Detection of medications associated with Alzheimer's disease using ensemble methods and cooperative game theory.

OBJECTIVE: To study the feasibility of evaluating feature importance with Shapley Values and ensemble methods in the context of pharmacoepidemiology and medication safety. METHODS: We detected medications associated with Alzheimer's disease (AD) by examining the additive feature attribution with combined approach of Gradient Boosting and Shapley Values in the Medication use and Alzheimer's disease (MEDALZ) study, a nested case-control study of 70,719 verified AD cases in Finland. Our methodological approach is to do binary classification using Gradient boosting (an ensemble of weak classifiers) in a supervised learning manner. Then we apply Shapley Values (from cooperative game theory) to analyze how feature combinations affect the classification result. Medication use with a five to one year time-window before AD diagnosis was ascertained from Prescription register. RESULTS: Antipsychotics with low or medium dose, antidepressants with medium to high dose, and cardiovascular medications with medium to high dose were identified as the contributing features for separating cases with AD from controls. Medium to high amount of irregularity in the purchase pattern were an indicating feature for separating AD cases from controls. The similarity of medication purchases between AD cases and controls made the feature evaluation challenging. CONCLUSIONS: The combined approach of Gradient Boosting and feature evaluation with Shapley Values identified features that were consistent with findings from previous hypothesis-driven studies. Additionally, the results from the additive feature attribution identified new candidates for future studies on AD risk factors. Our approach also shows promise for studies based on observational studies, where feature identification and interactions in populations are of interest; and the applicability of using Shapley Values for evaluating feature relevance in pattern recognition tasks.

Plerixafor is superior to conventional chemotherapy for first-line stem cell mobilisation, and is effective even in heavily pretreated patients.

This study (PHANTASTIC) compares first-line plerixafor with granulocyte colony-stimulating factor (G-CSF) in 98 myeloma and lymphoma patients with 151 historic controls mobilised by conventional chemotherapy+G-CSF. Eleven patients developed mild transient symptoms possibly related to plerixafor. No serious adverse events were seen. Seventy (71%) plerixafor-mobilised patients achieved both ⩾ 4 × 10(6) CD34(+) cells/kg in ⩽ 2 aphereses and no neutropenia (<1.0 × 10(9)/l). This is significantly > 48 (32%) of 151 historical chemotherapy+G-CSF-mobilised control patients achieving this end point (P<0.001). Ninety-six (98%) plerixafor-mobilised patients achieved ⩾ 2 × 10(6) CD34(+) cells/kg within one harvest round compared with 114 (75%) of controls (P=0.001). Engraftment times and 12-month outcome were comparable in both groups. Prior treatment was summarised by two scoring systems. Controls mobilising either >2.0 or >4.0 × 10(6) CD34(+) cells/kg have significantly lower scores than mobilisation failures (P=0.002), but this relationship was not seen for plerixafor-mobilised patients. Plerixafor is a more effective and less toxic mobilising agent than conventional chemotherapy (especially in heavily pretreated patients), with comparable subsequent outcome, and merits consideration as the first-line standard of care for stem cell mobilisation.

Catheter-directed thrombolysis for iliofemoral deep vein thrombosis.

BACKGROUND: Recent international guidance recommends the use of catheter-directed thrombolysis (CDT) in selected patients with symptomatic iliofemoral deep vein thrombosis (DVT). The aim of this study was to estimate the potential increase in workload as a result of this recommendation. METHODS: Using the radiology database, a review was performed of all DVTs diagnosed between August 2010 and February 2012 at a large tertiary referral hospital. The National Institute for Health and Clinical Excellence and American College of Chest Physicians guidance was applied retrospectively to this cohort, using case-note review by two independent clinicians to determine which patients would have been suitable for CDT. RESULTS: Some 563 patients had DVT confirmed radiologically over the 18-month interval. Fifty-three of the 128 patients with iliofemoral DVT would have been eligible for intervention with CDT, equivalent to 4·4 patients per 100 000 per year. Only eight (15 per cent) of the 53 were actually referred to vascular services for treatment. All eight patients had successful CDT, which involved a stay in critical care for monitoring (median 2 (range 1-3) sessions). CONCLUSION: Vascular units should be prepared for a major increase in the requirement for CDT for iliofemoral DVT. This increase will affect inpatient beds, the interventional radiology suite, critical care and interhospital referrals.

Mid-term results of endovascular aortic aneurysm repair in the young.

OBJECTIVES: To compare the mid-term outcome and secondary intervention rate following elective open and endovascular aortic aneurysm repair (EVAR) in patients aged 65 years and younger. METHODS: A retrospective analysis of patients aged 65 years and younger who had elective abdominal aortic aneurysm repair (AAA) between 1994 and 2012. RESULTS: One hundred and sixty-five patients under the age of 65 years (mean age: 61 years ± 4; 8 women) had elective abdominal aneurysm repair (97 EVAR and 68 open). The overall 30-day mortality rate was 3.7% (2.1% EVAR and 5.9% open). Forty per cent of patients had died at a median follow up of 77 months (interquartile range, 36-140). Most deaths were not related to aneurysm. There was no difference in the long-term mortality between the EVAR and open groups (hazard ratio [HR] = 1.22; 95% confidence interval [CI] 0.75-1.98, p = .43), but there was a trend of better outcomes with the use of commercially made endografts over open repair (HR = 2.9; 95% CI 0.9-10.0, p = .08) and custom-made endografts (HR = 3.1, 95% CI 0.9-10.3; p = .07). Eleven per cent of patients who had EVAR required a further procedure compared with 13% who had open repair. All but one of the re-interventions in the EVAR group was performed on patients who had custom-made endografts. CONCLUSIONS: Young patients with AAA have significant comorbidities and do not necessarily have long lifespans. In the less fit younger patients with AAA, the results with EVAR are comparable with fit patients who had open AAA repair. The management of fitter young patients with AAA remains controversial, but improving results with EVAR over time may increase the role of EVAR in this group.

An online patient completed Aberdeen Varicose Vein Questionnaire can help to guide primary care referrals.

OBJECTIVES: To determine the feasibility and reliability of an online patient completed Aberdeen Varicose Vein Questionnaire (AVVQ) as a tool to guide specialist referral. METHODS: This was a prospective qualitative and quantitative study. One hundred and six patients completed an online questionnaire. Some 43 (40%) completed the AVVQ questionnaire at home and 63 (60%) did it immediately before their appointment. Venous Clinical Severity Score (VCSS) and CEAP grades were assigned by a consultant vascular surgeon. In 11 patients, the questionnaire was repeated at the time of surgery to assess reproducibility and bias. RESULTS: The AVVQ correlated with the specialist's VCSS scores (Spearman coefficient 0.795; p < 0.01) and similarly with CEAP grade (P < 0.01, ANOVA test). AVVQ was reproducible with close agreement (Spearman coefficient 0.89; p < 0.01) between both 1st AVVQ score of 21.61 (sd 10.26; range 6.12-40.14) and 2nd AVVQ score of 21.03 (sd 10.50 range 4.51-42.57). Patients' feedback about the online AVVQ was positive. CONCLUSIONS: An online questionnaire is acceptable to patients, correlates with clinical findings and using a threshold value could be used by healthcare Commissioners to guide varicose vein referrals.

Radiofrequency-induced thermal therapy: results of a European multicentre study of resistive ablation of incompetent truncal varicose veins.

OBJECTIVES: To investigate the effectiveness of bipolar radiofrequency-induced thermal therapy (RFITT) in a multicentre non-randomized study. METHODS: Some 672 incompetent saphenous veins (85% great saphenous varicose vein, 15% short saphenous vein) in 462 patients (56.5% CEAP [clinical, aetiological, anatomical and pathological elements] class 3 or worse) were treated in eight European centres. Patients were assessed between 180 and 360 days postoperatively. Occlusion rates were determined by duplex ultrasound and compared with the power used for treatment, pull back rate and experience of the operating surgeon. RESULTS: Complete occlusion rates of 98.4% were achieved when treatments were performed by an experienced operator (more than 20 cases), when the maximum power setting on the RFITT generator was between 18 and 20 W and the applicator was withdrawn at a rate slower than 1.5 second/cm CONCLUSIONS: RFITT is efficacious, well tolerated by patients and has a low incidence of procedure-related post-operative complications.

Reprinted article "Neovascularisation is the principal cause of varicose vein recurrence: results of a randomised trial of stripping the long saphenous vein".

OBJECTIVES: To determine whether routine stripping of the long saphenous vein reduces recurrence after varicose vein surgery. DESIGN: Randomised controlled trial. All operations done by a consultant vascular surgeon. Two year follow-up. MATERIALS AND METHODS: One hundred patients with primary long saphenous varicose veins (133 legs) were randomised. Two year follow-up in 81 patients (113 legs) with questionnaire, clinical examination and Duplex scanning. RESULTS: Some 89% remained satisfied with the results of their surgery, though 35% had recurrent veins on clinical examination. Recurrence was reduced from 43 to 25% in patients who had their long saphenous vein stripped (p = 0.04, χ(2)). Neovascularisation (serpentine tributaries arising from the ligated saphenofemoral junction) was detected in 52% of limbs and was the commonest cause of recurrence. Most tributaries were less than 3 mm in diameter and only caused recurrence if the long saphenous vein or a major thigh vein was intact. Twelve patients had tributaries greater than 3 mm diameter and all had recurrent varicose veins. CONCLUSIONS: Recurrence is common after varicose vein surgery and in this study was caused principally by neovascularisation at the ligated saphenofemoral junction. Clinical recurrence is reduced by routine stripping of the long saphenous vein.

Laser and radiofrequency ablation study (LARA study): a randomised study comparing radiofrequency ablation and endovenous laser ablation (810 nm).

OBJECTIVES: There have been few randomised studies comparing Radiofrequency Ablation(RFA) with other endovenous techniques. The primary aim of this study was to determine whether RFA of the great saphenous vein (GSV) was associated with less pain and bruising than endovenous laser ablation (EVLA). MATERIALS AND METHODS: This trial had two cohorts--patients with bilateral GSV incompetence causing varicose veins (VV) and those with unilateral GSV VVs. In total 87 legs were treated in this study. Limbs in the bilateral group were treated with RFA in one leg and EVLA in the other. In the unilateral group limbs were randomised to RFA or EVLA. RFA was performed using the Celon RFiTT system (Teltow, Germany). EVLA was performed using an 810nm Laser (Biolitec AG, Germany). Phlebectomies were performed as required. Primary endpoints were patient assessed pain and bruising measured by visual analogue scale (VAS). Secondary endpoints were patency assessed by duplex ultrasound at 6 weeks and 6 months. RESULTS: In the bilateral group, RFA resulted in significantly less pain than EVLA on days 2-11 postoperatively. RFA also resulted in significantly less bruising than EVLA on days 3-9. There were no significant differences in mean post operative pain, bruising and activity scores in the unilateral group. Both RFA and EVLA resulted in occlusion rates of 95% at 10 days postoperatively. CONCLUSIONS: RFA was less painful for patients than EVLA and produced less bruising in the postoperative period with comparable success rates but there was no difference in the unilateral group.

The importance of anatomical suitability and fitness for the outcome of endovascular repair of ruptured abdominal aortic aneurysm.

INTRODUCTION: Endovascular repair of aortic aneurysm (EVAR) has a lower mortality than open repair. The aim of this study was to assess mortality from EVAR for emergency AAA repair and the impact of fitness for operation and adverse anatomy. METHODS: One-hundred and forty two patients who had EVAR for a ruptured AAA (80, REVAR) or a symptomatic AAA (62, SEVAR) between 1994 and 2007 in a single specialist endovascular centre were reviewed. Fitness for surgery was assessed by Hardman's index (age>76, loss of consciousness, Hb<9.0, Cr>190, ischaemic ECG). CT scans were reviewed, compared with operative images and operation notes for adverse anatomy. Details of perioperative complications, and outcome were recorded. RESULTS: Overall mortality at 24-h, 30-days and one year were, respectively: 17%, 36%, 50% for REVAR and 5%, 8%, 23% for SEVAR. Overall adverse anatomy increased 30-day mortality. Hardman's index of three or more increased mortality HR=2.59 (1.24-5.41), p=0.01. On Cox regression Univariate analysis increasing Hardman's index score and adverse anatomy increased the overall mortality over time. In multivariate Cox regression analysis (controlled for the Hardman's index) adverse anatomy was associated with significant increase in graft related mortality. CONCLUSION: The use of EVAR is feasible in patients who present with a ruptured or acutely symptomatic AAA. Care must be taken not to extend anatomical or clinical guidelines.

Suitability of varicose veins for endovenous treatments.

The aim of the study was to assess the suitability of radiofrequency ablation (RFA), endovenous laser ablation (EVLA), and foam sclerotherapy (FS) for patients with symptomatic varicose veins (VVs). The study comprised 403 consecutive patients with symptomatic VVs. Data on 577 legs from 403 consecutive patients with symptomatic VVs were collected for the year 2006. Median patient age was 55 years (interquartile range 45-66), and 62% patients were women. A set of criteria based on duplex ultrasonography was used to select patients for each procedure. Great saphenous vein (GSV) reflux was present in 77% (446 of 577) of legs. Overall, 328 (73%) of the legs were suitable for at least one of the endovenous options. Of the 114 legs with recurrent GSV reflux disease, 83 (73%) were suitable to receive endovenous therapy. Patients with increasing age were less likely to be suitable for endovenous therapy (P = 0.03). Seventy-three percent of patients with VVs caused by GSV incompetence are suitable for endovenous therapy.

The Immediate Management of the Patient with Rupture: Open Versus Endovascular repair (IMPROVE) aneurysm trial--ISRCTN 48334791 IMPROVE trialists.

BACKGROUND: Systematic reviews have suggested a survival advantage for patients with ruptured abdominal aortic aneurysm (AAA), who are managed by endovascular repair. These reviews are based on single centre experiences of selected patients. OBJECTIVE: To determine whether a policy of endovascular repair improves the survival of all patients with ruptured AAA. METHODS: A randomized controlled trial, IMPROVE (ISRCTN 48334791) will randomize patients with a clinical diagnosis of rAAA, made in hospital, either to immediate CT scan and endovascular repair whenever anatomically suitable (endovascular first), or to open repair, with CT scan being optional (normal care), The trial is set on a background of guidelines for emergency care, CT scanning and anaesthesia, which incorporate the protocol of permissive hypotension. Recruitment started in October 2009 and 600 patients are required to show a 14% survival benefit at 30 days (primary outcome) for the endovascular first policy. Recruitment will be from the UK and Europe. Secondary outcomes include 24h, in-hospital and 1 year survival, complications, major morbidities, costs and quality of life. DISCUSSION: This is a "real life" trial that will answer the fundamental relevant clinical dilemma, namely, do patients who present with ruptured AAA derive benefit from treatment in a system, which offers a preferential strategy of endovascular repair? The trial addresses whether the anticipated reduced mortality and morbidity associated with endovascular repair is offset by the relatively greater ease of access and speed to conventional surgery. This issue is pivotal to future patient care and provision of services.

A modular aortouniiliac endovascular stent-graft is a useful device for the treatment of symptomatic and ruptured infrarenal abdominal aortic aneurysms: one-year results from a multicentre study.

INTRODUCTION: Endovascular repair (EVAR) of acute symptomatic and ruptured abdominal aortic aneurysm (rAAA) can be difficult without a large stock of suitable graft sizes. We report a prospective European multicentre study of a modular aortouniiliac stent-graft. PATIENTS AND METHODS: Seven centres, with elective EVAR experience, participated in the study. Sixty-five patients were enrolled from September 2002 - April 2005. Some 45 patients had rAAA and 20 were acutely symptomatic. Their median age was 74 (69-80.3) years, 49 (75%) were men. From a choice of 4 body and 4 limb sizes, stent-grafts were deployed under local or general anaesthesia. RESULTS: The endovascular delivery system was introduced and the aneurysm excluded from the circulation in a median of 40 (30-60) minutes from the first incision. The median operative duration was 150 (120-190) mins, blood loss 300 ml (200-800). 33 (51%) operations were performed by a vascular surgeon alone. There were a total of 4 (6%) peri-operative re-interventions, endovascular (n=1), open (n=2) and thrombectomy (n=1). The peri-operative mortality in the rupture group was 40% and 10% in the symptomatic group. CONCLUSIONS: Aortouniiliac stent-grafts provide rapid exclusion of rAAA. Suitably trained surgeons can do the operation without a radiologist's support. The mortality rate from rAAA treated with EVAR remains high.

A randomised trial of endovascular and open surgery for ruptured abdominal aortic aneurysm - results of a pilot study and lessons learned for future studies.

INTRODUCTION: EVAR has the potential to improve outcome after ruptured abdominal aortic aneurysm (AAA). Published series have been based upon selected populations. METHODS: An interim analysis of a single centre prospective randomised controlled trial comparing endovascular aneurysm repair (EVAR) with open aneurysm repair (OAR) in patients with ruptured AAA was performed. Patients who had a ruptured AAA and who were considered fit for open repair were randomised to EVAR or OAR after consent had been obtained. Those in the EVAR group had pre-operative spiral computed tomographic angiography (CTA). The primary endpoint was operative (30-day) mortality and secondary endpoints were moderate or severe operative complications, hospital stay and time between diagnosis and operation. A power study calculation required 100 patients to be recruited. RESULTS: Between September 2002 and December 2004, 103 patients were admitted with suspected ruptured AAA. Only 32 patients were recruited to the study. Of these, four patients died before receiving surgical treatment. On an intention to treat basis the 30-day mortality rate was 53% in the EVAR group and 53% in the OAR group. Moderate or severe operative complications occurred in 77% in the EVAR group and in 80% in the OAR group. Median total hospital stay in the EVAR group was 10 days (inter-quartile range 6-28) and 12 days (4-52) in the OAR group. Median time between diagnosis and operation was 75 minutes (64-126) in the EVAR group and 100 minutes (48-138) in the OAR group. CONCLUSIONS: Despite the relative high operative mortality in the EVAR group, these preliminary results show that it is possible to recruit patients to a randomised trial of OAR and EVAR in patients with ruptured AAA. CT scanning does not delay treatment.

A prospective randomised controlled trial of VNUS closure versus surgery for the treatment of recurrent long saphenous varicose veins.

OBJECTIVE: This study aimed to assess the outcome of endoluminal thermal ablation (VNUS) and traditional redo groin surgery (RGS) and long saphenous vein (LSV) stripping in patients with bilateral recurrent long saphenous varicose veins. METHODS: This was a randomised patient controlled double blind study. Sample size calculations required 16 patients. Their median age was 54 and 11 were women. The median CEAP class was 3. At operation one leg, chosen at random, was treated with VNUS and avulsions using intra-operative duplex control. The other leg was treated with traditional RGS, exposure of the femoral vein, stripping of the LSV and multiple avulsions. Post-operatively patients completed 10 cm visual analogue scales for pain and bruising. Digital Image analysis was used to objectively assess bruising. Statistical analysis was done using Wilcoxon signed rank test for paired data. Results are expressed as median values (inter-quartile ranges). RESULTS: Time to perform VNUS was 25.5 (20.5-31.3) min compared with 40 (34.5-45.5) min it took for RGS (p=0.02). Pain score for VNUS was 1.7 (0.2-4), significantly lower than that for RGS 3.8 (0.6-6.3) (p=0.02). Bruise score for VNUS was 1.7 (0.4-4.4), and that for RGS was 5.2 (2.6-7) (p=0.03). All LSVs were sealed by VNUS at duplex follow up. Three legs in the RGS group and two in the VNUS group had a minor complication. CONCLUSIONS: VNUS caused less pain and bruising and was performed more quickly than RGS. VNUS should be considered the treatment of choice for recurrent long saphenous varicose veins.

The endovascular management of ruptured abdominal aortic aneurysms.

Endovascular aneurysm repair (EVAR) is a controversial technique, which remains the subject of a number of prospective randomised trials. Although questions remain regarding its long-term durability objective evidence exists which demonstrates its reduced physiological impact compared with conventional open repair. If this technique could be used in patients with ruptured abdominal aortic aneurysm (AAA) it may reduce the high peri-operative mortality. A review of the literature identified a limited experience with EVAR of ruptured AAA. Only a small number of case series with selected patients exist. The majority of patients were haemodynamically stable. However, the selective use of aortic occlusion balloons allowed successful endovascular management in a small number of unstable cases. All investigators had access to an "off the shelf" endovascular stent-graft (EVG). Per-operative mortality ranged from 9 to 45% and may reflect increasing experience and patient selection. A number of patients who underwent successful EVAR were turned down for open repair. A number of important lessons have been learned from these studies but questions remain regarding patient suitability and staffing issues. If these difficulties can be surmounted then the technique may offer an alternative to open repair.