reversed-phase ODS-C18 column and UV detector at the wavelength of 360 nm using a mixture of 0.01 mol/L oxalic acid solution/acetonitrile/methanol 80:16:4 (v/v/v) as mobile phase at a flow rate of 1 mL/mintetX.co was analyzed using CM40. BW25113 and BW25113 with pTi were cultured overnight and inoculated into M9 and LB media with 50 μg/mL of tetracycline. After 24 h, the culture was harvested by centrifugation at 5,000 rpm and filtered through 0.22-μm cellulose acetate membranes. The filtered cultures were regarded as CM. To fully explore the detoxification functions of TetX, glucose (4 g/L) was added into the CM from LB culture as an additional carbon source to support cell growth. The results were represented by OD12/OD0 of tested strains.The detoxification capability of strains with Supplementary Information


Surgical repair of isolated congenital tricuspid valve (TV) disease is rare with no well-defined indication and outcomes. Moreover, the role of right ventricle (RV) in this context has not yet been investigated.We sought to assess the impact of congenital TV repair on cardiac remodelling and clinical–functional status and the importance of the RV function in an adult congenital heart disease (ACHD) population.p < 0.01), clinical signs of heart failure , and left ventricular function . The RV and right atrium diameter were significantly reduced after surgery  and , respectively. The degree of postoperative pulmonary hypertension was also significantly reduced . The survival rate was 96.3% at 1 year and 93.7% at 5 years. One patient (3.7%) had early failure of the tricuspid repair requiring a reoperation.From January 2005 to December 2015, 304 patients underwent TV surgery in our centre. Of these, 27 (ACHD) patients had isolated TV repair. Patients were evaluated with preoperative and postoperative transthoracic echocardiogram. Survival rate has been investigated with a mean clinical follow-up (FU) of 3.7 ± 2.3 years, whereas the mean echocardiographic FU was 2.9 ± 1.8 years. The clinical and functional status of patients showed a statistically significant improvement after the surgical repair in terms of New York Heart Association class (66.7 vs 7.4%; Isolated TV repair for adult congenital disease significantly improved patients’ clinical and functional status and allowed right ventricular remodelling and functional improvement. Isolated severe congenital tricuspid regurgitation (TR) is an uncommon condition, most frequently associated with a variety of concomitant heart diseases. Regardless of the presentation, the surgical management is similar , 2. To dThe study was conducted in accordance with the principles of the Declaration of Helsinki. The local audit committee approved the study, and the requirement for individual patient consent was waived.From January 2005 to December 2015, a total of 304 adult patients underwent TV repair or replacement at Bristol Heart Institute. Patients with concomitant left heart valve diseases and/or other cardiac congenital diseases, those who underwent TV replacement and those with endocarditis were excluded  were defined as ACHD patients undergoing surgical TV repair for isolated TR.The clinical conditions were assessed following the classification proposed by the New York Heart Association (NYHA) and Canadian Cardiovascular Society (CCS). Both preoperatively and at the end of follow-up (FU), patients were assigned to a correlated class. Clinical signs and symptoms of RV failure and onset of newly discovered cardiac arrhythmias were regularly assessed during FU outpatient clinics. Short-term outcomes were derived from clinical notes: acute kidney injury was defined as an increase, during admission, of over 50% in serum creatinine compared to preoperative values, as previously recommended ; acute rAll patients underwent transthoracic echocardiography preoperatively, within 2 weeks after the operation and at FU. The following parameters were assessed: left ventricular ejection fraction (LVEF), left ventricular internal diastolic diameter, left ventricular internal systolic diameter, thickness of the interventricular septum in diastole, diameter of the posterior wall, RV functional assessment (RV failure), right ventricular internal diastolic diameter, right ventricle dilatation (RV dilatation), area of left atrium (LA area), area of right atrium (RA area), pulmonary artery pressure (PAP), grade of pulmonary hypertension, grade of TV regurgitation, tricuspid annular plane systolic excursion (tapse), and presence of haepatic veins backflow.t-test if normally distributed or Mann–Whitney U test if not normally distributed. In the case of dichotomous or categorical variables, Pearson chi-square or Fisher exact tests were used as appropriate. Overall long-term survival was estimated by Kaplan–Meier curve. All tests were two-sided with the alpha level set at 0.05 for statistical significance. The statistical analysis was computed using R version 3.0.2 for Windows .Data are presented as mean ± 1 SD for continuous variables or as number and percentages for dichotomous variables. Continuous variables were tested for normality using the Kolmogorov–Smirnov test and then compared between groups with unpaired Student’s Patient characteristics and preoperative variables are summarised in Table http://www.ctsnet.org/article/cone-reconstruction-tricuspid-valve-repair-ebstein-anomaly), seven patients (25.9%) had annuloplasty ring and the remaining patients (40.7%) had other types of repair . Most patients had isolated TV surgery; concomitant ASD closure was performed in four (14.8%) patients; antiarrhythmic surgery such as MAZE procedure was also performed in four (14.8%) patients. Mean cardiopulmonary bypass time was 104.9 ± 44.7 min, and mean cross-clamp time was 66.3 ± 32.4 min. In one case (3.7%), with Ebstein disorder, it was necessary to re-operate during the postoperative course for failure of TV repair; this patient eventually underwent TV replacement. One patient (3.7%) suffered a postoperative deep wound infection (mediastinitis), which required surgical re-exploration: this condition deteriorated to postoperative sepsis and subsequent death. No patient experienced episodes of cerebral ischaemia (CVA) or renal impairment in the perioperative period.Intraoperative and postoperative findings are shown in Table p < 0.01) and 22.2% in CCS class III–IV preoperatively vs 3.7% at FU (p < 0.01). Also, our study demonstrated a significant reduction of clinical signs of heart failure such as ascites and peripheral oedema . These data are shown in Table The clinical and functional status of patients assessed according to the NYHA and CCS classification shows a statistically significant improvement: 66.7% patients in NYHA class III-IV preoperatively vs 7.4% at FU (p < 0.01), while no significant differences were found regard to the left ventricular diameters and wall thickness. Similarly, no significant differences were found concerning the left atrial volumes. At FU, all patients showed a significant reduction in right ventricular diameters . We also observed a different remodelling in right atrial geometry . Regarding the functionality of TV, a clear reduction of valvular regurgitation has been observed at FU. Furthermore, TR significantly improved both in patients with moderate  and severe baseline TR . In addition, the pulmonary pressure  and the degree of pulmonary hypertension  were significantly reduced. A net reduction was also noticed in the number of patients with haepatic veins backflow . On the other hand, TAPSE values dropped significantly in this period of evaluation .Table p = 0.01) without supplementary modification of wall thickness.In Table p = 0.03) and RV dilatation .Similar to the main analysis, this sub group showed a substantial reduction in right ventricular diameters . Furthermore, the Ebstein population also showed a visible reduction of valvular regurgitation between the preoperative and the FU . In addition, TAPSE values were considerably reduced .An interesting reduction has been observed on right atrial area , and RA area ; this is most likely due to the effect of reduced RV pre-load. On the other hand, there was no significant change in RV function (p = 0.1); this is probably due to advanced structural modification of the RV which may have occurred before the time of the surgery .Annular repair also leads to increased stability of the cardiac skeleton, which might partially explain the reduction of the TAPSE at FU  despite there being no changes in the left ventricular diameters and wall thickness; possibly due to a reduction of volume of the RV which decreases the compression on the left ventricle.There was a marked improvement in left ventricular function , strengthening the idea that structural damage is a non-reversible phenomenon. As reported in the literature, AF has been recognised as an objective predictor of survival, rising mortality and morbidity due to thromboembolism risk and heart failure . The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.