Optical coherence tomography for presurgical delineation of basal cell carcinomas on the face-A comparison with histopathology.

BACKGROUND: To minimize the risk of incomplete excision of basal cell carcinomas (BCC) the macroscopic tumor margins should be adequately defined. Optical coherence tomography (OCT) is a non-invasive imaging tool that can provide structural and vascular information about skin cancer lesions. The study objective was to compare the presurgical delineation of facial BCC by clinical examination, histopathology, and OCT imaging in tumors undergoing full excision. METHODS: Ten patients with BCC lesions on the face were examined clinically, with OCT and histopathology at 3-mm intervals, from the clinical lesion border and beyond the resection line. The OCT scans were evaluated blinded and a delineation estimate of each BCC lesion was made. The results were compared to the clinical and histopathologic results. RESULTS: OCT evaluations and histopathology were in agreement in 86.6% of the collected data points. In three cases the OCT scans estimated a reduction of the tumor size compared to the clinical tumor border set by the surgeon. CONCLUSION: The results of this study support the notion that OCT can have a role in the clinical daily practice by aiding clinicians in delineating BCC lesions before surgery.

Assessment of the clinical and cost-effectiveness evidence in the reimbursement decisions of new cancer drugs.

BACKGROUND: This study aimed to describe the clinical and cost-effectiveness evidence supporting reimbursement decisions of new cancer drugs and analyze the influence of trial characteristics and the cost per quality-adjusted life years (QALYs) on the likelihood of reimbursement in Sweden. PATIENTS AND METHODS: Data were extracted from all appraisal dossiers for new cancer drugs seeking reimbursement in Sweden and claiming added therapeutical value between the years 2010 and 2020. The data were analyzed using descriptive statistics, and logistic regression models were also used with the cost per QALY, study design, comparator, and evidence on final outcomes in the clinical trials as predictors of reimbursement. RESULTS: All 60 included appraisals were based on trial evidence that assessed at least one final outcome (overall survival [OS] or quality of life [QoL]), although rarely as a primary outcome. Of the appraisals with a final decision (n = 58), 79% were approved for reimbursement. Among the reimbursed drugs, only half had trial evidence demonstrating improved OS or QoL. Only one drug had trial evidence supporting improvements in both OS and QoL. The average cost per QALY for reimbursed cancer drugs was estimated to be 748 560 SEK (€73 583). A higher cost per QALY was found to decrease the likelihood of reimbursement by 9.4% for every 100 000 SEK (€9830) higher cost per QALY (P = 0.03). For cost-effectiveness models without direct evidence of improvements in final outcomes, a larger QALY gain was observed compared with those with evidence mainly relying on intermediate and surrogate outcomes. CONCLUSIONS: There are substantial uncertainties in the clinical and cost-effectiveness evidence underlying reimbursement decisions of new cancer drugs. Decision makers should be cautious of the limited evidence on patient-centered outcomes and the implications of allocating resources to expensive treatments with uncertain value for money.

Cost-effectiveness of cervical length screening and progesterone treatment to prevent spontaneous preterm delivery in Sweden.

OBJECTIVE: To estimate the cost-effectiveness of strategies to prevent spontaneous preterm delivery (PTD) in asymptomatic singleton pregnancies, using prevalence and healthcare cost data from the Swedish healthcare context. METHODS: We designed a decision analytic model based on the Swedish CERVIX study to estimate the cost-effectiveness of strategies to prevent spontaneous PTD in asymptomatic women with a singleton pregnancy. The model was constructed as a combined decision-tree model and Markov model with a time horizon of 100 years. Four preventive strategies, namely 'Universal screening', 'High-risk-based screening' (i.e. screening of high-risk women only), 'Low-risk-based screening' (i.e. treatment of high-risk population and screening of remaining women) and 'Nullipara screening' (i.e. treatment of high-risk population and screening of nulliparous women only), included second-trimester cervical length (CL) screening by transvaginal ultrasound followed by vaginal progesterone treatment in the case of a short cervix. A fifth preventive strategy involved vaginal progesterone treatment of women with previous spontaneous PTD or late miscarriage but no CL screening ('No screening, treat high-risk group'). For comparison, we used a sixth strategy implying no specific intervention to prevent spontaneous PTD, reflecting the current situation in Sweden ('No screening'). Probabilities for a short cervix (CL ≤ 25 mm; base-case) and for spontaneous PTD at < 33 + 0 weeks and at 33 + 0 to 36 + 6 weeks were derived from the CERVIX study, and probabilities for stillbirth, neonatal mortality and long-term morbidity (cerebral palsy) from Swedish health data registers. Costs were based on Swedish data, except costs for cerebral palsy, which were based on Danish data. We assumed that vaginal progesterone reduces spontaneous PTD before 33 weeks by 30% and spontaneous PTD at 33-36 weeks by 10% (based on the literature). All analyses were from a societal perspective. We expressed the effectiveness of each strategy as gained quality-adjusted life years (QALYs) and presented cost-effectiveness as average (ACER; average cost per gained QALY compared with 'No screening') and incremental (ICER; difference in costs divided by the difference in QALYs for each of two strategies being compared) cost-effectiveness ratios. We performed deterministic and probabilistic sensitivity analysis. The results of the latter are shown as cost-effectiveness acceptability curves. Willingness-to-pay was set at a maximum of 500 000 Swedish krona (56 000 US dollars (USD)), as suggested by the Swedish National Board of Health and Welfare. RESULTS: All interventions had better health outcomes than did 'No screening', with fewer screening-year deaths and more lifetime QALYs. The best strategy in terms of improved health outcomes was 'Low-risk-based screening', irrespective of whether screening was performed at 18 + 0 to 20 + 6 weeks (Cx1) or at 21 + 0 to 23 + 6 weeks (Cx2). 'Low-risk-based screening' at Cx1 was cost-effective, while 'Low-risk-based screening' at Cx2 entailed high costs compared with other alternatives. The ACERs were 2200 USD for 'Low-risk-based screening' at Cx1 and 36 800 USD for 'Low-risk-based screening' at Cx2. Cost-effectiveness was particularly sensitive to progesterone effectiveness and to productivity loss due to sick leave during pregnancy. The probability that 'Low-risk-based screening' at Cx1 is cost-effective compared with 'No screening' was 71%. CONCLUSION: Interventions to prevent spontaneous PTD in asymptomatic women with a singleton pregnancy, including CL screening with progesterone treatment of cases with a short cervix, may be cost-effective in Sweden. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

NT-proBNP and stem cell factor plasma concentrations are independently associated with cardiovascular outcomes in end-stage renal disease hemodialysis patients.

Aims: End-stage renal disease (ESRD) treated by chronic hemodialysis (HD) is associated with poor cardiovascular (CV) outcomes, with no available evidence-based therapeutics. A multiplexed proteomic approach may identify new pathophysiological pathways associated with CV outcomes, potentially actionable for precision medicine. Methods and results: The AURORA trial was an international, multicentre, randomized, double-blind trial involving 2776 patients undergoing maintenance HD. Rosuvastatin vs. placebo had no significant effect on the composite primary endpoint of death from CV causes, nonfatal myocardial infarction or nonfatal stroke. We first compared CV risk-matched cases and controls (n = 410) to identify novel biomarkers using a multiplex proximity extension immunoassay (276 proteomic biomarkers assessed with OlinkTM). We replicated our findings in 200 unmatched cases and 200 controls. External validation was conducted from a multicentre real-life Danish cohort [Aarhus-Aalborg (AA), n = 331 patients] in which 92 OlinkTM biomarkers were assessed. In AURORA, only N-terminal pro-brain natriuretic peptide (NT-proBNP, positive association) and stem cell factor (SCF) (negative association) were found consistently associated with the trial's primary outcome across exploration and replication phases, independently from the baseline characteristics. Stem cell factor displayed a lower added predictive ability compared with NT-ProBNP. In the AA cohort, in multivariable analyses, BNP was found significantly associated with major CV events, while higher SCF was associated with less frequent CV deaths. Conclusions: Our findings suggest that NT-proBNP and SCF may help identify ESRD patients with respectively high and low CV risk, beyond classical clinical predictors and also point at novel pathways for prevention and treatment.

Adjunctive Rifampicin Increases Antibiotic Efficacy in Group A Streptococcal Tissue Infection Models.

Biofilm has recently been highlighted as a complicating feature of necrotizing soft tissue infections (NSTI) caused by Streptococcus pyogenes (i.e., group A Streptococcus [GAS]) contributing to a persistence of bacteria in tissue despite prolonged antibiotic therapy. Here, we assessed the standard treatment of benzylpenicillin and clindamycin with or without rifampin in a tissue-like setting. Antibiotic efficacy was evaluated by CFU determination in a human organotypic skin model infected for 24 or 48 h with GAS strains isolated from NSTI patients. Antibiotic effect was also evaluated by microcalorimetric metabolic assessment in in vitro infections of cellular monolayers providing continuous measurements over time. Adjunctive rifampin resulted in enhanced antibiotic efficacy of bacterial clearance in an organotypic skin tissue model, 97.5% versus 93.9% (P = 0.006). Through microcalorimetric measurements, adjunctive rifampin resulted in decreased metabolic activity and extended lag phase for all clinical GAS strains tested (P < 0.05). In addition, a case report is presented of adjunctive rifampin treatment in an NSTI case with persistent GAS tissue infection. The findings of this study demonstrate that adjunctive rifampin enhances clearance of GAS biofilm in an in vitro tissue infection model.

Marine n-3 Polyunsaturated Fatty Acid Supplementation and Quality of Life After Kidney Transplant.

Marine n-3 polyunsaturated fatty acids (PUFAs) may improve cardiovascular, renal, and mental health. No previous trial has investigated the effects of marine n-3 PUFA supplementation on quality of life (QoL) indices after renal transplant. METHODS: In this trial, 132 renal transplant recipients were randomized to receive daily either 2.6 g of marine n-3 PUFAs or an equivalent dose of olive oil (controls) on top of standard care for 44 weeks. We used a Short Form 36 (SF-36) questionnaire at baseline (8 weeks post transplant) and at the end of the study (1 year after transplant) to assess QoL. Results were expressed as net change (Δ) in SF-36 individual and composite mental and physical scores during follow-up. RESULTS: We found no improvement of Δ SF-36 individual or composite scores after marine n-3 PUFA supplementation compared with controls. In per-protocol analysis, patients who received marine n-3 PUFAs had a Δ emotional role function (mean, 17% [SD, 50%] vs mean, 3% [SD, 37%]; P = .11). In addition, plasma marine n-3 PUFA levels showed a weak but statistically significant correlation with Δ composite mental function score (r = .18; P = .04). CONCLUSION: Marine n-3 PUFA supplementation did not improve QoL after renal transplant.

Body composition in patients with primary neuromuscular disease assessed by dual energy X-ray absorptiometry (DXA) and three different bioimpedance devices.

BACKGROUND: Patients with primary neuromuscular disease have reduced muscle mass, and use of body mass index to assess nutritional status and body composition can therefore be questioned. Dual emission X-ray absorptiometry (DXA) can estimate muscle mass, but is not always readily available. Bioimpedance is a simple, portable and "easy to use" method for the assessment of body composition. OBJECTIVES: To assess muscle mass by DXA in 143 patients with primary neuromuscular disease and validate three bioimpedance devices; Impedimed SFB7, (BISIMPEDIMED), Xitron4200 (BISXITRON) and Tanita MC180MA (MFBIATANITA). METHODS: Body composition was assessed by DXA in 143, by BISIMPEDIMED in 116, by MFBIATANITA in 104 and by BISXITRON in 35 patients. RESULTS: Muscle mass assessed by DXA, and phase angle (PhA) were below reference values in all female and 96% of male patients. BISIMPEDIMED underestimated muscle mass by 6.5 ± 14.2 kg (p < 0.001), but this could be corrected after exclusion of resistance (Ri) values > 3500 Ohm (p = 0.84). MFBIATANITA overestimated muscle mass by 30.8 ± 9.1 kg (p < 0.001) with systematic bias, whereas BISXITRON was in agreement with DXA, and without systematic bias. Muscle mass was strongly correlated to PhA (rPEARSON = 0.75, p < 0.01). CONCLUSION: Patients with primary neuromuscular disease have proportionally more fat and less muscle mass than the population in general, despite normal BMI. Muscle mass can be assessed by bioimpedance in these patients, but performance and bias depends on device. Phase angle by bioimpedance correlates to muscle mass, and could therefore potentially be used a surrogate measure of muscle mass during follow up.

The 2016 ENFSI Fingerprint Working Group testing programme.

In 2016, the Fingerprint Working Group (EFP-WG) of the European Network of Forensic Science Institutes (ENFSI), officially established an advisory group with the task of organising proficiency tests (PTs), as well as collaborative exercises (CEs) as a way of raising standards within the fingerprint profession. This article will provide an overview of the Visualisation collaborative exercise and the Comparison proficiency test, which were carried out in 2016. Both the exercise and the test were organised and co-funded by the Prevention of and Fight against Crime Programme of the European Union [1-3], Direct Grant "Towards the Vision for European Forensic Science 2020 (TVEFS-2020)" HOME/2013/ISEC/MO/ENFSI/4000005962, work package T3 "Proficiency Tests and Collaborative Exercises for the Fingerprint Domain". The characteristics of the testing programme are summarised, followed by an overview of the knowledge that has been gained, including lessons learnt.

Cost-effectiveness of revascularization in patients with intermittent claudication.

BACKGROUND: Revascularization is a treatment option for patients with intermittent claudication. However, there is a lack of evidence to support its long-term benefits and cost-effectiveness. The aim of this study was to compare the cost-effectiveness of revascularization and best medical therapy (BMT) with that of BMT alone. METHODS: Data were used from the IRONIC (Invasive Revascularization Or Not in Intermittent Claudication) RCT where consecutive patients with mild-to-severe intermittent claudication owing to aortoiliac or femoropopliteal disease were allocated to either BMT alone (including a structured, non-supervised exercise programme) or to revascularization together with BMT. Inpatient and outpatient costs were obtained prospectively over 24 months of follow-up. Mean improvement in quality-adjusted life-years (QALYs) was calculated based on responses to the EuroQol Five Dimensions EQ-5D-3 L™ questionnaire. Cost-effectiveness was assessed as the cost per QALY gained. RESULTS: A total of 158 patients were randomized, 79 to each group. The mean cost per patient in the BMT group was €1901, whereas it was €8280 in the group treated with revascularization in addition to BMT, with a cost difference of €6379 (95 per cent c.i. €4229 to 8728) per patient. Revascularization in addition to BMT resulted in a mean gain in QALYs of 0·16 (95 per cent c.i. 0·06 to 0·24) per patient, giving an incremental cost-effectiveness ratio of €42 881 per QALY. CONCLUSION: The costs associated with revascularization together with BMT in patients with intermittent claudication were about four times higher than those of BMT alone. The incremental cost-effectiveness ratio of revascularization was within the accepted threshold for public willingness to pay according to the Swedish National Guidelines, but exceeded that of the UK National Institute for Health and Care Excellence guidelines.

Analysis of wild macaque stone tools used to crack oil palm nuts.

The discovery of oil palm (Elaeis guineensis) nut-cracking by wild long-tailed macaques (Macaca fascicularis) is significant for the study of non-human primate and hominin percussive behaviour. Up until now, only West African chimpanzees (Pan troglodytes verus) and modern human populations were known to use stone hammers to crack open this particular hard-shelled palm nut. The addition of non-habituated, wild macaques increases our comparative dataset of primate lithic percussive behaviour focused on this one plant species. Here, we present an initial description of hammerstones used by macaques to crack oil palm nuts, recovered from active nut-cracking locations on Yao Noi Island, Ao Phang Nga National Park, Thailand. We combine a techno-typological approach with microscopic and macroscopic use-wear analysis of percussive damage to characterize the percussive signature of macaque palm oil nut-cracking tools. These artefacts are characterized by a high degree of battering and crushing on most surfaces, which is visible at both macro and microscopic levels. The degree and extent of this damage is a consequence of a dynamic interplay between a number of factors, including anvil morphology and macaque percussive techniques. Beyond the behavioural importance of these artefacts, macaque nut-cracking represents a new target for primate archaeological investigations, and opens new opportunities for comparisons between tool using primate species and with early hominin percussive behaviour, for which nut-cracking has been frequently inferred.

The Medina Embolic Device: Karolinska experience.

Background The aim of this study was to report our single centre experience with the Medina Embolic Device (MED). Methods We performed a retrospective analysis of prospectively collected data to identify all patients treated with the MED. A total of 14 aneurysms (non-consecutive), in 13 patients, were treated including one ruptured and one partially thrombosed aneurysm. Fundus diameter was ≥5 mm in all cases. We evaluated the angiographic appearances, the clinical status, complications, and the need for adjunctive devices or repeat treatments. Results Aneurysm location was cavernous internal carotid artery (ICA; n = 1), supraclinoid ICA ( n = 1), terminal ICA ( n = 2), anterior communicating artery (AComA; n = 4), A2-3 ( n = 1), M1-2 junction ( n = 1), posterior communicating artery (PComA; n = 1), superior cerebellar artery (SCA; n = 1), and basilar tip ( n = 2). The average aneurysm fundus size was 8.6 mm (range 7-10 mm) and average neck size 3.75 mm (range 1.9-6.9 mm). Immediate angiographic results were modified Raymond-Roy occlusion classification (mRRC) I n = 2, mRRC II n = 1, mRRC IIIa n = 2, mRRC IIIb n = 2, the remaining 7 aneurysms showed complete opacification. At follow-up angiography (mean 5 months) mRRC I n = 5, mRRC II n = 5, mRRC IIIa n = 3, and persistent filling was seen in 1 aneurysm. Overall, four patients had repeat treatment and one is pending further treatment. Of the aneurysms treated with more than one MED, 75% showed complete occlusion at 6-month follow up whereas only one aneurysm treated with a single device showed complete occlusion. Overall, three patients had temporary complications and there were no deaths. Conclusions The MED is an intra-saccular flow-diverting device with satisfactory angiographic results and an acceptable safety profile. Use of a single MED cannot be recommended and further longer term studies are needed prior to widespread clinical use.

Recovery of Voice After Reconstruction of the Recurrent Laryngeal Nerve and Adjuvant Nimodipine.

BACKGROUND: Transection injury to the recurrent laryngeal nerve (RLN) has been associated with permanent vocal fold palsy, and treatment has been limited to voice therapy or local treatment of vocal folds. Microsurgical repair has been reported to induce a better function. The calcium channel antagonist nimodipine improves functional recovery after experimental nerve injury and also after cranial nerve injury in patients. This study aims to present voice outcome in patients who underwent repair of the RLN and received nimodipine during regeneration. METHODS: From 2002-2016, 19 patients were admitted to our center with complete unilateral injury to the RLN and underwent microsurgical repair of the RLN. After nerve repair, patients received nimodipine for 2-3 months. Laryngoscopy was performed repeatedly up to 14 months postoperatively. The Voice Handicap Index (VHI) was administered, and patients' maximum phonation time (MPT) was recorded during the follow-up. RESULTS: All patients recovered well after surgery, and nimodipine was well tolerated with no dropouts. None of the patients suffered from atrophy of the vocal fold, and some patients even showed a small ab/adduction of the vocal fold on the repaired side with laryngoscopy. During long-term follow-up (>3 years), VHI and MPT normalized, indicating a nearly complete recovery from unilateral RLN injury. CONCLUSIONS: In this cohort study, we report the results of the first 19 consecutive cases at our center subjected to reconstruction of the RLN and adjuvant nimodipine treatment. The outcome of the current strategy is encouraging and should be considered after iatrogenic RLN transection injuries.

The 2015 ENFSI Fingerprint Working Group testing programme.

As early as 2004, the Fingerprint Working Group (EFP-WG) of the European Network of Forensic Science Institutes (ENFSI) has organised proficiency tests (PT's), as well as collaborative exercises (CE's), as a way of raising standards within the fingerprint profession. This article provides an overview of the three collaborative exercises carried out in 2015. The characteristics of the testing programme are summarised, followed by an overview of the knowledge that has been gained, including depicting what lessons have been learnt.

Overweight, hyperglycemia and tobacco use are modifiable risk factors for onset of retinopathy 9 and 17years after the diagnosis of diabetes - A retrospective observational nation-wide cohort study.

BACKGROUND: The aims of this study were to estimate the risk for diabetic retinopathy (DR) and to identify risk factors. We investigated a nationwide population-based cohort with diabetes diagnosed at age 15-34years. PATIENTS AND METHODS: Of 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) 444 (56%) patients with retinal photos available for classification of retinopathy participated in a follow-up study 15-19 (median 17) years after diagnosis. Mean age was 42.3±5.7years, BMI 26.1±4.1kg/m2, 62% were male and 91% had type 1 diabetes. A sub-study was performed in 367 patients with retinal photos from both the 9 and 17year follow up and the risk for development of retinopathy between 9 and 17years of follow up was calculated. RESULTS: After median 17years 324/444 (73%, 67% of T1D and 71% of T2D), had developed any DR but only 5.4% proliferative DR. Male sex increased the risk of developing retinopathy (OR 1.9, 95% CI 1.2-2.9). In the sub-study obesity (OR 1.2, 95% CI 1.04-1.4), hyperglycemia (OR 2.5, 95% CI 1.6-3.8) and tobacco use (OR 2.9, 95% CI 1.1-7.3) predicted onset of retinopathy between 9 and 17years after diagnosis of diabetes. CONCLUSION: The number of patients with severe retinopathy after 17years of diabetes disease was small. The risk of developing retinopathy with onset between 9 and 17years after diagnosis of diabetes was strongly associated to modifiable risk factors such as glycemic control, obesity and tobacco use.

ENFSI collaborative testing programme for fingermarks: Past experiences and future perspectives.

As early as 2004 the Fingerprint Working Group of the European Network of Forensic Science Institutes (ENFSI) has organised proficiency tests (PT's) as well as collaborative exercises (CE's) as a way of raising standards within the fingerprint profession. Participation in PT's and CE's is a key element in the ISO/IEC accreditation process as they enable laboratories to monitor the quality of their analytical results. On the basis of the European Council Framework Decision 2009/905/JHA, of 30 November 2009, on Accreditation of forensic service providers carrying out laboratory activities[1], from November 15th of 2015, only accredited laboratories are allowed to exchange fingerprint data with other EU countries. This article will provide an overview of the ENFSI collaborative tests for fingermarks in the fields of visualisation, imaging and individualisation. The characteristics of the testing programme are summarised, followed by an overview of the knowledge that has been gained, including lessons learnt. It is hoped that this reflective process can outline the critical issues that should be addressed as well as highlight future opportunities in relation to Monopoly Project 2013, "Proficiency Tests and Collaborative Exercises for the Fingerprint Domain".

Quality of life and hernia development 5 years after open abdomen treatment with vacuum-assisted wound closure and mesh-mediated fascial traction.

PURPOSE: To report incisional hernia (IH) incidence, abdominal wall (AW) discomfort and quality of life (QoL) 5 years after open abdomen treatment with vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM). METHODS: Five-year follow-up of patients included in a prospective study 2006-2009. The protocol included physical examination, patient interview, chart review, questionnaires on abdominal wall and stoma complaints and the SF-36 questionnaire. RESULTS: Fifty-five (12 women, 43 men; median age 70 years) of 111 included patients were alive. Follow-up rate was 91 %. Cumulative IH incidence during the whole study was 62 %. One-third of the IHs was repaired. At 5-year follow-up 59 % of IHs were clinically detectable. AW symptoms were equivalent in patients with (15/23) and without (11/21) IH (p = 0.541). SF-36 scores were lower than population mean for component scores and all subscales except bodily pain. Patients with major co-morbidity had lower physical component score [31.6 (95 %, CI 25.6-37.4)] compared to those without [48.9 (95 %, CI 46.2-51.4)]. Major co-morbidity was not associated with IH (p = 0.56), AW symptoms (p = 0.54) or stoma (p = 0.10). Patients with IH or other AW symptoms had similar SF-36 results compared to those without, whereas patients with a stoma had >5 point lower mean scores for general health, social function and physical component score compared to those without. CONCLUSIONS: VAWCM treatment results in high incidence of IH. However, at five years, there was no detectable difference in abdominal wall complaints and QoL in patients with IH compared to those without. Lower QoL appeared mainly to be associated with the presence of major co-morbidity.

Plasma levels of marine n-3 fatty acids and cardiovascular risk markers in renal transplant recipients.

BACKGROUND/OBJECTIVES: Cardiovascular (CV) disease is the leading cause of death after renal transplantation. Marine n-3 polyunsaturated fatty acids (PUFAs) exert potential cardio-protective metabolic effects and might reduce CV morbidity and mortality in renal transplant recipients (RTRs). SUBJECTS/METHODS: In this cross-sectional study of 1990 Norwegian RTRs, transplanted between 1999 and 2011, associations between plasma phospholipid marine n-3 PUFA levels and various CV risk markers at 10 weeks after transplant were evaluated. RESULTS: Higher plasma marine n-3 PUFA levels were associated with lower resting heart rate (rHR), lower fasting plasma glucose (fPG) levels, lower plasma triglyceride levels and higher plasma high-density lipoprotein (HDL) cholesterol levels. Plasma levels of eicosapentaenoic acid, but not docosahexaenoic acid, showed a positive association with plasma HDL cholesterol levels. Plasma marine n-3 PUFA levels were not associated with plasma low-density lipoprotein cholesterol levels, pulse wave velocity or systolic and diastolic blood pressure. A negative association between plasma marine n-3 PUFA levels and CV mortality was weakened by additional adjustment for plasma triglyceride levels and rHR. The ratio of n-6 to n-3 PUFAs showed similar associations with CV risk markers as absolute plasma marine n-3 PUFA levels. CONCLUSIONS: This is the first study in RTRs showing that marine n-3 PUFAs are negatively associated with rHR and fPG in addition to beneficial effects on plasma HDL cholesterol and triglyceride levels. Especially, effects on autonomic nervous function and triglyceride metabolism might contribute to explain the lower CV mortality risk with higher plasma marine n-3 PUFA levels previously shown in this cohort.

In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions: link to spatial receptor occupancy.

The current study provides a novel in-depth assessment of the extent of antipsychotic drugs transport across the blood-brain barrier (BBB) into various brain regions, as well as across the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). This is combined with an estimation of cellular barrier transport and a systematic evaluation of nonspecific brain tissue binding. The study is based on the new Combinatory Mapping Approach (CMA), here further developed for the assessment of unbound drug neuropharmacokinetics in regions of interest (ROI), referred as CMA-ROI. We show that differences exist between regions in both BBB transport and in brain tissue binding. The most dramatic spatial differences in BBB transport were found for the P-glycoprotein substrates risperidone (5.4-fold) and paliperidone (4-fold). A higher level of transporter-mediated protection was observed in the cerebellum compared with other brain regions with a more pronounced efflux for quetiapine, risperidone and paliperidone. The highest BBB penetration was documented in the frontal cortex, striatum and hippocampus (haloperidol, olanzapine), indicating potential influx mechanisms. BSCB transport was in general characterized by more efficient efflux compared with the brain regions. Regional tissue binding was significantly different for haloperidol, clozapine, risperidone and quetiapine (maximally 1.9-fold). Spatial differences in local unbound concentrations were found to significantly influence cortical 5-HT2A receptor occupancy for risperidone and olanzapine. In conclusion, the observed regional differences in BBB penetration may potentially be important factors contributing to variations in therapeutic effect and side effect profiles among antipsychotic drugs.

Repeated Contrast Administration Is Associated With Low Risk of Postcontrast Acute Kidney Injury and Long-Term Complications in Patients With Severe Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) frequently require radiographic examinations. We investigated the impact of repeated contrast administrations on short- and long-term kidney function and mortality in kidney transplantation candidates. In a prospective study, 81 predialysis transplantation candidates underwent computed tomography angiography (CTA) and invasive coronary angiography (ICA) as part of a pretransplant cardiovascular evaluation. Postcontrast plasma creatinine (P-creatinine) changes were compared with a precontrast control period. We identified postcontrast acute kidney injury (AKI) in 10 patients (13%) after CTA and in two patients (3%) after ICA. Compared with the control period, relative changes in P-creatinine were significantly higher after CTA (p < 0.001) and ICA (p < 0.01). Diabetic kidney failure (p < 0.05) and contrast dose >0.8 mL/kg (p < 0.001) were associated with increases in P-creatinine. All cases of postcontrast AKI were reversible, and we found no differences between the progression rates of the kidney failure during 12 months before and after contrast exposure (p = 0.56). In a Cox regression analysis, creatinine changes after CTA or ICA were not associated with increased need for dialysis treatment or mortality. Contrast exposure and transient postcontrast AKI did not increase the risk of accelerated CKD progression or the time to initiation of dialysis or death.

Down-regulation of survivin alleviates experimental arthritis.

Survivin is a proto-oncogene that regulates cell division and apoptosis. It is a molecular marker of cancer. Recently, survivin has emerged as a feature of RA, associated with severe joint damage and poor treatment response. The present study examined if inhibition of survivin affects experimental arthritis, which was induced in mBSA-immunized mice by an injection of mBSA in the knee joint or developed spontaneously in collagen type II-immunized mice. The inhibition of survivin transcription by a lentivirus shRNA construct alleviated joint inflammation and reduced bone damage. The inhibition of survivin reduced the levels of metalloproteinases, ß-catenin, and vimentin, limiting the invasive capacity of synovia, while no inhibition of osteoclastogenesis could be found. The inhibition of survivin led to a p53-independent reduction of T cell proliferation and favored the transcription and activity of Blimp-1, which limited IL-2 production and facilitated formation of regulatory Foxp3(+)CD4(+) and effector CD8(+) T cells. The study shows that the inhibition of survivin is sufficient to reduce joint inflammation and bone damage in preclinical models of arthritis. Antiarthritic effects of survivin inhibition are related to p53-independent control of lymphocyte proliferation.