Changing guards: time to move beyond Body Mass Index for population monitoring of excess adiposity

With the obesity epidemic, and the effects of aging populations, human phenotypes have changed over two generations, possibly more dramatically than in other species previously. As obesity is an important and growing hazard for population health, we recommend a systematic evaluation of the optimal measure(s) for population-level excess body fat. Ideal measure(s) for monitoring body composition and obesity should be simple, as accurate and sensitive as possible, and provide good categorisation of related health risks. Combinations of anthropometric markers or predictive equations may facilitate better use of anthropometric data than single measures to estimate body composition for populations. Here we provide new evidence that increasing proportions of aging populations are at high health-risk according to waist circumference, but not body mass index (BMI), so continued use of BMI as the principal population-level measure substantially underestimates the health-burden from excess adiposity

Estimating the proportion of metabolic health outcomes attributable to obesity: a cross-sectional exploration of body mass index and waist circumference combinations

BACKGROUND: Recent evidence suggests that a substantial subgroup of the population who have a high-risk waist circumference (WC) do not have an obese body mass index (BMI). This study aimed to explore whether including those with a non-obese BMI but high risk WC as \u27obese\u27 improves prediction of adiposity-related metabolic outcomes. METHODS: Eleven thousand, two hundred forty-seven participants were recruited. Height, weight and WC were measured. Ten thousand, six hundred fifty-nine participants with complete data were included. Adiposity categories were defined as: BMI(N)/WC(N), BMI(N)/WC(O), BMI(O)/WC(N), and BMI(O)/WC(O) (N = non-obese and O = obese). Population attributable fraction, area under the receiver operating characteristic curve (AUC), and odds ratios (OR) were calculated. RESULTS: Participants were on average 48 years old and 50 % were men. The proportions of BMI(N)/WC(N), BMI(N)/WC(O), BMI(O)/WC(N) and BMI(O)/WC(O) were 68, 12, 2 and 18 %, respectively. A lower proportion of diabetes was attributable to obesity defined using BMI alone compared to BMI and WC combined (32 % vs 47 %). AUC for diabetes was also lower when obesity was defined using BMI alone (0.62 vs 0.66). Similar results were observed for all outcomes. The odds for hypertension, dyslipidaemia, diabetes and CVD were increased for those with BMI(N)/WC(O) (OR range 1.8-2.7) and BMI(O)/WC(O) (OR 1.9-4.9) compared to those with BMI(N)/WC(N). CONCLUSIONS: Current population monitoring, assessing obesity by BMI only, misses a proportion of the population who are at increased health risk through excess adiposity. Improved identification of those at increased health risk needs to be considered for better prioritisation of policy and resources

Erfolg: Institutionelle und narrative Dimensionen von Erfolgsratgebern (1890-1933)

Zwischen 1890 und 1933 etabliert sich im deutschen Sprachraum ein neues Genre der Ratgeberliteratur, in der Erfolg als etwas vorgestellt wird, das jeder durch Selbstformung erreichen kann. Zum Programm dieser Texte gehören neben Techniken der Rationalisierung oder Willenssteigerung auch unterschiedliche Lehrformate, Adressierungsstrategien und Erzählungen, die von erfolgreichen Unternehmern, ewigen Pessimisten und nervenstarken Aufsteigern handeln. In diesem Buch geben ein theoretischer Aufriss und 14 Einzelanalysen repräsentativer Erfolgsratgeber Einblicke in das Zusammenspiel institutioneller und narrativer Vermittlungsebenen, das bis heute die Selbstoptimierungsliteratur maßgeblich prägt

Translational research into the effects of cigarette smoke on inflammatory mediators and epithelial TRPV1 in Crohn’s disease

Crohn's disease is a pathological condition of the gastro-intestinal tract, causing severe transmural inflammation in the ileum and/or colon. Cigarette smoking is one of the best known environmental risk factors for the development of Crohn's disease. Nevertheless, very little is known about the effect of prolonged cigarette smoke exposure on inflammatory modulators in the gut. We examined the effect of cigarette smoke on cytokine profiles in the healthy and inflamed gut of human subjects and in the trinitrobenzene sulphonic acid mouse model, which mimics distal Crohn-like colitis. In addition, the effect of cigarette smoke on epithelial expression of transient receptor potential channels and their concurrent increase with cigarette smoke-augmented cytokine production was investigated. Active smoking was associated with increasedIL-8transcription in ileum of controls (p < 0,001; n = 18-20/group). In the ileum, TRPV1 mRNA levels were decreased in never smoking Crohn's disease patients compared to healthy subjects (p <0,001; n = 20/group). In the colon, TRPV1 mRNA levels were decreased (p = 0,046) in smoking healthy controls (n = 20/group). Likewise, healthy mice chronically exposed to cigarette smoke (n = 10/group) showed elevated ilealCxcl2(p = 0,0075) and colonicKcmRNA levels (p = 0,0186), whereas TRPV1 mRNA and protein levels were elevated in the ileum (p = 0,0315). Although cigarette smoke exposure prior to trinitrobenzene sulphonic acid administration did not alter disease activity, increased pro-inflammatory cytokine production was observed in the distal colon (Kc: p = 0,0273; Cxcl2: p = 0,104; Il1-beta: p = 0,0796), in parallel with the increase ofTrpv1mRNA (p < 0,001). We infer that CS affects pro-inflammatory cytokine expression in healthy and inflamed gut, and that the simultaneous modulation of TRPV1 may point to a potential involvement of TRPV1 in cigarette smoke-induced production of inflammatory mediators

Practical robustness evaluation in radiotherapy - A photon and proton-proof alternative to PTV-based plan evaluation

Background and purpose: A planning target volume (PTV) in photon treatments aims to ensure that the clinical target volume (CTV) receives adequate dose despite treatment uncertainties. The underlying static dose cloud approximation (the assumption that the dose distribution is invariant to errors) is problematic in intensity modulated proton treatments where range errors should be taken into account as well. The purpose of this work is to introduce a robustness evaluation method that is applicable to photon and proton treatments and is consistent with (historic) PTV-based treatment plan evaluations. Materials and methods: The limitation of the static dose cloud approximation was solved in a multi-scenario simulation by explicitly calculating doses for various treatment scenarios that describe possible errors in the treatment course. Setup errors were the same as the CTV-PTV margin and the underlying theory of 3D probability density distributions was extended to 4D to include range errors, maintaining a 90% confidence level. Scenario dose distributions were reduced to voxel-wise minimum and maximum dose distributions; the first to evaluate CTV coverage and the second for hot spots. Acceptance criteria for CTV D98 and D2 were calibrated against PTV-based criteria from historic photon treatment plans. Results: CTV D98 in worst case scenario dose and voxel-wise minimum dose showed a very strong correlation with scenario average D98 (R-2 > 0.99). The voxel-wise minimum dose visualised CTV dose conformity and coverage in 3D in agreement with PTV-based evaluation in photon therapy. Criteria for CTV D98 and D2 of the voxel-wise minimum and maximum dose showed very strong correlations to PTV D98 and D2 (R-2 > 0.99) and on average needed corrections of -0.9% and +2.3%, respectively. Conclusions: A practical approach to robustness evaluation was provided and clinically implemented for PTV-less photon and proton treatment planning, consistent with PTV evaluations but without its static dose cloud approximation. (C) 2019 The Authors. Published by Elsevier B.V

Visually guided inspiration breath-hold facilitated with nasal high flow therapy in locally advanced lung cancer

Background and purpose Reducing breathing motion in radiotherapy (RT) is an attractive strategy to reduce margins and better spare normal tissues. The objective of this prospective study (NCT03729661) was to investigate the feasibility of irradiation of non-small cell lung cancer (NSCLC) with visually guided moderate deep inspiration breath-hold (IBH) using nasal high-flow therapy (NHFT). Material and methods Locally advanced NSCLC patients undergoing photon RT were given NHFT with heated humidified air (flow: 40 L/min with 80% oxygen) through a nasal cannula. IBH was monitored by optical surface tracking (OST) with visual feedback. At a training session, patients had to hold their breath as long as possible, without and with NHFT. For the daily cone beam CT (CBCT) and RT treatment in IBH, patients were instructed to keep their BH as long as it felt comfortable. OST was used to analyze stability and reproducibility of the BH, and CBCT to analyze daily tumor position. Subjective tolerance was measured with a questionnaire at 3 time points. Results Of 10 included patients, 9 were treated with RT. Seven (78%) completed the treatment with NHFT as planned. At the training session, the mean BH length without NHFT was 39 s (range 15-86 s), and with NHFT 78 s (range 29-223 s) (p = .005). NHFT prolonged the BH duration by a mean factor of 2.1 (range 1.1-3.9s). The mean overall stability and reproducibility were within 1 mm. Subjective tolerance was very good with the majority of patients having no or minor discomfort caused by the devices. The mean inter-fraction tumor position variability was 1.8 mm (-1.1-8.1 mm;SD 2.4 mm). Conclusion NHFT for RT treatment of NSCLC in BH is feasible, well tolerated and significantly increases the breath-hold duration. Visually guided BH with OST is stable and reproducible. We therefore consider this an attractive patient-friendly approach to treat lung cancer patients with RT in BH

Replication studies in the Netherlands:Lessons learned and recommendations for funders, publishers and editors, and universities

Drawing on our experiences conducting replications we describe the lessons we learned about replication studies and formulate recommendations for researchers, policy makers, and funders about the role of replication in science and how it should be supported and funded. We first identify a variety of benefits of doing replication studies. Next, we argue that it is often necessary to improve aspects of the original study, even if that means deviating from the original protocol. Thirdly, we argue that replication studies highlight the importance of and need for more transparency of the research process, but also make clear how difficult that is. Fourthly, we underline that it is worth trying out replication in the humanities. We finish by formulating recommendations regarding reproduction and replication research, aimed specifically at funders, editors and publishers, and universities and other research institutes

Phase I/II trial evaluating carbon ion radiotherapy for the treatment of recurrent rectal cancer: the PANDORA-01 trial

<p>Abstract</p> <p>Background</p> <p>Treatment standard for patients with rectal cancer depends on the initial staging and includes surgical resection, radiotherapy as well as chemotherapy. For stage II and III tumors, radiochemotherapy should be performed in addition to surgery, preferentially as preoperative radiochemotherapy or as short-course hypofractionated radiation. Advances in surgical approaches, especially the establishment of the total mesorectal excision (TME) in combination with sophisticated radiation and chemotherapy have reduced local recurrence rates to only few percent. However, due to the high incidence of rectal cancer, still a high absolute number of patients present with recurrent rectal carcinomas, and effective treatment is therefore needed.</p> <p>Carbon ions offer physical and biological advantages. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increase relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the cell line as well as the endpoint analyzed.</p> <p>Japanese data on the treatment of patients with recurrent rectal cancer previously not treated with radiation therapy have shown local control rates of carbon ion treatment superior to those of surgery. Therefore, this treatment concept should also be evaluated for recurrences after radiotherapy, when dose application using conventional photons is limited. Moreover, these patients are likely to benefit from the enhanced biological efficacy of carbon ions.</p> <p>Methods and design</p> <p>In the current Phase I/II-PANDORA-01-Study the recommended dose of carbon ion radiotherapy for recurrent rectal cancer will be determined in the Phase I part, and feasibilty and progression-free survival will be assessed in the Phase II part of the study.</p> <p>Within the Phase I part, increasing doses from 12 × 3 Gy E to 18 × 3 Gy E will be applied.</p> <p>The primary endpoint in the Phase I part is toxicity, the primary endpoint in the Phase II part is progression-free survival.</p> <p>Discussion</p> <p>With conventional photon irradiation treatment of recurrent rectal cancer is limited, and the clinical effect is only moderate. With carbon ions, an improved outcome can be expected due to the physical and biological characteristics of the carbon ion beam. However, the optimal dose applicable in this clincial situation as re-irradiation still has to be determined. This, as well as efficacy, is to be evaluated in the present Phase I/II trial.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01528683">NCT01528683</a></p

Phosphorylation of GFAP is associated with injury in the neonatal pig hypoxic-ischemic brain

Glial fibrillary acidic protein (GFAP) is an intermediate filament protein expressed in the astrocyte cytoskeleton that plays an important role in the structure and function of the cell. GFAP can be phosphorylated at six serine (Ser) or threonine (Thr) residues but little is known about the role of GFAP phosphorylation in physiological and pathophysiological states. We have generated antibodies against two phosphorylated GFAP (pGFAP) proteins: p8GFAP, where GFAP is phosphorylated at Ser-8 and p13GFAP, where GFAP is phosphorylated at Ser-13. We examined p8GFAP and p13GFAP expression in the control neonatal pig brain and at 24 and 72 h after an hypoxic-ischemic (HI) insult. Immunohistochemistry demonstrated pGFAP expression in astrocytes with an atypical cytoskeletal morphology, even in control brains. Semi-quantitative western blotting revealed that p8GFAP expression was significantly increased at 24 h post-insult in HI animals with seizures in frontal, parietal, temporal and occipital cortices. At 72 h post-insult, p8GFAP and p13GFAP expression were significantly increased in HI animals with seizures in brain regions that are vulnerable to cellular damage (cortex and basal ganglia), but no changes were observed in brain regions that are relatively spared following an HI insult (brain stem and cerebellum). Increased pGFAP expression was associated with poor neurological outcomes such as abnormal encephalography and neurobehaviour, and increased histological brain damage. Phosphorylation of GFAP may play an important role in astrocyte remodelling during development and disease and could potentially contribute to the plasticity of the central nervous system

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harboring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20), delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: defective cell membrane expression (1), impaired LGI1-binding (2), and/or impaired interaction with the postsynaptic density protein PSD-95 (3). We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics