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The very first days of mammalian embryonic development are accompanied by epigenetic reprogramming and extensive changes in nuclear organization. In particular, genomic regions located at the periphery of the nucleus, termed lamina-associated domains (LADs), undergo major rearrangements after fertilization. However, the role of LADs in regulating gene expression as well as the interplay with various chromatin marks during preimplantation development remains elusive. In this study, we obtained single-cell LAD profiles coupled with the corresponding gene expression readout throughout the first days of mouse development. We detect extensive cell-cell LAD variability at the 2-cell stage, which surprisingly does not seem to functionally affect gene expression. This suggests an unusual uncoupling between 3D-nuclear genome organization and gene expression during totipotent developmental stages. By analyzing LAD dynamics and chromatin states across early developmental stages in an allelic-specific manner, we identify genomic regions that transiently detach from the nuclear lamina and are enriched by non-canonical H3K27me3. Upon maternal knock-out of a component of the Polycomb repressive complex 2 and concomitant loss of H3K27me3 during early embryogenesis, these regions relocate to the lamina at the 2-cell stage. Our results suggest that H3K27me3 is the prime determinant in establishing the atypical distribution of the genome at the nuclear periphery during the first days of embryonic development. This study provides insight into the molecular mechanisms regulating nuclear organization of parental genomes during very early mammalian development.

Gene expression programs result from the collective activity of many regulatory factors. To obtain insight into the mechanisms that govern gene regulation, it is imperative to study their combined mode of action and interconnectivity. However, it has been challenging to simultaneously measure a combination of these factors within one sample. Here, we introduce MAbID, a method that combines genomic profiling of many histone modifications and chromatin-binding proteins in a single reaction. MAbID employs antibody-DNA conjugates to enable genomic barcoding of chromatin at sites of epitope occupancy. This barcoding strategy allows for the combined incubation of multiple antibodies in a single sample to reveal the genomic distributions of many epigenetic states simultaneously. We used MAbID to profile both active and inactive chromatin types in human cell lines and multiplexed measurements in the same sample without loss of data quality. Moreover, we obtained joint measurements of six epitopes covering all major chromatin types in single cells during mousein vitroneural differentiation and captured associated changes in multifactorial chromatin states. Thus, MAbID holds the potential to gain unique insights into the interplay between gene regulatory mechanisms, especially in settings with limited sample material and in single cells.

Purpose To investigate the prevalence of adjustment disorder (AD) among cancer patients and the acceptance of psychological treatment, in relation to sociodemographic, clinical, and psychological factors. Methods Breast, prostate, and head and neck cancer patients of all stages and treatment modalities (N = 200) participated in this observational study. Patients completed the Hospital Anxiety and Depression Scale, Checklist Individual Strength, Distress Thermometer and problem list. Patients with increased risk on AD based on these questionnaires were scheduled for a diagnostic interview. Patients diagnosed with AD were invited to participate in a randomized controlled trial on the cost-effectiveness of psychological treatment. Participation in this trial was used as a proxy of acceptance of psychological treatment. Logistic regression analyses were used to investigate associated factors. Results The overall prevalence of AD was estimated at 13.1%. Sensitivity analyses showed prevalence rates of AD of 11.5%, 15.0%, and 23.5%. Acceptance of psychological treatment was estimated at 65%. AD was associated both with being employed (OR = 3.3, CI = 1.3–8.4) and having a shorter time since diagnosis (OR = 0.3, CI = 0.1–0.8). Conclusion Taking sensitivity analysis into account, the prevalence of AD among cancer patients is estimated at 13 to 15%, and is related to being employed and having a shorter time since diagnosis. The majority of cancer patients with AD accept psychological treatment.

Background: Colchicine reduces risk of cardiovascular events in patients post–myocardial infarction and in patients with chronic coronary disease. It remains unclear whether this effect is related to the time of onset of treatment following an acute coronary syndrome (ACS). Objectives: This study investigates risk for major adverse cardiovascular events in relation to history and timing of prior ACS, to determine whether the benefits of colchicine are consistent independent of prior ACS status. Methods: The LoDoCo2 (Low-Dose Colchicine 2) trial randomly allocated patients with chronic coronary disease to colchicine 0.5 mg once daily or placebo. The rate of the composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was compared between patients with no prior, recent (6-24 months), remote (2-7 years), or very remote (>7 years) ACS; interaction between ACS status and colchicine treatment effect was assessed. Results: In 5,522 randomized patients, risk of the primary endpoint was independent of prior ACS status. Colchicine consistently reduced the primary endpoint in patients with no prior ACS (incidence: 2.8 vs 3.4 events per 100 person-years; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.52-1.27), recent ACS (incidence: 2.4 vs 3.3 events per 100 person-years; HR: 0.75; 95% CI: 0.51-1.10), remote ACS (incidence: 1.8 vs 3.2 events per 100 person-years, HR: 0.55; 95% CI: 0.37-0.82), and very remote ACS (incidence: 3.0 vs 4.3 events per 100 person-years, HR: 0.70; 95% CI: 0.51-0.96) (P for interaction = 0.59). Conclusions: The benefits of colchicine are consistent irrespective of history and timing of prior ACS. (The LoDoCo2 Trial: Low Dose Colchicine for secondary prevention of cardiovascular disease [LoDoCo2] ACTRN12614000093684)

ObjectiveIn the Netherlands, the threshold for offering active treatment for spontaneous birth was lowered from 25+0 to 24+0 weeks’ gestation in 2010. This study aimed to evaluate the impact of guideline implementation on survival and causes and timing of death in the years following implementation.DesignNational cohort study, using data from the Netherlands Perinatal Registry.PatientsThe study population included all 3312 stillborn and live born infants with a gestational age (GA) between 240/7 and 266/7 weeks born between January 2011 and December 2017. Infants with the same GA born between January 2007 and December 2009 (N=1400) were used as the reference group.Main outcome measuresSurvival to discharge, as well as cause and timing of death.ResultsAfter guideline implementation, there was a significant increase in neonatal intensive care unit (NICU) admission rate for live born infants born at 24 weeks’ GA (27%–69%, pConclusionsImplementation of the 2010 guideline resulted as expected in increased NICU admissions rate and postnatal survival of infants born at 24 weeks’ GA. In the years after implementation, a shift in cause of death was seen from respiratory insufficiency towards necrotising enterocolitis and sepsis.

We examined the contributions of kinesthetic and skin stretch cues to static weight perception. In three psychophysical experiments, several aspects of static weight perception were assessed by asking participants either to detect on which hand a weight was presented or to compare between two weight cues. Two closed-loop controlled haptic devices were used to present cutaneous and kinesthetic weights, in isolation and together, with a precision of 0.05 g. Our results show that combining skin stretch and kinesthetic information leads to better weight detection thresholds than presenting uni-sensory cues does. For supra-threshold stimuli, Weber fractions were 22-44%. Kinesthetic information was less reliable for lighter weights, while both sources of information were equally reliable for weights up to 300 g. Weight was perceived as equally heavy regardless of whether skin stretch and kinesthetic cues were presented together or alone. Data for lighter weights complied with an Optimal Integration model, while for heavier weights, measurements were closer to predictions from a Sensory Capture model. The presence of correlated noise might explain this discrepancy, since that would shift predictions from the Optimal Integration model towards our measurements. Our experiments provide device-independent perceptual measures, and can be used to inform, for instance, skin stretch device design.

In recent years, there have been many modeling and control advances in the field of soft robotics, which resulted in a growing interest in practical, real-time applications. To further enable these developments, we present a desktop-sized testing and development platform intended for fast, precise, and reliable (closed-loop) control of pneumatic soft robots. The Soft Robotics Control-unit (SRC) is fully compatible with Matlab, Simulink, and Unity, allowing for real-time control tasks of various complexity. The system's performance is tested in three use-cases: model-based controller design, soft haptic feedback in virtual-reality, and tele-operation of a soft gripper. To promote the use of the SRC in the soft robotics community, all presented material is fully open-sourced such that it is easily reproducible by students or researchers from any technical background.

BACKGROUND: The diagnostic value of ST analysis of the fetal electrocardiogram (fECG) during labor is uncertain. False alarms (ST events) may be explained by physiological variation of the fetal electrical heart axis. Adjusted ST events, based on a relative rather than an absolute rise from baseline, correct for this variation and may improve the diagnostic accuracy of ST analysis.AIMS: Determine the optimal cut-off for relative ST events in fECG to detect fetal metabolic acidosis.STUDY DESIGN: Post-hoc analysis on fECG tracings from the Dutch STAN trial (STAN+CTG branch).SUBJECTS: 1328 term singleton fetuses with scalp ECG tracing during labor, including 10 cases of metabolic acidosis.OUTCOME MEASURES: Cut-off value for relative ST events at the point closest to (0,1) in the receiver operating characteristic (ROC) curve with corresponding sensitivity and specificity.RESULTS: Relative baseline ST events had an optimal cut-off at an increment of 85% from baseline. Relative ST events had a sensitivity of 90% and specificity of 80%.CONCLUSIONS: Adjusting the current definition of ST events may improve ST analysis, making it independent of CTG interpretation.

Background: Current knowledge regarding differences in verbal intelligence scores (VIQ) and performance intelligence scores (PIQ) in preterm born children is limited. As early motor performance may be essential for developing later visual-perceptual and visual-motor skills, early motor performance may be associated with PIQ. Aims: To evaluate whether in preterm born children motor performance at two years was associated with PIQ at eight years. Methods: Single-centre cohort study including 88 children born

The French EPIPAGE-2 study evaluated a large group of premature born children (24-34 weeks' gestational age (GA))) at age 5.5 years. Outcome information of the whole cohort was presented after careful imputation including/using the variable socio-economic-status (SES), because participation rate improved with increasing SES. Survival improved with increasing GA. Survival without moderate or severe impairment was 20% in children born at 24-26 weeks' GA, but among the survivors 75% had no or mild impairment. Mild cognitive impairment rates were comparable and common among all GA groups (25-28%) and thus frequent in prematures. School problems were also common. In addition to prematurity, SES is an important risk factor for developmental impairment. Follow-up programs for premature infants beyond 30 weeks' GA are less common and may need extra attention in low SES families. Future studies should focus on both prevention of prematurity and programs to improve outcome.

ObjectiveTo provide an overview of barriers and facilitators that healthcare professionals (HCPs) perceive regarding the implementation of lifestyle interventions (LIs) in patients with hip and/or knee osteoarthritis (OA).DesignScoping review.Data sourcesThe databases PubMed, Embase, CINAHL, PsycINFO and the Cochrane Library were searched from inception up to January 2021.Eligibility criteriaPrimary research articles with a quantitative, qualitative or mixed-methods design were eligible for inclusion if they reported: (1) perceptions of primary and/or secondary HCPs (population); (2) on implementing LIs with physical activity and/or weight management as key components (concept) and (3) on conservative management of hip and/or knee OA (context). Articles not published in English, German or Dutch were excluded.Data extraction and synthesisBarriers and facilitators were extracted by two researchers independently. Subsequently, the extracted factors were linked to a framework based on the Tailored Implementation for Chronic Diseases checklist.ResultsThirty-six articles were included. In total, 809 factors were extracted and subdivided into nine domains. The extracted barriers were mostly related to non-optimal interdisciplinary collaboration, patients’ negative attitude towards LIs, patients’ low health literacy and HCPs’ lack of knowledge and skills around LIs or promoting behavioural change. The extracted facilitators were mostly related to good interdisciplinary collaboration, a positive perception of HCPs’ own role in implementing LIs, the content or structure of LIs and HCPs’ positive attitude towards LIs.ConclusionsMultiple individual and environmental factors influence the implementation of LIs by HCPs in patients with hip and/or knee OA. The resulting overview of barriers and facilitators can guide future research on the implementation of LIs within OA care. To investigate whether factor frequency is related to the relevance of each domain, further research should assess the relative importance of the identified factors involving all relevant disciplines of primary and secondary HCPs.PROSPERO registration numberCRD42019129348.

PURPOSE: To identify factors affecting the implementation of lifestyle interventions (LIs) in patients with hip and/or knee osteoarthritis (OA) from the perspective of primary and secondary healthcare professionals (HCPs) in the Dutch healthcare system.METHODS: Multidisciplinary focus groups were composed. Data analysis was performed following thematic analysis. The Tailored Implementation for Chronic Diseases checklist was used to guide data analysis.RESULTS: Four focus groups meetings were conducted with 38 participating HCPs (general practitioners (or in-training), orthopedic surgeons (or in-training), physiotherapists, dieticians, a general practice assistant, lifestyle counselors, and nurse practitioners). Influencing factors were grouped into nine themes: (1) intervention factors; (2) individual HCP factors; (3) patient factors; (4) professional interactions; (5) incentives and resources; (6) capacity for organizational change; (7) social, political and legal factors; (8) patient and HCP interactions; and (9) disease factors.CONCLUSIONS: A wide variety of factors affecting the implementation of LIs was identified in this study, where the importance of effective interdisciplinary collaboration was emphasized by the multidisciplinary group of participants. This thorough analysis of influencing factors is an important first step toward improved implementation of LIs within OA care. Further research is required to identify the most significant targets for change in daily practice.Implications for RehabilitationThe implementation of lifestyle interventions (LIs) by healthcare professionals (HCPs) in patients with hip and/or knee osteoarthritis (OA) is affected by both individual and environmental factors.The influencing factors identified in this study can support the development of interventions aimed at improving the implementation of LIs in OA care.A multilevel approach is required when developing interventions to improve the implementation of LIs in OA care.Continued efforts of both primary and secondary HCPs and policymakers are needed in order to promote the use of LIs within OA care.

Background Since the coronavirus pandemic in 2020, there is not much reported about the disease course of COVID-19 in patients with allergic diseases. Objectives The aim of this study was to investigate the cumulative incidence and severity of COVID-19 among patients from the allergy department compared with the general Dutch population and people from their household. Design We conducted a comparative longitudinal cohort study. Methods In this study patients of the allergy department were included with their household members as a control group. Data from the beginning of the pandemic were systematically obtained through questionnaires by telephonic interviews and retrieved from electronic patient files between October 15, 2020 and January 29, 2021. Main outcomes were confirmed SARS-CoV-2 infection, disease duration, hospitalization, intensive care admission, and mortality. Questions regarding applied social distancing measures were inventoried as well. Results Three hundred and eighty nine patients (median age 39.1 (18.7-84.7) years, 69.9% female) and 441 household members (median age 42.0 (18.0-91.5), 44.1% female) were included. The cumulative COVID-19 incidence in patients was higher compared with the general population (10.5% vs 5.6%, P Conclusion The cumulative COVID-19 incidence in patients from the allergy cohort was higher compared with the general Dutch population, but similar compared with household members. There was no difference in symptoms, disease duration, or hospitalization rate between the allergy cohort and their household members.

Background Patients with suspected acute coronary syndrome in whom myocardial infarction has been ruled-out are at risk of future adverse cardiac events. However, the optimal approach to risk stratify and investigate these patients is uncertain. Methods We performed a prospective cohort study of 250 patients presenting to the Emergency Department with suspected acute coronary syndrome and troponin concentrations below the sex-specific 99th centile (16 ng/L for women and 34 ng/L for men). Patients were recruited in a 2:1 fashion stratified by peak high-sensitivity cardiac troponin I concentration above and below the early rule-out threshold of 5 ng/L (167 patients with intermediate troponin concentrations between 5 ng/L and the sex-specific 99th centile threshold and 83 patients with troponin concentrations Results Overall, 37.6% (94/250) of patients had normal coronary arteries whilst 36.0% (90/250) and 26.4% (66/250) had non-obstructive and obstructive coronary artery disease, respectively. Patients with intermediate troponin concentrations were more likely to have coronary artery disease than those with troponin concentrations Conclusions In patients with suspected acute coronary syndrome who have myocardial infarction ruled out, those with intermediate cardiac troponin concentrations are three-times more likely to have coronary artery disease than those with low troponin concentrations. Conversely anginal symptoms did not discriminate between those with and without coronary artery disease. Further studies are required to determine if targeting computed tomography coronary angiography to those with intermediate cardiac troponin concentrations can improve the use of preventative medical therapies and clinical outcomes. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The British Heart Foundation Odds ratio of coronary artery diseaseCumulative proportion with CAD

CONTEXT Prediction models can be a valuable tool in performing risk assessment of mortality in preterm infants. OBJECTIVE Summarizing prognostic models for predicting mortality in very preterm infants and assessing their quality. DATA SOURCES Medline was searched for all articles (up to June 2020). STUDY SELECTION All developed or externally validated prognostic models for mortality prediction in liveborn infants born DATA EXTRACTION Data were extracted by 2 independent authors. Risk of bias (ROB) and applicability assessment was performed by 2 independent authors using Prediction model Risk of Bias Assessment Tool. RESULTS One hundred forty-four models from 36 studies reporting on model development and 118 models from 34 studies reporting on external validation were included. ROB assessment revealed high ROB in the majority of the models, most often because of inadequate (reporting of) analysis. Internal and external validation was lacking in 42% and 94% of these models. Meta-analyses revealed an average C-statistic of 0.88 (95% confidence interval [CI]: 0.83–0.91) for the Clinical Risk Index for Babies score, 0.87 (95% CI: 0.81–0.92) for the Clinical Risk Index for Babies II score, 0.86 (95% CI: 0.78–0.92) for the Score for Neonatal Acute Physiology Perinatal Extension II score and 0.71 (95% CI 0.61–0.79) for the NICHD model. LIMITATIONS Occasionally, an external validation study was included, but not the development study, because studies developed in the presurfactant era or general NICU population were excluded. CONCLUSIONS Instead of developing additional mortality prediction models for preterm infants, the emphasis should be shifted toward external validation and consecutive adaption of the existing prediction models.

Transfusion-related acute lung injury (TRALI) is a life-threatening complication of acute respiratory distress occurring within 6 hours of blood transfusion. TRALI is one of the leading causes of transfusion-related fatalities and specific therapies are unavailable. Neutrophils are recognized as the major pathogenic cells, whereas T regulatory cells and dendritic cells appear to be important for protection against TRALI. The pathogenesis, however, is complex and incompletely understood. It is frequently postulated that the complement system plays an important role in the TRALI pathogenesis. In this article, we assess the evidence regarding the involvement of complement in TRALI from both human and animal studies. We hypothesize about the potential connection between the complement system and neutrophils in TRALI. Additionally, we draw parallels between TRALI and other acute pulmonary disorders of acute lung injury and acute respiratory distress syndrome regarding the involvement of complement. We conclude that, even though a role for complement in the TRALI pathogenesis seems plausible, studies investigating the role of complement in TRALI are remarkably limited in number and also present conflicting findings. Different types of TRALI animal models, diverse experimental conditions, and the composition of the gastrointestinal microbiota may perhaps all be factors which contribute to these discrepancies. More systematic studies are warranted to shed light on the contribution of the complement cascade in TRALI. The underlying clinical condition of the patient, which influences the susceptibility to TRALI, as well as the transfusion factor (antibody-mediated vs non–antibody-mediated), will be important to take into consideration when researching the contribution of complement. This should significantly increase our understanding of the role of complement in TRALI and may potentially result in promising new treatment strategies., Highlights • Studies investigating complement and TRALI are limited in number and present conflicting findings. • Systematic investigation is needed to better understand the contribution of the complement cascade in TRALI. • Future studies in this area should consider both the clinical susceptibility of the patient as well as the effect of transfusion factors.

Contains fulltext : 245483.pdf (Publisher’s version ) (Open Access) OBJECTIVE: This study systematically reviewed the association of psychological problems among cancer patients with healthcare and societal resource use and costs. METHODS: PubMed, PsycINFO, and Embase were searched (until 31 January 2021) for studies on psychological symptoms (anxiety, depression, distress, fear of recurrence) or psychiatric disorders (anxiety, depression, adjustment) and healthcare use (e.g., mental, inpatient healthcare), economic losses by patients and family, economic losses in other sectors (e.g., absence from work), and costs. The search, data extraction, and quality assessment were performed by two authors. RESULTS: Of the 4157 identified records, 49 articles were included (psychological symptoms (n = 34), psychiatric disorders (n = 14), both (n = 1)) which focused on healthcare use (n = 36), economic losses by patients and family (n = 5), economic losses in other sectors (n = 8) and/or costs (n = 13). In total, for 12 of the 94 associations strong evidence was found. Psychological symptoms and psychiatric disorders were positively associated with increased healthcare use (mental, primary, inpatient, outpatient healthcare), losses in other sectors (absence from work), and costs (inpatient, outpatient, total healthcare costs). Moderate evidence was found for a positive association between (any) psychiatric disorder and depression disorder with inpatient healthcare and medication use, respectively. CONCLUSIONS: Psychological problems in cancer patients are associated with increased healthcare use, healthcare costs and economic losses. Further research is needed on psychological problems in relation to understudied healthcare use or costs categories, productivity losses, and informal care costs.

Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 x 10(-6)), FHR-2 (p = 1.47 x 10(-4)), FHR-3 (p = 1.05 x 10(-5)) and FHR-4A (p = 1.22 x 10(-2)) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 x 10(-17)), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 x 10(-3) and p = 2.81 x 10(-6), respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 x 10(-16)). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus.

BACKGROUND: Improved imaging techniques have increased the incidence of subsegmental pulmonary embolism (ssPE). Indirect evidence is suggesting that ssPE may represent a more benign presentation of venous thromboembolism not necessarily requiring anticoagulant treatment. However, correctly diagnosing ssPE is challenging with reported low interobserver agreement, partly due to the lack of widely accepted diagnostic criteria. OBJECTIVES: We sought to derive uniform diagnostic criteria for ssPE, guided by expert consensus. METHODS: Based on an extensive literature review and expert opinion of a Delphi steering committee, two surveys including statements regarding diagnostic criteria and management options for ssPE were established. These surveys were conducted electronically among two panels, respectively: expert thoracic radiologists and clinical venous thromboembolism specialists. The Delphi method was used to achieve consensus after multiple survey rounds. Consensus was defined as a level of agreement >70%. RESULTS: Twenty-nine of 40 invited radiologists (73%) and 40 of 51 clinicians (78%) participated. Following two survey rounds by the expert radiologists, consensus was achieved on 15 of 16 statements, including on the established diagnostic criteria for ssPE (96% agreement): a contrast defect in a subsegmental artery, that is, the first arterial branch division of any segmental artery independent of artery diameter, visible in at least two subsequent axial slices, using a computed tomography scanner with a desired maximum collimator width of ≤1 mm. These criteria were approved by 83% of the clinical venous thromboembolism (VTE) specialists. The clinical expert panel favored anticoagulant treatment in case of prior VTE, antiphospholipid syndrome, pregnancy, cancer, and proximal deep vein thrombosis. CONCLUSION: The results of this analysis provide standard radiological criteria for ssPE that may be applicable in both clinical trials and practice. ispartof: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS vol:4 issue:8 pages:1251-1261 ispartof: location:United States status: published

A one-pot, three-component, Cu(I)-catalyzed coupling of primary hydrazines, 5-chloropentan-2-one, and terminal alkynes was developed. The resulting 1-aza-6,7-dehydrotropanes compose a new class of substances while related 1-azatropanes are scarcely described in literature and closely resemble tropane alkaloids. Hydrogenation of the double bond in 1-aza-6,7-dehydrotropanes triggered a rearrangement, involving a [1,3]-hydride shift, forming cyclic hydrazones.

Calcium carbide was used in a Cu-I-catalysed three-component coupling with omega-chlorinated ketones and primary amines to generate terminal 2-alkynyl-N-heterocycles. The formation of an imine and the subsequent intramolecular substitution results in an active electrophilic iminium species, which can be alkynylated by in situ formed copper acetylide. A number of aliphatic primary (functionalised) amines and aliphatic or aromatic alkynes together with different alkyl- or aryl-substituted gamma- or delta-chloroketones could be used. Simple acid-base workup instead of column chromatography can be applied to obtain the resulting 2-alkynylpyrrolidines and 2-alkynylpiperidines.

BackgroundInformation on the prevalence of adjustment disorders among cancer patients and the value of psychological interventions in this group of patients is limited. This study investigates the prevalence of adjustment disorders among cancer patients as well as the reach, effectiveness, cost-utility and budget impact of a tailored psychological intervention.MethodThis study consists of two parts. Part 1 is an observational study among a representative group of mixed cancer patients after cancer treatment on the prevalence of adjustment disorder as well as the uptake (i.e. reach) of psychological treatment. In Part 2, patients diagnosed with an adjustment disorder are invited to participate in a randomized controlled trial. Patients will be randomized to the intervention (access to the tailored psychological intervention) or control group (waitlist period of 6 months). The psychological intervention consists of three modules: one module containing psycho-education (3 sessions, all patients) and two additional modules (maximum of 6 sessions per module) provided as continuum, in case needed. Module 2 and 3 can consist of several evidence-based interventions (e.g. group interventions, mindfulness, eHealth) The primary outcome is psychological distress (HADS). Secondary outcomes are mental adjustment to cancer (MAC) and health-related quality of life (EORTC QLQ-C30). To assess the cost-utility and budget impact, quality of life (EQ-5D-5 L) and costs (iMCQ and iPCQ) will be measured. Measures will be completed at baseline and 3 and 6-months after randomization.DiscussionThis study will provide data of the prevalence of adjustment disorders and the reach, effectiveness, cost-utility and budget impact of a tailored psychological intervention.Trial registrationNetherlands Trial Register identifier:NL7763. Registered on 3 June 2019.