Time toxicity associated with early phase clinical trial participation.

BACKGROUND: Early phase cancer clinical trials (EPCTs) involve experimental drugs being used for the first time in humans. These studies are designed for dose determination and safety, and represent the most time intensive of all clinical trials for both clinicians and patients. We sought to quantify the amount of patient time consumed through EPCT participation. PATIENTS AND METHODS: A retrospective audit of patients treated in the EPCT unit at Liverpool Hospital, Sydney was carried out from 2013 to 2023. We defined 'time toxicity' (TT) as a composite measure where time-toxic days were considered days with any health care system contact, including clinic visits, infusions, procedures or blood work. RESULTS: A total of 219 patients across 36 EPCTs were included. The median age was 65 years (range 31-81 years). Patients spent a median of 29% (range 4%-100%) of their days in direct contact with the health care system during their study. Protocol-specified visits accounted for the greatest contribution to total TT in 101 (46%) patients. In 7% (n = 16) of patients, unscheduled visits due to either adverse events or cancer-related symptoms accounted for the greatest TT. TT reduced as patients completed additional cycles of treatment. Patients who completed >10 cycles spent 14% of their days interacting with health care systems compared with 35% for those who completed ≤2 cycles. No statistically significant difference in TT was noted between dose-expansion and dose-escalation studies or trials focusing on immune-oncology versus targeted therapy. CONCLUSIONS: Our study is the first to report TT in EPCTs with an extended follow-up. Clinicians should be aware of TT when discussing risks and benefits. TT also may not be the appropriate term when describing the time patients invest during EPCTs. Toxicity implies a negative impact, but for many patients, trial participation would be seen as positive. There should be efforts to streamline health care visits to limit TT in EPCTs.

Differentiation of follicular carcinomas from adenomas using histogram obtained from diffusion-weighted MRI.

AIM: To evaluate the role of histogram analysis of apparent diffusion coefficient (ADC) maps from diffusion-weighted imaging (DWI) in the differentiation of follicular thyroid carcinoma (FTC) from follicular adenoma (FA) in nodules indeterminate on ultrasound-guided core needle biopsy (USCNB). MATERIALS AND METHODS: This study was performed with institutional review board approval. Seventeen patients who were planned to undergo diagnostic lobectomy for an indeterminate thyroid nodule (atypical of unknown significance/follicular lesion of undetermined significance [AUS/FLUS] or suspicious for follicular neoplasm/follicular neoplasm [SFN]) on USCNB were enrolled prospectively. All patients underwent DWI on the day before surgery. Histogram parameters were derived from ADC values obtained from the whole extent of the tumours. The parameters were compared with the final diagnosis based on histopathological examination after surgery. The accuracy of the parameters in differentiating FTC from FA was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Twelve patients were confirmed as having FA and five patients as having FTC. Histogram parameters including the 10th (ADC10), 25th (ADC25), and 50th (ADC50) percentiles of the ADC values were significantly lower in FA than in FTC (p < 0.05, all). ROC curve analysis revealed that ADC25 resulted in the highest AUC (0.867; confidence interval, 0.616-0.980), with a cut-off value of 0.352×10-3 mm2/s. CONCLUSION: Histogram parameters from ADC maps could differentiate FTC from FA effectively in indeterminate nodules on USCNB, with ADC25 being the most promising parameter.

Prognostic Value of Labyrinthine 3D-FLAIR Abnormalities in Idiopathic Sudden Sensorineural Hearing Loss.

BACKGROUND AND PURPOSE: According to recent research, modern MR imaging can detect the presense of abnormalities on labyrinthine. Our aim was to report the patterns and prognostic role of abnormal findings on labyrinthine imaging in patients with sudden sensorineural hearing loss. MATERIALS AND METHODS: This study comprised 113 patients who were diagnosed with unilateral sudden sensorineural hearing loss and underwent 3T MR imaging, including pre-/postcontrast 3D fluid-attenuated inversion recovery and T1-weighted imaging. We analyzed abnormalities on MR imaging and correlated them with audiometric results. RESULTS: Thirty-one (27%) patients showed abnormal findings on labyrinthine MR imaging in the affected ear. The initial/final hearing levels of the MRI+ group (91 ± 25/73 ± 27 dB hearing loss) were significantly worse than those of the MRI- group (69 ± 30/48 ± 24 dB hearing loss). The incidence of abnormalities on labyrinthine MR imaging was significantly lower (3 of 40, 8%) in 40 patients with initial mild-to-moderate hearing loss than in those with profound hearing loss (16 of 34, 47%). Considering hearing improvement by the Siegel criteria, the rate of complete or partial recovery was significantly higher in the MRI- group (34%) than in the MRI+ group (10%). In patients with initial severe or profound hearing loss, the MRI- group showed greater hearing improvement (38 ± 21 dB) than the MRI+ group (23 ± 22 dB). CONCLUSIONS: Abnormalities on labyrinthine MR imaging were found in 27% of patients with sudden sensorineural hearing loss. The initial hearing loss was worse in the MRI+ group than in the MRI- group. In patients with initial severe and profound hearing loss, the presence of abnormalities on labyrinthine MR imaging indicated a poor prognosis.

Efficacy of HVT-IBD vector vaccine compared to attenuated live vaccine using in-ovo vaccination against a Korean very virulent IBDV in commercial broiler chickens.

The production performance, efficacy, and safety of two types of vaccines for infectious bursal disease virus (IBDV) were compared with in-ovo vaccination of Cobb 500 broiler chickens for gross and microscopic examination of the bursa of Fabricius, bursa/body weight (b/B) ratio, flow cytometry, and serologic response to Newcastle disease virus (NDV) vaccination. One vaccine was a recombinant HVT-IBD vector vaccine (HVT as for herpesvirus of turkeys) and the other was an intermediate plus live IBDV vaccine. A significant difference was detected at 21 d. Eight of 10 chickens that received the IBDV live vaccine had severe bursal lesions and a relatively low b/B ratio of 0.95, and an inhibited NDV vaccine response. On the other hand, the HVT-IBD vector vaccine resulted in mild bursal lesions and a b/B ratio of 1.89. Therefore, the live vaccine had lower safety than that of the HVT-IBD vector vaccine. To determine the protective efficacy, chickens were intraocularly challenged at 24 d. Eight of 10 chickens in the IBDV live vaccination group showed gross and histological lesions characterized by hemorrhage, cyst formation, lymphocytic depletion, and a decreased b/B ratio. In contrast, the HVT-IBD vector vaccinated chickens showed mild gross and histological lesions in three of 10 chickens with a b/B ratio of 1.36, which was similar to that of the unchallenged controls. Vaccinated chickens showed a significant increase in IBDV antibody titers, regardless of the type of vaccine used. In addition, significantly better broiler flock performance was observed with the HVT-IBD vector vaccine compared to that of the live vaccine. Our results revealed that the HVT-IBD vector vaccine could be used as an alternative vaccine to increase efficacy, and to have an improved safety profile compared with the IBDV live vaccine using in-ovo vaccination against the Korean very virulent IBDV in commercial broiler chickens.

Comparison of fine-needle aspiration and core needle biopsy under ultrasonographic guidance for detecting malignancy and for the tissue-specific diagnosis of salivary gland tumors.

BACKGROUND AND PURPOSE: Diagnostic test accuracy studies for ultrasonography-guided fine-needle aspiration and ultrasonography-guided core needle biopsy have shown inconclusive results due to their heterogenous study designs. Our aim was to compare the diagnostic accuracy of ultrasonography-guided fine-needle aspiration versus ultrasonography-guided core needle biopsy for detecting malignant tumors of the salivary gland and for the tissue-specific diagnosis of salivary gland tumors in a single tertiary hospital. MATERIALS AND METHODS: This retrospective study was approved by our institutional review board and informed consent was waived. Four hundred twelve patients who underwent ultrasonography-guided fine-needle aspiration (n = 155) or ultrasonography-guided core needle biopsy (n = 257) with subsequent surgical confirmation or clinical follow-up were enrolled. We compared the diagnostic accuracy of ultrasonography-guided fine-needle aspiration and ultrasonography-guided core needle biopsy regarding malignant salivary gland tumors and the correct tissue-specific diagnosis of benign and malignant tumors. We also tested the difference between these procedures according to the operator's experience and lesion characteristics. RESULTS: The inconclusive rates of ultrasonography-guided fine-needle aspiration and ultrasonography-guided core needle biopsy were 19% and 4%, respectively (P < .001). The overall accuracy of ultrasonography-guided core needle biopsy for diagnosing malignant tumors was significantly higher than that of ultrasonography-guided fine-needle aspiration (P = .024). The correct tissue-specific diagnosis rates of ultrasonography-guided fine-needle aspiration and ultrasonography-guided core needle biopsy were 95% versus 97% for benign tumors (P = .648) and 67% versus 80% for malignant tumors (P = .310). Trainees showed significantly lower accuracy with ultrasonography-guided fine-needle aspiration than with ultrasonography-guided core needle biopsy for diagnosing malignant tumors (P = .021). There was no difference between the diagnostic accuracy of ultrasonography-guided fine-needle aspiration and ultrasonography-guided core needle biopsy according to the internal composition of the lesions. There were no complications requiring intervention or hospitalization in our patients. CONCLUSIONS: Ultrasonography-guided core needle biopsy is superior to ultrasonography-guided fine-needle aspiration in detecting and characterizing malignant tumors of the salivary gland and could emerge as the diagnostic method of choice for patients presenting with a salivary gland mass.

Clinical significance of an increased cochlear 3D fluid-attenuated inversion recovery signal intensity on an MR imaging examination in patients with acoustic neuroma.

BACKGROUND AND PURPOSE: The increased cochlear signal on FLAIR images in patients with acoustic neuroma is explained by an increased concentration of protein in the perilymphatic space. However, there is still debate whether there is a correlation between the increased cochlear FLAIR signal and the degree of hearing disturbance in patients with acoustic neuroma. Our aim was to investigate the clinical significance of an increased cochlear 3D FLAIR signal in patients with acoustic neuroma according to acoustic neuroma extent in a large patient cohort. MATERIALS AND METHODS: This retrospective study enrolled 102 patients with acoustic neuroma, who were divided into 2 groups based on tumor location; 22 tumors were confined to the internal auditory canal and 80 extended to the cerebellopontine angle cistern. Pure tone audiometry results and hearing symptoms were obtained from medical records. The relative signal intensity of the entire cochlea to the corresponding brain stem was calculated by placing regions of interest on 3D FLAIR images. Statistical analysis was performed to compare the cochlear relative signal intensity between the internal auditory canal acoustic neuroma and the cerebellopontine angle acoustic neuroma. The correlation between the cochlear relative signal intensity and the presence of hearing symptoms or the pure tone audiometry results was investigated. RESULTS: The internal auditory canal acoustic neuroma cochlea had a significantly lower relative signal intensity than the cerebellopontine angle acoustic neuroma cochlea (0.42±0.15 versus 0.60±0.17, P<.001). The relative signal intensity correlated with the audiometric findings in patients with internal auditory canal acoustic neuroma (r=0.471, P=.027) but not in patients with cerebellopontine angle acoustic neuroma (P=.427). Neither internal auditory canal acoustic neuroma nor cerebellopontine angle acoustic neuroma showed significant relative signal intensity differences, regardless of the presence of hearing symptoms (P>.5). CONCLUSIONS: The cochlear signal on FLAIR images may be an additional parameter to use when monitoring the degree of functional impairment during follow-up of patients with small acoustic neuromas confined to the internal auditory canals.

Long-term bisphosphonate usage and subtrochanteric insufficiency fractures: a cause for concern?

For over a decade, bisphosphonate administration has evolved and become the cornerstone of the prevention and treatment of fragility fractures. Millions of post-menopausal women have relied on, and continue to depend on, the long-acting, bone density-maintaining pharmaceutical drug to prevent low-energy fractures. In return, we have seen the number of fragility fractures decrease, along with associated costs and emotional benefits. However, with any drug, there are often concerns with side effects and complications, and this unique drug class is seeing one such complication in atypical subtrochanteric femoral fracture, counterproductive to that which it was designed to prevent. This has created concern over long-term bisphosphonate administration and its potential link to these atypical fractures. There is controversial evidence surrounding such a definitive link, and no protocol for managing these fractures. This review offers the latest information regarding this rare but increasingly controversial adverse effect and its potential connection to one of the most successful forms of treatment that is available for the management of fragility fractures.

Effect of hydrophobicity on the stability of the wetting films of water formed on gold surfaces.

We have developed a methodology that can be used to determine disjoining pressures (Π) in both stable and unstable wetting films from the spatial and temporal profiles of dynamic wetting films. The results show that wetting films drain initially by the capillary pressure created by the changes in curvature at the air/water interface and subsequently by the disjoining pressure created by surface forces. The drainage rate of the film formed on a gold surface with a receding contact angle (θ(r)) of 17° decreases with film thickness due to a corresponding increase in positive Π, resulting in the formation of a stable film. The wetting film formed on a hydrophobic gold with θ(r)=81° drains much faster due to the presence of negative Π in the film, resulting in film rupture. Analysis of the experimental data using the Frumkin-Derjaguin isotherm suggests that short-range hydrophobic forces are responsible for film rupture and long-range hydrophobic forces accelerate film thinning.

Developmental dental defects linked with chemoradiotherapy: a case report.

Developmental orofacial dentoalveolar complications associated with chemoradiotherapy in an 8 year old child with a history of rhabdomyosarcoma are reported. This report details, clinically and radiographically, these effects in a child diagnosed at 3 years of age with a lesion primary to the left buccinator. Early evaluation is vital to determine potential dentoalveolar complications and long-term consequences.

Hydrolytic properties of a thermostable α-L-arabinofuranosidase from Caldicellulosiruptor saccharolyticus.

AIMS: To characterize of a thermostable recombinant α-L-arabinofuranosidase from Caldicellulosiruptor saccharolyticus for the hydrolysis of arabino-oligosaccharides to l-arabinose. METHODS AND RESULTS: A recombinant α-L-arabinofuranosidase from C. saccharolyticus was purified by heat treatment and Hi-Trap anion exchange chromatography with a specific activity of 28.2 U mg(-1). The native enzyme was a 58-kDa octamer with a molecular mass of 460 kDa, as measured by gel filtration. The catalytic residues and consensus sequences of the glycoside hydrolase 51 family of α-L-arabinofuranosidases were completely conserved in α-L-arabinofuranosidase from C. saccharolyticus. The maximum enzyme activity was observed at pH 5.5 and 80°C with a half-life of 49 h at 75°C. Among aryl-glycoside substrates, the enzyme displayed activity only for p-nitrophenyl-α-L-arabinofuranoside [maximum k(cat)/K(m) of 220 m(mol l(-1))(-1) s(-1)] and p-nitrophenyl-α-L-arabinopyranoside. This substrate specificity differs from those of other α-L-arabinofuranosidases. In a 1 mmol l(-1) solution of each sugar, arabino-oligosaccharides with 2-5 monomer units were completely hydrolysed to L-arabinose within 13 h in the presence of 30 U ml(-1) of enzyme at 75°C. CONCLUSIONS: The novel substrate specificity and hydrolytic properties for arabino-oligosaccharides of α-L-arabinofuranosidase from C. saccharolyticus demonstrate the potential in the commercial production of L-arabinose in concert with endoarabinanase and/or xylanase. SIGNIFICANCE AND IMPACT OF THE STUDY: The findings of this work contribute to the knowledge of hydrolytic properties for arabino-oligosaccharides performed by thermostable α-L-arabinofuranosidase.

Defibrillation current density imaging: comparison of in-vivo and post-mortem measurements in a pig.

Current density imaging (CDI) is an MRI technique used to measure electrical current density vectors throughout a volume of tissue. Previous work used CDI to measure current pathways through the heart and chest of a post-mortem pig when current is applied using external flexible defibrillation electrodes with typical anterior-anterior positioning. In these post-mortem studies, current pathways were probably influenced by the anisotropic conductivity of the tissues. This work aims to compare post-mortem ( approximately 15 min. and approximately 1 hour after death) results with new in vivo CDI measurements. These measurements indicate that the macroscopic (i.e. across the whole body) current pathways remain similar before and after death, however, at a smaller scale (i.e. distances of a few cm) current pathways are different, particularly in the heart. This comparison demonstrates the influence on current pathways of rapidly changing electric properties of tissue following death.

A new approach to current density impedance imaging.

Current density impedance imaging (CDII) is a new impedance imaging technique that utilizes current density vector measurements made using magnetic resonance imager (MRI). CDII provides a simple mathematical expression for the gradient of the logarithm of conductivity, nablaln(sigma), at each point in a region where two current density vector has been measured. From the images of the gradient of the logarithm of conductivity, ln(sigma) can be reconstructed through integration and of sigma by a priori knowledge of the conductivity at a single point in the object. The CDII technique was tested on a conductivity phantom made from tissue mimicking gel. The results showed accurate reconstruction of the gel conductivity from two current density measurements. This study, for the first time, has demonstrated a local reconstruction technique to calculate sample conductivity inside the phantom noninvasively.

Changes in the complex permittivity during spreading depression in rat cortex.

With recent developments in current density imaging (CDI), it is feasible to utilize this new technique in brain imaging applications. Since CDI's ability to measure changes in current density depends on a concomitant activity-dependent change in the conductivity of the brain tissue, we have examined the changes in complex conductivity during spreading depression (SD) in rodent neocortex using a coaxial probe. SD was chosen because it is often referred to as an animal model of cerebral ischemia and migraine with aura. The conductivity measurements revealed a change with short latency (30-60 s) followed by a change with a longer latency (200-300 s). This change in conductivity with short latency has not been reported before, and we conjecture that it may be the priming or triggering mechanism prior to the main SD episode. A 20% change in conductivity during SD is sufficiently large to be measured by CDI. Therefore, the ability to measure changes in the conductivity, as opposed to metabolic changes, makes CDI a viable approach to the study of ischemia and migraine with aura.

High-dose nevirapine in previously untreated human immunodeficiency virus type 1-infected persons does not result in sustained suppression of viral replication.

High-dose nevirapine treatment has been reported to confer sustained antiretroviral effects, despite a rapid development of resistance. The use of this strategy was evaluated in 20 previously untreated human immunodeficiency virus type 1 (HIV-1) p24 antigenemic persons with CD4 cell counts between 100 and 500/mm3. Treatment consisted of 400 mg of nevirapine, after a 2-week lead-in dose of 200 mg. Rash was the most frequently reported adverse event, occurring in 25%. While sustained declines in p24 antigen levels were observed in the majority, serum HIV-1 RNA load and CD4 cell counts returned to baseline values within 12 weeks in virtually all subjects. The resistance-conferring tyrosine-to-cysteine substitution at reverse transcriptase position 181 was detected after 4 weeks in most subjects. These observations suggest that plasma drug levels attained with high-dose nevirapine were not sufficient to inhibit nevirapine-resistant virus, although they were approximately 2-fold higher than reported IC50 values of resistant virus.

Characterization of cortical spreading depression by imaging of intrinsic optical signals.

The spatiotemporal progression of cortical spreading depression was investigated by imaging of activity-dependent intrinsic optical signals in rat sensorimotor cortex. In contrast to the traditional conception of a uniformly propagating event, the evolution of the spreading depression was characterized by an asymmetrical propagating wavefront and a non-uniform dispersion of optical signals behind the wavefront. As these optical signals are a reflection of underlying molecular and metabolic processes, the imaging approach to spreading depression might constitute a useful technique for investigating the functional organization as well the pathophysiology of the cerebral cortex.

Controlled trial evaluation of an asthma education programme for adults.

BACKGROUND: To improve asthma control and reduce readmission rates through increased knowledge and the development of self management skills, a brief (three hour) adult education programme was developed. METHODS: The course was designed to improve inhaler skills and to teach how to adjust drug doses according to peak flow (PEF) measurements and a treatment plan. It was evaluated in a randomised controlled trial in 76 patients admitted to hospital for asthma by using questionnaires, spirometry, and home monitoring of PEF at entry and at five and 10 months after intervention. The questionnaire provided measures of knowledge about asthma, self management behaviour appropriate to asthma control, asthma symptom frequency and severity, and psychosocial disturbance attributable to asthma. RESULTS: During the 10 months observation period the readmission rate for the educated group was one seventh that of the control group and attendance at accident and emergency departments also decreased. No consistent differential improvements were observed in spirometric results, average PEF, or mean daily variability of PEF. Both groups showed improvements in measures of asthma knowledge, behaviour, symptoms, and psychosocial disturbances. However, the intervention group showed a significantly greater improvement in some measures of asthma knowledge and self management skills. CONCLUSION: Despite minimal effect on measures of airway function, substantial changes in illness behaviour and use of health care facilities can be achieved by a brief asthma education programme.

Characteristics of attenders and non-attenders at an asthma education programme.

BACKGROUND: A controlled trial of asthma education was conducted but only 51 out of 164 eligible patients participated. METHODS: Differences between subjects who participated in the trial and those who expressed initial interest but subsequently declined were studied. RESULTS: Women, non-smokers, and those whose attending physician was concerned in the study were significantly more likely to attend the programme. Higher socioeconomic status was associated with greater attendance, but this did not reach significance. Psychosocial malfunctioning due to asthma was also associated with attendance, but this was not significant when sex and education level were taken into account. There was no difference between attenders and non-attenders with respect to age, number of previous admissions, airway function, self reported asthma severity, knowledge about asthma, and self management practices. CONCLUSION: The results suggest that many asthmatic patients recovering from a severe exacerbation of airflow obstruction will not participate in hospital based health education programmes. Alternative strategies may be required to improve the self management behaviour of these patients.

Multidimensional work sampling to quantify a pharmacokinetics resident's duties.

A multidimensional work-sampling technique was used to quantify a pharmacokinetics resident's duties. Four dimensions were measured: activity, contact, function, and location. A code list of 47 variables was developed to encompass all activities of the resident being observed. A combination of self-reporting and observer reporting was used to test the veracity of the resident's report and to determine whether differences in reporting occurred. Observation was done 20 times a day over a five-week period (24 working days). Random time periods separated the observation points. The observer and the resident recorded 260 and 220 observations, respectively, for a total of 480. The overall reliability measure was 78%, indicating good interobserver agreement. The resident spent about 36% of his time doing work related to pharmacokinetics consultations and 23% of his time attending meetings. He spent a large proportion of time (48.5%) working alone. Much of his remaining time was spent with the Pharm.D. students and the preceptors. Multidimensional work sampling based on a combination of self-reporting and observer reporting is a useful tool for quantifying the work practices of pharmacokinetics residents.