Delirium, neurofilament light chain, and progressive cognitive impairment: analysis of a prospective Norwegian population-based cohort.

BACKGROUND: Previous population-based, longitudinal studies have shown that delirium is associated with an increased risk of dementia and cognitive decline. However, the underlying biological mechanisms are largely unknown. We aimed to assess the effects of delirium on both cognitive trajectories and any neuronal injury, measured via neurofilament light chain (NfL). METHODS: In this analysis of a prospective, 2-year follow-up, cohort study of participants aged 65 years or older living in Sandefjord municipality, Norway, we included cohort participants who were receiving domiciliary care services at least once per week between May 12, 2015, and July 8, 2016. Individuals with a life expectancy of less than 1 week, with Lewy body dementia, with psychiatric illness (except dementia), or for whom substance misuse was the principal indication for domiciliary services were excluded. Participants had a comprehensive assessment at 6-month intervals for 2 years, which included the Montreal Cognitive Assessment (MoCA) and a blood sample for NfL to measure neuronal injury. All information on clinical diagnoses and medications were cross-referenced with medical records. During any acute change in mental status or hospitalisation (ie, admission to hospital), participants were assessed once per day for delirium with Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria. We also measured NfL from blood samples taken from participants who were acutely hospitalised. FINDINGS: Between May 12, 2015, and July 8, 2016, 210 participants were eligible for inclusion and assessed at baseline (138 [66%] of whom were female and 72 [34%] of whom were male), 203 completed cognitive assessment, and 141 were followed up for 2 years. 160 (76%) of 210 had moderate or severe frailty and 112 (53%) were living with dementia. During the 2-year follow-up, 89 (42%) of 210 participants were diagnosed with one or more episodes of delirium. Incident delirium was independently associated with a decrease in MoCA score at the next 6-month follow-up, even after adjustment for age, sex, education, previous MoCA score, and frailty (adjusted mean difference -1·5, 95% CI -2·9 to -0·1). We found an interaction between previous MoCA score and delirium (ß -0·254, 95% CI -0·441 to -0·066, p=0·010), with the largest decline being observed in people with better baseline cognition. Participants with delirium and good previous cognitive function and participants with a high peak concentration of NfL during any hospitalisation had increased NfL at the next 6-month follow-up. Mediation analyses showed independent pathways from previous MoCA score to follow-up MoCA score with contributions from incident delirium (-1·7, 95% CI -2·8 to -0·6) and from previous NfL to follow-up MoCA score with contributions from acute NfL concentrations (-1·8, -2·5 to -1·1). Delirium was directly linked with a predicted value of 1·2 pg/mL (95% CI 1·02 to 1·40, p=0·029) increase in NfL. INTERPRETATION: In people aged 65 years or older, an episode of delirium was associated with a decline in MoCA score. Greater neuronal injury during acute illness and delirium, measured by NfL, was associated with greater cognitive decline. For clinicians, our finding of delirium associated with both signs of acute neuronal injury, measured via NfL, and cognitive decline is important regarding the risk of long-term cognitive deterioration and to acknowledge that delirium is harmful for the brain. FUNDING: South-Eastern Norway Health Authorities, Old Age Psychiatry Research Network, Telemark Hospital Trust, Vestfold Hospital Trust, and Norwegian National Centre for Ageing and Health. TRANSLATION: For the Norwegian translation of the abstract see Supplementary Materials section.

Extremes of baseline cognitive function determine the severity of delirium: a population study.

Although delirium is a significant clinical and public health problem, little is understood about how specific vulnerabilities underlie the severity of its presentation. Our objective was to quantify the relationship between baseline cognition and subsequent delirium severity. We prospectively investigated a population-representative sample of 1510 individuals aged ≥70 years, of whom 209 (13.6%) were hospitalized across 371 episodes (1999 person-days assessment). Baseline cognitive function was assessed using the modified Telephone Interview for Cognitive Status, supplemented by verbal fluency measures. We estimated the relationship between baseline cognition and delirium severity [Memorial Delirium Assessment Scale (MDAS)] and abnormal arousal (Observational Scale of Level of Arousal), adjusted by age, sex, frailty and illness severity. We conducted further analyses examining presentations to specific hospital settings and common precipitating aetiologies. The median time from baseline cognitive assessment to admission was 289 days (interquartile range 130 to 47 days). In admitted patients, delirium was present on at least 1 day in 45% of admission episodes. The average number of days with delirium (consecutively positive assessments) was 3.9 days. Elective admissions accounted for 88 bed days (4.4%). In emergency (but not elective) admissions, we found a non-linear U-shaped relationship between baseline global cognition and delirium severity using restricted cubic splines. Participants with baseline cognition 2 standard deviations below average (z-score = -2) had a mean MDAS score of 14 points (95% CI 10 to 19). Similarly, those with baseline cognition z-score = + 2 had a mean MDAS score of 7.9 points (95% CI 4.9 to 11). Individuals with average baseline cognition had the lowest MDAS scores. The association between baseline cognition and abnormal arousal followed a comparable pattern. C-reactive protein ≥20 mg/l and serum sodium <125 mM/l were associated with more severe delirium. Baseline cognition is a critical determinant of the severity of delirium and associated changes in arousal. Emergency admissions with lowest and highest baseline cognition who develop delirium should receive enhanced clinical attention.

Predicting mortality in acutely hospitalised older patients: the impact of model dimensionality.

BACKGROUND: The prediction of long-term mortality following acute illness can be unreliable for older patients, inhibiting the delivery of targeted clinical interventions. The difficulty plausibly arises from the complex, multifactorial nature of the underlying biology in this population, which flexible, multimodal models based on machine learning may overcome. Here, we test this hypothesis by quantifying the comparative predictive fidelity of such models in a large consecutive sample of older patients acutely admitted to hospital and characterise their biological support. METHODS: A set of 804 admission episodes involving 616 unique patients with a mean age of 84.5 years consecutively admitted to the Acute Geriatric service at University College Hospital were identified, in whom clinical diagnoses, blood tests, cognitive status, computed tomography of the head, and mortality within 600 days after admission were available. We trained and evaluated out-of-sample an array of extreme gradient boosted trees-based predictive models of incrementally greater numbers of investigational modalities and modelled features. Both linear and non-linear associations with investigational features were quantified. RESULTS: Predictive models of mortality showed progressively increasing fidelity with greater numbers of modelled modalities and dimensions. The area under the receiver operating characteristic curve rose from 0.67 (sd = 0.078) for age and sex to 0.874 (sd = 0.046) for the most comprehensive model. Extracranial bone and soft tissue features contributed more than intracranial features towards long-term mortality prediction. The anterior cingulate and angular gyri, and serum albumin, were the greatest intracranial and biochemical model contributors respectively. CONCLUSIONS: High-dimensional, multimodal predictive models of mortality based on routine clinical data offer higher predictive fidelity than simpler models, facilitating individual level prognostication and interventional targeting. The joint contributions of both extracranial and intracranial features highlight the potential importance of optimising somatic as well as neural functions in healthy ageing. Our findings suggest a promising path towards a high-fidelity, multimodal index of frailty.

Life-space, frailty, and health-related quality of life.

INTRODUCTION: Life-space and frailty are closely linked to health-related quality of life and understanding their inter-relationship could indicate potential intervention targets for improving quality of life. We set out to examine the relationship between frailty and life-space and their relative impact on quality of life measures. METHODS: Using cross-sectional data from a population-representative cohort of people aged ≥ 70 years, we assessed quality of life with the EuroQol Health Index tool (5-levels) (EQ-5D-5L). We also undertook a life-space assessment and derived a frailty index. Linear regression models estimated EQ-5D-5L scores (dependent variable) using life-space assessment, frailty index and interactions between them. All models were adjusted by age, sex, lifestyle, and social care factors. RESULTS: A higher EQ-5D Index was associated with higher life-space (0.02 per life-space assessment score, 95%CI: 0.01 to 0.03, p < 0.01) and decreasing frailty (-0.1 per SD, 95%CI: -0.1 to -0.1, p < 0.01). There was evidence of an interaction between life-space and frailty, where the steepest gradient for life-space and EQ-5D was in those with the highest frailty (interaction term = 0.02 per SD of frailty, 95%CI: 0.01 to 0.03, p < 0.01). CONCLUSION: Individuals with the highest frailty were twice as likely to have higher quality of life in association with a larger life-space. Interventions designed to improve quality of life in frail older people could focus on increasing a person's life-space.

The effect of baseline cognition and delirium on long-term cognitive impairment and mortality: a prospective population-based study.

Background: There is an unmet public health need to understand better the relationship between baseline cognitive function, the occurrence and severity of delirium, and subsequent cognitive decline. Our aim was to quantify the relationship between baseline cognition and delirium and follow-up cognitive impairment. Methods: We did a prospective longitudinal study in a stable representative community sample of adults aged 70 years or older who were registered with a Camden-based general practitioner in the London Borough of Camden (London, UK). Participants were recruited by invitation letters from general practice lists or by direct recruitment of patients from memory clinics or patients recently discharged from secondary care. We quantified baseline cognitive function with the modified Telephone Interview for Cognitive Status. In patients who were admitted to hospital, we undertook daily assessments of delirium using the Memorial Delirium Assessment Scale (MDAS). We estimated the association of pre-admission baseline cognitive function with delirium prevalence, severity, and duration. We assessed subsequent cognitive function 2 years after baseline recruitment using the Telephone Interview for Cognitive Status. Regression models were adjusted by age, sex, education, illness severity, and frailty. Findings: We recruited 1510 participants (median age 77 [IQR 73-82], 57% women) between March, 2017, and October, 2018. 209 participants were admitted to hospital across 371 episodes (1999 person-days of assessment). Better baseline cognition was associated with a lower risk of delirium (odds ratio 0·63, 95% CI 0·45 to 0·89) and with less severe delirium (-1·6 MDAS point, 95% CI -2·6 to -0·7). Individuals with high baseline cognition (baseline Z score +2·0 SD) had demonstrable decline even without delirium (follow-up Z score +1·2 SD). However, those with a high delirium burden had an even larger absolute decline of 2·2 SD in Z score (follow-up Z score -0·2). Once individuals had more than 2 days of moderate delirium, the rates of death over 2 years were similar regardless of baseline cognition; a better baseline cognition no longer conferred any mortality benefit. Interpretation: A higher baseline cognitive function is associated with a good prognosis with regard to likelihood and severity of delirium. However, those with a high baseline cognition and with delirium had the highest degree of cognitive decline, a change similar to the decline observed in individuals with a high amyloid burden in other cohorts. Older people with a healthy baseline cognitive function who develop delirium stand to lose the most after delirium. This group could benefit from targeted cognitive rehabilitation interventions after delirium.

The relative impact of socioeconomic position and frailty varies by population setting.

Introduction: Frailty and socioeconomic position (SEP) are well-established determinants of health. However, we know less about the contributions of frailty and SEP in older adults, especially in acute settings. We set out to answer how frailty and SEP might influence health outcomes in older people, comparing a population sample and patients managed by a speciality acute frailty service. Methods: We used the Delirium and Population Health Informatics Cohort, a population sample of 1510 individuals aged ≥70 years from the London Borough of Camden and 1750 acute frailty patients. SEP was determined using the Index of Multiple Deprivation. Linear and Cox proportional hazard regression models were conducted to assess SEP on frailty, readmission, and mortality outcomes. Results: In the population sample, SEP was significantly associated with frailty and mortality with successive increases in rate of death for each IMD quintile (HR = 1.28, 95% CI 1.11 to 1.49, P < 0.005). Increasing SEP, age, and admission status among hospitalized individuals were associated with greater frailty. For individuals seen by the speciality frailty service, SEP was not associated with frailty, mortality, or readmission. Discussion: When older people experience acute illness severe enough to require secondary care, particularly specialist services, this overcomes any prior advantages conferred by a higher SEP.

Persistent delirium in older hospital patients: an updated systematic review and meta-analysis.

Introduction: Delirium is associated with future dementia progression. Yet whether this occurs subclinically over months and years, or persistent delirium merges into worsened dementia is not understood. Our objective was to estimate the prevalence of persistent delirium and understand variation in its duration. Methods: We adopted an identical search strategy to a previous systematic review, only including studies using a recognised diagnostic framework for ascertaining delirium at follow-up (persistent delirium). Studies included hospitalised older patients outside critical and palliative care settings. We searched MEDLINE, EMBASE, PsycINFO and the Cochrane Database of Systematic Reviews on 11th January 2022. We applied risk of bias assessments based on Standards of Reporting of Neurological Disorders criteria and assessed strength of recommendations using the grading of recommendation, assessment, development and evaluation (GRADE) approach. Estimates were pooled across studies using random-effects meta-analysis, and we estimated associations with follow-up duration using robust error meta-regression. Results: We identified 13 new cohorts, which we added to 10 from the previous systematic review (23 relevant studies, with 39 reports of persistent delirium at 7 time-points in 3186 individuals admitted to hospital care (mean age 82 years and 41% dementia prevalence). Studies were mainly at moderate risk of bias. Pooled delirium prevalence estimates at discharge were 36% (95% CI 22% to 51%, 13 studies). Robust error meta-regression did not show variation in prevalence of persistent delirium over time (-1.6% per month, 95% CI -4.8 to 1.6, p=0.08). Margins estimates for this model indicate a prevalence of persistent delirium of 16% (95% CI 6% to 25%) at 12 months. Conclusions: This systematic review emphasises the importance of delirium as a persistent and extensive problem (GRADE certainty = moderate), raising questions on chronic delirium as a clinical entity and how it might evolve into dementia. Addressing persistent delirium will require a whole-system, integrated approach to detect, follow-up and implement opportunities for recovery across all healthcare settings.

Mechanisms of peripheral neurotoxicity associated with four chemotherapy drugs using human induced pluripotent stem cell-derived peripheral neurons.

The awareness of the long-term toxicities of cancer survivors after chemotherapy treatment has been gradually strengthened as the population of cancer survivors grows. Generally, chemotherapy-induced peripheral neurotoxicity (CIPN) is studied by animal models which are not only expensive and time-consuming, but also species-specific differences. The generation of human induced pluripotent stem cells (hiPSCs) and differentiation of peripheral neurons have provided an in vitro model to elucidate the risk of CIPN. Here, we developed a drug-induced peripheral neurotoxicity model using hiPSC-derived peripheral neurons (hiPSC-PNs) to study the mechanisms of different chemotherapeutic agents on neuronal viability using LDH assay, a cell apoptosis assay determined by caspase 3/7 activation, neurite outgrowth, ion channel expression and neurotransmitter release following treatment of cisplatin, bortezomib, ixabepilone, or pomalidomide. Our data showed that the multiple endpoints of the hiPSC-PNs model had different sensitivity to various chemotherapeutic agents. Furthermore, the chemotherapeutics separated cell viability from the decrease in neurite lengthand changed levels of ion channels and neurotransmitters to a certain extent. Thus, we study the mechanisms of peripheral neurotoxicity induced by chemotherapeutic agents through changes in these indicators.

Do specific delirium aetiologies have different associations with death? A longitudinal cohort of hospitalised patients.

PURPOSE: To describe aetiology-specific associations with mortality among older hospital patients with delirium. METHODS: Over 21 months, a cohort of 1702 patients with 2471 acute hospital admissions (median age 85, IQR 80-90, 56% women) were assessed for delirium, categorised with inflammatory and metabolic aetiologies based on available laboratory results, and followed up for all-cause mortality. Interactions between aetiology and delirium were tested. RESULTS: The total mortality for the cohort was 35.2%. While inflammation, metabolic disturbance, and delirium at time of admission all demonstrated independent associations with mortality, there was no evidence for any interactions between delirium and these laboratory-measured aetiologies. CONCLUSIONS: Delirium remains an important predictor of death in older hospital patients, irrespective of underlying aetiology.

Juxtacrine signalling via Notch and ErbB receptors in the switch to fate commitment of bone marrow-derived Schwann cells.

The phenotypic instability of adult tissue-derived Schwann cell-like cells (SCLCs) as revealed upon withdrawal of glia-inducing culture supplements limits their clinical utility for cell therapy and disease modelling. We previously overcame this limitation by co-culturing bone marrow-derived SCLCs with neurons purified from developing rat and subsequently human sensory neurons such that direct contact between cell types accomplished the cell-intrinsic switch to the Schwann cell fate. Here, our search for juxtacrine instructive signals found both Notch ligands and neuregulin-1 type III localized on the surface of DRG neurons via live cell immunocytochemistry. Bypassing ligand-induced release of the Notch intracellular domain (NICD) by transient transfection of SCLCs with the pAdlox/V5-His-NICD construct was shown to upregulate ErbB2/3. Interaction of ErbB2/3 with neuregulin-1 type III (NRG1 type III) as presented on neurons then mediated the switch to the Schwann cell fate as demonstrated by expression of S100ß/p75/ Sox10/Krox20. In contrast, treatment of cocultures with γ-secretase inhibitor perturbed Notch signalling in SCLCs and consequently deterred both upregulation of ErbB2/3 and the transition to the Schwann cell fate. Taken together, juxtacrine signalling via Notch is key to the upregulation of ErbB receptors for neuregulin-driven commitment of SCLCs to the Schwann cell fate.

Longitudinal associations between diurnal cortisol variation and later-life cognitive impairment.

OBJECTIVE: To determine whether hypothalamus-pituitary-adrenal axis (HPAA) dysfunction is prospectively associated with global cognitive impairment in later life. METHODS: This cross-cohort study integrates 2 large longitudinal datasets, Whitehall II and the National Survey for Health and Development (NSHD), on data collected in the Whitehall II study between 2002-2004, 2007-2009, and 2012-2013; and for NSHD between 2006-2010 and in 2015. Serial salivary cortisol samples were collected multiple times within a 24-hour period at mean ages 61.2 and 65.9 years in Whitehall II and at age 60-64 years from NSHD participants. Cortisol profile is defined using cortisol awakening response and am:pm ratio. Cognitive function was measured using the Mini-Mental State Examination in Whitehall II and Addenbrooke's Cognitive Examination, third version, in NSHD, harmonized into a 30-point score. Models were adjusted for age, sex, diagnoses of hypertension and diabetes, body mass index (BMI), educational attainment, and interval between HPAA and cognitive assessments. RESULTS: In fully adjusted models, increased am:pm cortisol ratio was prospectively associated with better later-life cognitive function years later (0.02 fewer errors per SD increase in am:pm cortisol ratio, p < 0.01) and verbal fluency (0.03 SD increase in verbal fluency per SD increase in am:pm ratio, p < 0.01). Increasing age, lower educational attainment, diagnosis of hypertension, diagnosis of diabetes, and increased BMI were associated with worse cognitive function and poorer verbal fluency. There were no associations between depression and later-life cognition or reverse associations between cognition and later-life cortisol profiles. CONCLUSIONS: Loss of diurnal HPAA variation is evident in individuals subsequently experiencing more cognitive impairment. It may serve as an early preclinical marker of cognitive decline.

The Scottish Intercollegiate Guidelines Network: risk reduction and management of delirium.

Clinical and research interest in delirium has been rising over the last 15 years. The Scottish Intercollegiate Guidelines Network (SIGN) publication on delirium is a state-of-the-art synthesis of the field, and the first UK guideline since 2010. There is new guidance around delirium detection, particularly in recommending the 4 'A's Test (4AT). The 4AT has the advantage of being brief, embeds and operationalises cognitive testing, and is scalable with little training. The guidelines highlight the importance of non-pharmacological management for all hospital presentations involving the spectrum of cognitive disorders (delirium, dementia but at risk of delirium, delirium superimposed on dementia). Pharmacotherapy has a minimal role, but specific indications (e.g. intractable distress) are discussed. Advances in delirium research, education and policy, have come together with steady changes in the sociocultural context in which healthcare systems look after older people with cognitive impairment. However, there remains a gap between desired and actual clinical practice, one which might be bridged by re-engaging with compassionate, patient-centred care. In this respect, these SIGN guidelines offer a key resource.

Vascular risk factors for male and female urgency urinary incontinence at age 68 years from a British birth cohort study.

OBJECTIVE: To investigate the prevalence of urgency urinary incontinence (UUI) at age 68 years and the contribution of vascular risk factors to male and female UUI pathogenesis in addition to the associations with raised body mass index (BMI). SUBJECTS AND METHODS: In all, 1 762 participants from the Medical Research Council (MRC) National Survey for Health and Development birth cohort who answered the International Consultation on Incontinence Questionnaire short form (ICIQ-SF), at age 68 years, were included. Logistic regression was used to estimate associations between UUI and earlier life vascular risk factors including: lipid status, diabetes, hypertension, BMI, previous stroke or transient ischaemic attack (TIA) diagnosis; adjusting for smoking status, physical activity, co-presentation of stress UI symptoms, educational attainment; and in women only, type of menopause, age at period cessation, and use of hormone replacement therapy (HRT). RESULTS: UUI was reported by 12% of men and 19% of women at age 68 years. Female sex, previous stroke or TIA diagnosis, increased BMI and hypertension (in men only) at age 60-64 years were independent risk factors for UUI. Female sex, increased BMI, and a previous diagnosis of stroke/TIA increased the relative risk of more severe UUI symptoms. Type and timing of menopause and HRT use did not alter the estimated associations between UUI and vascular risk factors in women. CONCLUSION: Multifactorial mechanisms lead to UUI and vascular risk factors may contribute to the pathogenesis of bladder overactivity in addition to higher BMI. Severe UUI appears to be a distinct presentation with more specific contributory mechanisms than milder UUI.

Systemic inflammation and modifiable risk factors for cognitive impairment in older persons: Findings from a British birth cohort.

Serum pro-inflammatory markers may contribute to dementia pathophysiology and cognitive impairment. In a population-representative birth cohort, serum C-reactive protein (CRP), interleukin-6 (IL-6), and white cell count (WCC) were measured at age 60-64 years and cognition was assessed using the Addenbrooke's Cognitive Examination (ACE-III) at age 69 years. Higher baseline CRP and IL-6 were associated with lower ACE-III scores, but associations were attenuated on adjustment for educational attainment, sex, and other modifiable life course factors. No associations were found for CRP, IL-6, and WCC with visual search speed or verbal memory. In conclusion, the relationship between increased baseline systemic inflammation and poorer cognition in later life may be explained by, or share pathways with, education and other modifiable life course factors.

Systemic inflammation and causal risk for Alzheimer's dementia: Possibilities and limitations of a Mendelian randomization approach.

Epidemiological studies have implicated systemic inflammation in the development of Alzheimer's disease (AD). However, these observations have been subject to residual confounding and reverse causation. We applied Mendelian randomization approaches to address this. We did not identify any causal associations between serum interleukin (IL)-18, IL-1ra, IL-6, or erythrocyte sedimentation rate (ESR) concentrations and AD. Our findings are limited by the low number of available instruments, though some of those identified (e.g., IL-6) were of sufficient power to indicate true negative results. Taken together, it appears there is no evidence for a causal association between these serum inflammatory cytokines and AD.

Delirium symptoms are associated with decline in cognitive function between ages 53 and 69 years: Findings from a British birth cohort study.

INTRODUCTION: Few population studies have investigated whether longitudinal decline after delirium in mid-to-late life might affect specific cognitive domains. METHODS: Participants from a birth cohort completing assessments of search speed, verbal memory, and the Addenbrooke's Cognitive Examination at age 69 were asked about delirium symptoms between ages 60 and 69 years. Linear regression models estimated associations between delirium symptoms and cognitive outcomes. RESULTS: Period prevalence of delirium between 60 and 69 years was 4% (95% confidence interval 3.2%-4.9%). Self-reported symptoms of delirium over the seventh decade were associated with worse scores in the Addenbrooke's Cognitive Examination (-1.7 points; 95% confidence interval -3.2, -0.1; P = .04). In association with delirium symptoms, verbal memory scores were initially lower, with subsequent decline in search speed by the age of 69 years. These effects were independent of other Alzheimer's risk factors. DISCUSSION: Delirium symptoms may be common even at relatively younger ages, and their presence may herald cognitive decline, particularly in search speed, over this time period.

Improving recognition and management of acute kidney injury.

Acute kidney injury (AKI) is currently suboptimally recognised and managed in the UK, despite its association with significant patient morbidity, mortality and consequent implications for healthcare economics. Our prospective study, performed in a large urban London hospital, demonstrated that the introduction of a specially designed care bundle can significantly improve documentation of baseline creatinine, assessment and optimisation of fluid status, performance of urine dip, withholding of nephrotoxic drugs, appropriate monitoring of urine output, prescription of renal drug doses, and appropriate consideration of a renal ultrasound and urinary protein-creatinine ratio. Improved compliance of appropriate investigations and initial treatments translated to decreased requirement for intensive care admission and a trend towards shorter length of stays.

Globally optimal cortical surface matching with exact landmark correspondence.

We present a method for establishing correspondences between human cortical surfaces that exactly matches the positions of given point landmarks, while attaining the global minimum of an objective function that quantifies how far the mapping deviates from conformality. On each surface, a conformal transformation is applied to the Euclidean distance metric, resulting in a hyperbolic metric with isolated cone point singularities at the landmarks. Equivalently, each surface is mapped to a hyperbolic orbifold: a pillow-like surface with each point landmark corresponding to a pillow corner. An initial surface-to-surface mapping exactly aligns the landmarks, and gradient descent is used to find the single, global minimum of the Dirichlet energy of the remainder of the mapping. Using a population of real MRI-based cortical surfaces with manually labeled sulcus endpoints as landmarks, we evaluate the approach by how much it distorts surfaces and by its biological plausibility: how well it aligns previously-unseen anatomical landmarks and by how well it promotes expected associations between cortical thickness and age. We show that, compared to a painstakingly-tuned approach that balances a tradeoff between minimizing landmark mismatch and Dirichlet energy, our method has similar biological plausibility, superior surface distortion, a better theoretical foundation, and fewer arbitrary parameters to tune. We also compare to conformal mapper in the spherical domain to show that sacrificing exact conformality of the mapping does not cause noticeable reductions in biological plausibility.

Non-operative management of renal trauma in very young children: experiences from a dedicated South African paediatric trauma unit.

Blunt abdominal trauma results in renal injury in 10% of paediatric cases. Over the last twenty years, the management of paediatric renal trauma has shifted towards a primarily non-operative approach that is now well-established for children up to 18 years old. This retrospective study reviews our experiences of non-operatively managing blunt renal trauma in a very young cohort of patients up to 11 years old. Between June 2006 and June 2010, 118 children presented to the Red Cross War Memorial Children's Hospital in Cape Town with blunt abdominal trauma. 16 patients shown to have sustained renal injury on abdominal computed tomography (CT) scanning were included in this study. Medical records were reviewed for the mechanism of injury, severity of renal injury, clinical presentation, associated injuries, management method and clinical outcomes. All renal injuries were graded (I-V) according to the American Association for the Surgery of Trauma Organ Injury Severity Scale. All renal trauma patients included in this study were aged between 1 and 11 years (mean of 6.5 years). 1 patient sustained grade V injuries; 2 grade IV, 6 grade III and 7 grade I injuries. The majority of injuries (9/16) were caused by motor vehicle crashes, whilst 5 children fell from height, 1 was struck by a falling tree and 1 hit by a moving train. 1 of 16 patients was haemodynamically unstable on presentation as a result of multiple splenic and hepatic lacerations. He was resuscitated and underwent immediate laparotomy. However, his renal injuries were not indications for surgical management. 15 haemodynamically stable patients were non-operatively managed for their renal injuries. Following lengths of admissions ranging from 4 to 132 days, all 16 patients were successfully discharged with no mortalities. No significant complications of renal trauma, such as new-onset hypertension, were detected during their first follow up outpatient appointments. Our findings successfully extend non-operative management of haemodynamically stable renal injuries to a very young cohort up to 11 years old. However, we still advocate immediate resuscitation and surgical intervention for any haemodynamically unstable child who had sustained any abdominal injury. We also argue for a limited role for abdominal CT imaging for diagnosing renal injury and routine follow up, instead recommending a greater emphasis on clinical observations for possible complications.

Multiple sclerosis and pregnancy.

PURPOSE OF REVIEW: Multiple sclerosis (MS) is a chronic inflammatory neurological condition typically affecting women of childbearing age. This review addresses questions that often arise in this patient group during pregnancy including the effects of pregnancy on relapse rates and long-term disease course, up-to-date advice on the use of disease-modifying MS treatments during pregnancy, the management of relapses in pregnancy and postpartum and current advice on breast feeding. RECENT FINDINGS: Pregnancy is associated with a reduction in relapse frequency most marked in the final trimester with a comparable increase in relapse risk in the first 3 months postpartum. Studies examining exposure to MS therapies glatiramer acetate and interferon-beta during pregnancy have produced few negative outcomes offering the possibility of offering treatment until conception. Although initial data suggested breast feeding reduced MS relapses, the latest study demonstrated no significant benefit. SUMMARY: Pregnancy is safe in most MS patients and does not negatively influence MS disease course overall. Use of disease-modifying treatments around conception should be considered on a case-by-case basis, weighing risks of drug exposure against risks of relapses. Whether breast feeding produces beneficial effects on MS relapses remain inconclusive.