Rationale and design of the ICON-RELOADED study: International Collaborative of N-terminal pro-B-type Natriuretic Peptide Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department.

OBJECTIVES: The objectives were to reassess use of amino-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations for diagnosis and prognosis of acute heart failure (HF) in patients with acute dyspnea. BACKGROUND: NT-proBNP facilitates diagnosis, prognosis, and treatment in patients with suspected or proven acute HF. As demographics of such patients are changing, previous diagnostic NT-proBNP thresholds may need updating. Additionally, value of in-hospital NT-proBNP prognostic monitoring for HF is less understood. METHODS: In a prospective, multicenter study in the United States and Canada, patients presenting to emergency departments with acute dyspnea were enrolled, with demographic, medication, imaging, and clinical course information collected. NT-proBNP analysis will be performed using the Roche Diagnostics Elecsys proBNPII immunoassay in blood samples obtained at baseline and at discharge (if hospitalized). Primary end points include positive predictive value of previously established age-stratified NT-proBNP thresholds for the adjudicated diagnosis of acute HF and its negative predictive value to exclude acute HF. Secondary end points include sensitivity, specificity, and positive and negative likelihood ratios for acute HF and, among those with HF, the prognostic value of baseline and predischarge NT-proBNP for adjudicated clinical end points (including all-cause death and hospitalization) at 30 and 180days. RESULTS: A total of 1,461 dyspneic subjects have been enrolled and are eligible for analysis. Follow-up for clinical outcome is ongoing. CONCLUSIONS: The International Collaborative of N-terminal pro-B-type Natriuretic Peptide Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department study offers a contemporary opportunity to understand best diagnostic cutoff points for NT-proBNP in acute HF and validate in-hospital monitoring of HF using NT-proBNP.

Gamunex® in Guillain-Barré Syndrome: A Postmarketing, Retrospective, Observational Study.

BACKGROUND: The objective of this retrospective study was to evaluate the effectiveness and safety of Gamunex® (immune globulin [human] 10%; hereinafter "Gamunex") when administered intravenously in the initial treatment of Guillain-Barré syndrome (GBS). The study was conducted as a postapproval commitment for Health Canada. METHODS: A medical chart review for hospitalized patients diagnosed with GBS and treated with Gamunex (Gamunex 10% and IGIVnex® 10%; N=109; n=69 evaluable) was conducted at seven Canadian study centers in reverse chronological order. The primary endpoint for assessing effectiveness was the proportion of patients with treatment success compared with a prospectively defined historical effectiveness threshold for plasma exchange (PE) treatment (55.05%). Treatment success was assessed as ≥1 point improvement from baseline on the GBS Disability Scale or abbreviated GBS Disability Scale. Cases were not evaluable if treatment success, relapse, or treatment failure could not be determined by the available chart data. RESULTS: Applying a conservative estimate with all nonevaluable patients (n= 40) classified as treatment failures, Gamunex treatment success was estimated at 57.8% (63 of 109 patients), which exceeded the predefined historical PE effectiveness threshold. In the evaluable population of this study, Gamunex treatment was successful in 91.3% of patients (63/69). Some 23 (21.1%) of 109 Gamunex-treated patients experienced ≥1 adverse event; the profile and frequency were consistent with the adverse events reported for Gamunex in the product's labeling and with the natural clinical course of GBS. CONCLUSIONS: The effectiveness of Gamunex for treatment of GBS was comparable to PE therapy. Gamunex was observed to have an acceptable safety profile in this study population.

A Phase 3, Randomized, Active-controlled, Single-blind Clinical Trial to Evaluate the Efficacy of Fibrin Sealant Grifols in Achieving Hemostasis in Pediatric Surgery.

BACKGROUND: In this study, two fibrin sealant products, Fibrin Sealant Grifols (FS Grifols 80 mg/mL fibrinogen; 500 IU/mL thrombin) and Evicel (fibrinogen 55-85 mg/mL; thrombin 800-1200 IU/mL) were studied for efficacy in achieving hemostasis at a targeted bleeding site (TBS) on parenchymous or soft tissue in pediatric surgeries. METHODS: This phase 3, single-blind, active comparator, non-inferiority trial compared the number of patients achieving hemostasis at a TBS at four (T4 - primary endpoint), seven (T7) and 10 (T10) minutes after application, Safety and tolerability were assessed by recording adverse events during and after procedures. Eligible patients were <18 years old undergoing elective, open, non-cardiac thoracic, abdominal or pelvic surgeries. Preterm (<37 weeks gestation) and newborn (0-27 days) infants were eligible. RESULTS: At T4, 98.7% of FS Grifols group (n = 91) and 95.4% of the Evicel group (n = 87) achieved hemostasis. All patients with residual bleeding at T4 were undergoing soft tissue surgery. All patients achieved hemostasis by T7. At T10, all patients achieved hemostasis except one (FS Grifols (no observation recorded)). There were no incidents of persistent bleeding. For FS Grifols, 26.5% of patients had treatment-emergent adverse events (TEAEs) and 18.4% for Evicel. One TEAE (moderate procedural pain - FS Grifols group) was considered possibly related to study treatment. Three patients died for reasons unrelated to the study medications. CONCLUSIONS: FS Grifols was safe and effective at achieving hemostasis in pediatric patients having parenchymous or soft tissue surgeries. The efficacy of FS Grifols was non-inferior to Evicel. LEVEL OF EVIDENCE: I.

Electrophysiologic correlations with clinical outcomes in CIDP.

Data are lacking on correlations between changes in nerve conduction (NC) studies and treatment response in chronic inflammatory demyelinating polyneuropathy (CIDP). This report examined data from a randomized, double-blind trial of immune globulin intravenous, 10% caprylate/chromatography purified (IGIV-C [Gamunex]; n = 59) versus placebo (n = 58) every 3 weeks for up to 24 weeks in CIDP. Motor NC results and clinical measures were assessed at baseline and endpoint/week 24. Improvement from baseline in adjusted inflammatory neuropathy cause and treatment score correlated with improvement in proximally evoked compound muscle action potential (CMAP) amplitudes (r = -0.53; P < 0.001) of all nerves tested and with improvement in CMAP amplitude of the most severely affected motor nerve (r = -0.36; P < 0.001). Correlations were observed between improvement in averaged CMAP amplitudes and dominant-hand grip strength (r = 0.44; P < 0.001) and Medical Research Council sum score (r = 0.38; P < 0.001). Overall, the change in electrophysiologic measures of NC in CIDP correlated with clinical response to treatment.

Understanding the consequences of chronic inflammatory demyelinating polyradiculoneuropathy from impairments to activity and participation restrictions and reduced quality of life: the ICE study.

A randomized trial (ICE trial) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) demonstrated significantly more improvement with intravenous immunoglobulin (Gamunex(®), Talecris Biotherapeutics, Inc., Research Triangle Park, NC) than placebo. To understand the relationship between CIDP impairments, activity and participation restrictions, and quality of life (QoL) in this trial, we investigated the association between scales representing these outcome levels. Gamunex or placebo was given every 3 weeks for up to 24 weeks to 117 patients in an initial treatment period after which treatment failures were crossed over (alternative treatment). We assessed impairments, activity and participation, and SF-36 component mental (MCS) and physical summaries (PCS). Regression analyses of baseline data were performed (all subjects) and change from baseline to endpoint (Gamunex-treated group only) to determine correlations between outcomes. Grip strength, medical research council (MRC) sum score, and inflammatory neuropathy cause and treatment (INCAT) sensory sum score were the strongest explanatory variables of disability (at baseline: r(2) = 0.46; change from baseline: r(2) = 0.66). Only up to half of the variance in QoL scores (PCS at baseline: r(2) = 0.30; change from baseline: r(2) = 0.41; MCS: at baseline: r(2) = 0.10; change from baseline: r(2) = 0.24) was explained by impairment and activity and participation measures. Future studies are required to elucidate the impact of CIDP on disability and QoL changes, because the obtained correlations provide only partial explanation.

Phase 2, randomized, open-label study on catheter-directed thrombolysis with plasmin versus rtPA and placebo in acute peripheral arterial occlusion.

Background: Patients with acute peripheral arterial occlusion (aPAO) are candidates for operative thrombectomy, bypass, or catheter-directed thrombolysis (CDT) using a plasminogen activator. Human plasma-derived plasmin may offer another CDT option. Objectives: To evaluate the efficacy, safety, and tolerability of two intrathrombus delivery methods and two doses of plasmin compared with recombinant tissue plasminogen activator (rtPA) and placebo in patients with aPAO. Patients/methods: This was a phase 2, randomized, open-label study of intra-arterial CDT of plasmin in patients with aPAO. The study used infusion catheters with or without balloon occlusion (BOC) to evaluate 150 mg plasmin (2 and 5 h post-infusion) and 250 mg plasmin (5 h post-infusion). The efficacy of plasmin, rtPA and placebo was assessed. Results: One hundred and seventy-four subjects were enrolled. Overall, the thrombolytic efficacy (>50% thrombolysis) was 59% (58/99) for 150 mg plasmin without BOC, which is comparable to 89% (8/9) for rtPA without BOC (p = 0.149) and 40% (2/5) for placebo control (p = 0.648). The thrombolytic efficacy was 33% of the 250 mg plasmin group. There was no difference (p > 0.999) in thrombolytic efficacy with BOC (59%, 58/99) or without BOC (59%, 17/29). Plasmin-treated groups experienced treatment-emergent adverse events (TEAEs) at 71% (76/107) without BOC and 63% (24/38) with BOC; 78% (7/9) of the rtPA-treated group and 89% (8/9) of the placebo group had TEAEs. Serious AEs (SAEs) occurred in 29% (31/107) of the 150 mg plasmin group without BOC and 24% (9/38) with BOC. No SAEs occurred in the 250 mg plasmin group. Conclusions: Plasmin demonstrated less bleeding during catheter-directed administration at 150 mg and 250 mg doses compared to rtPA. BOC utilization did not improve efficacy. CDT with plasmin has a potential thrombolytic benefit in patients presenting with aPAO. ClinicalTrials.gov Identifier: NCT01222117.

Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial.

BACKGROUND: Short-term studies suggest that intravenous immunoglobulin might reduce disability caused by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but long-term effects have not been shown. We aimed to establish whether 10% caprylate-chromatography purified immune globulin intravenous (IGIV-C) has short-term and long-term benefit in patients with CIDP. METHODS: 117 patients with CIDP who met specific neurophysiological inflammatory neuropathy cause and treatment (INCAT) criteria participated in a randomised, double-blind, placebo-controlled, response-conditional crossover trial. IGIV-C (Gamunex) or placebo was given every 3 weeks for up to 24 weeks in an initial treatment period, and patients who did not show an improvement in INCAT disability score of 1 point or more received the alternate treatment in a crossover period. The primary outcome was the percentage of patients who had maintained an improvement from baseline in adjusted INCAT disability score of 1 point or more through to week 24. Patients who showed an improvement and completed 24 weeks of treatment were eligible to be randomly re-assigned in a blinded 24-week extension phase. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00220740. FINDINGS: During the first period, 32 of 59 (54%) patients treated with IGIV-C and 12 of 58 (21%) patients who received placebo had an improvement in adjusted INCAT disability score that was maintained through to week 24 (treatment difference 33.5%, 95% CI 15.4-51.7; p=0.0002). Improvements from baseline to endpoint were also recorded for grip strength in the dominant hand (treatment difference 10.9 kPa, 4.6-17.2; p=0.0008) and the non-dominant hand (8.6 kPa, 2.6-14.6; p=0.005). Results were similar during the crossover period. During the extension phase, participants who continued to receive IGIV-C had a longer time to relapse than did patients treated with placebo (p=0.011). The incidence of serious adverse events per infusion was 0.8% (9/1096) with IGIV-C versus 1.9% (11/575) with placebo. The most common adverse events with IGIV-C were headache, pyrexia, and hypertension. INTERPRETATION: This study, the largest reported trial of any CIDP treatment, shows the short-term and long-term efficacy and safety of IGIV-C and supports use of IGIV-C as a therapy for CIDP.

Safety and neutralizing rabies antibody in healthy subjects given a single dose of rabies immune globulin caprylate/chromatography purified.

BACKGROUND: Rabies immune globulin (RIG) and vaccination series are necessary for postexposure prophylaxis. A new formulation of RIG (human) purified by caprylate/chromatography (RIG-C) was evaluated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02139657. MATERIALS AND METHODS: This open-label, single-arm study in healthy subjects evaluated neutralizing rabies antibody concentrations produced from a single 20 IU/kg intramuscular (IM) dose of RIG-C as measured by rapid fluorescent focus inhibition test (50% neutralization endpoint) 1-hour postdose and on days 1, 2, 4, 6, 8, 10, 14, 18, and 21. RESULTS: Twelve subjects were enrolled into the study. No discontinuations, serious adverse events (AEs), or treatment-emergent clinically significant changes in laboratory parameters were observed. All AEs resolved and were mild except 1 moderate AE of oropharyngeal pain. Injection site pain (4 subjects) was most commonly reported. RIG-C produced a rapid increase in neutralizing rabies antibody: mean value 0.113 IU/mL at 24 hours after IM injection, peak on day 4 (0.132 IU/mL), persisting through day 21 (0.116 IU/mL). The mean reciprocal titer was 11.5 by day 2; the peak value of 12.1 was achieved on day 4; and a mean value ≥10.6 was maintained through day 21. CONCLUSION: RIG-C was well tolerated and provided neutralizing rabies antibodies, which combined with vaccine series after rabies exposure, should result in effective prophylaxis per World Health Organization/Centers for Disease Control and Prevention guidelines.

Arterial to end-tidal carbon dioxide tension difference (CO2 gap) as a prognostic marker for adverse outcomes in emergency department patients presenting with suspected sepsis.

OBJECTIVE: The arterial to end-tidal carbon dioxide tension difference (CO2 gap) correlates with physiologic dead space. The prognostic value of increased CO2 gap in trauma and respiratory distress patients is documented. Transpulmonary arteriovenous shunting is identified as a predictor of mortality in non-pulmonary sepsis. We set out to investigate the prognostic value of the CO2 gap in a pilot study of patients with suspected sepsis from non-respiratory causes. METHODS: Patients presenting to tertiary Australian ED with suspected sepsis (n = 215) underwent near-simultaneous end-tidal carbon dioxide and partial pressure of carbon dioxide measurements. We investigated the correlation of CO2 gap levels with the primary outcome of in-hospital mortality (IHM) and secondary outcomes of sepsis (ΔSOFA ≥2) and IHM and/or intensive care unit stay ≥72 h (IHM/ICU72h) in patients with sepsis because of non-respiratory causes. RESULTS: Among patients included in the analysis (n = 165), the CO2 gap showed modest positive correlation with qSOFA (ρ = 0.39) and weak positive correlation with SOFA scores (ρ = 0.29) (both P < 0.01). The CO2 gap had modest predictive value for primary outcome (IHM), area under receiver operating curve (AUROC 0.85, 95% confidence interval [CI] 0.78-0.90) and IHM/ICU72h outcome (AUROC 0.80, 95% CI 0.73-0.86), but lower predictive value for sepsis outcome (AUROC 0.64, 95% CI 0.55-0.71) (all P < 0.001). We report modest test performance for primary outcome at CO2 gap ≥5 and ≥10 mmHg cut-offs. CONCLUSION: In this pilot study of patients with suspected sepsis from non-respiratory causes, an increased CO2 gap demonstrates value in risk stratification and needs to be further evaluated and compared to other existent biomarkers.

Changing Trends What Patients with Thyroid Cancer Surgery Are Concerned About: Comparison between 2012 and 2020

Background and Objectives@#Given the major changes in spread of COVID-19 and the contribution of technological innovation, the objective of the current study was to compare the educational needs of thyroid cancer patients between 2012 and 2020. @*Materials and Methods@#The subject of this study were 159 patients in 2012 and 149 patients in 2020 who underwent thyroid cancer surgery. Data were collected from September 2020 to December 2020. Their responses were compared with response for the 2012 survey. The survey contained 36 questions regarding demographics and 5 areas of educational needs (Treatment plan after discharge, Management of the symptom and the complication after surgery, Medication management, Postoperative wound and dietary management, Daily life). @*Results@#The most preferred teaching method for thyroid cancer surgery patients has changed from small group education to self-study with videos. The Internet accounted for the largest proportion of source of information and the preferred educator for the patient were doctors and nurses in both 2012 and 2020. ‘Current disease condition and surgical result’ was the highest ranked in both 2012 and 2020. @*Conclusion@#It is necessary to develop and utilize an educational method using video centered on medical team including doctors and nurses.

Effect of Applying Exercise Movement Technique by Physical Therapist on Quality of Life in Breast Cancer Survivors: Meta-analysis

Purpose@#This study identified the effects of physical therapists on the quality of life when applying exercise-based movement techniques to breast cancer survivors. @*Methods@#To conduct meta-analysis, 186 RCT studies were searched in five databases (RISS, Pubmed, CINAHL, Medline, and Cochrane Library), without limitation, for the year of publication, and papers published in April 2018 were selected. Four studies met the inclusion criteria and were selected for meta-analysis based on the risk of bias. The basic demographic data, athletic characteristics, and outcome data were extracted from all included clinical trials. The data were analyzed using the RevMan 5.2 program. @*Results@#As a result of meta-analysis, exercise-based movement techniques applied by the control group (Pilates, yoga, tai chi, and qigong) or physical therapists showed no significant difference in the impact on the quality of life of breast cancer survivors. @*Conclusion@#In this study, exercise-based movement techniques mediated by control groups or physical therapists showed no significant difference in the quality of life of breast cancer survivors, but the types and duration of exercise in each study varied, and the number of subjects was small. Considering randomized studies, more randomized studies will be needed to draw conclusions.

Effect of Applying Exercise Movement Technique by Physical Therapist on Quality of Life in Breast Cancer Survivors: Meta-analysis

Purpose@#This study identified the effects of physical therapists on the quality of life when applying exercise-based movement techniques to breast cancer survivors. @*Methods@#To conduct meta-analysis, 186 RCT studies were searched in five databases (RISS, Pubmed, CINAHL, Medline, and Cochrane Library), without limitation, for the year of publication, and papers published in April 2018 were selected. Four studies met the inclusion criteria and were selected for meta-analysis based on the risk of bias. The basic demographic data, athletic characteristics, and outcome data were extracted from all included clinical trials. The data were analyzed using the RevMan 5.2 program. @*Results@#As a result of meta-analysis, exercise-based movement techniques applied by the control group (Pilates, yoga, tai chi, and qigong) or physical therapists showed no significant difference in the impact on the quality of life of breast cancer survivors. @*Conclusion@#In this study, exercise-based movement techniques mediated by control groups or physical therapists showed no significant difference in the quality of life of breast cancer survivors, but the types and duration of exercise in each study varied, and the number of subjects was small. Considering randomized studies, more randomized studies will be needed to draw conclusions.

Anti-inflammatory Effects of Sanguisorbae Radix on Contact Dermatitis Induced by Dinitrofluorobenzene in Mice / 中国结合医学杂志

OBJECTIVE@#To investigate the anti-inflflammatory effects of Sanguisorbae Radix on contact dermatitis (CD).@*METHODS@#Mice were sensitized by painting 30 µL of 1-fluoro-2,4-dinitrofluorobenzene (DNFB) onto each ear for 3 days. Four days later, mice were challenged by painting with 50 µL of DNFB onto the shaved dorsum every 2 days. Sanguisorbae Radix methanol extract (MESR) was applied onto the shaved dorsum every 2 days. The effects of MESR on skin thickness, skin weights, histopathological changes, skin lesions and cytokine production in DNFB-induced CD mice were investigated, as well as its effects on body weights and spleen/body weight ratio.@*RESULTS@#Topical application of MESR effectively inhibited enlargement of skin thickness and weight (P<0.05). MESR treatment also inhibited hyperplasia, spongiosis and immune cell infiltration induced by DNFB in inflamed tissues and improved lesions on dorsum skin in CD mice. Moreover, treatment with MESR suppressed the increase in the levels of tumor necrosis factor α (TNF-α,P<0.01) and interferon γ (IFN-γ,P<0.05), respectively. Finally, MESR had no effect on body weight gain or spleen/body weight ratio.@*CONCLUSION@#These data suggest that MESR acts as an anti-inflflammatory agent that decreases the production of TNF-α and IFN-γ, resulting in reductions of skin lesions and histopathological changes in inflamed skin tissues.

Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study.

An association has been reported between thrombotic events and the use of L-asparaginase (ASP) in children with acute lymphoblastic leukaemia (ALL). The mechanism for thrombosis is likely related to an acquired antithrombin deficiency. Since a primary prophylaxis using antithrombin concentrates may prevent thrombosis, the PARKAA (Prophylactic Antithrombin replacement in kids with ALL treated with L-asparaginase) study was performed. The objectives of PARKAA were to determine if there was a trend to efficacy and safety of antithrombin treatment as assessed by 1) incidence of thrombosis 2) incidence of bleeding and 3) plasma markers of endogenous thrombin generation as surrogate outcomes for thrombosis. The study was not powered to answer the question of efficacy and safety, but rather to detect a trend. PARKAA was an open, randomised, controlled study in children with ALL being treated with ASP. Children were randomised to receive antithrombin infusions or no antithrombin treatment. All thrombotic events were confirmed using bilateral venography, ultrasound, echocardiography and MRI. The incidence of thrombosis in patients treated with antithrombin was 28% (95% CI 10-46%), compared to 37% (95% CI 24-49%) in the non treated arm. Two minor bleeds occurred in patients in the treated arm, but were not considered to be related to antithrombin. No significant differences were seen in plasma markers by the treatment group. In conclusion, treatment with antithrombin concentrate shows a trend to efficacy and safety. In contrast, there was no difference in surrogate markers for thrombosis. Carefully designed clinical trials are needed to test the efficacy and safety of antithrombin in this population.

Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children: results of the PARKAA study. Prophylactic Antithrombin Replacement in Kids with ALL treated with Asparaginase.

Deep vein thrombosis (DVT) in children occurs primarily in the upper body venous system. This prospective diagnostic study compared bilateral venography and ultrasound for detection of DVT in the upper venous system in 66 children with acute lymphoblastic leukemia. Results were interpreted by central blinded adjudication. Deep venous thrombosis occurred in 29% (19/66) patients. While 15/19 DVT were detected by venography (sensitivity 79%), only 7/19 were detected by ultrasound (sensitivity 37%). The 12 DVT detected by venography but not by ultrasound were located in the subclavian vein or more central veins. Three of 4 DVT detected by ultrasound but not by venography were in the jugular vein. We conclude that ultrasound is insensitive for DVT in the central upper venous system but may be more sensitive than venography in the jugular veins. A combination of both venography and ultrasound is required for screening for DVT in the upper venous system.

Intravenous immune globulin use in Canada.

OBJECTIVES: To determine the amount of intravenous immune globulin (IVIG) used across indications in Canada and which Canadian medical specialties prescribe IVIG. To assess the proportion of IVIG that was used in appropriate off-label and labelled indications versus those deemed to be inappropriate off-label indications. METHODS: In Canada, all IVIG is distributed by the Canadian Blood System to Canadian blood banks within the hospital setting. Hospital blood banks then dispense IVIG to individual patients as it is prescribed and, as such, many institutions maintain a comprehensive database inventory on IVIG use. This study is a retrospective review of IVIG use as obtained from 10 teaching and community hospital blood bank databases in Ontario, Quebec, Alberta and British Columbia. Two of these 10 institutions were pediatric teaching hospitals whereas the remaining eight centres were adult care sites. Product usage was assessed between 1997 and 1999 in adult care sites, and 1997 and 1998 in the pediatric hospitals. The information collected included the number of grams of IVIG dispensed, the indications, the prescribing physician's specialty and the number of patients treated for a given indication, all assessed on an annual basis. A separate analysis was performed to determine the appropriateness of IVIG use where appropriateness was based on the published 1997 and 1999 Canadian Consensus Guidelines for IVIG use. RESULTS: IVIG was prescribed for 90 different indications, six of which are licensed in Canada. When considered as separate populations, adult and pediatric use accounted for 61 and 65 different indications, respectively. Licensed use for all known indications represented approximately 47% and 62% in adult and pediatric settings, respectively. Twenty-nine per cent of IVIG use in adult and 17% in pediatric settings was not reported and is therefore unknown. Although off-label use by definition is approximately 53% in adults and 38% in pediatrics, the majority of overall IVIG use (89% in both populations) is considered appropriate by guideline definition. Hematologists and neurologists were the most prevalent prescribers of IVIG. CONCLUSIONS: Based on guideline definition, appropriate off-label use of IVIG is very high in Canada.

CRISPR/Cas9-mediated knockout of Rag-2 causes systemic lymphopenia with hypoplastic lymphoid organs in FVB mice / 한국실험동물학회지

Recombination activating gene-2 (RAG-2) plays a crucial role in the development of lymphocytes by mediating recombination of T cell receptors and immunoglobulins, and loss of RAG-2 causes severe combined immunodeficiency (SCID) in humans. RAG-2 knockout mice created using homologous recombination in ES cells have served as a valuable immunodeficient platform, but concerns have persisted on the specificity of RAG-2-related phenotypes in these animals due to the limitations associated with the genome engineering method used. To precisely investigate the function of RAG-2, we recently established a new RAG-2 knockout FVB mouse line (RAG-2(−/−)) manifesting lymphopenia by employing a CRISPR/Cas9 system at Center for Mouse Models of Human Disease. In this study, we further characterized their phenotypes focusing on histopathological analysis of lymphoid organs. RAG-2(−/−) mice showed no abnormality in development compared to their WT littermates for 26 weeks. At necropsy, gross examination revealed significantly smaller spleens and thymuses in RAG-2(−/−) mice, while histopathological investigation revealed hypoplastic white pulps with intact red pulps in the spleen, severe atrophy of the thymic cortex and disappearance of follicles in lymph nodes. However, no perceivable change was observed in the bone marrow. Moreover, our analyses showed a specific reduction of lymphocytes with a complete loss of mature T cells and B cells in the lymphoid organs, while natural killer cells and splenic megakaryocytes were increased in RAG-2(−/−) mice. These findings indicate that our RAG-2(−/−) mice show systemic lymphopenia with the relevant histopathological changes in the lymphoid organs, suggesting them as an improved Rag-2-related immunodeficient model.

Challenges of clinical trial design when there is lack of clinical equipoise: use of a response-conditional crossover design.

Clinical equipoise is widely accepted as the basis of ethics in clinical research and requires investigators to be uncertain of the relative therapeutic merits of trial comparators. When clinical equipoise is in question, innovative trial designs are needed to reduce ethical tension while satisfying regulators' requirements. We report a novel response-conditional crossover study design used in a Phase 3, randomized, double-blind, placebo-controlled clinical trial of intravenous 10% caprylate-chromatography purified immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. During the initial 24-week period, patients crossed over to the alternative treatment at the first sign of deterioration or if they failed to improve or were unable to maintain improvement at any time after 6 weeks. This trial design addressed concerns about lack of equipoise raised by physicians interested in trial participation and proved acceptable to regulatory authorities. The trial design may be applicable to other studies where clinical equipoise is in question.

A Study on the Propensity of Koreans in Choosing Dementia Care Settings

OBJECTIVE: This study was to investigate the factors that influence the propensity of Koreans in choosing care settings of dementia patients. METHODS: This study analyzed the data from the '2014 Nationwide Survey on Dementia Awareness of Koreans' that was conducted by the National Institute of Dementia. Korean's perception of care burden for dementia was measured with grading on its types. Also its influences on preference for care between facilities and homes were evaluated using multivariate analysis with socio-demographic characteristics. RESULTS: In terms of preferred care settings, respondents preferred facilities over homes in case of themselves and their family, respectively 77.5% and 68.2%. The preference for facilities was significantly influenced by the respondents' age for both themselves and their family. Additionally, the perception of relatively higher emotional and physical burden compared to economic burden significantly influenced preference for facilities for their family. CONCLUSION: Improving public awareness and setting-up a practical social supporting system are needed to reduce emotional and physical burden as well as economic burden of dementia. Furthermore, building up an appropriate and safer communities for dementia patients and their caregivers is much demanded for reducing their burdens.