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Cardiovascular disease is a prevalent and prognostically important comorbidity among patients with kidney disease, and individuals with kidney disease make up a sizeable proportion (30%-60%) of patients with cardiovascular disease. However, several systematic reviews of cardiovascular trials have observed that patients with kidney disease, particularly those with advanced kidney disease, are often excluded from trial participation. Thus, currently available trial data for cardiovascular interventions in patients with kidney disease may be insufficient to make recommendations on the optimal approach for many therapies. The Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and the US Food and Drug Administration, convened a multidisciplinary, international work group and hosted a stakeholder workshop intended to understand and develop strategies for overcoming the challenges with involving patients with kidney disease in cardiovascular clinical trials, with a particular focus on those with advanced disease. These efforts considered perspectives from stakeholders, including academia, industry, contract research organizations, regulatory agencies, patients, and care partners. This article outlines the key challenges and potential solutions discussed during the workshop centered on the following areas for improvement: building the business case, re-examining study design and implementation, and changing the clinical trial culture in nephrology. Regulatory and financial incentives could serve to mitigate financial concerns with involving patients with kidney disease in cardiovascular trials. Concerns that their inclusion could affect efficacy or safety results could be addressed through thoughtful approaches to study design and risk mitigation strategies. Finally, there is a need for closer collaboration between nephrologists and cardiologists and systemic change within the nephrology community such that participation of patients with kidney disease in clinical trials is prioritized. Ultimately, greater participation of patients with kidney disease in cardiovascular trials will help build the evidence base to guide optimal management of cardiovascular disease for this population.

Surgical resection of meningioma leaves residual solid tumour in over 25% of patients. Selection for further treatment and follow-up strategy may benefit from knowledge of volumetric growth and factors associated with re-growth. The aim of this review was to evaluate volumetric growth and variables associated with growth in patients that underwent incomplete resection of a meningioma without the use of adjuvant radiotherapy. A systematic review was conducted in accordance with the PRISMA statement and registered a priori with PROSPERO (registration number: CRD42020177052). Six databases were searched up to May 2020. Full text articles analysing volumetric growth rates in at least 10 patients who had residual meningioma after surgery were assessed. Four single-centre, retrospective studies totalling 238 patients were included, of which 99% of meningioma were WHO grade 1. The absolute tumour growth rate ranged from 0.09 to 4.94 cm3 per year. The relative growth rate ranged from 5.11 to 14.18% per year. Varying methods of volumetric assessment and definitions of growth impeded pooled analysis. Pre-operative and residual tumour volume, and hyperintensity on T2 weighted MRI were identified as variables associated with residual meningioma growth, however this was inconsistent across studies. Risk of bias was high in all studies. Radiological regrowth occurred in 42–67% of cases. Our review identified that volumetric growth of residual meningioma is scarcely reported. Sufficiently powered studies are required to delineate volumetric growth and prognostic factors to stratify management.

Purpose To review the use of different valve types in infants with hydrocephalus, in doing so, determining whether an optimal valve choice exists for this patient cohort. Methods We conducted (1) a literature review for all studies describing valve types used (programmable vs. non-programmable, valve size, pressure) in infants (≤ 2 years) with hydrocephalus, (2) a review of data from the pivotal BASICS trial for infant patients and (3) a separate, institutional cohort study from Alder Hey Children’s Hospital NHS Foundation Trust. The primary outcome was any revision not due to infection. Results The search identified 19 studies that were included in the review. Most did not identify a superior valve choice between programmable and non-programmable, small compared to ultra-small, and differential pressure compared to flow-regulating valves. Five studies investigated a single-valve type without a comparator group. The BASICS data identified 391 infants, with no statistically significant difference between gravitational and programmable subgroups. The institutional data from our tertiary referral centre did not reveal any significant difference in failure rate between valve subtypes. Conclusion Our review highlights the challenges of valve selection in infant hydrocephalus, reiterating that the concept of an optimal valve choice in this group remains a controversial one. While the infant-hydrocephalic population is at high risk of valve failure, heterogeneity and a lack of direct comparison between valves in the literature limit our ability to draw meaningful conclusions. Data that does exist suggests at present that there is no difference in non-infective failure rate are increasing in number, with the British valve subtypes in infant hydrocephalus, supported by both the randomised trial and institutional data in this study.

Purpose Achieving decompression without CSF over-drainage remains a challenge in hydrocephalus. Differential pressure valves are a popular treatment modality, with evidence suggesting that incorporation of gravitational units helps minimise over-drainage. This study seeks to describe the utility of the proGAV®2.0 programmable valve in a paediatric population. Methods Clinical records and imaging of all patients fitted with proGAV®2.0 valves and Miethke fixed-pressure valves between 2014 and 2019 at our tertiary centre were analysed. Patient demographics, indication for shunt and valve insertion/revision and time to shunt/valve revision were collected. Ventricular linear metrics (fronto-occipital horn ratio (FOHR) and fronto-occipital horn width ratio (FOHWR)) were collected pre- and post-valve insertion. Microsoft Excel and SPSS v24 were used for data collection and statistical analysis. Results Eighty-eight proGAV®2.0 valves were inserted in a population of 77 patients (n = 45 males (58%), mean age 5.1 years (IQR: 0.4–11.0 years)). A total of 102 Miethke fixed-pressure valves were inserted over the same time period. Median follow-up was 17.5 months (1.0–47.3). One (1.1%) proGAV®2.0 was revised due to over-drainage, compared to 2 (1.9%) fixed-pressure valves (p > 0.05). ProGAV®2.0 insertion resulted in a significant decrease in the mean number of revisions per patient per year (1.77 vs 0.25; p = 0.01). Overall shunt system survival with the proGAV®2.0 was 80.4% at 12 months, and mean time to revision was 37.1 months, compared to 31.0 months (95%CI: 25.7–36.3) and 58.3% in fixed-pressure valves (p < 0.01). Significant decreases were seen following proGAV®2.0 insertion in both FOHR and FOHWR, by 0.014 (95%CI: 0.006–0.023, p = 0.002) and 0.037 (95%CI: 0.005–0.069, p = 0.024) respectively. Conclusion The proGAV®2.0 provides effective decompression of hydrocephalic patients, significantly reduces the number of valve revisions per patient and had a significantly greater mean time to revision than fixed-pressure valves.

Simple Summary This study investigated patients who underwent more than one operation for a meningioma, a type of brain tumor. Currently, there is little evidence available for this specific patient group. The purpose of this study was to determine if patients had an improvement or deterioration following a second operation for a recurrent meningioma, and to identify any factors that may influence this change. The results demonstrated that following a second operation for meningioma, patients have poorer outcomes. The findings of this study provide supporting information for surgeons and patients, thereby informing decisions related to patient care and re-operation. Abstract The outcomes following re-operation for meningioma are poorly described. The aim of this study was to identify risk factors for a performance status outcome following a second operation for a recurrent meningioma. A retrospective, comparative cohort study was conducted. The primary outcome measure was World Health Organization performance. Secondary outcomes were complications, and overall and progression free survival (OS and PFS respectively). Baseline clinical characteristics, tumor details, and operation details were collected. Multivariable binary logistic regression was used to identify risk factors for performance status outcome following a second operation. Between 1988 and 2018, 712 patients had surgery for intracranial meningiomas, 56 (7.9%) of which underwent a second operation for recurrence. Fifteen patients (26.8%) had worsened performance status after the second operation compared to three (5.4%) after the primary procedure (p = 0.002). An increased number of post-operative complications following the second operation was associated with a poorer performance status following that procedure (odds ratio 2.2 [95% CI 1.1–4.6]). The second operation complication rates were higher than after the first surgery (46.4%, n = 26 versus 32.1%, n = 18, p = 0.069). The median OS was 312.0 months (95% CI 257.8–366.2). The median PFS following the first operation was 35.0 months (95% CI 28.9–41.1). Following the second operation, the median PFS was 68.0 months (95% CI 49.1–86.9). The patients undergoing a second operation for meningioma had higher rates of post-operative complications, which is associated with poorer clinical outcomes. The decisions surrounding second operations must be balanced against the surgical risks and should take patient goals into consideration.

BACKGROUND Meningioma is the commonest primary brain tumour. Despite surgery, meningiomas can recur. Surgery is usually the first line treatment for recurrent meningioma. The aim was to determine the risk factors associated with clinical outcomes (performance status, morbidity, mortality, recurrence) following re-operation for recurrence of intracranial meningioma. MATERIAL AND METHODS Retrospective cohort study (1998–2018). Eligible patients had reoperation for local recurrence of a previously operated meningioma. Collected data included baseline clinical and imaging characteristic. Primary outcome measure was performance status after each reoperation. Secondary outcome measures were medical and surgical morbidity, recurrence-free survival (RFS) and overall survival (OS). RESULTS Fifty-eight patients were eligible (37 female, mean age at 1st re-operation 56.1 years (SD=11.6)). Eleven patients (19.6%) had 2 re-operations and 3 patients (5.4%) had 3 re-operations. Median follow up was 128.5 months (IQR=73–194.5). Median time to 1st recurrence and 1st re-operation were 36.5 (IQR=24.3–81.0) and 43.8 months (IQR=20.3–103.4), respectively. Fifteen patients (26.8%) had worse performance status after 1st reoperation, compared to 5.4% (n=3) after the primary operation. Complication rate was 32.1% (n=18) after the primary operation compared to 48.2% (n=27) after 1st reoperation. At primary operation, there were 29 (51.8%) grade 1, 24 (42.9%) grade 2, and 1 (1.8%) grade 3 tumours. Median RFS after first re-operation was 36.5 months (95% CI 29.3–43.9). Median OS was 312 months (95 % CI 257.8–366.2). Increased number of post-operative complications were a risk factor for worsened performance status following reoperation (OR 2.2 [95% CI 1.1–4.6], P=0.029). CONCLUSION Re-operation is associated with a worse performance status and increased risk of complications. Re-operating meningiomas for radiological recurrence without symptoms increases patient morbidity. Shared-care management decision should be made with patients when considering operating for radiological recurrence only.

The impact of Covid-19 on surgical patients worldwide has been substantial. In the United Kingdom (UK) and the Republic of Ireland (RoI), the first wave of the pandemic occurred in March 2020. The aims of this study were to: (1) evaluate the volume of neurosurgical operative activity levels, Covid-19 infection rate and mortality rate in April 2020 with a retrospective cross-sectional cohort study conducted across 16 UK and RoI neurosurgical centres, and (2) compare patient outcomes in a single institution in April-June 2020 with a comparative cohort in 2019. Across the UK and RoI, 818 patients were included. There were 594 emergency and 224 elective operations. The incidence rate of Covid-19 infection was 2.6% (21/818). The overall mortality rate in patients with a Covid-19 infection was 28.6% (6/21). In the single centre cohort analysis, an overall reduction in neurosurgical operative activity by 65% was observed between 2020 (n = 304) and 2019 (n = 868). The current and future impact on UK neurosurgical operative activity has implications for service delivery and neurosurgical training.

Background: Following the publication of the Management of Myelomeningocele study (MOMS), fetal repair of myelomeningocele (MMC) has become increasingly prevalent worldwide. However, limited case presentations exist illustrating the potential mechanical and embryological effects of fetal repair. We present a unique case report of a complex embryological cervicomedullary junction (CMJ) malformation and cerebellar hypoplasia following fetal repair of MMC. Case Description: A 1-day-old female was referred to the paediatric neurosurgical team after having successful surgical intrauterine closure of MMC abroad at 25 weeks gestation. The patient was born by emergency caesarean section at 33 weeks gestation and had a ventricular-peritoneal shunt inserted at 25 days old due to resulting hydrocephalus. Neonatal MRI scans revealed a complex number of malformations that included a split cord located at the CMJ, hypoplasia of the cerebellum and vermis, and a Chiari type II malformation. Conclusion: It is possible that the clefting of the upper cervical spinal cord was undetected at preoperative MRI; however, this is unlikely given the antenatal images. It is our hypothesis that the malformation may have exhibited mechanical change after the repair, as the preoperative MRI showed only a Chiari II malformation without any of the complex abnormalities being present and the split cord was already there but not obvious. There are no existing reports of such a complex malformation following antenatal surgery in the literature. This should be further explored as more cases and trials become available.

Chronic pain and restricted knee motion is a significant problem following the total knee arthroplasty (TKA). The molecular pathogenesis of pain post‐TKA is not known and no targeted therapeutic intervention is available. The aim of this study was to investigate whether pro‐inflammatory mediators are elevated in revision knee patients, indicating an active, ongoing inflammatory process that may contribute to pain. Twelve key markers (pro‐inflammatory cytokines granulocyte‐macrophage colony‐stimulating factor [GM‐CSF], interleukin 5 [IL‐5], IL‐8 and IL‐10, chemokines CCL2, CCL3, CCL4, and CCL13, mediators of angiogenesis Flt‐1, vascular endothelial growth factor, and cell migration vascular cell adhesion molecule 1 and intercellular adhesion molecule 1) were measured in knee tissue and synovial fluid (SF) from primary TKA (n = 29) and revision patients (n = 32). Indications for surgery were osteoarthritis (OA) for primary TKA, and component loosening (n = 11), stiffness (n = 11), laxity pattern (n = 8), or progression of OA in patella resurfacing (n = 3) for revision surgery. Pain levels (WOMAC score) were higher in revision than primary patients (p ≤ 0.05). Time from primary to revision ranged from 8 months to 30 years (median 10 years). All markers were elevated in revision TKA; there was no trend toward decreasing levels with greater time from primary surgery for any marker studied in SF. Similar results were seen in knee tissue. We found no differences comparing indications for revision surgery (p ≥ 0.05). The elevation of inflammatory mediators in painful post‐TKA knees requiring revision suggests active, chronic inflammation. Characterization of upregulated markers provides rationale for targeted therapy, even many years from the primary surgery. © 2019 The Authors. Journal of Orthopaedic Research ® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2316–2324, 2019

OBJECTIVE An estimated 37 million Americans have chronic kidney disease (CKD). Nearly 90% do not know about their condition because of low awareness about the importance of CKD testing and diagnosis among practitioners and people at risk for CKD. This study uses data from a national clinical laboratory to identify guideline-recommended CKD testing rates across the U.S. RESEARCH DESIGN AND METHODS Patients with Laboratory Corporation of America Holdings (Labcorp) testing between 2013 and 2019 were defined as at risk for CKD if they had any testing ordered with diagnosis codes for diabetes and/or hypertension. Guideline-concordant CKD assessment was defined by estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (uACR) testing within the study year. RESULTS We identified 28,295,982 at-risk patients (mean age 60.6 ± 14.8 years; 53.6% women): 16.2% had diabetes, 63.8% had hypertension, and 20.1% had both comorbidities. Of these, 80.3% did not receive guideline-concordant assessment during the study period. Furthermore, only 21.0% had uACR testing versus 89.6% with eGFR. CKD assessment occurred at least once in 28.7% of patients with diabetes, 10.5% of patients with hypertension, and 41.4% of patients with both conditions. In a state-by-state comparison, annual testing rates ranged from 5 to 30%. The nationwide rate increased modestly each year between 2013 and 2018 (from 10.7% to 15.2%). CONCLUSIONS Despite guideline recommendations, testing for CKD with uACR and eGFR in U.S. adults with diabetes and hypertension is low in routine clinical care. These data highlight the need for strategies to improve routine CKD assessment nationwide.

Background This is an updated version of the Cochrane review published in 2015. Around half of people with epilepsy will not achieve seizure freedom on their first antiepileptic drug; many will require add-on therapy. Around a third of people fail to achieve complete seizure freedom despite multiple antiepileptic drugs. Lacosamide has been licenced as an add-on therapy for drug-resistant focal epilepsy. Objectives To evaluate the efficacy and tolerability of lacosamide as an add-on therapy for children and adults with drug-resistant focal epilepsy. Search methods We searched the following databases (22 August 2019): the Cochrane Register of Studies (CRS Web), including the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946 to 20 August 2019), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP), with no language restrictions. We contacted UCB Pharma (sponsors of lacosamide). Selection criteria Randomised controlled trials of add-on lacosamide in people with drug-resistant focal epilepsy. Data collection and analysis We used standard Cochrane methodology, assessing the following outcomes: 50% or greater reduction in seizure frequency; seizure freedom; treatment withdrawal; adverse events; quality of life; and cognitive changes. The primary analyses were intention-to-treat. We estimated summary risk ratios (RR) for each outcome presented with 99% confidence intervals (CI), except for 50% or greater seizure reduction, seizure freedom and treatment withdrawal which were presented with 95% CIs. We performed subgroup analyses according to lacosamide dose and sensitivity analyses according to population age, whereby data from children were excluded from the meta-analysis. Main results We included five trials (2199 participants). The risk of bias for all studies was low to unclear. All studies were placebo-controlled and assessed doses from 200 mg to 600 mg per day. One study evaluated lacosamide in children; all other studies were in adults. Trial duration ranged from 24 to 26 weeks. All studies used adequate methods of randomisation and were double-blind. Overall, the certainty of the evidence for the outcomes was judged as moderate to high, with the exception of seizure freedom which was low. The RR for a 50% or greater reduction in seizure frequency for all doses of lacosamide compared with placebo was 1.79 (95% CI 1.55 to 2.08; 5 studies; 2199 participants; high-certainty evidence). The RR for seizure freedom for all doses of lacosamide compared with placebo was 2.27 (95% CI 1.35 to 3.83; 5 studies; 2199 participants; low-certainty evidence). The RR for treatment withdrawal for all doses of lacosamide compared with placebo was 1.57 (95% CI 1.24 to 1.98; 5 studies; 2199 participants; moderate-certainty evidence). The estimated effect size for most outcomes did not change considerably following sensitivity analysis. For seizure freedom, however, the RR nearly doubled upon the exclusion of data from children (RR 4.04, 95% CI 1.52 to 10.73). Adverse events associated with lacosamide included: abnormal co-ordination (RR 6.12, 99% CI 1.35 to 27.77), blurred vision (RR 4.65, 99% CI 1.24 to 17.37), diplopia (RR 5.59, 99% CI 2.27 to 13.79), dizziness (RR 2.96, 99% CI 2.09 to 4.20), nausea (RR 2.35, 99% CI 1.37 to 4.02), somnolence (RR 2.04, 99% CI 1.22 to 3.41), vomiting (RR 2.94, 99% CI 1.54 to 5.64), and number of participants experiencing one or more adverse events (RR 1.12, 99% CI 1.01 to 1.24). Adverse events that were not significant were: vertigo (RR 3.71, 99% CI 0.86 to 15.95), rash (RR 0.58, 99% CI 0.17 to 1.89), nasopharyngitis (RR 1.41, 99% CI 0.87 to 2.28), headache (RR 1.34, 99% CI 0.90 to 1.98), fatigue (RR 2.11, 99% CI 0.92 to 4.85), nystagmus (RR 1.47, 99% CI 0.61 to 3.52), and upper respiratory tract infection (RR 0.70, 99% CI 0.43 to 1.15). Authors' conclusions Lacosamide is effective and well-tolerated in the short term when used as add-on treatment for drug-resistant focal epilepsy. Lacosamide increases the number of people with 50% or greater reduction in seizure frequency and may increase seizure freedom, compared to placebo. Higher doses of lacosamide may be associated with higher rates of adverse events and treatment withdrawal. Additional evidence is required assessing the use of lacosamide in children and on longer-term efficacy and tolerability.

Background Unruptured brain arteriovenous malformations (bAVMs) carry a lifetime risk of haemorrhage. Treatment strategies include conservative management, microsurgical excision, endovascular treatment (EVT) and radiosurgery (SRS). Optimal treatment selection remains unclear. Method A single-centre retrospective cohort study of adult unruptured bAVMs (2007-2019). Patients who underwent intervention were propensity matched using baseline features (age, sex, size, deep drainage, eloquence, and Spetzler-Martin grade) with patients conservatively managed. Rates of neurological disability and mortality due to intervention or bleed were compared. Results 137 patients (mean age 48 years [SD = 16], males 64) were included; 34 (25%) EVT, 20 (15%) surgery, 31 (22%) SRS and 51 (37%) conservative. After a median follow-up of 49 months (IQR 23-75), rates of disability were as follows: surgery 35%, EVT 21%, SRS 13% and conservative 8%. Matched cohorts (intervention/conservative) were: surgery-19/18, SRS-30/22 and EVT-33/34. Comparison of disability rates across matched cohorts revealed no statistically significant differences (surgery p = 0.07, SRS p = 0.65 and EVT p = 0.11). Three conservatively managed patients died. Conclusions Unruptured bAVMs carry a significant risk of neurological morbidity, regardless of intervention choice. Treatment choice may have an impact on patient outcomes but requires investigation of stratified cohorts. Findings are consistent with the nuances of AVM treatment selection.

Aims Meningioma is the commonest primary brain tumour. Despite surgery, meningiomas can recur. Surgery is usually the first line treatment for recurrent meningioma. The aim was to determine the risk factors associated with clinical outcomes (performance status, morbidity, mortality, recurrence) following re-operation for recurrence of intracranial meningioma. Method Retrospective cohort study (1998-2018). Eligible patients had re-operation for local recurrence of a previously operated meningioma. Collected data included baseline clinical and imaging characteristic. Primary outcome measure was performance status after each re-operation. Secondary outcome measures were medical and surgical morbidity, recurrence-free survival (RFS) and overall survival (OS). Results Fifty-eight patients were eligible (38 female, mean age at 1st re-operation 56 years (SD=11.4)). Eleven patients (18.9%) had 2 re-operations and 3 patients (3.4%) had 3 re-operations. Median follow up was 125.5 months (IQR 73-191.5). Median time to 1st recurrence and 1st re-operation were 36.5 (IQR 24.2–79.1) and 43.8 months (IQR 22.9–102.7), respectively. Fifteen patients (25.9%) had worse performance status after 1st re-operation, compared to 6.9% (n=4) after the primary operation (Figure 1). Complication rate was 32.8% (n=19) after the primary operation compared to 46.6% (n=27) after 1st re-operation. At primary operation, there were 29 (50%) grade 1, 26 (44.8%) grade 2, and 1 (1.7%) grade 3 tumours. Median RFS after first re-operation was 68 months (95% CI 45.5-90.5) (figure 2). Median OS was 312 months (95% CI 236.9-387.1) (Figure 3). Post-operative complications were a risk factor for worsened performance status following re-operation (OR 4.91, 95% CI 1.3-18.4). Conclusion Re-operation is associated with a worse performance status and increased risk of complications. Re-operating meningiomas for radiological recurrence without symptoms increases patient morbidity. Shared-care management decision should be made with patients when considering operating for radiological recurrence only.

Aims Bone infiltration in association with intracranial meningioma (4.5% of cases) and primary intraosseous meningioma (2%) are rare. Management can be challenging, as cranial vault reconstruction may be required. This study aimed to examine the surgical techniques used and outcomes in this patient population. Method A single-centre, retrospective cohort study was conducted between January 2010 and September 2020. All adult patients who required cranial reconstruction due to bone involvement of their meningioma were included. Patient demographics, tumour characteristics, operative details, complications, and outcomes were examined. Statistical analyses were performed using SPSS v24.0. Results There were 30 patients (17 female; 56.7%), median age 54 yrs (range 28-86 yrs), of whom 25 (83.3%) had bone infiltration, and 5 (16.7%) had primary intraosseous meningioma. Only 10 patients had a Simpson I or II resection. Twenty-eight had 'on-table' primary cranioplasties. Materials used were titanium (n=13; 43.3%), acrylic (n=10; 33.3%), PMMA (n=5; 16.7%), and hydroxyapatite (n=2; 6.7%). There were 9 (mostly minor) surgical complications and only one wound infection. Twelve patients had WHO grade II tumours, and 14 required radiotherapy. Ten patients (33.3%) had re-operation for recurrent tumour, with a median time to progression of 41 months. At 6 months, 24 patients had a performance score less than 2. Conclusion On-table cranioplasty provides a lower risk surgical option for patients with high risk meningiomas.

BACKGROUND Long-term Health-Related Quality of Life (HRQoL) is an important measure of patient wellbeing. There is a paucity of studies evaluating HRQoL in meningioma patients. MATERIAL AND METHODS Cross-sectional study of adult patients with an incidental or symptomatic intracranial meningioma. Patients with less than 5 years of follow-up, a history of craniospinal radiation or neurofibromatosis type 2 were excluded. HRQoL was evaluated with SF-36, EORTC QLQ-C30 and EORTC QLQ-BN20 questionnaires. Outcome determinants were evaluated using a multi-variable linear regression analysis, adjusted for patient, tumour and treatment characteristics, and duration of follow-up. RESULTS 699 patients were invited to participate and 246 responded: 118 (48%) had an incidental meningioma. Mean age at diagnosis was 56.8 years (SD=13) and 81% were female. Median time from diagnosis to completion of questionnaire was 8.5 years (IQR 6.8–11.5). During follow-up, 158 patients (64.2%) had at least one operation for their meningioma and 47 patients (19.1%) had radiotherapy. Of those operated, 126 (79.7%) had WHO grade 1 and 24 (15.2%) had grade 2 meningiomas. Compared to normative population values, meningioma patients reported a worse SF-36 general health score (mean 61.9 vs 56.5, P=0.003) but a similar QLQ-C30 global health score (mean 62.3 vs 65.8, P=0.039), worse SF-36 and QLQ-C30 physical functioning scores (mean 74.1 vs 64.6, P CONCLUSION Meningioma patients have long-term HRQoL impairments affecting their physical and cognitive functions. An understanding that multiple surgeries affects cognitive function, and the need for anti-epileptic drugs equate to poorer emotional health, could help target appropriate therapies and support in the future.

PURPOSE Medical students across the United Kingdom helped the National Health Service (NHS) with the increased workload caused by the COVID-19 pandemic. This study was conducted to better understand the implications of COVID-19 on the intricate relationship between the psychological wellbeing of students and working within the NHS. METHOD This was a cross-sectional, national UK study analyzing the self-reported pandemic anxiety scale (PAS) of participants during the pandemic, using an online questionnaire. RESULTS 25.2% of participants worked within the NHS. Working significantly reduced anxiety levels of participants. Concerns around the training and information provided on personal protective equipment (PPE) (odds ratio [OR] 2.57, 95% confidence interval [CI] OR: 1.93, 3.43) (P

IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment’s effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment’s effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment’s effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) has been recognized as a distinct entity in recent years. To the best of our knowledge, all patients with PGNMID reported thus far were older than 20 years of age. We now report five cases of PGNMID in patients under 20 years of age. The clinical database was searched for patients with native kidney biopsies from 9/2011 to 8/2017, and cases with a diagnosis of PGNMID were retrieved. Light microscopy specimens and immunofluorescence and electron microscopy images were revisited. Clinical data and kidney biopsy findings for patients under the age of 20 were recorded. Five (0.78%) of a total of 637 patients younger than 20 with native renal biopsies had a diagnosis of PGNMID, including three males and two females with an average age of 14 years old (range 10–19). All five patients presented with microscopic hematuria and proteinuria. Three patients were nephrotic and their C3 levels were low. All five cases showed a membranoproliferative pattern with abundant mesangial and subendothelial monoclonal IgG3 deposits (3 κ and 2 λ light chain, respectively). The patients were followed up to 56 months. Two patients had re-biopsies 28 and 18 months after initial diagnosis and both showed similar morphologic changes. Various treatments were attempted including prednisone, mycophenolate mofetil, tacrolimus, rituximab, and eculizmab, with mixed responses. PGNMID does occur in children and young adults. Membranoproliferative glomerulonephritis pattern with monoclonal IgG3 deposits is a common feature. Despite various immunosuppressive treatments, the disease appears slowly progressive.

BACKGROUND Resection of meningioma leaves residual solid tumour in ~25% of patients. Selection for further treatment and follow-up strategy may benefit from knowledge of volumetric growth and associated prognostic factors. MATERIAL AND METHODS Growth rates were assessed using a linear mixed effects model, in a retrospective adult cohort that underwent subtotal resection of meningioma (2004–2018). Endpoints were re-treatment, end of follow-up or death. Cox regression analysis was used to identify prognostic factors for progression, defined using the Response Assessment in Neuro-Oncology (RANO) volumetric criteria. RESULTS 236 patients were included. Mean age at surgery was 56.3 years (SD=13.7) and 73.7% were female. WHO grades were 1 (n=195, 82.6%), 2 (n=40, 16.9%) and 3 (n=1, 0.5%). Adjuvant fractionated radiotherapy (fRT) was administered to 34 patients (14.4%), with no propensity towards higher WHO grade or residual volume. Median pre-operative meningioma and post-operative residual volumes were 34.0cm3 (IQR 16.0–63.0) and 2.0cm3 (IQR 0.8–5.2), respectively. Median follow-up was 64 months (IQR 42–104). Median absolute growth rate (AGR) and relative growth rate (RGR) were 0.1cm3/year and 4.3%/year, respectively. According to RANO criteria, 132 (55.9%) patients progressed, of which 13 (9.8%) developed symptoms. Median progression-free survival was 56 months (95% CI 43.1–69.0). Multivariable analysis identified adjuvant fRT (HR 1.7, [95% CI 1.0–2.8], P=0.046), skull base location (HR 1.5, [95% CI 1.0–2.4], P=0.047) and Ki-67 index (HR 3.7 [95% CI 1.3–10.8], P=0.017) as prognostic factors for volumetric progression. WHO grade was not significant (HR 1.0, [95% CI 0.5–1.7], P=0.905). Forty-nine patients who progressed (37.1%) underwent further treatment: fRT (n=19), re-operation (n=15), Stereotactic radiosurgery (SRS) (n=10) and surgery+adjuvant fRT (n=5). Of those, 8 (16.3%) progressed further (after re-operation [n=6] and SRS [n=2]). Seven were treated with a 2nd re-operation (n=3), fRT (n=3), and SRS (n=1). One patient progressed after a 2nd reoperation and was treated with SRS, after which they remained stable. Median survival was not reached. 5- and 10-year overall survival (OS) was 96% and 86% respectively. CONCLUSION Growth rates of a residual meningioma vary with a dichotomy observed in progression rates. Half of patients with a residual meningioma showed radiological progression requiring multiple treatment to control the tumour. The other half demonstrate a more indolent course. Skull base location and higher Ki67 are important prognostic factors for progression and therefore, should be considered to stratify patients for adjuvant radiotherapy.

Introduction: A radiological scoring system to define a ‘surgically significant’ mild Traumatic Brain Injury (TBI) could stratify neurosurgical referrals, and improve communication between referral...

Background With the increased rate of childhood cancer survivors, a marked rise in the incidence of secondary intracranial meningiomas has been established. Objective Determine the outcomes of patients diagnosed with radiation-induced meningiomas (RIM). Methods Single-centre retrospective cohort study of patients with new or recurrent RIM (2007–2018). Results 47 patients were identified (21 females). Mean age at radiation was 15 years (SD=14) and the most common indications were leukaemia (n=8) and childhood brain tumours (n=35; medulloblastoma and pilocytic astrocytoma (n=7 each)). 93 de-novo meningiomas were identified. The median latency period between radiation and diagnosis was 28.5 years (IQR 22–37). 61% were asymptomatic whilst the remainder manifested headache (20%), focal neurological deficit (12%) and epilepsy (5%). 32 operated de-novo RIM revealed WHO grade I (n=19; 59%), WHO grade II (n=11; 34%) and 2 intraosseous meningiomas (n=2; 6%). After a median of 5 years (IQR 3–10), 9 (28%) operated RIM recurred/progressed. At recurrence, 5 were operated (3 WHO grade I, 2 WHO grade II and 1 WHO grade III), 2 patients were palliated and 2 remain under active observation. By the end of the study period, 20 patients were harbouring multiple meningiomas and 8 patients were deceased. Conclusion Radiation-induced meningioma should be monitored until symptomatic. Operated RIMs have a high recurrence rate. Further radiotherapy is not effective. Further clinical and genetic analyses as part of an international multi-centre collaboration are planned.

ObjectivesTo develop and implement a radiological scoring system to define a ‘surgically significant’ mild Traumatic Brain Injury (TBI), stratify neurosurgical referrals and improve communication between referral centres and neurosurgical units.DesignRetrospective single centre case-control analysis of ten continuous months of mild TBI referrals.SettingA major tertiary neurosurgery centre in England, UK.ParticipantsAll neurosurgical referrals with a mild TBI (GCS 13-15) during the period of 1st January to 30th October 2017 were eligible for the study. 1248 patients were identified during the study period, with 1144 being included in the final analysis.InterventionsAll patients’ CT head results from the referring centres were scored retrospectively using the scoring system and stratified according to their mean score, and if they were accepted for transfer to the neurosurgical centre or managed locally.Main outcome measureDetermine the discriminatory and diagnostic power, sensitivity and specificity of the scoring system for predicting a ‘surgically significant’ mild TBI.ResultsMost patients referred were male (59.4%, N=681), with a mean age of 69 years (SD=21.1). Of the referrals to the neurosurgical centre, 17% (n=195) were accepted for transfer and 83% (n=946) were not accepted. The scoring system was 99% sensitive and 51.9% specific for determining a surgically significant TBI. Diagnostic power of the model was fair with an area under the curve of 0.79 (95% CI 0.76 to 0.82). The score identified 495 (52.2%) patients in ten months of referrals that could have been successfully managed locally without neurosurgical referral if the scoring system was correctly used at the time of injury.ConclusionThe Liverpool Head Injury Tomography Score (HITS) score is a CT based scoring system that can be used to define a surgically significant mild TBI. The scoring system can be easily used by multiple healthcare professionals, has high sensitivity, will reduce neurosurgical referrals, and could be incorporated into local, regional and national head injury guidance.

The Infusional Services Team at a large cancer centre in Belfast, Northern Ireland, performed a cross-sectional analysis of two catheter securement technologies to address an area of frequent, but underestimated concern – peripherally inserted central catheter migration and dislodgement. Healthcare practitioner and patient feedback, along with economic impact, were assessed. The costs associated with catheter replacement during the adhesive device group study period were calculated using an average cost per insertion, based on material costs required for the procedure. Other factors were the replacement cost of the adhesive engineered securement device with each dressing change. In the subcutaneous securement group, the material costs were adjusted for use of the subcutaneous device as it remained in situ for the duration of the catheters’ dwell time. This review found that subcutaneous securement offers both patient and facilities a safe, effective and economical alternative for device securement with patients who are unable to tolerate or have successful securement with adhesive securement devices. The use of subcutaneous devices provided for reduced risks for peripherally inserted central catheters in terms of dislodgement, migration or malposition, alleviating the potential risks to develop catheter-related thrombosis and device-related infection.

OBJECTIVES: Availability of donor lungs suitable for transplant falls short of current demand and contributes to waiting list mortality.\ud Ex vivo lung perfusion (EVLP) offers the opportunity to objectively assess and recondition organs unsuitable for immediate transplant.\ud Identifying robust biomarkers that can stratify donor lungs during EVLP to use or non-use or for specific interventions could further improve its clinical impact.\ud METHODS: In this pilot study, 16 consecutive donor lungs unsuitable for immediate transplant were assessed by EVLP. Key inflammatory mediators and tissue injury markers were measured in serial perfusate samples collected hourly and in bronchoalveolar lavage fluid (BALF) collected before and after EVLP. Levels were compared between donor lungs that met criteria for transplant and those that did not.\ud RESULTS: Seven of the 16 donor lungs (44%) improved during EVLP and were transplanted with uniformly good outcomes. Tissue and vascular injury markers lactate dehydrogenase, HMGB-1 and Syndecan-1 were significantly lower in perfusate from transplanted lungs. A model combining IL-1b and IL-8 concentrations in perfusate could predict final EVLP outcome after 2 h assessment. In addition, perfusate IL-1b concentrations showed an inverse correlation to recipient oxygenation 24 h post-transplant.\ud CONCLUSIONS: This study confirms the feasibility of using inflammation and tissue injury markers in perfusate and BALF to identify donor lungs most likely to improve for successful transplant during clinical EVLP. These results support examining this issue in a larger study.

Complex fracture subluxations of the proximal interphalangeal joint are often difficult to treat and their outcome variable. A number of methods for treatment of these injuries have been described. We have used a ligamentotaxis device ( Ligamentotaxor, Arex, Palaiseau Cedex, France) since 2008. We performed 28 operations in 28 patients with complex proximal interphalangeal joint injuries over a 3-year period. Patients followed a standardized postoperative rehabilitation regime, including fixator adjustment as necessary. The mean age was 33 years (range 18–67). The mean time to surgery was 7 days. At final follow-up (mean 22 months, range 6–52) the mean proximal interphalangeal joint range of motion was 85° (range 60°–110°). The mean QuickDASH functional outcome score was 4.8 (range 0–36.4). Our results compare favourably with other devices reported in the literature.

Objectives B-cell activating factor (BAFF), β-2 microglobulin (β2M) and serum free light chains (FLCs) are elevated in primary SS (pSS) and associated with disease activity. We aimed to investigate their association with the individual disease activity domains of the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) in a large well-characterized pSS cohort. Methods Sera from pSS patients enrolled in the UK Primary Sjögren’s Syndrome Registry (UKPSSR) (n = 553) and healthy controls (n = 286) were analysed for FLC (κ and λ), BAFF and β2 M. Pearson correlation coefficients were calculated for patient clinical characteristics, including salivary flow, Schirmer’s test, EULAR Sjögren’s Syndrome Patient Reported Index and serum IgG levels. Poisson regression was performed to identify independent predictors of total ESSDAI and ClinESSDAI (validated ESSDAI minus the biological domain) scores and their domains. Results Levels of BAFF, β2M and FLCs were higher in pSS patients compared to controls. All three biomarkers associated significantly with the ESSDAI and the ClinESSDAI. BAFF associated with the peripheral nervous system domain of the ESSDAI, whereas β2M and FLCs associated with the cutaneous, biological and renal domains. Multivariate analysis showed BAFF, β2M and their interaction to be independent predictors of ESSDAI/ClinESSDAI. FLCs were also shown to associate with the ESSDAI/ClinESSDAI but not independent of serum IgG. Conclusion All biomarkers were associated with total ESSDAI scores but with differing domain associations. These findings should encourage further investigation of these biomarkers in longitudinal studies and against other disease activity measures.

Despite the high costs of treatment of people with kidney disease and associated comorbid conditions, the amount of reliable information available to guide the care of such patients is very limited. Some treatments have been assessed in randomized trials, but most such trials have been too small to detect treatment effects of a magnitude that would be realistic to achieve with a single intervention. Therefore, KDIGO convened an international, multidisciplinary controversies conference titled “Challenges in the Conduct of Clinical Trials in Nephrology” to identify the key barriers to conducting trials in patients with kidney disease. The conference began with plenary talks focusing on the key areas of discussion that included appropriate trial design (covering identification and evaluation of kidney and nonkidney disease outcomes) and sensible trial execution (with particular emphasis on streamlining both design and conduct). Break out group discussions followed in which the key areas of agreement and remaining controversy were identified. Here we summarize the main findings from the conference and set out a range of potential solutions. If followed, these solutions could ensure future trials among people with kidney disease are sufficiently robust to provide reliable answers and are not constrained by inappropriate complexities in design or conduct.

Objectives This article reports relationships between serum cytokine levels and patient-reported levels of fatigue, in the chronic immunological condition primary Sjögren's syndrome (pSS).\ud \ud Methods Blood levels of 24 cytokines were measured in 159 patients with pSS from the United Kingdom Primary Sjögren's Syndrome Registry and 28 healthy non-fatigued controls. Differences between cytokines in cases and controls were evaluated using Wilcoxon test. Patient-reported scores for fatigue were evaluated, classified according to severity and compared with cytokine levels using analysis of variance. Logistic regression was used to determine the most important predictors of fatigue levels.\ud \ud Results 14 cytokines were significantly higher in patients with pSS (n=159) compared to non-fatigued healthy controls (n=28). While serum levels were elevated in patients with pSS compared to healthy controls, unexpectedly, the levels of 4 proinflammatory cytokines—interferon-γ-induced protein-10 (IP-10) (p=0.019), tumour necrosis factor-α (p=0.046), lymphotoxin-α (p=0.034) and interferon-γ (IFN-γ) (p=0.022)—were inversely related to patient-reported levels of fatigue. A regression model predicting fatigue levels in pSS based on cytokine levels, disease-specific and clinical parameters, as well as anxiety, pain and depression, revealed IP-10, IFN-γ (both inversely), pain and depression (both positively) as the most important predictors of fatigue. This model correctly predicts fatigue levels with reasonable (67%) accuracy.\ud \ud Conclusions Cytokines, pain and depression appear to be the most powerful predictors of fatigue in pSS. Our data challenge the notion that proinflammatory cytokines directly mediate fatigue in chronic immunological conditions. Instead, we hypothesise that mechanisms regulating inflammatory responses may be important.

Purpose To evaluate, in a phase III, single-arm study, the safety and efficacy of the thrombolytic agent tenecteplase in restoring function to dysfunctional central venous catheters (CVCs). Materials and Methods Pediatric and adult patients with dysfunctional CVCs were eligible to receive as much as 2 mL (2 mg) of intraluminal tenecteplase, which was left to dwell in the CVC lumen for a maximum of 120 minutes. If CVC function was not restored at 120 minutes, a second dose was instilled for an additional 120 minutes. Results Tenecteplase was administered to 246 patients. Mean patient age was 44 years (range, 0–92 y); 72 patients (29%) were younger than 17 years of age. Chemotherapy was the most common reason for catheter insertion. Restoration of CVC function was achieved in 177 patients (72%) within 120 minutes after the first dose. After instillation of a maximum of two doses of tenecteplase, CVC function was restored in 200 patients (81%), with similar frequencies in pediatric (83%) and adult (80%) patients. Adverse events (AEs) were reported in 31 patients (13%); fever (2%), neutropenia (1%), and nausea (0.8%) were most common. One serious AE, an allergic hypersensitivity reaction, was judged to be related to tenecteplase and/or a chemotherapeutic agent that the patient was receiving concurrently. Conclusions Consecutive administration of one or two doses of tenecteplase into CVCs showed efficacy in the restoration of catheter function in patients with dysfunctional CVCs.

Background and objectives: Estimating equations for calculating glomerular filtration rate (eGFR) occasionally identify patients with elevated eGFR, yet the prognostic significance remains to be determined. This study sought to define the association of an elevated eGFR on the risk for death and cardiovascular outcomes among subjects with atherosclerotic cardiovascular disease. Design, setting, participants, & measurements: Data from 8941 subjects who had a history of atherosclerotic vascular disease and were enrolled in the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion trial were analyzed. Time to the composite end point of death, congestive heart failure, myocardial infarction, or stroke was modeled using Cox proportion hazards regression. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease and Cockcroft-Gault formulas. Results: Compared with subjects with eGFR of 100 to 125 ml/min per 1.73 m 2 , subjects with eGFR >125 (n 462) were younger, female, and nonwhite. In addition, subjects with an elevated eGFR were more likely to have diabetes and congestive heart failure. In adjusted analyses, every 10-ml/min per 1.73 m 2 decrease in eGFR 100 was associated with a 9% increased hazard for the composite end point. Conclusions: In individuals with a history of vascular disease, the relationship between eGFR and cardiovascular outcomes may be parabolic, with increased risk among patients with both reduced and elevated eGFR. Clin J Am Soc Nephrol 2: 1215–1222, 2007. doi: 10.2215/CJN.00930207

Background. Cardiac interventions are underutilized in patients with chronic kidney disease (CKD) following acute coronary syndrome (ACS) partly due to nephrotoxicity concerns. Methods. We analyzed outcomes of 4631 subjects with ACS enrolled in the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion trial, including time to death, time to reduced renal function (50% reduction in estimated glomerular filtration rate (eGFR) or development of end-stage renal disease (ESRD)) and percent change in eGFR from baseline. Results. Subjects with a lower baseline eGFR were more likely to be older, female and have diabetes, hypertension, congestive heart failure or peripheral vascular disease (all P < 0.0001); they were less likely to be taking aspirin ≥162 mg or to have undergone a percutaneous coronary intervention (PCI) prior to enrollment (P < 0.0001). As eGFR declined, the proportion of subjects experiencing death versus reduced eGFR or ESRD qualitatively increased. In adjusted analyses, every 10 ml/min/1.73 m 2 decrease in eGFR ≤ 90 was associated with a 15% increased hazard of death (HR 1.15, P = 0.01). In adjusted analyses of predictors of percent change in eGFR, catheterization (cath) with or without PCI compared to medical therapy during follow-up was not associated with significant differences in long-term eGFR (P = 0.09). Conclusions. Among CKD subjects in this study, the risk of death greatly outweighed the risk of reduced eGFR or development of ESRD following ACS and the occurrence of cath ± PCI was not associated with significant differences in long-term renal function. The presence of CKD should not preclude potentially beneficial interventions and research should focus on reducing the high cardiovascular burden in this population.

The relationship between blood pressure (BP) and clinical outcomes among hemodialysis patients is complex and incompletely understood. This study sought to assess the relationship between blood pressure changes with hemodialysis and clinical outcomes during a 6-month period. This study is a secondary analysis of the Crit-Line Intradialytic Monitoring Benefit Study, a randomized trial of 443 hemodialysis subjects, designed to determine whether blood volume monitoring reduced hospitalization. Logistic regression was used to estimate the association between BP changes with hemodialysis (Deltasystolic blood pressure=postdialysis-predialysis systoic BP (SBP) and the primary outcome of non-access-related hospitalization and death. Subjects whose systolic blood pressure fell with dialysis were younger, took fewer blood pressure medications, had higher serum creatinine, and higher dry weights. After controlling for baseline characteristics, lab variables, and treatment group, subjects whose SBP remained unchanged with hemodialysis (N=150, DeltaSBP -10 to 10 mm Hg) or whose SBP rose with hemodialysis (N=58, DeltaSBPor =10 mm Hg) had a higher odds of hospitalization or death compared to subjects whose SBP fell with hemodialysis (N=230, DeltaSBPor =-10 mm Hg) (odds ratio: 1.85, confidence interval: 1.15-2.98; and odds ratio: 2.17, confidence interval: 1.13-4.15). Subjects whose systolic blood pressure fell with hemodialysis had a significantly decreased risk of hospitalization or death at 6 months, suggesting that hemodynamic responses to dialysis are associated with short-term outcomes among a group of prevalent hemodialysis subjects. Further research should attempt to elucidate the mechanisms behind these findings.

Bacterial infections after lung transplantation cause airway epithelial injury and are associated with an increased risk of developing bronchiolitis obliterans syndrome. The damaged epithelium is a source of alarmins that activate the innate immune system, yet their ability to activate fibroblasts in the development of bronchiolitis obliterans syndrome has not been evaluated. Two epithelial alarmins were measured longitudinally in bronchoalveolar lavages from lung transplant recipients who developed bronchiolitis obliterans syndrome and were compared to stable controls. In addition, conditioned media from human airway epithelial cells infected with Pseudomonas aeruginosa was applied to lung fibroblasts and inflammatory responses were determined. Interleukin‐1 alpha (IL‐1α) was increased in bronchoalveolar lavage of lung transplant recipients growing P. aeruginosa (11.5 [5.4–21.8] vs. 2.8 [0.9–9.4] pg/mL, p, This study demonstrates that a Pseudomonas aeruginosa challenge of lung epithelial cells causes the release of IL‐1α and the induction of an inflammatory phenotype in lung fibroblasts, and provides evidence of an association between infection with P. aeruginosa, IL‐1α levels in bronchoalveolar lavage fluid, and the development of bronchiolitis obliterans syndrome following lung transplantation.

Post-transplant anemia is a widespread problem among pediatric renal transplant recipients. Many clinicians treat post-transplant anemia in a manner similar to treatment of anemia in dialysis patients, including the use of intravenous iron, such as sodium ferric gluconate (SFG). Data on pediatric dosing of SFG are limited to rare small series containing few or no renal transplant recipients. We conducted a retrospective chart review of practice patterns at our institution to evaluate doses used, hemoglobin response and adverse events. We identified 15 renal transplant recipients who received SFG during the 28-month study period. Data from 14 of these patients were available for analysis. Patients received between one and six doses of SFG to yield a total dose of 100-1000 mg or 2.7-23.7 mg/kg. The largest doses given during a single infusion ranged from 1.9 to 6.4 mg/kg. The mean hemoglobin level increased from 101 +/- 16 to 114 +/- 21 g/L (p = 0.0092) following SFG therapy. Adverse events were recorded for three patients. Treatment with SFG appears to yield some improvement in anemia in renal transplant recipients, but the paucity of published information on this topic highlights the need for stronger data, particularly with respect to pediatric patients.

Continuous renal replacement therapy (CRRT) is used to treat renal failure in children. Despite widespread use of the technique, little research has evaluated how variations in dose of replacement fluid or degree of fluid overload at initiation relate to outcomes. We conducted a retrospective review of patients treated with convective CRRT at our institution, using a multivariable Cox regression model. Children with high fluid overload (>10%) at CRRT initiation were at 3.02 times greater risk of mortality than those with low or no fluid overload [95% confidence interval (CI) 1.50–6.10, P =0.002]. The hazard ratio for death in children treated with high-dose convective clearance was not statistically significant. Our data support previous findings that volume overload in excess of 10% is strongly correlated with poor outcome. We favor early institution of CRRT, before excessive fluid overload occurs. In contrast to findings in adults, we find no advantage to higher rates of convective clearance. Given the risks and increased complexity associated with high-volume hemofiltration, we recommend further study prior to widespread adoption of high-level convection in children treated with continuous veno-venous hemofiltration.

Dialysis guidelines recommend aggressive management of anemia, including the use of intravenous iron (i.v.Fe) when indicated. However, few published data are available to guide the use of i.v.Fe in children, and studies are difficult to compare. In this meta-analysis we sought to combine evidence by pooling clinical trial data to determine if i.v.Fe therapy helped increase hematocrit, serum levels of hemoglobin, ferritin, and transferrin saturation (TSAT), and reduce erythropoietin use. We searched MEDLINE and other databases, publications, and other sources to identify as many published and unpublished trials as possible. Of 379 possible studies, nine met the criteria for inclusion and analysis. Across all nine studies, 141 patients were studied, for durations of 2 weeks to 12 months. Pooled results identified an increase in hemoglobin, hematocrit, ferritin, and TSAT levels, and reduced use of erythropoietin, with effect sizes (in standardized weighted mean differences) ranging from 0.62 (95% confidence interval 0.11-1.13) to 1.86 (1.58-2.15) standard deviation improvements. Current practice is based largely on extrapolation from adult data and a few small pediatric trials. The pooled pediatric data suggest that i.v.Fe is effective and produces moderate to large effects on the reported outcomes. Prospective, multi-center trials are needed to determine the optimal utilization of i.v.Fe in children.

The accumulation of damage to cellular biomolecules, including DNA, over time may play a significant role in the aetiology of the ageing process. We have previously quantified DNA damage and mutation within cultured lymphocytes from healthy human male subjects in three different age groups (35–39, 50–54 and 65–69 years). The results of that study showed an age-related increase in DNA damage and mutations in lymphocytes. In addition, an age-related decrease in the capacity of the lymphocytes to repair H 2 O 2 -induced DNA damage was found. In this article, we report the findings of an extension to the earlier study. Thirty-one generally healthy male and female subjects between the ages of 75 and 80 years were recruited. Using a number of bioassays, we were able to determine; basal levels of DNA damage (for 18 subjects) and mutant frequency at the hypoxanthine phosphoribosyltransferase ( hprt ) gene locus (for 16 subjects) within cultured lymphocytes. In addition, in vivo antioxidant status (for all study subjects) and the capacity of lymphocytes to repair H 2 O 2 -induced DNA damage (for 18 subjects) were also assessed. The results obtained showed: that the mean basal level of DNA damage in lymphocytes from subjects in the 75- to 80-year age group (12.6±4.7%) was similar to that of the 35- to 39-year age group (13.3±3.3%), p =0.42 (Mann–Whitney); there was no significant difference between log mean mutant frequency at the hprt gene locus in lymphocytes from the 75- to 80-year age group (0.31±0.33) compared to that observed in the 35- to 39-year age group (0.24±0.21; Student's t -test, t =0.68, p >0.05). Levels of the antioxidants glutathione peroxidase (GPx EC 1.11.1.9), catalase (CAT; EC 1.11.1.6) and caeruloplasmin (CPL; EC 1.16.3.1) were significantly elevated in the 75- to 80-year age group, compared to the 35- to 39-, 50- to 54- and 65- to 69-year age groups. Levels of bilirubin (BR) were reduced in the 75- to 80-year age group, the decrease being contributed by the female subjects. No differences in levels of superoxide dismutase (SOD; EC 1.15.1.1) or uric acid (UA) were found between the 4 age groups. Following treatment of lymphocytes with H 2 O 2 , we did not find any difference in the susceptibility of lymphocytes to DNA damage in the 75- to 80-year age group, compared to the other age groups. The DNA repair capacity in lymphocytes from individuals in the 75- to 80-year age group was similar to that of the 35- to 39-year age group, for all time points assessed. These results highlight the importance of DNA repair processes and antioxidant defence systems for maintaining genomic stability in vivo.

1. Urine was the major route of excretion of radioactivity (95% dose in 0-24 h) following the oral, intravenous or intraperitoneal administration of [14C]-trimethylamine N-oxide dihydrate (1 mmol/kg body wt) to the adult male Wistar rat. A further 3-4% was voided in the urine during 24-72 h. Only fractional amounts were detected in the faeces, or were retained within tissues 3 days after administration. 2. Biliary secretion of radioactivity was insignificant (0.18% in 0-4 h) but larger amounts were secreted directly into the lumen of the gastrointestinal tract, especially the small intestine (2.6% in 0-1 h). 3. The only radioactive compounds identified in the urine were trimethylamine N-oxide and dimethylamine. Larger amounts of dimethylamine were excreted following oral administration (10%) as opposed to intravenous (2.5%) or intraperitoneal (1.5%) input. This production of dimethylamine occurred over a 100-fold oral trimethylamine N-oxide dose range (0.3-30 mmol/kg body wt). Incubation of trimethylamine N-oxide with gut contents (especially colon and rectum) led to the formation of dimethylamine.

Infiltrative disorders and myofibrillar diseases, corresponding histologically to extracellular amyloid fibrils and intracellular aggregates, are important causes of cardiovascular and skeletal muscle disorders. Those proteinacious deposits in cardiomyocytes and the ventricular wall are infrequent causes of “idiopathic” heart failure but their insidious onset and progression pose diagnostic challenges with poor therapeutic options. The pathogenic mechanisms are likely similar, but not identical, to age-related neurodegenerative Alzheimer’s disease, which is linked to insoluble plaques and toxic aggregates. Both arise from imbalances in proteostasis boundaries, loss of function, and gain of “toxic” function mechanisms ( http://www.ncbi.nlm.nih.gov/omim/605906 ). Yet, the field of cardiovascular medicine has not met the challenge of unraveling the mechanisms that limit cell survival and trigger organ dysfunction. In this chapter, we focus on the myocardial manifestations in which protein handling abnormalities feature prominently, as reviews of similar processes in skeletal muscle have been handled elsewhere. First, we explore the basic concepts and the cellular mechanism(s) by which protein misfolding and aggregation contribute to disease pathogenesis. We conclude with an in-depth discussion of protein aggregation cardiomyopathy (e.g., desmin, αB-crystallin) and infiltrative disorders (e.g., cardiac amyloidosis) of the cardiovascular system.

Background The aim of this study was to assess the content validity of a questionnaire to measure melanoma risk, knowledge and protective behaviour in a convenience sample of Scots and Australians. Australia has the highest melanoma incidence worldwide but has developed a culture of skin cancer avoidance with a long history of skin cancer primary prevention campaigns of proven effectiveness. Scotland has lower incidence, but has shown a greater rate of increase between 1985 and 2007. There is an urgent need in Scotland, therefore, to identify those groups at greatest risk and provide them with effective preventative advice. Method A self-administered postal survey was completed by four groups formed from convenience samples in two geographical locations (Northeast Scotland and Western Australia). In univariate analysis scores on personal risk, level of concern, protective behaviour, and knowledge were compared by nationality, previous skin cancer diagnosis and personally knowing someone with melanoma. Multivariate linear regression analysis modelled the influence of potential predictor variables upon each of the scores. Results 540 people completed the questionnaire, 273 Scots (50.6%). 133 (24.6%) Scots and 83 (15.4%) Australians previously had melanoma or non-melanoma skin cancer, whilst 120 (22.2%) Scots and 190 (35.2%) Australians personally knew someone with melanoma. Australians had higher knowledge (p < 0.001), level of concern (p < 0.001) and protective behaviour (p < 0.001) scores than the Scottish. Australian nationality was the strongest independent predictor of a higher knowledge score (p < 0.001), followed by a previous skin cancer diagnosis (p = 0.003), personal knowledge of someone with melanoma (p = 0.011), female gender (p = 0.005) and higher education status (p < 0.001) (R 2 = 0.163). Conclusion The questionnaire detected higher levels of knowledge and skin cancer protective behaviours in Australians than in Scottish people. This was expected and supports the content validity of the questionnaire and its value as a future research tool in the Scottish population.