Discovery and development of labdane-oxindole hybrids as small-molecule inhibitors against chikungunya virus infection.

Chikungunya virus (CHIKV) infection, a febrile illness caused by a mosquito-transmitted alphavirus, has afflicted millions of people worldwide. There is currently no approved effective antiviral treatment for CHIKV infection. In this study, we report a new class of small-molecule CHIKV inhibitors, the oxindole-labdanes, that potently block the replication of CHIKV with good selectivity. Andrographolide, a previously reported inhibitor of CHIKV infection, was used as the lead compound for our initial structure-activity relationship (SAR) study. From a focused library of 72 andrographolide analogues, we identified the lead compound (E)-2 with improved antiviral activities. Further optimization of (E)-2 led to the discovery of the normal-labdane 7-chloro-oxindole (E)-42 as potent inhibitor against two low-passage CHIKV isolates from human patients with an EC50 of 1.55 µM against CHIKV-122508 and 0.14 µM against CHIKV-6708. Compound (E)-42 displayed minimal cytotoxic liability (CC50 > 100 µM), thus furnishing good selectivity relative to the host cells. Mechanistically, (E)-42 does not inactivate the viral particles but rather acts on the host cells to interfere with the viral replication, demonstrating both prophylactic and therapeutic effects. Our findings open a new avenue for the development of oxindole-labdane compounds as promising antiviral drugs against CHIKV infection.

Accounting for inflation within NICE cost-effectiveness thresholds.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) makes recommendations on the reimbursement of new drugs utilizing an Incremental Cost-Effectiveness Ratio (ICER) threshold range that has been in use since 2004 and has remained unchanged. RESEARCH DESIGN AND METHODS: To model how the NICE cost-effectiveness thresholds would vary if inflation was accounted for and their potential effects on appraisal outcomes, all single technology appraisal (STA) recommendations published in 2019 were identified. The outcome and most plausible ICERs were then evaluated against thresholds, after taking inflation into account. RESULTS: 41 STAs with base-case ICERs were identified. For general STAs, 46% of ICERs were ≤£20,000/QALY, 27% were £20,000-£30,000/QALY and 27% >£30,000/QALY. Cumulatively, there was a 43% decrease in the purchasing power of the pound from 2004 to 2019 due to inflation. To compensate, the NICE ICER threshold would have to increase to £28,584-£42,876/QALY. Using inflation-adjusted thresholds led to an absolute increase of 18% and 12% of STAs whose ICERs fell below the lower and upper bounds of this threshold range, respectively. CONCLUSION: By not adjusting for inflation, the NICE ICER thresholds have declined in real terms. Whether ICER thresholds should be dynamic to reflect factors like inflation requires further research.

Measuring the burden and mortality of hospitalisation in Parkinson's disease: A cross-sectional analysis of the English Hospital Episodes Statistics database 2009-2013.

BACKGROUND: Patients with Parkinson's disease have higher hospital admission rates than the general population. We examined the reasons for admission, length of stay, costs, and in-hospital mortality in a national sample of Parkinson's disease patients. METHODS: We used hospital admission data from the English Hospital Episodes Statistics database (2009-2013). Patients with Parkinson's disease or Parkinson's disease dementia and aged over 35 years were compared to all other admissions, excluding the above, with the same age criteria. We examined reasons for admissions (ICD-10), length of stay and in-hospital mortality. We used indirect standardisation and Poisson modelling to derive proportional ratios adjusting for age group and sex. RESULTS: There were 324,055 Parkinson's disease admissions in 182,859 patients over 4 years which included 232,905 non-elective admissions (72%). This resulted in expenditure of £907 million (£777 million for non-elective admissions). The main reasons for admission were pneumonia (13.5%), motor decline (9.4%), urinary tract infection (9.2%), and hip fractures (4.3%). These conditions occurred 1.5 to 2.6 times more frequently in patients than controls. Patients with Parkinson's disease were almost twice as likely to stay in hospital for more than 3 months (ratio 1.90, 95% CI 1.83, 1.97) and even more likely die in hospital (ratio 2.46, 95% CI 2.42, 2.49). CONCLUSIONS: Parkinson's disease patients in England have higher rates of emergency admissions with longer hospital stays, higher costs and in-hospital mortality. Urgent attention should be given to developing cost-effective interventions to reduce the burden of hospitalisation for patients, carers and healthcare systems.

Complications of laparoscopic adjustable gastric banding: our local experience.

Obesity is a major medical problem both within Australia as well as throughout the developed world. Achievement of weight loss for any individual patient brings an additional desirable benefit of improvement or resolution of a wide range of comorbid conditions. Bariatrics is the branch of medicine that deals with the causes, prevention and treatment of obesity and allied diseases. The term bariatrics was created around 1965, from the Greek root baro ('weight' as in barometer), suffix-iatr (relating to medical treatment) and suffix -ic ('pertaining to'). Besides the pharmacotherapy of obesity, it is concerned with obesity surgery. Bariatric surgery refers to surgical procedures of the gastrointestinal tract that are designed to induce weight loss. The treatment of obesity traditionally relied on non-surgical techniques to modify behaviour in regard to diet and exercise. This has variable and limited success. More recently, bariatric surgery has become the most rapidly growing form of treatment for obesity in recent years. In fact, it is the only current therapy that has been shown to achieve major and durable weight loss. It is important for the radiologist to be familiar with the normal anatomical appearance of the more common bariatric operations and to be able to recognise their potential complications on imaging. The aim of this pictorial essay is to give an insight into some of the more common complications of laparoscopic adjustable gastric banding surgery encountered in our centre during the period of 2001-2007.

Pharyngeal dysphagia in inflammatory muscle diseases resulting from impaired suprahyoid musculature.

Dysphagia has previously been reported in the inflammatory myopathies (IMs): inclusion body myositis (IBM), dermatomyositis (DM), and polymyositis (PM). Patients report coughing, choking, and bolus sticking in the pharynx. Myotomy has been the treatment of choice, with variable success reported. We sought to determine underlying causes of dysphagia in IM patients using instrumental evaluation. Eighteen subjects participated in the study: four with DM, six with PM, and eight with IBM. They underwent simultaneous videofluoroscopy and manometry, yielding 214 swallows for analysis regarding function of the upper esophageal sphincter (UES), swallow initiation, hyolaryngeal excursion, and pharyngeal residue. Penetration and aspiration were also recorded. UES failed to relax in two participants. High incidence of pharyngeal dysphagia was noted; 72% of participants demonstrated abnormalities, including delayed swallow initiation (24%), decreased hyolaryngeal excursion (22%), pyriform residue (17%), and penetration (22%). Dysphagia in IM patients appears to be more due to impaired muscle contraction and reduced hyolaryngeal excursion than the often held belief of failed UES relaxation. The distinction between mechanisms causing patients' dysphagia should be examined, particularly if CP myotomy is being considered as it may be contraindicated for patients with normal UES relaxation. More studies investigating IM patients pre- and post-myotomy are needed.

Prolonged Intestinal Mucosal Barium Coating due to Ischemic Necrosis.

A case of a 63-year-old man with small bowel ischemia six weeks after transplantation surgery is presented. Plain abdominal radiograph obtained several days after ingestion of barium shows the sign of prolonged barium coating indicating severe mucosal damage. Abdominal CT scan demonstrates small bowel wall thickening as well as pockets of peritoneal fluid collections. Most critically, CT allows visualization of subtle traces of dense barium within the dependent portions of this fluid indicating bowel perforation.

Survival of patients with bladder cancer from a UK hospital: a 10-year follow-up study.

OBJECTIVE: To compare 10-year overall (OS) and cancer-specific survival (CSS) of a cohort of consecutively presenting patients with bladder cancer of all pT categories from one UK institution. PATIENTS AND METHODS: Data were collected on 144 patients with newly diagnosed bladder tumours presenting from 1983 to 1985 followed up for 10 years. Histological variables were reviewed by one pathologist who had no knowledge of the clinical details. Bladder muscle was present in 95% of the transurethral resection specimens. Date and causes of death were ascertained through death certificates, primary care physicians and/or hospital case notes. Data were analysed using the Kaplan-Meier method and Cox model. RESULTS: There were 69 patients (48%) with pTa, 32 (22%) with pT1 and 43 (30%) with pT2/3/4 tumours. The 10-year OS was 54%, 34% and 16% and the CSS was 97%, 50% and 29%, respectively. There were only two cancer-related deaths in the pTa category whereas half the pT1 cases and half the muscle-invasive cases died within 5 and 2 years of diagnosis, respectively. CONCLUSIONS: This study compared the 10-year OS and CSS of a cohort of patients with bladder cancer from the UK, where such data are lacking, and showed marked differences. The CSS was higher in all pT categories compared with OS, especially within pTa cancers in which almost all patients died of competing causes. It is important to be aware of such a significant difference between the two survival measures and to use them appropriately in the right context.

Biodegradability of naltrexone-poly(DL) lactide implants in vivo assessed under ultrasound in humans.

Ultrasound was used to assess the in vivo biodegradability of a sustained release poly(DL)lactide naltrexone implant in 71 persons previously treated for heroin dependence. We assessed 139 implant sites ranging from 2 to 1808 days post implant. Ultrasound assessment showed that implant tablets were initially well demarcated from each other and from the surrounding tissues. Biodegradation resulted in less demarcated tablets followed by clumping into a single mass-like structure. This mass subsequently dispersed by approximately 1201 days post implant with no implant material visualized by ultrasound. The biodegradation was also assessed by visual clinical examination and palpation of the implant site as well as patient self-report. These measures were generally well correlated with ultrasound results. Clinical assessment of the biodegradation process concluded that the implant changed from 'firm' to 'less firm' and from 'initial square edge' to 'rounded edge' tablets. Collectively, these data provide direct evidence of the in vivo absorption of the Go Medical implant over time, and its biodegradability in humans.

Superior vena cava obstruction by tumour thrombus in invasive thymoma: diagnosis and surgical management.

Thymomas are common mediastinal tumours. We report a rare case of thymoma invasion into the superior vena cava with resultant venous obstruction. The tumour was resected. The superior vena cava and left brachiochephalic vein were reconstructed with autologous pericardial patch.

Comparison of radiologists and technologists in the performance of air-contrast barium enemas.

OBJECTIVE: The purpose of this study was to determine whether the rate of polyp detection and the quality of air-contrast barium enema (ACBE) procedures performed by technologists differ from those performed by radiologists. CONCLUSION: Our results showed that well-trained certified technologists can perform ACBE similar in overall quality and accuracy to ACBE performed by attending physicians and residents. Training technologists to perform ACBE may help to alleviate the radiology staffing shortage in the United States.

Causes of errors in polyp detection at air-contrast barium enema examination.

PURPOSE: To retrospectively determine the cause of errors in air-contrast barium enema (ACBE) examination for detection of polyps 6 mm or larger. MATERIALS AND METHODS: The study had institutional review board approval. Informed consent was waived for this HIPAA-compliant study. ABCE findings in 41 subjects with 56 missed polyps were evaluated by two radiologists to determine if the cause of errors was perceptual or technical. A comparison was made between total number of polyps in the proximal and distal colon and those missed at each location (Fisher exact test). The 288 ACBE examinations were assessed on a scale of 0-4 (0, excellent; 4, very poor) for six colonic segments (paired t test). RESULTS: Of 17 polyps 1 cm or larger not detected in 15 subjects, 11 (65%) were missed because of technical errors and six (35%) because of perceptual errors. Eight (72%) technical and four (67%) perceptual errors occurred proximal to the splenic flexure. One 3.5-cm cecal carcinoma was not diagnosed prospectively (perceptual error). Of 39 6-9-mm polyps not detected in 26 subjects, 35 (90%) were missed because of technical errors and four (10%) because of perceptual errors. Eighty percent of technical and 75% of perceptual errors were in the proximal colon. When the proportion of polyps in the proximal and distal colon was compared, 22 (63%) of 35 polyps in the distal colon and 15 (26%) of 58 in the proximal colon were detected (P = .0009). There were no detectable differences in the quality of studies in subjects whose polyps were detected and subjects whose polyps were missed (P > .05). CONCLUSION: Technical errors were more common than perceptual errors. The majority of missed polyps were in the proximal colon. Detection rates of polypoid lesions might increase if the quality of ACBE examination can be improved, especially in the proximal colon.

Renal trauma in Australian rules football: an institutional experience.

BACKGROUND: Australian rules football is the most popular team sport in Australia. Literature on severe abdominal injuries in this sport is limited. The present study aims to review cases of renal trauma in Australian football at our institution. METHODS: A retrospective study was performed. All men admitted to our institution with renal trauma or haematuria associated with Australian football from July 1995 to July 2001 were analysed. RESULTS: There were 13 cases of renal trauma; two were grade V injuries requiring nephrectomy. CONCLUSION: Renal injury will be intermittently encountered owing to the popularity of Australian football. Renal injuries are often difficult to assess and early recognition, management and referral to a district hospital is crucial.