Abstract
Despite commercial availability of software to facilitate sleep–wake scoring of electroencephalography (EEG) and electromyography (EMG) in animals, automated scoring of rodent models of ...abnormal sleep, such as narcolepsy with cataplexy, has remained elusive. We optimize two machine-learning approaches, supervised and unsupervised, for automated scoring of behavioral states in orexin/ataxin-3 transgenic mice, a validated model of narcolepsy type 1, and additionally test them on wild-type mice. The supervised learning approach uses previously labeled data to facilitate training of a classifier for sleep states, whereas the unsupervised approach aims to discover latent structure and similarities in unlabeled data from which sleep stages are inferred. For the supervised approach, we employ a deep convolutional neural network architecture that is trained on expert-labeled segments of wake, non-REM sleep, and REM sleep in EEG/EMG time series data. The resulting trained classifier is then used to infer on the labels of previously unseen data. For the unsupervised approach, we leverage data dimensionality reduction and clustering techniques. Both approaches successfully score EEG/EMG data, achieving mean accuracies of 95% and 91%, respectively, in narcoleptic mice, and accuracies of 93% and 89%, respectively, in wild-type mice. Notably, the supervised approach generalized well on previously unseen data from the same animals on which it was trained but exhibited lower performance on animals not present in the training data due to inter-subject variability. Cataplexy is scored with a sensitivity of 85% and 57% using the supervised and unsupervised approaches, respectively, when compared to manual scoring, and the specificity exceeds 99% in both cases.
Narcolepsy type 1 (NT1, narcolepsy with cataplexy) is a disabling neurological disorder caused by loss of excitatory orexin neurons from the hypothalamus and is characterized by decreased motivation, ...sleep-wake fragmentation, intrusion of rapid-eye-movement sleep (REMS) during wake, and abrupt loss of muscle tone, called cataplexy, in response to sudden emotions.
We investigated whether subcortical stimulation, analogous to clinical deep brain stimulation (DBS), would ameliorate NT1 using a validated transgenic mouse model with postnatal orexin neuron degeneration.
Using implanted electrodes in freely behaving mice, the immediate and prolonged effects of DBS were determined upon behavior using continuous video-electroencephalogram-electromyogram (video/EEG/EMG) and locomotor activity, and neural activation in brain sections, using immunohistochemical labeling of the immediate early gene product c-Fos.
Brief 10-s stimulation to the region of the lateral hypothalamus and zona incerta (LH/ZI) dose-responsively reversed established sleep and cataplexy episodes without negative sequelae. Continuous 3-h stimulation increased ambulation, improved sleep-wake consolidation, and ameliorated cataplexy. Brain c-Fos from mice sacrificed after 90 min of DBS revealed dose-responsive neural activation within wake-active nuclei of the basal forebrain, hypothalamus, thalamus, and ventral midbrain.
Acute and continuous LH/ZI DBS enhanced behavioral state control in a mouse model of NT1, supporting the feasibility of clinical DBS for NT1 and other sleep-wake disorders.
•Hypothalamic DBS dose-responsively reverses sleep and cataplexy in mouse narcolepsy.•Hypothalamic DBS consolidates wakefulness and ameliorates cataplexy in mouse narcolepsy.•DBS activates Fos expression in wake-active nuclei of the hypothalamus, thalamus, and brainstem.•Neuromodulation of sleep-wakefulness for a primary sleep disorder appears feasible.
Despite the development of efficient anti–human immunodeficiency virus-1 (HIV-1) therapy, HIV-1 associated pathogens remain a major clinical problem. Human cytomegalovirus (CMV) is among the most ...common HIV-1 copathogens and one of the main causes of persistent immune activation associated with dysregulation of the immune system, cerebrovascular and cardiovascular pathologies, and premature aging. Here, we report on the development of dual-targeted drugs with activity against both HIV-1 and CMV. We synthesized seven compounds that constitute conjugates of molecules that suppress both pathogens. We showed that all seven compounds exhibit low cytotoxicity and efficiently inhibited both viruses in cell lines. Furthermore, we chose a representative compound and demonstrated that it efficiently suppressed replication of HIV-1 and CMV in human lymphoid tissue ex vivo coinfected with both viruses. Further development of such compounds may lead to the development of dual-targeted anti-CMV/HIV-1 drugs.
•We synthetized seven dual-targeted anti-CMV/HIV heterodimers.•AZT or 3 TC were used as anti HIV molecules while 1-ω-(phenoxy)alkyluracil derivatives were used as anti CMV molecules.•These compounds inhibited CMV and HIV respectively in WS1 and MT-4 cell cultures.•Both AZT and 3 TC-based heterodimers inhibited CMV and HIV replication in coinfected human lymphoid tissues.
Dilated Cardiomyopathy is a common form of heart failure. Determining how this disease affects the structure and organization of cardiomyocytes in the human heart is important in understanding how ...the heart becomes less effective at contraction. Here we isolated and characterised Affimers (small non-antibody binding proteins) to Z-disc proteins ACTN2 (α-actinin-2), ZASP (also known as LIM domain binding protein 3 or LDB3) and the N-terminal region of the giant protein titin (TTN Z1-Z2). These proteins are known to localise in both the sarcomere Z-discs and the transitional junctions, found close to the intercalated discs that connect adjacent cardiomyocytes. We use cryosections of left ventricles from two patients diagnosed with end-stage Dilated Cardiomyopathy who underwent Orthotopic Heart Transplantation and were whole genome sequenced. We describe how Affimers substantially improve the resolution achieved by confocal and STED microscopy compared to conventional antibodies. We quantified the expression of ACTN2, ZASP and TTN proteins in two patients with dilated cardiomyopathy and compared them with a sex- and age-matched healthy donor. The small size of the Affimer reagents, combined with a small linkage error (the distance from the epitope to the dye label covalently bound to the Affimer) revealed new structural details in Z-discs and intercalated discs in the failing samples. Affimers are thus useful for analysis of changes to cardiomyocyte structure and organisation in diseased hearts.
Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ ...systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.
The Molecular Transducers of Physical Activity Consortium aims to create a comprehensive, integrative multi-omic map of the effects of exercise across tissues in rodents and healthy people.
Abstract Background For women who have had a previous low transverse cesarean delivery, the decision to undergo a trial of labor after cesarean (TOLAC) or an elective repeat cesarean delivery (ERCD) ...has important clinical and economic ramifications. Objectives To evaluate the cost-effectiveness of the alternative choices of a TOLAC and an ERCD for women with low-risk, singleton gestation pregnancies. Methods We searched EMBASE, MEDLINE, CINAHL, Cochrane Library, EconLit, and the Cost-Effectiveness Analysis Registry with no language, publication, or date restrictions up until October 2015. Studies were included if they were primary research, compared a TOLAC with an ERCD, and provided information on the relative cost of the alternatives. Abstracts and partial economic evaluations were excluded. Results Of 310 studies initially reviewed, 7 studies were included in the systematic review. In the base-case analyses, 4 studies concluded that TOLAC was dominant over ERCD, 1 study found ERCD to be dominant, and 2 studies found that although TOLAC was more costly, it offered more benefits and was thus cost-effective from a population perspective when considering societal willingness to pay for better outcomes. In sensitivity analyses, cost-effectiveness was found to be dependent on a high likelihood of TOLAC success, low risk of uterine rupture, and low relative cost of TOLAC compared with ERCD. Conclusions For women who are likely to have a successful vaginal delivery, routine ERCD may result in excess morbidity and cost from a population perspective.
Abstract Background Ocular trauma is recognized as the leading cause of unilateral blindness. However, few studies to date have focused on the clinical features of hospital-based ocular emergencies. ...Effectiveness of trauma centers in treating ocular emergencies was compared with treatment in traditional community hospital emergency departments. Demographics, causes, and nature of ocular emergencies, as well as visual outcome in community hospitals emergency departments and trauma centers, were also examined. Methods Records of 1027 patients with ocular emergencies seen between July 2007 and November 2010 at 3 community hospitals emergency departments and 2 hospitals with level II trauma centers were retrospectively examined. Unpaired t test and Pearson χ2 test were used to determine statistical significance. Results The incidence of patients requiring ophthalmic intervention was 77.2 per 100 000 in the community hospitals and 208.9 per 100 000 in the trauma centers. Rates of ocular emergencies were higher in middle-aged, white men. Orbital fractures were found in 86% of all orbital contusion cases in trauma centers, whereas 66.7% of patients with fall injuries and open globe diagnoses resulted in legal blindness. Conclusions The middle-aged, white men are more vulnerable to ocular injuries caused mainly by motor vehicle accidents. The ability of trauma centers to provide comparable increases in vision outcomes, despite treating more severe ocular emergencies, demonstrates the effectiveness of trauma centers. Patients diagnosed as having orbital contusions or who have fall injuries deserve careful evaluation because they are more likely to have more severe sight-threatening injuries.
Transformer-based models have pushed state of the art in many areas of NLP, but our understanding of what is behind their success is still limited. This paper is the first survey of over 150 studies ...of the popular BERT model. We review the current state of knowledge about how BERT works, what kind of information it learns and how it is represented, common modifications to its training objectives and architecture, the overparameterization issue, and approaches to compression. We then outline directions for future research.
To assess the feasibility of an ante- and post-natal lifestyle intervention for women with gestational diabetes mellitus (GDM) to reduce type 2 diabetes risk.
A partially randomised patient ...preference feasibility trial.
Diabetes antenatal clinics in two inner-London hospitals, UK.
Pregnant women ≥18 years with a GDM diagnosis and pre-pregnancy body mass index of ≥25kg/m2.
Participants in the intervention group were offered four motivational interview-based sessions (two antenatally and two postnatally, at 3 and 6 months postpartum), a WhatsApp support group, a FitBit and electronic self-help resources.
Recruitment; retention; intervention dose received; data completion; adaptions; proportion achieving ≥5% weight loss; weight change, blood glucose; blood pressure; diet, physical activity, breastfeeding and depression. Clinical outcomes were measured at baseline and 6 months postpartum.
50 participants were recruited from 155 eligible women (32% recruitment rate). Thirty-four were recruited to the intervention group (23 following randomisation (RI-group) and 11 based on preference (PI-group)); and 16 to the control group (13 randomised (RC-group) and 3 preference (PC-group)). Attrition was 44% (n = 22/50). Forty-six percent (n = 6) of the intervention group (25% (n = 2) of the RI-group and 80% (n = 4) of the PI-group) achieved ≥5% weight loss compared to 8% (n = 1) in the control group (95% confidence interval (CI) -0.69 to 0.07). Mean weight change was -2.1kg±9.0 in the intervention group (0kg±5.4 in the RI-group and -5.4kg±13.0 in the PI-group) compared to +4.4kg±4.9 in the control group (RC +4.4kg ±5.3 and PC +4.7kg ±3.1, 95% CI -12.4 to 0.2).
Recruitment was feasible, but strategies to improve retention are needed. The findings suggest the intervention can support women with GDM to lose weight. The observed weight loss was primarily in women who preferred the intervention. Therefore, future trials may need to adopt a preference design and consider factors associated with preference.
Trial registration: ISRCTN52675820 https://www.isrctn.com/ISRCTN52675820?q=ISRCTN52675820&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-search.
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