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Frailty is known to predict dementia. However, its link with neurodegenerative alterations of the central nervous system (CNS) is not well understood at present. We investigated the association between the biomechanical response of the CNS and frailty in older adults suspected of normal pressure hydrocephalus (NPH) presenting with markers of multiple co-existing pathologies. The biomechanical response of the CNS was characterized by the CNS elastance coefficient inferred from phase contrast magnetic resonance imaging and intracranial pressure monitoring during a lumbar infusion test. Frailty was assessed with an index of health deficit accumulation. We found a significant association between the CNS elastance coefficient and frailty, with an effect size comparable to that between frailty and age, the latter being the strongest known risk factor for frailty. Results were independent of CSF dynamics, showing that they are not specific to the NPH neuropathological condition. The CNS biomechanical characterization may help to understand how frailty is related to neurodegeneration and detect the shift from normal to pathological brain ageing.

\"A riveting thriller reminiscent of The Hot Zone, this true story dives into the mystery surrounding one of the most controversial and misdiagnosed conditions of our time--Lyme disease--and of Willy Burgdorfer, the man who discovered the microbe behind it, revealing his secret role in developing bug-borne biological weapons, and raising terrifying questions about the genesis of the epidemic of tick-borne diseases affecting millions of Americans today. While on vacation on Martha's Vineyard, Kris Newby was bitten by an unseen tick. That one bite changed her life forever, pulling her into the abyss of a devastating illness that took ten doctors to diagnose and years to recover: Newby had become one of the 300,000 Americans who are afflicted with Lyme disease each year. As a science writer, she was driven to understand why this disease is so misunderstood, and its patients so mistreated. This quest led her to Willy Burgdorfer, the Lyme microbe's discoverer, who revealed that he had developed bug-borne bioweapons during the Cold War, and believed that the Lyme epidemic was started by a military experiment gone wrong. In a superb, meticulous work of narrative journalism, Bitten takes readers on a journey to investigate these claims, from biological weapons facilities to interviews with biosecurity experts and microbiologists doing cutting-edge research, all the while uncovering darker truths about Willy. It also leads her to uncomfortable questions about why Lyme can be so difficult to both diagnose and treat, and why the government is so reluctant to classify chronic Lyme as a disease. A gripping, infectious page-turner, Bitten will shed a terrifying new light on an epidemic that is exacting an incalculable toll on us, upending much of what we believe we know about it\"-- Provided by publisher.

Background Therapeutic hypothermia reduces death and disability after moderate or severe neonatal encephalopathy in high-income countries and is used as standard therapy in these settings. However, the safety and efficacy of cooling therapy in low- and middle-income countries (LMICs), where 99% of the disease burden occurs, remains unclear. We will examine whether whole body cooling reduces death or neurodisability at 18–22 months after neonatal encephalopathy, in LMICs. Methods We will randomly allocate 408 term or near-term babies (aged ≤ 6 h) with moderate or severe neonatal encephalopathy admitted to public sector neonatal units in LMIC countries (India, Bangladesh or Sri Lanka), to either usual care alone or whole-body cooling with usual care. Babies allocated to the cooling arm will have core body temperature maintained at 33.5 °C using a servo-controlled cooling device for 72 h, followed by re-warming at 0.5 °C per hour. All babies will have detailed infection screening at the time of recruitment and 3 Telsa cerebral magnetic resonance imaging and spectroscopy at 1–2 weeks after birth. Our primary endpoint is death or moderate or severe disability at the age of 18 months. Discussion Upon completion, HELIX will be the largest cooling trial in neonatal encephalopathy and will provide a definitive answer regarding the safety and efficacy of cooling therapy for neonatal encephalopathy in LMICs. The trial will also provide important data about the influence of co-existent perinatal infection on the efficacy of hypothermic neuroprotection. Trial registration ClinicalTrials.gov, NCT02387385 . Registered on 27 February 2015.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Background After renal transplantation, many patients experience adverse effects from maintenance immunosuppressive drugs. When these adverse effects occur, patient adherence with immunosuppression may be reduced and impact allograft survival. If these adverse effects could be prospectively monitored in an objective manner and possibly prevented, adherence to immunosuppressive regimens could be optimized and allograft survival improved. Prospective, standardized clinical approaches to assess immunosuppressive adverse effects by health care providers are limited. Therefore, we developed and evaluated the application, reliability and validity of a novel adverse effects scoring system in renal transplant recipients receiving calcineurin inhibitor (cyclosporine or tacrolimus) and mycophenolic acid based immunosuppressive therapy. Methods The scoring system included 18 non-renal adverse effects organized into gastrointestinal, central nervous system and aesthetic domains developed by a multidisciplinary physician group. Nephrologists employed this standardized adverse effect evaluation in stable renal transplant patients using physical exam, review of systems, recent laboratory results, and medication adherence assessment during a clinic visit. Stable renal transplant recipients in two clinical studies were evaluated and received immunosuppressive regimens comprised of either cyclosporine or tacrolimus with mycophenolic acid. Face, content, and construct validity were assessed to document these adverse effect evaluations. Inter-rater reliability was determined using the Kappa statistic and intra-class correlation. Results A total of 58 renal transplant recipients were assessed using the adverse effects scoring system confirming face validity. Nephrologists (subject matter experts) rated the 18 adverse effects as: 3.1 ± 0.75 out of 4 (maximum) regarding clinical importance to verify content validity. The adverse effects scoring system distinguished 1.75-fold increased gastrointestinal adverse effects (p = 0.008) in renal transplant recipients receiving tacrolimus and mycophenolic acid compared to the cyclosporine regimen. This finding demonstrated construct validity. Intra-class correlation was 0.81 (95% confidence interval: 0.65-0.90) and Kappa statistic of 0.68 ± 0.25 for all 18 adverse effects and verified substantial inter-rater reliability. Conclusions This immunosuppressive adverse effects scoring system in stable renal transplant recipients was evaluated and substantiated face, content and construct validity with inter-rater reliability. The scoring system may facilitate prospective, standardized clinical monitoring of immunosuppressive adverse drug effects in stable renal transplant recipients and improve medication adherence.

Key Points The brain is a complex, interconnected network; the connection topology of the brain thus fundamentally shapes the onset, expression and progression of brain disease. To understand disorders of the brain requires knowledge of how brain networks respond — either adaptively or maladaptively — to pathological perturbation. The burgeoning field of connectomics is providing new tools for describing and modelling these responses. The effects of brain disease depend critically on the topological centrality and degeneracy of the affected regions; pathology of central regions exacerbates maladaptive responses, whereas degeneracy facilitates adaptive responses Pathological perturbations of the brain can be described and modelled using network science. In this Review, Fornito, Zalesky and Breakspear discuss adaptive and maladaptive neural responses to such insults and consider how connectomics can be used to map, track and predict disease progression. Pathological perturbations of the brain are rarely confined to a single locus; instead, they often spread via axonal pathways to influence other regions. Patterns of such disease propagation are constrained by the extraordinarily complex, yet highly organized, topology of the underlying neural architecture; the so-called connectome. Thus, network organization fundamentally influences brain disease, and a connectomic approach grounded in network science is integral to understanding neuropathology. Here, we consider how brain-network topology shapes neural responses to damage, highlighting key maladaptive processes (such as diaschisis, transneuronal degeneration and dedifferentiation), and the resources (including degeneracy and reserve) and processes (such as compensation) that enable adaptation. We then show how knowledge of network topology allows us not only to describe pathological processes but also to generate predictive models of the spread and functional consequences of brain disease.

Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well as in clinical practice for diagnosis of neurological diseases, e.g., Alzheimer’s disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related inter-individual variability. Here we use a data-driven approach to demonstrate the existence of inter-individual variability in mean standardized CSF protein levels. We show that these non-disease related differences cause many commonly reported CSF biomarkers to be highly correlated, thereby producing misleading results if not accounted for. To adjust for this inter-individual variability, we identified and evaluated high-performing reference proteins which improved the diagnostic accuracy of key CSF AD biomarkers. Our reference protein method attenuates the risk for false positive findings, and improves the sensitivity and specificity of CSF biomarkers, with broad implications for both research and clinical practice. CSF biomarker concentrations may be influenced by non-disease related interindividual variability. Here, the authors show that reference proteins can capture this variability and enhance the accuracy of Alzheimer’s disease biomarkers.