Effect modification of dosing strategy (AUC or trough) on AKI associated with vancomycin in combination with piperacillin/tazobactam or cefepime and meropenem.

Piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) and vancomycin (VAN) are commonly used in combination for sepsis. Studies have shown an increased risk of acute kidney injury (AKI) with TZP and VAN compared to FEP or MEM. VAN guidelines recommend area under the curve (AUC) monitoring over trough (Tr) to minimize the risk of AKI. We investigated the association of AKI and MAKE-30 with the two VAN monitoring strategies when used in combination with TZP or FEP/MEM. Adult patients between 2015 and 2019 with VAN > 72 hours were included. Patients with AKI prior to or within 48 hours of VAN or baseline CrCl of ≤30 mL/min were excluded. Four cohorts were defined: FEP/MEM/Tr, FEP/MEM/AUC, TZP/Tr, and TZP/AUC. A Cox Proportional Hazard Model was used to model AKI as a function of the incidence rate of at-risk days, testing monitoring strategy as a treatment effect modification. Multivariable logistic regression was used to model MAKE-30. Overall incidence of AKI was 18.6%; FEP/MEM/Tr = 115 (14.6%), FEP/MEM/AUC = 52 (14.9%), TZP/Tr = 189 (26%), and TZP/AUC = 96 (17.1%) (P < 0.001). Both drug group [(TZP; P = 0.0085)] and monitoring strategy [(Tr; P = 0.0007)] were highly associated with the development of AKI; however, the effect was not modified with interaction term [(TZP*Tr); 0.085)]. The odds of developing MAKE-30 were not different between any group and FEP/MEM/AUC. The effect of VAN/TZP on the development of AKI was not modified by the VAN monitoring strategy (AUC vs trough). MAKE-30 outcomes were not different among the four cohorts.

Prenatal acrylamide exposure results in time-dependent changes in liver function and basal hematological, and oxidative parameters in weaned Wistar rats.

Acrylamide (ACR) is a toxic compound commonly found in fried, baked and heat-processed starchy foods. The current study investigated the time-dependent effects of maternal exposure to non-toxic ACR doses on the oxidative stress, liver function, and basal blood morphology of the rat offspring. Pregnant, Wistar rats were randomly divided into the control group or the groups administrated with ACR (3 mg/kg b.w./day): long exposure for 15 days, medium exposure for 10 days and short exposure for 5 days during pregnancy. Body mass, blood morphology and hematology, serum concentrations of growth hormone, IGF-1, TNF-α, IL-1ß, IL-6 and insulin, liver histomorphometry, liver activity of beclin1, LC2B and caspase3, markers of oxidative stress and the activity of antioxidative enzymes in blood serum and the liver were measured in offspring at weaning (postnatal day 21). Even short prenatal exposure to ACR led to oxidative stress and resulted in changes in liver histomorphometry and upregulation of autophagy/apoptosis. However, the most significant changes were observed following the long period of ACR exposure. This study has shown for the first time that ACR is responsible for changes in body mass in a time-dependent manner, which could lead to more serious illnesses like overweight and diabetes later in life.

Treatment outcomes of bladder stones in children with intact bladders in developing countries: A systematic review of >1000 cases on behalf of the European Association of Urology Bladder Stones Guideline panel.

INTRODUCTION: Bladder stones (BS) are still endemic in children in developing nations and account for a high volume of paediatric urology workload in these areas. The aim of this systematic review is to comparatively assess the benefits and risks of minimally invasive and open surgical interventions for the treatment of bladder stones in children. METHODS: This systematic review was conducted in accordance with Cochrane Guidance. Database searches (January 1970- March 2021) were screened, abstracted, and assessed for risk of bias for comparative randomised controlled trials (RCTs) and non-randomised studies (NRSs) with >10 patients per group. Open cystolithotomy (CL), transurethral cystolithotripsy (TUCL), percutaneous cystolithotripsy (PCCL), extracorporeal shock wave lithotripsy (ESWL) and laparoscopic cystolithotomy (LapCL) were evaluated. RESULTS: In total, 3040 abstracts were screened, and 8 studies were included. There were 7 retrospective non-randomised studies (NRS's) and 1 quasi-RCT with 1034 eligible patients (CL: n=637, TUCL: n=196, PCCL: n=138, ESWL: n=63, LapCL n=0). Stone free rate (SFR) was given in 7 studies and measured 100%, 86.6%-100%, and 100% for CL, TUCL and PCCL respectively. CL was associated with a longer duration of inpatient stay than PCCL and TUCL (p<0.05). One NRS showed that SFR was significantly lower after 1 session with outpatient ESWL (47.6%) compared to TUCL (93.5%) and CL (100%) (p<0.01 and p<0.01 respectively). One RCT compared TUCL with laser versus TUCL with pneumatic lithotripsy and found that procedure duration was shorter with laser for stones <1.5cm (n=25, p=0.04). CONCLUSION: In conclusion, CL, TUCL and PCCL have comparable SFRs but ESWL is less effective for treating stones in paediatric patients. CL has the longest duration of inpatient stay. Information gathered from this systematic review will enable paediatric urologists to comparatively assess the risks and benefits of all urological modalities when considering surgical intervention for bladder stones.

Pharmacotherapy in Coronavirus Disease 2019 and Risk of Secondary Infections: A Single-Center Case Series and Narrative Review.

Since the onset of the coronavirus disease 2019 pandemic, immune modulators have been considered front-line candidates for the management of patients presenting with clinical symptoms secondary to severe acute respiratory syndrome coronavirus 2 infection. Although heavy emphasis has been placed on early clinical efficacy, we sought to evaluate the impact of pharmacologic approach to coronavirus disease 2019 within the ICU on secondary infections and clinical outcomes. DATA SOURCES: PubMed (inception to March 2021) database search and manual selection of bibliographies from selected articles. STUDY SELECTION AND DATA EXTRACTION: Articles relevant to coronavirus disease 2019, management of severe acute respiratory syndrome coronavirus 2-associated respiratory failure, and prevalence of secondary infections with pharmacotherapies were selected. The MeSH terms "COVID-19," "secondary infection," "SARS-CoV-2," "tocilizumab," and "corticosteroids" were used for article identification. Articles were narratively synthesized for this review. DATA SYNTHESIS: Current data surrounding the use of tocilizumab and/or corticosteroids for coronavirus disease 2019 management are limited given the short follow-up period and conflicting results between studies. Further complicating the understanding of immune modulator role is the lack of definitive understanding of clinical impact of the immune response in coronavirus disease 2019. CONCLUSIONS: Based on the current available literature, we suggest prolonged trials and follow-up intervals for those patients managed with immune modulating agents for the management of coronavirus disease 2019.

The immunomodulatory effects of opioids and implications for intensive care unit populations.

Analgesia within the intensive care unit (ICU) is often achieved via the utilization of opioids in alignment with current guidelines. Recent evidence has not only demonstrated the potential impact of opioids in suppression of immune function, but also the potential harm of immunosuppression of patients within the ICU. Despite the potential immunosuppression seen with opioids in this at-risk population, their use remains frequent. In this review, we highlight the potential immunomodulatory impact of opioids within the critically ill and considerations for their use.

A narrative review of pharmacologic de-resuscitation in the critically ill.

Despite evidence highlighting harms of fluid overload, minimal guidance exists on counteraction via utilization of diuretics in the de-resuscitation phase. While diuretics have been shown to decrease net volume and improve clinical outcomes in the critically ill, a lack of standardization surrounding selection of diuretic regimen or monitoring of de-resuscitation exists. Current monitoring parameters of de-resuscitation often rely on clinical signs of fluid overload, end organ recovery and other biochemical surrogate markers which are often deemed unreliable. The majority of evidence suggests that achieving a net-negative fluid balance within 72 h after shock resolution may be of benefit; however, approaches to such goal are uncertain. Loop diuretics are a widely available type of diuretic for removal of volume in patients with sufficient kidney function, with the potential for adjunct diuretics in special circumstances. At present, administration of diuretics within the broad critically ill population fails to find uniformity and often efficacy. Given the lack of randomized controlled trials in this susceptible population, we aim to provide a thorough therapeutic understanding of diuretic pharmacotherapy which is necessary in order to achieve desired goal of fluid balance and improve overall outcomes.

Histomorphometrical changes in intestine structure and innervation following experimental fumonisins intoxication in male Wistar rats.

Fumonisins are highly toxic metabolites produced by Fusarium proliferatum and Fusarium verticillioides. Little is known about the effects of a chronic low level of fumonisins on intestinal structure and innervation in monogastric animals, even though the intestine is the first organ exposed to fumonisins. The influence of the most prevalent strains of fumonisins, FB1 and FB2, on intestinal and liver morphology, the enteric nervous system and intestinal epithelial cell prolif- eration was investigated in an experimental rat model of fumonisin intoxication. Adolescent (5-weeks-old), male Wistar rats were randomly divided into a control group (C group) not treated with fumonisins or intoxicated with fumonisins (FB group). FB1 together with FB2 were daily administered intragastrically at a dose of 90 mg/kg body weight for 21 days. The damaging effect was assessed by determination of the activity of ALAT and AspAT. Samples from the small intes- tine and liver were taken and blood samples were collected to determine the activity of gamma- -glutamyl transferase (GGT) and amylase. The exposure to FBs resulted in histopathological degenerative alterations in hepatocytes, including mild vacuolar degeneration and ballooning. FB exposure was also toxic in the duodenum and jejunum, where significant changes in morphology, cell proliferation, collagen wall fibres and innervation were observed. Taken together, the results obtained strengthen the hypothesis that chronic exposure to FBs could induce intestinal damage, including damage to the enteric nervous system and may have consequences for general health.

To Block or Not: Updates in Neuromuscular Blockade in Acute Respiratory Distress Syndrome.

Objective: To review and evaluate neuromuscular blocking agents (NMBAs) in critically ill patients with acute respiratory distress syndrome (ARDS). Data Sources: A literature search utilizing PubMed was performed (January 1991 to January 2020) using the following search terms: (neuromuscular blocking agents OR neuromuscular blockade OR cisatracurium OR rocuronium OR vecuronium OR pancuronium OR atracurium) AND *acute respiratory distress syndrome OR acute lung injury). Publications in English were evaluated. Study Selection and Data Extraction: Relevant clinical studies in humans were considered. Data Synthesis: Although NMBAs have been used for decades in the setting of ARDS, questions regarding mortality benefit remain. Early NMBA, within 48 hours of lung injury, have been historically used in critically ill patients with ARDS to aid in increasing alveolar recruitment, improving patient-ventilator synchrony, and promoting oxygenation by the prevention of contraction of respiratory muscles. Until recently, the literature showed an improvement in 90-day adjusted mortality. However, recent literature has demonstrated the lack of a mortality benefit. The continued receipt of NMBAs, with no clear benefit, could potentially lead to increased costs, skin breakdown, corneal abrasions, venous thromboembolisms, intensive care unit acquired weakness, and awareness with inappropriate sedation. Relevance to Patient Care and Clinical Practice: This review aims at discussing the preferred NMBA based on mechanism of action and reviews specific clinical trial data for the use of NMBAs in ARDS, clinical implications of these trial data, complications for the use of NMBAs, and needed future directions. Conclusions: The mortality benefit of NMBAs in ARDS has contradicting evidence with potentially serious adverse effects and notable controversies.

Modelling the radioluminescence of Sm2+ and Sm3+ in the dosimeter material NaMgF3:Sm.

Photoluminescence (PL) and radioluminescence (RL) measurements were made on NaMgF3:Sm before, during and after exposure to high doses of ionising radiation. Magnetic measurements prior to irradiation showed that approximately 10% of the total Sm concentration was in the divalent state. The RL from Sm3+ was found to increase while the Sm2+ RL decreased with increasing x-ray dose before reaching steady-state values for high doses. This behaviour is opposite to that previously reported for Sm3+ and Sm2+ PL. We show that this apparent discrepancy can be accounted for by a RL model where there is a hole trap, an electron trap, and direct x-ray induced carrier recombination at Sm2+ and Sm3+. Furthermore, a good fit to the dose-dependence of all of the Sm RL emissions can be obtained by assuming that the relevant electron and hole traps are close to Sm3+. Our model accounts for F3-centre production during irradiation that affects some of the Sm3+ RL emissions via reabsorption of the RL by the F3-centres. Thus, the rate of F3-centre production can be conveniently monitored by the RL intensity ratio, I RL(567 nm)/I RL(650 nm). Additionally, the Sm2+ RL emissions may be expressed as [1.94 × I RL(721 nm)] - I RL(695 nm) to determine the real-time dose rate, independent of dose history.

New onset dysphagia and pulmonary aspiration following sclerotherapy for a complex cervical venolymphatic malformation in an infant: Case report and review of the literature.

We present the case of a 2-year-old male with a complex left cervical venolymphatic malformation who underwent doxycycline sclerotherapy at 12 months of age complicated by new onset pulmonary aspiration. A review of the literature reveals this to be a rare complication of sclerotherapy and only the second reported case. METHODS: Procedural details with associated imaging including endoscopic airway and swallowing evaluation are included. A literature review of cervical and laryngeal sclerotherapy complications was performed and discussed. RESULTS: A 12-month-old male underwent sclerotherapy with doxycycline for a complex parapharyngeal and paralaryngeal venolymphatic malformation. The postoperative course was complicated by new onset dysphagia, aspiration, and decreased laryngeal sensation. Gastric feeding and swallowing therapy were necessary due to prolonged difficulty. The sclerotherapy treatment resulted in near elimination of the cervical components of the lesion at 12 months follow up. The child progressed to total oral feeding by 17 months post-treatment with no evidence of decreased laryngeal sensation. An extensive literature review identified only one reported case of new onset dysphagia and decreased laryngeal sensation after doxycycline sclerotherapy. CONCLUSIONS: Doxycycline sclerotherapy for cervical venolymphatic malformations rarely can cause adjacent neural injury resulting in laryngeal complications. Our case report and literature review suggest that symptom management and appropriate aspiration precautions are necessary in infants or children with presumed vagus or laryngeal nerve injury, and injury is likely only temporary.

Left Ventricular Function and Cardiac Biomarker Release-The Influence of Exercise Intensity, Duration and Mode: A Systematic Review and Meta-Analysis.

OBJECTIVE: We performed a systematic review, meta-analysis and meta-regression of exercise studies that sought to determine the relationship between cardiac troponin (cTn) and left ventricular (LV) function. The second objective was to determine how study-level and exercise factors influenced the variation in the body of literature. DATA SOURCES: A systematic search of Pubmed Central, Science Direct, SPORTDISCUS and MEDLINE databases. ELIGIBILITY CRITERIA: Original research articles published between 1997 and 2018 involving > 30 mins of continuous exercise, measuring cardiac troponin event rates and either LV ejection fraction (LVEF) or the ratio of the peak early (E) to peak late (A) filling velocity (E/A ratio). DESIGN: Random-effects meta-analyses and meta-regressions with four a priori determined covariates (age, exercise heart rate [HR], duration, mass). REGISTRATION: The systematic search strategy was registered on the PROSPERO database (CRD42018102176). RESULTS: Pooled cTn event rates were evident in 45.6% of participants (95% confidence interval (CI) 33.6-58.2); however, the overall effect was non-significant (P > 0.05). There were significant (P < 0.05) reductions in E/A ratio of - 0.38 (SMD = - 1.2, 95% CI - 1.4 to - 1.0), and LVEF of - 2.02% (SMD = - 0.38, 95% CI - 0.7 to - 0.1) pre- to post-exercise. Increased exercise HR was a significant predictor of troponin release and E/A ratio. Participant age was negatively associated with cTn release. There was a significant negative association between E/A ratio with increased rates of cTn release (P < 0.05). CONCLUSIONS: High levels of statistical heterogeneity and methodological variability exist in the majority of EICF studies. Our findings show that exercise intensity and age are the most powerful determinants of cTn release. Diastolic function is influenced by exercise HR and cTn release, which implies that exercise bouts at high intensities are enough to elicit cTn release and reduce LV diastolic function. Future EICF studies should (1) utilise specific echocardiographic techniques such as myocardial speckle tracking, (2) ensure participants are euhydrated during post-exercise measurements, and (3) repeat measures in the hours following exercise to assess symptom progression or recovery. It is also recommended to further explore the relationship between aging, training history, and exercise intensity on cTn release and functional changes.

Structural changes in the small intestine of female turkeys receiving a probiotic preparation are dose and region dependent.

Gut microbiota have been shown to play a critical role in the maintenance of host health. Probiotics, which regulate gut microbiota balance, could serve as an effective alternative to antibiotic growth promoters. Since changes in the gastrointestinal tract, caused by a variety of different strains, groups and amounts of microorganisms, may be reflected in its histological structure, the aim of the present study was to examine the effects of rising doses of a mixed probiotic preparation on the structure and development of the small intestine of female turkeys. Eighty, three-day-old, healthy, female turkeys (Big-6 breed) were used in the current (16-week) study. The turkeys were randomly allocated to four weight-matched (59.70 ± 0.83 g) groups (n = 20), according to probiotic treatment dose (0, 107 cfu•g-1, 108 cfu•g-1 or 109 cfu•g-1, in 500 g•1000 kg-1) (cfu - a colony-forming unit). Three, non-genetically modified strains of probiotic cultures obtained from poultry, four bacterial and one yeast culture, were used. Histomorphometric analysis of the structure of the small intestinal wall of the duodenum and jejunum was performed. All probiotic doses used in the current study exerted a beneficial effect on the histological structure of the small intestine; however, the observed effect was dose and region dependent. Significant increases in villi height, crypt depth, villi and crypt width, mucosa thickness, epithelial height, enterocyte number, absorption surface and intestinal ganglia geometric indices were observed, specifically in the duodenum of birds receiving an intermediate dose of probiotic (108 cfu•g-1). The probiotic doses used in the current study differed significantly in their effect on the small intestine (P < 0.01), with the intermediate dose (108 cfu•g-1) significantly improving 58% of the parameters assessed, compared to the control. The duodenum was more susceptible to the favourable effects of the probiotic than the jejunum (56% v. 31% improvement in the parameters assessed) (P < 0.01). The weakest favourable effect was observed in the group that received the highest dose of probiotic.

Comparative Biology of Cycad Pollen, Seed and Tissue - A Plant Conservation Perspective.

Cycads are the most endangered of plant groups based on IUCN Red List assessments; all are in Appendix I or II of CITES, about 40% are within biodiversity 'hotspots,' and the call for action to improve their protection is long-standing. We contend that progress in this direction will not be made until there is better understanding of cycad pollen, seed and tissue biology, which at the moment is limited to relatively few (<10%) species. We review what is known about germplasm (seed and pollen) storage and germination, together with recent developments in the application of contemporary technologies to tissues, such as isotype labelling, biomolecular markers and tissue culture. Whilst progress is being made, we conclude that an acceleration of comparative studies is needed to facilitate the integration of in situ and ex situ conservation programmes to better safeguard endangered cycads.

First detection of Edwardsiella ictaluri (Proteobacteria: Enterobacteriaceae) in wild Australian catfish.

The bacterium Edwardsiella ictaluri is considered to be one of the most significant pathogens of farmed catfish in the United States of America and has also caused mortalities in farmed and wild fishes in many other parts of the world. E. ictaluri is not believed to be present in wild fish populations in Australia, although it has previously been detected in imported ornamental fishes held in quarantine facilities. In an attempt to confirm freedom from the bacterium in Australian native fishes, we undertook a risk-based survey of wild catfishes from 15 sites across northern Australia. E. ictaluri was detected by selective culturing, followed by DNA testing, in Wet Tropics tandan (Tandanus tropicanus) from the Tully River, at a prevalence of 0.40 (95% CI 0.21-0.61). The bacterium was not found in fishes sampled from any of the other 14 sites. This is the first report of E. ictaluri in wild fishes in Australia.

Use of a novel oleaginous microorganism as a potential source of lipids for weanling pigs.

Weanling pigs are at risk of succumbing to illness due to an immature immune system and insufficient supply of available energy at the time of weaning. This study was aimed at determining whether oleaginous bacteria could serve as a source of lipids to weanling pigs. Weanling pigs were provided a daily dose of 1×109 colony fomring unit (CFU) = kg-1 of the novel oleaginous Enterobacter cloacae strain JD6301 or JD8715 (which is a variant form of JD6301 capable of producing extracellular triglycerides) via oral gavage for 5 d. Serum was collected every 6 h and intestinal samples were collected at 6 d. Providing pigs with JD6301 or JD8715 significantly increased serum concentrations of triglycerides and non-esterified fatty acids (NEFA) within 72 h. Additionally, the JD6301 and JD8715 strains were able to survive within the gastrointestinal tract throughout the duration of the study. These results suggest that providing Enterobacter cloacae can increase the serum lipids in the pigs, thus potentially providing an additional source of energy to animals during times of stress. This could potentially help improve the metabolic response of animals during times of stress.

Listeria monocytogenes infection of HD11, chicken macrophage-like cells.

Listeria monocytogenes can be carried by and infect poultry, although the clinical disease in birds is rare. Escape from macrophage phagocytosis is a key step in pathogenesis for L. monocytogenes. Therefore, we investigated the infection of the chicken macrophage-like cell line HD11 with 2 strains of L. monocytogenes EGD-e and Scott A. After infection, L. monocytogenes was quantified by spread plating and HD11 was quantified with trypan blue exclusion stain before enumeration. The standard macrophage killing protocols require washing the cell monolayers 3 times with PBS, which was found to negatively influence HD11 monolayers. Maximum bacterial densities within macrophages were not different between the 2 Listeria strains. HD11 required more than 11 h to effectively reduce intracellular L. monocytogenes Scott A, and Scott A was more susceptible to HD11 killing than EGD-e. It appears that Listeria infection initially causes attenuation of HD11 growth, and infected HD11 cells do not begin to lyse until at least 11 h post infection. These results suggest that there are subtle strain to strain differences in response to HD11 macrophage phagocytosis. The long lead-time required for HD11 to kill L. monocytogenes cells means that there is sufficient time available for chicken macrophages to circulate in the blood and transfer the intracellular Listeria to multiple tissues.

Revision surgery for the stiff total knee arthroplasty.

AIMS: The aim of this study was to examine the results of revision total knee arthroplasty (TKA) undertaken for stiffness in the absence of sepsis or loosening. PATIENTS AND METHODS: We present the results of revision surgery for stiff TKA in 48 cases (35 (72.9%) women and 13 (27.1%) men). The mean age at revision surgery was 65.5 years (42 to 83). All surgeries were performed by a single surgeon. Stiffness was defined as an arc of flexion of < 70° or a flexion contracture of > 15°. The changes in the range of movement (ROM) and the Western Ontario and McMasters Osteoarthritis index scores (WOMAC) were recorded. RESULTS: At a mean follow up of 59.9 months (12 to 272) there was a mean improvement in arc of movement of 45.0°. Mean flexion improved from 54.4° (5° to 100°) to 90° (10° to 125°) (p < 0.05) and the mean flexion contracture decreased from 12.0° (0° to 45°) to 3.5° (0° to 25°) (p < 0.05). The mean WOMAC scores improved for pain, stiffness and function. In patients with extreme stiffness we describe a novel technique, which we have called the 'sloppy' revision. This entails downsizing the polyethylene insert by 4 mm and using a more constrained liner to retain stability. CONCLUSION: To our knowledge, this is the largest series of revision surgeries for stiffness reported in the literature where infection and loosening have been excluded. TAKE HOME MESSAGE: Whilst revision surgery is technically demanding, improvements in ROM and outcome can be achieved, particularly when the revision is within two years of the primary surgery. Cite this article: Bone Joint J 2016;98-B:622-7.

Subcutaneous Administration of Otelixizumab is Limited by Injection Site Reactions: Results of an Exploratory Study in Type 1 Diabetes Mellitus Patients.

Targeting CD3 antigens on human T lymphocytes with monoclonal antibodies has been shown to reduce the rate of decline of C-peptides in recent-onset type 1 diabetes mellitus patients. However, effective doses are associated with infusion reactions typical of "cytokine release syndrome" and appear to be dose-limiting when administered as short-duration infusions. A possible alternative approach, which may reduce the rate of T cell activation and consequent systemic cytokine release, is to inject subcutaneously. We investigated single- and repeat-dose subcutaneous administration of the anti-CD3 monoclonal antibody otelixizumab in small cohorts of patients with type 1 diabetes. Transient reductions in free or unbound CD3 antigen on CD4+ and CD8+ cells and absolute lymphocyte count were observed in the blood of these patients during treatment, consistent with the known mechanism of action of otelixizumab and other anti-CD3 monoclonal antibodies. This was despite the very low systemic exposure of antibodies measured during the same time period. With the exception of sporadic headaches, other symptoms associated with cytokine release syndrome, such as fever, nausea, vomiting, myalgia, and arthralgia, were absent in treated patients. However, treatment-related injection site reactions were consistently observed. The reactions were erythematous and their sizes were dose-dependent; in some cases, reactions persisted for up to 2 weeks following the start of treatment. While patients responded well to topical corticosteroid treatment and prophylaxis reduced the intensity of injection site reactions, the reactions were considered dose-limiting and higher doses were not investigated.

Urinary C-peptide analysis in an intervention study: experience from the DEFEND-2 otelixizumab trial.

AIMS: To demonstrate that analysis of urinary C-peptide across multiple study sites in the context of an intervention trial (DEFEND-2) is a viable alternative to mixed meal testing and delivers results that correlate to mixed meal testing estimation of endogenous insulin production. METHODS: Second morning void urine was collected for analysis and was available from 161 subjects at baseline (55 placebo, 106 otelixizumab), and 146 subjects (47 placebo, 99 otelixizumab) at month 12. Urinary C-peptide concentration was corrected for urinary creatinine [urinary C-peptide/creatinine ratio (UCPCR)] and serum C-peptide from the mixed meal tolerance test was calculated using area under the plasma concentration-time curve (AUC) normalized over 120 min. The correlation between mixed meal stimulated C-peptide AUC (mmol/l/min) and UCPCR (nmol/mmol), as well as the correlation between insulin use (IU/kg), and HbA1c (%) with UCPCR, was determined. RESULTS: UCPCR and mixed meal testing C-peptide AUC were correlated, with a correlation coefficient of 0.4172. UCPCR was not correlated with exogenous insulin use (r = -0.089) or with HbA1c (r = -0.032). CONCLUSIONS: Urinary C-peptide estimation should be considered as a measure of endogenous insulin production in future Type 1 diabetes mellitus outcome trials. A change in the timing for urine collection (to 120 min post standard meal) may provide a tighter correlation to C-peptide measured via a traditional mixed meal test.