The purpose of this pretest-posttest study was to evaluate effects of a training program designed to improve primary care physicians’ (PCPs) ability to recognize mental health problems (MHP) and to ...diagnose and manage depression according to clinical guidelines. The primary care settings were in the northern part of The Netherlands. There were eight intensive, hands-on training sessions of 2.5 hours, each of which three were targeting depression (7.5 hours). In the pretraining phase we screened 1778 consecutive patients of 17 PCPs with the 12-item General Health Questionnaire (GHQ-12) and interviewed a stratified sample of 518 patients about presence of current depression with the Primary Health Care version of the Composite International Diagnostic Interview (CIDI-PHC). PCPs registered patient’s mental health (status, severity, diagnosis) and treatment prescribed. Then we trained the PCPs. In the posttraining phase, we screened a new group of 1724 consecutive patients of the same PCPs and a new stratified sample of 498 patients went through the same interview and rating procedures as patients in the pretraining phase. Knowledge about depression was assessed pre- and posttraining. PCPs’ knowledge of depression improved significantly. Recognition of MHP and accuracy of depression diagnosis improved, but was not statistically significant. The proportion of patients receiving treatment according to the clinical guidelines increased significantly. It was observed that training PCPs improves the management of depression.
The tumor-associated self-antigen p53 is commonly overexpressed in cancer, including colorectal cancer, and can serve as a target for immunotherapy. The safety and immunogenicity of a p53 synthetic ...long peptide (p53-SLP) vaccine were investigated in patients treated for metastatic colorectal cancer.
Ten patients were vaccinated twice with a set of 10 overlapping p53-SLP in a phase I/II trial. Both the safety and the breadth, magnitude, and polarization of vaccine-induced p53-specific T cells was evaluated in blood samples drawn before and after vaccination by IFN-gamma enzyme-linked immunospot, proliferation, cytokine secretion, and multiparameter flow cytometry. The migratory capacity of p53-specific T cells was evaluated by assessing their presence in a biopsy of the second vaccination site.
Toxicity was limited to grade 1/2, mostly at the vaccination site. p53-specific T-cell responses were induced in 9 of 10 colorectal cancer patients as measured by IFN-gamma enzyme-linked immunospot, proliferation, and cytokine bead array. In 6 of 9 tested patients, p53-specific T-cell reactivity persisted at least 6 months. Furthermore, p53-specific T cells isolated from the vaccination site were characterized as CD4+ T cells producing both T-helper types 1 and 2 cytokines on stimulation with p53 peptide and p53 protein. Multiparameter flow cytometry revealed that only a minor population of the p53-specific CD4+ T cells was optimally polarized.
The p53-SLP vaccine is safe and capable to induce p53-specific T-cell responses in patients treated for colorectal cancer. New trials should focus on improving the polarization of the p53-SLP vaccine-induced T-cell response.
To investigate the natural course of scoliosis and to estimate lifetime probability of scoliosis surgery in spinal muscular atrophy (SMA).
We analyzed cross-sectional data from 283 patients from our ...population-based cohort study. Additional longitudinal data on scoliosis progression and spinal surgery were collected from 36 consecutive patients who received scoliosis surgery at our center.
The lifetime probability of receiving scoliosis surgery was ≈80% in SMA types 1c and 2. Patients with type 2 who only learned to sit (type 2a) were significantly younger at time of surgery than those who learned to sit and stand (type 2b). The lifetime risk of surgery was lower in type 3a (40%) and strongly associated with age at loss of ambulation: 71% in patients losing ambulation before 10 years of age vs 22% losing ambulation after the age of 10 years (
= 0.005). In type 3a, preserving the ability to walk 1 year longer corresponded to a 15% decrease in lifetime risk of scoliosis surgery (hazard ratio 0.852,
= 0.017). Scoliosis development was characterized by initial slow progression, followed by acceleration in the 1.5- to 2-year period before surgery.
The lifetime probability of scoliosis surgery is high in SMA types 1c and 2 and depends on age at loss of ambulation in type 3. Motor milestones such as standing that are not part of the standard classification system are of additional predictive value. Our data may act as a reference to assess long-term effects of new SMA-specific therapies.
Patients with stage II–III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents. Although increasing the number of chemotherapy ...cycles improves pathological complete response rates, early complete responses are common. We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response.
TRAIN-3 is a single-arm, phase 2 study in 43 hospitals in the Netherlands. Patients with stage II–III HER2-positive breast cancer aged 18 years or older and a WHO performance status of 0 or 1 were enrolled. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2 of body surface area on day 1 and 8 of each 21 day cycle), trastuzumab (loading dose on day 1 of cycle 1 of 8 mg/kg bodyweight, and then 6 mg/kg on day 1 on all subsequent cycles), and carboplatin (area under the concentration time curve 6 mg/mL per min on day 1 of each 3 week cycle) and pertuzumab (loading dose on day 1 of cycle 1 of 840 mg, and then 420 mg on day 1 of each subsequent cycle), all given intravenously. The response was monitored by breast MRI every three cycles and lymph node biopsy. Patients underwent surgery when a complete radiological response was observed or after a maximum of nine cycles of treatment. The primary endpoint was event-free survival at 3 years; however, follow-up for the primary endpoint is ongoing. Here, we present the radiological and pathological response rates (secondary endpoints) of all patients who underwent surgery and the toxicity data for all patients who received at least one cycle of treatment. Analyses were done in hormone receptor-positive and hormone receptor-negative patients separately. This trial is registered with ClinicalTrials.gov, number NCT03820063, recruitment is closed, and the follow-up for the primary endpoint is ongoing.
Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative cancer and 232 with hormone receptor-positive cancer were enrolled. Median follow-up was 26·4 months (IQR 22·9–32·9) for patients who were hormone receptor-negative and 31·6 months (25·6–35·7) for patients who were hormone receptor-positive. Overall, the median age was 51 years (IQR 43–59). In 233 patients with hormone receptor-negative tumours, radiological complete response was seen in 84 (36%; 95% CI 30–43) patients after one to three cycles, 140 (60%; 53–66) patients after one to six cycles, and 169 (73%; 66–78) patients after one to nine cycles. In 232 patients with hormone receptor-positive tumours, radiological complete response was seen in 68 (29%; 24–36) patients after one to three cycles, 118 (51%; 44–57) patients after one to six cycles, and 138 (59%; 53–66) patients after one to nine cycles. Among patients with a radiological complete response after one to nine cycles, a pathological complete response was seen in 147 (87%; 95% CI 81–92) of 169 patients with hormone receptor-negative tumours and was seen in 73 (53%; 44–61) of 138 patients with hormone receptor-positive tumours. The most common grade 3–4 adverse events were neutropenia (175 37% of 467), anaemia (75 16%), and diarrhoea (57 12%). No treatment-related deaths were reported.
In our study, a third of patients with stage II–III hormone receptor-negative and HER2-positive breast cancer had a complete pathological response after only three cycles of neoadjuvant systemic therapy. A complete response on breast MRI could help identify early complete responders in patients who had hormone receptor negative tumours. An imaging-based strategy might limit the duration of chemotherapy in these patients, reduce side-effects, and maintain quality of life if confirmed by the analysis of the 3-year event-free survival primary endpoint. Better monitoring tools are needed for patients with hormone receptor-positive and HER2-positive breast cancer.
Roche Netherlands.
Reply de Jonge, Peter; van den Brink, Rob HS; Spijkerman, Titia A ...
Journal of the American College of Cardiology,
05/2007, Letnik:
49, Številka:
17
Journal Article
Recenzirano
Using 2 indicators for MI severity, left ventricular ejection fraction (LVEF)<40% and Killip class>1, we assessed whether combinations of dysfunctions of the brain and the heart predict new ...cardiovascular events. The same pattern emerges for all other interaction effects. ...we believe the heart and the brain exert additive effects on cardiovascular prognosis, and these effects appear to be restricted to incident post-MI depression.
Per- and polyfluoroalkyl substances (PFAS) are a group of emerging substances that have proved to be persistent and highly bioaccumulative. They are broadly used in various applications and are known ...for their long-distance migration and toxicity. In this study, 65 recent specimens of a terrestrial apex predator (Common buzzard), freshwater and marine apex predators (Eurasian otter, harbour porpoise, grey seal, harbour seal) and their potential prey (bream, roach, herring, eelpout) from northern Europe (United Kingdom, Germany, the Netherlands and Sweden) were analyzed for the presence of legacy and emerging PFAS, employing a highly sensitive liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method. 56 compounds from 14 classes were measured; 13 perfluoroalkyl carboxylic acids (PFCAs), 7 perfluoroalkyl sulphonic acids (PFSAs), 3 perfluorooctane sulfonamides (FOSAs), 4 perfluoroalkylphosphonic acids (PFAPAs), 3 perfluoroalkylphosphinic acids (PFPi's), 5 telomer alcohols (FTOHs), 2 mono-substituted polyfluorinated phosphate esters (PAPs), 2 di-substituted polyfluorinated phosphate esters (diPAPs), 6 saturated fluorotelomer acids (FTAS), 3 unsaturated fluorotelomer acids (FTUAs), 2 N-Alkyl perfluorooctane sulfonamidoethanols (FOSEs), 3 fluorotelomer sulphonic acids (FTSAs), 2 perfluoroether carboxylic acids (PFECAs) and 1 chlorinated perfluoroether sulphonic acid (Cl-PFESA). All samples were lyophilized before analysis, in order to enhance extraction efficiency, improve the precision and achieve lower detection limits. The analytes were extracted from the dry matrices through generic methods of extraction, using an accelerated solvent extraction (ASE), followed by clean-up through solid phase extraction (SPE). Method detection limits and method quantification limits ranged from 0.02 to 1.25 ng/g wet weight (ww) and from 0.05 to 3.79 ng/g (ww), respectively. Recovery ranged from 40 to 137%. Method precision ranged from 3 to 20 %RSD. The sum of PFAS concentration in apex predators livers ranged from 0.2 to 20.2 μg/g (ww), whereas in the fish species muscle tissues it ranged from 16 to 325 ng/g (ww). All analyzed specimens were primarily contaminated with PFOS, while the three PFPi's included in this study exhibited frequency of appearance (FoA) 100 %. C9 to C13 PFCAs were found at high concentrations in apex predator livers, while the overall PFAS levels in fish fillets also exceeded ecotoxicological thresholds. The findings of our study show a clear association between the PFAS concentrations in apex predators and the geographical origin of the specimens, with samples that were collected in urban and agricultural zones being highly contaminated compared to samples from pristine or semi-pristine areas. The high variety of PFAS and the different PFAS composition in the apex predators and their prey (AP&P) samples is alarming and strengthens the importance of PFAS monitoring across the food chain.
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•PFAS were determined for marine, freshwater and terrestrial apex predators.•ΣPFAS concentrations were one to four orders of magnitude higher in apex predators.•PFOS, long-chain PFCAs and PFPi's were detected in all species studied.•PFAS concentrations were highest in Eurasian otters.•First report of F–53B in Eurasian otters.
The filamentous fungus Aspergillus niger exhibits great diversity in its phenotype. It is found globally, both as marine and terrestrial strains, produces both organic acids and hydrolytic enzymes in ...high amounts, and some isolates exhibit pathogenicity. Although the genome of an industrial enzyme-producing A. niger strain (CBS 513.88) has already been sequenced, the versatility and diversity of this species compel additional exploration. We therefore undertook whole-genome sequencing of the acidogenic A. niger wild-type strain (ATCC 1015) and produced a genome sequence of very high quality. Only 15 gaps are present in the sequence, and half the telomeric regions have been elucidated. Moreover, sequence information from ATCC 1015 was used to improve the genome sequence of CBS 513.88. Chromosome-level comparisons uncovered several genome rearrangements, deletions, a clear case of strain-specific horizontal gene transfer, and identification of 0.8 Mb of novel sequence. Single nucleotide polymorphisms per kilobase (SNPs/kb) between the two strains were found to be exceptionally high (average: 7.8, maximum: 160 SNPs/kb). High variation within the species was confirmed with exo-metabolite profiling and phylogenetics. Detailed lists of alleles were generated, and genotypic differences were observed to accumulate in metabolic pathways essential to acid production and protein synthesis. A transcriptome analysis supported up-regulation of genes associated with biosynthesis of amino acids that are abundant in glucoamylase A, tRNA-synthases, and protein transporters in the protein producing CBS 513.88 strain. Our results and data sets from this integrative systems biology analysis resulted in a snapshot of fungal evolution and will support further optimization of cell factories based on filamentous fungi.
Substance-dependent patients automatically and involuntarily allocate their attention to drug cues in the environment, a process referred to as attentional bias. Attentional bias is increased during ...periods of subjective craving and predictive of treatment outcome and relapse in substance dependence. Despite recent theoretical and clinical advances with regard to attentional bias, the underlying neurobiological mechanisms are largely unknown. The objective of the current study was to investigate the neural substrate of attentional bias and associated subjective craving in smokers. A group of smokers (n=20) and a group of age- and gender-matched nonsmoking controls (n=22) were recruited from the general population and participated in a single session of fMRI scanning while attentional processes were manipulated. Main outcome measures were blood oxygen level-dependent (BOLD) fMRI activation during an attentional bias paradigm and self-reported cigarette craving. Results of the current study show that the dorsal anterior cingulate cortex, the superior parietal gyrus, and the superior temporal gyrus were more strongly activated in smokers, as compared to controls, when they had to pay attention to task-relevant information (line counting) while smoking cues were present as distracters (attentional bias). Subjective craving measures during attentional bias correlated with brain activation in the insula and putamen. To our knowledge, this is the first controlled study that shows the brain regions involved in attentional bias in smokers. The current study demonstrates that brain regions contributing to top-down attentional processing are implicated in attentional bias in smokers, suggesting that smokers have to employ more attentional resources to focus on a standard cognitive task when smoking cues are present.
►The dACC, SPL, and STG are involved in attentional bias (AB) in smokers. ►dACC effects are specific for AB and exclude other cue exposure processes. ►Subjective craving during AB correlated with activation in the insula and putamen.
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