Promoter-centred chromatin interactions associated with EVI1 expression in EVI1+3q- myeloid leukaemia cells.

EVI1 expression is associated with poor prognosis in myeloid leukaemia, which can result from Chr.3q alterations that juxtapose enhancers to induce EVI1 expression via long-range chromatin interactions. More often, however, EVI1 expression occurs unrelated to 3q alterations, and it remained unclear if, in these cases, EVI1 expression is similarly caused by aberrant enhancer activation. Here, we report that, in EVI1+3q- myeloid leukaemia cells, the EVI1 promoter interacts via long-range chromatin interactions with promoters of distally located, active genes, rather than with enhancer elements. Unlike in 3q+ cells, EVI1 expression and long-range interactions appear to not depend on CTCF/cohesin, though EVI1+3q- cells utilise an EVI1 promoter-proximal site to enhance its expression that is also involved in CTCF-mediated looping in 3q+ cells. Long-range interactions in 3q- cells connect EVI1 to promoters of multiple genes, whose transcription correlates with EVI1 in EVI1+3q- cell lines, suggesting a shared mechanism of transcriptional regulation. In line with this, CRISPR interference-induced silencing of two of these sites minimally, but consistently reduced EVI1 expression. Together, we provide novel evidence of features associated with EVI1 expression in 3q- leukaemia and consolidate the view that EVI1 in 3q- leukaemia is largely promoter-driven, potentially involving long-distance promoter clustering.

Subject-independent meta-learning framework towards optimal training of EEG-based classifiers.

Advances in deep learning have shown great promise towards the application of performing high-accuracy Electroencephalography (EEG) signal classification in a variety of tasks. However, many EEG-based datasets are often plagued by the issue of high inter-subject signal variability. Robust deep learning models are notoriously difficult to train under such scenarios, often leading to subpar or widely varying performance across subjects under the leave-one-subject-out paradigm. Recently, the model agnostic meta-learning framework was introduced as a way to increase the model's ability to generalize towards new tasks. While the original framework focused on task-based meta-learning, this research aims to show that the meta-learning methodology can be modified towards subject-based signal classification while maintaining the same task objectives and achieve state-of-the-art performance. Namely, we propose the novel implementation of a few/zero-shot subject-independent meta-learning framework towards multi-class inner speech and binary class motor imagery classification. Compared to current subject-adaptive methods which utilize large number of labels from the target, the proposed framework shows its effectiveness in training zero-calibration and few-shot models for subject-independent EEG classification. The proposed few/zero-shot subject-independent meta-learning mechanism performs well on both small and large datasets and achieves robust, generalized performance across subjects. The results obtained shows a significant improvement over the current state-of-the-art, with the binary class motor imagery achieving 88.70% and the accuracy of multi-class inner speech achieving an average of 31.15%. Codes will be made available to public upon publication.

Deep Unsupervised Representation Learning for Feature-Informed EEG Domain Extraction.

In electroencephalography (EEG) classification paradigms, data from a target subject is often difficult to obtain, leading to difficulties in training a robust deep learning network. Transfer learning and their variations are effective tools in improving such models suffering from lack of data. However, many of the proposed variations and deep models often rely on a single assumed distribution to represent the latent features which may not scale well due to inter- and intra-subject variations in signals. This leads to significant instability in individual subject decoding performances. The presence of non-trivial domain differences between different sets of training or transfer learning data causes poorer model generalization towards the target subject. However, the detection of these domain differences is often difficult to perform due to the ill-defined nature of the EEG domain features. This study proposes a novel inference model, the Joint Embedding Variational Autoencoder, that offers conditionally tighter approximation of the estimated spatiotemporal feature distribution through the use of jointly optimised variational autoencoders to achieve optimizable data dependent inputs as an additional variable for improved overall model optimisation and scaling without sacrificing model tightness. To learn the variational bound, we show that maximising the marginal log-likelihood of only the second embedding section is required to achieve conditionally tighter lower bounds. Furthermore, we show that this model provides state-of-the-art EEG data reconstruction and deep feature extraction. The extracted domains of the EEG signals across each subject displays the rationale as to why there exists disparity between subjects' adaptation efficacy.

Case of human rabies despite post-exposure prophylaxis (PEP) and complete recovery after intrathecal rabies immunoglobulin (RIG).

Rabies, a fatal viral zoonotic disease, has become a public health concern in Sarawak, Malaysia. Despite pre-exposure and post-exposure prophylaxis being available, there has been limited progress in developing treatments for rabies, emphasising the pressing need for productive solutions. We present a laboratory-confirmed human rabies case in which the patient survived without neurological sequelae after receiving intrathecal rabies immunoglobulin.

Targeted engagement of ß-catenin-Ikaros complexes in refractory B-cell malignancies.

In most cell types, nuclear ß-catenin functions as prominent oncogenic driver and pairs with TCF7-family factors for transcriptional activation of MYC. Surprisingly, B-lymphoid malignancies not only lacked expression and activating lesions of ß-catenin but critically depended on GSK3ß for effective ß-catenin degradation. Our interactome studies in B-lymphoid tumors revealed that ß-catenin formed repressive complexes with lymphoid-specific Ikaros factors at the expense of TCF7. Instead of MYC-activation, ß-catenin was essential to enable Ikaros-mediated recruitment of nucleosome remodeling and deacetylation (NuRD) complexes for transcriptional repression of MYC. To leverage this previously unrecognized vulnerability of B-cell-specific repressive ß-catenin-Ikaros-complexes in refractory B-cell malignancies, we examined GSK3ß small molecule inhibitors to subvert ß-catenin degradation. Clinically approved GSK3ß-inhibitors that achieved favorable safety prof les at micromolar concentrations in clinical trials for neurological disorders and solid tumors were effective at low nanomolar concentrations in B-cell malignancies, induced massive accumulation of ß-catenin, repression of MYC and acute cell death. Preclinical in vivo treatment experiments in patient-derived xenografts validated small molecule GSK3ß-inhibitors for targeted engagement of lymphoid-specific ß-catenin-Ikaros complexes as a novel strategy to overcome conventional mechanisms of drug-resistance in refractory malignancies. HIGHLIGHTS: Unlike other cell lineages, B-cells express nuclear ß-catenin protein at low baseline levels and depend on GSK3ß for its degradation.In B-cells, ß-catenin forms unique complexes with lymphoid-specific Ikaros factors and is required for Ikaros-mediated tumor suppression and assembly of repressive NuRD complexes. CRISPR-based knockin mutation of a single Ikaros-binding motif in a lymphoid MYC superenhancer region reversed ß-catenin-dependent Myc repression and induction of cell death. The discovery of GSK3ß-dependent degradation of ß-catenin as unique B-lymphoid vulnerability provides a rationale to repurpose clinically approved GSK3ß-inhibitors for the treatment of refractory B-cell malignancies. GRAPHICAL ABSTRACT: Abundant nuclear ß-cateninß-catenin pairs with TCF7 factors for transcriptional activation of MYCB-cells rely on efficient degradation of ß-catenin by GSK3ßB-cell-specific expression of Ikaros factors Unique vulnerability in B-cell tumors: GSK3ß-inhibitors induce nuclear accumulation of ß-catenin.ß-catenin pairs with B-cell-specific Ikaros factors for transcriptional repression of MYC.

Freehand transperineal prostate biopsy with a coaxial needle under local anesthesia: Experience from a single institution in Malaysia.

Background: Freehand transperineal prostate biopsy (TPPBx) using a coaxial needle technique offers an alternative to probe-mounted freehand or template-guided techniques in the diagnosis of prostate cancer (PCa). It only requires the same equipment used for transrectal ultrasound-guided (TRUS) biopsy. Our study is the first in Malaysia to report this experience and its outcomes. We aim to determine PCa detection rate and pain tolerability of freehand TPPBx utilizing a coaxial needle under local anesthesia (LA). Methods: Institutional review board approval was obtained from National Medical Research Register (NMRR ID-21-02052-VIL). We retrospectively reviewed the medical records of patients who underwent TPPBx between August 2020 and April 2022. Records were reviewed for patients' characteristics, prostate volume, prostate-specific antigen (PSA) results, biopsy results and pain tolerability. Data was analyzed to determine PCa and clinically significant prostate cancer (csPCa) detection rate. LA was achieved using perineal skin infiltration and a periprostatic nerve block. The commonly used standard side-firing transrectal ultrasound with its Prostate Biplane Transducer was used as an imaging guide. The principles of the Ginsburg protocol were followed. Pain tolerability was assessed using a visual analog scale. Results: A total of 55 patients with elevated PSA levels underwent freehand TPPBx under LA. The mean age was 67.3 years, the median PSA was 14.2 ng/mL, and the median PSA density (PSAD) was 0.33 ng/mL/cc. The optimal PSAD cutoff for predicting csPCa was 0.35 ng/mL/cc (area under the curve [AUC], 0.792; sensitivity, 87.5%; specificity, 69.2%). PCa was detected in 24 patients (43.6%), of whom 16 (29.1%) had csPCa. The median pain scores during LA infiltration and biopsy were four and two, respectively, which were significant different (P < 0.05). TPPBx exhibited an infection rate of zero. Conclusion: The PCa detection rate and patient tolerability of freehand TPPBx using a coaxial needle are similar to those of a contemporary published series. The use of existing equipment that is used for TRUS biopsy allows for widespread use and transition from TRUS biopsy.

Bilateral medial medullary stroke: A rare stroke syndrome masquerading as myasthenia crisis in a young diabetic lady.

Bilateral medial medullary stroke is a rare stroke syndrome. The clinical presentation of bilateral medial medullary stroke is heterogenous and often overlaps with other non-stroke neurology emergencies such as Guillain-Barrésyndrome, myasthenic crisis and acute vestibular syndrome, leading to misdiagnosis. We wish to present a case of a young lady with type 1 diabetes mellitus, who had presented with subacute neuromuscular weakness which was erroneously treated as myasthenic crisis. Her case was subsequently diagnosed as bilateral medial medullary stroke, following evolving clinical signs and magnetic resonance imaging (MRI) findings of a heart-shaped abnormality at the rostral medulla. This rare stroke syndrome represented a diagnostic challenge which necessitated a strong clinical suspicion and an urgent MRI scan of the brain for prompt diagnosis to enable appropriate treatment initiation.

Association of transplant center market concentration and local organ availability with deceased donor kidney utilization.

Although there is a shortage of kidneys available for transplantation, many transplantable kidneys are not procured or are discarded after procurement. We investigated whether local market competition and/or organ availability impact kidney procurement/utilization. We calculated the Herfindahl-Hirschman Index (HHI) for deceased donor kidney transplants (2015-2019) for 58 US donation service areas (DSAs) and defined 4 groups: HHI ≤ 0.32 (high competition), HHI = 0.33-0.51 (medium), HHI = 0.53-0.99 (low), and HHI = 1 (monopoly). We calculated organ availability for each DSA as the number kidneys procured per incident waitlisted candidate, grouped as: <0.42, 0.42-0.69, >0.69. Characteristics of procured organs were similar across groups. In adjusted logistic regression, the HHI group was inconsistently associated with composite export/discard (reference: high competition; medium: OR 1.16, 95% CI 1.11-1.20; low 1.01, 0.96-1.06; monopoly 1.19, 1.13-1.26) and increasing organ availability was associated with export/discard (reference: availability <0.42; 0.42-0.69: OR 1.35, 95% CI 1.30-1.40; >0.69: OR 1.83, 95% CI 1.73-1.93). When analyzing each endpoint separately, lower competition was associated with higher export and only market monopoly was weakly associated with lower discard, whereas higher organ availability was associated with export and discard. These results indicate that local organ utilization is more strongly influenced by the relative intensity of the organ shortage than by market competition between centers.

Genomic Surveillance for SARS-CoV-2 Variants: Predominance of the Delta (B.1.617.2) and Omicron (B.1.1.529) Variants - United States, June 2021-January 2022.

Genomic surveillance is a critical tool for tracking emerging variants of SARS-CoV-2 (the virus that causes COVID-19), which can exhibit characteristics that potentially affect public health and clinical interventions, including increased transmissibility, illness severity, and capacity for immune escape. During June 2021-January 2022, CDC expanded genomic surveillance data sources to incorporate sequence data from public repositories to produce weighted estimates of variant proportions at the jurisdiction level and refined analytic methods to enhance the timeliness and accuracy of national and regional variant proportion estimates. These changes also allowed for more comprehensive variant proportion estimation at the jurisdictional level (i.e., U.S. state, district, territory, and freely associated state). The data in this report are a summary of findings of recent proportions of circulating variants that are updated weekly on CDC's COVID Data Tracker website to enable timely public health action.† The SARS-CoV-2 Delta (B.1.617.2 and AY sublineages) variant rose from 1% to >50% of viral lineages circulating nationally during 8 weeks, from May 1-June 26, 2021. Delta-associated infections remained predominant until being rapidly overtaken by infections associated with the Omicron (B.1.1.529 and BA sublineages) variant in December 2021, when Omicron increased from 1% to >50% of circulating viral lineages during a 2-week period. As of the week ending January 22, 2022, Omicron was estimated to account for 99.2% (95% CI = 99.0%-99.5%) of SARS-CoV-2 infections nationwide, and Delta for 0.7% (95% CI = 0.5%-1.0%). The dynamic landscape of SARS-CoV-2 variants in 2021, including Delta- and Omicron-driven resurgences of SARS-CoV-2 transmission across the United States, underscores the importance of robust genomic surveillance efforts to inform public health planning and practice.

Intention Estimation Based Adaptive Unscented Kalman Filter for Online Neural Decoding.

The commonly used fixed discrete Kalman filters (DKF) in neural decoders do not generalize well to the actual relationship between neuronal firing rates and movement intention. This is due to the underlying assumption that the neural activity is linearly related to the output state. They also face the issues of requiring large amount of training datasets to achieve a robust model and a degradation of decoding performance over time. In this paper, an adaptive adjustment is made to the conventional unscented Kalman filter (UKF) via intention estimation. This is done by incorporating a history of newly collected state parameters to develop a new set of model parameters. At each time point, a comparative weighted sum of old and new model parameters using matrix squared sums is used to update the neural decoding model parameters. The effectiveness of the resulting adaptive unscented Kalman filter (AUKF) is compared against the discrete Kalman filter and unscented Kalman filter-based algorithms. The results show that the proposed new algorithm provides higher decoding accuracy and stability while requiring less training data.

To Be, or Notch to Be: Mediating Cell Fate from Embryogenesis to Lymphopoiesis.

Notch signaling forms an evolutionarily conserved juxtacrine pathway crucial for cellular development. Initially identified in Drosophila wing morphogenesis, Notch signaling has since been demonstrated to play pivotal roles in governing mammalian cellular development in a large variety of cell types. Indeed, abolishing Notch constituents in mouse models result in embryonic lethality, demonstrating that Notch signaling is critical for development and differentiation. In this review, we focus on the crucial role of Notch signaling in governing embryogenesis and differentiation of multiple progenitor cell types. Using hematopoiesis as a diverse cellular model, we highlight the role of Notch in regulating the cell fate of common lymphoid progenitors. Additionally, the influence of Notch through microenvironment interplay with lymphoid cells and how dysregulation influences disease processes is explored. Furthermore, bi-directional and lateral Notch signaling between ligand expressing source cells and target cells are investigated, indicating potentially novel therapeutic options for treatment of Notch-mediated diseases. Finally, we discuss the role of cis-inhibition in regulating Notch signaling in mammalian development.

A retrospective analysis of emerging rabies: a neglected tropical disease in Sarawak, Malaysia.

BACKGROUND: Rabies, a neglected tropical disease (NTD), is a viral infection which is often fatal. Since 2017, a rabies epidemic has been declared in Sarawak, Malaysia. However, there is a lack of local epidemiological data and descriptions of local presentations of this disease. METHOD: This was a retrospective analysis of a series of rabies cases encountered in Sibu Hospital, Sarawak from March 2020 to February 2021. RESULT: Six cases of rabies were identified in this series, all with a mixture of upper motor neuron and lower motor neuron findings. Most cases did not seek medical attention upon dog bite and therefore effective post-exposure prophylaxis was not given. The incubation period varied from 17 days to 2 years. All cases died, with five cases succumbing to the illness within two weeks of symptom onset. The cumulative incidence for rabies in Sibu was estimated at 1.7 per 100,000 population. CONCLUSION: The lack of public awareness of the implication of animal bites and the immediate management in rabies-endemic regions are factors contributing to high rabies mortality.

Notch signaling induces a transcriptionally permissive state at the Complement C3d Receptor 2 (CR2) promoter in a pre-B cell model.

During mammalian lymphoid development, Notch signaling is necessary at multiple stages of T lymphopoiesis, including lineage commitment, and later stages of T cell effector differentiation. In contrast, outside of a defined role in the development of splenic marginal zone B cells, there is conflicting evidence regarding whether Notch signaling plays functional roles in other B cell sub-populations. Complement receptor 2 (CR2) modulates BCR-signaling and is tightly regulated throughout differentiation. During B lymphopoiesis, CR2 is detected on immature and mature B cells with high surface expression on marginal zone B cells. Here, we have explored the possibility that Notch regulates human CR2 transcriptional activity using in vitro models including a co-culture system, co-transfection gene reporters and chromatin accessibility assays. We provide evidence that Notch signaling regulates CR2 promoter activity in a mature B cell line, as well as the induction of endogenous CR2 mRNA in a non-expressing pre-B cell line. The dynamics of endogenous gene activation suggests additional unidentified factors are required to mediate surface CR2 expression on immature and mature B lineage cells.

Forme fruste anti-GQ1b-negative Miller Fischer syndrome masquerading as posterior circulation stroke.

Miller Fischer syndrome (MFS) is a variant of Guillain-Barré syndrome first described in 1956 and is characterised by the clinical triad of ophthalmoplegia, ataxia and areflexia. However, since its discovery, forme fruste and overlapping syndrome have been described. A forme fruste of MFS implies an attenuated form where not all of the clinical triad are present. In this report, a case of MFS is highlighted that was mistakenly treated as posterior circulation stroke, as well as the challenges faced in reaching the correct diagnosis and hence the appropriate treatment.

Disease-associated missense variants in ZBTB18 disrupt DNA binding and impair the development of neurons within the embryonic cerebral cortex.

The activities of DNA-binding transcription factors, such as the multi-zinc-finger protein ZBTB18 (also known as RP58, or ZNF238), are essential to coordinate mammalian neurodevelopment, including the birth and radial migration of newborn neurons within the fetal brain. In humans, the majority of disease-associated missense mutations in ZBTB18 lie within the DNA-binding zinc-finger domain and are associated with brain developmental disorder, yet the molecular mechanisms explaining their role in disease remain unclear. To address this, we developed in silico models of ZBTB18, bound to DNA, and discovered that half of the missense variants map to residues (Asn461, Arg464, Glu486) predicted to be essential to sequence-specific DNA contact, whereas others map to residues (Leu434, Tyr447, Arg495) with limited contributions to DNA binding. We studied pathogenic variants to residues with close (N461S) and limited (R495G) DNA contact and found that each bound DNA promiscuously, displayed altered transcriptional regulatory activity in vitro, and influenced the radial migration of newborn neurons in vivo in different ways. Taken together, our results suggest that altered transcriptional regulation could represent an important pathological mechanism for ZBTB18 missense variants in brain developmental disease.

Idiopathic CD4 lymphopenia in a case of disseminated cryptococcosis with brain, vertebral spine and reproductive organ involvement.

Cryptococcosis is an opportunistic fungal infection commonly seen in HIV cases. We present a case of disseminated cryptococcosis with multiple non-continuous infective foci in a non-HIV, non-transplant case.

Prognostic factors for mortality due to pneumonia among adults from different age groups in Singapore and mortality predictions based on PSI and CURB-65.

INTRODUCTION: Pneumonia is associated with considerable mortality. However, there is limited information on age-specific prognostic factors for death from pneumonia. METHODS: Patients hospitalised with a diagnosis of pneumonia through the emergency department were stratified into three age groups: 18-64 years, 65-84 years and ≥ 85 years. Multivariate logistic regression and receiver operating characteristic curve analyses were conducted to evaluate prognostic factors for mortality and the performance of pneumonia severity scoring tools for mortality prediction. RESULTS: A total of 1,902 patients were enrolled (18-64 years: 614 [32.3%]; 65-84 years: 944 [49.6%]; ≥ 85 years: 344 [18.1%]). Mortality rates increased with age (18-64 years: 7.3%; 65-84 years: 16.1%; ≥ 85 years: 29.7%; p < 0.001). Malignancy and tachycardia were prognostic of mortality among patients aged 18-64 years. Male gender, malignancy, congestive heart failure and eight other parameters reflecting acute disease severity were associated with mortality among patients aged 65-84 years. For patients aged ≥ 85 years, altered mental status, tachycardia, blood urea nitrogen, hypoxaemia, arterial pH and pleural effusion were significantly predictive of mortality. The Pneumonia Severity Index (PSI) was more sensitive than CURB-65 (confusion, uraemia, respiratory rate ≥ 30 per minute, low blood pressure, age ≥ 65 years) for mortality prediction across all age groups. CONCLUSION: The predictive effect of prognostic factors for mortality varied among patients with pneumonia from the different age groups. PSI performed significantly better than CURB-65 for mortality prediction, but its discriminative power decreased with advancing age.

Measuring the effectiveness of a novel CPRcard™ feedback device during simulated chest compressions by non-healthcare workers.

INTRODUCTION: There is a need for a simple-to-use and easy-to-carry CPR feedback device for laypersons. We aimed to determine if a novel CPRcard™ feedback device improved the quality of chest compressions. METHODS: We compared participants' chest compression rate and depth with and without feedback. Compression data was captured through the CPRcard™ or Resusci Anne's SimPad® SkillReporter™. Compression quality was defined based on 2010 international guidelines for rate, depth and flow fraction. RESULTS: Overall, the CPRcard group achieved a better median compression rate (CPRcard 117 vs. control 122, p = 0.001) and proportion of compressions within the adequate rate range (CPRcard 83% vs. control 47%, p < 0.001). Compared to the no-card and blinded-card groups, the CPRcard group had a higher proportion of adequate compression rate (CPRcard 88% vs. no-card 46.8%, p = 0.037; CPRcard 73% vs. blinded-card 43%, p = 0.003). Proportion of compressions with adequate depth was similar in all groups (CPRcard 52% vs. control 48%, p = 0.957). The CPRcard group more often met targets for compression rate of 100-120/min and depth of at least 5 cm (CPRcard 36% vs. control 4%, p = 0.022). Chest compression flow fraction rate was similar but not statistically significant in all groups (92%, p = 1.0). Respondents using the CPRcard expressed higher confidence (mean 2.7 ± 2.4; 1 = very confident, 10 = not confident). CONCLUSION: Use of the CPRcard by non-healthcare workers in simulated resuscitation improved the quality of chest compressions, thus boosting user confidence in performing compressions.

The risk of tuberculosis in SLE patients from an Asian tertiary hospital.

Systemic lupus erythematosus (SLE) has been associated with increased risk of tuberculosis (TB). However, little is known about the extent and risk factors for TB among Asian patient with SLE. We aimed to assess the rate of TB in patients with SLE, and investigate the risk of SLE on TB development using hospital administrative database. This is an historical cohort study of hospital discharge database from 2004 to 2011 to identify cases with SLE and TB using International Statistical Classification of Diseases and Related Health Problems, 9th Revision, Australian Modification (ICD-9-AM) codes. Of 301568 hospitalized patients, 841 (0.3%) patients had SLE, 1843 (0.6%) patients had TB, including 17 SLE patients (2.0%). SLE patients had a significantly higher rate of TB (2.0 vs. 0.6%, p < 0.001) compared to that of patients without SLE. The differences in the higher rate after breaking down was in the pulmonary TB group (1.7 vs. 0.5%, p < 0.00) but not in extrapulmonary TB group (0.4 vs. 0.1%, p = 0.060). Logistic regression analyses showed that SLE was a significant and independent predictor of TB (odds ratio 4.6, 95% CI 2.8-7.5, p < 0.001) after adjustment for factors such as age group, gender, ethnicity, admission class, nutritional deficiency, organ transplantation, and Charlson comorbidity index. SLE patients were found to experience higher rates of tuberculosis in this group of Asian patient population. Patients with SLE should be considered as a high-risk group for TB, active screening for latent patients and treatment for positive TB patients is needed.