Improving BOLD sensitivity with real-time multi-echo echo-planar imaging - Towards a cleaner neurofeedback signal

Real-time functional magnetic resonance imaging (rtfMRI) suffers from known issues related to T2*-weighted single-echo echo-planar imaging (EPI). These include image dropout in areas with increased local magnetic susceptibility susceptibility gradients; suboptimal whole-brain blood oxygen level-dependent (BOLD) contrast due to average T2*-weighting; and confounders like subject motion and physiology. During fMRI neurofeedback a metric calculated from real-time brain activity is presented visually to the subject in the scanner. To prevent sham feedback, new methods should focus on improving BOLD signal quality in real-time. In this work, presented as a poster at the 11th annual meeting of the ISMRM Benelux chapter (17 January 2019), we present our work on real-time multi-echo fMRI and its usefulness in increasing the temporal signal-to-noise ratio (tSNR) of rtfMRI

Signal processing with Levy information

Levy processes, which have stationary independent increments, are ideal for modelling the various types of noise that can arise in communication channels. If a Levy process admits exponential moments, then there exists a parametric family of measure changes called Esscher transformations. If the parameter is replaced with an independent random variable, the true value of which represents a "message", then under the transformed measure the original Levy process takes on the character of an "information process". In this paper we develop a theory of such Levy information processes. The underlying Levy process, which we call the fiducial process, represents the "noise type". Each such noise type is capable of carrying a message of a certain specification. A number of examples are worked out in detail, including information processes of the Brownian, Poisson, gamma, variance gamma, negative binomial, inverse Gaussian, and normal inverse Gaussian type. Although in general there is no additive decomposition of information into signal and noise, one is led nevertheless for each noise type to a well-defined scheme for signal detection and enhancement relevant to a variety of practical situations.Comment: 27 pages. Version to appear in: Proc. R. Soc. London

Tapasin assembly surveillance by the RNF185/Membralin ubiquitin ligase complex regulates MHC-I surface expression

\ua9 The Author(s) 2024.Immune surveillance by cytotoxic T cells eliminates tumor cells and cells infected by intracellular pathogens. This process relies on the presentation of antigenic peptides by Major Histocompatibility Complex class I (MHC-I) at the cell surface. The loading of these peptides onto MHC-I depends on the peptide loading complex (PLC) at the endoplasmic reticulum (ER). Here, we uncovered that MHC-I antigen presentation is regulated by ER-associated degradation (ERAD), a protein quality control process essential to clear misfolded and unassembled proteins. An unbiased proteomics screen identified the PLC component Tapasin, essential for peptide loading onto MHC-I, as a substrate of the RNF185/Membralin ERAD complex. Loss of RNF185/Membralin resulted in elevated Tapasin steady state levels and increased MHC-I at the surface of professional antigen presenting cells. We further show that RNF185/Membralin ERAD complex recognizes unassembled Tapasin and limits its incorporation into PLC. These findings establish a novel mechanism controlling antigen presentation and suggest RNF185/Membralin as a potential therapeutic target to modulate immune surveillance

Tuberculosis patients' reasons for, and suggestions to address non-uptake of HIV testing: a cross-sectional study in the Free State Province, South Africa

<p>Abstract</p> <p>Background</p> <p>South Africa endorses the global policy shift from primarily client-initiated voluntary counselling and testing (VCT) to routine/provider-initiated testing and counselling (PITC). The reason for this policy shift has been to facilitate uptake of HIV testing amongst at-risk populations in high-prevalence settings. Despite ostensible implementation of routine/PITC, uptake amongst tuberculosis (TB) patients in this country remains a challenge. This study presents the reasons that non-tested TB patients offered for their refusal of HIV testing and reflects on all TB patients' suggestions as to how this situation may be alleviated.</p> <p>Methods</p> <p>In February-March 2008, a cross-sectional survey was conducted amongst 600 TB patients across 61 primary health care facilities in four sub-districts in the Free State. Patient selection was done proportionally to the numbers registered at each facility in 2007. Data were subjected to bivariate tests and content analysis of open-ended questions.</p> <p>Results</p> <p>Almost one-third (32.5%) of the respondents reported that they had not undertaken HIV testing, with the most often offered explanation being that they were '<it>undecided</it>' (37.0%). Other self-reported reasons for non-uptake included: fear (e.g. of testing HIV-positive, 19.0%); perception of being at low risk of HIV infection (13.4%); desire first to deal with TB 'on its own' (12.5%); and because HIV testing had not been offered to them (12.0%). Many patients expressed the need for support and motivation not only from health care workers (33.3%), but also from their significant others (56.6%). Patients further expressed a need for (increased) dissemination of TB-HIV information by health care workers (46.1%).</p> <p>Conclusions</p> <p>Patients did not undergo HIV testing for various patient-/individual-related reasons. Non-uptake of HIV testing was also due to health system limitations such as the non-offer of HIV testing. Other measures may be necessary to supplement routine/provider-initiation of HIV testing. From the TB patient's perspective, there is a need for (improved) dissemination of information on the TB-HIV link. Patients also require (repeated) motivation and support to undergo HIV testing, the onus for which rests not only on the public health authority and health care workers, but also on other people in the patients' social support networks.</p

Constraints to Implementing the Essential Health Package in Malawi

Increasingly seen as a useful tool of health policy, Essential or Minimal Health Packages direct resources to interventions that aim to address the local burden of disease and be cost-effective. Less attention has been paid to the delivery mechanisms for such interventions. This study aimed to assess the degree to which the Essential Health Package (EHP) in Malawi was available to its population and what health system constraints impeded its full implementation. The first phase of this study comprised a survey of all facilities in three districts including interviews with all managers and clinical staff. In the second and third phase, results were discussed with District Health Management Teams and national level stakeholders, respectively, including representatives of the Ministry of Health, Central Medical Stores, donors and NGOs. The EHP in Malawi is focussing on the local burden of disease; however, key constraints to its successful implementation included a widespread shortage of staff due to vacancies but also caused by frequent trainings and meetings (only 48% of expected man days of clinical staff were available; training and meetings represented 57% of all absences in health centres). Despite the training, the percentage of health workers aware of vital diagnostic and therapeutic approaches to EHP conditions was weak. Another major constraint was shortages of vital drugs at all levels of facilities (e.g. Cotrimoxazole was sufficiently available to treat the average number of patients in only 27% of health centres). Although a few health workers noted some improvement in infrastructure and working conditions, they still considered them to be widely inadequate. In Malawi, as in similar resource poor countries, greater attention needs to be given to the health system constraints to delivering health care. Removal of these constraints should receive priority over the considerable focus on the development and implementation of essential packages of interventions

Airway Management in the Paediatric Difficult Intubation Registry: A Propensity Score Matched Analysis of Outcomes Over Time

BACKGROUND: The Paediatric Difficult Intubation Collaborative identified multiple attempts and persistence with direct laryngoscopy as risk factors for complications in children with difficult tracheal intubations and subsequently engaged in initiatives to reduce repeated attempts and persistence with direct laryngoscopy in children. We hypothesised these efforts would lead to fewer attempts, fewer direct laryngoscopy attempts and decrease complications. METHODS: Paediatric patients less than 18 years of age with difficult direct laryngoscopy were enrolled in the Paediatric Difficult Intubation Registry. We define patients with difficult direct laryngoscopy as those in whom (1) an attending or consultant obtained a Cormack Lehane Grade 3 or 4 view on direct laryngoscopy, (2) limited mouth opening makes direct laryngoscopy impossible, (3) direct laryngoscopy failed in the preceding 6 months, and (4) direct laryngoscopy was deferred due to perceived risk of harm or poor chance of success. We used a 5:1 propensity score match to compare an early cohort from the initial Paediatric Difficult Intubation Registry analysis (August 6, 2012-January 31, 2015, 785 patients, 13 centres) and a current cohort from the Registry (March 4, 2017-March 31, 2023, 3925 patients, 43 centres). The primary outcome was first attempt success rate between cohorts. Success was defined as confirmed endotracheal intubation and assessed by the treating clinician. Secondary outcomes were eventual success rate, number of attempts at intubation, number of attempts with direct laryngoscopy, the incidence of persistence with direct laryngoscopy, use of supplemental oxygen, all complications, and severe complications. FINDINGS: First-attempt success rate was higher in the current cohort (42% vs 32%, OR 1.5 95% CI 1.3-1.8, p \u3c 0.001). In the current cohort, there were fewer attempts (2.2 current vs 2.7 early, regression coefficient -0.5 95% CI -0.6 to -0.4, p \u3c 0.001), fewer attempts with direct laryngoscopy (0.6 current vs 1.0 early, regression coefficient -0.4 95% CI -0.4 to 0.3, p \u3c 0.001), and reduced persistence with direct laryngoscopy beyond two attempts (7.3% current vs 14.1% early, OR 0.5 95% CI 0.4-0.6, p \u3c 0.001). Overall complication rates were similar between cohorts (19% current vs 20% early). Severe complications decreased to 1.8% in the current cohort from 3.2% in the early cohort (OR 0.55 95% CI 0.35-0.87, p = 0.011). Cardiac arrests decreased to 0.8% in the current cohort from 1.8% in the early cohort. We identified persistence with direct laryngoscopy as a potentially modifiable factor associated with severe complications. INTERPRETATION: In the current cohort, children with difficult tracheal intubations underwent fewer intubation attempts, fewer attempts with direct laryngoscopy, and had a nearly 50% reduction in severe complications. As persistence with direct laryngoscopy continues to be associated with severe complications, efforts to limit direct laryngoscopy and promote rapid transition to advanced techniques may enhance patient safety. FUNDING: None

Outer membrane utilisomes mediate glycan uptake in gut Bacteroidetes

Bacteroidetes are abundant members of the human microbiota, utilizing a myriad of diet- and host-derived glycans in the distal gut1. Glycan uptake across the bacterial outer membrane of these bacteria is mediated by SusCD protein complexes, comprising a membrane-embedded barrel and a lipoprotein lid, which is thought to open and close to facilitate substrate binding and transport. However, surface-exposed glycan-binding proteins and glycoside hydrolases also play critical roles in the capture, processing and transport of large glycan chains. The interactions between these components in the outer membrane are poorly understood, despite being crucial for nutrient acquisition by our colonic microbiota. Here we show that for both the levan and dextran utilization systems of Bacteroides thetaiotaomicron, the additional outer membrane components assemble on the core SusCD transporter, forming stable glycan-utilizing machines that we term utilisomes. Single-particle cryogenic electron microscopy structures in the absence and presence of substrate reveal concerted conformational changes that demonstrate the mechanism of substrate capture, and rationalize the role of each component in the utilisome