Granule cells perform frequency-dependent pattern separation in a computational model of the dentate gyrus.

Mnemonic discrimination (MD) may be dependent on oscillatory perforant path input frequencies to the hippocampus in a "U"-shaped fashion, where some studies show that slow and fast input frequencies support MD, while other studies show that intermediate frequencies disrupt MD. We hypothesize that pattern separation (PS) underlies frequency-dependent MD performance. We aim to study, in a computational model of the hippocampal dentate gyrus (DG), the network and cellular mechanisms governing this putative "U"-shaped PS relationship. We implemented a biophysical model of the DG that produces the hypothesized "U"-shaped input frequency-PS relationship, and its associated oscillatory electrophysiological signatures. We subsequently evaluated the network's PS ability using an adapted spatiotemporal task. We undertook systematic lesion studies to identify the network-level mechanisms driving the "U"-shaped input frequency-PS relationship. A minimal circuit of a single granule cell (GC) stimulated with oscillatory inputs was also used to study potential cellular-level mechanisms. Lesioning synapses onto GCs did not impact the "U"-shaped input frequency-PS relationship. Furthermore, GC inhibition limits PS performance for fast frequency inputs, while enhancing PS for slow frequency inputs. GC interspike interval was found to be input frequency dependent in a "U"-shaped fashion, paralleling frequency-dependent PS observed at the network level. Additionally, GCs showed an attenuated firing response for fast frequency inputs. We conclude that independent of network-level inhibition, GCs may intrinsically be capable of producing a "U"-shaped input frequency-PS relationship. GCs may preferentially decorrelate slow and fast inputs via spike timing reorganization and high frequency filtering.

Ceftriaxone-resistant Neisseria gonorrhoeae detected in England, 2015-24: an observational analysis.

OBJECTIVES: Since June 2022, there has been a rise in the number of ceftriaxone-resistant Neisseria gonorrhoeae cases detected in England (n = 15), of which a third were XDR. We describe the demographic and clinical details of the recent cases and investigate the phenotypic and molecular characteristics of the isolates. For a comprehensive overview, we also reviewed 16 ceftriaxone-resistant cases previously identified in England since December 2015 and performed a global genomic comparison of all publicly available ceftriaxone-resistant N. gonorrhoeae strains with mosaic penA alleles. METHODS: All N. gonorrhoeae isolates resistant to ceftriaxone (MIC > 0.125 mg/L) were whole-genome sequenced and compared with 142 global sequences of ceftriaxone-resistant N. gonorrhoeae. Demographic, behavioural and clinical data were collected. RESULTS: All cases were heterosexual, and most infections were associated with travel from the Asia-Pacific region. However, some had not travelled outside England within the previous few months. There were no ceftriaxone genital treatment failures, but three of five pharyngeal infections and the only rectal infection failed treatment. The isolates represented 13 different MLST STs, and most had the mosaic penA-60.001 allele. The global genomes clustered into eight major phylogroups, with regional associations. All XDR isolates belonged to the same phylogroup, represented by MLST ST16406. CONCLUSIONS: Most cases of ceftriaxone-resistant N. gonorrhoeae detected in England were associated with travel from the Asia-Pacific region. All genital infections were successfully treated with ceftriaxone, but there were extragenital treatment failures. Ceftriaxone resistance continues to be associated with the penA-60.001 allele within multiple genetic backgrounds and with widespread dissemination in the Asia-Pacific region.

An Information-Geometric Formulation of Pattern Separation and Evaluation of Existing Indices.

Pattern separation is a computational process by which dissimilar neural patterns are generated from similar input patterns. We present an information-geometric formulation of pattern separation, where a pattern separator is modeled as a family of statistical distributions on a manifold. Such a manifold maps an input (i.e., coordinates) to a probability distribution that generates firing patterns. Pattern separation occurs when small coordinate changes result in large distances between samples from the corresponding distributions. Under this formulation, we implement a two-neuron system whose probability law forms a three-dimensional manifold with mutually orthogonal coordinates representing the neurons' marginal and correlational firing rates. We use this highly controlled system to examine the behavior of spike train similarity indices commonly used in pattern separation research. We find that all indices (except scaling factor) are sensitive to relative differences in marginal firing rates, but no index adequately captures differences in spike trains that result from altering the correlation in activity between the two neurons. That is, existing pattern separation metrics appear (A) sensitive to patterns that are encoded by different neurons but (B) insensitive to patterns that differ only in relative spike timing (e.g., synchrony between neurons in the ensemble).

PivNG primers and probes set used in the cobas omni Utility Channel is a reliable supplemental test for detection of Neisseria gonorrhoeae in oropharyngeal, urogenital and rectal specimens collected in cobas PCR Media.

OBJECTIVE: To evaluate the clinical performance of the novel PivNG primers and probes set (PivNG test) used in the cobas omni Utility Channel for supplemental testing of Neisseria gonorrhoeae (NG). METHODS: Oropharyngeal, urogenital and rectal samples were self-collected during routine testing at Barts Health sexual health clinics, London, UK. Samples were tested by the cobas CT/NG test and PivNG cobas omni Utility Channel test on cobas 6800/8800 Systems. Supplemental testing was carried out with the Xpert CT/NG test. PivNG overall percent agreements, positive percent agreements (PPAs)/negative percent agreements (NPAs) and positive/negative predictive values were calculated for each sample type. Microscopy and/or culture data were included for a randomised subset of concordant/discordant results, and a composite reference standard (cobas CT/NG, Xpert CT/NG and culture results) adjusted for partial verification bias was used to determine PivNG PPA and NPA. RESULTS: Of 447 evaluable samples with valid results from all three assays (cobas CT/NG, PivNG and Xpert CT/NG), 288 (64.4%) were NG-positive by both PivNG and cobas CT/NG; 117 (26.2%) were NG-negative in both tests; and 42 (9.4%) had discordant results (with NG-negative supplementary Xpert) CT/NG results in 40/42 instances). Of 19 PivNG/Xpert CT/NG-discordant samples, 11 were confirmed NG-positive by microscopy and/or culture results. PivNG PPA and NPA were 100% and 91% for oropharyngeal swabs, 100% and 100% for vaginal swabs, 100% and 100% for male urine samples, and 100% and 97% for rectal swabs, respectively, compared with the partially adjusted composite reference standard. CONCLUSIONS: PivNG is a reliable supplementary test with high sensitivity for confirming NG infection when used in conjunction with the cobas CT/NG test and samples collected in cobas PCR Media. Moreover, the PivNG test offers a convenient, high-throughput solution for supplemental NG testing of various sample types, with the potential to reduce the number of indeterminate reports.

A computational model to characterize the time-course of response to rapid antidepressant therapies.

Our objective is to propose a method capable of disentangling the magnitude, the speed, and the duration or decay rate of the time course of response to rapid antidepressant therapies. To this end, we introduce a computational model of the time course of response to a single treatment with a rapid antidepressant. Numerical simulation is used to evaluate whether model parameters can be accurately estimated from observed data. Finally, we compare our computational modelling-based approach with linear mixed effects modelling in terms of their ability to detect changes in the magnitude and time-course of response to rapid antidepressant therapies in simulated randomized trials. Simulation experiments show that the parameters of our computational model can be accurately recovered using nonlinear least squares. Parameter estimation accuracy is stable over noise levels reaching as high as 25% of the true antidepressant effect magnitude. Comparison of our approach to mixed effects modelling using simulated randomized controlled trial data demonstrates an inability of linear mixed models to disentangle effect magnitude and time course, while our computational model accurately separates these response components. Our modelling approach may accurately identify the (A) magnitude, (B) speed, and (C) durability or decay rate of response to rapid antidepressant therapies. Future studies should fit this model to data from real clinical trials, and use resulting parameter estimates to uncover predictors and causes of different elements of the temporal course of antidepressant response.

A pilot study examining the impact of lithium treatment and responsiveness on mnemonic discrimination in bipolar disorder.

INTRODUCTION: Mnemonic discrimination (MD), the ability to discriminate new stimuli from similar memories, putatively involves dentate gyrus pattern separation. Since lithium may normalize dentate gyrus functioning in lithium-responsive bipolar disorder (BD), we hypothesized that lithium treatment would be associated with better MD in lithium-responsive BD patients. METHODS: BD patients (N = 69; NResponders = 16 [23 %]) performed the Continuous Visual Memory Test (CVMT), which requires discriminating between novel and previously seen images. Before testing, all patients had prophylactic lithium responsiveness assessed over ≥1 year of therapy (with the Alda Score), although only thirty-eight patients were actively prescribed lithium at time of testing (55 %; 12/16 responders, 26/53 nonresponders). We then used computational modelling to extract patient-specific MD indices. Linear models were used to test how (A) lithium treatment, (B) lithium responsiveness via the continuous Alda score, and (C) their interaction, affected MD. RESULTS: Superior MD performance was associated with lithium treatment exclusively in lithium-responsive patients (Lithium x AldaScore ß = 0.257 [SE 0.078], p = 0.002). Consistent with prior literature, increased age was associated with worse MD (ß = -0.03 [SE 0.01], p = 0.005). LIMITATIONS: Secondary pilot analysis of retrospectively collected data in a cross-sectional design limits generalizability. CONCLUSION: Our study is the first to examine MD performance in BD. Lithium is associated with better MD performance only in lithium responders, potentially due to lithium's effects on dentate gyrus granule cell excitability. Our results may influence the development of behavioural probes for dentate gyrus neuronal hyperexcitability in BD.

Pregnancy Management in HIV Viral Controllers: Twenty Years of Experience.

(1) Background: The evidence base for the management of spontaneous viral controllers in pregnancy is lacking. We describe the management outcomes of pregnancies in a series of UK women with spontaneous HIV viral control (<100 copies/mL 2 occasions before or after pregnancy off ART). (2) Methods: A multi-centre, retrospective case series (1999-2021) comparing pre- and post-2012 when guidelines departed from zidovudine-monotherapy (ZDVm) as a first-line option. Demographic, virologic, obstetric and neonatal information were anonymised, collated and analysed in SPSS. (3) Results: A total of 49 live births were recorded in 29 women, 35 pre-2012 and 14 post. HIV infection was more commonly diagnosed in first reported pregnancy pre-2012 (15/35) compared to post (2/14), p = 0.10. Pre-2012 pregnancies were predominantly managed with ZDVm (28/35) with pre-labour caesarean section (PLCS) (24/35). Post-2012 4/14 received ZDVm and 10/14 triple ART, p = 0.002. Post-2012 mode of delivery was varied (5 vaginal, 6 PLCS and 3 emergency CS). No intrapartum ZDV infusions were given post-2012 compared to 11/35 deliveries pre-2012. During pregnancy, HIV was detected (> 50 copies/mL) in 14/49 pregnancies (29%) (median 92, range 51-6084). Neonatal ZDV post-exposure prophylaxis was recorded for 45/49 infants. No transmissions were reported. (4) Conclusion: UK practice has been influenced by the change in guidelines, but this has had little impact on CS rates.

Mechanisms of Sustained Increases in γ Power Post-Ketamine in a Computational Model of the Hippocampal CA3: Implications for Ketamine's Antidepressant Mechanism of Action.

Subanaesthetic doses of ketamine increase γ oscillation power in neural activity measured using electroencephalography (EEG), and this effect lasts several hours after ketamine administration. The mechanisms underlying this effect are unknown. Using a computational model of the hippocampal cornu ammonis 3 (CA3) network, which is known to reproduce ketamine's acute effects on γ power, we simulated the plasticity of glutamatergic synapses in pyramidal cells to test which of the following hypotheses would best explain this sustained γ power: the direct inhibition hypothesis, which proposes that increased γ power post-ketamine administration may be caused by the potentiation of recurrent collateral synapses, and the disinhibition hypothesis, which proposes that potentiation affects synapses from both recurrent and external inputs. Our results suggest that the strengthening of external connections to pyramidal cells is able to account for the sustained γ power increase observed post-ketamine by increasing the overall activity of and synchrony between pyramidal cells. The strengthening of recurrent pyramidal weights, however, would cause an additional phase shifted voltage increase that ultimately reduces γ power due to partial cancellation. Our results therefore favor the disinhibition hypothesis for explaining sustained γ oscillations after ketamine administration.

A critical evaluation of dynamical systems models of bipolar disorder.

Bipolar disorder (BD) is a mood disorder involving recurring (hypo)manic and depressive episodes. The inherently temporal nature of BD has inspired its conceptualization using dynamical systems theory, which is a mathematical framework for understanding systems that evolve over time. In this paper, we provide a critical review of the dynamical systems models of BD. Owing to the heterogeneity of methodological and experimental designs in computational modeling, we designed a structured approach that parallels the appraisal of animal models by their face, predictive, and construct validity. This tool, the validity appraisal guide for computational models (VAG-CM), is not an absolute measure of validity, but rather a guide for a more objective appraisal of models in this review. We identified 26 studies published before November 18, 2021 that proposed generative dynamical systems models of time-varying signals in BD. Two raters independently applied the VAG-CM to the included studies, obtaining a mean Cohen's κ of 0.55 (95% CI [0.45, 0.64]) prior to establishing consensus ratings. Consensus VAG-CM ratings revealed three model/study clusters: data-driven models with face validity, theory-driven models with predictive validity, and theory-driven models lacking all forms of validity. We conclude that future modeling studies should employ a hybrid approach that first operationalizes BD features of interest using empirical data to achieve face validity, followed by explanations of those features using generative models with components that are homologous to physiological or psychological systems involved in BD, to achieve construct validity. Such models would be best developed alongside long-term prospective cohort studies involving a collection of multimodal time-series data. We also encourage future studies to extend, modify, and evaluate the VAG-CM approach for a wider breadth of computational modeling studies and psychiatric disorders.

Childhood Obesity and Cardiovascular Disease Risk: Working Toward Solutions.

The prevalence of obesity in childhood is high and continues to increase globally. It is currently estimated that 381 million children worldwide have overweight or obesity. This disease stems from multiple complex pathways that can present early in life. This is particularly concerning because childhood obesity is associated with cardiovascular risk factors that can lead to early atherosclerosis and premature cardiovascular disease (CVD). Hypertension, dysglycemia, dyslipidemia, and systemic inflammation are associated with vascular changes in childhood, and these contribute to increased risk of cardiovascular events in adulthood if not adequately treated. Interventions to treat childhood obesity include multicomponent family-based behaviour modification programs, which have been demonstrated to have moderate short-term effects on weight-related outcomes; their effects on cardiovascular risk factors, however, are less well understood. Although supervised, structured exercise interventions result in improvements in blood pressure, inflammation, carotid artery intima media thickness, dysglycemia, dyslipidemia, and endothelial dysfunction in children with obesity in the short term, our understanding of how to translate these interventions into long-term sustainable exercise or physical activity recommendations remains uncertain. Research focus in these areas will help in treating childhood obesity and associated CVD risk factors to prevent CVD development in adulthood.

The characterisation of a recent syphilis outbreak in Sheffield, UK, and an evaluation of contact tracing as a method of control.

OBJECTIVE: To explore the factors around and the success of contact-tracing in a recent major outbreak of infectious syphilis in Sheffield, and to evaluate the effectiveness of it, our hitherto standard strategy of control. METHOD: Retrospective chart review RESULTS: Over a period of 18 months, an outbreak of 21 cases was, on closer inspection, the result of several, discrete "micro" outbreaks in different groups. Two major patterns emerged, a relatively straightforward and more accessible cluster in heterosexual persons (a "spread" network), and more sporadic, "starburst" networks in men who have sex with men. CONCLUSION: Our traditional method of control, contact-tracing, was seen to be most effective in the spread network in heterosexuals. In the face of an apparent outbreak, clinicians should explore the nature and parameters of their local epidemic and engage a mixture of control methods. These may include, but not excusively so, contact-tracing to interrupt transmission by case-finding and by treatment.