Estimating Systemic Cognitive States from a Mixture of Physiological and Brain Signals.

As human-machine teams are being considered for a variety of mixed-initiative tasks, detecting and being responsive to human cognitive states, in particular systematic cognitive states, is among the most critical capabilities for artificial systems to ensure smooth interactions with humans and high overall team performance. Various human physiological parameters, such as heart rate, respiration rate, blood pressure, and skin conductance, as well as brain activity inferred from functional near-infrared spectroscopy or electroencephalogram, have been linked to different systemic cognitive states, such as workload, distraction, or mind-wandering among others. Whether these multimodal signals are indeed sufficient to isolate such cognitive states across individuals performing tasks or whether additional contextual information (e.g., about the task state or the task environment) is required for making appropriate inferences remains an important open problem. In this paper, we introduce an experimental and machine learning framework for investigating these questions and focus specifically on using physiological and neurophysiological measurements to learn classifiers associated with systemic cognitive states like cognitive load, distraction, sense of urgency, mind wandering, and interference. Specifically, we describe a multitasking interactive experimental setting used to obtain a comprehensive multimodal data set which provided the foundation for a first evaluation of various standard state-of-the-art machine learning techniques with respect to their effectiveness in inferring systemic cognitive states. While the classification success of these standard methods based on just the physiological and neurophysiological signals across subjects was modest, which is to be expected given the complexity of the classification problem and the possibility that higher accuracy rates might not in general be achievable, the results nevertheless can serve as a baseline for evaluating future efforts to improve classification, especially methods that take contextual aspects such as task and environmental states into account.

De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy.

Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys∗11], c.399_400del [p.Glu133Aspfs∗37], c.747G>T [p.Gln249His], c.928-2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.

The novel Mechanical Ventilator Milano for the COVID-19 pandemic.

This paper presents the Mechanical Ventilator Milano (MVM), a novel intensive therapy mechanical ventilator designed for rapid, large-scale, low-cost production for the COVID-19 pandemic. Free of moving mechanical parts and requiring only a source of compressed oxygen and medical air to operate, the MVM is designed to support the long-term invasive ventilation often required for COVID-19 patients and operates in pressure-regulated ventilation modes, which minimize the risk of furthering lung trauma. The MVM was extensively tested against ISO standards in the laboratory using a breathing simulator, with good agreement between input and measured breathing parameters and performing correctly in response to fault conditions and stability tests. The MVM has obtained Emergency Use Authorization by U.S. Food and Drug Administration (FDA) for use in healthcare settings during the COVID-19 pandemic and Health Canada Medical Device Authorization for Importation or Sale, under Interim Order for Use in Relation to COVID-19. Following these certifications, mass production is ongoing and distribution is under way in several countries. The MVM was designed, tested, prepared for certification, and mass produced in the space of a few months by a unique collaboration of respiratory healthcare professionals and experimental physicists, working with industrial partners, and is an excellent ventilator candidate for this pandemic anywhere in the world.

[Treatment of non-small cell lung cancer]. / Niet-kleincellig longcarcinoom.

In this review article we discuss the diagnostic workup and current treatment strategies for non-small cell lung cancer (NSCLC). Anatomical resection and systematic lymph node dissection is the recommended treatment for early-stage NSCLC. Stereotactic body radiotherapy (SBRT) is an alternative for non-operable patients. Locally advanced NSCLC could be treated with a combination of chemotherapy, radiotherapy and immunotherapy, and in select cases followed by surgical resection. Treatment for patients with metastasized NSCLC depends on molecular tumor characteristics, PD-L1 expression and could consist of chemotherapy, immunotherapy, targeted therapy or a combination of these modalities. In all stages, best supportive care is an option to consider. Because of the success of immunotherapy and targeted therapy for stage IV NSCLC, numerous trials have started to investigate the efficacy of these modalities in early-stage NSCLC as well, further optimizing treatment strategies for this patient group.

De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females.

PURPOSE: MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes. METHODS: By international matchmaking we assembled variant and clinical data on 18 females presenting with variable neurodevelopmental disorders (NDDs) and harboring de novo variants in MED12. RESULTS: Five nonsense variants clustered in the C-terminal region, two splice variants were found in the same exon 8 splice acceptor site, and 11 missense variants were distributed over the gene/protein. Protein truncating variants were associated with a severe, syndromic phenotype consisting of intellectual disability (ID), facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. De novo missense variants were associated with a less specific, but homogeneous phenotype including severe ID, autistic features, limited speech and variable other anomalies, overlapping both with females with truncating variants as well as males with missense variants. CONCLUSION: We establish de novo truncating variants in MED12 as causative for a distinct NDD and de novo missense variants as causative for a severe, less specific NDD in females.

Mouse models in the era of large human tumour sequencing studies.

Cancer is a complex disease in which cells progressively accumulate mutations disrupting their cellular processes. A fraction of these mutations drive tumourigenesis by affecting oncogenes or tumour suppressor genes, but many mutations are passengers with no clear contribution to tumour development. The advancement of DNA and RNA sequencing technologies has enabled in-depth analysis of thousands of human tumours from various tissues to perform systematic characterization of their (epi)genomes and transcriptomes in order to identify (epi)genetic changes associated with cancer. Combined with considerable progress in algorithmic development, this expansion in scale has resulted in the identification of many cancer-associated mutations, genes and pathways that are considered to be potential drivers of tumour development. However, it remains challenging to systematically identify drivers affected by complex genomic rearrangements and drivers residing in non-coding regions of the genome or in complex amplicons or deletions of copy-number driven tumours. Furthermore, functional characterization is challenging in the human context due to the lack of genetically tractable experimental model systems in which the effects of mutations can be studied in the context of their tumour microenvironment. In this respect, mouse models of human cancer provide unique opportunities for pinpointing novel driver genes and their detailed characterization. In this review, we provide an overview of approaches for complementing human studies with data from mouse models. We also discuss state-of-the-art technological developments for cancer gene discovery and validation in mice.

Repair: The Interface Between Interaction and Cognition.

Conversational repair is the process people use to detect and resolve problems of speaking, hearing, and understanding. Through repair, participants in social interaction display how they establish and maintain communication and mutual understanding. We argue that repair provides a crucial theoretical interface for research between diverse approaches to studying human interaction. We provide an overview of conversation analytic findings about repair in order to encourage further cross-disciplinary research involving both detailed inductive inquiry and more theory-driven experimental approaches. We outline CA's main typologies of repair and its methodological rationale, and we provide transcripts and examples that readers can explore for themselves using open data from online corpora. Since participants in interaction use repair to deal with problems as they emerge at the surface level of talk, we conclude that repair can be a point of convergence for studying mis/communication from multiple methodological perspectives.

Follow-up of implantable cardioverter-defibrillator therapy: comparison of coronary artery disease and dilated cardiomyopathy.

PURPOSE: Since several large trials have proven the effectiveness of implantable cardioverter-defibrillators (ICDs) in patients with left ventricular dysfunction, disadvantages have become more apparent. As the prognosis of patients with cardiovascular diseases is improving, assessment of ICD patients and re-evaluation of the current guidelines is mandatory. We aimed to evaluate differences in mortality and occurrence of (in)appropriate shocks in ICD patients with coronary artery disease (CAD) or dilated cardiomyopathy (DCM). METHODS: In a large teaching hospital, all consecutive patients with systolic dysfunction due to CAD or DCM who received an ICD with and without resynchronisation therapy, were collected in a database. RESULTS: A total of 320 consecutive patients (age 67 ± 10 years) were classified as CAD patients and 178 (63 ± 11 years) as DCM patients. Median follow-up was 40 months (interquartile range [IQR] 23─57 months). All-cause mortality was 14 % (CAD 15 % vs DCM 13 %). Appropriate shocks occurred in 13 % of all patients (CAD 15 % vs DCM 11 %, p = 0.12) and inappropriate shocks occurred in 10 % (CAD 8 % vs DCM 12 %, p = 0.27). Multivariate analysis demonstrated impaired left ventricular ejection fraction, QRS >120, age ≥75 years and low estimated glomerular filtration rate as predictors for all-cause mortality. Predictors for inappropriate shocks were permanent and paroxysmal atrial fibrillation. CONCLUSION: Mortality rates were similar in patients with CAD and DCM who received an ICD. Furthermore, no differences were found in the occurrence of appropriate and inappropriate ICD interventions between these patient groups.

Success of electrocardioversion on the elderly.

BACKGROUND: There are two treatment strategies for medication-resistant atrial fibrillation (AF): rhythm control or rate control. It has been suggested that rate control is a valid strategy in well-tolerated AF because it does not result in increased mortality. We aimed to investigate the 1-year outcome of rhythm control in an elderly population of AF patients. METHOD: The study was retrospective, using the data collected from electrocardioversions (ECV) of elderly patients and the data of their follow-up visits to the outpatient clinic. We looked for recurrence of AF within the first year after ECV. Furthermore, we investigated possible predictors of recurrence. RESULTS: From February 2008 till November 2011, 436 consecutive elderly patients admitted for ECV were included. The 1-year recurrence rate of AF was 51.3 %. We found that being female and a large left atrial diameter were independent predictors of recurrence. CONCLUSION: The AF recurrence rate in our elderly population is comparable with reported AF recurrence rates in a younger population; we conclude that rhythm control can be regarded as the viable strategy in persistent AF in elderly patients.

Robotic control of a traditional flexible endoscope for therapy.

In therapeutic flexible endoscopy a team of physician and assistant(s) is required to control all independent translations and rotations of the flexible endoscope and its instruments. As a consequence the physician lacks valuable force feedback information on tissue interaction, communication errors easily occur, and procedures are not cost-effective. Current tools are not suitable for performing therapeutic procedures in an intuitive and user-friendly way by one person. A shift from more invasive surgical procedures that require external incisions to endoluminal procedures that use the natural body openings could be expected if enabling techniques were available. This paper describes the design and evaluation of a robotic system which interacts with traditional flexible endoscopes to perform therapeutic procedures that require advanced maneuverability. The physician uses one multi-degree-of-freedom input device to control camera steering as well as shaft manipulation of the motorized flexible endoscope, while the other hand is able to manipulate instruments. We identified critical use aspects that need to be addressed in the robotic setup. A proof-of-principle setup was built and evaluated to judge the usability of our system. Results show that robotic endoscope control increases efficiency and satisfaction. Participants valued its intuitiveness, its accuracy, the feeling of being in control, and its single-person setup. Future work will concentrate on the design of a system that is fully functional and takes safety, cleanability, and easy positioning close to the patient into account.

Prediction of turn-ends based on anticipation of upcoming words.

During conversation listeners have to perform several tasks simultaneously. They have to comprehend their interlocutor's turn, while also having to prepare their own next turn. Moreover, a careful analysis of the timing of natural conversation reveals that next speakers also time their turns very precisely. This is possible only if listeners can predict accurately when the speaker's turn is going to end. But how are people able to predict when a turn-ends? We propose that people know when a turn-ends, because they know how it ends. We conducted a gating study to examine if better turn-end predictions coincide with more accurate anticipation of the last words of a turn. We used turns from an earlier button-press experiment where people had to press a button exactly when a turn-ended. We show that the proportion of correct guesses in our experiment is higher when a turn's end was estimated better in time in the button-press experiment. When people were too late in their anticipation in the button-press experiment, they also anticipated more words in our gating study. We conclude that people made predictions in advance about the upcoming content of a turn and used this prediction to estimate the duration of the turn. We suggest an economical model of turn-end anticipation that is based on anticipation of words and syntactic frames in comprehension.

Clinical variability of isovaleric acidemia in a genetically homogeneous population.

Isovaleric acidemia (IVA) is one of the most common organic acidemias found in South Africa. Since 1983, a significant number of IVA cases have been identified in approximately 20,000 Caucasian patients screened for metabolic defects. IVA is caused by an autosomal recessive deficiency of isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of isovaleryl-CoA and its metabolites. In total, 10 IVA patients and three carriers were available for phenotypic and genotypic investigation in this study. All patients were found to be homozygous for a single c.367 G > A (p.G123R) mutation. The amino acid substitution of a glycine to arginine resulted in a markedly reduced steady-state level of the IVD protein, which explains the nearly complete lack of IVD enzyme activity as assessed in fibroblast homogenates. Despite the genetic homogeneity of this South African IVA group, the clinical presentation varied widely, ranging from severe mental handicap and multiple episodes of metabolic derangement to an asymptomatic state. The variation may be due to poor dietary intervention, delayed diagnosis or even epigenetic and polygenetic factors of unknown origin.

Observation of tool use and modification for apparent hygiene purposes in a mandrill.

Tool making or modification to produce a tool of apparent improved functionality has rarely been reported in monkeys, especially when tools are used outside the context of food acquisition. We report on an observation of selection, modification and use of splinters for hygiene purposes in a male mandrill. The zoo-housed animal was video-recorded breaking splinters in sequence to use them underneath his toenails. This record brings forward new evidence that the ability to use and modify tools is not limited to apes and some New World monkeys but is also apparent in Old Word monkeys.

Recurrent and founder mutations in the Netherlands: mutation p.K217del in troponin T2, causing dilated cardiomyopathy.

Background. About 30% of dilated cardiomyopathy (DCM) cases are familial. Mutations are mostly found in the genes encoding lamin A/C, beta-myosin heavy chain and the sarcomeric protein cardiac troponin-T (TNNT2). Mutations in TNNT2 are reported in approximately 3% of DCM patients. The overall phenotype caused by TNNT2 mutations is thought to be a fully penetrant, severe disease. This also seems to be true for a recurrent deletion in the TNNT2 gene; p.K217del (also known as p.K210del). Methods. We compared the phenotype of all Dutch patients identified as carrying the TNNT2 p.K217del mutation with those described in the literature. All index patients underwent cardiological evaluation. Family screening was done in all described families. Results. Six DCM patients carrying the TNNT2 p.K217del mutation were identified from four Dutch families. Mean age of disease manifestation was 33 years. Heart transplantation was required in three of them at ages 12, 18 and 19 years. These outcomes are comparable with those described in the literature. Conclusion. Carriers of the TNNT2 p.K217del mutation in our Dutch families, as well as in families described in the literature before, generally show a severe, early-onset form of DCM. (Neth Heart J 2010;18:478-85.).

Ventricular asystole due to inhibition of ventricular backup pacing by a dual chamber pacemaker: possible pitfalls of default settings.

A 62-year-old patient presented with dizzy spells after her dual chamber pacemaker (Medtronic Enrhythm P1501DR), implanted for complete AV block, had been reprogrammed to deliver antitachycardia therapy (ATP) for paroxysmal atrial tachycardia. Her symptoms were caused by inhibition of ventricular backup pacing during ATP, leading to ventricular asystoles. Inhibition was the result of premature ventricular beats occurring prior to ATP: when ventricular backup pacing is left in the default setting, this pacemaker withholds backup pacing if any of the four preceding events is a sensed event. This case illustrates the possibly hazardous effects of default pacemaker settings, especially in pacemaker-dependent patients. (Neth Heart J 2010;18:323-6.).

The epidemiology of intra-abdominal flora in critically ill patients with secondary and tertiary abdominal sepsis.

BACKGROUND: Background: Different micro-organisms can be cultured from abdominal fluid obtained from patients with intra-abdominal infection resulting from a perforated digestive tract. We evaluated a cohort of patients with abdominal sepsis admitted to the intensive care with the aim of obtaining more insight into the type of microorganisms involved and the efficacy of treatment. MATERIALS AND METHODS: A 5-year prospective observational cohort study was performed in patients admitted to the intensive care unit with abdominal sepsis syndrome, defined as a perforation of the digestive tract and inflammatory response with organ failure. Abdominal fluid was obtained for microbial culture during the surgical procedures and from abdominal drains. The initial treatment protocol was cefotaxim, ciprofloxacin, metronidazole, and amphotericin B, tailored according to microbiological results. Selective decontamination of the digestive tract was administered to prevent secondary endogenous infections. RESULTS: Abdominal fluid was taken for microbial culture from 221 of the 239 patients admitted with abdominal sepsis. Aerobic Gram-negative bacteria (AGNB) were found in 52.9% of the cultures of abdominal fluid taken at the time of operation, of which 45% were Escherichia coli; in 36% of patients more than one AGNB was found. The incidence of AGNB was highest in colorectal perforations (68.6%) and perforated appendicitis (77.8%) and lowest in gastroduodenal perforations (20.5%). Gram-positive bacteria were found in 42.5% of the abdominal fluid cultures and most frequently in colorectal perforations (50.0%). Candida was found in 19.9% of patients, with 59.1% of these cultures being Candida albicans. The incidence of Candida was 41.0% in gastroduodenal perforations and 11.8% in colorectal perforation. Anaerobic bacteria were cultured in 77.8% of patients with perforated appendicitis. Over time, the prevalence of AGNB in abdominal fluid decreased from 117 patients (52.9%) in the first culture to one patient (6.7%) in week 4 (efficacy 87%). The prevalence of Gram-positive bacteria increased from 42.5% to 86.7% in a 4-week period. CONCLUSION: The composition of the intra-abdominal flora found in critically ill patients with abdominal sepsis varies depending on the location of the perforation. The efficacy of combined surgical and antibiotic treatment was 87% in 4 weeks for AGNB.

Permanent cardiac pacing for neurocardiogenic syncope.

Vasovagal syncope is not a benign condition in the elderly population. In patients not responsive to conservative therapy and whose abrupt faints are associated with serious injuries and seriously affected quality of life, pacemaker therapy was suggested. However, the usefulness of cardiac pacing for the prevention of recurrences of vasovagal syncope remains controversial because of the dominant role of the vasodepressor component during the episode. In the Medical Center Alkmaar, the Head-Up Tilt Test (HUTT) has been used since 1996 during the work-up of patients who present with vasovagal syncope. The HUTT showed a dominant cardioinhibitory response in 4.5% of our patients; in elderly patients with vasovagal syncope without prodromal symptoms and refractory on conservative therapy, pacemaker therapy was very effective in preventing syncope during long-term follow-up. (Neth Heart J 2008;16(Suppl1):S15-S19.).

Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review.

Valproic acid (VPA; 2-n-propylpentanoic acid) is widely used as a major drug in the treatment of epilepsy and in the control of several types of seizures. Being a simple fatty acid, VPA is a substrate for the fatty acid beta-oxidation (FAO) pathway, which takes place primarily in mitochondria. The toxicity of valproate has long been considered to be due primarily to its interference with mitochondrial beta-oxidation. The metabolism of the drug, its effects on enzymes of FAO and their cofactors such as CoA and/or carnitine will be reviewed. The cumulative consequences of VPA therapy in inborn errors of metabolism (IEMs) and the importance of recognizing an underlying IEM in cases of VPA-induced steatosis and acute liver toxicity are two different concepts that will be emphasized.