Direct costs of first-generation protease inhibitors for the treatment of genotype 1 chronic hepatitis C viral infection.

To evaluate the cost-effectiveness of Hepatitis C therapy, robust real-world data are needed to understand the costs and benefits of treatment alternatives. The objective of this study was to evaluate the true direct cost of treatment in an unselected sequential population of patients treated at a tertiary care centre for hepatitis C virus genotype 1. A total of 200 consecutive patients were treated with interferon, ribavirin and a first-generation direct-acting antiviral agent (DAA) between 2011 and 2013. A total of 41% had cirrhosis, 31% were prior relapsers, and 41% were prior partial or null responders. Costs used were wholesale acquisition cost prices for medications, average hospital costs per day for each diagnosis code based on US inpatient hospital charges. All costs were adjusted to 2013 dollars. Sustained virologic response (SVR) was achieved in 97 patients (48.5%). A total of 14% experienced relapse, 19% breakthrough or nonresponse, and 18.5% discontinued secondary to side effects. Twenty per cent of patients had at least one hospitalization attributable to a complication of therapy. Thirty-seven per cent of patients required erythropoietin-stimulating agents, 16% received filgastrim, and 15% needed a red blood cell transfusion. The mean overall cost of treatment was $83,851 per patient. The cost per SVR was $172,889; $266,670 for patients with cirrhosis. The costs per SVR after treatment with first-generation DAAs are dependent on the stage of disease and therapy side effects. These real-world costs significantly exceed those described in prior cost-effectiveness assessments and should be used instead for future studies.

Notch signalling in cancer progression and bone metastasis.

Classically known for its indispensible role in embryonic development, the Notch signalling pathway is gaining recognition for its regulation of adult tissue homoeostasis and aberrant activation in disease pathogenesis. The pathway has been implicated in cancer initiation and development, as well as early stages of cancer progression by regulating conserved cellular programs such as the epithelial-to-mesenchymal transition. We recently extended the role of Notch signalling to late stages of tumour progression by elucidating a stroma-dependent mechanism for the pathway in osteolytic bone metastasis. Of clinical significance, disrupting the Notch pathway and associated molecular mediators of Notch-dependent bone metastasis may provide novel therapeutic strategies to combat aggressive bone metastatic disease.

Standardized delivery room management for neonates with a prenatal diagnosis of congenital heart disease: A model for improving interdisciplinary delivery room care.

Precise characterization of cardiac anatomy and physiology through fetal echocardiography can predict early postnatal clinical course. Some neonates with prenatally defined critical congenital heart disease have anticipated precipitous compromise during perinatal transition for which specialized, diagnosis-specific delivery room care can be arranged to expeditiously stabilize cardiopulmonary hemodynamics. In this article, we describe our institutional approach to the delivery room care of neonates with prenatally diagnosed congenital heart disease, emphasizing our diagnosis-specific care pathways for newborns with critical disease.

Is nasal packing really required after septoplasty?

OBJECTIVE: Septoplasty is one of the most common operations performed by otorhinolaryngologists. Nasal packing is not an innocuous procedure. The most common problem encountered by the patients after septoplasty is the pain and discomfort during removal of the nasal packs. The objective of this study was to evaluate the results of septoplasty without postoperative nasal packing. METHODS: Septoplasty was performed by standard technique. No nasal packing was used in these cases. RESULTS: Seventy-eight patients were included in the study. The majority of the patients (64.1%; 50/78) on a morning list were operated. Sixty-two patients were discharged home the same day, the remaining others were discharged the next day. Our postoperative haemorrhage rate was 7.7% (6/78) and only 3.8% (3/78) patients required nasal packing. Majority (84.6%) of the patients were satisfied with the operation at the postoperative follow up 3 months later. CONCLUSIONS: Septoplasty can be safely performed without postoperative nasal packing. Only 3.8% patients required nasal packing in this study.

Long-term results with a simple technique of stoma creation after laryngectomy.

Stomal stenosis after laryngectomy has a major impact on patient rehabilitation. The major contributory factor is the operative technique. The goal is to achieve a widely patent stoma. The objective of the study was to review the long-term results of the technique of stoma creation used by the senior author (CJW). The simple technique, using skin triangles for tracheostoma creation after laryngectomy, has been used by the senior author for past 6 years. Review of 59 cases of total laryngectomy with or without partial pharyngectomies in whom this technique was used for stomaplasty. The technique described for stoma creation after total laryngectomy has been used in 59 patients (48 male, 11 female) over 6 years. The follow-up of these patients varies from 6 months to 6 years. Of these patients 54/59 (91.5%) did not have any problems with the stoma. A total of 5/59 (8.5%) patients, the stoma was narrow. Amongst these patients with narrow stoma, only 1 patient (1.7%) has had dilatation done and the others are managing reasonably with a stoma button. None of the patients in this study has required revision procedures on the stoma. The simple technique of stoma creation described in this study has good long-term results.

Clinical outcomes of total laryngectomy for laryngeal carcinoma.

BACKGROUND: Controversy exists as to the management of advanced laryngeal carcinoma. In general primary radical surgery is favoured. OBJECTIVE: The aim of this study was to analyse the clinical outcome of patients having total laryngectomy for cancer of larynx. MATERIALS AND METHODS: This study was a retrospective case note review and questionnaires were used for evaluating voice handicap. These laryngectomies included in this study were performed by the senior author (CJW) from January 2001 till June 2007 at Leeds General Infirmary, Leeds. Some of the patients had partial or total pharyngectomy in addition to total laryngectomy. RESULTS: In this study a total of 59 patients were included. Seventeen (28.8%) of these patients had preoperative radiotherapy and laryngectomy was performed for residual or recurrent disease. The initial TNM staging of the tumour ranged from T(1)N(0) to T(4)N(2C). Tracheoesophageal puncture for speech prosthesis was done in 48/59 (81.4%) patients. Post-operative complications were seen in 30.5% (18/59) patients. In this study group 9 patients (15.2%) developed pharyngocutaneous fistulas. For communication 31/51 (60.8%) patients were using speech valves. In this study 30.4% had minimal, 26.1% moderate and the rest 43.4% feeling severely handicapped with regards to voice use after total laryngectomy. Five year survival after laryngectomy in this study was 65.2%. CONCLUSION: Long term disease control and survival is achievable with total laryngectomy with or without postoperative radiotherapy with minimal risks in patients with advanced carcinoma of larynx.

Elective neck dissection for the node-negative neck during salvage laryngectomy: an analysis of survival outcomes and complication rates.

OBJECTIVES: This study aimed to evaluate the effect of neck dissection on survival and complication rates in patients with no clinical or radiological evidence of cervical nodal disease (N0) undergoing salvage laryngectomy. METHODS: A retrospective study was conducted of patients with squamous cell carcinoma of the larynx following primary radiotherapy that required salvage laryngectomy. Disease-free and overall survival rates were compared over three years using Kaplan-Meier analysis. Pharyngocutaneous fistula rate, hospitalisation length and the requirement for further surgical intervention were also compared across cohorts. RESULTS: Twenty-three cases met the inclusion criteria (17 neck dissections, 6 undissected). No significant differences in survival outcomes were identified. One patient who underwent neck dissection for advanced, recurrent transglottic squamous cell carcinoma showed evidence of occult lymph node metastases. Fistula rates did not differ significantly between dissected and non-dissected groups; however, two patients required surgical repair of post-operative pharyngocutaneous fistula following neck dissection. CONCLUSION: In this study, elective neck dissection did not appear to alter survival outcomes or complication rates during salvage laryngectomy. Given the small but significant risk of occult neck metastases, its true value remains unclear.

EMG artifact in brain death electroencephalogram, is it a cry of "medullary death"?

The Uniform Determination of Death Act (UDDA) defines death as irreversible cessation of the functions of the entire brain including the brainstem. Many individuals meeting the clinical criteria of brain death can be documented to have some residual sub-cortical and brainstem function on careful testing. Determination of brain death still remains a persistently unresolved issue in health law and bioethics. The determination of brain death is clinical and involves testing for the integrity of brainstem functions. Documentation of irreversible cessation of brainstem functions when the cause of coma is established is usually sufficient to make a diagnosis of brain death. Confirmatory tests like four-vessel angiogram and electroencephalogram (EEG) are required in cases where the clinical testing is inconclusive or unreliable. EEG criteria for electrocerebral silence (ECS) is absence of any detectable cortical activity above 2 microV in a study performed as per the guidelines developed by the American Electroencephalographic Society. EEG studies carried out for ECS are at times contaminated by electromyographic (EMG) artifacts reflecting scalp motor unit activity. A secure EEG diagnosis of ECS cannot be made in such cases. What exactly is the relevance of scalp EMG activity in these clinically brain dead patients? What is the mechanism of generation of this spontaneous scalp EMG activity and how can the diagnosis of brain death be secured in these patients? These issues are explored in this article by highlighting a case.

Ipsilateral hemispheric ischaemic hypoxic changes during central line placement: a video-electroencephalogram correlate.

When venous access is needed for intravenous fluids or antibiotics and a peripheral site is unavailable or not suitable, a central line is placed either in the neck or the groin. Complications have been reported during central line placement including (but not limited to) pneumothorax, haemothorax, arrhythmias, air embolism and introduction of infection. The case history is reported of a patient who developed ipsilateral hemispheric ischaemic hypoxic changes during central line placement. This was represented on the surface electroencephalogram by ipsilateral hemispheric voltage attenuation.

Genomic analysis to assess disease progression and recurrence in patients with oral squamous cell carcinoma: - a preliminary study.

We studied the progression from dysplasia to invasive carcinoma and subsequent second primaries or locoregional recurrences in 11 patients with recurrent squamous cell carcinoma (SCC). Between one and six samples were sequenced/patient. DNA samples were prepared, and libraries multiplexed to between 40 and 80 samples/lane of an Illumina HiSeq 3000 and sequenced with 2×100bp paired end sequencing. Copy number data were generated by CNAnorm (Bioconductor package). Samples of recurrent SCC showed unique patterns of descent when compared with earlier samples from the primary tumour, and three main patterns emerged. In four patients there was convincing evidence that the later lesion was descended directly from cells from the first, and in a further four there were no detectable genomic events between the two lesions. Three patients had some shared events between the early and later lesions, but although there were enough differences to deduce that the two lesions had a shared ancestor, they were not directly descended from each other. We present the patients' characteristics in detail, including the overall survival in each group. There was a distinct genomic pattern after a second episode of SCC in all the groups. A larger study that uses similar methods and a longer duration could provide reliable conclusions with respect to survival. With the use of new techniques, genomic data can be available to clinical teams during the planning of treatment.

The CDC20 gene product of Saccharomyces cerevisiae, a beta-transducin homolog, is required for a subset of microtubule-dependent cellular processes.

Previous analysis of cdc20 mutants of the yeast Saccharomyces cerevisiae suggests that the CDC20 gene product (Cdc20p) is required for two microtubule-dependent processes, nuclear movements prior to anaphase and chromosome separation. Here we report that cdc20 mutants are defective for a third microtubule-mediated event, nuclear fusion during mating of G1 cells, but appear normal for a fourth microtubule-dependent process, nuclear migration after DNA replication. Therefore, Cdc20p is required for a subset of microtubule-dependent processes and functions at multiple stages in the life cycle. Consistent with this interpretation, we find that cdc20 cells arrested by alpha-factor or at the restrictive temperature accumulate anomalous microtubule structures, as detected by indirect immunofluorescence. The anomalous microtubule staining patterns are due to cdc20 because intragenic revertants that revert the temperature sensitivity have normal microtubule morphologies. cdc20 mutants have a sevenfold increase in the intensity of antitubulin fluorescence in intranuclear spindles compared with spindles from wild-type cells, yet the total amount of tubulin is indistinguishable by Western immunoblot analysis. This result suggests that Cdc20p modulates microtubule structure in wild-type cells either by promoting microtubule disassembly or by altering the surface of the microtubules. Finally, we cloned and sequenced CDC20 and show that it encodes a member of a family of proteins that share homology to the beta subunit of transducin.

Myoclonic epilepsy masquerading as a tic disorder.

Myoclonic epilepsies comprise a heterogeneous group of epileptic syndromes characterized by myoclonic jerks, generalized tonic-clonic seizures (GTCSs), and sometimes absence seizures (multiplicity of seizure types). JME (Juvenile Myoclonic Epilepsy) is relatively common and usually responds well to treatment with appropriate anticonvulsants. Others like the progressive myoclonic epilepsy syndromes are relentlessly progressive, associated with cognitive decline and respond poorly to anticonvulsants. Myoclonic epilepsy is frequently misdiagnosed until the patient is specifically asked about the leading symptom, i.e., jerky movements occurring in the morning. We present here a patient who had been misdiagnosed as a tic disorder and treated for the past many years before the correct diagnosis of myoclonic epilepsy was made during an admission for Video-EEG monitoring.

Local Anaesthesia for Fiberoptic Intubation : A Comparison of Three Techniques.

BACKGROUND: The successful conduct of fiberoptic aided intubation is dependent upon effective local anaesthesia. The aim of the study was to compare three different methods of anaesthetizing the airway. METHODS: 60 adult patients (American Society of Anaesthesiologists status I-III and Mallampati class III & IV), scheduled for elective surgery, received sedation followed by spraying of the nares and posterior pharyngeal wall with 4% lignocaine. Thereafter the patients received 4 ml of 4% lignocaine either by transtracheal injection (n=20, group A), via intubating fiberscope (Pentax F1-10P2) using 'spray as you go' technique (n=20, group B) or by nebulizer (Devilbiss 5610W) 20 min before intubation, (n=20, group C). Patients were asked to score the procedure using visual analog scale (VAS) and severity scores. Episodes of coughing, choking, stridor, extra / total local anaesthetic used and intubation times were recorded. Patients were monitored continuously for vital parameters. RESULTS: Group B patients showed better VAS scores with shorter intubation times and had a lower incidence of coughing and choking. The endoscopists' VAS scores also showed a preference for group B. CONCLUSION: In conclusion the 'spray as you go' technique was safe, provided effective local anaesthesia and was preferred by both patients and endoscopists.