Step-up Group Research Articles

Effect of the Step-Jump Approach in Infected Pancreatic Necrosis: A Propensity Score-Matched Study.

The effects of the step-jump approach on the survival and prognosis of infected pancreatic necrosis (IPN) patients have not yet been determined. Between November 2018 and June 2023, 188 patients were included in this study. There were 144 patients in the step-up group (the SU group) and 44 in the step-jump group (the SJ group). In the SU group, patients successfully treated with percutaneous catheter drainage (PCD) alone were classified into the SU-1 group (n=101), while those requiring additional surgery after PCD were categorized into the SU-2 group (n=43). In the SJ group, patients who underwent minimally invasive necrosectomy (MIN) without PCD were assigned to the SJ-1 group (n=34), whereas those who initially underwent PCD followed by immediate open surgery were placed in the SJ-2 group (n=10). Propensity score matching (PSM) was used to mitigate bias. After PSM, a total of 34 pairs were successfully matched. A comparison of the SU group with the SJ-1 group (upfront MIN without PCD) revealed similar mortality rates (P=0.239); however, the incidences of multiple drug-resistant organisms (MDROs) (P=0.029) and surgical complications (P<0.001) were significantly lower in the SJ-1 group. After comparing the SU-2 and SJ-2 groups (patients who underwent direct open necrosectomy without MIN after PCD failure), the incidences of surgical complications and MDRO in the SJ-2 group were significantly lower (P<0.05). Compared with the step-up approach, the step-jump approach is safer and more effective and can significantly reduce the incidence of MDRO and surgical complications.

Transbronchial cryobiopsy followed by as-needed surgical lung biopsy versus immediate surgical lung biopsy for diagnosing interstitial lung disease (the COLD study): a randomised controlled trial

An adequate diagnosis for interstitial lung disease (ILD) is important for clinical decision making and prognosis. In most patients with ILD, an accurate diagnosis can be made by clinical and radiological data assessment, but in a considerable proportion of patients, a lung biopsy is required. Surgical lung biopsy (SLB) is the most common method to obtain tissue, but it is associated with high morbidity and even mortality. More recently, transbronchial cryobiopsy has been introduced, with fewer adverse events but a lower diagnostic yield than SLB. The aim of this study is to compare two diagnostic strategies: a step-up strategy (transbronchial cryobiopsy, followed by SLB if the cryobiopsy is insufficiently informative) versus immediate SLB. The COLD study was a multicentre, randomised controlled trial in six hospitals across the Netherlands. We included patients with ILD with an indication for lung biopsy as assessed by a multidisciplinary team discussion. Patients were randomly assigned in a 1:1 ratio to the step-up or immediate SLB strategy, with follow-up for 12 weeks from the initial procedure. Patients, clinicians, and pathologists were not masked to the study treatment. The primary endpoint was unexpected chest tube drainage, defined as requiring any chest tube after transbronchial cryobiopsy, or prolonged (>24 h) chest tube drainage after SLB. Secondary endpoints were diagnostic yield, in-hospital stay, pain, and serious adverse events. A modified intention-to-treat analysis was performed. This trial is registered with the Dutch Trial Register, NL7634, and is now closed. Between April 8, 2019, and Oct 24, 2021, 122 patients with ILD were assessed for study participation; and 55 patients were randomly assigned to the step-up strategy (n=28) or immediate SLB (n=27); three patients from the immediate SLB group were excluded. Unexpected chest tube drainage occurred in three of 28 patients (11%; 95% CI 4-27%) in the step-up group, and the number of patients for whom the chest tube could not be removed within 24 h was 11 of 24 patients (46%; 95% CI 2-65%) in the SLB group, with an absolute risk reduction of 35% (11-56%; p=0·0058). In the step-up strategy, the multidisciplinary team diagnostic yield after transbronchial cryobiopsy alone was 82% (64-92%), which increased to 89% (73-96%) when subsequent SLB was performed after inconclusive transbronchial cryobiopsy. In the immediate surgery strategy, the multidisciplinary team diagnostic yield was 88% (69-97%). Total in-hospital stay was 1 day (IQR 1-1) in the step-up group versus 5 days (IQR 4-6) in the SLB group. One (4%) serious adverse event occurred in step-up strategy versus 12 (50%) in the immediate SLB strategy. In ILD diagnosis, if lung tissue assessment is required, a diagnostic strategy starting with transbronchial cryobiopsy, followed by SLB when transbronchial cryobiopsy is inconclusive, appears to result in a significant reduction of patient burden and in-hospital stay with a similar diagnostic yield versus immediate SLB. Netherlands Organisation for Health Research and Development (ZonMW) and Amsterdam University Medical Centers.

A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial

Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 μg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. Wellcome and PredictImmune Ltd.

Upfront endoscopic necrosectomy or step-up endoscopic approach for infected necrotising pancreatitis (DESTIN): a single-blinded, multicentre, randomised trial

Although the preferred management approach for patients with infected necrotising pancreatitis is endoscopic transluminal stenting followed by endoscopic necrosectomy as step-up treatment if there is no clinical improvement, the optimal timing of necrosectomy is unclear. Therefore, we aimed to compare outcomes between performing upfront necrosectomy at the index intervention versus as a step-up measure in patients with infected necrotising pancreatitis. This single-blinded, multicentre, randomised trial (DESTIN) was done at six tertiary care hospitals (five hospitals in the USA and one hospital in India). We enrolled patients (aged ≥18 years) with confirmed or suspected infected necrotising pancreatitis with a necrosis extent of at least 33% who were amenable to endoscopic ultrasound-guided drainage. By use of computer-generated permuted block randomisation (block size four), eligible patients were randomly assigned (1:1) to receive either upfront endoscopic necrosectomy or endoscopic step-up treatment. Endoscopists were not masked to treatment allocation, but participants, research coordinators, and the statistician were. Lumen-apposing metal stents (20 mm diameter; 10 mm saddle length) were used for drainage in both groups. In the upfront group, direct necrosectomy was performed immediately after stenting in the same treatment session. In the step-up group, direct necrosectomy or additional drainage was done at a subsequent treatment session if there was no clinical improvement (resolution of any criteria of systemic inflammatory response syndrome or sepsis or one or more organ failure and at least a 25% percentage decrease in necrotic collection size) 72 h after stenting. The primary outcome was the number of reinterventions per patient to achieve treatment success from index intervention to 6 months' follow-up, which was defined as symptom relief in conjunction with disease resolution on CT. Reinterventions included any endoscopic or radiological procedures performed for necrosectomy or additional drainage after the index intervention, excluding the follow-up procedure at 4 weeks for stent removal. All endpoints and safety were analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT05043415 and NCT04113499, and recruitment and follow-up have been completed. Between Nov 27, 2019, and Oct 26, 2022, 183 patients were assessed for eligibility and 70 patients (24 [34%] women and 46 [66%] men) were randomly assigned to receive upfront necrosectomy (n=37) or step-up treatment (n=33) and included in the intention-to-treat population. At the time of index intervention, seven (10%) of 70 patients had organ failure and 64 (91%) patients had walled-off necrosis. The median number of reinterventions was significantly lower for upfront necrosectomy (1 [IQR 0 to 1] than for the step-up approach (2 [1 to 4], difference -1 [95% CI -2 to 0]; p=0·0027). Mortality did not differ between groups (zero patients in the upfront necrosectomy group vs two [6%] in the step-up group, difference -6·1 percentage points [95% CI -16·5 to 4·5]; p=0·22), nor did overall disease-related adverse events (12 [32%] patients in the upfront necrosectomy group vs 16 [48%] patients in the step-up group, difference -16·1 percentage points [-37·4 to 7·0]; p=0·17), nor procedure-related adverse events (four [11%] patients in the upfront necrosectomy group vs eight [24%] patients in the step-up group, difference -13·4 percentage points [-30·8 to 5·0]; p=0·14). In stabilised patients with infected necrotising pancreatitis and fully encapsulated collections, an approach incorporating upfront necrosectomy at the index intervention rather than as a step-up measure could safely reduce the number of reinterventions required to achieve treatment success. None.

WONDER-01: immediate necrosectomy vs. drainage-oriented step-up approach after endoscopic ultrasound-guided drainage of walled-off necrosis—study protocol for a multicentre randomised controlled trial

BackgroundWith the increasing popularity of endoscopic ultrasound (EUS)-guided transmural interventions, walled-off necrosis (WON) of the pancreas is increasingly managed via non-surgical endoscopic interventions. However, there has been an ongoing debate over the appropriate treatment strategy following the initial EUS-guided drainage. Direct endoscopic necrosectomy (DEN) removes intracavity necrotic tissue, potentially facilitating early resolution of the WON, but may associate with a high rate of adverse events. Given the increasing safety of DEN, we hypothesised that immediate DEN following EUS-guided drainage of WON might shorten the time to WON resolution compared to the drainage-oriented step-up approach.MethodsThe WONDER-01 trial is a multicentre, open-label, superiority, randomised controlled trial, which will enrol WON patients aged ≥ 18 years requiring EUS-guided treatment in 23 centres in Japan. This trial plans to enrol 70 patients who will be randomised at a 1:1 ratio to receive either the immediate DEN or drainage-oriented step-up approach (35 patients per arm). In the immediate DEN group, DEN will be initiated during (or within 72 h of) the EUS-guided drainage session. In the step-up approach group, drainage-based step-up treatment with on-demand DEN will be considered after 72–96 h observation. The primary endpoint is time to clinical success, which is defined as a decrease in a WON size to ≤ 3 cm and an improvement of inflammatory markers (i.e. body temperature, white blood cell count, and C-reactive protein). Secondary endpoints include technical success, adverse events including mortality, and recurrence of the WON.DiscussionThe WONDER-01 trial will investigate the efficacy and safety of immediate DEN compared to the step-up approach for WON patients receiving EUS-guided treatment. The findings will help us to establish new treatment standards for patients with symptomatic WON.Trial registrationClinicalTrials.gov NCT05451901, registered on 11 July 2022. UMIN000048310, registered on 7 July 2022. jRCT1032220055, registered on 1 May 2022.

Imaging classification and analysis of the diagnosis and treatment of infected pancreatic necrosis:a report of 126 cases

Objective: To explore the clinical characteristics of various types of infected pancreatic necrosis(IPN) and the prognosis of different treatment methods in the imaging classification of IPN proposed. Methods: The clinical data of 126 patients with IPN admitted to the Department of Pancreatic and Biliary Surgery, the First Affiliated Hospital of Harbin Medical University from December 2018 to December 2021 were analyzed retrospectively. There were 70 males(55.6%) and 56 females(44.4%), with age(M(IQR)) of 44(17)years (range: 12 to 87 years). There were 67 cases(53.2%) of severe acute pancreatitis and 59 cases (46.8%) of moderately severe acute pancreatitis. All cases were based on the diagnostic criteria of IPN. All cases were divided into Type Ⅰ(central IPN)(n=21), Type Ⅱ(peripheral IPN)(n=23), Type Ⅲ(mixed IPN)(n=74) and Type Ⅳ(isolated IPN)(n=8) according to the different sites of infection and necrosis on CT.According to different treatment strategies,they were divided into Step-up group(n=109) and Step-jump group(n=17). The clinical indicators and prognosis of each group were observed and analyzed by ANOVA,t-test,χ2 test or Fisher exact test,respectively. Results: There was no significant difference in mortality, complication rate and complication grade in each type of IPN(all P>0.05). Compared with other types of patients, the length of stay (69(40)days vs. 19(19)days) and hospitalization expenses(323 000(419 000)yuan vs. 60 000(78 000)yuan) were significantly increased in Type Ⅳ IPN(Z=-4.041, -3.972; both P<0.01). The incidence of postoperative residual infection of Type Ⅳ IPN was significantly higher than that of other types (χ2=16.350,P<0.01). There was no significant difference in the mortality of patients with different types of IPN between different treatment groups. The length of stay and hospitalization expenses of patients in the Step-up group were significantly less than those in the Step-jump group(19(20)days vs. 33(35)days, Z=-2.052, P=0.040;59 000(80 000)yuan vs. 122 000(109 000)yuan,Z=-2.317,P=0.020). Among the patients in Type Ⅳ IPN, the hospitalization expenses of Step-up group was significantly higher than that of Step-jump group(330 000(578 000)yuan vs. 141 000 yuan,Z=-2.000,P=0.046). The incidence of postoperative residual infection of Step-up group(17.4%(19/109)) was significantly lower than that of Step-jump group(10/17)(χ2=11.980, P=0.001). Conclusions: Type Ⅳ IPN is more serious than the other three types. It causes longer length of stay and more hospitalization expenses. The step-up approach is safe and effective in the treatment of IPN. However, for infected lesions which are deep in place,difficult to reach by conventional drainage methods, or mainly exhibit "dry necrosis", choosing the step-jump approach is a more positive choice.

Pharmacodynamic Biomarkers of Mosunetuzumab Efficacy and Safety in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma: Results from a Phase I/II Study

Background: Mosunetuzumab (Mosun) is a CD20xCD3 bispecific antibody that engages T cells and B cells to induce a synthetic synapse leading to T-cell activation and production of cytokines involved in immune-directed B-cell killing. Mosun is being developed as a fixed-duration, off-the-shelf therapy for the treatment of non-Hodgkin lymphoma (NHL). A Phase I/II study (NCT02500407) is investigating Mosun monotherapy in patients (pts) with relapsed or refractory NHL (aggressive NHL [aNHL; n=278]: DLBCL, MCL, RS, transformed FL, FL3b; indolent NHL [iNHL; n=168]: FL, MZL, SLL) using fixed (Group A; n=33) and step-up (Group B; n=414) dosing schedules. We report exploratory pharmacodynamic (PD) biomarker analyses from this study across dosing cohorts and histologies in relation to mechanism of action, dose, safety, and clinical activity. Methods: In Group A, the target dose (TD) of intravenous Mosun was administered on Cycle (C) 1 Day (D) 1 (0.05-2.8mg). In Group B, step-up doses (SUD) were administered on C1D1 (0.4-1mg), C1D8 (1-2mg) and the TD on C1D15 (2.8mg-60mg). In both groups, TD was given on D1 of subsequent cycles (up to C8 for pts achieving a complete response or C17 for pts achieving partial response or stable disease). The recommended dose was confirmed as C1D1 (1mg), C1D8 (2mg), C1D15 and C2D1 (60mg) and C3D1-C8/C17 (30mg). Cytokines (IL-6, INF-γ, TNF-α, IL-2, IL-10) were measured by ELISA or SIMOA assays and peripheral blood (PB) immune-cell subsets by flow cytometry. Baseline (BL) tumor biopsies and on-treatment (on-Tx) biopsies collected between C1D15 and C3D1 were assessed by CD8 immunofluorescence (IF) and RNAseq. Results: In Group A, cytokine release was observed at Mosun doses of ≥0.4mg. Cytokine release was acute and transient, occurring early after Mosun administration and returning to BL levels by 24 hours. Despite a low to moderate correlation across cytokines at BL, a similar pattern of cytokine secretion was observed following administration of Mosun. High levels of cytokines were detected in pts who experienced cytokine release syndrome (CRS). In Group B, SUD was initiated as a CRS mitigating strategy, using the identified, pharmacodynamically active dose as the initial dose. Although a second cytokine peak was observed at C1D15 during SUD, with a trend towards higher peaks with increasing Mosun doses, significantly higher doses could be administered without corresponding cytokine release. While Mosun exhibited linear pharmacokinetics, dose-dependent PD relationships can be confounded by variables that affect target binding including residual anti-CD20 monoclonal antibodies from prior treatment. Taking CD20 receptor occupancy into account, exposure-response analyses using IL-6 or INF-γ confirmed that SUD ameliorates cytokine release to enable higher Mosun dosing to achieve clinically active exposure (Figure). T-cell margination, activation (CD69), and proliferation (Ki67) were observed in CD4+ and CD8+ T cells in a time-dependent manner that paralleled PD changes observed with cytokines in both aNHL and iNHL. CD4+ and CD8+ T-cell activation was observed after the initial Mosun dose and to a lesser extent with subsequent doses. In contrast, B-cell depletion was observed early after initial Mosun administration and was sustained throughout treatment. At BL, higher levels of PB B cells were associated with improved response in pts with aNHL. However, this may reflect prognostic features and prolonged time since prior therapy. On-Tx increases in activated T-cell subsets (% CD4+DR+GzB+ and % CD4/8 Tn DR+) were also associated with improved response. Changes in biomarker levels were observed predominantly with the first dose of Mosun; associations with response were primarily seen in pts with aNHL vs iNHL, possibly reflective of the distinct immune biology. Importantly, PD changes observed in PB were also observed in tumors. Increases in CD8+ T cells (CD8 IF) in on-Tx tumor biopsies were predominantly, but not exclusively, reported in pts who achieved a response. Consistent with PB observations, changes in RNA levels of CD8, cytokines and markers of T-cell activation (i.e. GZMB and TIM3) were also observed by RNAseq at the tumor site. Conclusions: PD biomarkers of Mosun in PB and tumor biopsies confirm immune-cell activity associated with Mosun treatment and demonstrate the benefit of SUD as a CRS mitigation strategy to enable administration of clinically active doses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Timing, approach, and treatment strategies for infected pancreatic necrosis: a narrative review

Timing, approach, and treatment strategies for infected pancreatic necrosis: a narrative review

One-step laparoscopic pancreatic necrosectomy verse surgical step-up approach for infected pancreatic necrosis: a case-control study.

The surgical step-up approach often requires multiple debridements and might not be suitable for infected pancreatic necrosis (IPN) patients with various abscesses or no safe route for percutaneous catheter drainage (PCD). This case-control study aimed to investigate the safety and effectiveness of one-step laparoscopic pancreatic necrosectomy (LPN) in treating IPN. This case-control study included IPN patients undergoing one-step LPN or surgical step-up in our center from January 2015 to December 2020. The short-term and long-term complications after surgery, length of hospital stay, and postoperative ICU stays in both groups were analyzed. Univariate and multivariate logistic regression analyses were performed to explore the risk factors of major complications or death. A total of 53 IPN patients underwent one-step LPN and 37 IPN patients underwent surgical step-up approach in this study. There was no significant difference in the incidence of death, major complications, new-onset diabetes, or new-onset pancreatic exocrine insufficiency between the two groups. However, the length of hospital stay in the one-step LPN group was significantly shorter than that in the surgical step-up group. Univariate regression analysis showed that the surgical approach (one-step/step-up) was not the risk factor for major complications or death. Multivariate logistic regression analysis indicated that computed tomography (CT) severity index, American Society of Anesthesiologists (ASA) class IV, and white blood cell (WBC) were the significant risk factors for major complications or death. One-step LPN is as safe and effective as the surgical step-up approach for treating IPN patients, and reduces total hospital stay.

Effect of multidirectional and unidirectional wobble board lateral step-upexercise in pain, symptom and ADLamong unilateral medial compartmental osteoarthrosis of knee

Introduction and Aim:Osteoarthrosis is defined as degenerative condition of the synovial joints. Weak thigh muscle will cause impaired walking and balance and leads to risk of fall during activities of daily living. Use of MD and UD wobble board is hypothesized to improve balance and proprioception. So, pain, muscle power and proprioception are clinically important for balance control. Hence there is a need to study weight bearing exercise to hip abductor in various balance strategies to achieve muscle strength, joint position sense, balance, and activity of daily living.&#x0D; &#x0D; Methodology: Knee osteoarthrosis subjects(n=219) were selected according to selection criteria andwere randomly allocated into 3 groups as multidirectional wobble board lateral step-up exercise group, unidirectional wobble board lateral step-up exercise group and control group. The pre-test KOOS pain, symptoms and ADL measurements were taken before the intervention and another measurement during the 2nd week of intervention and at the end of the intervention period during 4thweek post-test measurements were measured and statistically analysed.&#x0D; &#x0D; Results: At the end of 4th week control, UD and MD was found to be statistically significant with H=200.192 with p&lt;0.001. KOOS symptoms between 3 groups was found to be statistically significant with H=200.288 and p &lt;0.001. KOOS ADL values was found to be statistically significant between 3 groups with H=193.640 and p&lt;0.001.&#x0D; &#x0D; Conclusion: This study concludes that both unidirectional and multidirectional wobble board lateral step-up exercise showed improvement with KOOS pain, symptom and ADL scores compared to control group.

329 Supplementing Native Rumen Microorganisms Improves Feedlot Steer Digestive Health and Performance

Abstract The rumen microbiome functions as a synchronized entity that digests feed in order to provide nutrients for its host. High-concentrate diets destabilize the rumen microbiome by biasing the community towards microorganisms that readily ferment simple carbohydrates resulting in decreased pH, increased CO2, and an increased solvent concentration in the rumen content. This chemical shift interrupts rumen fermentation and can lead to the development of metabolic diseases that negatively impact animal performance. This study evaluated the benefit of a daily, in-feed microbial feed supplement (MFS; Magnius, Native Microbials Inc, San Diego, CA) containing three native rumen microbes (Chordicoccus ruminifurens ASCUSBF65, Prevotella albensis ASCUSBF41, and Succinivibrio dextrinosolvens ASCUSBF53) on commercial feedlot steer performance and rumen microbiome composition. The trial was conducted by HMS Veterinary Development in Reedley, CA using 200 steers in 20 pens over 109 days with a 2x2 factorial design (with and without step-up period x with and without MFS). The without step-up group was directly fed the finisher ration (94% concentrate, 0.95 Mcal/lb NEm), while the step-up group was adapted to the finisher ration over a period of 21 days. Rumen microbiome samples were collected via stomach tubing periodically throughout the trial. At the end of 109 days, the FCR of the animals receiving MFS were significantly lower than the control animals (7.67% improvement, P = 0.013) in the step-up group, although no significant differences were observed in ADG and DMI. No significant performance differences were observed in the group without a step-up (Table 1). The relationship between rumen pH, dissolved CO2, and the observed changes in the microbiome suggest a potential interplay between acetogenesis and methanogenesis where CO2 consuming bacteria may be important in improving rumen digestive health. Collectively, these results suggest that feeding native rumen microorganisms can improve rumen resilience and health of high-grain consuming cattle.

Comparison of inflammatory bowel disease relapse after top-down or step-up therapy: a population-based cohort study.

The therapeutic effect of top-down therapy for inflammatory bowel disease (IBD) has not been fully evaluated in real-world clinical settings. We compared the effectiveness of top-down and step-up therapies for IBD. We retrospectively evaluated patients who were admitted with IBD (Crohn's disease [CD] or ulcerative colitis [UC]) between 2012 and 2019 using the nationwide Japan Diagnosis Procedure Combination database. Patients who received immunomodulators or biologic agents at the start of observation were assigned to the top-down group and those who did not were enrolled in the step-up group. Relapse was the primary outcome, a composite outcome defined as surgery, new steroid or immunomodulator use, hospitalization, a new biologic agent, or switching biologic agents. We analyzed 6715 patients (CD, N = 3643; UC, N = 3072). Relapse occurred in 1982 CD cases (54.4%). The cumulative CD relapse incidence was 32.9% at 1year and 61.3% at 5years in the top-down group and 30.7% at 1year and 58.6% at 5years in the step-up group. Relapse occurred in 2032 UC cases (47.8%). The cumulative relapse incidence was 33.5% at 1year and 50.0% at 5years in the top-down group and 35.2% at 1year and 51.6% at 5years in the step-up group. No clinical factors associated with relapse were identified in patients with CD or UC. Compared with step-up therapy, top-down therapy was not associated with a decreased relapse risk in a real-world population of patients with CD or UC.

Group sequential Holm and Hochberg procedures.

The problem of testing multiple hypotheses using a group sequential procedure often arises in clinical trials. We review several group sequential Holm (GSHM) type procedures proposed in the literature and clarify the relationships between them. In particular, we show which procedures are equivalent or, if different, which are more powerful and what are their pros and cons. We propose a step-up group sequential Hochberg (GSHC) procedure as a reverse application of a particular step-down GSHM procedure. We conducted an extensive simulation study to evaluate the familywise error rate (FWER) and power properties of that GSHM procedure and the GSHC procedure and found that the GSHC procedure controls FWER more closely and is more powerful. All procedures are illustrated with a common numerical example, the data for which are chosen to bring out the differences between them. A real case study is also presented to illustrate application of these procedures. R programs for applying the proposed procedures, additional simulation results, and the proof of the FWER control of the GSHC procedure in a special case are provided in Supplementary Material.

Safety of Once-Daily Single-Inhaler Triple Therapy with Fluticasone Furoate/Umeclidinium/Vilanterol in Japanese Patients with Asthma: A Long-Term (52-Week) Phase III Open-Label Study.

PurposeThe pivotal CAPTAIN study reported a favorable safety profile with once-daily inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist (ICS/LAMA/LABA) triple combination of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) in patients with inadequately controlled asthma, some of whom were Japanese. Here, we evaluate the long-term (52 weeks) safety of FF/UMEC/VI in Japanese patients with asthma.Patients and MethodsThis was a Phase III, 52-week, multicenter, non-comparator, non-randomized, open-label study (NCT03184987) in Japanese adults receiving maintenance therapy with ICS/LABA, with or without LAMA. At enrollment, patients were allocated to either FF/UMEC/VI 100/62.5/25mcg (Group 1) or 200/62.5/25mcg (Group 2). Patients in Group 1 could have their treatment stepped up to 200/62.5/25mcg at Week 24 if their Asthma Control Questionnaire (ACQ)-7 score was >0.75. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs). Secondary endpoints included vital signs, electrocardiogram measurements, and clinical laboratory tests (biochemistry, hematology, urinalysis). Efficacy was assessed as “other” endpoints.ResultsA total of 111 Japanese patients were included in the intention-to-treat (ITT) population. Overall, 77 (69%) patients reported ≥1 AE (Group 1: n=30 [64%]; step-up group: n=7 [78%]; Group 2: n=40 [73%]). SAEs were reported for 1 (2.1%) and 2 (3.6%) patients in Groups 1 and 2, respectively. All SAEs were considered unrelated to study treatment. One AE and one SAE led to study withdrawal: oropharyngeal discomfort (Group 1); eosinophilic granulomatosis with polyangiitis (Group 2). No new safety concerns were identified throughout the 52-week treatment period.ConclusionIn this uncontrolled open-label study, no new safety concerns were observed with long-term (52 weeks) treatment with once-daily FF/UMEC/VI among 111 Japanese patients with asthma.

Experience in the implementation of a modified step-up approach in the treatment of infected pancreatic necrosis

Aim.Analysis of the results of the application of the modified step-up approach in the treatment of infected pancreatonecrosis in a third-level hospital.Materials and methods.The study included 52 patients over 18 years of age with acute pancreatitis and suspected or proven infection with pancreatic or peripancreatic necrosis .The control group included 27 patients who underwent primary open necrectomy. The comparison group included 25 patients who underwent surgical treatment within the framework of the modified concept of the stepwise surgical approach (Step-up). In the groups compared mortality rates, early postoperative complications (IIIb-IVb grade Clavien-Dindo), late postoperative complications (ventral hernias, pseudocysts, diabetes mellitus), the duration of inpatient treatment, and the duration of treatment in the intensive care unit. The indicator "Full return to primary social activity after treatment" was also proposed.Results.In the Step-up approach group, in comparison with the control group, there was a decrease in the overall incidence of postoperative complications of IIIb-IVb grade Clavien-Dindo (24% and 51.9%, respectively, p &lt;0.05), the frequency of arrosive bleeding (0% and 14 , 8%, respectively, p &lt;0.05), the need for necrsequestrectomy (64 and 100%, respectively, p &lt;0.01), the total average duration of treatment in the intensive care unit (3.2 ± 0.6 and 9.2 ± 1.6 days, respectively, p &lt;0.05), and the average duration of treatment in the intensive care unit after execution of necrosectomy (1,4±0,4 7,2±1,3 days, respectively, p&lt;0.01). A complete return to social activity in the control group was noted only in 10 (37%) patients compared with 19 (76%) in the Step-up group (p &lt;0.01). In the Step-up group, in comparison with the control group, a tendency towards a decrease in mortality was revealed (16% and 34.5%, respectively, p&gt; 0.05).Conclusion.The step-up approach can improve the results of treatment of infected pancreatic necrosis. The most important advantage of this concept is reproducibility - that is, the possibility of using it not only in the leading metropolitan clinics, but also in the regions of the Russian Federation. The step-up approach, however, has not yet acquired a complete form, and there is room for improvement.

Infliximab Therapy for Children with Moderate to Severe Ulcerative Colitis: A Step-Up versus a Top-Down Strategy.

PurposeWe aimed to investigate clinical outcomes between top-down (TD) and conventional step-up (SU) therapies in pediatric patients with moderate to severe ulcerative colitis (UC).Materials and MethodsAll patients underwent clinical and endoscopic evaluation at diagnosis and 4 months and 1 year after treatment. Patients who started treatment with corticosteroid were grouped in the SU group, while those that initiated early infliximab (IFX) were grouped in the TD group. Among the SU group, patients who eventually changed to IFX treatment due to steroid resistance or dependency were included in the SU(R) group.ResultsIn total, 44 children with moderate to severe UC were included for analysis. Twenty-one patients were included in the SU group, 23 were included in the TD group, and 10 were enrolled in the SU(R) group. Relapse rates were 47.6% (10/21) in the SU group and 17.4% (4/23) in the TD group (p=0.033). Among relapsed patients, the durations from remission to relapse were 17.3 months (0.9–46.9) in the SU group and 24.3 months (1.8–44.9) in the TD group. There was no statistically significant difference in the sustained durations of remission after IFX administration between the SU(R) and TD groups [3.9 (1.4–6.3) and 2.3 (0.3–5.2) years, respectively (p>0.05)].ConclusionAccording to our study, early use of IFX without corticosteroid treatment for children with moderate to severe UC helps to lower relapse rates. We also found that IFX was a very effective treatment for pediatric UC, with a sustained duration of remission similar between TD and SU(R) groups.

Four-steps surgery for infected pancreatic necrosis based on "Step-up" strategy: a retrospective study

Objective: To examine the effect of the "four-steps" treatment on infectious pancreatic necrosis(IPN). Methods: The data of 207 patients who were diagnosed with IPN from January 2013 to December 2017 at Department of Pancreaticobiliary Surgery, the First Affiliated Hospital of Harbin Medical University were analyzed retrospectively. Among 207 patients, 132(63.8%) were males and 75(36.2%) were females. The median age was 45 years old (range: 19 to 80 years old). One hundred and fifty-eight patients(76.3%) suffered severe acute pancreatitis and 49 patients(23.7%) suffered moderately severe acute pancreatitis. Percutaneous catheter drainage(PCD) was performed on all the patients(Step 1). Patients received "four-steps" minimally invasive treatment strategy in step-up group(173 patients). The following steps after PCD were mini-incision access pancreatic necrosectomy(MIAPN) (Step 2), sinus tract endoscopic debridement and(or) PCD for residual infections(Step 3) and finally conventional open pancreatic necrosectomy(OPN) (Step 4). Patients(34 cases) received conventional open pancreatic necrosectomy after invalided PCD in OPN group. The perioperative parameters and prognosis were compared between Step-up group and OPN group. Normally distributed quantitative variables were analyzed by t-test, non-normally distributed quantitative variables were analyzed by Wilcoxon chi-square test and categorical variables were analyzed by χ(2) test or Fisher exact test, respectively. Results: The basic characteristics of the two groups of patients were similar, but the referral rate of patients and the rate of preoperative 3 days organ failure in the OPN group were significantly higher than those of step-up group patients(47.1% vs. 28.9%, χ(2)=4.313, P=0.038; 26.5% vs. 9.2%, χ(2)=2.819, P=0.011). The frequency of PCD and the number of PCD tube (root) were less than those in the step-up group(1(1) vs. 2(1), Z=-3.373, P=0.018; 2(1) vs. 3(2), Z=-2.208, P=0.027). Compared with the OPN group, the interval time from onset to surgery and the MIAPN operation time were significantly shorter in the step-up group(29(15) days vs. 36(17)days, Z=-0.567, P=0.008; 58(27)minutes vs. 90(56)minutes, Z=-3.908, P<0.01); postoperative mortality was lower(5.8% vs.17.6%, χ(2)=4.070, P=0.044); the overall incidence of postoperative complications was reduced(23.1% vs. 55.9%, χ(2)=14.960, P<0.01) and the incidence of new-onset organ failure was decreased after operation in the step-up group(37.5% vs.47.4%, χ(2)=7.133, P=0.007). The incidence of local abdominal complications (pancreatic fistula, intra-abdominal hemorrhage, gastrointestinal fistula) showed no significant difference between the two groups (P>0.05). Fewer patients required ICU treatment after operation in the step-up group compared with OPN group(22.0% vs. 44.1%, χ(2)=6.204, P=0.013). Patients in the Step-up group has shorter hospital stay than patients in OPN group (46(13) days vs. 52(13)days, Z=-1.993, P=0.046). Conclusions: The clinical effects of "four-steps" exhibited the superiority of minimally invasive treatment of IPN.And MIAPN is a simple, safe and effective procedure to remove pancreatic necrotic tissue and decrease complications.

One-Step verse Step-Up Laparoscopic-Assisted Necrosectomy for Infected Pancreatic Necrosis

Background: Percutaneous or endoscopic drainage was usually performed as the first step in step-up approach for infected pancreatic necrosis (IPN). However, drainage was unnecessary or unavailable in some patients. Objective: To estimate the safety and effect of one-step laparoscopic-assisted necrosectomy in IPN patients. Methods: A retrospective analysis of IPN patients received surgical therapy in our center between January 2015 and December 2017 was performed. Patients were assigned to either one-step or step-up groups according to the received therapeutic approach. Incidence of complications, death, total number of interventions, and total hospital stay were compared. Logistic regression and nomogram were used to explore the risk factors and probability for patients undergoing interventions ≥3 times. Results: There were 45 and 49 patients included in one-step and step-up groups, respectively. No significant difference between groups in terms of new organ failure (14.29 vs. 14.33%, p = 0.832), death (8.89 vs.8.17%, p = 0.949), and long-term complications (18.37 vs. 15.56%, p = 0.717). However, the number of interventions in one-step group was significantly less than in step-up group with shorter hospital stay. After multivariate analysis, C-reactive protein, interleukin-6, and surgical approach were independent predicators for patients undergoing interventions ≥3. A nomogram was built with area under ROC curve 0.891. Conclusion: Compared with step-up approach, one-step surgery was safe and effective in selected IPN patients with less interventions and shorter hospital stay.

Prognostic factors of critical acute pancreatitis: A prospective cohort study

BackgroundPatients with critical acute pancreatitis (CAP) have the highest risk of mortality. However, there have been no studies specifically designed to evaluate the prognostic factors of CAP. Aims & methodsThis was a prospective observational cohort study involving patients with CAP. Three aspects including organ failure, (peri)pancreatic necrotic fluid cultures and surgical interventions were analyzed specifically to identify prognostic factors. ResultsOf the 102 consecutive patients with CAP, 83 patients (81.4%) received step-up surgical treatment, the mortality of the step-up group was 25.3% (21/83). 19 patients (18.6%) underwent step-down surgical treatment, the mortality of the step-down group was 57.9% (11/19). Overall mortality in the whole cohort was 31.4% (32/102). Multivariate analysis of death predictors indicated that multiple organ failure (MOF) (OR = 5.3; 95% CI, 1.5–18.2; p = 0.008), long duration (≥5 days) of organ failure (OR = 6.4; 95% CI, 1.2–54.3; p = 0.029), multidrug-resistant organisms (MDROs) infection (OR = 4.6; 95% CI, 1.3–15.8; p = 0.013), OPN (OR = 3.7; 95% CI, 1.5–8.8; p = 0.004) and step-down surgical treatment (OR = 3.5; 95% CI, 1.2–10.1; p = 0.019) were significant factors. ConclusionAmong patients with CAP, MOF, long duration (≥5 days) of organ failure, MDROs infection, OPN and step-down surgical treatment were identified as the predictors of mortality.

Superiority of Step-up Approach vs Open Necrosectomy in Long-term Follow-up of Patients With Necrotizing Pancreatitis

In a 2010 randomized trial (the PANTER trial), a surgical step-up approach for infected necrotizing pancreatitis was found to reduce the composite endpoint of death or major complications compared with open necrosectomy; 35% of patients were successfully treated with simple catheter drainage only. There is concern, however, that minimally invasive treatment increases the need for reinterventions for residual peripancreatic necrotic collections and other complications during the long term. We therefore performed a long-term follow-up study. We reevaluated all the 73 patients (of the 88 patients randomly assigned to groups) who were still alive after the index admission, at a mean 86 months (±11 months) of follow-up. We collected data on all clinical and health care resource utilization endpoints through this follow-up period. The primary endpoint was death or major complications (the same as for the PANTER trial). We also measured exocrine insufficiency, quality of life (using the Short Form-36 and EuroQol 5 dimensions forms), and Izbicki pain scores. From index admission to long-term follow-up, 19 patients (44%) died or had major complications in the step-up group compared with 33 patients (73%) in the open-necrosectomy group (P= .005). Significantly lower proportions of patients in the step-up group had incisional hernias (23% vs 53%; P= .004), pancreatic exocrine insufficiency (29% vs 56%; P= .03), or endocrine insufficiency (40% vs 64%; P= .05). There were no significant differences between groups in proportions of patients requiring additional drainage procedures (11% vs 13%; P= .99) or pancreatic surgery (11% vs 5%; P= .43), or in recurrent acute pancreatitis, chronic pancreatitis, Izbicki pain scores, or medical costs. Quality of life increased during follow-up without a significant difference between groups. In an analysis of long-term outcomes of trial participants, we found the step-up approach for necrotizing pancreatitis to be superior to open necrosectomy, without increased risk of reinterventions.