The Impact of Tumor Regression on Prognosis After Neoadjuvant Chemoradiotherapy in Surgically Treated Esophageal Adenocarcinoma.

BACKGROUND: The 5-year survival for patients with esophageal carcinoma remains poor despite neoadjuvant therapy and surgery. The eighth American Joint Committee on Cancer (AJCC) staging, based on the neoadjuvant treated TNM (ypTNM) stage of the resection specimen, is used for prognosis. Tumor characteristics such as tumor grade, subtype of adenocarcinoma, and tumor regression scores are not included in this classification. This study aimed to determine the impact of these tumor characteristics on overall survival (OS) and disease-free survival (DFS). METHODS: This retrospective cohort study included 228 patients with esophageal adenocarcinoma. Tumor regression was determined by the Mandard tumor regression (MTR) score. Subtype and grade of adenocarcinoma were confirmed using either the preoperative biopsy or residual tumor tissue after surgery. The MTR was modified to a three-tier classification. The study classified MTR 1 and 2 in one group as a "major response," with MTR 4 and 5 classified in one group as a "minimal response." RESULTS: The median follow-up period was 2.1 years. Combining MTR with AJCC staging did not improve the prognostic value for the prediction of OS. However, the multivariate analysis showed that the prognostic value of AJCC staging for DFS was improved by adding the three-tiered MTR (odds ratio for MTR4+5: 2.46; 95 % confidence interval, 1.07-5.67). Grade or subtype correlated with neither OS nor DFS in the univariate analyses and did not improve the prognostic value of the AJCC staging. CONCLUSION: Neither adenocarcinoma subtype nor grade influenced OS or DFS. However, the eighth AJCC staging combined with a three-tier MTR provided a better prognostic tool for DFS in esophageal adenocarcinoma treated with esophagectomy after neoadjuvant chemoradiotherapy.

Cross-calibration of a combined electrostatic and time-of-flight analyzer for energy- and charge-state-resolved spectrometry of tin laser-produced plasma.

We present the results of the calibration of a channeltron-based electrostatic analyzer operating in time-of-flight mode (ESA-ToF) using tin ions resulting from laser-produced plasma, over a wide range of charge states and energies. Specifically, the channeltron electron multiplier detection efficiency and the spectrometer resolution are calibrated, and count rate effects are characterized. With the obtained overall response function, the ESA-ToF is shown to accurately reproduce charge-integrated measurements separately and simultaneously obtained from a Faraday cup (FC), up to a constant factor the finding of which enables absolute cross-calibration of the ESA-ToF using the FC as an absolute benchmark. Absolute charge-state-resolved ion energy distributions are obtained from ns-pulse Nd:YAG-laser-produced microdroplet tin plasmas in a setting relevant for state-of-the-art extreme ultraviolet nanolithography.

Recency-Weighted Statistical Modeling Approach to Attribute Illnesses Caused by 4 Pathogens to Food Sources Using Outbreak Data, United States.

Foodborne illness source attribution is foundational to a risk-based food safety system. We describe a method for attributing US foodborne illnesses caused by nontyphoidal Salmonella enterica, Escherichia coli O157, Listeria monocytogenes, and Campylobacter to 17 food categories using statistical modeling of outbreak data. This method adjusts for epidemiologic factors associated with outbreak size, down-weights older outbreaks, and estimates credibility intervals. On the basis of 952 reported outbreaks and 32,802 illnesses during 1998-2012, we attribute 77% of foodborne Salmonella illnesses to 7 food categories (seeded vegetables, eggs, chicken, other produce, pork, beef, and fruits), 82% of E. coli O157 illnesses to beef and vegetable row crops, 81% of L. monocytogenes illnesses to fruits and dairy, and 74% of Campylobacter illnesses to dairy and chicken. However, because Campylobacter outbreaks probably overrepresent dairy as a source of nonoutbreak campylobacteriosis, we caution against using these Campylobacter attribution estimates without further adjustment.

Extreme ultraviolet light from a tin plasma driven by a 2-µm-wavelength laser.

An experimental study of laser-produced plasmas is performed by irradiating a planar tin target by laser pulses, of 4.8 ns duration, produced from a KTP-based 2-µm-wavelength master oscillator power amplifier. Comparative spectroscopic investigations are performed for plasmas driven by 1-µm- and 2-µm-wavelength pulsed lasers, over a wide range of laser intensities spanning 0.5 - 5 × 1011 W/cm 2. Similar extreme ultraviolet (EUV) spectra in the 5.5-25.5 nm wavelength range and underlying plasma ionicities are obtained when the intensity ratio is kept fixed at I1µm/I2µm = 2.4(7). Crucially, the conversion efficiency (CE) of 2-µm-laser energy into radiation within a 2% bandwidth centered at 13.5 nm relevant for industrial applications is found to be a factor of two larger, at a 60 degree observation angle, than in the case of the denser 1-µm-laser-driven plasma. Our findings regarding the scaling of the optimum laser intensity for efficient EUV generation and CE with drive laser wavelength are extended to other laser wavelengths using available literature data.

Epidemiologic patterns of human Salmonella serotype diversity in the USA, 1996-2016.

Although researchers have described numerous risk factors for salmonellosis and for infection with specific common serotypes, the drivers of Salmonella serotype diversity among human populations remain poorly understood. In this retrospective observational study, we partition records of serotyped non-typhoidal Salmonella isolates from human clinical specimens reported to CDC national surveillance by demographic, geographic and seasonal characteristics and adapt sample-based rarefaction methods from the field of community ecology to study how Salmonella serotype diversity varied within and among these populations in the USA during 1996-2016. We observed substantially higher serotype richness in children <2 years old than in older children and adults and steadily increasing richness with age among older adults. Whereas seasonal and regional variation in serotype diversity was highest among infants and young children, variation by specimen source was highest in adults. Our findings suggest that the risk for infection from uncommon serotypes is associated with host and environmental factors, particularly among infants, young children and older adults. These populations may have a higher proportion of illness acquired through environmental transmission pathways than published source attribution models estimate.

Temporal patterns in principal Salmonella serotypes in the USA; 1996-2014.

Analysing temporal patterns in foodborne illness is important to designing and implementing effective food safety measures. The reported incidence of illness due to Salmonella in the USA. Foodborne Diseases Active Surveillance Network (FoodNet) sites has exhibited no declining trend since 1996; however, there have been significant annual trends among principal Salmonella serotypes, which may exhibit complex seasonal patterns. Data from the original FoodNet sites and penalised cubic B-spline regression are used to estimate temporal patterns in the reported incidence of illness for the top three Salmonella serotypes during 1996-2014. Our results include 95% confidence bands around the estimated annual and monthly curves for each serotype. The results show that Salmonella serotype Typhimurium exhibits a statistically significant declining annual trend and seasonality (P < 0.001) marked by peaks in late summer and early winter. Serotype Enteritidis exhibits a significant annual trend with a higher incidence in later years and seasonality (P < 0.001) marked by a peak in late summer. Serotype Newport exhibits no significant annual trend with significant seasonality (P < 0.001) marked by a peak in late summer.

Post-Campylobacter Guillain Barré Syndrome in the USA: secondary analysis of surveillance data collected during the 2009-2010 novel Influenza A (H1N1) vaccination campaign.

Guillain Barré syndrome (GBS), which is triggered by autoantibodies produced in response to antigenic stimuli such as certain infections and vaccinations, is the most common cause of acute flaccid paralysis worldwide. Campylobacter, the most common bacterial enteric infection in the USA, is reported to be the most commonly diagnosed antecedent of GBS, yet little information is available about the risk of post-Campylobacter GBS. Data collected through active, population-based surveillance in the Emerging Infections Program during the 2009-2010 novel Influenza A (H1N1) vaccination campaign allowed us to compare confirmed and probable GBS cases to non-cases to determine whether antecedent Campylobacter infection (or a diarrhoeal illness consistent with campylobacteriosis) was more common among cases and to assess the risk of GBS following Campylobacter infection. We estimate that 8-12% of GBS cases in the USA are attributable to Campylobacter infection (or a diarrhoeal illness consistent with campylobacteriosis), with 434-650 cases of post-diarrhoeal GBS annually and about 49 cases of GBS per 100 000 Campylobacter infections. These results provide updated estimates for post-Campylobacter GBS incidence in the USA and highlight an important benefit of effective measures to prevent Campylobacter infections.

[Bipolar disorder and alcohol use disorder: practical recommendations for treatment, based on a literature review]. / Bipolaire stoornissen en alcoholafhankelijkheid; praktische aanbevelingen voor behandeling op basis van een systematische literatuurstudie.

BACKGROUND: A fairly large proportion (25-50%) of patients with bipolar disorder (bd) also suffer from comorbid alcohol use disorder (aud). However, little is known how this type of morbidity should be treated. It is also unclear whether the current guidelines on bd have been influenced by aud.
AIM: To provide an overview of recent literature concerning the diagnosis and treatment of comorbid bd and aud.
METHOD: We systematically reviewed studies that have addressed three treatment options for this group of patients: pharmaco-therapy, psychological interventions and self-management techniques.
RESULTS: If health professionals decide to treat bd using a pharmaco-therapeutic intervention, they must proceed with caution because the patient may also be suffering from aud. From the very limited number of published articles on this subject, we conclude that the best solution to the problem is to add valproate to the lithium-based treatment. There is also limited evidence that other effective treatments may include the use of integrated psychological interventions, cognitive behavioural therapy and self-management techniques, but these possibilities need further investigation.
CONCLUSION: Treatment of patients suffering from both bd and aud should always focus on both disorders, either simultaneously or separately. If this approach is successful it is vitally important that care is better organised and that there is cooperation between institutions involved in treating addiction disorders and departments that specialise in the care of bd. These improvements are likely to lead to further developments and to more research into new forms of integrated treatment.

Advances in methods for characterization of hepatic urea cycle enzymatic activity in HepaRG cells using UPLC-MS/MS.

Current methodologies for the assessment of urea cycle (UC) enzymatic activity are insufficient to accurately evaluate this pathway in biological specimens where lower UC is expected. Liver cell lines, including HepaRG, have been described to have limited nitrogen fixation through the UC, limiting their applicability as biocomponents for Bioartificial Livers (BAL). This work aims to develop novel and sensitive analytical solutions using Mass Spectrometry-based methodology to measure the activity of four UC enzymes in human liver and HepaRG cells. Activity of carbamoyl-phosphate synthetase I (CPS I), ornithine transcarbamylase (OTC), argininosuccinate lyase (ASL) and arginase (ARG I and II) was determined on homogenates from normal human liver and HepaRG cells cultured in monolayer or in the AMC-BAL. Enzyme products were determined by stable-isotope dilution UPLC-MS/MS. Activity of CPS I, OTC and ARG I/II enzymes in HepaRG monolayer cultures was considerably lower than in human control livers albeit an increase was achieved in HepaRG-BAL cultures. Improved analytical assays developed for the study of UC enzyme activity, contributed to gain understanding of UC function in the HepaRG cell line. The decreased activity of CPS I suggests that it may be a potential rate-limiting factor underlying the low UC activity in this cell line.

A comparative VUV absorption mass-spectroscopy study on protonated peptides of different size.

The ionization of gas-phase protonated peptides and proteins can induce molecular responses ranging from purely non-dissociative ionization to extensive multifragmentation of the system. In the case of soft X-ray photoionization, a monotonic transition between both regimes occurs in the mass range between 0.5 and 10 kDa. Despite the localized nature of the photoabsorption, excitation energy equilibrates before fragmentation sets in and the transition reflects the increase of the heat capacity with protein size. Here, we have investigated the influence of peptide size on vacuum ultraviolet (VUV) photoionization of protonated proteins, where photoexcitation and ionization are limited to valence electrons rather than inner shell electrons and the photoexcitation contribution is markedly lower. Gas phase protonated peptides with masses ranging from 0.6-2.8 kDa were trapped in a radiofrequency ion trap and exposed to synchrotron radiation. Time of flight mass spectrometry was employed for the investigation of the photoionization and photofragmentation processes. The relationship between peptide fragmentation and peptide size exhibits a similar trend as observed for soft X-ray absorption. Due to the lower excitation energies involved, however, dissociation is already quenched at smaller masses and peptide amino acid compositions, protonation states and ionization potentials lead to deviations from the general trend.

High educational performance is a distinctive feature of bipolar disorder: a study on cognition in bipolar disorder, schizophrenia patients, relatives and controls.

BACKGROUND: Schizophrenia is associated with lower intelligence and poor educational performance relative to the general population. This is, to a lesser degree, also found in first-degree relatives of schizophrenia patients. It is unclear whether bipolar disorder I (BD-I) patients and their relatives have similar lower intellectual and educational performance as that observed in schizophrenia. METHOD: This cross-sectional study investigated intelligence and educational performance in two outpatient samples [494 BD-I patients, 952 schizophrenia spectrum (SCZ) patients], 2231 relatives of BD-I and SCZ patients, 1104 healthy controls and 100 control siblings. Mixed-effects and regression models were used to compare groups on intelligence and educational performance. RESULTS: BD-I patients were more likely to have completed the highest level of education (odds ratio 1.88, 95% confidence interval 1.66-2.70) despite having a lower IQ compared to controls (ß = -9.09, S.E. = 1.27, p < 0.001). In contrast, SCZ patients showed both a lower IQ (ß = -15.31, S.E. = 0.86, p < 0.001) and lower educational levels compared to controls. Siblings of both patient groups had significantly lower IQ than control siblings, but did not differ on educational performance. IQ scores did not differ between BD-I parents and SCZ parents, but BD-I parents had completed higher educational levels. CONCLUSIONS: Although BD-I patients had a lower IQ than controls, they were more likely to have completed the highest level of education. This contrasts with SCZ patients, who showed both intellectual and educational deficits compared to healthy controls. Since relatives of BD-I patients did not demonstrate superior educational performance, our data suggest that high educational performance may be a distinctive feature of bipolar disorder patients.

Near edge X-ray absorption mass spectrometry of gas phase proteins: the influence of protein size.

Multiply protonated peptides and proteins in the gas phase can respond to near edge X-ray absorption in three different ways: (i) non dissociative ionization and ionization accompanied by loss of small neutrals, both known to dominate for proteins with masses in the 10 kDa range. (ii) Formation of immonium ions, dominating for peptides in the 1 kDa range. (iii) Backbone scission leading to sequence ions which is typically weaker and has mainly been observed for peptides in the 1 kDa range. We have studied carbon 1s photoexcitation and photoionization for a series of peptides and proteins with masses covering the range from 0.5 kDa to more than 10 kDa. The gas phase protonated molecules were trapped in a radiofrequency ion trap and exposed to synchrotron radiation. Time of flight mass spectrometry was employed for investigation of the photoionization and photofragmentation processes. A smooth transition from the photofragmentation regime to the non-dissociative photoionization regime is observed. Mass spectra are most complex in the few kDa regime, where non-dissociative ionization, backbone scission and immonium ion formation coexist. The observed correlation between protein size and fragmentation, i.e. radiation damage, is of relevance for soft X-ray microscopy.

Spatial sorting and range shifts: consequences for evolutionary potential and genetic signature of a dispersal trait.

Species are shifting their ranges under climate change, with genetic and evolutionary consequences. As a result, the spatial distribution of genetic diversity in a species' range can show a signature of range expansion. This genetic signature takes time to decay after the range stops expanding and it is important to take that lag time into account when interpreting contemporary spatial patterns of genetic diversity. In addition, the return to spatial equilibrium on an ecologically relevant timescale will depend on migration of genetic diversity across the species' range. However, during a range shift alleles may go extinct at the retracting range margin due to spatial sorting. Here we studied the spatial pattern of genotypes that differ in dispersal rate across the species range before, during and after a range shift, assessed the effect of range retraction on this pattern, and quantified the duration of the ephemeral genetic signature of range expansion for this trait. We performed simulation experiments with an individual-based metapopulation model under several contemporary climate change scenarios. The results show an increase of the number of individuals with high dispersal rate. If the temperature increased long enough the allele coding for low dispersal rate would go extinct. The duration of the genetic signature of range expansion after stabilisation of the species' distribution lasted up to 1200 generations after a temperature increase for 60 years at the contemporary rate. This depended on the total displacement of the climate optimum, as the product of the rate of temperature increase and its duration. So genetic data collected in the field do not necessarily reflect current selection pressures but can be affected by historic changes in species distribution, long after the establishment of the current species' range. Return to equilibrium patterns may be hampered by loss of evolutionary potential during range shift.

Use of random forest to estimate population attributable fractions from a case-control study of Salmonella enterica serotype Enteritidis infections.

To design effective food safety programmes we need to estimate how many sporadic foodborne illnesses are caused by specific food sources based on case-control studies. Logistic regression has substantive limitations for analysing structured questionnaire data with numerous exposures and missing values. We adapted random forest to analyse data of a case-control study of Salmonella enterica serotype Enteritidis illness for source attribution. For estimation of summary population attributable fractions (PAFs) of exposures grouped into transmission routes, we devised a counterfactual estimator to predict reductions in illness associated with removing grouped exposures. For the purpose of comparison, we fitted the data using logistic regression models with stepwise forward and backward variable selection. Our results show that the forward and backward variable selection of logistic regression models were not consistent for parameter estimation, with different significant exposures identified. By contrast, the random forest model produced estimated PAFs of grouped exposures consistent in rank order with results obtained from outbreak data, with egg-related exposures having the highest estimated PAF (22·1%, 95% confidence interval 8·5-31·8). Random forest might be structurally more coherent and efficient than logistic regression models for attributing Salmonella illnesses to sources involving many causal pathways.

An assessment of the human health impact of seven leading foodborne pathogens in the United States using disability adjusted life years.

We explored the overall impact of foodborne disease caused by seven leading foodborne pathogens in the United States using the disability adjusted life year (DALY). We defined health states for each pathogen (acute illness and sequelae) and estimated the average annual incidence of each health state using data from public health surveillance and previously published estimates from studies in the United States, Canada and Europe. These pathogens caused about 112 000 DALYs annually due to foodborne illnesses acquired in the United States. Non-typhoidal Salmonella (32 900) and Toxoplasma (32 700) caused the most DALYs, followed by Campylobacter (22 500), norovirus (9900), Listeria monocytogenes (8800), Clostridium perfringens (4000), and Escherichia coli O157 (1200). These estimates can be used to prioritize food safety interventions. Future estimates of the burden of foodborne disease in DALYs would be improved by addressing important data gaps and by the development and validation of US-specific disability weights for foodborne diseases.

Near edge X-ray absorption mass spectrometry on coronene.

We have investigated the photoionization and photodissociation of free coronene cations C24H12 (+) upon soft X-ray photoabsorption in the carbon K-edge region by means of a time-of-flight mass spectrometry approach. Core excitation into an unoccupied molecular orbital (below threshold) and core ionization into the continuum both leave a C 1s vacancy, that is subsequently filled in an Auger-type process. The resulting coronene dications and trications are internally excited and cool down predominantly by means of hydrogen emission. Density functional theory was employed to determine the dissociation energies for subsequent neutral hydrogen loss. A statistical cascade model incorporating these dissociation energies agrees well with the experimentally observed dehydrogenation. For double ionization, i.e., formation of intermediate C24H12 (3+⋆)trications, the experimental data hint at loss of H(+) ions. This asymmetric fission channel is associated with hot intermediates, whereas colder intermediates predominantly decay via neutral H loss.

Deexcitation dynamics of superhydrogenated polycyclic aromatic hydrocarbon cations after soft-x-ray absorption.

We have investigated the response of superhydrogenated gas-phase coronene cations upon soft x-ray absorption. Carbon (1s)⟶π^{⋆} transitions were resonantly excited at hν=285 eV. The resulting core hole is then filled in an Auger decay process, with the excess energy being released in the form of an Auger electron. Predominantly highly excited dications are thus formed, which cool down by hydrogen emission. In superhydrogenated systems, the additional H atoms act as a buffer, quenching loss of native H atoms and molecular fragmentation. Dissociation and transition state energies for several H loss channels were computed by means of density functional theory. Using these energies as input into an Arrhenius-type cascade model, very good agreement with the experimental data is found. The results have important implications for the survival of polyaromatic hydrocarbons in the interstellar medium and reflect key aspects of graphene hydrogenation.

Attributing sporadic and outbreak-associated infections to sources: blending epidemiological data.

Common sources of shiga toxin-producing Escherichia coli (STEC) O157 infection have been identified by investigating outbreaks and by case-control studies of sporadic infections. We conducted an analysis to attribute STEC O157 infections ascertained in 1996 and 1999 by the Foodborne Diseases Active Surveillance Network (FoodNet) to sources. Multivariable models from two case-control studies conducted in FoodNet and outbreak investigations that occurred during the study years were used to calculate the annual number of infections attributable to six sources. Using the results of the outbreak investigations alone, 27% and 15% of infections were attributed to a source in 1996 and 1999, respectively. Combining information from both data sources, 65% of infections in 1996 and 34% of infections in 1999 were attributed. The results suggest that methods to incorporate data from multiple surveillance systems and over several years are needed to improve estimation of the number of illnesses attributable to exposure sources.

Attentional switching forms a genetic link between attention problems and autistic traits in adults.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) symptoms and autistic traits often occur together. The pattern and etiology of co-occurrence are largely unknown, particularly in adults. This study investigated the co-occurrence between both traits in detail, and subsequently examined the etiology of the co-occurrence, using two independent adult population samples. Method Data on ADHD traits (Inattention and Hyperactivity/Impulsivity) were collected in a population sample (S1, n = 559) of unrelated individuals. Data on Attention Problems (AP) were collected in a population-based family sample of twins and siblings (S2, n = 560). In both samples five dimensions of autistic traits were assessed (social skills, routine, attentional switching, imagination, patterns). RESULTS: Hyperactive traits (S1) did not correlate substantially with the autistic trait dimensions. For Inattention (S1) and AP (S2), the correlations with the autistic trait dimensions were low, apart from a prominent correlation with the attentional switching scale (0.47 and 0.32 respectively). Analyses in the genetically informative S2 revealed that this association could be explained by a shared genetic factor. CONCLUSIONS: Our findings suggest that the co-occurrence of ADHD traits and autistic traits in adults is not determined by problems with hyperactivity, social skills, imagination or routine preferences. Instead, the association between those traits is due primarily to shared attention-related problems (inattention and attentional switching capacity). As the etiology of this association is purely genetic, biological pathways involving attentional control could be a promising focus of future studies aimed at unraveling the genetic causes of these disorders.