Development and internal validation of clinical prediction models for outcomes of complicated intra-abdominal infection.

BACKGROUND: Complicated intra-abdominal infections (cIAIs) are associated with significant morbidity and mortality. The aim of this study was to describe the clinical characteristics of patients with cIAI in a multicentre study and to develop clinical prediction models (CPMs) to help identify patients at risk of mortality or relapse. METHODS: A multicentre observational study was conducted from August 2016 to February 2017 in the UK. Adult patients diagnosed with cIAI were included. Multivariable logistic regression was performed to develop CPMs for mortality and cIAI relapse. The c-statistic was used to test model discrimination. Model calibration was tested using calibration slopes and calibration in the large (CITL). The CPMs were then presented as point scoring systems and validated further. RESULTS: Overall, 417 patients from 31 surgical centres were included in the analysis. At 90 days after diagnosis, 17.3 per cent had a cIAI relapse and the mortality rate was 11.3 per cent. Predictors in the mortality model were age, cIAI aetiology, presence of a perforated viscus and source control procedure. Predictors of cIAI relapse included the presence of collections, outcome of initial management, and duration of antibiotic treatment. The c-statistic adjusted for model optimism was 0.79 (95 per cent c.i. 0.75 to 0.87) and 0.74 (0.73 to 0.85) for mortality and cIAI relapse CPMs. Adjusted calibration slopes were 0.88 (95 per cent c.i. 0.76 to 0.90) for the mortality model and 0.91 (0.88 to 0.94) for the relapse model; CITL was -0.19 (95 per cent c.i. -0.39 to -0.12) and - 0.01 (- 0.17 to -0.03) respectively. CONCLUSION: Relapse of infection and death after complicated intra-abdominal infections are common. Clinical prediction models were developed to identify patients at increased risk of relapse or death after treatment, these now require external validation.

Current concepts in imaging for local staging of advanced rectal cancer.

Imaging of rectal cancer has an increasingly pivotal role in the diagnosis, staging, and treatment stratification of patients with the disease. This is particularly true for advanced rectal cancers where magnetic resonance imaging (MRI) findings provide essential information that can change treatment. In this review we describe the rationale for the current imaging standards in advanced rectal cancer for both morphological and functional imaging on the baseline staging and reassessment studies. In addition the clinical implications and future methods by which radiologists may improve these are outlined relative to TNM8.

Maximising platelet availability by delaying cold storage.

BACKGROUND AND OBJECTIVES: Cold-stored platelets may be an alternative to conventional room temperature (RT) storage. However, cold-stored platelets are cleared more rapidly from circulation, reducing their suitability for prophylactic transfusion. To minimise wastage, it may be beneficial to store platelets conventionally until near expiry (4 days) for prophylactic use, transferring them to refrigerated storage to facilitate an extended shelf life, reserving the platelets for the treatment of acute bleeding. MATERIALS AND METHODS: Two ABO-matched buffy-coat-derived platelets (30% plasma/70% SSP+) were pooled and split to produce matched pairs (n = 8 pairs). One unit was stored at 2-6°C without agitation (day 1 postcollection; cold); the second unit was stored at 20-24°C with constant agitation until day 4 then stored at 2-6°C thereafter (delayed-cold). All units were tested for in vitro quality periodically over 21 days. RESULTS: During storage, cold and delayed-cold platelets maintained a similar platelet count. While pH and HSR were significantly higher in delayed-cold platelets, other metabolic markers, including lactate production and glucose consumption, did not differ significantly. Furthermore, surface expression of phosphatidylserine and CD62P, release of soluble CD62P and microparticles were not significantly different, suggesting similar activation profiles. Aggregation responses of delayed-cold platelets followed the same trend as cold platelets once transferred to cold storage, gradually declining over the storage period. CONCLUSION: The metabolic and activation profile of delayed-cold platelets was similar to cold-stored platelets. These data suggest that transferring platelets to refrigerated storage when near expiry may be a viable option for maximising platelet inventories.

Ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic hepatitis C and bleeding disorders.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia. AIM: We evaluated the efficacy and safety of ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic HCV genotype 1-4 infection and an inherited bleeding disorder. METHODS: Ledipasvir-sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment-experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received sofosbuvir plus ribavirin for 12 and 24 weeks respectively. RESULTS: The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment-experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non-bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment. CONCLUSION: Treatment with ledipasvir-sofosbuvir for patients with HCV genotype 1 or 4 infection or sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders.

Once daily ledipasvir/sofosbuvir fixed-dose combination with ribavirin in patients with inherited bleeding disorders and hepatitis C genotype 1 infection.

AIM: People with inherited bleeding disorders have been disproportionally affected by HCV. We assessed the fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) with the NS5B polymerase inhibitor sofosbuvir (SOF) with ribavirin (RBV) in patients with genotype 1 HCV and inherited bleeding disorders. METHODS: To be eligible, patients had to be over 18 years of age and have an inherited bleeding disorder. HCV treatment-naïve and -experienced patients could enrol. All patients received LDV 90 mg per SOF 400 mg once daily and weight-based RBV in a divided dose for 12 weeks. The primary efficacy endpoint was sustained virologic response (SVR), defined as HCV RNA below the limit of detection (15 IU mL-1 ) 12 weeks after the end of treatment (SVR12). RESULTS: Of the 14 patients enrolled, 8 (57%) had haemophilia A, 3 (21%) had haemophilia B and 2 (14%) had von Willebrand disease, and 1 (7%) had factor XIII deficiency. All 14 patients (100%, 95% CI: 77-100%) achieved SVR12. Treatment was well tolerated: all patients completed therapy, with mostly mild adverse events. No specific safety concerns associated with the patient's underlying bleeding disorders were noted. CONCLUSION: These results appear to suggest that people with HCV and inherited bleeding disorders can be safely and effectively treated with 12 weeks of LDV/SOF plus RBV.

Evolution of the HCV viral population from a patient with S282T detected at relapse after sofosbuvir monotherapy.

Clinical phase II/III studies of the nucleotide analogue HCV NS5B inhibitor sofosbuvir (SOF) have demonstrated high efficacy in HCV-infected patients in combination therapy. To date, resistance to SOF (S282T in NS5B) has rarely been detected in patients. In this study, we investigated the evolution of S282T viral variants detected in one HCV genotype 2b-infected patient who relapsed following 12 weeks of SOF monotherapy. Deep sequencing of the NS5B gene was performed on longitudinal plasma samples at baseline, days 2 and 3 on SOF, and longitudinal samples post-SOF treatment through week 48. Intrapatient HCV evolution was analysed by maximum-likelihood phylogenetic analysis. Deep sequencing analysis revealed a low level pre-existence of S282T at 0.05% of viral sequences (4/7755 reads) at baseline and 0.03% (6/23 415 reads) at day 2 on SOF. Viral relapse was detected at week 4 post-treatment where 99.8% of the viral population harboured S282T. Follow-up analysis determined that S282T levels diminished post-treatment reaching undetectable levels 24-48 weeks post-SOF. Phylogenetic analysis together with the persistence of unique post-treatment mutations in all post-SOF samples suggested that growth of wild type resulted from reversion of the S282T mutant to a wild type and not outgrowth of the baseline wild-type population. Our data suggest that a very low level of pre-existing S282T at baseline in this patient was enriched and transiently detected following SOF monotherapy. Despite relapse with drug resistance to SOF, this patient was successfully retreated with SOF plus ribavirin for 12 weeks and is now cured from HCV infection.

Preoperative assessment of retrorectal tumours.

BACKGROUND: Retrorectal tumours present diagnostic and surgical challenges. This study aimed to identify whether preoperative imaging and/or biopsy provide diagnostic accuracy. METHODS: A consecutive series of patients who had undergone excision of a retrorectal tumour were identified from a database (2002-2013). Details of patient demographics, preoperative presentation, imaging, biopsy, surgical procedure, and gross and microscopic pathology were reviewed. Preoperative imaging and/or biopsies were compared with eventual pathology findings. RESULTS: In total, 76 patients were identified, all of whom had undergone preoperative cross-sectional imaging whereas only 22 had preoperative biopsy. Imaging correctly discriminated benign from malignant tumours in 72 of the 76 patients (specificity 97 per cent, sensitivity 88 per cent, positive predictive value 88 per cent and negative predictive value 97 per cent). The corresponding values for preoperative biopsy (benign versus malignant) were 100, 83, 100 and 93 per cent. None of the four patients who were assessed incorrectly as having benign or malignant disease on imaging would have undergone an alternative procedure had this been known before surgery. Preoperative biopsy did not significantly influence patient management, and the absence of preoperative biopsy had no detrimental effect; a definitive preoperative histological diagnosis would not have influenced subsequent management. CONCLUSION: Preoperative imaging was accurate in the assessment of retrorectal tumours, whereas biopsy did not add to the surgical strategy.

Do implant-supported dentures facilitate efficacy of eating more healthily?

UNLABELLED: Edentulous persons have poor diet quality demonstrating a need for dietary intervention. Implant-supported mandibular overdentures (IODs) have functional advantages over conventional dentures (CD), but whether they enhance the ability to eat more healthily following dietary advice is unknown. OBJECTIVES: This study aimed to compare the effectiveness of dietary intervention between IODs and CD patients. METHODS: Edentulous adults (28 IOD and 26 CD) received customised dietary advice. The percentage contribution of dietary fats, carbohydrate and protein to energy (kcal) intake, dietary intakes of fibre, fruits, vegetables and antioxidants, and plasma antioxidants were assessed pre- and at 3 and 6 months post-dietary intervention. RESULTS: Both groups increased fruit and vegetable intake at 3 and 6 months following dietary intervention but intakes between groups did not differ. The IOD group had reduced % energy from total fat at 3 and 6 months and from saturated fat at 3 months. The CD group had reduced % energy from saturated by 6 months. The IOD group had a significantly lower % energy intake from saturated fat at 3 months and higher intake of non-starch polysaccharide (NSP) compared with the CD group. Both groups showed improvements in serum antioxidant status but the IOD group had significantly higher plasma antioxidant capacity post intervention compared with the CD group. CONCLUSIONS: Dietary intervention benefits denture patients. IOD patients showed moderately greater dietary improvements compared with conventional denture patients.

Development of a patient-based questionnaire about emotional and social issues related to eating with dentures.

OBJECTIVES: In order to fully assess the impact of prosthetic rehabilitation and to formulate appropriate dietary advice, in-depth information about patients' experiences of eating with dentures is needed. The objective of this study was to develop and validate a questionnaire that accurately reflected the real concerns of patients with dental prostheses about the aspects of their life related to eating, using detailed information derived from qualitative interviews with patients. METHODS: Themes around factors related to eating with dentures were derived from interviews with patients (n=66) with either implant-supported mandibular over-dentures or conventional dentures. The themes were used to design a self-completed questionnaire with questions scored on a visual analogue scale and additionally questions answered using free text. The content and face validity of the questionnaire was tested on a different group of patients (n=10) with implant-supported mandibular over-dentures ('implant-supported') or conventional dentures. Test-retest reliability analysis was conducted on a further group of 30 patients (n=15 implant-supported; n=15 conventional dentures). RESULTS: A questionnaire has been developed with 33 questions scored on a visual analogue scale and 31 open questions designed to collect further information as free text. Themes identified were around social, emotional and practical issues about eating. The instrument has good internal reliability with a Cronbach alpha values of 0.86-0.95 and good test-retest reliability with intra-class correlation coefficients 0.87-0.92 across the domains. CONCLUSIONS: A patient-based instrument has been developed to measure emotional and social issues related to eating with dentures (ESIRE questionnaire). The questionnaire will be a useful tool in future trials of prosthetic rehabilitation.

Retrorectal tumours: optimization of surgical approach and outcome.

AIM: The aim was to identify the radiological features of retrorectal tumours that influence management and to highlight technical points that facilitate safe surgical excision. METHOD: A consecutive series of patients was identified from a prospective database. All cases were discussed within a multidisciplinary team. Medical records, radiology and pathology reports were also checked retrospectively. RESULTS: Fifty-six patients [37 women; median age 51 (20-88) years] underwent excision of retrorectal tumours between 2002 and 2010 under the care of one surgeon. Seventeen (37.5%) had a malignant tumour. The commonest symptom was pain or discomfort. Features identified after MRI that suggested malignancy included heterogenous signal intensity (15/17 malignant lesions vs 5/39 benign lesions), an irregular infiltrative margin (14/17 malignant lesions vs 4/39 benign lesions) and enhancement (14/17 malignant lesions vs 2/39 benign lesions) (all P < 0.05). An abdominal approach was used in 27 (48%) patients, a perineal/trans-sacral approach in 20 (36%) and a composite abdomino-sacral approach in nine (16%). The perineal approach was used if the tumours were below the middle of S3 without sacral, pelvic side-wall or visceral involvement. The three most common types of tumour were schwannoma (n = 11), tail gut cyst (n = 13) and chordoma (n = 9). Over a median follow-up period of 46 (6-90) months there were two local recurrences among the malignant tumours (both resected) and two deaths (both sarcomas). CONCLUSION: MR imaging, avoidance of routine preoperative biopsy and careful clinical evaluation result in a good outcome after surgical excision of retrorectal tumours.

Postoperative omental infarction following colonic resection.

AIM: To illustrate the computed tomography (CT) appearances and natural history of postoperative omental infarction following colonic resection and to highlight the important clinical implications of this radiological diagnosis. MATERIALS AND METHODS: Over a 3 year period, 15 patients with a history of colonic resection were identified as having a CT diagnosis of postoperative omental infarction. Relevant clinical and pathological data were retrospectively collected from the institution's electronic patient records system and all relevant imaging was reviewed, including serial CT images in 10 patients. RESULTS: A diagnosis of postoperative omental infarction was made in symptomatic and asymptomatic patients who had undergone open or laparoscopic colonic resection for benign or malignant disease. CT appearances ranged from diffuse omental stranding to discrete masses, which typically appeared within weeks of surgery and could persist for years. In four (36%) of the patients with colorectal cancer, the CT appearances raised concern for recurrent malignancy, but percutaneous biopsy and/or serial CT allowed a confident diagnosis of omental infarction to be made. Although most cases were self-limiting, three (20%) cases were complicated by secondary infection and required radiological or surgical intervention. CONCLUSION: Postoperative omental infarction is an under-recognized complication of colonic resection. It has the potential to mimic recurrent malignancy and may require radiological or surgical intervention for secondary infection.

Parental perceptions of weight status in children: the Gateshead Millennium Study.

OBJECTIVES: To investigate parents' perceptions of weight status in children and to explore parental understanding of and attitudes to childhood overweight. DESIGN: Questionnaires and focus groups within a longitudinal study. SUBJECTS: 536 parents of Gateshead Millennium Study children, of which 27 attended six focus groups. MAIN OUTCOME MEASURES: Parents' perception of their child's weight status according to actual weight status as defined by International Obesity Taskforce (IOTF) cutoffs. Focus group outcomes included parental awareness of childhood overweight nationally and parental approaches to identifying overweight children. RESULTS: The sensitivity of parents recognising if their child was overweight was 0.31. Prevalence of child overweight was underestimated: 7.3% of children were perceived as 'overweight' or 'very overweight' by their parents, 23.7% were identified as overweight or obese using IOTF criteria. 69.3% of parents of overweight or obese children identified their child as being of 'normal' weight. During focus groups parents demonstrated an awareness of childhood overweight being a problem nationally but their understanding of how it is defined was limited. Parents used alternative approaches to objective measures when identifying overweight in children such as visual assessments and comparisons with other children. Such approaches relied heavily on extreme and exceptional cases as a reference point. The apparent lack of relevance of childhood overweight to their child's school or own community along with scepticism towards both media messages and clinical measures commonly emerged as grounds for failing to engage with the issue at a personal level. CONCLUSION: Parents' ability to identify when their child was overweight according to standard criteria was limited. Parents did not understand, use or trust clinical measures and used alternative approaches primarily reliant on extreme cases. Such approaches underpinned their reasoning for remaining detached from the issue. This study highlights the need to identify methods of improving parental recognition of and engagement with the problem of childhood overweight.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

CT features of jejunal pathology.

The imaging of duodenal and ileal diseases is well documented in radiological literature but the jejunum has been relatively neglected. The aim of this review is to outline the current methods of investigation of the jejunum, and provide a comprehensive review of common pathologies affecting the jejunum, with particular emphasis on investigation by computed tomography.

Rhinoscleroma causing upper airway obstruction.

Rhinoscleroma is a chronic granulomatous condition of the respiratory tract, and is not uncommon in tropical regions; particularly, Mexico, Central America and the Middle East. A few cases have been reported in North America, primarily involving immigrants from endemic countries. The causative organism is Klebsiella rhinoscleromatis, a Gram-negative coccobacillus. Diagnosis is made on the basis of culture of the organism and the characteristic pathology of Mikulicz cells on light microscopy. The condition primarily affects the upper airway, and frequently presents with nasal discharge, nasal obstruction or frontal facial pain. Despite the term 'rhinoscleroma', there may be involvement of the entire respiratory tract. Although the condition is slowly progressive, its natural course portends extensive destruction. Laryngotracheal involvement occurs in approximately 15% to 80% of cases, but patients rarely present with isolated laryngotracheal disease. In the present paper, a case of rhinoscleroma presenting with symptoms of upper airway obstruction is described.

Evaluation of the role of the asialoglycoprotein receptor in the clearance of UK-279,276 (recombinant neutrophil inhibitory factor).

1. UK-279,276 or recombinant neutrophil inhibitory factor (rNIF) is a glycoprotein that has been investigated as an intravenous treatment for stroke. Previous data indicate that the asialoglycoprotein receptor (ASGPR) in the liver might have a role in the uptake and clearance of UK-279,276 from plasma in rats and dogs. 2. Biliary elimination of sialo UK-279,276 can be inhibited by the co-administration of asialo fetuin, a known substrate for ASGPR. These data are in keeping with sialo UK-279,276 being cleared by ASGPR. 3. In vitro experiments have demonstrated that asialo UK-279,276 (Sialo UK-279,276 treated to remove the sialic acid residues present on the glycans) shows a significantly greater uptake in rat, dog and human precision-cut liver slices than the sialylated protein. The addition of asialo fetuin to precision-cut liver slice incubations (rat, dog and man) containing asialo UK-279,276 reduced the uptake to levels similar to those seen for the sialylated protein. These data support the potential role of the ASGPR in the clearance of UK-279,276 in rat, dog and man.

Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole.

Voriconazole is a triazole antifungal agent with potent activity against a broad spectrum of clinically significant pathogens. In vivo and in vitro studies have demonstrated that voriconazole is extensively metabolized, with the major circulating metabolite resulting from N-oxidation. In the present study, we report on the human cytochrome P450 enzymes responsible for the generation of this metabolite. In human liver microsomes voriconazole N-oxidation exhibited biphasic kinetics with K(m1) of 8.1 microM, and K(m2) of 835 microM. Studies at 2500 microM voriconazole identified CYP3A4 as the low-affinity component, with activity correlating strongly with CYP3A4 activity in a bank of human liver microsomes (r = 0.90) and inhibited by ketoconazole. At 25 microM, voriconazole N-oxidation showed strong correlation with CYP2C19 and CYP3A4 activity (r = 0.77 and 0.74, respectively) and was inhibited by both sulfaphenazole and ketoconazole. Incubations with recombinant enzymes suggested both CYP2C9 and CYP2C19 as high-affinity enzymes (K(m) values of 20 and 3.5 microM, respectively). Further studies used chemical inhibitors in human liver microsomes prepared from individual donors, including two CYP2C19 poor metabolizers. No inhibition was observed with sulfaphenazole, indicating a minor role for CYP2C9 in human liver, but inhibition by ketoconazole was most potent in the CYP2C19 poor metabolizer livers, suggesting an increased role for CYP3A4 in individuals lacking CYP2C19. These data indicate that voriconazole is a substrate for CYP2C9, CYP2C19, and CYP3A4, with CYP2C9 involvement being minimal in human liver microsomes. Genotype status for CYP2C19 and/or coadministration of drugs that modulate CYP2C19 or CYP3A4 activities could effect voriconazole plasma levels.

Surgical removal of a fish hook from the oesophagus of a turtle.

An adult male Macquarie turtle was presented for examination after swallowing a fish hook. Radiographs taken to determine the position of this foreign body within the gastrointestinal tract revealed the fish hook lodged in the turtle's oesophagus. Surgical removal of the fish hook involved an approach through the soft tissues of the lateral neck. The turtle recovered well and was returned to the wild.

Potential role for P-glycoprotein in the non-proportional pharmacokinetics of UK-343,664 in man.

1. UK-343,664 is a potent and specific PDE5 inhibitor. Following single oral doses to human volunteers, it exhibited non-proportional pharmacokinetics over the dose range 30-800 mg. Over this 27-fold dose range, Cmax and AUCt increased 247- and 287-fold respectively. The half-life (4-6 h) was similar at all doses. No systemic exposure was quantifiable at doses <10 mg. 2. UK-343,664 is a lipophilic molecule (log D7.4 = 3.1) and as such is expected to be cleared mainly by metabolism. Based on studies with expressed human P450 enzymes it was concluded that the metabolism of UK-343,664 was predominantly mediated by CYP3A4. With a moderate Km = 76 microM for this enzyme, saturation of first-pass metabolism alone was considered unlikely to account for the non-proportional pharmacokinetics. 3. UK-343,664 showed high affinity for P-glycoprotein in vitro, with a Km = 7.3 microM. In transport studies in LLC-PK1 cell monolayers transfected with P-glycoprotein, UK343,664 showed marked polarized transport which was concentration dependent. 4. The high affinity of UK-343,664 for P-glycoprotein is considered to be the primary source of the non-proportional pharmacokinetic profile observed in man.