NICE rapid guidelines: exploring political influence on guidelines.

The National Institute for Health and Care Excellence (NICE) has been presented as politically independent, asserting it is free from industry influence and conflicts of interest so that its decisions may be led by evidence and science. We consider the ways in which soft political factors operate in guideline development processes at NICE such that guidelines are not truly led by science. We suggest that while NICE procedures explicitly incorporate scientific principles and mechanisms, including independent committees and quality assurance, these fail to operate as scientific practices because, for example, decisions may only be challenged through the courts, which regard NICE as a scientific authority. We then examine what the NICE rapid guideline procedure for COVID-19 reveals about the practical reality of claims about the scientific integrity of NICE guidelines. Changes to guideline development processes during the COVID-19 emergency demonstrated how easy it is to undermine the scientific integrity of NICE's decision-making. The cancellation of the guideline programme and the publication of a rapid guideline process specifically to address the COVID-19 pandemic removed scientific checks and balances, including independent committees, stakeholder consultation and quality assurance, demonstrating that the relationship between NICE and the UK government is more complex than a scientific principle truism. We suggest that NICE is not (and indeed cannot be) truly independent of government in practice, nor can it be truly led by science, in part because of its relationship to the state, which it is simultaneously constituted by and constitutive of.

Endovascular management of mycotic aortic aneurysms- A 20-year experience from a single UK centre.

AIM: To present the authors' experience of endovascular treatment of confirmed and presumed (microbiology negative) mycotic aortic aneurysms (MAA). MATERIALS AND METHODS: Patients undergoing endovascular aortic repair were identified retrospectively from 1998 using the radiology information system and an internally kept database until 2018. The primary aim was to assess the technical success and peri-operative morbidity and mortality. The secondary aim was to assess progression of infection, re-interventions, late mortality, and correlation to antibiotic duration pre- and post-procedure. RESULTS: Thirty-four endovascular aortic procedures were performed for MAA, excluding aorto-enteric fistulas, inflammatory aneurysms, and infected grafts without a new aneurysm. Seventy-six percent of these were thoracic and 24% abdominal. The technical success was 100%. Additional procedures were undertaken in four patients with two requiring a further endovascular procedure. There were two inpatient aneurysm-related mortalities and no inpatient conversions to open repair. The 30-day re-admission and re-intervention rate was 0%. Blood cultures were positive in 45%. There were no secondary graft infections. CONCLUSION: This is the largest European single-centre study. It supports endovascular management of MAA as a lower-risk alternative to open surgery with the majority of patients presenting acutely, later in life and requiring emergency management.

Lessons from a national audit of acute pancreatitis: A summary of the NCEPOD report 'Treat the Cause'.

The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) is an independent organisation whose remit is to review the quality of medical and surgical care provided in the United Kingdom. We undertook a review into the care provided to patients treated for acute pancreatitis during a 6 month study period between 1st January and 30th June 2014. This included assessment of care at an organisational level, clinical level within hospitals and external peer review. From a random sample, 712 patients underwent hospital clinician review and 418 patients had external peer review. Overall, we found that there was room for improvement in care in over 50% of patients with acute pancreatitis. Case reviewers felt that efforts to prevent recurrent episodes due to gallstones and alcohol were inadequate as 21% of patients in the study had one or more previous episodes of acute pancreatitis. Aspects of general care where improvements could be made include better antibiotic stewardship; as 1/5 of patients were considered to have been given antibiotics unnecessarily. Overall management of the patients' nutrition was considered adequate by the case reviewers in only 85% of cases. The use of an early warning score was omitted in 31% of emergency department admissions. Recommendations include standardised early warning scoring systems to be used throughout the hospital and commenced in the emergency department. The development of better networking arrangements and regional pancreatitis units, with shared management guidelines, is also essential to improve the coordination of care.

Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality.

Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1, we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo. In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa.

Aberrant medial sural artery causing popliteal vein entrapment syndrome.

Isolated popliteal venous entrapment is unusual and often caused by variation or aberrant origins of the gastrocnemius muscle, thickened perivenous fascia or an abnormal vascular bundle. We report a unique case of a fit and well 35-year-old man with popliteal venous entrapment after presenting to the vascular unit with symptomatic varicose veins. The cause of the entrapment was found to be an aberrant medial sural artery on operative exploration. The artery was ligated, releasing the entrapped vein. The patient made an uneventful recovery with resolution of symptoms of venous insufficiency without evidence of muscle ischaemia.

Embolization for non-variceal upper gastrointestinal tract haemorrhage: a systematic review.

AIM: To assess the published evidence on the endovascular treatment of non-variceal upper gastrointestinal haemorrhage. MATERIALS AND METHODS: An Ovid Medline search of published literature was performed (1966-2009). Non-English literature, experimental studies, variceal haemorrhage and case series with fewer than five patients were excluded. The search yielded 1888 abstracts. Thirty-five articles were selected for final analysis. RESULTS: The total number of pooled patients was 927. The technical and clinical success of embolization ranged from 52-100% and 44-100%, respectively. The pooled mean technical/clinical success rate in primary upper gastrointestinal tract haemorrhage (PUGITH) only, trans-papillary haemorrhage (TPH) only, and mixed studies were 84%/67%, 93%/89%, and 93%/64%, respectively. Clinical outcome was adversely affected by multi-organ failure, shock, corticosteroids, transfusion, and coagulopathy. The anatomical source of haemorrhage and procedural variables did not affect the outcome. A successful embolization improved survival by 13.3 times. Retrospective comparison with surgery demonstrated equivalent mortality and clinical success, despite embolization being applied to a more elderly population with a higher prevalence of co-morbidities. CONCLUSIONS: Embolization is effective in this very difficult cohort of patients with outcomes similar to surgery.

Assessment of apparent internal carotid occlusion on ultrasound: prospective comparison of contrast-enhanced ultrasound, magnetic resonance angiography and digital subtraction angiography.

OBJECTIVES: Modern conventional ultrasound is sensitive to slow flow, but may misclassify some tight stenoses as occlusion. Symptomatic patients with tight proximal internal carotid artery stenoses may benefit from carotid endarterectomy but those with occlusion or long-segment disease do not. DESIGN: A prospective study of the diagnostic accuracy of contrast-enhanced ultrasound (CE-US), 2D time-of-flight magnetic resonance angiography (2D-TOF MRA) and contrast-enhanced magnetic resonance angiography (CE-MRA) against a reference standard of digital subtraction angiography (DSA) in patients with apparent carotid occlusion on conventional ultrasound. MATERIALS AND METHODS: Thirty-one patients with apparent carotid occlusion on conventional ultrasound and with recent ispilateral hemispheric transient ischaemeic attacks (TIAs) were studied. The primary endpoint was confirmation of occlusion with a secondary endpoint of identification of a surgically correctible lesion. RESULTS: The sensitivity and specificity of CE-US, 2D-TOF MRA and CE-MRA for patency were 1 & 1, 0.33 & 1 and 0.6 & 1 respectively and for the detection of a surgically correctible lesion were 1 & 0.96, 0.67 & 1 and 1 and 0.96 respectively. CE-US was difficult to interpret, precluding confident diagnosis in 5 cases. CONCLUSIONS: 2D-TOF MRA had poor sensitivity for patency and cannot be recommended as a second-line investigation to assess vessels apparently occluded on conventional ultrasound. Confident diagnosis on CE-US and CE-MRA accurately identified occlusion. If occlusion is confirmed by either of these modalities, no further imaging is required. The relative advantages of CE-US or CE-MRA in this situation are uncertain.

Cryoplasty for arterial restenosis.

OBJECTIVE: A prospective follow-up study of patients with arterial restenosis undergoing cryoplasty. MATERIALS & METHODS: Between May 2004 and June 2005, 10 patients with restenosis following ilio-femoral endovascular treatment underwent twelve cryoplasty procedures. All patients had had at least one previous episode of stenosis treated by conventional endovascular methods and had suffered further restenosis. The indications for treatment were grafts at risk (n=5) and symptomatic in-stent restenosis (n=5). Two patients underwent re-cryoplasty. Cryoplasty was performed in accordance with manufacturer's instructions using 6-8mm balloons. All patients had Doppler ultrasound evaluation at 1, 3, 6 and 12 months. RESULTS: All procedures had angiographically successful immediate outcome with <30% residual stenosis. Non flow limiting dissection was evident in two cases. In six procedures (50%), restenosis was evident within 6 months post-procedure, whilst in the other six, there was progressive restenosis appearing between 6-12 months. Five cryoplasty procedures have needed endovascular re-intervention due to symptomatic high-grade restenosis and a sixth is awaiting surgery. CONCLUSION: Cryoplasty is of no value in patients with restenosis in the iliofemoral segment with half the procedures failing within six months and all of them within the first year. Evidence to support the use of cryoplasty in the peripheral arterial restenotic lesions is lacking.

Endovascular embolization of visceral artery aneurysms with ethylene-vinyl alcohol (Onyx): a case series.

We report the application of the liquid embolic agent ethylene-vinyl alcohol (Onyx; MicroTherapeutics, Irvine, CA, USA) in the management of visceral artery aneurysms. The technique and indications for using Onyx are discussed with emphasis on the management of wide-necked aneurysms and maintenance of patency of the parent vessel. None of the cases was considered suitable for stent-grafting or embolization with conventional agents. Two aneurysms of the renal artery bifurcation and one aneurysm of the inferior pancreaticoduodenal artery were treated. Following treatment there was complete exclusion of all aneurysms. There was no evidence of end-organ infarction. Follow-up with intervals up to 6 months has shown sustained aneurysm exclusion. Onyx is known to be effective in the management of intracranial aneurysms. Our experience demonstrates the efficacy and applicability of the use of Onyx in the treatment of complex visceral artery aneurysms.

The role of Eralpha and ERbeta in the prostate: insights from genetic models and isoform-selective ligands.

Androgens are known regulators of the growth and differentiation of the prostate gland and are effective during development and maturity as well as in disease. The role of estrogens is less well characterized, but dual direct and indirect actions on prostate growth and differentiation have been demonstrated, facilitated via both ERalpha, and ERbeta. Previous studies using animal models to determine the role of ERbeta in the prostate have been problematic due to the centrally mediated responses to estrogen administration via ERalpha that can lower androgen levels and lead to epithelial regression, thereby masking any direct effects on the prostate mediated by ERbeta. Our alternate approach was to use the estrogen-deficient aromatase knockout (ArKO) mouse and the method of tissue recombination to provide new insight into estrogen action on prostate growth and pathology. Firstly, utilizing homo- and heterotypic tissue recombinants, we demonstrate that stromal aromatase deficiency results in the induction of hyperplasia in previously normal prostatic epithelium and that this response is the result of local changes to the paracrine interaction between stroma and epithelium. Secondly, using tissue recombination and an ERbeta-specific agonist, we demonstrate that the activation of ERbeta results in an anti-proliferative response that is not influenced by alterations to systemic androgen levels or activation of ERalpha. Finally, using intact ArKO mice this study demonstrates that the administration of an ERbeta-specific agonist abrogates existing hyperplastic epithelial pathology specifically in the prostate but an ERbeta-specific agonist does not. Therefore, in the absence of stromal aromatase gene expression, epithelial proliferation, leading to prostatic hypertrophy and hyperplasia, may result from a combination of androgenic stimulation of proliferation and failed activation of ERbeta by locally synthesized estrogens. These data demonstrate essential and beneficial effects of estrogens that are necessary for normal growth of the prostate and distinguish them from those that adversely alter prostate growth and differentiation. This indicates the potential of antiandrogens and SERMS, as opposed to aromatase inhibitors, for the management of prostate hyperplasia and hypertrophy.

Carbon dioxide angiography: a simple and safe system of delivery.

Carbon dioxide (CO2) is an established alternate angiographic contrast agent, which can be delivered by pump or hand injection. We describe a simple, safe and inexpensive hand injection system that delivers a known volume of CO2 at atmospheric pressure and prevents contamination with room air.

Oestrogens and prostate cancer.

Androgens are essential for stimulating normal development, growth and secretory activities of the prostate whereas oestrogens are generally regarded as inhibitors of growth. Evidence for the local synthesis of oestrogens includes the detection of aromatase mRNA and protein in the stroma of human non-malignant tissues and in malignant tissue, where it is detected in epithelial tumour cells. As well, aromatase activity was measured by biochemical assay and protein was detected in prostatic non-malignant and tumour cell lines. Taken together with the identification of direct oestrogenic actions on the prostate, these results suggest that alterations in local oestrogen synthesis may have significant consequences in malignancy of these organs. Genetically modified mouse models were studied in order to evaluate the action of oestrogens alone or in combination with androgens on the prostate gland. Hypogonadal (hpg) mice are deficient in gonadotrophins and androgens but showed direct proliferative responses to oestradiol. The responses were characterised by discrete lobe-specific changes including smooth-muscle regression, fibroblast proliferation, inflammation, and basal epithelial cell proliferation and metaplasia. The aromatase knockout (ArKO) mouse, deficient in oestrogens due to a non-functional aromatase enzyme, developed prostatic hyperplasia during the lifelong exposure to elevated androgens, however, no malignant changes were detected in the prostate at any time. In contrast, combined androgen and oestrogen treatment has been shown to induce prostatic dysplasia and adenocarcinoma. These results demonstrate that malignant changes to the prostate gland are dependent upon both androgenic and oestrogenic responses and that neither hormone alone is sufficient to evoke aberrant patterns of growth, resulting in malignancy.

Venous covered stent: successful occlusion of a symptomatic internal iliac arteriovenous fistula.

We report the placement of a covered stent within the internal iliac vein (IIV) to occlude a symptomatic iatrogenic internal iliac arteriovenous fistula following an abdominal aortic graft. Angiography revealed a direct communication between an internal iliac graft to artery anastomosis and the right IIV with rapid shunting into the inferior vena cava and a small associated pseudoaneurysm. Femoral, brachial or axillary arterial access was precluded. The fistula was successfully occluded by a stent-graft placed in the IIV. Arteriovenous fistula can be treated in a number of ways including covered stent placement on the arterial side. To the best of our knowledge this is the first time placement in a vein has been described. Where access is difficult or the procedure carries a high risk of complication, a venous covered stent may offer an alternative.

The contribution of inhibins and activins to malignant prostate disease.

The normal human prostate expresses inhibin and activin subunits. In prostate cancer, the inhibin alpha subunit gene is down regulated and this is associated with loss of heterozygosity (LOH) at the gene locus and methylation of the promoter. These data support the hypothesis that the inhibin alpha subunit is tumor suppressive in the prostate. The pluripotent effects of activins and the similarities to transforming growth factor beta (TFGbeta) suggest a role for activins in progression to malignancy, whereby, the normal growth inhibitory action of activin A observed on benign cells is lost with the acquisition of activin resistance in prostate cancer cells. The mechanisms of rendering tumor cells resistant to activin A may include: alteration in activin binding protein (follistatin) synthesis and/or dimerisation with activin beta(C) to form novel activin dimers. The contribution of the activin signalling cascade to malignancy requires further evaluation to identify the synergies and differences to other members of the TGFbeta superfamily.

Elevated androgens and prolactin in aromatase-deficient mice cause enlargement, but not malignancy, of the prostate gland.

Although androgens are the main steroids controlling the growth of the mammalian prostate, increasing evidence demonstrates that estrogens also regulate prostate development and growth. This study describes the effects of estrogen deficiency using aromatase knockout mice (ArKO) with targeted disruption of the cyp19 gene. Serum and tissue testosterone and 5alpha-dihydrotestosterone as well as serum PRL levels are significantly (P < 0.05) elevated in mature male ArKO mice. Histological, stereological, and immunohistochemical studies demonstrated enlargement of the ventral, anterior, and dorsolateral lobes of the prostate in young and older ArKO mice. Hyperplasia of the epithelial, interstitial, and luminal compartments was identified and associated with up-regulation of androgen receptors. There was no evidence of malignancy as the animals aged (up to 56 weeks). The changes observed in the prostates of ArKO mice were unaffected by maintaining mice on regular or soy-free diets. It is concluded in ArKO mice that, despite the long-term elevation of androgens and PRL, the absence of estrogen in these animals does not result in induction of malignancy in the prostate gland.

Expression of activin A and follistatin core proteins by human prostate tumor cell lines.

Activin and follistatin (FS) messenger RNA and protein are expressed and localized to human prostate tissue from men with high grade cancer and to human prostate tumor cell lines LNCaP, DU145, and PC3. Although activin A induces apoptosis and inhibits cell proliferation in LNCaP cells, PC3 cells are insensitive to the effect of exogenous addition of activin A. The results of this study show that activin A and FS are produced and can be measured by specific enzyme-linked immunosorbent assays in PC3 cells and media but are not detectable in LNCaP cells. Over 10 days in culture, the production of activin A by PC3 cells declines and is inversely correlated (r = -0.779) to FS288 production, which steadily increases and is significantly elevated compared with Day 1 of culture. The presence of FS288 and FS315 proteins was confirmed by immunocytochemistry and showed that only PC3 cells produced the FS288 isoform. Western blotting of PC3 cell media confirmed the presence of the FS288 isoform. Blockade of FS288 activity with a neutralizing antibody rendered PC3 cells responsive to activin A, as measured by inhibition of proliferation. Collectively, these results suggest that PC3 tumor cells are insensitive to activin A because they produce measurable amounts of activin ligand and FS288 protein, which is capable of blocking the autocrine response of these cells to activin A.

Spiral CT of the abdomen: increased diagnostic potential.

Over the last 10 years, spiral CT has become the optimal method of performing all CT within the abdomen and pelvis. Not only has the technique improved the quality of individual examinations, it has also opened up many new diagnostic possibilities which are currently being evaluated and compared with the concurrent advances in ultrasound and MRI. These new diagnostic possibilities are discussed in this review article. So too are the economic advantages of the shorter data-acquisition times which also make the examination much better tolerated by the patient.

Subclavian and internal jugular veins at Doppler US: abnormal cardiac pulsatility and respiratory phasicity as a predictor of complete central occlusion.

In 21 consecutive patients, the authors analyzed changes in venous Doppler waveforms of damped or diminished cardiac pulsatility and respiratory phasicity. Each patient was suspected of having upper limb venous thrombosis, but thrombus was not visible at gray-scale ultrasonography (US) in the subclavian and brachiocephalic veins. US findings were compared with phlebographic findings. The results show that US can be used to establish the presence or absence of thrombosis in the distal portion of the brachiocephalic or subclavian veins, which are inaccessible to direct insonation.