Exaggeration of PFS by blinded, independent, central review (BICR).

BACKGROUND: Recent published studies have shown meaningful discrepancies between local investigator and blinded, independent, central review (BICR) assessed median progression-free survival (PFS). When the local review but not BICR shows progression, generally, no further assessments are carried out and patients are censored in the BICR analysis, leading to violation of the statistical assumptions of independence between censoring and outcome used in survival analysis methods. METHODS: We carried out a simulation study to assess methodological reasons behind these discrepancies and corroborated our findings in a case study of three BRCA-mutated ovarian cancer trials. We briefly outline possible methodological solutions that may lead to improved estimation of the BICR medians. RESULTS: The Kaplan-Meier (KM) curve for the BICR PFS can often be exaggerated. The degree of bias is largest when there is reasonably strong correlation between BICR and local PFS, especially when PFS is long compared with assessment frequency. This can result in an exaggeration of the medians and their difference; however, the hazard ratio (HR) is much less susceptible to bias. Our simulation shows that when the true BICR median PFS was 19 months, and patients assessed every 12 weeks, the estimated KM curves were materially biased whenever the correlation between BICR and local PFS was 0.4 or greater. This was corroborated by case studies where, in the active arm, the BICR median PFS was between 6 and 11 months greater than the local median PFS. Further research is required to find improved methods for estimating BICR survival curves. CONCLUSIONS: In general, when there is a difference between local and BICR medians, the true BICR KM curve is likely to be exaggerated and its true median will probably lie somewhere between the observed local and BICR medians. Presentation of data should always include both BICR and local results whenever a BICR is carried out.

A novel quantitative real-time PCR diagnostic assay for fecal and nasal swab detection of an otariid lungworm, Parafilaroides decorus.

Parafilaroides decorus, also known as sea lion lungworm, is a metastrongyloid nematode that infects otariid hosts, such as the charismatic California sea lion, Zalophus californianus. P. decorus causes bronchointerstitial pneumonia, respiratory distress, reduced ability to swim, dive and hunt and as a result, increased mortality particularly in young animals. Respiratory disease is a leading cause of stranding and admission to rehabilitation centers on the Pacific coast. Low-coverage genomic sequencing of four P. decorus individuals analyzed through Galaxy's RepeatExplorer identified a novel repeat DNA family we employed to design a sensitive quantitative PCR (qPCR) assay for diagnosing infections from fecal or sputum samples. The assay detects as little as 10 fg of P. decorus DNA and a linear regression model developed using a standard curve can be used to estimate the concentration of P. decorus DNA in a sample, ± 0.015 ng. This knowledge can be leveraged to estimate the level of parasite burden, which can be used to design improved treatments for animals in rehabilitation. Improved treatment of infections will aid in more animals being successfully released back into the wild.

Repeatability of measuring knee flexion angles with wearable inertial sensors.

BACKGROUND: As assessment with inertial-measurement-units (IMUs) increases in research and in clinics, it is important to be aware of the repeatability of these sensors. The objectives of this experiment were to evaluate the measurement repeatability of IMU joint angles using a repeatable robot controller and an anthropomorphic leg phantom and to determine effects of joint speed and sensor positioning on the angles collected by these sensors. Comparisons to an electro-goniometer and three-dimensional (3D) motion capture cameras were also completed. METHODS: Two dual-IMU setups (posterior and lateral) were tested concurrently with an electro-goniometer and 3D motion capture cameras using a repeatable robot controller and a leg phantom. All modalities were attached to the phantom, which was flexed 10 times using a pre-programmed motion pathway during each test. Mean angles were compared across tests. Effects of joint speed, sensor re-positioning, and anatomical placement of the sensors on repeatability were assessed. RESULTS: Re-positioning caused greater deviation to the maximum and minimum angles than differences in speed. Overall, the means ±â€¯standard deviations, and 95% confidence intervals of the maximum angles across all tests for the 3D camera markers, electro-goniometer, posterior IMUs, and lateral IMUs were 119.4 ±â€¯0.3° (119.4, 119.5), 112.4 ±â€¯0.5° (112.3, 112.5), 116.2 ±â€¯2.4° (115.7, 116.7), and 118.3 ±â€¯1.1° (118.1, 118.6). CONCLUSIONS: Both posterior and lateral IMU setups demonstrated acceptable repeatability in measurement of range of motion that was advantageous to manual goniometer methods. Posterior and lateral IMU setups demonstrated overlapping standard deviations about their means.

Methylnitrosourea-induced carcinoma in organ-cultured fetal human pancreas.

Explants from 12- to 14-week-old human fetal pancreases were organ cultured in a chemically defined medium and cultured for up to 12 months in the presence or absence of methylnitrosourea (MNU). Differentiation of the exocrine pancreas occurred in vitro, and explants cultured in the absence of MNU for 4 weeks or longer revealed normal acinar structures with zymogen granules. Ducts and ductules also developed normally. The undifferentiated tubular structures of the 12- to 14-week fetal pancreas expressed neither ductal nor acinar cell markers. Acinar cell surface marker appeared first after 2 weeks of culture, and the development of centroacinar and ductal cell markers followed 2 to 4 weeks later. MNU-treated explants showed minimal degeneration and necrosis. MNU caused early loss of apical cytoplasm and zymogen granules in acinar cells, resulting in dilation of acinar lumens, concomitant proliferation of cells bearing duct cell markers, and ductal hyperplasia. Enhanced foci of proliferation and carcinoma developed within 3 and 5 months of treatment, respectively. Cells derived from 4- to 5-month MNU-treated explants were tumorigenic in nude mice. Tumor cells revealed a human karyotype and expressed duct cell surface markers.

Blood pressure monitor-induced petechiae and ecchymoses.

A case is presented of a diabetic, hypertensive, female patient who suffers from a bleeding complication from application of an ambulatory blood pressure monitor. A recent literature search is referred to and practitioners are cautioned against this adverse reaction.

Effect of doxazosin monotherapy on blood pressure and plasma lipids in patients with essential hypertension.

The efficacy and safety of doxazosin (DOX) for the treatment of hypertension was investigated. A multicenter, double-blind, placebo-controlled, parallel design was employed. A 4-week placebo runin period was followed by a 9-week double-blind period during which patients were randomly assigned to placebo or 2, 4, or 8 mg doxazosin. Blood pressures (BP) and heart rates (HR) were measured 24 hours postdose. The mean changes in standing BP (mmHg) were -6.2/-6.9 (2-mg regimen), -5.7/-5.8 (4-mg regimen), -8.5/-7.7 (8-mg regimen) for DOX patients and 0.7/-2.9 for placebo patients. The mean changes in supine BP (mmHg) were -3.2/-4.7 (2-mg regimen), -4.0/-5.1 (4-mg regimen), -4.6/-5.6 (8-mg regimen) for DOX patients and -0.5/-3.3 for placebo patients. There was no evidence of a dose-response relationship for DOX; however, DOX serum levels were linearly related to the dose. Responder rate for the combined DOX patients was 38% (32/84) and for the placebo patients 27% (8/30). HR (24 hours postdose) was not modified by DOX. Patients in the 8-mg regimen had a significantly higher gain in mean body weight (+ 1.3 +/- 0.3 kg; P less than 0.05) compared to the 2-mg regimen, 4-mg regimen, and placebo groups. Plasma norepinephrine was not significantly modified by DOX. DOX had a favorable effect on plasma lipids. DOX lowered LDL cholesterol (P less than 0.05), total cholesterol, and apoprotein B and increased HDL/(LDL + VLDL) ratio (0.05 less than or equal to P less than 0.1) compared to placebo. Dropout rate and treatment-related side effects were equally distributed among the DOX and placebo groups. No patients had the dose of medication reduced because of side effects. Three DOX patients were withdrawn because of postural dizziness.

Cavernous hemangioma of the retina, cutaneous angiomas, and intracranial vascular lesion by computed tomography and nuclear magnetic resonance imaging.

In a 32-year-old man with a right-sided retinal cavernous hemangioma and cutaneous angiomas, computed tomography and nuclear magnetic resonance imaging confirmed the presence of cerebrovascular lesions. This supports the inclusion of cavernous hemangioma of the retina in the established group of neuro-oculo-cutaneous phacomatoses.

Plasma volume in resistant hypertension: guide to pathophysiology and therapy.

It might be expected that the tremendous increase in available antihypertensives would eliminate resistant hypertension by allowing many alternatives to its treatment. In spite of this, resistant hypertension remains a common problem due, the authors feel, to a poor understanding of the pathophysiology of this condition, particularly an understanding of whether plasma volume expansion mediates resistance to antihypertensive therapy. The authors evaluated the status of plasma volume as a major determinant of response to therapy in nine patients with resistant hypertension. Measuring plasma volume using I125 radiolabeled albumin, they found eight patients with elevated plasma volumes and one patient with a contracted plasma volume at the time of presentation with resistant hypertension. In all eight patients with plasma volume expansion, aggressive diuretic therapy allowed goal blood pressure to be achieved. The patient with plasma volume contraction achieved goal blood pressure with vasodilator therapy. Plasma volume expansion is common in resistant hypertension and it mediates resistance to therapy. Measurement of plasma volume gives the clinician important insight into the pathophysiology of resistant hypertension and increases the likelihood of successful management of the resistant hypertensive patient.

Herpes simplex in gynecology and obstetrics.

The problems of herpes simplex in gynecology and obstetrics are reviewed. There were 40 patients showing the characteristic cellular changes of herpetic infection among the 79,357 Papanicolaou smears taken. Four patients, with cytologic evidence of herpes virus, also had cervical dysplasia. The relationship between herpes virus and dysplasia, carcinoma in situ, and invasive carcinoma is discussed. The use of a properly timed Papanicolaou smear to alert the physician to the danger of an infected birth canal is described. Three cases of neonatal herpes are cited.

The placenta: a diagnostic tool in sickle cell disorders.

Examination of the placenta for the presence of sickling is an accurate, simple, inexpensive, and readily available technique for determining the presence of sickle cell disorders. There were 24 placental specimens out of 904 which showed evidence of sickling. The importance of this confirming procedure can be seen in the uncovering of two cases of false negative reports from conventional testing.

Transplacental transfer of Bancroftian filariasis.

A pregnant patient with Bancroftian filariasis and documented evidence of transplacental transfer of the larvae is the basis of this report.

Clinical experiences with a single use Y bagless CAPD system applying a quick disconnect clamp for external occlusion.

The Single Use Y set is a disposable CAPD system that incorporates the use of a Quick Disconnect Clamp (QDC) for external occlusion. The system is designed using two types of twist lock connectology. The twist lock bag connector located at the distal end of the set is designed with a flange that provides a safety shelf for proper hand position during bag connection. The proximal patient connector on the Y set is a twist lock design requiring placement of povidone-iodine in the disinfectant chamber of the connector prior to patient connection. The Single Use Y is discarded after use.

Zearalenone intoxication of pigs.

Mycotoxicosis due to ingestion of zearalenone was detected on 2 pig farms on the Atherton Tableland in northern Queensland. In one herd of 200 pigs, this resulted from feeding maize which had been stored with a high moisture content. In the other herd of 1400 pigs, it resulted from feeding sorghum grain which was rain affected before harvest. Concentrations of zearalenone in the feeds ranged up to 8 mg/kg. Most prepubertal gilts in the herds displayed enlarged teats and signs of oestrus such as having red, swollen vulvas. In several cases both rectal and vaginal prolapses occurred. On one of the farms, 25 pigs died as a direct result of prolapses. Autopsy of a 3-month-old gilt revealed apparently enlarged ovaries and uterine horns. Sows and boars seemed to be unaffected. Four gilts failed to conceive following mating during the period of zearalenone ingestion, but apart from this and the deaths from prolapses, production of the herds appeared to be unaffected.

The pharmacokinetics of a single intramuscular dose of amikacin in red-tailed hawks (Buteo jamaicensis).

The pharmacokinetic parameters of amikacin were determined in red-tailed hawks (Buteo jamaicensis) following the i.m. administration of a single 20 mg/kg dose. After a rapid absorption phase, mean amikacin serum concentrations peaked at 65 +/- 12 micrograms/ML 30-45 min following injection. The serum amikacin concentrations decreased to 2.3 +/- 2 micrograms/ml at 12 hr postinjection. Amikacin was eliminated with first-order kinetics characteristic of a single-compartment model with a half-life of 2.02 +/- 0.63 hr. The volume of distribution was estimated to be 0.28 +/- 0.03 L/kg. Forty-two isolates of gram-negative bacteria and coagulase-positive Staphylococcus species were cultured from birds of prey presented to the Veterinary Medical Teaching Hospital at the University of California-Davis. The minimum inhibitory concentration (MICs) of amikacin ranged from 0.5 to 8.0 micrograms/ml (mean = 2.5 micrograms/ml). The 20 mg/kg dose used in this study resulted in serum concentrations at or above the MICs for > 12 hr for most of the isolates examined. The heaviest birds had the lowest peak serum amikacin concentrations, and the lightest birds had the highest, despite exact volume replacement for each sample drawn. This observation suggests that doses should be based on factors other than weight alone. Amikacin administered at 15-20 mg/kg/day, either as a single dose or divided into two or three doses, is effective in treating sensitive pathogens of the red-tailed hawk.

Effects of oral calcium carbonate on blood pressure in subjects with mildly elevated arterial pressure.

Recent investigations suggest that calcium supplementation may cause a lower arterial pressure in hypertensive individuals. We studied 32 patients with mildly elevated arterial pressure (diastolic pressure 88-95 mmHg) and inadequate dietary calcium intake (less than 750 mm/day), who were randomly assigned to placebo or 1500 mg/day elemental calcium for 4 weeks. Baseline and post-treatment urinary calcium concentrations and 3 biweekly supine blood pressures were recorded. Supine systolic blood pressure in the calcium group rose during the first 2 weeks of treatment (delta systolic blood pressure +5.9 mmHg; P less than 0.025) compared with no change in supine blood pressure for the placebo group. Within the calcium group, seven out of 15 patients had decreased or unchanged supine blood pressure during treatment. A lower urinary calcium concentration and a lower dietary sodium intake were found in this subgroup compared with those whose supine blood pressure increased with calcium administration.

Randomised clinical trial: certolizumab pegol for fistulas in Crohn's disease - subgroup results from a placebo-controlled study.

BACKGROUND: Treatment options for fistulizing Crohn's disease (CD) are limited. AIM: To examine whether fistula closure is maintained at week 26 following treatment with certolizumab pegol. METHODS: Patients with draining fistulas at baseline from PRECiSE 2 (n = 108) received open-label induction with certolizumab pegol 400 mg at weeks 0 (baseline), 2 and 4. Response was defined as ≥100-point decrease from baseline in the Crohn's Disease Activity Index. Nonresponders (50/108) were excluded. At week 6, responders with draining fistulas (N = 58) were randomised to certolizumab pegol 400 mg (n = 28) or placebo (n = 30) every 4 weeks across weeks 8-24. Fistula closure was evaluated throughout the study, with a final assessment at week 26. RESULTS: The majority of patients (55/58) had perianal fistula. At week 26, 36% of patients in the certolizumab pegol group had 100% fistula closure compared with 17% of patients receiving placebo (P = 0.038). Protocol-defined fistula closure (≥50% closure at two consecutive post-baseline visits ≥3 weeks apart) was not statistically significant (P = 0.069) with 54% and 43% of patients treated with certolizumab pegol and placebo achieving this end point, respectively. CONCLUSION: Continuous treatment with certolizumab pegol improves the likelihood of sustained perianal fistula closure compared with placebo.

Clinical trial: impact of prior infliximab therapy on the clinical response to certolizumab pegol maintenance therapy for Crohn's disease.

BACKGROUND: Certolizumab pegol (CZP) is an effective therapy for Crohn's disease refractory to aminosalicylates, corticosteroids and immunosuppressants. In PRECiSE 2, patients were also eligible for enrolment if prior infliximab therapy was terminated due to loss of response. AIM: To evaluate prior infliximab therapy on sustained response and remission to CZP for Crohn's disease. METHODS: PRECiSE 2 were was analysed for predictors of sustained response and remission. Covariates included prior infliximab therapy, and baseline Crohn's Disease Activity Index (CDAI). RESULTS: Week 26 response (> or =100-point decrease from baseline CDAI) and remission (CDAI < or = 150) were greater with CZP vs. placebo in patients previously receiving infliximab (response: 44.2% vs. 25.5%, P = 0.018; remission: 32.7% vs. 13.7, P = 0.008) and infliximab-naïve patients (response: 68.7% vs. 39.6%, P < 0.001; remission: 52.8% vs. 33.3%, P < 0.001). Prior infliximab use was the only independent predictor of week 26 response and remission in both groups [response OR(CZP vs. placebo) = 3.06 (95% CI: 1.21-7.77); remission OR(CZP vs. placebo) = 4.22 (95% CI: 1.45-12.28)]. Adverse events were similar for both groups. CONCLUSIONS: Certolizumab pegol is an effective maintenance therapy in Crohn's disease regardless of prior infliximab use. Efficacy is higher in patients receiving CZP therapy as a first-line biologic, but approximately 50% of infliximab-experienced patients benefited from second-line CZP therapy.