Therapeutic Endpoints Research Articles

Early Hepatitis B Surface Antigen Seroclearance Following Antiviral Treatment in Patients with Reactivation of Resolved Hepatitis B.

Long-term results on hepatitis B virus (HBV) reactivation in patients with resolved infection during anti-cancer therapy are unknown. This study investigated long-term risk and therapeutic endpoints including hepatitis B surface antigen (HBsAg) seroclearance following antiviral therapy in patients developing reactivation of resolved HBV. The study included 528 consecutive HBsAg-negative/hepatitis B core antibody-positive patients who underwent rituximab treatment or hematopoietic stem cell transplantation (HSCT) between 2006 and 2016. Long-term outcomes of patients with reactivation after antiviral therapy were examined in comparison with 37 HBsAg-positive chronic carriers under the same medical settings. The 7-year cumulative rate of HBV reactivation was 10.8% and 57.9% in patients receiving rituximab treatment and HSCT, respectively. After antiviral initiation, patients with reactivation of resolved HBV showed significantly higher 1-year cumulative rates of hepatitis B e antigen seroconversion (69.2% vs. 22.6%, P = 0.008) and HBsAg seroclearance (61.8% vs. 3.3%, P < 0.001) than chronic HBsAg carriers. Reactivation of resolved HBV was independently predictive of HBsAg seroclearance in a combined group of reactivated patients and chronic HBsAg carriers. Low viral load at reactivation was predictive of HBsAg seroclearance in reactivated patients. The majority of patients with HBsAg seroclearance developed anti-HBs. None of the reactivated patients who achieved HBsAg seroclearance relapsed after cessation of antiviral therapy. HBsAg seroclearance rapidly occurs following antiviral therapy for reactivation of resolved HBV infection, suggesting distinct clinical phenotypes as well as shorter duration of HBV infection associated with this particular disease setting-HBV reactivation.

Absence of Therapeutic Benefit of the Anti-Inflammatory Protein TSG-6 for Corneal Alkali Injury in a Rat Model

ABSTRACTPurpose: To investigate the therapeutic efficacy of tumor necrosis factor (TNF)-α stimulated gene/protein 6 (TSG-6) in a rat model of corneal alkali injury.Methods: Corneal alkali injury was produced by placing an NaOH-soaked filter paper disk on the central cornea of the right eye of an anesthetized male Lewis (LEW/Crl) rat. Recombinant human TSG-6, or an equal volume of phosphate-buffered saline (PBS), was administered intravenously (IV), by anterior chamber (AC) injection, or as a topical drop. The affected eyes were photographed daily using a dissecting microscope and documented for clinical time course analysis of corneal opacification. Corneal tissue was excised at pre-determined therapeutic endpoints, with subsequent qRT-PCR or histological analyses.Results: The continuous monitoring of corneal alkali injury progression revealed TSG-6 treatments do not show sufficient effectiveness in vivo regardless of IV injection, AC injection, or topical application. Corneal opacification and neovascularization were not diminished, and gene expression was not impacted by these treatments. However, both IV and AC administration of TSG-6 significantly suppressed pro-inflammatory cytokines compared to PBS-treated eyes.Conclusion: We conclude that the therapeutic potential of TSG-6 is insufficient in a rat corneal alkali injury model.

Management Recommendations for Dupilumab Partial and Non-durable Responders in Atopic Dermatitis.

As the first targeted systemic agent for the treatment of moderate to severe atopic dermatitis (AD), dupilumab represents a novel therapeutic opportunity for both patients and providers. However, a subset of patients receiving dupilumab are either partial responders who exhibit some improvement in Investigator's Global Assessment score but not sufficient to meet the primary endpoint, or are non-durable responders who achieve therapeutic endpoint with subsequent partial loss of efficacy. We propose a therapeutic algorithm for the management of dupilumab partial responders and non-durable responders that involves maximizing topical therapy, seeking alternative diagnoses, and using dupilumab in conjunction with traditional systemic immunosuppressive agents. With a number of targeted agents for AD in the drug development pipeline, we encourage patients who do not have an adequate response to dupilumab to remain patient and optimistic as the arsenal of AD treatment modalities continues to expand.

Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis

Invitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that invitro drug responses in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two invivo therapeutic endpoints. We measured individual invitro efficaciousness using a functional assay inrectum-derived organoids based on forskolin-induced swelling and studied the correlation with invivo effects. The invitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-to-excellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an invitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner.

A Study Protocol of a Prospective, Open-label, Single-arm, Clinical Trial to Evaluate the Efficacy of Classical Ayurveda Medicines in the Management of Vicharchika (Atopic Eczema)

Background: In Ayurveda, Vicharchika (atopic eczema, AE) has been discussed under the heading of Kshudra kustha. It is a variety of inflammatory skin disorders diagnosed as a chronic, widespread, noninfective inflammatory condition that causes severe pruritus, erythema with variable degree of exudates and scaling, which can impact at any age. The etiology of AE is complex and not fully understood. Although the traditional Ayurveda medicine is used as an alternative therapy for AE, available evidence relating to its effectiveness and mechanism are not fully implicit. Hence, a protocol of a prospective, multicenter, single-arm, open-label clinical trial using traditional Ayurveda medicine to investigate the effectiveness, mechanism, and safety for patients with Vicharchika (eczema) is being reported. Materials and methods: This is a multicenter, single-arm, open-label clinical trial to evaluate the safety and efficacy of traditional Ayurveda formulations Panchatikta Ghrita and Nalpamaradi Taila in the management of Vicharchika (eczema). A total of 120 patients with Vicharchika (eczema) will be selected based on the inclusion and exclusion criteria. All the patients will be provided with classical Ayurvedic formulation, i.e., Panchatikta Ghrita 6 g orally twice daily before food and oil Nalpamaradi Taila 20 mL twice daily externally on the affected skin. Each participant will undergo a 12-week treatment period and a follow-up after 4 weeks. A total of seven visits will be scheduled for each participant: 1 visit each in week 0, week 2, week 4, week 6, week 8, week 10, and week 12. The primary outcome will be measured by the assessment of change in eczema area severity index (EASI) score before and after the recommended therapy. The secondary outcomes will be measured by—changes in clinical sign and symptoms per the Ayurvedic classics; changes in patient-oriented eczema measure (POEM) and changes in dermatology life quality index (DLQI) questionnaire. Therapeutic mechanism outcomes, safety outcomes, and end point outcomes will also be assessed. Discussion: Protocol was designed with projected outcome as better clinical deliverables and safety profile in Vicharchika patients and reduced relapse rate of disease during post treatment period. If found effective, the selected drug will be listed in the management protocol of Vicharchika at clinical practice level in terms of better efficacy, safety, and cost-effective treatment. The selected drug may lead to a step ahead of better understanding and management of additional skin disorders. Trial registration: Trial has been registered under clinical trials registry-India (CTRI); the registration number for this trial is CTRI/2019/12/022236.

Thrombotic thrombocytopenic purpura: A 5-year tertiary care centre experience.

Thrombotic thrombocytopenic purpura (TTP) is associated with high mortality if not managed timeously with therapeutic plasma exchange (TPE). TTP secondary to human immunodeficiency virus (HIV) infection is unique to sub-Saharan Africa. The management and outcome of TTP in the era of improved access to therapy has not been described. The present study describes the clinical presentation, treatment, therapeutic endpoints, and outcome of TTP patients at the Charlotte Maxeke Johannesburg Academic Hospital, South Africa. The inpatient and outpatient records of 41 consecutive adults with TTP were reviewed between 2012 and 2016. Patients were classified according to aetiology and treatment response. TTP was the initial presenting feature of HIV infection in 78.0%, and 12.5% were noncompliant with antiretroviral therapy (ART). Most study patients were of black ethnicity (95%) and female gender (78.1%). Treatment included initial TPE (87.8%), plasma infusion (78.1%), antiretroviral therapy (78.3%), corticosteroids (61.0%) intensive care admission (41.5%), renal dialysis (12.2%), and other immunosuppressive agents (4.9%). The median (range) number of TPEs was 10.0 (7.0-15.0). A high rate of refractory disease (63.4%) was reported. Haemoglobin, platelet count, lactate dehydrogenase, red cell distribution width, and creatinine were reliable therapeutic end-points (P < .05). The relapse rate was 9.8% and the mortality rate was 29.3%. The high mortality rate emphasises the importance of early diagnosis, referral, and appropriate management of TTP. Anti-retroviral therapy and adherence monitoring are essential to TTP management associated with HIV. Future studies to identify patients at risk for refractory disease are indicated.

Treat-to-target in Crohn's disease: Will transmural healing become a therapeutic endpoint?

Crohn’s disease (CD) represents a chronic transmural inflammatory condition of the gastrointestinal tract, which usually leads to structural damage and significant disability. Deep remission - defined by both clinical and endoscopic remission, signifying mucosal healing - represents the current endpoint in the treat-to-target strategy, significantly improving patients’ long-term outcomes. Transmural healing (TH) could be a more effective target, but this possibility remains unclear. This narrative review aims to critically review and summarize the available literature relating TH to long-term outcomes, being the first of its kind and to the best of the author’s knowledge. A systematic literature search (from inception to March 31 2018) was performed, using multiple databases, and identifying seven full-text manuscripts. In those studies, long-term favorable outcomes (≥ 52 wk) included sustained clinical remission, as well as fewer therapeutic changes, CD-related hospitalizations, and surgeries. Despite heterogeneous design and methodological limitations, six of the studies demonstrated that TH or intestinal healing (TH plus mucosal healing) were predictive for the aforementioned favorable outcomes. Therefore, TH may become a reasonable therapeutic target and be included in the concept of deep remission. Further prospective, well-designed, multicenter trials aiming to better define the role of TH in personalized therapy for CD and to determine the long-term influence of TH on bowel damage and disability are warranted.

A comparison of the effectiveness of cyclophosphamide, leflunomide, corticosteroids, or conservative management alone in patients with IgA nephropathy: a retrospective observational study

To compare the long-term efficacy of corticosteroids (P) alone or in combination with cyclophosphamide (CTX), leflunomide (LEF), or Angiotensin-convertase inhibitors or angiotensin II receptor blockers (ACEI/ARB) in treatment for IgA nephropathy (IgAN), 311 patients with IgAN were identified. Therapeutic effectiveness (including progression, partial remission, complete remission) and combined renal endpoint (defined as 30% reduction in eGFR or ESRD) were compared based on different therapies. After immunosuppressive and ACEI/ARB treatment, the levels of eGFR, proteinuria and albumin were significantly improved at the last follow-up, the extent of improvement of eGFR, proteinuria, and albumin was more notable in P + CTX group and P + LEF group. 41%, 52.2%, 55.3% and 55.2% in P + CTX, P + LEF, P and ACEI/ARB group achieved complete remission, respectively. Multivariate regression analysis indicated that only proteinuria (Relative risk (RR) 0.82(0.72–0.94), P = 0.004) and tubular atrophy/interstitial fibrosis (RR 0.26(0.13–0.57), P = 0.001) were predictors for complete remission. The optimal cutoffs of eGFR was 47.085 ml/min/1.73 m2 predicting renal function recovery in P + CTX therapy. In conclusion, tubular atrophy/interstitial fibrosis and massive proteinuria were poor predictors for complete remission in IgAN, it appears as though patients may have benefited from immunosuppressive treatment but that comparison to a well-matched contemporary control group or, ideally, a randomized controlled clinical trial, would be required to show this.

Endovascular treatment of transplant renal artery stenosis based on hemodynamic assessment using a pressure wire: a case report

BackgroundTransplant renal artery stenosis (TRAS) is a serious complication after renal transplantation, leading to hypertension, deterioration in renal function, and/or graft loss. The incidence of TRAS reportedly varies from 1 to 23%, depending on its definition or diagnostic tools. The hemodynamic definition or therapeutic indication of TRAS is unclear.Case presentationA 66-year-old man with a history of diabetes, chronic kidney disease, and angina presented with a 2-week history of dyspnea and leg edema. He had undergone living-donor kidney transplantation for end-stage renal disease secondary to diabetic nephropathy 7 years earlier. He developed acute deterioration in renal function after the administration of an angiotensin II receptor blocker and required emergency hospitalization owing to acute congestive heart failure with pulmonary edema. A vasodilator and loop diuretics were administered following his admission, and the patient’s symptoms resolved quickly. Further investigation, including magnetic resonance angiography and ultrasonography, revealed severe stenosis of the transplant renal artery. Renal arteriography and pressure gradient measurement using a 0.014-inch pressure wire were performed. The systolic pressure gradient was 40 mmHg, and the resting Pd/Pa ratio (ratio of mean distal to lesion and mean proximal pressures) was 0.90 without hyperemia. Hemodynamically significant stenosis was suspected. Intravascular ultrasonography revealed vessel shrinkage in the stenotic area, suggestive of the end-to-end anastomosis site. Pre-dilation using a 4-mm balloon, implantation of a 6-mm self-expandable stent, and post-dilatation using a 5-mm balloon were performed. Although the moderate stenosis persisted angiographically, the systolic pressure gradient dropped to 20 mmHg with the mean systolic pressure ratio increased to 0.95, which was considered an acceptable result. One month after the procedure, the patient’s renal function and blood pressure control had significantly improved.ConclusionsHemodynamic assessment using a pressure wire is useful in determining the appropriate therapeutic indication and endpoint of endovascular treatment of TRAS.

Surgical treatment of peri-implantitis lesions with or without the use of a bone substitute-a randomized clinical trial.

To assess whether the treatment outcome differed between surgical debridement, with or without a bone substitute. Forty-one adults with three- or four-wall peri-implant bone defects were enrolled in a 1-year RCT. Surgical debridement (control group), or in combination with a bone substitute (Endobon®) (test group) was performed. Radiographic evidence of defect fill (primary outcome) was only significant in the test group (P=0.004). At year 1, no bleeding on probing (BOP) in the control and test groups were 7/20 (35%) and 10/21 (47.6%), respectively (χ2 =0.67, P=0.41). Plaque scores did not differ by study group at baseline (P=0.31), or at year 1 (P=0.08). Mid-buccal soft tissue recession changes did not differ by groups (P=0.76). Successful treatment outcome (defect fill ≥1.0mm, PPD values at implant ≤5mm, no BOP, and no suppuration was identified in 1/20 (5.0%) control, and 9/21 (42.9%) test individuals (F=7, 9, P<0.01). Number needed to treat analysis identified an absolute risk reduction of 32.8% in benefit of the test procedure. (F=7, 9, P<0.01). Successful treatment outcome using a bone substitute was more predictable when a composite therapeutic endpoint was considered.

Abstract O-12: INTERMITTENT VERSUS CONTINUOUS SCVO2 MONITORING DURING EARLY GOAL DIRECTED THERAPY IN SEPTIC SHOCK: A RANDOMIZED TRIAL

Aims & Objectives: To compare the effect of ‘intermittent’ central venous oxygen saturation (ScvO2) monitoring with ‘continuous’ ScvO2 monitoring on shock resolution and mortality in children with septic shock. Methods We randomly assigned children <17 years’ age with septic shock to ‘intermittent ScvO2’ or ‘continuous ScvO2’ groups. All children were subjected to subclavian/internal jugular line insertion and managed as per the Surviving Sepsis Campaign Guidelines. ScvO2 – estimated at 1, 3, 6, 12, 24, 48 and 72 hours in the ‘intermittent’ group and continuously using the central venous oximetry catheter in the ‘continuous’ group – was used to guide resuscitation; other clinical and laboratory parameters were monitored similarly in the two groups. Major outcomes were achievement of therapeutic goals within first 6 hours and in-hospital mortality. Data were analysed using STATA 13. Results We enrolled 101 [62 boys; median (IQR) age: 6 (1.5 to 10) years] children: 50 and 51 in ‘intermittent’ and ‘continuous’ groups, respectively. Baseline characteristics including organ dysfunction and mortality risk scores were comparable between the groups. When compared to ‘intermittent’ group, more children in the ‘continuous’ group achieved therapeutic end points within first 6 hours (33% vs. 16%; RR 2.08, 95% CI 0.98 to 4.38) but there was no difference in mortality (43% vs. 46%; RR 1.06, 0.69 to1.64) between the groups. Conclusions Continuous ScvO2 monitoring resulted in higher proportion of children attaining therapeutic end points in the first 6 hours. However, this did not seem to affect the mortality. Larger studies are required to compare the effect on mortality.

Abstract O-10: RANDOMIZED CONTROLLED TRIAL COMPARING HEMODYNAMIC RESPONSE OF VASOPRESSIN AND NORADRENALINE IN DOPAMINE RESISTANT FLUID REFRACTORY WARM SHOCK IN PAEDIATRIC ICU

Aims & Objectives: To compare the haemodynamic response of Vasopressin with Noradrenaline in Dopamine resistant, fluid refractory warm shock among children in Paediatric Intensive Unit and to assess overall outcome. Methods We randomized patients into Vasopressin and Noradrenaline groups. Low doses were started (Vasopressin = 0.02 IU/kg/hr versus Noradrenaline 0.02 mcg/kg/min) and dose titration was done to achieve the therapeutic end points at 6 hours. Data was analyzed using student’s t-test, chi-square test, Mann-Whitney test and Regression analysis. Kaplan-Meier Survival curves were used to analyze the mortality outcome. Results Forty patients were randomized into Vasopressin and Noradrenaline groups (20 in each group). The baseline characteristics between the groups were comparable with no statistical difference. Improvement in the heart rate, lactate and base excess were better seen in the Vasopressin group, though not statistically significant (p = 0.65, p = 0.26 and p = 0.64 respectively). In the 40 participants, 37(92.5%) achieved the therapeutic end points of SBP at end of 6 hours, among which 18 (90%) were in Vasopressin group and 19 (95%) were in Noradrenaline group. However there was no statistical significance in the 28-day mortality rate among the two groups (Vasopressin = 48% and Noradrenaline = 42%, p = 0.77) Conclusions •Vasopressin is comparable and non-inferior to Noradrenaline on the hemodynamic status in Fluid Refractory Dopamine Resistant warm septic shock without any significant difference in the critical adverse events Larger trials are required to authenticate the effectiveness of Vasopressin in Pediatric Septic shock.

Severity, therapeutic, and activity tear biomarkers in dry eye disease: An analysis from a phase III clinical trial

PurposeTo evaluate the effect of 0.1%-fluorometholone (FML) on tear inflammatory molecule levels after 22-days treatment in dry eye disease (DED) patients exposed to an adverse controlled environment (ACE), identifying different biomarkers. MethodsAnalysis of a double-masked randomized clinical trial. Forty-one DED patients received 4-drops daily of topical FML (FML-group) or polyvinyl-alcohol (PA-group) for 22 days. At day 21, patients were exposed to an ACE. Tear samples were collected at V1 (baseline), V2 (pre-ACE), V3 (post-2-h-ACE) and V4 (24-h post-ACE). Concentrations of 18 molecules (EGF, IFN-γ, TNF-α, IL-1β, IL-1RA, IL-2, IL-4, IL-6, IL-8/CXCL8, IL-10, IL-12, IL-13, IL-17A, IP-10/CXCL10, MCP-1/CCL2, MIP-1α/CCL3, RANTES/CCL5 and MMP-9) were analyzed. Similarities among patients in molecule concentrations at V1 were evaluated. A linear-mixed effect model analyzed the influence of different variables on concentrations changes. ResultsMultidimensional scaling (MDS) divided patients into two groups based on differences in EGF, IFN-γ, IL-8/CXCL8, RANTES/CCL5, and MMP-9 levels at V1. Groups had different clinical severities based on Schirmer test and conjunctival and corneal staining. IL-1RA, IL-2, and TNF-α were differentially affected by time, depending on treatment. Between V2-V3, there were significant changes in EGF, IL-1RA, IL-2, IL-8/CXCL8, IL-13, IP-10/CXCL10, TNF-α, and MMP-9. The strongest biomarker candidates were IFN-γ, RANTES/CCL5, and MMP-9 as DED severity biomarkers; IL-2 as DED therapeutic biomarker; and EGF as DED activity biomarker. ConclusionsThis clinical trial design using a controlled environment and the identified tear biomarkers could be useful to objectively select target patients, to define stress response, and to evaluate therapeutic endpoints in clinical trials.

Do Second-Time Users of Topical Imiquimod have a More Rapid Onset of Clinical Response?

Introduction: Topical imiquimod is commonly used in dermatology for treatment of actinic keratoses (AK). Prior studies in humans and mice have suggested the potential for immune recall with imiquimod based on higher degrees of AK clearance and activation of memory γδ T-cells in a mouse model. Anecdotal reports suggest a more rapid time-to-onset of clinical response with second time use of imiquimod. However, the potential for immune recall demonstrated by time-to-onset of clinical response has not been formally investigated.Objective: The primary objective of this study was to determine if there is a difference in time-to-onset of clinical response between naïve and prior users of topical imiquimod for the treatment of actinic keratoses.Methods: A total of 92 patients were treated with 5% imiquimod cream for actinic keratoses of the head and neck. Patients were instructed to apply 5% imiquimod cream to the affected areas once daily until reaching a therapeutic endpoint of crusting/scabbing. The primary endpoints in the study were time (days) to onset of erythema and time to onset of crusting/scabbing. Results were self-reported.Results: The average time (days) to onset of erythema was 5.48 ± 3.19 days in naïve users and 4.7 ± 2.91 days in prior users (p= 0.22). Average time to onset of crusting/scabbing was 9.2 ± 4.34 days in naïve users and 9.02 ± 3.65 days in prior users (p=0.35).Conclusion: Our study revealed there is no difference in time-to-onset of erythema or scabbing/crusting with second-time use of imiquimod. While immune recall may be possible with use of imiquimod, the results of this study indicate that it may be independent of time-to-onset of clinical response.

Advances in the Management of Pediatric Septic Shock: Old Questions, New Answers

Septic shock in children is associated with high mortality, especially in developing countries. Management includes early recognition, timely antibiotics, aggressive fluid resuscitation, and appropriate vasoactive therapy, to achieve the therapeutic end points. The evidence at each step in management has evolved over the past decade with a paradigm shift in emphasis from a 'protocolized care' to an 'individualized physiology-based care'. This shift mirrors the general trend one observes in critical care with respect to various treatment modalities i.e. moving away from a liberal to a more conservative approach be it fluids, ventilation, transfusion, antibiotics or insulin. The age-old questions of how much fluid to give, what inotropes to start, when to administer antibiotics, are steroids indicated and when to consider extracorporeal therapies in refractory shock are finding new answers from the recent spate of evidence. It is therefore imperative for all of us to be aware of the recent changes in management, to enable us to adopt an evidenced based approach while managing children with septic shock. In this review, we have tried to summarize the key changes in evidence that have occurred over the past decade at various steps in the management of pediatric septic shock.

Ethnic minorities with critical limb ischemia derive equal amputation risk reduction from autologous cell therapy compared with whites

ObjectiveEthnic minorities (nonwhites) with critical limb ischemia (CLI) have historically performed worse compared with whites with regard to major amputation risk reduction and amputation-free survival (AFS) after peripheral vascular intervention. This post hoc analysis was completed to determine whether this precedent also extended to treatment of CLI without a suitable revascularization option with intramuscular injections of concentrated bone marrow aspirate (cBMA). MethodsThe treatment arm of the randomized, double-blind, multicenter MarrowStim PAD Kit for the Treatment of Critical Limb Ischemia in Subjects with Severe Peripheral Arterial Disease (MOBILE) trial was stratified by ethnicity and evaluated for demographics, comorbidities, and outcomes. The primary and therapeutic end point was 1-year AFS and major amputation, respectively. Noninferiority analysis was performed with the margin set at historically reported hazard ratios. ResultsThirty-seven minority (African American, Hispanic, other) CLI patients (9 placebo, 28 cBMA) with no suitable revascularization option were randomized to cBMA or placebo at a 3:1 ratio during the MOBILE trial. At 1-year follow-up for the treatment group, overall AFS was 80%. Of the 28 minority patients randomized to cBMA intervention, an 89% AFS rate was observed compared with 77% in whites. Specifically, 22 of 24 (92%) African Americans survived amputation free at 1-year follow-up. Noninferiority testing confirmed no difference between whites and the ethnic minority treated with cBMA with respect to major amputation reduction; however, noninferiority could not be confirmed with regard to AFS. No significant differences favoring whites treated with cBMA were noted in the secondary end points of vascular quality of life, limb pain, ankle-brachial index, toe-brachial index, transcutaneous oximetry, and 6-minute walk testing. ConclusionsThis post hoc analysis of the MOBILE trial demonstrates noninferiority of cBMA intervention in minorities with no-option CLI for the therapeutic end point of major amputation prevention. cBMA represents a novel treatment paradigm and should be explored for minorities with poor revascularization options who face impending amputation secondary to progressive CLI.

Optimising drug dosing in patients receiving extracorporeal membrane oxygenation.

Optimal pharmacological management during extracorporeal membrane oxygenation (ECMO) involves more than administering drugs to reverse underlying disease. ECMO is a complex therapy that should be administered in a goal-directed manner to achieve therapeutic endpoints that allow reversal of disease and ECMO wean, minimisation of complications (treatment of complications when they do occur), early interruption of sedation and rehabilitation, maximising patient comfort and minimising risks of delirium. ECMO can alter both the pharmacokinetics (PK) and pharmacodynamics (PD) of administered drugs and our understanding of these alterations is still evolving. Based on available data it appears that modern ECMO circuitry probably has a less significant impact on PK when compared with critical illness itself. However, these findings need further confirmation in clinical population PK studies and such studies are underway. The altered PD associated with ECMO is less understood and more research is indicated. Until robust dosing guidelines become available, clinicians will have to rely on the principles of drug dosing in critically ill and known PK alterations induced by ECMO itself. This article summarises the PK alterations and makes preliminary recommendations on possible dosing approaches.

The option of critical patients with cancer for ICU

With the improvement of diagnosis and treatment, tumor has become a chronic disease, and an increasing number of older patients will live with tumors. This change has led to an increase in demand for intensive care unit (ICU) and a challenge to the traditional ICU treatment concept. The option of ICU consists of two parts. The first is the option for admission. Since classic predictors of mortality are no longer relevant, we suggest broadening the criteria for ICU admission. Patients during the first course of cancer therapies should be treated with a full-code status similar to that of other patients without malignancy. Patients whose clinical response to therapy was not available or undetermined should be allowed an ICU trial that consists of unlimited invasive support, including anti-cancer therapies such as ambulatory chemotherapy. Do everything that can be done to save the patients who might benefit from ICU treatment. The second is the option of therapeutic end point. An interdisciplinary meeting, including an ethics consultation, should be held after 3-6 days'ICU trial to make end-of-life decisions with relatives of patients if the SOFA score shows clinical deterioration with no available therapeutic options. The treatment goals should shift from curative or supportive therapies to end-of-life care. we could integrate hospice and palliative care with intensive care more effectively and efficiently. That would be the future of oncological ICUs.

Comparison of different histological indexes in the assessment of UC activity and their accuracy regarding endoscopic outcomes and faecal calprotectin levels

ObjectiveHistological remission is being increasingly acknowledged as a therapeutic endpoint in patients with UC. The work hereafter described aimed to evaluate the concordance between three histological classification systems—Geboes Score (GS),...

Rational Management of Iron-Deficiency Anaemia in Inflammatory Bowel Disease.

Anaemia is the most frequent, though often neglected, comorbidity of inflammatory bowel disease (IBD). Here we want to briefly present (1) the burden of anaemia in IBD, (2) its pathophysiology, which mostly arises from bleeding-associated iron deficiency, followed by (3) diagnostic evaluation of anaemia, (4) a balanced overview of the different modes of iron replacement therapy, (5) evidence for their therapeutic efficacy and subsequently, (6) an updated recommendation for the practical management of anaemia in IBD. Following the introduction of various intravenous iron preparations over the last decade, questions persist about when to use these preparations as opposed to traditional and other novel oral iron therapeutic agents. At present, oral iron therapy is generally preferred for patients with quiescent IBD and mild iron-deficiency anaemia. However, in patients with flaring IBD that hampers intestinal iron absorption and in those with inadequate responses to or side effects with oral preparations, intravenous iron supplementation is the therapy of choice, although information on the efficacy of intravenous iron in patients with active IBD and anaemia is scare. Importantly, anaemia in IBD is often multifactorial and a careful diagnostic workup is mandatory for optimized treatment. Nevertheless, limited information is available on optimal therapeutic start and end points for treatment of anaemia. Of note, neither oral nor intravenous therapies seem to exacerbate the clinical course of IBD. However, additional prospective studies are still warranted to determine the optimal therapy in complex conditions such as IBD.