Training generative adversarial networks for optical property mapping using synthetic image data.

We demonstrate the training of a generative adversarial network (GAN) for the prediction of optical property maps (scattering and absorption) using spatial frequency domain imaging (SFDI) image data sets that are generated synthetically with a free open-source 3D modelling and rendering software, Blender. The flexibility of Blender is exploited to simulate 5 models with real-life relevance to clinical SFDI of diseased tissue: flat samples containing a single material, flat samples containing 2 materials, flat samples containing 3 materials, flat samples with spheroidal tumours and cylindrical samples with spheroidal tumours. The last case is particularly relevant as it represents wide-field imaging inside a tubular organ e.g. the gastro-intestinal tract. In all 5 scenarios we show the GAN provides an accurate reconstruction of the optical properties from single SFDI images with a mean normalised error ranging from 1.0-1.2% for absorption and 1.1%-1.2% for scattering, resulting in visually improved contrast for tumour spheroid structures. This compares favourably with the ∼10% absorption error and ∼10% scattering error achieved using GANs on experimental SFDI data. Next, we perform a bi-directional cross-validation of our synthetically-trained GAN, retrained with 90% synthetic and 10% experimental data to encourage domain transfer, with a GAN trained fully on experimental data and observe visually accurate results with an error of 6.3%-10.3% for absorption and 6.6%-11.9% for scattering. Our synthetically trained GAN is therefore highly relevant to real experimental samples but provides the significant added benefits of large training datasets, perfect ground-truths and the ability to test realistic imaging geometries, e.g. inside cylinders, for which no conventional single-shot demodulation algorithms exist. In the future, we expect that the application of techniques such as domain adaptation or training on hybrid real-synthetic datasets will create a powerful tool for fast, accurate production of optical property maps for real clinical imaging systems.

A systematic review of the evidence for hip surveillance in children with cerebral palsy.

We reviewed the evidence for hip surveillance in children with cerebral palsy from the published literature. Publications were identified using the Cochrane controlled trials register, the MEDLINE, EMBASE and CINAHL databases and by hand searching key journals and their references. Studies were included if they reported the frequency, associated risk factors or surveillance measures undertaken to identify subluxation or dislocation of the hip in children with cerebral palsy. Assessment of the quality of the methodology was undertaken independently by two researchers. Four studies described the natural history, incidence and risk factors for dislocation of the hip. Two reported their surveillance results. Approximately 60% of children who were not walking by five years of age were likely to develop subluxation of the hip, with the greatest risk in those with severe neurological involvement. The introduction of surveillance programmes allowed earlier identification of subluxation and reduced the need for surgery on dislocated hips. Surveillance can identify children most at risk of subluxation using radiological methods which are widely available.

A phase II trial of 9-aminocaptothecin (9-AC) as a 120-h infusion in patients with non-small cell lung cancer.

In a previous phase II trial of the synthetic topoisomerase I inhibitor, 9-aminocamptothecin (9-AC), given as a 72-h infusion, we identified modest single agent activity of 9% in patients with previously untreated advanced non-small cell lung cancer (NSCLC). Preclinical studies suggested that a more prolonged continuous infusion of the drug might lead to greater antitumor activity. A phase I study recommended a phase II dose of 25 microg/m2/hr for 120 h (3000 microg/m2 over 5 days), administered for 2 consecutive weeks of a 3-week cycle. We utilized this schedule and enrolled 13 chemotherapy-naïve patients with Stage IIIB and IV NSCLC in this trial: median age 67 (range 57-74); 46% male; 92% stage IV; and median performance status 1. Twelve patients are available for response and toxicity evaluation after 2 cycles of therapy. One patient achieved a partial response. Four patients had stable disease while seven patients had progressive disease. Patients with stable or progressive disease after two cycles received no additional 9-AC, and were offered conventional chemotherapy. The median survival time was 10.2 months and the one-year survival rate 28% (95% confidence interval, 5-58%). Significant toxicities included myelosuppression, fatigue, and anorexia. One patient had grade 4 neutropenia following the first week of cycle 2, and did not receive additional therapy. There were no neutropenia-related infections. These data suggest that this prolonged schedule is unlikely to increase 9-AC's very modest activity in NSCLC above that seen with the simpler 72-h administration schedule. Further evaluation of 9-AC in NSCLC is not recommended.

DNA segregation in bacteria.

Segregation of DNA in bacterial cells is an efficient process that assures that every daughter cell receives a copy of genomic and plasmid DNA. In this review, we focus primarily on observations in recent years, including the visualization of DNA and proteins at the subcellular level, that have begun to define the events that separate DNA molecules. Unlike the process of chromosome segregation in higher cells, segregation of the bacterial chromosome is a continuous process in which chromosomes are separated as they are replicated. Essential to separation is the initial movement of sister origins to opposite ends of the cell. Subsequent replication and controlled condensation of DNA are the driving forces that move sister chromosomes toward their respective origins, which establishes the polarity required for segregation. Final steps in the resolution and separation of sister chromosomes occur at the replication terminus, which is localized at the cell center. In contrast to the chromosome, segregation of low-copy plasmids, such as Escherichia coli F, P1, and R1, is by mechanisms that resemble those used in eukaryotic cells. Each plasmid has a centromere-like site to which plasmid-specified partition proteins bind to promote segregation. Replication of plasmid DNA, which occurs at the cell center, is followed by rapid partition protein-mediated separation of sister plasmids, which become localized at distinct sites on either side of the division plane. The fundamental similarity between chromosome and plasmid segregation-placement of DNA to specific cell sites-implies an underlying cellular architecture to which both DNA and proteins refer.

A phase I study of STEALTH cisplatin (SPI-77) and vinorelbine in patients with advanced non small-cell lung cancer.

STEALTH cisplatin (SPI-77) is a liposomal formulation of cisplatin that has activity in animal models of non small-cell lung cancer (NSCLC). Vinorelbine has documented clinical activity in NSCLC. The purpose of this study was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of SPI-77 when administered in combination with a fixed dose of vinorelbine to patients with stage IIIB or IV NSCLC refractory to or recurrent following previous chemotherapy. SPI-77 was given on day 1 in combination with vinorelbine at a fixed dose of 25 mg/m2 on days 1 and 8 of a 3-week treatment cycle. Dose escalation of SPI-77 progressed as follows: 20, 40, 80, 100, 120, and 140 mg/m2. Twenty patients were entered (11 men and nine women; median age, 63 years). Sixty-four complete cycles of therapy were administered, and 19 of 20 patients completed at least 1 cycle of combination chemotherapy. Neutropenia was dose limiting at a SPI-77 dose of 140 mg/m2. Neuropathy and nephrotoxicity were minimal and not dose related. A partial response was observed in three of 17 patients eligible for a response evaluation and response duration ranged from 6 weeks to 5 months. In conclusion, treatment with combination SPI-77 and vinorelbine was well tolerated, and our recommended phase II dose is 120 mg/m2 of SPI-77 in combination with vinorelbine at 25 mg/m2. Activity was observed in this patient population, and additional phase II testing of this regimen in a less extensively pretreated cohort of patients with NSCLC is indicated.

Chemoradiation for locally advanced, unresectable NSCLC. New standard of care, emerging strategies.

The optimal therapy for locally advanced, unresectable, stage III non-small-cell lung cancer (NSCLC) continues to evolve. The critical determinants of overall survival include local tumor control and the eradication of subclinical micrometastatic disease. Historically, standard radiation therapy resulted in a median survival of 7 to 10 months. In a randomized trial, the Cancer and Leukemia Group B (CALGB) established the superiority of induction cisplatin (Platinol) and vinblastine chemotherapy followed by radiation therapy. Additional studies revealed that induction chemotherapy improved survival rates by decreasing metastatic disease progression. Three independent meta-analyses confirmed the survival benefit afforded by cisplatin-based induction chemotherapy followed by radiotherapy, and helped to establish this as the new standard of care. Other investigators have demonstrated improvements in local tumor control and survival with either concurrent chemoradiotherapy or hyperfractionated radiotherapy. Most recently, attention has focused on radiation dose intensity and the utilization of newer, highly active chemotherapeutic agents with concurrent or sequential radiation therapy. These newer drugs, including paclitaxel (Taxol), docetaxel (Taxotere), gemcitabine (Gemzar), vinorelbine (Navelbine), and irinotecan (Camptosar), enhance radiation cytotoxicity and, when administered in systemically active dosages, may also control micrometastatic disease. Phase I and II studies of novel chemoradiation regimens continue to demonstrate encouraging results, and several large randomized clinical trials are currently enrolling patients.

DNA segregation: putting chromosomes in their place.

Recent studies provide evidence that bacterial chromosomes are replicated by an enzyme factory, the replisome, located at a fixed position at the center of the cell; the fixed replisome could be a major factor in determining chromosome order in the cell, and may provide the force that drives chromosome segregation.

Chromosome and low copy plasmid segregation in E. coli: visual evidence for distinct mechanisms.

We have investigated DNA segregation in E. coli by inserting multiple lac operator sequences into the chromosome near the origin of replication (oriC), in the hisC gene, a terminus marker, and into plasmids P1 and F. Expression of a GFP-LacI fusion protein allowed visualization of lac operator localization. oriC was shown to be specifically localized at or near the cell poles, and when duplicated, one copy moved to the site of new pole formation near the site of cell division. In contrast, P1 and F localized to the cell center and on duplication appeared to move rapidly to the quarter positions in the cell. Our analysis suggests that different active processes are involved in movement and localization of the chromosome and of the two plasmids during segregation.

A survey of lamotrigine and vigabatrin treatment in children with severe epilepsy.

A retrospective survey was carried out of add-on treatment with lamotrigine (LTG) and vigabatrin (GVG) in 109 children with severe epilepsy, treated between 1987 and 1994, identified from a total population of 300 patients seen annually, in a tertiary referral outpatient clinic in Cardiff, Wales. Of 79 patient treatments with LTG and 86 with GVG, 42 patients were treated with add-on LTG, 52 with add-on GVG and 20 with both drugs simultaneously. A Kaplan-Meier curve, applied to each of the two index drugs, indicated that 71 and 62% of patients would be expected to continue taking LTG or GVG, respectively after 40 months. Improved seizure control (> or = 50%) at the time of audit was seen in 65% of LTG and 58% of GVG patient treatments for all epilepsy syndromes, but there was a higher proportion of patients with generalized epilepsy improved by LTG (28/41, 68%) than that improved by GVG (8/20, 40%), and only those with generalized epilepsy treated with LTG became seizure free (8/38, 21%). Similar proportions of patients discontinued LTG (16%) and GVG (15%) due to an adverse experience, but a higher proportion discontinued GVG (18%) compared with LTG (6%) because of lack of efficacy. This study supports the relative clinical effectiveness of LTG and GVG in the real world, where children with severe epilepsy are treated in clinical practice and serves to generate hypotheses to enable design of prospectively controlled trials, which should enable more rational use of these two drugs in the paediatric population with epilepsy.

Severe envenomation by the taipan (Oxyuranus scutellatus)

We describe cases of five patients with taipan envenomation which indicate that patients with paresis benefit from repeated doses of antivenom, even if given long after the bite, and that fresh frozen plasma should be given to correct coagulopathy that persists after reversal of neuromuscular blockade. We reiterate the importance of compression bandages.

Intracranial tumours during the first two years of life: presenting features.

Between 1979 and 1994, 21 children (nine females, 12 males) with intracranial tumours diagnosed before the age of 2 years (range 2-23 months) were treated at the University Hospital of Wales. The commonest presenting symptoms were vomiting (n = 9) and unsteadiness (n = 8); the commonest presenting sign was enlarged occipitofrontal circumference (> 97th centile in 16 and > 90th centile in a further two). In five cases with signs of raised intracranial pressure, meningitis was the clinical diagnosis, and a lumbar puncture was performed. For cases with long delays in diagnosis, multiple other disorders had been considered and the significance of head enlargement had not been recognised. In very early childhood, intracranial tumours are uncommon and can mimic other disorders, especially meningitis. Early neuroimaging is advised when a child presents with recent onset of neurological symptoms and a disproportionately large head.

Thinness at birth and glucose tolerance in seven-year-old children.

Adults who had low birthweight and were thin at birth have an increased risk of Type 2 diabetes and impaired glucose tolerance. To discover whether thinness at birth is associated with reduced glucose tolerance in children, 250 7-year-old children underwent an abbreviated oral glucose tolerance test. Children who were thin at birth, as measured by a low ponderal index (birthweight length-3) had higher plasma glucose concentrations. Plasma glucose concentration 30 min after a glucose load rose by 0.07 mmol l-1 (95% confidence interval 0.00 to 0.14; p = 0.04) for every unit (kg m-3) fall in ponderal index. Children in the lowest quarter of the distribution of ponderal index (23 kg m-3 or less) had a mean 30 min plasma glucose concentration of 8.49 mmol l-1 compared to a mean of 7.97 mmol l-1 for those in the highest quarter (> 27.5 kg m-3). These associations were independent of duration of gestation, gender, social class or the child's current weight. This is consistent with the hypothesis that Type 2 diabetes originates in utero.

Costs, effects and C/E-ratios alongside a clinical trial.

A general approach is discussed to assess the uncertainty surrounding the cost effectiveness ratio (C/E-ratio) estimated on the basis of data from a randomised clinical trial. The approach includes the calculation of a 95% probability ellipse and introduces the concept of a so called C/E-acceptability curve. This last curve defines for each predefined C/E-ratio the probability that the C/E-ratio found in the study is acceptable. The approach is illustrated by estimates of costs per life saved and costs per patient discharged alive on the basis of data from a phase II trial addressing the value of anakinra in treating sepsis syndrome.

Hospital drug formularies and use of hospital services.

Many hospitals have introduced formularies to reduce hospital pharmacy expense, among other reasons. This study provides empirical evidence of the influence of hospital formulary restrictions on pharmacy charges, all other hospital charges, and on length of stay, using a survey of hospital drug policies and hospital discharge data from Washington State in 1989. Limiting the number of drugs in particular therapeutic categories reduced total charges incurred for gastrointestinal disease and asthma patients, increased total charges for cardiovascular disease patients, and had no effect on charges for infectious diseases patients. Restricting availability of drugs reduced pharmacy charges, but these savings tended to be offset by increases in other charges. Combining the categories, we found that restricting availability of drugs did not affect charges. We conclude that across-the-board restrictions do not result in cost savings, although savings may be realized for particular drug categories.

Second-degree atrioventricular block: Mobitz type II.

Acute atrioventricular (AV) block occurs frequently in patients with myocardial infarction. Atrioventricular block is also a common manifestation of sclerodegenerative conduction system disease. Occasionally, heart block results from drug toxicity, hyperkalemia, cardiac valvular calcification, myocarditis, or infiltrative cardiomyopathy. Second-degree AV block is a form of "incomplete" heart block, in which some, but not all, atrial beats are blocked before reaching the ventricles. Mobitz type II second-degree block is an old term, which refers to periodic atrioventricular block with constant PR intervals in the conducted beats. The distinction between type II and type I block is descriptive; of greater importance to the clinician is the anatomic site of the block and the prognosis. In Mobitz type II block the site is almost always below the AV node; in Mobitz type I block the site is usually within the AV node. Type II AV block is more likely to progress to complete heart block and Stokes-Adams arrest. In most cases of second-degree heart block, including cases of 2:1 conduction, it is possible to determine the site of the AV block (intranodal or infranodal) using information about the age of the patient, the clinical setting, and the width of the QRS complex on the surface electrocardiogram. Second-degree atrioventricular block must be distinguished from other "causes of pauses." Nonconducted premature atrial contractions and atrial tachycardia with block are common conditions, which may mimic second-degree AV block.