Search

Objective: An assessment of functional gastrointestinal disorders (FGIDs) in premature infants in their first year of life and neonatal factors influencing the progression of FGIDs is conducted in this research. Methods: Subjects selected for the retrospective study involved preterm infants being hospitalized in the neonatal department of Northern Jiangsu People’s Hospital from September 2018 to September 2021. Data on neonatal risk factors such as gestational age, gender, birth weight, mode of delivery, feeding pattern, antibiotic administration and addition of probiotics, duration of hospitalization, maternal history of smoking, and mental condition, were all collected and analyzed. FGIDs were diagnosed as per Rome IV criteria and a multivariate logistic regression model has been applied for determining factors linked to it. Results: This study included 988 preterm infants, with 725 (73.4%) having at least one FGID, 449 (45.4%) having infant colic, 411 (41.6%) having infant regurgitation, 237 (24.0%) having infant dyschezia, 190 (19.2%) having functional constipation, and 34 (3.4%) having functional diarrhea throughout the first year of life. There was no evidence identified for infant rumination syndrome and recurrent vomiting syndrome. In total, 263 infants (26.6%) without FGID symptoms were included in the control group. Infant colic and infant regurgitation were found as the most prevalent FGIDs. Further, a higher prevalence of FGIDs was observed in preterm infants with infant colic as well as infant regurgitation in particular as being characterized by a low gestational age (Conclusion: Therefore, unnecessary antibiotic use in the neonatal period, cesarean delivery, passive smoking, lack of breastfeeding, along with inappropriate probiotics usage are major risk factors for FGIDs, and their systematic control may be effective in reducing the susceptibility to and prevalence of FGIDs in preterm infants in the first year of life.

To investigate the relationship between the nutrition status of infants with bronchopulmonary dysplasia (BPD) at the first 4 weeks of life and the likelihood of developing neonatal malnutrition.A total of 1064 infants were divided into a BPD group and a non-BPD group. After propensity score matching, there were 282 infants in each group. Infants were further divided into a neonatal malnutrition （NM） group and a well-nourished （WN） group. Clinical factors, nutrition intake, and growth parameters were collected and analyzed. Multivariate logistic regression model was used to determine the factors associated with neonatal malnutrition.1. Compared with infants in the non-BPD group, the infants in BPD group had more fluid intake and lower calorie and protein intake after the second week, longer invasive ventilation time, and longer time to total oral feeding and parenteral nutrition (PN), and the difference was more significant in NM infants than in WN infants (P0.05). 2. The weight/length, body mass index, triponderal mass index, and weight gain velocity in the BPD group were significantly lower than in the non-BPD group (P0.05) and lower in NM infants than in WN ones (P0.05). 3. Multivariable system regression analysis showed that invasive ventilation time, lipid intake in week 4, time to reach full feeding, and duration of PN were independent risk factors for NM.Enhancing calorie and macronutrient intake, reducing invasive ventilation, and achieving full gastrointestinal feeding early may be effective measures to avoid malnutrition in infants with BPD.

ImportanceUse of tyrosine kinase inhibitors (TKIs) is the standard therapy for epidermal growth factor receptor (EGFR)–mutated non–small cell lung cancer (NSCLC) with brain metastases. Several studies have shown that adding chemotherapy to EGFR-TKIs could improve progression-free survival (PFS) in patients with EGFR-mutant advanced NSCLC; however, the efficacy of these agents in patients with brain metastases remains unclear.ObjectiveTo investigate the efficacy and safety of gefitinib plus chemotherapy (pemetrexed with platinum) compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases.Design, Setting, and ParticipantsThis open-label prospective, multicenter, phase 3 randomized clinical trial was conducted in 6 centers in China from January 13, 2016, to August 27, 2021. The median follow-up time was 21.1 months (IQR, 13.5-31.8 months). Patients with untreated confirmed brain metastases and EGFR-sensitive mutated NSCLC were enrolled.InterventionsThe eligible patients were randomly assigned (1:1) to receive gefitinib plus chemotherapy or gefitinib alone.Main Outcomes and MeasuresThe primary end point was intracranial PFS; secondary end points included PFS, overall survival (OS), intracranial objective response rate, overall objective response rate, and safety. Intention-to-treat analysis was performed.ResultsA total of 161 patients (87 [54.0%] women; mean [SD] age, 55 [9.8] years; range, 26-80 years) were enrolled and randomized to receive gefitinib (n = 81) or gefitinib plus chemotherapy (n = 80). The median intracranial PFS was 15.6 months (95% CI, 14.3-16.9 months) in the gefitinib plus chemotherapy group vs 9.1 months (95% CI, 8.0-10.2 months) in the gefitinib group (hazard ratio, 0.36; 95% CI, 0.25-0.53; P P P = .002) and overall objective response rate (80.0%; 95% CI, 71.0%-89.0% vs 64.2%; 95% CI, 53.5%-74.9%; P = .03) than gefitinib alone. At data cutoff, the median OS was also significantly longer in the gefitinib plus chemotherapy group vs the gefitinib group (35.0 vs 28.9 months; hazard ratio, 0.65; 95% CI, 0.43-0.99; P = .04). Grade 3 or worse adverse events were more common with gefitinib plus chemotherapy, most of which were manageable.Conclusions and RelevanceIn this randomized clinical trial, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases and could be an optional first-line treatment for these patients.Trial RegistrationClinicalTrials.gov Identifier: NCT01951469

Previous studies have revealed that dietary

9095 Background: Combination of tyrosine kinase inhibitor (TKI) and chemotherapy has shown improved clinical outcomes in advanced epidermal growth factor receptor ( EGFR) mutated non-small cell lung cancer (NSCLC) patients. We conducted this phase 3, randomized, controlled trial to further investigate the clinical efficacy and safety of gefitinib combined with chemotherapy in EGFR mutated NSCLC patients with brain metastases. Methods: Treatment-naïve, confirmed brain metastases and EGFR sensitive mutated NSCLC patients were screened from six centers in China. The eligible patients were randomly assigned (1:1) to receive gefitinib alone or gefitinib plus pemetrexed-platinum chemotherapy until intracranial progressive diseases, unacceptable adverse, or any cause of death. Theprimary endpoint was intracranial progression-free survival (iPFS), secondary endpoints were PFS, overall survival, intracranial objective response rate, overall objective response rate, and safety. This study is registered at ClinicalTrials. gov, number NCT01951469. Results: From January 2017 to June 2021, 161 patients were randomly assigned to receive gefitinib (n = 81) or gefitinib plus pemetrexed-platinum chemotherapy (n = 80), the median follow-up time was 18.2 (IQR 11.8-29.7) months. The median intracranial PFS was 15.6 (14.3-16.9) months in gefitinib plus chemotherapy group versus 9.1 (8.0-10.2) months in gefitinib group (HR = 0.36, 95% CI, 0.25-0.53, P < 0.001). Similarly, the median PFS was also significantly longer in gefitinib plus chemotherapy than gefitinib alone (16.3 months vs 9.5 months, P < 0.001). In addition, gefitinib plus chemotherapy had better intracranial objective response rate (85.0% versus 63.0%, P = 0.002) and overall objective response rate (80.0% versus 64.2%, P = 0.035) than gefitinib alone. At the data cutoff, 50.3% of patients (35 patients in gefitinib plus chemotherapy group and 46 patients in gefitinib group) had died. The 3-year OS rate was significantly higher in gefitinib plus chemotherapy group (47.4%, 95% CI 36.3-58.7) than in gefitinib group (24.9%, 95% CI 15.1-34.3, P = 0.003). And median overall survival was 35.0 months (95% CI, 28.8-41.3 months) in gefitinib plus chemotherapy group versus 28.9 months (95% CI, 23.4-34.4 months) in gefitinib group (HR = 0.66, 95% CI, 0.42-1.03, P = 0.065). Grade 3 or worse adverse events were more common in gefitinib plus chemotherapy group (40.0% versus 21.0%, P = 0.010), but most of them were manageable. Conclusions: Inuntreated EGFR mutated NSCLC patients with brain metastases, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS and a tendency of OS than gefitinib alone, and could be the optional first-line treatment. Clinical trial information: NCT01951469.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. We report the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mavorixafor from a phase 2 open-label dose-escalation and extension study in 8 adult patients with genetically confirmed WHIM syndrome. Mavorixafor is an oral small molecule selective antagonist of the CXCR4 receptor that increases mobilization and trafficking of white blood cells from the bone marrow. Patients received escalating doses of mavorixafor, up to 400 mg once daily. Five patients continued on the extension study for up to 28.6 months. Mavorixafor was well tolerated with no treatment-related serious adverse events. At a median follow-up of 16.5 months, we observed dose-dependent increases in absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). At doses ≥300 mg/d, ANC was maintained at >500 cells per microliter for a median of 12.6 hours, and ALC was maintained at >1000 cells per microliter for up to 16.9 hours. Continued follow-up on the extension study resulted in a yearly infection rate that decreased from 4.63 events (95% confidence interval, 3.3-6.3) in the 12 months prior to the trial to 2.27 events (95% confidence interval, 1.4-3.5) for patients on effective doses. We observed an average 75% reduction in the number of cutaneous warts. This study demonstrates that mavorixafor, 400 mg once daily, mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. The trial was registered at www.clinicaltrials.gov as #NCT03005327.

L-arginine (Arg) is a semiessential amino acid with several physiological functions. N-Carbamylglutamate (NCG) can promote the synthesis of endogenous Arg in mammals. However, the roles of Arg or NCG on hepatic inflammation and apoptosis in suckling lambs suffering from intrauterine growth restriction (IUGR) are still unclear. The current work is aimed at examining the effects of dietary Arg and NCG on inflammatory and hepatocyte apoptosis in IUGR suckling lambs. On day 7 after birth, 48 newborn Hu lambs were selected from a cohort of 432 twin lambs. Normal-birthweight and IUGR Hu lambs were allocated randomly (n=12/group) to control (CON), IUGR, IUGR+1% Arg, or IUGR+0.1% NCG groups. Lambs were fed for 21 days from 7 to 28 days old. Compared with CON lambs, relative protein 53 (P53), apoptosis antigen 1 (Fas), Bcl-2-associated X protein (Bax), caspase-3, cytochrome C, tumor necrosis factor alpha (TNF-α), nuclear factor kappa-B (NF-κB) p65, and NF-κB pp65 protein levels were higher (P<0.05) in liver from IUGR lambs, whereas those in liver from IUGR lambs under Arg or NCG treatment were lower than those in IUGR lambs. These findings indicated that supplementing Arg or NCG reduced the contents of proinflammatory cytokines at the same time when the apoptosis-related pathway was being suppressed, thus suppressing the IUGR-induced apoptosis of hepatic cells.

Introduction: Peripheral leukocyte deficiency is a common feature of multiple diseases and may render affected individuals susceptible to infections, both common and opportunistic. The CXCR4 chemokine receptor regulates the trafficking of leukocytes among the bone marrow, blood, and lymphatic system (Al Ustwani O, et al. Br J Haematol. 2014;164:15-23). Mavorixafor is an orally available investigational, small-molecule, selective antagonist of the CXCR4 receptor with potential to restore physiological trafficking and maturation of white blood cells (WBCs). Mavorixafor was previously shown to increase totals and subsets of WBCs in healthy volunteers and in a phase 2 clinical trial in adults with WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) syndrome (Stone N, et al. Antimicrob Agents Chemother. 2007;51(7):2351-2358; Dale D, et al. Blood. 2020;136(26):2994-3003). Here, we report the effect of daily oral administration of mavorixafor on peripheral WBC counts and subsets in patients with clear cell renal cell carcinoma (ccRCC), WHIM syndrome, and Waldenström's macroglobulinemia (WM). Methods: Percentage changes in total peripheral WBC count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and absolute monocyte count (AMC) from pretreatment levels were evaluated in the following settings: a phase 1/2 trial evaluating mavorixafor (200 mg twice daily or 400 mg once daily [QD]) in combination with axitinib (5 mg twice daily) in patients with advanced ccRCC who received ≥1 prior therapy; a phase 1b trial evaluating mavorixafor (400 mg QD) in combination with nivolumab (240 mg QD) in patients with metastatic ccRCC unresponsive to prior nivolumab monotherapy; a long-term extension of the aforementioned phase 2 trial evaluating mavorixafor 300 or 400 mg QD in patients with WHIM syndrome with pathogenic CXCR4 gain-of-function mutation and ANC ≤400/μL and/or ALC ≤650/μL; and an ongoing phase 1b trial evaluating mavorixafor (200 mg QD for 4 weeks, increased to 400 mg and 600 mg QD thereafter) in combination with ibrutinib (420 mg QD) in patients with WM with MYD88 and CXCR4 mutations. Results: In the study evaluating combination mavorixafor (400 mg QD) and axitinib in ccRCC, total WBC count, ANC, ALC, and AMC increased to 153%, 158%, 143%, and 182% of baseline after 4 weeks (n=49), and with increases sustained at 159%, 171%, 139% and 166% of baseline after 6 months' treatment (n=20). In the study evaluating mavorixafor in combination with nivolumab in ccRCC, total WBC count, ANC, ALC, and AMC increased to 146%, 143%, 141%, and 179% of baseline after 4 weeks (n=9), and with increases sustained at 147%, 136%, 152%, and 191% of baseline after 6 months (n=2). In an interim analysis of the phase 1b trial in WM, compared to screening values, total WBC count, ANC, ALC, and AMC increased to 192%, 170%, 219%, and 186% of baseline after 4 weeks (n=8), and with increases sustained at 163%, 192%, 106%, 172% of baseline after 6 months' (n=5) treatment. In the WHIM syndrome phase 2 extension, total WBC count, ANC, ALC, and AMC increased to 339%, 652%, 239%, and 486% of baseline after 6 months' (n=5) treatment, with annualized infection rate decreasing from 5.6 (SD ± 3.13) events at baseline to 2.2 (SD ± 0.93) events after 40 months. Mavorixafor was generally well tolerated, with manageable safety profile across all indications either alone or in combination with other drugs. Conclusions: Mavorixafor alone or in combination with other therapies is the first oral treatment to either acutely or chronically increase total peripheral WBCs 1.5- to 3-fold and WBC subsets across all disease populations examined, in both the presence (WHIM syndrome and WM) and absence (ccRCC and healthy volunteers) of CXCR4 gain-of-function mutation. Increases in WBC subsets occurred rapidly and were sustained during chronic treatment, with a larger treatment effect in patients with pre-existing cytopenia (WHIM syndrome) compared to patients without cytopenia at baseline (ccRCC and WM). Co-occurring reduction in infection burden was observed in the phase 2 trial in WHIM syndrome. Assessment of the beneficial effects of mavorixafor on total and WBC subsets is ongoing in a phase 3 trial of WHIM syndrome and a phase 1 trial of severe chronic neutropenia (SCN) that will assess the potential to correct cytopenias by elevating total WBC counts. Disclosures Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Treon: AbbVie: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; BMS: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; X4: Research Funding. McDermott: Johnson and Johnson: Consultancy, Honoraria; Genentech: Research Funding; Eisia Inc.: Consultancy, Honoraria; Werewolf Therapeutics: Consultancy, Honoraria; Calithera Biosciences: Consultancy, Honoraria; X4 Pharmaceuticals: Research Funding; Iovance: Consultancy, Honoraria; EMD Serono: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Exelixis: Research Funding; Alkermes, Inc.: Consultancy, Honoraria, Research Funding; Eli Lilly and Company: Consultancy, Honoraria. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Luo: X4 Pharmaceuticals: Consultancy. Garg: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chen: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Bhandari: X4 Pharmaceuticals: Current Employment.

Background: WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is a rare primary immunodeficiency associated with broad cytopenia, including neutropenia. It is caused by gain-of-function mutations in C XCR4, leading to dysregulated immune cell trafficking with retention of neutrophils, lymphocytes, and monocytes in the bone marrow and in some cases, hypogammaglobulinemia. As a result, patients with WHIM syndrome have recurrent bacterial and viral infections, and unusual susceptibility to human papillomavirus infection predisposing individuals to recalcitrant warts and malignancy (McDermott D, et al. Immunol Rev. 2019;91-102). Therapeutic options are limited and do not address the underlying pathogenic mechanism of WHIM syndrome. The investigational oral CXCR4 antagonist mavorixafor directly targets the underlying cause of disease and has been shown to increase absolute neutrophil, lymphocyte, and monocyte counts, and to decrease annualized infection rate, and reduce cutaneous wart burden in a phase 2 trial of adults with WHIM syndrome (NCT03005327; Dale D, et al. Blood. 2020;136: 2994-3003). Findings from an ongoing long-term extension of this study support a sustained clinical benefit of long-term mavorixafor treatment in patients with WHIM syndrome. Here, we describe the design of a global phase 3 registrational trial evaluating the safety and efficacy of mavorixafor in WHIM syndrome in participants aged ≥12 years while reporting on preliminary baseline characteristics of the enrolled population. Methods: This phase 3 trial (4WHIM; NCT03995108) is a randomized, double-blind, placebo-controlled study with open-label extension (OLE) and planned enrollment of 18 to 28 patients from sites in Asia, Australia, Europe, Israel, and the United States. Patients aged ≥12 years with a confirmed CXCR4 mutation consistent with WHIM syndrome phenotype and a screening absolute neutrophil count (ANC) ≤400 cells/µL without clinical evidence of active systemic infection are eligible for enrollment. Patients are randomized 1:1 to receive mavorixafor (400 mg in adults, and adolescents weighing >50 kg; 200 mg in adolescents weighing ≤50 kg) or matching placebo once daily for a total of 52 weeks (≥9 patients per group). Patients who complete the randomized period or are granted early release due to recurrent infections requiring treatment (≤2 requiring hospitalization or 4 requiring intravenous antibiotic or granulocyte colony-stimulating factor) are eligible to enroll in the OLE and receive mavorixafor until commercial availability or study termination. The primary end point is the number of hours above ANC threshold of 500 cells/µL over a 24-hour period, assessed prior to treatment, and 4 times (every 3 months) over the 52-week randomized period. Secondary end points include infection rates adjudicated by a blinded, independent committee, change from baseline in cutaneous warts also with blinded assessment, number of hours above absolute lymphocyte count (ALC) of 1000 cells/µL over a 24-hour period, and patient-reported outcomes such as work/school absence and quality of life assessment using age-appropriate questionnaires. Patient Demographics and Characteristics: As of July 15 2021, the first 18 patients have enrolled from 10 countries and 15 sites. Of these, 56% are pediatric patients, 56% are males, 56% of the patients have warts, 94% have nonsense and 6% have frameshift CXCR4 mutations. All patients had severe neutropenia (ANC ≤400 cells/μL) and majority had significant lymphopenia (ALC ≤1000 cells/μL). Conclusions: Evidence supporting efficacy of current therapies in WHIM syndrome is lacking, and approved therapies targeting the underlying molecular mechanisms and hence, able to address the full clinical spectrum of this condition, are needed. The 4WHIM study is the first double-blind, placebo-controlled, randomized trial in patients with this syndrome and is an important next step in the clinical development of a novel, orally bioavailable targeted therapy for WHIM syndrome and potentially for other individuals with related cellular immunodeficiencies. This robust study will build on the findings of the phase 2 trial that suggested a clinical benefit of mavorixafor for WHIM syndrome by incorporating a broader, global population of patients observed for a longer period of time. Full phase 3 trial results are anticipated in late 2022. Disclosures Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Azar: X4 Pharmaceuticals: Research Funding. Badolato: Angelini: Consultancy; X4 Pharmaceuticals: Consultancy; Janssen: Consultancy; SOBI (IDMC): Other. Bhandari: X4 Pharmaceuticals: Current Employment. Belschner: X4 Pharmaceuticals: Current Employment. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Dickerson: Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Hoffman: Zomagen: Research Funding; Novartis: Consultancy, Speakers Bureau; Takeda: Research Funding; Jecure: Research Funding. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kang: Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kulagin: Roche: Speakers Bureau; Sanofi: Speakers Bureau; Generium: Speakers Bureau; Biocad: Research Funding; Apellis: Research Funding; Alexion: Research Funding; X4 Pharmaceuticals: Research Funding; Novartis: Speakers Bureau; Johnson & Johnson: Speakers Bureau; Pfizer: Speakers Bureau. Langguth: RCPA: Membership on an entity's Board of Directors or advisory committees. MacLeod: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Sharathkumar: Amgen: Research Funding; BMS: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharmaceuticals: Research Funding; NIH Trials of Pediatric VTE: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Shcherbina: X4 Pharmaceuticals: Speakers Bureau. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Vossen: X4 Pharmaceuticals: Other: PI in WHIM Trial; Brothers of St. John: Consultancy; Austrian National Bank: Research Funding; Menarini: Honoraria; Gilead: Honoraria; Astro Pharma: Honoraria.

Background: WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is a rare, autosomal-dominant primary immunodeficiency. Gain-of-function (GOF) mutations in the CXCR4 gene are the most common cause of WHIM syndrome, manifesting as panleukopenia with severe neutropenia, lymphopenia, and monocytopenia, recurrent bacterial infections, unusual susceptibility to human papillomavirus infections with intractable mucocutaneous warts, and increased risk of malignancy (McDermott DH, et al. Immunol Rev. 2019;2878:91-102). Mavorixafor is an investigational, small-molecule, selective antagonist of the CXCR4 receptor being developed as an oral, once-daily (QD) treatment for patients with WHIM syndrome (Dale DC, et al. Blood. 2020;136(26):2994-3003). Objective: We present an update on the clinical outcomes of patients with WHIM syndrome who continued in the long-term extension of the phase 2 study, highlighting long-term safety and efficacy. Methods: A long-term extension is ongoing as part of the open-label, prospective, dose-escalation, phase 2 study evaluating the safety and efficacy of mavorixafor (NCT03005327) in adults with WHIM syndrome. Individuals with a pathogenic GOF CXCR4 mutation and absolute neutrophil count ≤400/μL and/or absolute lymphocyte count ≤650/μL were included. All provided written informed consent. The primary objectives were to evaluate safety and tolerability and assess safe dosage. Exploratory efficacy end points included changes in infection rates, number of cutaneous warts, and white blood cell counts, compared to baseline. Researchers completed detailed interviews of 4 participants continuing in the study to assess their overall study experience and perceived treatment effects. Results: Five of 8 patients in the dose-finding phase 2 study entered into the long-term extension (LTE); median treatment duration was 148.4 weeks. One patient left the LTE because of study fatigue, and all 5 patients had dose escalation to 400 mg oral QD as of May 2021. As of the November 2020 data cutoff, annualized infection rates decreased from 5.6/year at study baseline to 2.2/year at 40 months' treatment, providing evidence of persistent reduction of infections over time. At doses of 300 and 400mg QD (n=7), the mean time above threshold for ANC and ALC were 12.7 hours (SD ± 9.8) and 16.9 hours (SD ± 5.9) compared to 2.1 hours (SD ± 3.3) and 11.5 hours (SD ± 5.9) at doses ≤200 mg QD, respectively. One patient experienced a 79% reduction in warts. Safety data review at May 2021 showed that there were 12 minor treatment-emergent adverse events (grade 1) with long-term treatment (46 months), no treatment-related infections of grade 3 or higher, no treatment-related serious adverse events, and no clinically significant laboratory abnormalities with mavorixafor treatment. Patient interviews revealed that all 4 LTE participants experienced good tolerability of mavorixafor and decreased frequency, severity, and duration of infections and decreased hospital/doctor visits. Three of 4 participants reported previous need for prophylactic treatment to prevent infection of minor wounds, but with mavorixafor, minor wounds healed without infection or need for prophylaxis. The mechanism of action of mavorixafor was of interest to 3 of 4 participants, who found it important that treatment address the underlying cause of disease, not simply the symptoms. Two participants reported a QOL improvement, and the other 2 reported that WHIM syndrome never affected their QOL Conclusion: Ongoing long-term treatment of adults with WHIM syndrome with mavorixafor 300 to 400mg shows durable increase in neutrophils and lymphocytes and sustained improvements in infections and warts. Detailed patient interviews for patient global impression of changes are consistent with sustained clinical benefit of long-term treatment. Mavorixafor has the potential to be a safe, effective, and long-term therapy targeting the underlying cause of WHIM syndrome. A global phase 3 registrational study is ongoing. Disclosures Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Firkin: X4 Pharmaceuticals: Research Funding. Bolyard: X4 Pharmaceuticals: Research Funding. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. MacLeod: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hu: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

In linear regression models, covariate-adjusted analysis is not expected to change the estimates of the treatment effect in the clinical trials with randomized treatment assignment but rather to increase the precision of the estimates. However, the covariate-adjusted treatment effect estimates are generally not equivalent to the unadjusted estimates in logistic regression analysis for binary clinical trial data. In this article, we report the results of a simulation study conducted to quantify the magnitude of difference between the estimands underlying the two estimators in logistic regression. The simulation results demonstrated that both unadjusted and adjusted analyses preserved Type I error at the nominal level. The covariate-adjusted analysis produced unbiased, larger treatment effect estimates, larger standard error, and increased power comparedwith the unadjusted analysiswhen the sample sizewas large. The unadjusted analysis resulted in biased estimates of treatment effect. Analysis results for five phase 3 diabetes trials of the same compound were consistent with the simulation findings. Therefore, covariate-adjusted analysis is recommended for evaluating binary outcomes in clinical data.

The purpose of this paper is to improve the safety of chaotic image encryption algorithm. Firstly, to achieve this goal, it put forward two improved chaotic system logistic and henon, which covered an promoted henon chaotic system with better probability density, and an 2-dimension logistic chaotic system with high Lyapunov exponents. Secondly, the chaotic key stream was generated by the new 2D logistic chaotic system and optimized henon mapping, which mixed in dynamic proportions. The conducted sequence has better randomness and higher safety for image cryptosystem. Thirdly, we proposed algorithm takes advantage of the compounded chaotic system Simulation experiment results and security analysis showed that the proposed scheme was more effective and secure. It can resist various typical attacks, has high security, satisfies the requirements of image encryption theoretical.

Aims To evaluate the safety and efficacy of once-weekly dulaglutide 1.5 mg, a long-acting glucagon-like peptide-1 receptor agonist, compared with placebo in patients with type 2 diabetes (T2D) on glimepiride monotherapy. Methods This phase III, randomized (4 : 1; dulaglutide:placebo), double-blind, placebo-controlled, 24-week study compared the safety and efficacy of once-weekly dulaglutide 1.5 mg with placebo in sulphonylurea-treated (≥half-maximal dose, stable ≥3 months) patients (N = 300) with T2D and inadequate glycaemic control [glycated haemoglobin (HbA1c) ≥7.5 and ≤9.5% (≥58 mmol/mol and ≤80 mmol/mol)]. Analysis was carried out according to intention-to-treat. Results At baseline, the mean participant age was 58 years; mean HbA1c was 8.4% (68 mmol/mol) and mean weight was 85.5 kg. Dulaglutide 1.5 mg was superior to placebo at 24 weeks for HbA1c reduction from baseline with a between-group HbA1c difference of −1.3% [95% confidence interval (CI) −1.6, −1.0] or -14 mmol/mol (95% CI −17, −11); p

Weeding is an effective way to increase crop yields. Reliable and accurate weed recognition is a prerequisite for achieving high-precision site-specific weed control in precision agriculture. To improve weed and crop recognition accuracy, a CNN feature based graph convolutional network (GCN) based approach is proposed. A GCN graph was constructed based on extracted weed CNN features and their Euclidean distances. Based on the semi-supervised learning, the GCN graph enriched the model by exploiting labeled and unlabeled image features, and testing samples obtain label information from labeled weed data by performing propagation over the graph. The proposed GCN-ResNet-101 approach achieved 97.80%, 99.37%, 98.93% and 96.51% recognition accuracies on four different weed datasets respectively, which outperformed the state-of-the-art methods (AlexNet, VGG16 and ResNet-101). Additionally, the runtime of the proposed approach also satisfies the real-time requirement of field weed control. The proposed CNN feature based GCN approach is favorable for multi-class crops and weeds recognition with limited labeled data, which is a promising approach in dealing with similar agricultural recognition tasks. Furthermore, the used datasets and source code are publicly available to facilitate the research in the recognition of field weeds.

This study evaluated the proportions of prandial (PHG) vs fasting hyperglycaemia (FHG) over 24h in a group of patients with type 2 diabetes (overall and for Caucasian vs Asian patients), and tested the hypothesis that an insulin regimen with a prandial component allows a greater response than basal insulin at low glycated haemoglobin (HbA1c) levels with a higher proportion of PHG than FHG.Relative contributions of PHG and FHG to overall hyperglycaemia were analyzed by baseline HbA1c quartiles and by ethnicity at baseline and after 24-week treatment with either insulin glargine or insulin lispro mix 25 in the DURABLE study.With increasing baseline HbA1c, the mean relative contribution of PHG to the total area under the curve decreased (from 41% to 27%) while FHG was increased (from 59% to 73%). Both insulins decreased FHG, but only insulin lispro mix 25 decreased PHG. More patients with baseline HbA1c9%, where PHG was more relevant, achieved the target HbA1c of7% at endpoint with insulin lispro mix 25 compared with glargine. On average, Asians had a 10% larger contribution of PHG at all HbA1c quartiles, and a lower proportion of Asians reached the HbA1c target of7% with either insulin treatment compared with Caucasians.At baseline, the contribution of FHG to overall hyperglycaemia predominated at all HbA1c quartiles, whereas PHG was more clinically relevant at lower HbA1c levels and with a greater response to insulin lispro mix 25. Asians had a greater proportion of PHG and a lesser response to either insulins compared with Caucasians. Thus, responses to diabetes drugs by baseline HbA1c and ethnicity are worth investigating to better target and individualize treatment.

For patients with type 2 diabetes who do not achieve target glycaemic control with conventional insulin treatment, advancing to a basal-bolus insulin regimen is often recommended. We aimed to compare the efficacy and safety of long-acting glucagon-like peptide-1 receptor agonist dulaglutide with that of insulin glargine, both combined with prandial insulin lispro, in patients with type 2 diabetes.We did this 52 week, randomised, open-label, phase 3, non-inferiority trial at 105 study sites in 15 countries. Patients (aged ≥18 years) with type 2 diabetes inadequately controlled with conventional insulin treatment were randomly assigned (1:1:1), via a computer-generated randomisation sequence with an interactive voice-response system, to receive once-weekly dulaglutide 1·5 mg, dulaglutide 0·75 mg, or daily bedtime glargine. Randomisation was stratified by country and metformin use. Participants and study investigators were not masked to treatment allocation, but were unaware of dulaglutide dose assignment. The primary outcome was a change in glycated haemoglobin A1c (HbA1c) from baseline to week 26, with a 0·4% non-inferiority margin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01191268.Between Dec 9, 2010, and Sept 21, 2012, we randomly assigned 884 patients to receive dulaglutide 1·5 mg (n=295), dulaglutide 0·75 mg (n=293), or glargine (n=296). At 26 weeks, the adjusted mean change in HbA1c was greater in patients receiving dulaglutide 1·5 mg (-1·64% [95% CI -1·78 to -1·50], -17·93 mmol/mol [-19·44 to -16·42]) and dulaglutide 0·75 mg (-1·59% [-1·73 to -1·45], -17·38 mmol/mol [-18·89 to -15·87]) than in those receiving glargine (-1·41% [-1·55 to -1·27], -15·41 mmol/mol [-16·92 to -13·90]). The adjusted mean difference versus glargine was -0·22% (95% CI -0·38 to -0·07, -2·40 mmol/mol [-4·15 to -0·77]; p=0·005) for dulaglutide 1·5 mg and -0·17% (-0·33 to -0·02, -1·86 mmol/mol [-3·61 to -0·22]; p=0·015) for dulaglutide 0·75 mg. Five (1%) patients died after randomisation because of septicaemia (n=1 in the dulaglutide 1·5 mg group); pneumonia (n=1 in the dulaglutide 0·75 mg group); cardiogenic shock; ventricular fibrillation; and an unknown cause (n=3 in the glargine group). We recorded serious adverse events in 27 (9%) patients in the dulaglutide 1·5 mg group, 44 (15%) patients in the dulaglutide 0·75 mg group, and 54 (18%) patients in the glargine group. The most frequent adverse events, arising more often with dulaglutide than glargine, were nausea, diarrhoea, and vomiting.Dulaglutide in combination with lispro resulted in a significantly greater improvement in glycaemic control than did glargine and represents a new treatment option for patients unable to achieve glycaemic targets with conventional insulin treatment.Eli Lilly and Company.

Summary Background Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors improve glycaemic control and reduce bodyweight in patients with type 2 diabetes through different mechanisms. We assessed the safety and efficacy of the addition of the once-weekly GLP-1 receptor agonist dulaglutide to the ongoing treatment regimen in patients whose diabetes is inadequately controlled with SGLT2 inhibitors, with or without metformin. Methods AWARD-10 was a phase 3b, double-blind, parallel-arm, placebo-controlled, 24-week study done at 40 clinical sites in Austria, Czech Republic, Germany, Hungary, Israel, Mexico, Spain, and the USA. Eligible adult patients (≥18 years) with inadequately controlled type 2 diabetes (HbA 1c concentration ≥7·0% [53 mmol/mol] and ≤9·5% [80 mmol/mol]), a BMI of 45 kg/m 2 or less, and taking stable doses (>3 months) of an SGLT2 inhibitor (with or without metformin) were randomly assigned (1:1:1) via an interactive web-response system to subcutaneous injections of either dulaglutide 1·5 mg, dulaglutide 0·75 mg, or placebo once per week for 24 weeks. Patients and investigators were masked to dulaglutide and placebo assignment, and those assessing outcomes were masked to study drug assignment. The primary objective was to test for the superiority of dulaglutide (1·5 mg or 0·75 mg) versus placebo for change in HbA 1c concentration from baseline at 24 weeks. All analyses were done in the intention-to-treat population, defined as all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02597049. Findings Between Dec 7, 2015, and Feb 3, 2017, 424 patients were randomly assigned to dulaglutide 1·5 mg (n=142), dulaglutide 0·75 mg (n=142), and placebo (n=140). One patient in the dulaglutide 0·75 mg group was excluded from the analysis because they did not receive any dose of the study drug. The reduction in HbA 1c concentration at 24 weeks was larger in patients receiving dulaglutide (least squares mean [LSM] for dulaglutide 1·5 mg −1·34% [SE 0·06] or −14·7 mmol/mol [0·6]; dulaglutide 0·75 mg −1·21% [0·06] or −13·2 mmol/mol [0·6]) than in patients receiving placebo (−0·54% [0·06] or −5·9 mmol/mol [0·6]; p vs placebo). The LSM differences were −0·79% (95% CI −0·97 to −0·61) or −8·6 mmol/mol (−10·6 to −6·7) for dulaglutide 1·5 mg and −0·66% (−0·84 to −0·49) or −7·2 mmol/mol (−9·2 to −5·4) for dulaglutide 0·75 mg (p vs seven [5%] in the dulaglutide 0·75 mg group vs five [4%] in the placebo group), diarrhoea (eight [6%] vs 14 [10%] vs four [3%]), and vomiting (five [4%] vs four [3%] vs one [1%]) were more common with dulaglutide than with placebo. One episode of severe hypoglycaemia was reported in the dulaglutide 0·75 mg group. Two (1%) patients receiving dulaglutide 1·5 mg died, but these deaths were not considered to be related to study drug; no deaths occurred in the other groups. Interpretation Dulaglutide as add-on treatment to SGLT2 inhibitors (with or without metformin) resulted in significant and clinically relevant improvements in glycaemic control, with acceptable tolerability that is consistent with the established safety profile of dulaglutide. Funding Eli Lilly and Company.

Background Sucrose combined with non-nutritive sucking provided better pain relief than sucrose or non-nutritive sucking alone in a single painful procedure. However, whether the combination of non-nutritive sucking with sucrose could obtain a significant difference in analgesic effect of the repeated procedural pain than any single intervention has not been established. Objective To compare the effect of non-nutritive sucking and sucrose alone and in combination of repeated procedural pain in preterm infants. Design Randomized controlled trial. Setting A level III neonatal intensive care unit of a university hospital in China. Method Preterm infants born before 37 weeks of gestation were randomly assigned to four groups: routine care group (routine comfort through gentle touch when infants cried; n = 21), non-nutritive sucking group (n = 22), sucrose group (0.2 ml/kg of 20%; n = 21), sucrose (0.2 ml/kg of 20%) plus non-nutritive sucking group (n = 22). Each preterm infant received three nonconsecutive routine heel sticks. Each heel stick included three phases: baseline (the last 1 min of the 30 min without stimuli), blood collection, recovery (1 min after blood collection). Three phases of 3 heel stick procedures were videotaped. Premature infant pain profile (PIPP) score, heart rate, oxygen saturation and percentage of crying time were assessed by five independent evaluators who were blinded to the purpose of the study at different phases across three heel sticks. Data were analyzed by analysis of variance, with repeated measures at different evaluation phases of heel stick. Results 86 preterm infants completed the protocol. During the blood collection and recovery phases, combination group, had lower PIPP score (4.4 ± 1.5; 3.0 ± 0.8), lower heart rate (138.6 ± 7.9; 137.4 ± 4.7), higher oxygen saturation (95.2 ± 1.6; 96.0 ± 1.2), and smaller percentage of crying time (11.5 ± 8.6; 4.6 ± 3.4), compared with the group has given non-nutritive sucking (9.3 ± 1.3, 6.8 ± 1.4; 154.2 ± 9.0, 148.0 ± 9.3; 92.9 ± 2.4, 94.1 ± 1.0; 44.2 ± 9.6, 31.2 ± 10.5; respectively) or sucrose (10.1 ± 2.0, 7.4 ± 1.6; 151.6 ± 9.6, 147.9 ± 6.9; 93.5 ± 1.7, 94.5 ± 1.2; 53.8 ± 16.7, 35.2 ± 13.9; respectively) or routine care (13.3 ± 1.6, 10.6 ± 1.9; 156.8 ± 7.2, 151.7 ± 7.9; 92.9 ± 2.1, 93.8 ± 1.6; 80.6 ± 7.6, 68.2 ± 9.9; respectively). Both non-nutritive sucking and sucrose were more effective in reducing preterm infants' PIPP score and percentage of crying time than routine care. There was no difference in PIPP score, heart rate, oxygen saturation and percentage of crying time between the non-nutritive sucking and sucrose groups. Conclusion The combination of non-nutritive sucking with sucrose provided better pain relief during repeated painful procedures than when non-nutritive sucking or sucrose was used alone. The effect of non-nutritive sucking was similar to that of sucrose on repeated procedural pain.

Aim: To compare the addition of weekly dulaglutide vs the addition of placebo to titrated glargine in patients with type 2 diabetes (T2D) with sub‐optimum glycated haemoglobin (HbA1c) concentration. Materials and Methods: Patients (N = 300) from this phase III, double‐blind, parallel‐arm, placebo‐controlled study were randomized to weekly subcutaneous injections of dulaglutide 1.5 mg or placebo with titrated daily glargine (mean ± standard deviation baseline dose: 39 ± 22 U), with or without metformin (≥1500 mg/d). The primary endpoint was superiority of dulaglutide/glargine to placebo/glargine with regard to change from baseline in HbA1c level at 28 weeks. Results: Least squares (LS) mean ± standard error (s.e.) HbA1c changes from baseline were −1.44 ± 0.09% (−15.74 ± 0.98 mmol/mol) with dulaglutide/glargine and −0.67 ± 0.09% (−7.32 ± 0.98 mmol/mol) with placebo/glargine at 28 weeks (LS mean difference [95% confidence interval] −0.77% [−0.97, −0.56]; P

The aim of the present study was to investigate whether the measurement of cytokines from abdominal exudate is valuable for the early diagnosis of prolonged postoperative ileus (PPOI) following colorectal surgery. In the present study, 100 consecutive patients who were scheduled to undergo elective resection for carcinoma of the sigmoid or rectum were investigated. Abdominal exudate was obtained via a drain tube following surgery for the detection of interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α. The correlation among the cytokine levels on postoperative days 1, 3 and 5 and the development of PPOI was investigated. Eight patients developed PPOI which was diagnosed 10-15 days postoperatively. No significant differences were observed among the peritoneal cytokine levels on postoperative days 1 and 3 in the 8 patients who developed PPOI when compared with those of the 92 patients that did not develop PPOI. By contrast, cytokine levels on postoperative day 5 were significantly higher in patients who developed PPOI when compared with those of patients that did not develop PPOI. The cytokine levels significantly increased during the first 5 days postoperatively in patients who developed PPOI and significantly decreased in patients who did not develop PPOI. The results of the present study showed that the increase in peritoneal IL-1β, IL-6 and TNF-α levels may be an additional early diagnostic predictor of PPOI following colorectal surgery.

Aim To conduct a substudy, using 24-hour continuous glucose monitoring (CGM), of the AWARD-4 trial, which was designed to compare insulin + glucagon-like peptide-1 receptor agonist treatment with an insulin-only regimen. Methods The AWARD-4 trial randomized 884 conventional insulin regimen-treated patients to dulaglutide 1.5 mg, dulaglutide 0.75 mg and glargine, all in combination with prandial insulin lispro. The CGM substudy included 144 patients inserted with a Medtronic CGMS iPro CGM device to enable 3-day glucose monitoring. CGM sessions were completed at weeks 0, 13, 26 and 52. CGM measures included mean 24-hour glucose, percentage time in target glucose ranges, hyper- and hypoglycaemia and glucose variability. The primary objective was treatment comparison for percentage time spent with CGM glucose values in the 3.9-7.8 mmol/L range after 26 weeks. Results At week 26, mean CGM values decreased in all treatment groups (change from baseline −2.8 ± 0.3, −2.4 ± 0.3 and −2.5 ± 0.3 mmol/L for dulaglutide 1.5 mg, dulaglutide 0.75 mg and glargine, respectively); between-group differences were not statistically significant. Treatment groups were similar for percentage time in the 3.9-7.8 mmol/L range. Percentage time in the 3.9-10.0 mmol/L range was greater for dulaglutide 1.5 mg than for glargine (p

La información sobre el inicio de regímenes de insulina en poblaciones específicas con diabetes tipo 2 (DT2) es limitada. Se comparó eficacia y seguridad de dos regímenes de inicio: insulina lispro mix 25 (LM25) e insulina glargina basal (GL). Se evaluaron 193 pacientes no tratados previamente con insulina, en la fase de iniciación de 24 semanas del ensayo DURABLE; edades: 30-79 años, DT2 controlada inadecuadamente (HbA1c > 7.0%) con = 2 medicaciones orales antidiabéticas (MOAs), aleatorizados para LM25 (25% de insulina lispro, 75% de insulina lispro protamina en suspensión) dos veces/día, o GL (insulina glargina basal) una vez/ día, a las MOAs previas. La eficacia primaria se midió por HbA1c a las 24 semanas. Se midió eficacia secundaria por: proporción de pacientes que alcanzaron HbA1c= 6.5% y= 7.0%, cambio en peso corporal, valores de automonitoreo glucémico e índices de hipoglucemia. LM25 demostró mayor reducción de la HbA1c (- 2.4% ± 0.16 vs. -2.0% ± 0.16, P = 0.002), mayor proporción de pacientes alcanzaron HbA1c= 7.0% (P = 0.012) y niveles de glucemia menores después del desayuno (P = 0.028) y de la cena (P = 0.011), y a las 3 a.m. (P = 0.005) comparada con GL. La glucemia en ayunas (GA) y la proporción de pacientes que alcanzaron una HbA1c= 6.5% fueron similares. En ambos grupos hubo aumento del peso corporal, mayor en la valoración final con LM25 (6.35 kg vs. 4.23 kg, P < 0.001). No hubieron diferencias en índices de hipoglucemia entre grupos, ni eventos adversos serios en ninguno. Con LM25 fue mejor el control de glucosa, riesgo de hipoglucemia similar y mayor aumento de peso que GL.Information on starting insulin regimens in specific populations with type 2 diabetes (T2D) is limited. This analysis compared efficacy and safety of two starter insulin regimens: insulin lispro mix 25 (LM25) and basal insulin glargine (GL) in patients from Argentina. This post-hoc analysis evaluated 193 insulin-naïve patients who participated in the DURABLE trial 24-week initiation phase. Patients 30-79 years with T2D inadequately controlled (HbA1c > 7.0%) with = 2 oral antihyperglycemic medications (OAMs), were randomized to add LM25 (25% insulin lispro, 75% insulin lispro protamine suspension) twice daily or GL (basal insulin glargine) once daily to pre-study OAMs. Primary efficacy was measured by HbA1c at 24-week endpoint. Secondary measures included: proportion of patients achieving HbA1c= 6.5% and= 7.0%, body weight change, self-monitored blood glucose (BG) values, and hypoglycemia rates. LM25 demonstrated greater HbA1c reduction (- 2.4% ± 0.16 vs. -2.0% ± 0.16, P = 0.002), a higher proportion of patients achieving HbA1c= 7.0% (P = 0.012), and lower BG levels after the morning (P = 0.028) and evening (P = 0.011) meals, and at 3:00AM (P = 0.005) compared with GL. Fasting BG and proportion of patients achieving HbA1c= 6.5% were similar between groups. Both groups increased body weight, although the gain was higher at endpoint with LM25 (6.35 kg vs. 4.23 kg, P < 0.001). No differences in hypoglycemia rates were observed between groups, and no serious adverse events were reported for either group. In this subgroup from Argentina, LM25 demonstrated greater improvement in glucose control with similar risk of hypoglycemia and more weight gain than GL.

� Objective: To explore the impact of race/ethnicity on the efficacy and safety of commonly used insulin regimens in patients with type 2 diabetes mellitus. � Methods: In this post hoc analysis, pooled data from 11 multinational clinical trials involving 1455 patients with type 2 diabetes were used to compare specific insulin treatments in Latino/Hispanic, Asian, African-descent, and Caucasian patients. Insulin treatments included once daily insulin glargine or neutral protamine Hagedorn (BASAL), insulin lispro mix 75/25 twice daily (LMBID), or insulin lispro mix 50/50 three times daily (LMTID). � Results: Race/ethnicity was associated with signifi cant outcome differences for each of the insulin regimens. BASAL therapy was associated with greater improvement in several measures of glycemic control among Latino/ Hispanic patients compared with Caucasian patients (lower end point hemoglobin A 1c , greater reduction in hemoglobin A 1c from baseline, and a larger proportion of patients achieving hemoglobin A 1c level

Content: Recent studies have reported hemoglobin A(1c) (A1c) differences across racial/ethnic groups. Our diverse population allows for further investigation of potential differences in measurements of glycemia.Objectives: Our objectives were to describe and explore baseline racial/ethnic differences in self-monitored plasma glucose profiles, A1c, and 1,5-anhydroglucitol (1,5-AG) in patients with type 2 diabetes enrolled in the Assessing DURAbility of Basal vs. Lispro Mix 75/25 Insulin Efficacy trial.Design, Setting, Patients: The trial enrolled 2094 patients with type 2 diabetes, ages 30-80 yr, from 11 countries.Main Outcome Measures: Estimated mean plasma glucose (MPG), A1c, and 1,5-AG were compared among racial/ethnic groups before and after adjusting for factors affecting glycemia: age, sex, duration of diabetes, body mass index, and MPG.Results: Baseline estimated MPG +/- SD was 220.0 +/- 82.0 mg/dl, mean A1c was 9.0 +/- 1.3%, and 1,5-AG was 5.0 +/- 4.1 mu g/ml. Estimated MPG did not differ between Caucasian and non-Caucasian groups. A1c was higher in Hispanics (9.4 +/- 1.4%; P Conclusions: There were differences in A1c and 1,5-AG, but not MPG, among racial/ethnic groups. Comparisons of glycemia across racial/ethnic groups using these parameters may be problematic due to inherent biological variability and methodological issues. (J Clin Endocrinol Metab 94:1689-1694, 2009)

Time-to-event outcomes are common for oncology clinical trials. Conventional methods of analysis for these endpoints include logrank or Wilcoxon tests for treatment group comparisons, Kaplan-Meier survival estimates, and Cox proportional hazards models to estimate the treatment group hazard ratio (both unadjusted and adjusted for relevant covariates). Adjusting for covariates reduces bias and may increase precision and power (Statist. Med. 2002; 21:2899-2908). However, the appropriateness of the Cox proportional hazards model depends on parametric assumptions. One way to address these issues is to use non-parametric analysis of covariance (J. Biopharm. Statist. 1999; 9:307-338). Here, we carry out simulations to investigate the type I error and power of the unadjusted and covariate-adjusted non-parametric logrank test and Wilcoxon test, and the Cox proportion hazards model. A comparison between the covariate-adjusted and unadjusted methods is also illustrated with an oncology clinical trial example.

OBJECTIVE—The purpose of this study was to compare two analog insulin therapies (prandial premixed therapy [PPT] versus basal/bolus therapy [BBT]) in type 2 diabetic patients previously treated with insulin glargine (≥30 units/day) plus oral agents, with the aim of demonstrating noninferiority of PPT to BBT. RESEARCH DESIGN AND METHODS—Patients were randomly assigned to PPT (lispro mix 50/50: 50% insulin lispro protamine suspension and 50% lispro; n = 187) t.i.d. with meals or BBT (glargine at bedtime plus mealtime lispro; n = 187) in a 24-week, multicenter, open-label, noninferiority trial. Investigators could replace lispro mix 50/50 with lispro mix 75/25 at the evening meal if the fasting plasma glucose target was unachievable. RESULTS—Baseline A1C was similar (PPT 8.8%; BBT 8.9%; P = 0.598). At week 24, A1C was lower with BBT (6.78 vs. 6.95%, P = 0.021). A1C was reduced significantly from baseline for both therapies (P < 0.0001). The difference in A1C change from baseline to the end point (BBT minus PPT) was −0.22% (90% CI −0.38 to −0.07). Noninferiority of PPT to BBT was not demonstrated based on the prespecified noninferiority margin of 0.3%. The percentages of patients achieving target A1C CONCLUSIONS—Although noninferiority of PPT to BBT was not demonstrated, findings for A1C reduction, percentage of patients achieving A1C targets, hypoglycemia, and number of required injections should be considered in the individual decision-making process of advancing insulin replacement to PPT versus BBT in type 2 diabetes.

Current methods for estimation of age- and year-specific instantaneous mortality rates based on multiyear, multiple-age tagging studies assume that it is feasible to tag fish in a wide range of ages. For some species, however, only the youngest one or two age-classes are readily available for tagging. Given the practical advantages of tagging young fish only, an important question is whether such studies would provide the information needed for estimation of age-dependent mortality rates. We investigated three designs: tagging only the youngest available age-class, tagging the two youngest age-classes, and tagging the first five age-classes. We carried out simulation studies to assess estimator performance under these three designs, in each case assuming the same total number of tagged fish. Data were generated assuming fishing mortality rates to be age and year dependent and natural mortality rates to be constant or with limited age dependence. Estimator performance is best when fish are tagged ...

Tag return studies play an important role in providing estimates of mortality rates needed for management of many fisheries, but current methods of estimation do not allow age dependence of instantaneous mortality rates. We present models that allow age-dependent fishing and natural mortality rates, an important advance, because there is often substantial variation in age (and size) of fish at tagging. Age dependence of fishing mortality is modeled by assuming that availability to the fishery, that is, selectivity, depends on age but is constant over years. We assume that all age classes are tagged each year, and allow for incomplete mixing of newly tagged fish and for fisheries that are year-long or limited to a fishing season. We investigate parameter redundancy and estimator performance using analytic and simulation methods, and show that estimator properties are poor if the tag reporting rate is estimated (without auxiliary data such as planted tags). We analyzed multiple age class tag return data from a 13-year study on striped bass (Morone saxatilis) and saw clear evidence that selectivity increases with age. Assuming that the tag reporting rate is constant and known, results also demonstrate age dependence of natural mortality rates, and an increase in natural mortality rates from about 1999 coinciding with observation of a bacterial disease in the fish.

Catch-and-release fisheries have become very important in the management of overexploited recreational fish stocks. Tag return studies, where the tag is removed regardless of fish disposition, have been used to assess the effectiveness of restoration efforts for these fisheries. We extend the instantaneous rate formulation of tag return models to allow for catch and release as well as harvest. The key point of our methods is that, given an estimate of the tag reporting rate, the fishing mortality rate (F) is separated into two components: the mortality on harvested fish and the “mortality” on tags (because the tags are removed) of fish released alive. The total fishing mortality rate for untagged fish is the sum of the Fs due to harvest and hooking mortality suffered by fish released alive. Natural mortality rates can also be estimated. Both age-independent models and age-dependent models are constructed, and the age-dependent models are illustrated by application to data from a study of striped ...

© 2015, © American Statistical Association. Little research has been done to evaluate the effect of adjusting for baseline in the analysis of repeated incomplete binary data through simulation study. In this article, covariate adjusted and unadjusted implementations of the following methods were compared in analyzing incomplete repeated binary data when the outcome at the study endpoint is of interest: logistic regression with the last observation carried forward (LOCF), generalized estimating equations (GEE), weighted GEE (WGEE), generalized linear mixed model (GLMM), and multiple imputation (MI) with analyses via GEE. Incomplete data mimicking several clinical trial scenarios were generated using missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR) mechanisms. Across the various analytic methods and scenarios covariate adjusted analyses generally yielded larger, less biased treatment effect estimates and larger standard errors compared with their unadjusted counterpart. The net result of these factors was increased power from the covariate adjusted analyses without increasing Type I error rates. Although all methods were biased in at least some of the MNAR scenarios, the Type I error rates from LOCF exceeded 20% whereas the highest rate from any other method in any scenario was less than 10%. LOCF also yielded biased results in MCAR and MAR data whereas the other methods were not biased or had smaller biases than LOCF. These results support longitudinal modeling of repeated binary data over LOCF logistic regression of the study endpoint only. These results also support covariate adjustment for baseline severity in these longitudinal models. peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=usbr20 ispartof: Statistics in Biopharmaceutical Research vol:7 issue:3 pages:238-250 status: published

The traditional multiple-year tag return method is a fundamental approach to estimating fishing and natural mortality rates in fisheries. It can provide reliable and precise estimation of the parameters when the tag reporting rate, λ, is known. However, it is often difficult to estimate λ accurately. An additional disadvantage is that this method has to estimate natural mortality indirectly because natural deaths are not observable. Recently, fisheries biologists have begun to implement telemetry methods to estimate fishing and natural mortality. The advantage of a telemetry method is that it contains direct information about natural mortality and survival. A shortcoming is that there is no direct information on fishing deaths. In this paper, we combine the two methods, using direct information about both fishing and natural mortality to obtain more precise and effectively unbiased parameter estimates, including reporting rate estimates for the regular tags. Using simulation when the telemetry ta...

In randomized clinical trials with time-to-event outcomes, the hazard ratio is commonly used to quantify the treatment effect relative to a control. The Cox regression model is commonly used to adjust for relevant covariates to obtain more accurate estimates of the hazard ratio between treatment groups. However, it is well known that the treatment hazard ratio based on a covariate-adjusted Cox regression model is conditional on the specific covariates and differs from the unconditional hazard ratio that is an average across the population. Therefore, covariate-adjusted Cox models cannot be used when the unconditional inference is desired. In addition, the covariate-adjusted Cox model requires the relatively strong assumption of proportional hazards for each covariate. To overcome these challenges, a nonparametric randomization-based analysis of covariance method was proposed to estimate the covariate-adjusted hazard ratios for multivariate time-to-event outcomes. However, empirical evaluations of the performance (power and type I error rate) of the method have not been studied. Although the method is derived for multivariate situations, for most registration trials, the primary endpoint is a univariate outcome. Therefore, this approach is applied to univariate outcomes, and performance is evaluated through a simulation study in this paper. Stratified analysis is also investigated. As an illustration of the method, we also apply the covariate-adjusted and unadjusted analyses to an oncology trial.

Hypoglycemia has long been recognized as a major barrier to achieving normoglycemia with intensive diabetic therapies. It is a common safety concern for the diabetes patients. Therefore, it is important to apply appropriate statistical methods when analyzing hypoglycemia data. Here, we carried out bootstrap simulations to investigate the performance of the four commonly used statistical models (Poisson, negative binomial, analysis of covariance [ANCOVA], and rank ANCOVA) based on the data from a diabetes clinical trial. Zero-inflated Poisson (ZIP) model and zero-inflated negative binomial (ZINB) model were also evaluated. Simulation results showed that Poisson model inflated type I error, while negative binomial model was overly conservative. However, after adjusting for dispersion, both Poisson and negative binomial models yielded slightly inflated type I errors, which were close to the nominal level and reasonable power. Reasonable control of type I error was associated with ANCOVA model. Rank ANCOVA model was associated with the greatest power and with reasonable control of type I error. Inflated type I error was observed with ZIP and ZINB models.

Background Prolonged postoperative ileus (PPOI) is a common problem after major abdominal surgery and can cause postoperative morbidity, extended hospitalization, as well as increased health care costs. Aim To investigate whether the levels of cytokines from abdominal exudate are predictive for early diagnosis of PPOI after colorectal surgery. Methods One hundred patients who had undergone elective resection for carcinoma of the sigmoid or rectum were recruited. The abdominal exudate was obtained from a drain tube after surgery to examine the levels of C-reactive protein (CRP), procalcitonin (PCT), and tumor necrosis factor alpha (TNF-α). The relationship between cytokine levels on postoperative day 1, 3 and 5 and the occurrence of PPOI was analyzed. Results Eight patients developed PPOI, which was diagnosed on postoperative day 10-15. PCT levels on postoperative day 1 and 3 were not significantly different between the 8 patients who developed PPOI and the 92 patients without PPOI. In contrast, PCT levels on day 5 were significantly higher in patients who developed PPOI than in patients without PPOI. The levels of CRP and TNF-α were irregular from day 1 to 5, and were not significantly different. Conclusions Increased PCT levels in abdominal exudate may predict PPOI in the early period following colorectal surgery.