Reliability of panel-based mutational signatures for immune-checkpoint-inhibition efficacy prediction in non-small cell lung cancer.

OBJECTIVES: Mutational signatures (MS) are gaining traction for deriving therapeutic insights for immune checkpoint inhibition (ICI). We asked if MS attributions from comprehensive targeted sequencing assays are reliable enough for predicting ICI efficacy in non-small cell lung cancer (NSCLC). METHODS: Somatic mutations of m = 126 patients were assayed using panel-based sequencing of 523 cancer-related genes. In silico simulations of MS attributions for various panels were performed on a separate dataset of m = 101 whole genome sequenced patients. Non-synonymous mutations were deconvoluted using COSMIC v3.3 signatures and used to test a previously published machine learning classifier. RESULTS: The ICI efficacy predictor performed poorly with an accuracy of 0.51-0.09+0.09, average precision of 0.52-0.11+0.11, and an area under the receiver operating characteristic curve of 0.50-0.09+0.10. Theoretical arguments, experimental data, and in silico simulations pointed to false negative rates (FNR) related to panel size. A secondary effect was observed, where deconvolution of small ensembles of point mutations lead to reconstruction errors and misattributions. CONCLUSION: MS attributions from current targeted panel sequencing are not reliable enough to predict ICI efficacy. We suggest that, for downstream classification tasks in NSCLC, signature attributions be based on whole exome or genome sequencing instead.

Correction: Environmentally responsive hydrogel composites for dynamic body thermoregulation.

Correction for 'Environmentally responsive hydrogel composites for dynamic body thermoregulation' by M. Garzón Altamirano et al., Soft Matter, 2023, 19, 2360-2369, https://doi.org/10.1039/D2SM01548J.

Environmentally responsive hydrogel composites for dynamic body thermoregulation.

Hydrogel composites exhibiting dynamic thermo-hydro responsive modulation of infrared radiation (IR) in the 5-15 µm range are designed for personalized body thermoregulation. Fabrication of the proposed system relies on the periodic arrangement of submicron-sized spherical fine silica (SiO2) particles within poly(N-isopropylacrylamide) (PNIPAM)-based hydrogels. The dependence of the SiO2 particles content on the IR reflection, followed by its modulation in response to any immediate environmental changes are thereby investigated. The addition of 20 wt% of SiO2 allowed the hydrogel composites to reflect 20% of the IR emitted by the human body at constant temperature (i.e. T = 20 °C) and relative humidity (i.e. RH = 0%). According to Bragg's law, we found that the smaller the distance between the SiO2 particles, the higher the IR reflection. The IR reflection further increased to a maximum of 42% when the resulting hydrogel composites are subjected to changes in relative humidity (i.e. RH = 60%) and temperature (i.e. T = 35 °C). Thermography is used to map the IR radiation emitted from the hydrogel composites when placed on the skin of the human body, demonstrating that the composite is actually reflecting IR. The latter results are supported by theoretical models that define the IR reflection profile of the resulting hydrogel composites with respect to the silica content, relative humidity and temperature.

PRECISION: the Belgian molecular profiling program of metastatic cancer for clinical decision and treatment assignment.

PRECISION is an initiative from the Belgian Society of Medical Oncology (BSMO) in collaboration with several stakeholders, encompassing four programs that aim to boost genomic and clinical knowledge with the ultimate goal to offer patients with metastatic solid tumors molecularly guided treatments. The PRECISION 1 study has led to the creation of a clinico-genomic database. The Belgian Approach for Local Laboratory Extensive Tumor Testing (BALLETT) and GeNeo studies will increase the number of patients with advanced cancer that have comprehensive genotyping of their cancer. The PRECISION 2 project consists of investigator-initiated phase II studies aiming to provide access to a targeted drug for patients whose tumors harbor actionable mutations in case the matched drug is not available through reimbursement or clinical trials in Belgium.

Transition metal-catalysed carbene- and nitrene transfer to carbon monoxide and isocyanides.

Transition metal-catalysed carbene- and nitrene transfer to the C1-building blocks carbon monoxide and isocyanides provides heteroallenes (i.e. ketenes, isocyanates, ketenimines and carbodiimides). These are versatile and reactive compounds allowing in situ transformation towards numerous functional groups and organic compounds, including heterocycles. Both one-pot and tandem processes have been developed providing valuable synthetic methods for the organic chemistry toolbox. This review discusses all known transition metal-catalysed carbene- and nitrene transfer reactions towards carbon monoxide and isocyanides and in situ transformation of the heteroallenes hereby obtained, with a special focus on the general mechanistic considerations.

Gastrointestinal tract involvement in hepatocellular carcinoma: two cases illustrating duodenal and oesophageal invasion.

We present here two hepatocellular carcinoma (HCC) patients with gastrointestinal tract involvement (GITI). Hemorrhage due to duodenal involvement was the inaugural event of the HCC for the first patient. Dysphagia due to HCC recurrence in the oesophagus four years after left hepatectomy was the call symptom for the second. As incidence of HCC increases, and overall survival improves, incidence of GITI in HCC patients is expected to increase.

Manual signing throughout the day: Influence from staff's sign use and type of activity.

BACKGROUND: Both individuals with intellectual disabilities (ID) and staff may be more inclined to use manual signs during formal than informal activities. In addition, the sign use of individuals with ID and staff is positively related. It is unclear if activity type and the sign use of staff interact as they shape the sign use of individuals with ID. METHODS: Through non-continuous partial interval coding, we observed frequency of manual sign usage in adults with ID during communicative activities, non-communicative activities and mealtimes in four special schools and 4-day centres. Using loglinear analysis and partial associations, we measured how sign use varied by activity between the people with ID and the staff. RESULTS: When staff used signs, clients and students did not vary their spontaneous signing rate between types of activities. When staff did not use signs, a differential influence appeared according to the type of activity: clients and students were significantly more likely to also refrain from using signs during mealtimes and leisure or work activities such as crafts (84% to 89% of the time) than during communicative activities such as signing sessions (65% of the time). CONCLUSIONS: Reluctance of staff to model sign use seemed to hinder signing implementation by the people with ID. Future studies should take into account various levels of sign prompting and increasing pragmatic functions of individuals' sign use.

Rapid construction of substituted 3-amino-1,5-benzothiazepin-4(5H)-one dipeptide scaffolds through an Ugi-4CR - Ullmann cross-coupling sequence.

A 3-step methodology for the synthesis of 1,5-benzothiazepin-4(5H)-one dipeptidomimetics has been elaborated via an Ugi-4CR followed by a S-trityl deprotection and an intramolecular Cu(i)-catalyzed Ullmann condensation with moderate to good yields. In silico and NMR conformational studies showed that the lowest energy conformers stabilize γ- and ß-turn structures.

Use of key word signing by staff in special schools and in day centres for adults with intellectual disabilities.

BACKGROUND: Staff may encourage individuals with intellectual disabilities to use manual signs by modelling its use, but implementing key word signing during daily activities can be demanding. METHOD: Staff's use of manual signs was observed in four special schools and four day centres for adults with intellectual disabilities during communicative group activities, non-communicative group activities and mealtimes. Using in situ partial interval coding, we measured staff's communication rate, semantic diversity of manual signs, sign reinforcement and sign imitation. With Chi-squared tests, associations were measured between these variables, the two settings and the three activity types. RESULTS: During communicative activities, staff used manual signs significantly more in adult services than special schools. During non-communicative activities and mealtimes, staff seldom used or reinforced signs. CONCLUSIONS: Staff communicated frequently but did not often model sign use during daily activities. To investigate influence from training background, further detailed measurements are warranted.

Targeted next-generation sequencing using a multigene panel in myeloid neoplasms: Implementation in clinical diagnostics.

INTRODUCTION: Detection of mutations in patients with myeloid neoplasms (MNs) has shown great potential for diagnostic and prognostic purposes. Next-generation sequencing (NGS) is currently implemented for the diagnostic profiling of the four major MN subgroups. METHODS: First, we validated the targeted NGS approach using the TruSight Myeloid panel. Next, we screened 287 patients with a clinical suspicion of MN and 61 follow-up patients with documented MN. RESULTS: Validation of the NGS workflow resulted in maximal precision, accuracy, sensitivity, and specificity for gene variants with an allele frequency of at least 5% and a minimal read depth of 300. In our diagnostic screen, we identified at least one somatic mutation in 89% of patients with proven MN. Of the 155 newly diagnosed MN cases, 126 (81%) showed at least one mutation, confirming clonality. Moreover, the co-occurrence of mutated genes in the different MN subentities facilitates their classification and justifies the diagnostic use of a pan-myeloid panel. Furthermore, several of these mutations provide additional prognostic information independently of traditional prognostic scoring systems. CONCLUSION: Pan-myeloid targeted NGS fits elegantly in the routine diagnostic approach of MNs allowing for an improved diagnosis, subclassification, and prognosis.

A novel approach for BCR-ABL1 standardization to improve International Scale estimation.

INTRODUCTION: Standardization of BCR-ABL1 messenger RNA quantification by real-time PCR on the International Scale (IS) is critical for monitoring therapy response in chronic myelogenous leukaemia. Since 2006, BCR-ABL1 IS standardization is propagated along reference laboratories by calculating a laboratory-specific conversion factor (CF), co-ordinated in Europe through the European Treatment and Outcome Study project. Although this process has proven successful to some extent, it has not been achievable for all laboratories due to the complexity of the process and the stringent requirements in terms of numbers of samples to be exchanged. In addition, several BCR-ABL1 IS quantification methods and secondary reference materials became commercially available. However, it was observed that different IS methods generate consistently different results. METHODS: To overcome these difficulties, we have developed an alternative and simple approach of CF calculation, based on the retrospective analysis of existing external quality assessment (EQA) data. Our approach does not depend on the exchange of samples and is solely based on the mathematical CF calculation using EQA results. RESULTS AND CONCLUSION: We have demonstrated by thorough statistical validation that this approach performs well in converting BCR-ABL1 measurements to improve IS estimation. In expectation of a true golden standard method for BCR-ABL1 IS quantification, the proposed method is a valuable alternative.

Making a difference? A comparison between multi-sensory and regular storytelling for persons with profound intellectual and multiple disabilities.

BACKGROUND: Multi-sensory storytelling (MSST) was developed to include persons with profound intellectual and multiple disabilities in storytelling culture. In order to increase the listeners' attention, MSST stories are individualised and use multiple sensory stimuli to support the verbal text. In order to determine the value of MSST, this study compared listeners' attention under two conditions: (1) being read MSST books and (2) being read regular stories. METHOD: A non-randomised control study was executed in which the intervention group read MSST books (n = 45) and a comparison group (n = 31) read regular books. Books were read 10 times during a 5-week period. The 1st, 5th and 10th storytelling sessions were recorded on video in both groups, and the percentage of attention directed to the book and/or stimuli and to the storyteller was scored by a trained and independent rater. Two repeated measure analyses (with the storytelling condition as a between-subject factor and the three measurements as factor) were performed to determine the difference between the groups in terms of attention directed to the book/stimuli (first analysis) and storyteller (second analysis). A further analysis established whether the level of attention changed between the reading sessions and whether there was an interaction effect between the repetition of the book and the storytelling condition. RESULTS: The attention directed to the book and/or the stimuli was significantly higher in the MSST group than in the comparison group. No significant difference between the two groups was found in the attention directed to the storyteller. For MSST stories, most attention was observed during the fifth reading session, while for regular stories, the fifth session gained least attentiveness from the listener. CONCLUSION: The persons with profound intellectual and multiple disabilities paid more attention to the book and/or stimuli in the MSST condition compared with the regular story telling group. Being more attentive towards the book and stimuli might give persons with PIMD the opportunity to apprehend the story and to be included in storytelling culture.

Children with PIMD in interaction with peers with PIMD or siblings.

BACKGROUND: The complex disabilities of children with profound intellectual and multiple disabilities (PIMD) impede their presentation of peer directed behaviours. Interactions with typically developing peers have been observed to be more frequent than those with peers with PIMD. The typically developing peers with whom people with PIMD have frequent contact are their siblings. In this study, the amount of peer directed behaviours was compared between an interaction with a sibling and an interaction with a peer with PIMD. In addition, the attention directing strategies of the siblings, and how these affect the presentation of peer directed behaviours, were examined. METHOD: Thirteen children and young people with PIMD, who had a typically developing sibling, were identified. For each of these thirteen children, a peer with PIMD and a sibling were selected. The child with PIMD was observed together with a peer with PIMD and together with a sibling. In both conditions, video observations were conducted. A coding scheme for the peer directed behaviours of the children and young people with PIMD and a coding scheme for the attention directing behaviours of the siblings were used. Descriptive, comparative and sequential analyses were conducted. RESULTS: Significantly, more peer directed behaviours of the children with PIMD were observed in the condition with the sibling (30.76%) compared with that of the condition with the peer with PIMD (13.73%). The siblings presented attention directing behaviours in 30% of the time; the most frequently used was nonverbal behaviour. When the siblings presented a combination of verbal and nonverbal attention directing behaviours, they elicited multiple peer directed behaviours in the children and young people with PIMD. CONCLUSIONS: Persons with PIMD interact more with their siblings compared with their peers with PIMD. Interacting with siblings may probably be more motivating and encouraging. Presenting a combination of verbal and nonverbal behaviours attracts more attention of the persons with PIMD.

The nature of peer-directed behaviours in children with profound intellectual and multiple disabilities and its relationship with social scaffolding behaviours of the direct support worker.

BACKGROUND: The multiple and complex disabilities of persons with profound intellectual and multiple disabilities (PIMD) form a barrier for peer interactions and peer-directed behaviours. In this study, we further explore the nature of peer-directed behaviours in persons with PIMD and its relationship with social scaffolding behaviour of direct support workers (DSWs). METHODS: Fourteen dyads of children with PIMD, who knew each other for at least 12 months, participated. They were sitting in close proximity while they were filmed with and without the presence of the DSW. Video recordings were coded continuously making use of observation schemes for the peer-directed behaviours of the children and the peer interaction influencing behaviours of the DSW. RESULTS: Significantly more singular peer-directed behaviour (without DSW: 18.00%; with DSW: 3.81%) was observed than multiple peer-directed behaviour (without DSW: 4.01%; with DSW: 0.52%). The amount of time the singular and multiple peer-directed behaviours were observed was significantly lower in the presence of a DSW. When the DSW shows peer interaction influencing behaviour, it was mostly social scaffolding behaviour (2.17%). The conditional probability of observing social scaffolding behaviour in the 10 s following on singular peer-directed behaviour was 0.02 with a Yule's Q of 0.04 and following on multiple peer-directed behaviour 0.04 with a Yule's Q of 0.33. CONCLUSION: The way in which peer interactions in children with PIMD are defined could have an impact on the amount of observed peer-directed behaviours and on the effect of the social scaffolding behaviours presented by DSW.

Antiprotozoal activity of synthetic amino substituted 1-methyl-1 H-alpha-carbolines.

The antiprotozoal properties of a series of amino substituted 1-methyl-1 H-alpha-carbolines were investigated in a broad panel of parasites. Various substituents were systematically introduced at various positions on the carbocyclic ring of the parent 1-methyl-1 H-alpha-carboline. Most compounds showed a potent antiprotozoal activity, although mostly accompanied by cytotoxicity on MRC-5 cells. One compound, containing the same amino-substitution as chloroquine, showed an IC50 against Plasmodium falciparum of 2.37 microM and was reasonably selective.

Catch the wave! Time-window sequential analysis of alertness stimulation in individuals with profound intellectual and multiple disabilities.

BACKGROUND: While optimally activities are provided at those moments when the individual with profound intellectual and multiple disabilities (PIMD) is 'focused on the environment' or 'alert', detailed information about the impact that the design and timing of the activity has on alertness is lacking. Therefore, the aim of the present study is to shed light on the sequential relationship between different stimuli and alertness levels in individuals with PIMD. METHOD: Video observations were conducted for 24 participants during one-on-one interactions with a direct support person in multisensory environments. Time-window sequential analyses were conducted for the 120 s following four different stimuli. RESULTS: For the different stimuli, different patterns in terms of alertness became apparent. Following visual stimuli, the alertness levels of the individuals with PIMD changed in waves of about 20 s from 'active alert' to 'passive alert'. While auditory and tactile stimuli led to 'alert' reactions shortly after the stimulation, alertness levels decreased between seconds 20 and 120. Reactions to vestibular stimuli were only visible after 60 s; these were 'active alert' or 'withdrawn'. CONCLUSIONS: The results of the present study show that individuals with PIMD show their reactions to stimuli only slightly, so that 'waves' might reflect the optimal alertness pattern for learning and development. Consequently, it is especially important that direct support persons follow and stimulate these individual 'waves' in the activities they provide to their clients.

Temporal analysis of attentional processes in spontaneous interactions between people with profound intellectual and multiple disabilities and their support workers.

BACKGROUND: Few studies examined joint attention in interactions with people with profound intellectual and multiple disabilities (PIMD), although being an important component of high-quality interaction. The purpose of this study is to describe initiating joint attention behaviour from people with PIMD and their support workers as well as the sequential relationship between initiating joint attention behaviour and attention episodes in spontaneous interactions. METHOD: Video observations of 28 support worker-client dyads were coded using partial interval coding. RESULTS: Results show much variation across persons and dyads. Within the support worker-client dyad, there is not much joint attention but shared attention is frequently occurring. In general, people with PIMD are directing the attention of their interaction partner at low rates. The support workers are frequently directing the attention of the clients towards a topic of interest but not often through the tactile modality. The occurrence of an attention episode cannot be predicted on the basis of preceding initiating joint attention behaviour of the interaction partners. CONCLUSION: This study presents directions for future research and implications for practice. It may increase support workers' knowledge of their own contributions, strengths and weaknesses in directing and maintaining attention within interactions with people with PIMD.

Revealing interdyad differences in naturally occurring staff reactions to challenging behaviour of clients with severe or profound intellectual disabilities by means of Clusterwise Hierarchical Classes Analysis (HICLAS).

BACKGROUND: Investigating interdyad (i.e. couples of a client and their usual caregiver) differences in naturally occurring patterns of staff reactions to challenging behaviour (e.g. self-injurious, stereotyped and aggressive/destructive behaviour) of clients with severe or profound intellectual disabilities is important to optimise client-staff interactions. Most studies, however, fail to combine a naturalistic setup with a person-level analysis, in that they do not involve a careful inspection of the interdyad differences and similarities. METHOD: In this study, the recently proposed Clusterwise Hierarchical Classes Analysis (HICLAS) method is adopted and applied to data of in which video fragments (recorded in a naturalistic setting) of a client showing challenging behaviour and the staff reacting to it were analysed. In a Clusterwise HICLAS analysis, the staff-client dyads are grouped into a number of clusters and the prototypical behaviour-reaction patterns that are specific for each cluster (i.e. interdyad differences and similarities) are revealed. RESULTS: Clusterwise HICLAS discloses clear interdyad differences (and similarities) in the prototypical patterns of clients' challenging behaviour and the associated staff reactions, complementing and qualifying the results of earlier studies in which only general patterns were disclosed. CONCLUSIONS: The usefulness and clinical relevance of Clusterwise HICLAS is demonstrated. In particular, Clusterwise HICLAS may capture idiosyncratic aspects of staff-client interactions, which may stimulate direct support workers to adopt person-centred support practices that take the specific abilities of the client into account.

A new method to graft titania using Grignard reagents.

A new method to graft titania with organic groups has been developed. In contrast to common condensation based grafting methods, this method uses organometallic chemistry to bond organic groups directly at the surface. Thereby the introduction of hetero elements at the bonding interface is avoided.

See me, feel me. Using physiology to validate behavioural observations of emotions of people with severe or profound intellectual disability.

BACKGROUND: Behavioural observations are the most frequently used source of information about emotions of people with severe or profound intellectual disabilities but have not yet been validated against other measures of emotion. In this study we wanted to validate the behavioural observations of emotions using respiration (rib cage contribution, total breath duration, inspiratory time, expiratory time, tidal volume, mean inspiratory flow, minute ventilation) and heart rate variability. METHOD: Twenty-seven participants were presented with four negative and four positive stimuli. During the presentation the participants' respiration and heart rate variability was measured. Each behaviour of the participant was coded as emotive or not. RESULTS: We found the hypothesised higher percentage rib cage contribution, marginal lower mean inspiratory flow and lower heart rate variability when the expressed emotions became more positive. CONCLUSIONS: These results validate the use of behavioural observations to make inferences about emotions.