Full-dose Group Research Articles

A dose-ranging study in older adults to compare the safety and immunogenicity profiles of MF59®-adjuvanted and non-adjuvanted seasonal influenza vaccines following intradermal and intramuscular administration

Strategies to optimize responses to seasonal influenza vaccination in older adults include the use of adjuvants, higher antigen doses, and intradermal delivery. In this study adults aged ≥65 years (n = 450) received a single dose of 1 of 2 non-adjuvanted trivalent influenza vaccine (TIV) formulations administered intradermally (ID), both containing 6 µg of A/H1N1 and B, differing in A/H3N2 content (6 µg or 12 µg), or a single dose of 1 of 8 TIV formulations administered intramuscularly (IM) all containing 15 µg of A/H1N1 and B, differing in A/H3N2 hemagglutinin (HA) content (15 µg or 30 µg) and/or in MF59® adjuvant content (0%, 25%, 50%, or 100% of the standard dose). This paper focuses on the comparisons of low-dose non-adjuvanted ID, full-dose non-adjuvanted IM and full-dose MF59-adjuvanted IM formulations (n = 270). At day 22 post-vaccination, at least one European licensure immunogenicity criterion was met by all groups against all 3 strains; however, all three criteria were met against all 3 vaccine strains by the low-dose non-adjuvanted ID and the full-dose MF59-adjuvanted IM groups only. The full-dose MF59-adjuvanted IM group elicited significantly higher immune response vs. the low-dose non-adjuvanted ID formulations for most comparisons. The full-dose MF59 adjuvanted IM groups were associated with increased pain at the site of injection (P < 0.01) compared to the ID groups, and the low-dose non-adjuvanted ID groups were associated with increased erythema, induration, and swelling at the injection site (P < 0.0001) and unsolicited AEs compared with the IM groups. There were no differences between IM and ID groups in the frequencies of subjects experiencing solicited systemic reactions. Overall, while MF59 adjuvantation increased pain at the site of injection, and intradermal delivery increased unsolicited adverse events, erythema, induration, and swelling at the injection site, both strategies of vaccination strongly enhanced the immunogenicity of seasonal influenza vaccine in older adults compared with conventional non-adjuvanted intramuscular delivery.Trial registration: http://www.clinicaltrials.gov: NCT00848848The authors wish to thank Dr Jamie Stirling and Dr Hari Sai Priya Baddela (Novartis Vaccines) and Dr Patricia de Groot and Dr Amanda Prowse (CHC Europe) for editorial assistance in the preparation of this manuscript.

Effect of different doses of mannitol injection on the time and vessel damage of indwelling needle among patients with brain trauma

Objective To compare the effect and safety of full-doses and half-doses mannitol on the indwelling time and vessel damage of the indwelling needles when treating patients with moderate or severe brain trauma.Methods One hundred and fifty-four patients with moderate or severe brain trauma treated with 20%mannitol were randomly divided into the full-dose group and the half-dose group, 77 cases each.The patients in＆amp;nbsp;the full-dose group were intravenously given 20% mannitol for 250 ml, and the patients in the half-dose group were intravenously given 20% mannitol for 125 ml.Compare the indwelling time and vessel damage of the injection sites between the two groups .Results In the full-dose group, the indwelling time below 4 days, between 4-6 days, between 7 -10 days and over 10 days were 37.67%, 41.56%, 20.77%, 0.00%, respectively .In the half-dose group, the indwelling time below 4 days, between 4-6 days, between 7-10 days and over 10 days were 22.08%, 36.36%, 38.96%, 2.60%, respectively.The differences between groups were significant （χ2 =5.774, P＆lt;0.05）.For patients in coma, the safe indwelling time over 10 days in the half-dose group was 4.25% and 0.00% in the full-dose group, which was significantly higher （χ2 =6.720, P＆lt;0.05）.The number of cases with vessel damage was 25 cases in degreeⅠ, 21 in degreeⅡand 15 in degreeⅢin the full-dose group .The degree of vessel damage was significant sever in the full-dose group than that in the half-dose group （Z=6.469, P＆lt;0.05）.Conclusions When treating patients with long -term intravenous transfusions, the retention time of indwelling needles should be paid attention , especially for the unconscious , comatose or the elderly patients .At the meantime , nurses should improve the nursing care of patients ’ skin, and prevent the vessel from the medication damage , and promote the phase of patients ’ recovery . Key words: Brain trauma; Mannitol; Indwelling time; Vessel damage

Comparison of half-dose and full-dose triple therapy regimens for Helicobacter pylori eradication in patients with end-stage renal disease.

The aim of this study was to compare the half-dose and full-dose triple therapy regimens for Helicobacter pylori (Hp) eradication in patients with end-stage renal disease. H. Pylori is one the most important causes of dyspepsia in patients with end-stage renal disease (ESRD). Sixty-six patients with ESRD were enrolled in the study with Hp infection and peptic disease with a need of Hp eradication. Patients were randomly assigned to full-dose (A=35 patients) or half-dose group (B=31 patients). Patients received clarithromycin 500 mg, amoxicillin 1000 mg and omeprazole 20 mg twice daily in group A and clarithromycin 250 mg and amoxicillin 500 mg twice daily and omeprazole 20 mg once daily in group B for two weeks. Patients provided stool samples 4 weeks of completing study to assess the success of Hp eradication by Hp-specific stool antigen. Finally, the rate of eradication and complications were compared between two groups. The successful Hp eradication was achieved in 26 patients (74%) in group A and in 22 patients (74%) in group B. The difference between 2 groups was not statistically significant (p=0.973) (per protocol analysis). Half-dose triple-therapy with clarithromycin, amoxicillin and omeprazole is as effective as full-dose triple-therapy to eradicate the Hp in patients with ESRD. According to lower toxicity level, complications and cost in half-dose regimen in this subset of patients, this protocol is advised.

Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach

The combination of oral melphalan and dexamethasone is considered standard therapy for patients with light-chain amyloidosis ineligible for autologous stem cell transplantation. However, previous trials reported different rates of response and survival, mainly because of the different proportions of high-risk patients. In the present study, including a total of 259 subjects, we treated 119 patients with full-dose melphalan and dexamethasone (dexamethasone 40 mg days 1-4), and 140 patients with advanced cardiac disease with an attenuated dexamethasone schedule (20 mg). Hematologic response rates were 76% in the full-dose group and 51% in the patients receiving the attenuated schedule; the corresponding complete response rates were 31% and 12%, respectively. The median survival was 7.4 years in the full-dose group and 20 months in the attenuated-dose group. Use of high-dose dexamethasone, amino-terminal pro-natriuretic peptide type-B >1800 ng/L, a difference between involved and uninvolved free light chains of >180 mg/L, troponin I >0.07 ng/mL, and response to therapy were independent prognostic determinants. In relapsed/refractory subjects bortezomib combinations granted high hematologic response rates (79% and 63%, respectively), proving the most effective rescue treatment after melphalan and dexamethasone. In summary, melphalan plus dexamethasone was highly effective with minimal toxicity, confirming its central role in the treatment of AL amyloidosis. Future randomized trials will clarify whether bortezomib is best used in frontline combination with melphalan and dexamethasone or as rescue treatment.

The virological response in Koreans infected with HCV genotype 1 did not differ between groups treated with a full dose or reduced dose (≥80% full dose) of peginterferon alfa-2a: a prospective randomized multicenter trial.

A high rate of sustained viral response (SVR) in Koreans with chronic hepatitis C (CHC) is related to a favorable IL28B genotype. We compared two dosing strategies for peginterferon alfa-2a in Koreans with CHC and defined the combined effect of polymorphisms and dosing on the virological response. A total of 178 treatment-naïve patients with CHC genotype 1 were prospectively enrolled. All patients were randomly assigned to treatment with one of two peginterferon alfa-2a regimens: 180μg per week for 48weeks (full-dose group) or 180μg per week during the first 12weeks followed by 135μg per week for the next 36weeks (dose-reduction group). Polymorphisms related to IL28B, ITPA, C20orf194 and SLC29A1 were studied. SVR rates did not differ between the full-dose and dose-reduction groups (56.5 and 51.2%, respectively, p=0.474). The frequency of additional reductions of the peginterferon dose because of adverse events was higher in the full-dose group than in the dose-reduction group. SVR rates in patients homozygous for the IL28B major allele were higher than those in patients for the other IL28B alleles. For patients with unfavorable IL28B genotypes, SVR was less likely to be achieved in the dose-reduction group than in the full-dose group. In Koreans with HCV genotype 1, the virological response to treatment did not differ between a full dose and reduced dose (≥80% of full dose) of peginterferon alfa-2a. However, in the patients with unfavorable IL28B genotypes, the full-dose treatment of peginterferon alfa-2a may be beneficial.

Su1279 The Beneficial Effect of Pentadecapeptide BPC 157 on Healing of Rectovaginal Fistulas in Rats

G A A b st ra ct s who tend to be non-ambulatory, older, and more frail, intolerance and thus, noncompliance with the bowel purge, is a critical factor influencing the quality of bowel prep during colonoscopy. Aims: To evaluate patient compliance, feasibility and efficacy of a split-dose PEG-based lavage in the inpatient setting. Methods: Single-center, prospective observational pilot study of a consecutive convenience sample comparing inpatients that received 4-L PEG solution versus split dose solution (2-L PEG the evening prior and 2-L after midnight on the day of the procedure). The Boston Bowel Preparation Scale was used to evaluate the quality of the bowel prep. Tolerability, patient preferences and adverse events were recorded using a self-administered patient survey completed prior to colonoscopy and through chart review. The Student's t test was used for continuous variables and the Fisher's exact test was used for all categorical variables. A p value less than 0.05 was considered significant. Results: Patient demographics are shown in Table 1. All patients in the split dose group (SPLIT) completed the bowel prep successfully while 4 patients in the full dose group (FULL) did not; resulting in cancellation of the procedure. The majority of patients in the SPLIT group (85%) would prefer split dose over full dose for future colonoscopies while 39% of patients in the FULL group would not choose full dose lavage again. There were no significant differences in adverse events or quality of bowel prep between the two groups (Table 2). Conclusions: This pilot study demonstrates that the split dose 4-L PEG solution is a well-tolerated, feasible bowel cleansing method among hospitalized patients. The higher rates of completion of the bowel prep among the split dose bowel cleansing group suggest that split dose lavage may enhance compliance with bowel prep before colonoscopy among hospitalized patients. Table 1. Baseline Characteristics of Patients

Utility of halofuginone lactate for the prevention of natural cryptosporidiosis of calves, in the presence of co-infection with rotavirus and Salmonella Typhimurium

Halofuginone lactate (HL) is registered in several countries for the prevention of calf cryptosporidiosis, but the compound's utility in the presence of co-infection with other enteropathogens is not well understood. We performed a randomized controlled field trial of the efficacy of HL for the prevention of natural calf cryptosporidiosis, in the presence of co-infection with rotavirus and Salmonella Typhimurium. Newborn calves on one farm were sequentially enrolled and allocated to a full dose (n=15), half dose (n=15), or a placebo control group (n=15), using a randomized block design. The Cryptosporidium oocysts in fecal specimens collected on Days 6, 8, 10, 14 and 20 were counted and the severity of the diarrhea was assessed using fecal consistency scores (solid, semisolid, or liquid). The oocyst numbers and fecal consistency scores were statistically compared between the groups. Ninety one percent of the calves shed Cryptosporidium parvum oocysts during the trial. The full dose group had a longer prepatent period than the control group, but no statistical difference in the number of oocysts was identified between the groups after controlling for the effects of sex and breed. The fecal consistency scores and mortality rates did not differ between the groups. These results indicated that the anti-Cryptosporidium activity and clinical benefit of HL were limited. It is concluded that in order to maximize the clinical efficacy of HL in the field, diagnostic efforts should aim to rule out the presence of other enteropathogens.

Feasibility of myocardial perfusion imaging with half the radiation dose in obese patients using ordered-subset expectation maximization with resolution recovery software

BackgroundWe previously described the feasibility of myocardial perfusion imaging (MPI) with nearly half the radiation dose using ordered-subset expectation maximization with resolution recovery (OSEM-RR) processing. This study sought to determine if the findings can be expanded to obese patients. MethodsFifty obese patients (>100 kg) referred for MPI underwent stress-rest or rest-stress studies with a half dose of Tc-99m sestamibi in a 1-day protocol using OSEM-RR processing. Image quality and clinical results were compared with matched patients (by age, sex, weight, presence/probability of coronary artery disease) evaluated with standard “full-dose” Tc-99m sestamibi, mostly in a 2-day protocol. Dose activities were adjusted individually by weight. ResultsMean Tc-99m activity was 33.4 ± 13.9 mCi in the half-dose group and 60 ± 10 mCi in the full-dose group (P < .0001). Respective mean effective doses per study were 10 ± 4 and 18 ± 3 mSv (P < .0001). Overall image quality was good-to-excellent in 94% of the half-dose group and 80% of the full-dose group (P < .045). There was no between-group difference in rate or size of ischemia or infarction, except for stress left ventricular ejection fraction. ConclusionsMPI with half the radiation dose is feasible in obese patients. Image quality is better than for full-dose MPI, and the procedure can be performed in 1 day.

In a ‘Real-World’, Clinic-Based Community Setting, Sorafenib Dose of 400 mg/day is as Effective as Standard Dose of 800 mg/day in Patients with Advanced Hepatocellular Carcimona, with Better Tolerance and Similar Survival

Sorafenib, an oral multityrosine kinase inhibitor, has been approved for treatment of unresectable hepatocellular carcinoma (HCC). British Columbia (BC) was the first province in Canada to provide drug coverage for sorafenib. To review the BC experience with sorafenib to assess its effectiveness and tolerance in a 'real-world' clinical setting. A retrospective clinic chart review identified 99 patients referred to the BC Cancer Agency from 2008 to 2010 with a diagnosis of HCC who qualified for treatment with sorafenib. Therapy with sorafenib was initiated and continued at a reduced dosage of 400 mg⁄day in 66 of 99 patients, with 22 patients requiring further dose reduction. Full- and reduced-dose group patients had similar baseline characteristics, except for a higher proportion of female patients (P=0.02) and individuals with alcoholic liver disease (P=0.04) in the full-dose group. The incidence of any grade of adverse effects was higher in the full-dose group (94% versus 77% in the reduced-dose group; P=0.04). Dose reduction rates were significantly higher in the full-dose group, occurring in 66% versus 24% of reduced-dose group patients (P=0.001). The overall survival rates were similar between the two groups: 7.8 months versus 7.1 months in full- versus reduced-dose groups (P=0.14), as were radiological progression rates and alpha-fetoprotein levels. In a review of 99 patients in a 'real-world' community setting, a sorafenib dose of 400 mg⁄day was better tolerated and had similar efficacy compared with a sorafenib dose of 800 mg⁄day with respect to survival and outcomes.

Coronary CT angiography: Comparison of a novel iterative reconstruction with filtered back projection for reconstruction of low-dose CT—Initial experience

ObjectiveTo prospectively compare subjective and objective image quality in 20% tube current coronary CT angiography (cCTA) datasets between an iterative reconstruction algorithm (SAFIRE) and traditional filtered back projection (FBP). Materials and methodsTwenty patients underwent a prospectively ECG-triggered dual-step cCTA protocol using 2nd generation dual-source CT (DSCT). CT raw data was reconstructed using standard FBP at full-dose (Group_1a) and 80% tube current reduced low-dose (Group_1b). The low-dose raw data was additionally reconstructed using iterative raw data reconstruction (Group_2). Attenuation and image noise were measured in three regions of interest and signal-to-noise-ratio (SNR) as well as contrast-to-noise-ratio (CNR) was calculated. Subjective diagnostic image quality was evaluated using a 4-point Likert scale. ResultsMean image noise of group_2 was lowered by 22% on average when compared to group_1b (p<0.0001–0.0033), while there were no significant differences in mean attenuation within the same anatomical regions. The lower image noise resulted in significantly higher SNR and CNR ratios in group_2 compared to group_1b (p<0.0001–0.0232). Subjective image quality of group_2 (1.88±0.63) was also rated significantly higher when compared to group_1b (1.58±0.63, p=0.004). ConclusionsImage quality of 80% tube current reduced iteratively reconstructed cCTA raw data is significantly improved when compared to standard FBP and consequently may improve the diagnostic accuracy of cCTA.

Donor-Type Aplasia After Bone Marrow Transplantation in Children with Aplastic Anemia: A Nationwide Retrospective Study

AbstractAbstract 959Survival after bone marrow transplantation (BMT) in children with aplastic anemia (AA) has improved markedly over the last 3 decades. However, we have experienced a certain number of patients who presented with bone marrow aplasia with full donor chimerism after BMT (donor-type aplasia), especially in the recent years. Since the 2000s, fludarabine (FLU)-based conditioning regimen has been often used for Japanese children with AA. The present study therefore evaluated whether patient and transplantation characteristics (especially the FLU regimen) could associate with donor-type aplasia in a large population of children with AA.To identify the risk factors for donor-type aplasia, we reviewed the clinical data of 660 patients (< 20 years) with AA who received BMT from 1980 to 2010 and whose records were available in the Japan Society for Hematopoietic Cell Transplantation Registry. The influence of potential risk factors on donor-type aplasia was assessed according to patient and transplantation characteristics, including the conditioning regimen. The median age at transplantation was 11 years, and 238 patients received immunosuppressive therapy (IST) before BMT. The median interval between diagnosis and BMT was 9 months. Regarding transplantation, 419 patients received BMT from related donors, whereas 241 received BMT from unrelated donors. Totally, 220 patients received a regimen that included FLU.Primary graft failure was observed in 25 patients. Of the 635 patients who achieved primary engraftment, 46 developed secondary graft failure or relapse: 11 were of the recipient-type and 35 were of the donor-type. The cumulative incidence of donor-type aplasia was 5.7%, and the 10-year overall survival of patients who presented with donor-type aplasia was 87%. Notably, the incidence of donor-type aplasia was significantly higher in FLU regimen group than in non-FLU regimen group (11.6% vs. 2.7%; P < 0.0001), and multivariate analysis confirmed that the FLU regimen was an independent risk factor for donor-type aplasia. Low infused cells (≤ 3×108/kg) (P = 0.008) and IST before BMT (P = 0.04) were also associated with a high incidence of donor-type aplasia. Age at BMT, gender, etiology, severity, interval between diagnosis and BMT, transfusion times, donor type (related or unrelated), human leukocyte antigen disparity, acute or chronic graft versus host disease (GVHD), GVHD prophylaxis, and viral reactivation or infection did not influence the incidence of donor-type aplasia in multivariate analysis.When FLU was introduced in the regimen for Japanese children with AA, the dose of cyclophosphamide (CY) was reduced by half, to reduce the toxicity; the conventional dose of CY was 200 mg/kg before the introduction of FLU. Therefore, we investigated the impact of the dose reduction of CY in the FLU regimen group. In patients receiving the FLU regimen, the incidence of donor-type aplasia in the CY half-dose group (n = 175) was 14%, whereas donor-type aplasia was not observed in the CY full-dose group (n = 35) (P = 0.04). In contrast, the addition of antithymocyte globulin or irradiation did not influence the incidence of donor-type aplasia in the FLU regimen group. Of note, the incidence of heart failure as a result of CY administration was higher in the CY full-dose group (5.7%) than in the CY half-dose group (0.6%), although this difference was not statistically significant.In conclusion, the FLU regimen was identified as an independent risk factor for donor-type aplasia in children with AA, which could possibly be ascribed to the CY dose reduction. However, the high incidence of heart failure associated with the regimen including a full dose of CY is an important issue that needs to be resolved. To develop optimal treatment, the conditioning regimen for children with AA needs to be reconsidered. Disclosures:No relevant conflicts of interest to declare.

The influence of time and dose of mannitol on neural and renal functions in the treatment of hepertensive cerebral hemorrhage

Objective To explore the influence of time and dose of mannitol on neural and renal functions in the treatment of hepertensive cerebral hemorrhage.Methods 300 patients with hepertensive cerebral hemorrhage were divided into full-dose group and half-dose group.Full-dose group was divided into group A and group B,and half-dose group was divided into group C and group D.Full-dose group given 20％ mannitol 250ml,and half-dose group was given 20％ mannitol 125ml.Groups A and C were given drug 12h after incerebral hemorrhage occurs,and groups B and D were given drug in the occurrence of cerebral hemorrhage within 12h.The neural and renal functions of every group were compared before the treatment and one week after that.Results The treatment of full-dose group and hulf-dose group was all better,the total effective rate was 71.3％,72.7％,respectively,and there was no significant difference between the two groups ( P ＞ 0.05 ).The total effective rate of groups A,C ( 92.0％,90.7 ％ ) was significantly higher than that of groups B,D (53.3％,50.7％ ) ( all P ＜ 0.05 ).The number of cases [ ( BUN increased more than 7remol/L,61 cases) and(Cr increased more than 133remol/L,64 cases)] in full-dose group was significantly higher than that of half-dose group( 17 cases,17 cases) ( all P ＜ 0.05 ).Conclusion The effect of full-dose and half-dose mannitol in the treatment of hypertensive intracerebral hemorrhage is all better,but renal injury in halfdose mannitol was lower.Giving drug 12h after incerebral hemorrhage occurs is more conducive to hypertensive intracerebral hemorrhage controlled,and could better improve the prognosis. Key words: Mannitol; Hepertensive cerebral hemorrhage; Renal function

High dose estrogen in endometrium preparation increases pregnancy rates in fresh oocyte donation cycles

To evaluate whether endometrial priming with a full dose of estrogens yields a higher pregnancy rate than with a gradually progressive dose when transferring fresh embryos proceeding from oocyte donors. Prospective analysis of a consecutive cohort of patients receiving the full dose of estrogen. A control group receiving the progressive dose was selected for demographics and timeframe. The full dose group (study, n=90) received 6 mg of estradiol orally per day or 150 μg transdermally every three days from the first day of the period. The progressive dose group (control, n=491) received an increasing dose of estradiol, orally (increasing from 2 mg to 6 mg on day 12) or transdermally (increasing from 50 μg to 150 μg on day 7); 400 mg of progesterone were added vaginally twice a day from the follicular punction, regardless of dosage. Endometrial thicknesses on the day of the embryo transfer and b-HCG result 14 days after were compared between groups. Endometrial thickness did not change significantly in the two groups (10.19±5.81 vs. 9.76±2.34 mm, P=0.57, respectively). Pregnancy rates (n=445 controls; n=77 study) were higher in the full dose group (61% vs. 47%, P=0.02). Irrespective of the dose, pregnancy rates were higher in the transdermal group (61% vs. 48%) than in the oral one (58% vs. 46%), perhaps due to different estradiol metabolism through the two routes. The results of this study suggest that a full dose of estrogen throughout endometrial preparation in recipients leads to a substantial increase in the pregnancy rate. These results might be confirmed with a larger cohort of patients currently under treatment.

Acute exercise enhancement of pneumococcal vaccination response: A randomised controlled trial of weaker and stronger immune response

Acute exercise at the time of vaccination can enhance subsequent immune responses. However, the potential benefit of this effect will be its efficacy in boosting poor responses, and thus protection in at-risk populations. The current study tested the effect of exercise on the response to either a full- or half-dose Pneumococcal (Pn) vaccination to elicit stronger and weaker responses. Subjects were 133 young healthy adults, randomised to one of four groups: exercise or control task, receiving a full- or half-dose Pn vaccination. Prior to vaccination, exercise groups completed a 15min arm and shoulder exercise task, control groups rested quietly. Antibody levels to 11 Pn strains were evaluated at baseline and 1-month. Across all participants, exercise groups showed significantly greater increase in antibody levels than control groups. When doses were compared, it emerged that those who exercised had significantly larger responses than those who rested in the half-dose group, but in the full-dose groups responses were similar. This data indicates the effectiveness of exercise as a vaccine adjuvant, particularly in weaker responses. Thus, given the potential public health benefits of no-cost behavioural intervention to enhance response to vaccination, testing in at-risk populations should be pursued.

Immunotherapy for Type 1 Diabetes: Getting beyond a Negative First Impression

GAD-alum; two injections of 20 μg GAD-alum and one of alum; or three injections of alum. However, the primary end point of a higher area under the curve of stimulated C-peptide at 1 year (9 months after the end of the treatment), as compared with placebos, was not met [3]. The second one, conducted on a larger sample (434 T1D subjects) and using a higher total dose (four injections of 20 μg) obtained similar results [2]. Although disappointing, these findings are not completely unexpected. Experimental studies in the nonobese diabetic mouse have shown that several factors such as timing of the disease process, route of administration and dose may affect effectiveness of the intervention. Experimental studies showed that an effective antigen therapy needs to be started before the disease develops, a timing that is certainly different from the clinical trial settings. Moreover, antigen-based therapies have also failed in other autoimmune diseases such as multiple sclerosis [4]. Broad-based immunosuppressive therapies aiming to restore the altered balance between ‘effector’ T cells and Tregs have also been tested. Teplizumab and otelixizumab are two humanized anti-CD3 antibodies that target the T-cell receptor complex for antigen recognition. Phase III trials with antibodies were meant to confirm on a large scale encouraging results obtained in previous academic trials. Although the trial with teplizumab, Protege, did not meet the primary composite end point (glycated hemoglobin A1c [HbA1c] <6.5% and insulin dose <0.5 U/kg/day), patients in the fulldose group (~9 mg/m over 14 days) showed a slower reduction in b-cell function (change of C-peptide area under the curve from baseline) compared with placebo [5]. Furthermore, a subgroup analysis suggested that treatment with Type 1 diabetes (T1D) results from the immunemediated destruction of insulin-producing b-cells by autoreactive CD4 and CD8 T cells. T1D ranks as the most common chronic childhood disease and its prevalence is increasing. Presently, insulin therapy rescues patients with T1D from certain death but does not satisfactorily prevent long-term chronic complications typically occurring at a relatively young age. Therefore, an early intervention delaying or completely halting disease progression is warranted. Immunotherapeutic strategies targeting autoimmune mechanism(s) involved in the disease have been explored. An increasing number of large-scale clinical trials of immunotherapy have recently been completed and more are currently ongoing. A major outcome is the preservation of stimulated C-peptide (a measure of endogenous insulin production), based on the assumption that a better b-cell function will delay or reduce the development of future chronic complications [1]. The trials rely on two main immunotherapeutic approaches: using antigen-specific tolerance strategies or broad-based immunosuppressive therapies (Table 1). The former approach aims to inactivate safely the pathogenic autoreactive T cells only in an antigen-specific manner, while functionally preserving the remainder of the immune system. Two recent Phase III trials tested the feasibility of the main T1D autoantigen glutamic acid decarboxylase (GAD) in alum formulation in preserving b-cell function in subjects with new-onset (<3 months) disease [2,3]. Both trials contradicted encouraging findings from previous studies. The first one, conducted by the US NIH-supported consortium TrialNet, randomly assigned 145 T1D patients to receive one of three treatments: three injections of 20 μg

Feasibility of myocardial perfusion imaging with half the radiation dose using ordered-subset expectation maximization with resolution recovery software

ObjectiveThis study sought to assess the feasibility of performing myocardial perfusion imaging (MPI) with half the technetium activity using ordered-subset expectation maximization with resolution recovery (OSEM-RR), an iterative reconstruction software developed to improve count statistics and acquisition time. MethodsTwo hundred eighteen patients referred for MPI were randomly allocated to undergo stress-rest or rest-stress protocols with standard full-dose (FD) injections of technetium (Tc)-99m sestamibi or half-dose (HD) injections and OSEM-RR processing. Dose activities were adjusted individually by weight. The groups were compared for image quality and clinical results. ResultsThe groups were similar for mean patient age, weight, and body mass index, sex distribution, pre-test probability of CAD and CAD prevalence. Mean Tc-99m activities for the low-dose and high-dose stages were as follows: FD group: 429 ± 85 MBq and 1132 ± 200 MBq; HD group: 263 ± 129 MBq and 629 ± 85 MBq (P < .0001 for both). Mean effective dose per study was 13.6 ± 1.4 mSv in the FD group and 7.7 ± 1.0 mSv in the HD group (P < .001). Over all image quality was good-to-excellent in 98% and 95% of the groups, respectively. However, when we analyzed the low-dose stage separately, image quality was slightly worse in the HD than the FD, though still within the good-to excellent range. ConclusionsMPI with nearly half the radiation dose is feasible with good image quality.

Dose Equivalence of Immediate-Release Hydromorphone and Once-Daily Osmotic-Controlled Extended-Release Hydromorphone: A Randomized, Double-Blind Trial Incorporating a Measure of Assay Sensitivity

Dose selection of a once-daily, osmotic-controlled extended-release (ER) hydromorphone assumes that this drug and immediate-release (IR) hydromorphone are dose equivalent. This trial evaluated dose equivalence using a measure of assay sensitivity. Patients were converted to open-label IR hydromorphone, underwent dose titration, and those on a satisfactory dose entered a randomized, double-blind phase receiving 7 days of: 1) hydromorphone IR 5 times/day at approximately this dose; 2) once-daily hydromorphone ER at this dose; or 3) once-daily hydromorphone ER at one-half this dose. Efficacy was measured using breakthrough medication use, pain, sleep, and global assessments. Of 148 patients, 113 (76%) were randomized. IR and full-dose ER groups produced comparable effects on all measures. Although the prespecified primary analysis of the difference in total daily dose of breakthrough medication between the full-dose ER and half-dose ER groups was not significant, more patients in the half-dose ER group required an increase in breakthrough medication (P = .026) and the half-dose ER group both increased the number of breakthrough doses (P = .026) and had greater percent change in the total daily dose of breakthrough medication (P = .037) than the full-dose group, suggesting that switching from IR to ER hydromorphone at the same daily dose provides equivalent analgesia. PerspectiveIn a randomized, double-blind trial, the same total daily dose of immediate-release hydromorphone and once-daily osmotic-controlled extended-release hydromorphone had comparable effects. Detection of different effects between blinded dose levels was used as a measure of assay sensitivity. The measure of assay sensitivity can enhance the interpretation of dose equivalence or noninferiority trials.

Glial activation in a pilocarpine rat model for epileptogenesis: A morphometric and quantitative analysis

In this work we examined the correlation between long-term glial resilience and slow epileptogenesis using the pilocarpine-insult rat model. We assessed, quantitatively and morphometrically, glial fibrillary acidic protein (GFAP) expression and cell densities in hippocampus in a dose–response manner 2, 4 and 8 weeks after the pilocarpine insult. GFAP changes were correlated with observations on microglial activation. We used a commonly applied epileptogenic pilocarpine dose (380mg/kg) and its fractions of 1/10, 1/4 and 1/2. GFAP expression evaluated at 2 weeks revealed dose-dependent cytoskeletal hypertrophy and loss of GFAP+ cell densities in hippocampus. At 4-week timepoint, recoveries of the above mentioned parameters were observed in all groups, except for the full dose group in which the astrocytic hypertrophy reached the highest level, while its density dropped to the lowest level. Strong and localized microgliosis revealed by CD11b immunoreactivity was observed in hilus in the full dose group at 2- and 4-, persisting at 8-week timepoints. Through changing pattern analysis, we conclude that the loss of astroglial resilience is likely to be a determining factor for spontaneous recurrent seizure onset.

Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial

Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A(1c) (HbA(1C)) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.

Strategies for Nevirapine Initiation in HIV‐Infected Children Taking Pediatric Fixed‐Dose Combination “Baby Pills” in Zambia: A Randomized Controlled Trial

Fixed-dose combination scored dispersible stavudine, lamivudine, and nevirapine minitablets (Triomune Baby and Junior; Cipla Ltd) are simpler and cheaper than liquid formulations and have correct dose ratios for human immunodeficiency virus-infected children. However, they cannot be used for dose escalation (DE) of nevirapine. Children were randomized to initiate antiretroviral therapy with full-dose (FD) nevirapine (Triomune Baby or Junior in the morning and evening) versus DE (half-dose nevirapine for 14 days [Triomune in the morning and stavudine-lamivudine {Lamivir-S} in the evening], then FD), in accordance with World Health Organization weight-band dosing tables. The primary end point was nevirapine-related clinical or laboratory grade 3 or 4 adverse events (AEs). In total, 211 children (median [interquartile range {IQR}] age, 5 [ 2-9 ] years; median [IQR] CD4 cell percentage, 13% [8%-18%]) were enrolled and followed up for a median (IQR) of 92 (68-116) weeks. There were 31 grade 3 or 4 AEs that were definitely/probably or uncertainly related to nevirapine in the FD group (18.0 per 100 child-years), compared with 29 in the DE group (16.5 per 100 child-years) (incidence rate ratio, 1.09; 95% confidence interval, 0.63&#x2013;1.87; P = .74). All were asymptomatic; 11 versus 3 were single grade 3 or 4 elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, all of which resolved without a change in nevirapine dose or interruption. Thirteen (12%) FD versus 2 (2%) DE children had grade 1 (2 in FD) or grade 2 (11 in FD and 2 in DE) rashes. Three (2 in FD and 1 in DE) substituted efavirenz, 3 (FD) continued FD nevirapine, and 9 (8 in FD and 1 in DE) temporarily interrupted nevirapine, followed by successful DE. Predictors of nevirapine rash were older age (P = .003) and higher CD4 cell count for age (P = .03). Twenty-two children died (12 in FD and 10 in DE), 1 FD and 5 DE children at <4 weeks; none were considered to be drug related by independent review. Rash was more frequent with FD nevirapine, but 88% had no clinical toxicity; elevated AST or ALT levels were transient and resolved spontaneously, suggesting that routine laboratory monitoring has limited value. Dual pediatric stavudine-lamivudine minitablets are preferred for safe and simple DE; if unavailable, initiating FD Triomune requires timely review for rash, which could be managed by temporary reduction to half-dose Triomune or efavirenz substitution. Current Controlled Trials identifier: ISRCTN31084535 .