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.

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.

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.

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.

The initiator element of the Drosophila beta2 tubulin gene core promoter contributes to gene expression in vivo but is not required for male germ-cell specific expression.

The tissue-specific expression of the Drosophila beta 2 tubulin gene ( B2t ) is accomplished by the action of a 14-bp activator element (beta2UE1) in combination with certain regulatory elements of the TATA-less, Inr-containing B2t core promoter. We performed an in vivo analysis of the Inr element function in the B2t core promoter using a transgenic approach. Our experiments demonstrate that the Inr element acts as a functional cis -regulatory element in vivo and quantitatively regulates tissue-specific reporter expression in transgenic animals. However, our mutational analysis of the Inr element demonstrates no essential role of the Inr in mediating tissue specificity of the B2t promoter. In addition, a downstream element seems to affect promoter activity in combination with the Inr. In summary, our data show for the first time the functionality of the Inr element in an in vivo background situation in Drosophila.

Tumor-associated peripheral eosinophilia: two unusual cases.

Peripheral eosinophilia is a rare but recognized accompaniment of malignant disease. Two unusual cases, one with a histiocytic lymphoma and the other with cervical carcinoma, are described. In the first patient, pulmonary infiltrates developed at the height of the eosinophilia and in the second, the peripheral eosinophilia heralded the onset of disseminated disease. Tumor-associated peripheral eosinophilia is reviewed, and it is concluded that peripheral eosinophilia associated with a malignant setting is a marker of extensive disease and is thus associated with a poor prognosis.

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.

The role of the cysteine-rich region of the beta2 integrin subunit in the leukocyte function-associated antigen-1 (LFA-1, alphaLbeta2, CD11a/CD18) heterodimer formation and ligand binding.

The cysteine-rich region (CRR) of the beta2 integrin subunit was replaced by that of beta1 to give the chimera beta2NV1. Beta2NV1 can combine with alphaL to form a variant leukocyte-function-associated antigen (LFA)-1 on COS cell surface, suggesting that the specificity of the beta2 interaction with alphaL does not lie in the CRR. Unlike those expressing wild-type LFA-1, COS cells expressing alphaL beta2NV1 are constitutively active in intercellular adhesion molecule (ICAM)-1 adhesion. These results suggest that activation of LFA-1 involves the release of an intramolecular constraint, which is maintained, in part, by the authentic beta2 CRR.

Small-airways disease in recipients of allogeneic bone marrow transplants. An analysis of 11 cases and a review of the literature.

In a retrospective review of 116 consecutive allogeneic bone marrow transplants (BMT), severe obstructive airways disease was identified in 11 patients. Lung pathology demonstrated bronchiolitis in 9 patients and physiologic studies showed small-airways disease consistent with bronchiolitis in the other 2. None of the 5 patients with associated infection survived, while 3 of the 6 patients without an identified pathogen stabilized or improved. Analysis of the 11 cases presented and all 25 cases reported in the literature (1982 to 1985) supports the conclusion that graft-versus-host disease is a major risk factor for bronchiolitis in BMT recipients. Among the proposed mechanisms for the development of bronchiolitis after allogeneic BMT, the 2 most likely are graft-versus-host disease directly causing bronchiolitis, and increased immunosuppressive therapy given for graft-versus-host disease predisposing to viral bronchiolitis. The available evidence would suggest that it is prudent to obtain serial pulmonary function tests even in asymptomatic patients post-BMT, and particularly in those with chronic graft-versus-host disease, in the hope that early detection will allow for early intervention that will arrest or reverse the progression of the obstructive airways disease.

Idiopathic small airways pathology in patients with graft-versus-host disease following allogeneic bone marrow transplantation.

In a retrospective analysis (July 1979 to March 1984) of 120 allogeneic adult bone marrow transplant recipients, we identified seven patients with small-airway disease for whom no microbiologic agent was detected. Six had pulmonary function studies demonstrating air flow obstruction. Five of the seven patients had an open-lung biopsy showing pathologic changes within small airways; these varied from early bronchiolar wall damage to bronchiolitis obliterans. The inflammatory cell infiltrate was peribronchiolar, and consisted of polymorphonuclear leukocytes and lymphocytes in varying proportions. Three of the seven patients recovered following increased immunosuppressive therapy; the other four died. Because all seven patients had acute and chronic graft-versus-host disease, in the absence of any identifiable pathogen, we postulate that small-airway damage represents one of the facets of graft-versus host-disease. An additional analysis of 26 patients with respiratory symptomatology and available histologic material supports the hypothesis that small-airway disease in bone marrow transplant patients represents a risk factor for the subsequent development of respiratory opportunistic infections.

Angiotensin-converting enzyme inhibitors reduce neointimal thickening and maintain endothelial nitric oxide function in rabbit carotid arteries.

Application of periarterial collars induced atheroma-like lesions in the carotid arteries of normocholesterolemic rabbits. Vessel segments taken from the mid-region of the collar (cuffed region) and control regions of the same artery were studied at 7 days after surgery. A group of placebo rabbits was provided ad libitum with regular tap water, and treated animals were supplied for 14 days (beginning 7 days before collar application) with water containing perindopril (daily intake of approximately 0.3 mg/kg). Perindopril treatment reduced plasma angiotensin-converting enzyme (ACE) activity by 88% but did not significantly alter arterial blood pressure or heart rate. The sensitivity of arterial rings to angiotensins I and II did not differ between control and cuffed arteries in either placebo or perindopril-treated rabbits, but in rings from both groups of rabbits the sensitivity to the vasoconstrictor action of serotonin was higher in the cuffed segments, as in previous studies. In addition, in placebo rabbits the endothelium-dependent vasorelaxant response to acetylcholine (which results from the release of nitric oxide) was weaker in cuffed arteries than in controls, whereas in the perindopril-treated animals, this impairment of relaxation was restored to the extent that, in cuffed vessels, it was no longer significantly different from the controls. Similar results were obtained in rabbits treated with another ACE inhibitor (ramipril). In contrast, acute treatment with the metabolite, perindoprilat, in vitro (1.0 microM) did not alter the response to acetylcholine in control or cuffed rings from placebo rabbits. Morphologically, vessel segments taken from the center of the cuffed artery of placebo rabbits showed a thickened intima with marked smooth muscle cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Chimeras of the integrin beta subunit mid-region reveal regions required for heterodimer formation and for activation.

A central region of the beta2 integrin subunit, RN (residues D300 to C459), was replaced by the equivalent sequences from beta1 and beta7 to give the chimeras beta2RN1 and beta2RN7. Whilst the former construct failed to form heterodimer at the cell surface with alphaL, the later of these could be expressed together with the alphaL subunit to form a variant LFA-1. Based on recent modelling work, the RN region consists of two parts, one is the C-terminal end of the putative A-domain (RB, residues D300 to A359), and the other the mid-region (BN, residues Y360 to C459). Chimeras exchanging the two component regions were made. Of the four resultant chimeras, only the beta2RB1 chimera failed to support LFA-1 expression. Thus the beta1 specific residues of this region affect the interaction with the alphaL subunit. Whereas the alphaL/beta2RB7 LFA-1 variant is wildtype like with respect to ICAM-1 adhesion, the alphaLbeta2BN1 and alphaLbeta2BN7, as well as the alphaLbeta2RN7, variants are more adhesive than the wildtype. These results suggest that an authentic beta2 mid-region is, in part, required for maintaining the LFA-1 in a resting state.