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Aims To determine if urine C-peptide/creatinine ratio is a useful tool for monitoring β-cell function in new-onset Type 1 diabetes. Methods Data were obtained from a prospective immunomodulation study in people with Type 1 diabetes ≤ 3 months from diagnosis, with a standard mixed-meal tolerance test and measurement of urine C-peptide/creatinine ratio carried out at 0, 3, 6, 9 and 12 months. The change in the insulin-dose-adjusted HbA1c level was also correlated with the change in serum/urine C-peptide level during the 12-month follow-up period. Results A significant reduction in urine C-peptide/creatinine ratio, measured after a mixed-meal, was reached at 9 months (−45.4%), whilst the reduction in stimulated serum C-peptide level reached significance after 3 months (−54.7%) in placebo-treated participants. Neither change in stimulated serum C-peptide nor change in urine C-peptide level correlated with each other, and nor did change in insulin-dose-adjusted HbA1c level in the first 6 months, but all measures correlated significantly in the second half of the 12-month follow-up period. Conclusion Mixed-meal-stimulated urine C-peptide/creatinine ratio was similar to, although less sensitive than, stimulated serum C-peptide level in monitoring β-cell function during the first year after diagnosis. Because the former is significantly less invasive, it warrants inclusion in further studies in Type 1 diabetes and may represent an attractive alternative outcome measure in cohort studies and in children. [ABSTRACT FROM AUTHOR]

Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (T H 1 and T H 17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12-18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (T H 17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of T H 17.1 cells co-expressing IL-2 and granulocyte-macrophage colony-stimulating factor (IL-2 + GM-CSF + T H 17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of T H 17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380)., (© 2024. The Author(s).)

Introduction: Most individuals newly diagnosed with type 1 diabetes (T1D) have 10%-20% of beta-cell function remaining at the time of diagnosis. Preservation of residual beta-cell function at diagnosis may improve glycaemic control and reduce longer-term complications.Immunotherapy has the potential to preserve endogenous beta-cell function and thereby improve metabolic control even in poorly compliant individuals. We propose to test ustekinumab (STELARA), a targeted and well-tolerated therapy that may halt T-cell and cytokine-mediated destruction of beta-cells in the pancreas at the time of diagnosis., Methods and Analysis: This is a double-blind phase II study to assess the safety and efficacy of ustekinumab in 72 children and adolescents aged 12-18 with new-onset T1D.Participants should have evidence of residual functioning beta-cells (serum C-peptide level >0.2nmol/L in the mixed-meal tolerance test (MMTT) and be positive for at least one islet autoantibody (GAD, IA-2, ZnT8) to be eligible.Participants will be given ustekinumab/placebo subcutaneously at weeks 0, 4 and 12, 20, 28, 36 and 44 in a dose depending on the body weight and will be followed for 12 months after dose 1.MMTTs will be used to measure the efficacy of ustekinumab for preserving C-peptide area under the curve at week 52 compared with placebo. Secondary objectives include further investigations into the efficacy and safety of ustekinumab, patient and parent questionnaires, alternative methods for measuring insulin production and exploratory mechanistic work., Ethics and Dissemination: This trial received research ethics approval from the Wales Research Ethics Committee 3 in September 2018 and began recruiting in December 2018.The results will be disseminated using highly accessed, peer-reviewed medical journals and presented at conferences., Trial Registration Number: ISRCTN14274380., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen-DR4( DRB1*0401 )-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group's daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell-specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: In a non-inferiority (NI) trial, analysis based on the intention-to-treat (ITT) principle is anti-conservative, so current guidelines recommend analysing on a per-protocol (PP) population in addition. However, PP analysis relies on the often implausible assumption of no confounders. Randomisation-based efficacy estimators (RBEEs) allow for treatment non-adherence while maintaining a comparison of randomised groups. Fischer et al. have developed an approach for estimating RBEEs in randomised trials with two active treatments, a common feature of NI trials. The aim of this paper was to demonstrate the use of RBEEs in NI trials using this approach, and to appraise the feasibility of these estimators as the primary analysis in NI trials., Methods: Two NI trials were used. One comparing two different dosing regimens for the maintenance of remission in people with ulcerative colitis (CODA), and the other comparing an orally administered treatment to an intravenously administered treatment in preventing skeletal-related events in patients with bone metastases from breast cancer (ZICE). Variables that predicted adherence in each of the trial arms, and were also independent of outcome, were sought in each of the studies. Structural mean models (SMMs) were fitted that conditioned on these variables, and the point estimates and confidence intervals compared to that found in the corresponding ITT and PP analyses., Results: In the CODA study, no variables were found that differentially predicted treatment adherence while remaining independent of outcome. The SMM, using standard methodology, moved the point estimate closer to 0 (no difference between arms) compared to the ITT and PP analyses, but the confidence interval was still within the NI margin, indicating that the conclusions drawn would remain the same. In the ZICE study, cognitive functioning as measured by the corresponding domain of the QLQ-C30, and use of chemotherapy at baseline were both differentially associated with adherence while remaining independent of outcome. However, while the SMM again moved the point estimate closer to 0, the confidence interval was wide, overlapping with any NI margin that could be justified., Conclusion: Deriving RBEEs in NI trials with two active treatments can provide a randomisation-respecting estimate of treatment efficacy that accounts for treatment adherence, is straightforward to implement, but requires thorough planning during the design stage of the study to ensure that strong baseline predictors of treatment are captured. Extension of the approach to handle nonlinear outcome variables is also required., Trial Registration: The CODA study: ClinicalTrials.gov, identifier: NCT00708656 . Registered on 8 April 2008. The ZICE study trial: ClinicalTrials.gov, identifier: NCT00326820 . Registered on 16 May 2006.

Background: Adherence to medication is an issue of great importance for patients with ulcerative colitis. Once daily mesalazine seems to be no worse than divided doses in preventing relapse in remitting patients. Although this has been attributed to improved adherence, detailed measures of adherence have been lacking from previous studies., Methods: A 1-year substudy was conducted alongside a trial that compared 2 different dosing regimens (once daily versus three times daily) of mesalazine for patients in remission with ulcerative colitis. Participants in the substudy had their adherence monitored electronically using the medication event monitoring system, self-report, and tablet counts. We compared measures, determined factors associated with adherence and associations between adherence and relapse, modeled adherence over time, and explored behavioral aspects., Results: We included 58 participants. Adherence was high across all measures (89.3% self-report, 96.7% tablet counts, and 89.2% medication event monitoring system). Agreement between the measures was poor at times. Adherence according to the medication event monitoring system best distinguished between the participants who relapsed (71.4%) and those who remained in remission (93.4%), although this difference was not statistically discernible at the 5% level. Adherence deteriorated over the study period, with three times daily participants generally less adherent than once-daily participants (odds ratio, 0.03; 95% confidence interval, 0.01-0.08). Adherence was higher on weekdays (odds ratio, 1.47; 95% confidence interval, 1.31-1.65) and around clinic visit dates (odds ratio, 1.43; 95% confidence interval, 1.18-1.72)., Conclusions: Simple dosing regimens are preferable to multiple daily dosing regimens. Electronic monitoring of adherence should be used more often in clinical studies. Self-reported adherence and tablet counts may underestimate adherence. Adherence declined over time, and adherence was generally lower and more varied for those allocated to the three times daily regimen.

Background: Mesalazine (Asacol) is still widely prescribed in divided doses for ulcerative colitis (UC), despite evidence that adherence is improved by once-daily (OD) prescribing. We aimed to investigate whether OD Asacol was as effective as three times (TDS) daily dosing, and to evaluate the role of treatment adherence., Methods: An investigator-blind randomized trial was undertaken comparing OD Asacol (three 800 mg tablets) versus one 800 mg TDS in maintenance of remission of UC over 1 year. The primary endpoint was relapse rate, and noninferiority would be concluded if the lower limit of the two-sided 95% confidence interval (CI) of the difference in proportions relapsing (TDS-OD) exceeded -10%. Adherence was measured by tablet counts and self-reported adherence. A subgroup of patients used a bottle cap that recorded all bottle opening events., Results: In all, 213 patients were randomized. In the intention-to-treat (ITT) population, relapse rates were 31% (95% CI 22%-40%) in the OD and 45% (95% CI 35%-54%) in the TDS group. Primary analysis confirmed the noninferiority of OD dosing. Two of the study populations, ITT and per-protocol (PP), showed potential superiority of OD dosing. All measures of adherence showed that it was significantly better in the OD group. Multivariate analysis, however, showed OD dosing was associated with lower relapse risk independently of adherence., Conclusions: OD dosing with Asacol 2.4 g is as safe and effective as TDS dosing, and secondary analysis confirmed significantly reduced relapse rates. The benefit, however, was clinically borderline and may relate in part to ease of adherence., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

The commercial production of recombinant human monoclonal antibody therapeutics demands robust processes. In this article we describe the development of a pH-conductivity hybrid gradient for a cation-exchange chromatography step to obtain high binding capacity and consistent purification resolution in scale process. Operational parameters and their ranges were characterized with DOE statistical method. Aggregate, DNA and leached protein A removal were examined during development. The advantages and disadvantages of hybrid gradient elution compared to sodium chloride gradient elution were explored. As this step was designed as a good fit for the compatibility of the feed and operating pH/conductivity conditions for next step, the effects of elution by either changing sodium chloride concentration or changing pH of elution buffers on overall separation efficiency were compared. The operation condition was further confirmed in six 2000 L scale runs. The thorough evaluation demonstrated process reliability of hybrid gradient cation-exchange chromatography with high step purity and yield.

Objective: To report the incidence of Crohn's disease in the city of Cardiff between 1991 and 1995, in relation to the data of the preceding 65 years., Methods: The incidence of Crohn's disease was studied by collecting information from clinical records, the department of pathology database and a questionnaire sent to local family practitioners., Results: Eighty-four new patients with Crohn's disease, and resident in Cardiff, were diagnosed between 1991 and 1995. The mean incidence for this quinquennium was 56 cases per 10(6) population per year (95% confidence interval, 44-68). There was a female predominance, particularly in young adults, with an overall male to female ratio of 0.47. Colorectal disease was the most common site of disease at the time of diagnosis., Conclusions: In relation to the findings of our previous studies, the data suggest that the overall incidence of Crohn's disease is now stable, but that the proportion with colorectal disease continues to increase and there is a marked female preponderance in Crohn's disease presenting in young people.

The Kidney Stone Center of the Pacific (KSCoP) currently provides statewide services for kidney lithotripsy. The non-invasive technique uses shock waves to disintegrate kidney stones. Extracorporeal shock wave lithotripsy (ESWL) can be used successfully in 85% to 90% of kidney stone patients when surgery is indicated.

A patient with FIGO Stage IIB cervical carcinoma underwent an extraperitoneal lymphadenectomy with exploratory laparotomy and washings for surgical staging. Intraperitoneal tumor was found. Seven months later, the tumor recurred as a subcutaneous nodule in the surgical incision. The implications of this recurrence are discussed.

Expensive diagnostic and treatment services and equipment are naturally suited to large, populous medical market areas, with sufficient forecasted service demand to justify the large investment in capital, construction and staffing. Only major tertiary or secondary medical centers with shared resources can justify the first-generation investment in the multimillion-dollar purchases of magnetic resonance imaging (MRI), megavoltage linear accelerators, or lithotripters. The regional referral system in most nations accommodates the outlying population in the less developed rural sectors.

Throughout the 1980s, Medicare has 'turned against its service suppliers' and began to literally rewrite the rules of the health insurance game. This paper is set in that changing environment and describes one supplier's response.

Fifty-seven patients with acute myocardial infarction were observed for early postmyocardial infarction angina and associated transient ST-segment changes. Nine patients had postinfarction angina with transient ST-segment elevation (group 1), seventeen patients had postinfarction angina with ST-segment depression or no ST-segment changes (Group 2), and 31 patients had no postinfarction angina (Group 3). The patients in Group 1 had a statistically significant increased incidence of early reinfarction and death, when compared with the other two groups, singly or combined. There was no significant difference in the incidence of reinfarction and death when Group 2 is compared with Group 3. Patients with transient ST-segment elevation associated with early postmyocardial infarction angina may be an appropriate group in whom to consider newer, more aggressive modes of postinfarction management.

All currently marketed neuroleptics induce extrapyramidal symptoms (EPS). These EPS are a function of biological sensitivity, neuroleptic molecular structure, dose, age, sex, and duration of neuroleptic treatment. Because of their association with EPS, at times irreversible, and their modest efficacy in the non-schizophrenic patients, neuroleptic administration should be limited predominantly to schizophrenic patients. Furthermore EPS should not be used as a guideline for the efficacy of neuroleptics as formerly assumed. For EPS may occur at subtherapeutic doses of neuroleptics and may be absent in patients experiencing clinical response. Neuroleptic dose should be the lowest efficacious dose required to provide symptom remission. In addition, antiparkinsonian (AP) agents should be administered predominently contraactively and not routinely in combination with neuroleptics. With the judicious administration of neuroleptic agents and AP medication, distressing EPS can be prevented or minimized, while providing control of schizophrenic symptoms.

Two patients with chest pain had angiographically-demonstrated communications between the three coronary arteries and the left ventricular chamber. Communications between coronary arteries and the left ventricle are unusual and communications between all three coronary arteries and the left ventricle are rare. These anomalies are, however, commonly associated with symptoms of chest pain. The presence of left ventricular hypertrophy and a widened pulse pressure may suggest a greater hemodynamic effect of the shunt flow than often suspected angiographically.