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1.
Dev Psychopathol ; : 1-11, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38757405

ABSTRACT

The reward positivity (RewP) is an event-related potential that indexes reinforcement learning and reward system activation. The RewP has been shown to increase across adolescence; however, most studies have examined the RewP across two assessments, and no studies have examined within-person changes across adolescence into young adulthood. Moreover, the RewP has been identified as a neurobiological risk factor for adolescent-onset depression, but it is unclear whether childhood psychosocial risk factors might predict RewP development across adolescence. In a sample of 317 8- to 14-year-old girls (Mage = 12.4, SD = 1.8), the present study examined self-report measures of depression symptoms and stressful life events at baseline and the ΔRewP during the doors guessing task across three timepoints. Growth modeling indicated that, across all participants, the ΔRewP did not demonstrate linear change across adolescence. However, baseline anhedonia symptoms predicted within-person changes in the ΔRewP, such that individuals with low anhedonia symptoms demonstrated a linear increase in the ΔRewP, but individuals with high anhedonia symptoms had no change in the ΔRewP across adolescence. Similar patterns were observed for stressful life events. The present study suggests that childhood risk factors impact the development of reward-related brain activity, which might subsequently increase risk for psychopathology.

2.
eNeuro ; 11(1)2024 Jan.
Article in English | MEDLINE | ID: mdl-38164578

ABSTRACT

The well-known arcuate fasciculus that connects the posterior superior temporal region with the language production region in the ventrolateral frontal cortex constitutes the classic peri-Sylvian dorsal stream of language. A second temporofrontal white matter tract connects ventrally the anterior to intermediate lateral temporal cortex with frontal areas via the extreme capsule. This temporofrontal extreme capsule fasciculus (TFexcF) constitutes the ventral stream of language processing. The precise origin, course, and termination of this pathway has been examined in invasive tract tracing studies in macaque monkeys, but there have been no standard protocols for its reconstruction in the human brain using diffusion imaging tractography. Here we provide a protocol for the dissection of the TFexcF in vivo in the human brain using diffusion magnetic resonance imaging (MRI) tractography which provides a solid basis for exploring its functional role. A key finding of the current dissection protocol is the demonstration that the TFexcF is left hemisphere lateralized. Furthermore, using the present dissection protocol, we demonstrate that the TFexcF is related to lexical retrieval scores measured with the category fluency test, in contrast to the classical arcuate fasciculus (the dorsal language pathway) that was also dissected and was related to sentence repetition.


Subject(s)
Diffusion Magnetic Resonance Imaging , Frontal Lobe , Humans , Neural Pathways/diagnostic imaging , Frontal Lobe/diagnostic imaging , Diffusion Tensor Imaging , Temporal Lobe/diagnostic imaging
3.
Philos Trans A Math Phys Eng Sci ; 380(2233): 20210315, 2022 Oct 03.
Article in English | MEDLINE | ID: mdl-35965458

ABSTRACT

The English SARS-CoV-2 epidemic has been affected by the emergence of new viral variants such as B.1.177, Alpha and Delta, and changing restrictions. We used statistical models and the agent-based model Covasim, in June 2021, to estimate B.1.177 to be 20% more transmissible than the wild type, Alpha to be 50-80% more transmissible than B.1.177 and Delta to be 65-90% more transmissible than Alpha. Using these estimates in Covasim (calibrated 1 September 2020 to 20 June 2021), in June 2021, we found that due to the high transmissibility of Delta, resurgence in infections driven by the Delta variant would not be prevented, but would be strongly reduced by delaying the relaxation of restrictions by one month and with continued vaccination. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Models, Statistical , SARS-CoV-2/genetics , Systems Analysis
4.
J Math Anal Appl ; 514(2): 126050, 2022 Oct 15.
Article in English | MEDLINE | ID: mdl-35153332

ABSTRACT

Following the resurgence of the COVID-19 epidemic in the UK in late 2020 and the emergence of the alpha (also known as B117) variant of the SARS-CoV-2 virus, a third national lockdown was imposed from January 4, 2021. Following the decline of COVID-19 cases over the remainder of January 2021, the question of when and how to reopen schools became an increasingly pressing one in early 2021. This study models the impact of a partial national lockdown with social distancing measures enacted in communities and workplaces under different strategies of reopening schools from March 8, 2021 and compares it to the impact of continual full national lockdown remaining until April 19, 2021. We used our previously published agent-based model, Covasim, to model the emergence of the alpha variant over September 1, 2020 to January 31, 2021 in presence of Test, Trace and Isolate (TTI) strategies. We extended the model to incorporate the impacts of the roll-out of a two-dose vaccine against COVID-19, with 200,000 daily vaccine doses prioritised by age starting with people 75 years or older, assuming vaccination offers a 95% reduction in disease acquisition risk and a 30% reduction in transmission risk. We used the model, calibrated until January 25, 2021, to simulate the impact of a full national lockdown (FNL) with schools closed until April 19, 2021 versus four different partial national lockdown (PNL) scenarios with different elements of schooling open: 1) staggered PNL with primary schools and exam-entry years (years 11 and 13) returning on March 8, 2021 and the rest of the schools years on March 15, 2020; 2) full-return PNL with both primary and secondary schools returning on March 8, 2021; 3) primary-only PNL with primary schools and exam critical years (years 11 and 13) going back only on March 8, 2021 with the rest of the secondary schools back on April 19, 2021 and 4) part-rota PNL with both primary and secondary schools returning on March 8, 2021 with primary schools remaining open continuously but secondary schools on a two-weekly rota-system with years alternating between a fortnight of face-to-face and remote learning until April 19, 2021. Across all scenarios, we projected the number of new daily cases, cumulative deaths and effective reproduction number R until April 30, 2021. Our calibration across different scenarios is consistent with alpha variant being around 60% more transmissible than the wild type. We find that strict social distancing measures, i.e. national lockdowns, were essential in containing the spread of the virus and controlling hospitalisations and deaths during January and February 2021. We estimated that a national lockdown over January and February 2021 would reduce the number of cases by early March to levels similar to those seen in October 2020, with R also falling and remaining below 1 over this period. We estimated that infections would start to increase when schools reopened, but found that if other parts of society remain closed, this resurgence would not be sufficient to bring R above 1. Reopening primary schools and exam critical years only or having primary schools open continuously with secondary schools on rotas was estimated to lead to lower increases in cases and R than if all schools opened. Without an increase in vaccination above the levels seen in January and February, we estimate that R could have increased above 1 following the reopening of society, simulated here from April 19, 2021. Our findings suggest that stringent measures were integral in mitigating the increase in cases and bringing R below 1 over January and February 2021. We found that it was plausible that a PNL with schools partially open from March 8, 2021 and the rest of the society remaining closed until April 19, 2021 would keep R below 1, with some increase evident in infections compared to continual FNL until April 19, 2021. Reopening society in mid-April, without an increase in vaccination levels, could push R above 1 and induce a surge in infections, but the effect of vaccination may be able to control this in future depending on the transmission blocking properties of the vaccines.

5.
Eur Arch Paediatr Dent ; 23(1): 109-115, 2022 Feb.
Article in English | MEDLINE | ID: mdl-33844182

ABSTRACT

PURPOSE: Molar-Incisor Hypomineralisation (MIH) remains a widespread developmental disorder of the teeth with a still largely unknown etiology. Perinatal events were blamed in previous studies for the development of MIH. The aim of the present study was to evaluate the influence of perinatal hypoxia-determined by the pH value of the umbilical cord blood-and to investigate its correlation with severe MIH retrospectively. In addition, cesarean section was recorded as differentiation variable. METHODS: A total number of 138 children (mean age 8.0 years ± 1.7), who were treated for severe MIH in a dental office in Berlin between the years 2008 and 2019, were included in the study. The control group was comprised of patients with the same date of birth (44 children, mean age 7.7 years ± 1.7). Information on the pH value of the arterial blood from the umbilical cord taken immediately after birth, whose recording is mandatory in Germany, was received from the parents by letter survey requesting the entries from the German Child Health Booklet. RESULTS: In the group of the male children born without cesarean section, the pH value of the control group was significantly lower (7.19 ± 0.09) than the pH value of the MIH group (7.27 ± 0.07, p = 0.0008). In female children born with or without cesarean section as well as in male children born by cesarean section there were no significant differences between the MIH and control group. CONCLUSIONS: No significant association between MIH and the pH value of the umbilical cord blood or birth by cesarean section could be found in the examined patient population.


Subject(s)
Dental Enamel Hypoplasia , Incisor , Cesarean Section/adverse effects , Child , Dental Enamel Hypoplasia/epidemiology , Dental Enamel Hypoplasia/etiology , Female , Fetal Blood , Humans , Hydrogen-Ion Concentration , Hypoxia/complications , Male , Molar , Pregnancy , Prevalence , Retrospective Studies
6.
Dalton Trans ; 50(46): 17008-17022, 2021 Nov 30.
Article in English | MEDLINE | ID: mdl-34738604

ABSTRACT

The synthesis and characterisation of novel chelate nitrogen ligands with phasmidic tails (pyridine-triazole ligand 1b; 2,2'-bipyrimidine ligands 2b and 3b) as well as their titanium(IV) coordination complexes are reported. The analogous ligands 1a, 2a and 3a with methoxy substituents instead of the tails were also synthesized, together with titanium complexes that could be crystallographically characterised. A good agreement is noticed between analytical data of the complexes in solution (NMR) and in the solid state (X-ray diffraction). The complexes are overall robust on phases like alumina or silica, so that they could be characterised by TLC and sometimes chromatographied. Supramolecular architectures were generated from an equimolar solution of titanium(IV) isopropoxide, ligand 1a and a polyphenol ligand 5-H4, leading to a double-stranded helicate characterised by MS, NMR and crystallography, which was then converted into a trinuclear complex as shown by MS and NMR DOSY data. The liquid-crystalline behaviour of the ligands 1b, 2b and 3b incorporating the long alkyl tails and that of the complexes derived from these ligands have been investigated.

7.
Sci Rep ; 11(1): 8747, 2021 04 22.
Article in English | MEDLINE | ID: mdl-33888818

ABSTRACT

As the UK reopened after the first wave of the COVID-19 epidemic, crucial questions emerged around the role for ongoing interventions, including test-trace-isolate (TTI) strategies and mandatory masks. Here we assess the importance of masks in secondary schools by evaluating their impact over September 1-October 23, 2020. We show that, assuming TTI levels from August 2020 and no fundamental changes in the virus's transmissibility, adoption of masks in secondary schools would have reduced the predicted size of a second wave, but preventing it would have required 68% or 46% of those with symptoms to seek testing (assuming masks' effective coverage 15% or 30% respectively). With masks in community settings but not secondary schools, the required testing rates increase to 76% and 57%.


Subject(s)
COVID-19/prevention & control , COVID-19/transmission , COVID-19 Testing/statistics & numerical data , Humans , Masks , Models, Theoretical , Schools , United Kingdom/epidemiology
8.
Rev. cir. (Impr.) ; 73(2): 212-216, abr. 2021. ilus, tab
Article in Spanish | LILACS | ID: biblio-1388798

ABSTRACT

Resumen Introducción Los tumores del estroma gastrointestinal (GIST) corresponden al 1% de todas las neoplasias gastrointestinales, sin embargo, sólo el 3-5% de estos se desarrollan en el duodeno. Objetivo Reportar el caso de un paciente masculino con localización atípica de un tumor de estroma gastrointestinal y su manejo. Caso clínico paciente masculino de 50 años con antecedente de traumatismo encefalo craneano (TEC) con daño orgánico cerebral secundario, tabaquismo, consumidor de alcohol ocasional y sometido a quistectomía branquial en la infancia, que consulta en el servicio de urgencias por cuadro de hemorragia digestiva alta con compromiso hemodinámico. Tras realizar endoscopia digestiva alta (EDA), resonancia nuclear magnética (RNM) y tomografía computada (TC) de abdomen, se pesquisa masa tumoral en segunda porción de duodenal. Discusión A pesar de que la presentación clínica de los GIST es variable, lo más frecuente es que sean pacientes asintomáticos. En algunas ocasiones, al igual que en este reporte, pueden presentarse con dolor abdominal y/o hemorragia digestiva alta. El diagnóstico preoperatorio fue difícil ya que el estudio con imágenes (TC, RNM, EDA) sólo permite establecer la sospecha; el diagnóstico definitivo se realizó con biopsia (no contamos con endosonografía en nuestro centro). Debido a los sitios de reparo anatómico, no existe una cirugía estandarizada; en este caso, debido a la localización, infiltración y características, se decidió realizar una pancreatoduodenectomía.


Introduction Gastrointestinal stromal tumors (GIST), corresponds to 1%, of all gastrointestinal neoplasms, however, only 3%-5% developed in duodenum. Aim To report a case of a male patient with atypical location of gastrointestinal stroma tumor and the treatment proposed. Case report 50-year-old male patient, with medical history of organic brain damage secondary a traumatic brain injury, smoker, occasional alcohol consumer and branquial cystomy during childhood. Consulted in the emergency department for a high digestive hemorrhage case with hemodynamic compromise. Upper digestive endoscopy, computed tomography and nuclear magnetic resonance were performed, which impresses tumor-like lesion in the second duodenal portion. Discussion Although the GIST clinical presentation is variable, most often they are asymptomatic patients. In some times, as in this report, they may present with abdominal pain and/or upper gastrointestinal bleeding. The preoperative diagnosis was difficult, because the imaging study (CT, RNM, EDA) only stablished the suspicion and the final diagnosis was made by biopsy (we don't have endosonography in our center). Due to the anatomic repair, there is not a standardized surgery, in this case, due tumor location, infiltration and characteristics, it was decided to perform a pancreatoduodenectomy.


Subject(s)
Humans , Male , Middle Aged , Gastrointestinal Stromal Tumors/diagnosis , Gastrointestinal Neoplasms/pathology , Gastrointestinal Hemorrhage/etiology , Tomography, X-Ray Computed , Gastrointestinal Stromal Tumors/complications , Gastrointestinal Stromal Tumors/pathology , Gastrointestinal Hemorrhage/complications
9.
Rev. cir. (Impr.) ; 73(1): 73-79, feb. 2021. tab, ilus
Article in Spanish | LILACS | ID: biblio-1388791

ABSTRACT

Resumen Objetivo: Describir resultados en términos de morbilidad y mortalidad del tratamiento de quistes hidatídicos hepáticos (QHH) por vía laparoscópica en una serie de pacientes consecutivos. Comparar calidad de vida (CV) de pacientes sometidos a quistectomía laparoscópica (QL) con pacientes llevados a colecistectomía laparoscópica. Materiales y Método: Serie de casos con seguimiento de pacientes con QHH, sometidos a QL. Analizamos datos con Stata® 10.0, mediante medidas de tendencia central y dispersión. Describimos 4 variables, realizando seguimiento con tomografía computada (TC) abdominal. Aplicamos encuesta de calidad de vida SF-36. Resultados: Incluimos 12 pacientes, 58,3% de género femenino. Número de quistes 2,02 ± 1,56, volumen quístico mayor 809,16 ± 766,05 ml, diámetro de quiste mayor 11,77 ± 4,33 cm, predominando en lóbulo hepático derecho (58%). Tiempo operatorio promedio 234,1 ± 52,9 minutos. Estadía hospitalaria promedio 11,5 ± 14,5 días. Morbilidad en 16,6%, sin mortalidad posoperatoria. Seguimiento con imágenes promedio fue 7,9 ± 4,3 meses, encontrando cavidades residuales pequeñas y asintomáticas en 50% de pacientes. No reportamos recidivas. Al comparar CV con grupo de colecistectomía sólo encontramos diferencia respecto a vitalidad (p = 0,04). Discusión: Aunque nuestra serie es pequeña y presenta mayor tiempo quirúrgico (por selección de pacientes) y mayor estancia hospitalaria que en otras series de QL, presenta menor porcentaje de recidivas, de fístulas biliares y no presenta mortalidad, concordando con otras series de QL que la recomiendan como opción terapéutica. Conclusiones: La QL para el tratamiento de los QHH resulta una cirugía aceptable, con morbilidad y mortalidad comparable con reportes de cirugía abierta.


Aim: To describe results in morbidity and mortality terms of the hepatic hydatidosis (HHC) treatment by laparoscopic route in selected patients. In addition, compare the quality of life (QL) of cystomectized vs cholecystectomized patients, both laparoscopically. Materials and Method: Case series with follow-up of patients with HHC, undergoing laparoscopic cystectomy (LC). Data analysis, through measures of central tendency and dispersion, performed with Stata® 10.0. Analyzing 4 variables followed-up with abdominal computed tomography. A quality of life survey SF-36" was applied. Results: 12 patients were included, 58.3% female gender. Cysts number 2.02 ± 1.56, largest cystic volume 809.16 ± 766.05 ml, larger cyst diameter 11,77 ± 4,33 cm. Right hepatic lobe is predominantly 58%. Surgical time, 234.16 ± 52.95 minutes. Hospital stay, 11.58 ± 14.55 days. Morbidity 16.6%, with no postoperative mortality. Follow-up, performed at 7.9 ± 4.3 months, finding residual cavity in 50%, no recurrences were reported. At comparing QL with cholecystectomy group, we only found differences at the vitality item (p = 0,04). Discussion: Although our series is small and has a longer surgical time (by patient selection) and a longer hospital stay than in other LC series, it has a lower recurrences percentage, biliary fistulas, and no mortality, agreeing with other LC series that recommend it as a therapeutic option. Conclusions: The laparoscopic approach for the HHC treatment, is an acceptable surgery, with morbidity and mortality comparable to the reports of laparotomy surgery.


Subject(s)
Humans , Cystectomy/adverse effects , Laparoscopy/adverse effects , Echinococcosis, Hepatic/surgery , Postoperative Period , Quality of Life , Cysts/surgery , Echinococcosis, Hepatic/diagnosis , Echinococcosis, Hepatic/mortality
11.
Space Sci Rev ; 215(1): 12, 2019.
Article in English | MEDLINE | ID: mdl-30880848

ABSTRACT

By the end of 2018, 42 years after the landing of the two Viking seismometers on Mars, InSight will deploy onto Mars' surface the SEIS (Seismic Experiment for Internal Structure) instrument; a six-axes seismometer equipped with both a long-period three-axes Very Broad Band (VBB) instrument and a three-axes short-period (SP) instrument. These six sensors will cover a broad range of the seismic bandwidth, from 0.01 Hz to 50 Hz, with possible extension to longer periods. Data will be transmitted in the form of three continuous VBB components at 2 sample per second (sps), an estimation of the short period energy content from the SP at 1 sps and a continuous compound VBB/SP vertical axis at 10 sps. The continuous streams will be augmented by requested event data with sample rates from 20 to 100 sps. SEIS will improve upon the existing resolution of Viking's Mars seismic monitoring by a factor of ∼ 2500 at 1 Hz and ∼ 200 000 at 0.1 Hz. An additional major improvement is that, contrary to Viking, the seismometers will be deployed via a robotic arm directly onto Mars' surface and will be protected against temperature and wind by highly efficient thermal and wind shielding. Based on existing knowledge of Mars, it is reasonable to infer a moment magnitude detection threshold of M w ∼ 3 at 40 ∘ epicentral distance and a potential to detect several tens of quakes and about five impacts per year. In this paper, we first describe the science goals of the experiment and the rationale used to define its requirements. We then provide a detailed description of the hardware, from the sensors to the deployment system and associated performance, including transfer functions of the seismic sensors and temperature sensors. We conclude by describing the experiment ground segment, including data processing services, outreach and education networks and provide a description of the format to be used for future data distribution. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11214-018-0574-6) contains supplementary material, which is available to authorized users.

12.
Eur J Cancer ; 109: 137-153, 2019 03.
Article in English | MEDLINE | ID: mdl-30721788

ABSTRACT

INTRODUCTION: Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. METHODS & RESULTS: Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor-pretreated compared with MAPK-inhibitor-naïve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1Bhigh cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death. CONCLUSION: The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.


Subject(s)
Brain Neoplasms/therapy , Drug Resistance, Neoplasm , Melanoma/therapy , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Radiation Tolerance , Radiotherapy , Adult , Aged , Aged, 80 and over , Apoptosis , Brain Neoplasms/genetics , Brain Neoplasms/secondary , Cell Cycle , Cell Movement , Cell Proliferation , Chemoradiotherapy , Female , Follow-Up Studies , Humans , MAP Kinase Signaling System/drug effects , Male , Melanoma/genetics , Melanoma/pathology , Middle Aged , Mutation , Prognosis , Proto-Oncogene Proteins B-raf/genetics , Retrospective Studies , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
13.
HIV Med ; 20(1): 19-26, 2019 01.
Article in English | MEDLINE | ID: mdl-30178911

ABSTRACT

OBJECTIVES: We evaluated the association of HIV infection and immunodeficiency with acute coronary syndrome (ACS) recurrence, and with all-cause mortality as a secondary outcome, after hospitalization for ACS among HIV-infected and HIV-uninfected individuals. METHODS: We conducted a retrospective cohort study within Kaiser Permanente Northern California of HIV-infected and HIV-uninfected adults discharged after ACS hospitalization [types: ST-elevation myocardial infarction (STEMI), non-STEMI, or unstable angina] during 1996-2010. We compared the outcomes of ACS recurrence and all-cause mortality within 3 years, both overall by HIV status and stratified by recent CD4 count, with HIV-uninfected individuals as the reference group. Hazard ratios (HRs) were obtained from Cox regression models with adjustment for age, sex, race/ethnicity, year, ACS type, smoking, and cardiovascular risk factors. RESULTS: Among 226 HIV-infected and 86 321 HIV-uninfected individuals with ACS, HIV-infected individuals had a similar risk of ACS recurrence compared with HIV-uninfected individuals [HR 1.08; 95% confidence interval (CI) 0.76-1.54]. HIV infection was independently associated with all-cause mortality after ACS hospitalization overall (HR 2.52; 95% CI 1.81-3.52). In CD4-stratified models, post-ACS mortality was higher for HIV-infected individuals with CD4 counts of 201-499 cells/µL (HR 2.64; 95% CI 1.66-4.20) and < 200 cells/µL (HR 5.41; 95% CI 3.14-9.34), but not those with CD4 counts ≥ 500 cells/µL (HR 0.67; 95% CI 0.22-2.08), compared with HIV-uninfected individuals (P trend < 0.001). CONCLUSIONS: HIV infection and immunodeficiency were not associated with recurrence of ACS after hospitalization. All-cause mortality was higher among HIV-infected compared with HIV-uninfected individuals, but there was no excess mortality risk among HIV-infected individuals with high CD4 counts.


Subject(s)
Acute Coronary Syndrome/epidemiology , HIV Infections/complications , Hospitalization/statistics & numerical data , Acute Coronary Syndrome/immunology , Acute Coronary Syndrome/mortality , CD4 Lymphocyte Count , Case-Control Studies , Cause of Death , Female , HIV Infections/immunology , HIV Infections/mortality , Humans , Logistic Models , Male , Recurrence , Retrospective Studies
14.
Intensive Care Med ; 44(12): 2205-2212, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30470853

ABSTRACT

PURPOSE: The EUPHRATES trial examined the impact of polymyxin B hemoperfusion (PMX) on mortality in patients with septic shock and endotoxemia, defined as EAA ≥ 0.60. No difference was found in 28-day all-cause mortality. However, the trial showed that in some patients with septic shock the burden of endotoxin activity was extreme (EAA ≥ 0.9). In a post hoc analysis, we evaluated the impact of PMX use in patients with septic shock and endotoxin activity measured between 0.6-0.89. METHODS: Post-hoc analysis of the EUPHRATES trial for the 194 patients with EAA ≥ 0.6-0.89 who completed two treatments (PMX or sham). The primary end point was mortality at 28 days adjusted for APACHE II score and baseline mean arterial pressure (MAP). Additional end points included changes in MAP, cumulative vasopressor index (CVI), median EAA reduction, ventilator-free days (VFD), dialysis-free days (DFD) and hospital length of stay. Subpopulations analyzed were site and type of infection and those with norepinephrine dose > 0.1 mcg/kg/min at baseline. RESULTS: At 28 days, 23 patients of 88 (26.1%) in the PMX group died versus 39 of 106 (36.8%) in the sham group [risk difference 10.7%, OR 0.52, 95% CI (0.27, 0.99), P = 0.047]. When unadjusted for baseline variables, P = 0.11. The 28-day survival time in the PMX group was longer than for the sham group [HR 0.56 (95% CI 0.33, 0.95) P = 0.03]. PMX treatment compared with sham showed greater change in MAP [median (IQR) 8 mmHg (- 0.5, 19.5) vs. 4 mmHg (- 4.0, 11) P = 0.04] and VFD [median (IQR) 20 days (0.5, 23.5) vs. 6 days (0, 20), P = 0.004]. There were no significant differences in other end points. There was a significant difference in mortality in PMX-treated patients with no bacterial growth on culture [PMX, 6/30 (20%) vs. sham, 13/31 (41.9%), P = 0.005]. The median EAA change in the population was - 12.9% (range: increase 49.2%-reduction 86.3%). The mortality in the above median EAA change group was PMX: 6/38 (15.7%) vs. sham 15/49 (30.6%), P = 0.08. CONCLUSIONS: These hypothesis-generating results, based on an exploratory post hoc analysis of the EUPHRATES trial, suggest measurable responses in patients with septic shock and an EAA ≥ 0.6 to 0.89 on changes in mean arterial pressure, ventilator-free days and mortality. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01046669. Funding Spectral Medical Incorporated.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Critical Care , Endotoxemia/drug therapy , Hemoperfusion , Polymyxin B/administration & dosage , Shock, Septic/drug therapy , Adult , Aged , Arterial Pressure , Endotoxemia/complications , Endotoxemia/mortality , Female , Humans , Length of Stay , Male , Middle Aged , Shock, Septic/etiology , Shock, Septic/mortality , Survival Rate
16.
Nat Commun ; 9(1): 3025, 2018 08 02.
Article in English | MEDLINE | ID: mdl-30072689

ABSTRACT

In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach in CMT1A and possibly other dysmyelinating neuropathies.


Subject(s)
Charcot-Marie-Tooth Disease/therapy , Lipid Metabolism , Myelin Sheath/metabolism , Animals , Axons/metabolism , Axons/ultrastructure , Dietary Fats/pharmacology , Lipid Metabolism/drug effects , Lipids/biosynthesis , Myelin Sheath/ultrastructure , Phospholipids/metabolism , Rats, Transgenic , Schwann Cells/drug effects , Schwann Cells/metabolism , Schwann Cells/pathology
17.
Article in English | MEDLINE | ID: mdl-29732240

ABSTRACT

OBJECTIVE: Community-based, family-centered obesity prevention/treatment initiatives have been shown to be effective in reducing body mass index (BMI) and improving healthy habits in children if implemented with high intensity and sufficient duration. Let's Go! 5-2-1-0 Program (5-2-1-0) was incorporated into family-centered, monthly physical activity classes and cooking classes over six months delivered by Young Men's Christian Association (YMCA) staff. We hypothesized that implementation of this intervention would improve 5-2-1-0 knowledge attainment, increase healthy behavior (based on 5- 2-1-0 curriculum), and improve BMI and waist circumference measurements in children. METHODS: Children attending YMCA summer camps in Rochester, MN, during 2016 were recruited via study packets mailed to their families. Height, weight, and waist circumference measurements as well as the results of the Modified Healthy Habits Survey and the 5-2-1-0 Knowledge Acquisition Survey were recorded for each participating child at baseline and 6-month follow-up. The intervention group received monthly healthy habit reminder emails, and was invited to monthly evening cooking and physical activity classes for 7 sessions over a 6-month period. RESULTS: Fifteen families in the intervention group attended classes. Of those, 13 families regularly participated in (attended at least 5 out of 7) both the monthly physical activity and cooking classes. The children in the intervention group had a significant improvement in the number of Knowledge Acquisition Survey questions answered correctly (p<0.001), while there was no improvement in the control group. As compared to children in the control group, there was no significant change in BMI or waist circumference or healthy habits in the intervention group. CONCLUSION: Our study findings indicate that our intervention resulted in improved knowledge about healthy habits, but did not significantly impact healthy habits or BMI. Potential reasons for this were the small sample size and the attenuated length and/or intensity of the intervention.

18.
Toxicol Lett ; 294: 105-115, 2018 Sep 15.
Article in English | MEDLINE | ID: mdl-29758360

ABSTRACT

Di-(2-propylheptyl) phthalate (DPHP) is used as a plasticizer for polyvinyl chloride products. A tolerable daily intake of DPHP of 0.2 mg/kg body weight has been derived from rat data. Because toxicokinetic data of DPHP in humans were not available, it was the aim of the present work to monitor DPHP and selected metabolites in blood and urine of 6 male volunteers over time following ingestion of a single DPHP dose (0.7 mg/kg body weight). Concentration-time courses in blood were obtained up to 24 h for DPHP, mono-(2-propylheptyl) phthalate (MPHP), mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPHP), and mono-(2-propyl-6-oxoheptyl) phthalate (oxo-MPHP); amounts excreted in urine were determined up to 46 h for MPHP, OH-MPHP, oxo-MPHP, and mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). All curves were characterized by an invasion and an elimination phase the kinetic parameters of which were determined together with the areas under the concentration-time curves in blood (AUCs). AUCs were: DPHP > MPHP > oxo-MPHP > OH-MPHP. The amounts excreted in urine were: oxo-MPHP > OH-MPHP> > cx-MPHP > MPHP. The AUCs of MPHP, oxo-MPHP, or OH-MPHP could be estimated well from the cumulative amounts of urinary OH-MPHP or oxo-MPHP excreted within 22 h after DPHP intake. Not considering possible differences in species-sensitivity towards unconjugated DPHP metabolites, it was concluded from a comparison of their AUCs in DPHP-exposed humans with corresponding earlier data in rats that there is no increased risk of adverse effects associated with the internal exposure of unconjugated DPHP metabolites in humans as compared to rats when receiving the same dose of DPHP per kg body weight.


Subject(s)
Endocrine Disruptors/toxicity , Phthalic Acids/toxicity , Plasticizers/toxicity , Acylation , Administration, Oral , Adult , Animals , Area Under Curve , Biotransformation , Deuterium , Endocrine Disruptors/blood , Endocrine Disruptors/metabolism , Endocrine Disruptors/urine , Glucuronides/blood , Glucuronides/chemistry , Glucuronides/metabolism , Glucuronides/urine , Heptanes/blood , Heptanes/chemistry , Heptanes/metabolism , Heptanes/urine , Humans , Hydrolysis , Limit of Detection , Male , Middle Aged , Molecular Structure , Oxidation-Reduction , Phthalic Acids/blood , Phthalic Acids/metabolism , Phthalic Acids/urine , Plasticizers/administration & dosage , Plasticizers/chemistry , Plasticizers/metabolism , Renal Elimination , Species Specificity , Toxicokinetics
19.
Science ; 360(6394): 1218-1222, 2018 06 15.
Article in English | MEDLINE | ID: mdl-29724904

ABSTRACT

Magnetic insulators are a key resource for next-generation spintronic and topological devices. The family of layered metal halides promises varied magnetic states, including ultrathin insulating multiferroics, spin liquids, and ferromagnets, but device-oriented characterization methods are needed to unlock their potential. Here, we report tunneling through the layered magnetic insulator CrI3 as a function of temperature and applied magnetic field. We electrically detect the magnetic ground state and interlayer coupling and observe a field-induced metamagnetic transition. The metamagnetic transition results in magnetoresistances of 95, 300, and 550% for bilayer, trilayer, and tetralayer CrI3 barriers, respectively. We further measure inelastic tunneling spectra for our junctions, unveiling a rich spectrum consistent with collective magnetic excitations (magnons) in CrI3.

20.
J Anxiety Disord ; 51: 22-31, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28886420

ABSTRACT

The Screen for Child Anxiety and Related Emotional Disorder (SCARED) may be differentially sensitive to detecting specific or comorbid anxiety diagnoses in treatment-seeking and non-treatment-seeking youth. We assessed the SCARED's discriminant validity, diagnostic utility, and informant agreement using parent- and self-report from healthy and treatment-seeking anxious youth (Study 1, N=585) and from non-treatment-seeking anxious youth (Study 2, N=331) diagnosed with generalized anxiety disorder (GAD), social anxiety disorder (SAD), or comorbid GAD+SAD. Among treatment-seeking youth, the SCARED showed good diagnostic utility and specificity, differentiating healthy, comorbid, and non-comorbid anxious youth. Child-parent agreement was modest: healthy child self-reports were higher than parent-reports whereas anxious child self-reports were similar or lower than parent-reports. Less consistent results emerged for diagnostic utility, specificity, and informant agreement among non-treatment-seeking youth. Given the number of non-treatment seeking anxious youth (N=33), generalizability of these findings may be limited. Together, results suggest informants may provide distinct information about children's anxiety symptoms.


Subject(s)
Anxiety/complications , Mood Disorders/diagnosis , Mood Disorders/etiology , Parents , Surveys and Questionnaires/standards , Adolescent , Child , Discriminant Analysis , Fear , Female , Humans , Male , Psychometrics , Reproducibility of Results , Self Report , Sensitivity and Specificity
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