Asymmetry in the Perception of Electrical Chirps Presented to Cochlear Implant Listeners.

INTRODUCTION: Although a broadband acoustic click is physically the shortest duration sound we can hear, its peripheral neural representation is not as short because of cochlear filtering. The traveling wave imposes frequency-dependent delays to the sound waveform so that in response to a click, apical nerve fibers, coding for low frequencies, are excited several milliseconds after basal fibers, coding for high frequencies. Nevertheless, a click sounds like a click and these across-fiber delays are not perceived. This suggests that they may be compensated by the central auditory system, rendering our perception consistent with the external world. This explanation is difficult to evaluate in normal-hearing listeners because the contributions of peripheral and central auditory processing cannot easily be disentangled. Here, we test this hypothesis in cochlear implant listeners for whom cochlear mechanics is bypassed. METHOD: Eight cochlear implant users ranked in perceived duration 12 electrical chirps of various physical durations and spanning the cochlea in the apex-to-base or base-to-apex direction (Exp. 1). Late-latency cortical potentials were also recorded in response to a subset of these chirps (Exp. 2). RESULTS: We show that an electrical chirp spanning the cochlea from base-to-apex is perceived as shorter than the same chirp spanning the cochlea in the opposite direction despite having the same physical duration. Cortical potentials also provide neural correlates of this asymmetry in perception. CONCLUSION: These results demonstrate that the central auditory system processes frequency sweeps differently depending on the direction of the frequency change and that this processing difference is not simply the result of peripheral filtering.

Superior performance by two new methods in identifying the online reaction time of reaching movements.

Reaching movements can be redirected during their progress to handle unexpected visual changes, such as a change in target location. It is important to know when these redirections start, i.e. the online reaction time (oRT), but this information is not readily evident since redirections are embedded within a time-varying baseline movement which differs from trial to trial. The one previous study that evaluated the performance of different oRT identification methods utilized simulated redirections with the exact same onset, rather than a range of onsets as would be typically encountered. We addressed this gap by utilizing batches of "hybrid" trials with temporal spread in their oRTs. Each hybrid trial combined a sampled baseline movement with an idealized corrective response. Two new methods had the most accurate identification of online reaction times: i) a threshold-aligned grand mean regression and ii) a template-based approach we term the canonical correction search. The threshold-aligned grand mean regression is simple to implement and effective. The canonical correction search is a more complex procedure but arguably better linked to the underlying response. Applying the two methods to a published dataset revealed more delayed oRTs than was previously reported along with new information such as the width of oRT distributions. Taken together, our results demonstrate the utility of two new methods for dissecting corrective action from ongoing movement.

Asbestos Surveillance Program Aachen (ASPA): Cancer mortality among asbestos exposed power industry workers.

BACKGROUND: The time between initial asbestos exposure and asbestos-related disease can span several decades. The Asbestos Surveillance Program aims to detect early asbestos-related diseases in a cohort of 8,565 power industry workers formerly exposed to asbestos. RESEARCH QUESTION: How does asbestos exposure patterns affect cancer mortality and the duration of latency until death? METHODS: A mortality follow-up was conducted with available vital status for 8,476 participants (99 %) and available death certificates for 89.9 % of deceased participants. Standardised mortality ratios (SMR) were calculated for asbestos-related cancers. The SMR of mesothelioma and lung cancer were stratified by exposure duration, cumulative asbestos exposure and smoking. The effect of age at first exposure, cumulative asbestos exposure and smoking on the duration of latency until death was examined using multiple linear regression analysis. RESULTS: The mortality risk of mesothelioma (n = 104) increased with cumulative asbestos exposure but not with exposure duration; the highest mortality (SMR: 23.20; 95 % CI: 17.62-29.99) was observed in participants who performed activities with short extremely high exposures (steam turbine revisions). Lung cancer mortality (n = 215) was not increased (SMR: 1.03; 95 % CI: 0.89-1.17). Median latency until death was 46 (15-63) years for mesothelioma and 44 (15-70) years for lung cancer and deaths occurred between age 64 and 82 years. Latency until death was not influenced by age at first exposure, cumulative exposure, or smoking. CONCLUSION: Cumulative dose seems to be more appropriate than exposure duration for estimating the risk of mesothelioma death. Additionally, exposure with high cumulative doses in short time should be considered. Since only lung cancer mortality, not incidence, was recorded in this study, lung cancer risk associated with asbestos exposure could not be assessed and the lung cancer mortality was lower than expected probably due to screening effects and improved treatments. The critical time window of death from asbestos-related cancer is between the seventh and ninth decade of life. Future studies should further explore the concept of latency, especially since large ranges are reported throughout the literature.

Association of Anthropometry With Nerve Conduction Parameters of Median Nerve: A Cross-Sectional Study in a North Indian Medical University Hospital.

Background Nerve conduction studies ease the understanding of the various pathologies of the peripheral nervous system. It helps physicians to delineate between the two principal types of peripheral etiologies: axonal degeneration and demyelination. An increase in weight in the form of excessive fat deposition or obesity could have a worrisome effect on nerve conduction. So, to find the association of various anthropometric parameters (age, gender, height, weight, waist-hip ratio and body mass index) with motor and sensory median nerve conduction parameters (latency, amplitude and velocity) this cross-sectional study was conducted. Materials and method A total of 87 subjects were taken and their height, weight, waist-hip ratio and body mass index were measured using standard techniques. Motor and sensory nerve conduction parameters were measured on an electromyography machine. Data was stored, tabulated and analyzed. Results The average height of male and female subjects ± SD was 1.699 ± 0.072 m and 1.589 ± 0.067 m respectively. The average weight of male and female subjects ± SD was 64.089 ± 11.497 kg and 52.949 ± 8.404 kg, respectively. The average BMI of normal, underweight and overweight subjects ± SD was 21.668 ± 2.048 kg/m2, 17.074 ± 0.794 kg/m2 and 26.595 ± 0.915 kg/m2 respectively. Weight showed a significant (p = 0.0025) correlation with the latency of motor median nerve conduction. Waist-hip ratio showed a significant (p = 0.042 and p = 0.036) correlation with motor median nerve conduction velocity in both male and female subjects, respectively. BMI in the overweight category showed a significant (p = 0.0156 and p = 0.0290) correlation with latency and amplitude of motor median nerve conduction study, respectively. Conclusions This study exemplifies that an increase in BMI of our body can affect nerve conduction. This could serve as a preliminary study to assess the effect of obesity on peripheral nerve conduction, especially in the Indian population.

Analysis of visual evoked potentials in patients with neurofibromatosis type 1: new concepts.

Introduction: Neurofibromatosis type 1 (NF type 1) is an autosomal dominant disease with typical clinical manifestations, such as skin lesions, Lisch nodules, optic pathway gliomas, and neurofibromas, caused by the mutation of the NF1 gene. Visual evoked potentials (VEP) present a measure of the electrophysiological response of visual cortex to a visual stimulus. The role of VEP in the pathophysiology of NF type 1 is very complex and requires additional research. The Aim: We examined the differences between NF type 1 patients with normal and altered VEP and analyzed the correlation between the prolongation of P100 latency and disease severity. Materials and methods: Two groups were formed: a control group and a study group with NF type 1 patients. Based on the control group analysis, a threshold value for a normal VEP finding of 116 ms was obtained, and it was used to divide the study group into subgroups with normal and altered VEP. We proceeded with examining the differences in clinical manifestations of the disease between the subgroups, after which we checked if there is a correlation between the prolongation of the P100 latency and the severity of the clinical picture according to the Riccardi scale. Statistical analysis was performed using the Pearson chi-square test and the Spearman correlation test in the program SPSS 28.0, with levels of statistical significance p = 0.05 and p = 0.001. Results: In the group with the abnormal VEP we found a statistically significant more frequent occurrence of optic tract glioma (p = 0.008), tumors (p = 0.032), epilepsy (p = 0.043), and cognitive disorders (p = 0.028), while the other clinical signs had an equal prevalence in both groups. A moderately strong correlation (r s = 0.665) was observed between the prolongation of P100 latency and the severity of the clinical picture. Conclusion: Our results showed the important role of VEP in the description of clinical phenotypes of NF type 1. The authors of the study propose VEP to be included in the diagnostic algorithms designed for patients with NF type 1.

Suppression of HSV-1 infection and viral reactivation by CRISPR-Cas9 gene editing in 2D and 3D culture models.

Although our understanding of herpes simplex virus type 1 (HSV-1) biology has been considerably enhanced, developing therapeutic strategies to eliminate HSV-1 in latently infected individuals remains a public health concern. Current antiviral drugs used for the treatment of HSV-1 complications are not specific and do not address latent infection. We recently developed a CRISPR-Cas9-based gene editing platform to specifically target the HSV-1 genome. In this study, we further used 2D Vero cell culture and 3D human induced pluripotent stem cell-derived cerebral organoid (CO) models to assess the effectiveness of our editing constructs targeting viral ICP0 or ICP27 genes. We found that targeting the ICP0 or ICP27 genes with AAV2-CRISPR-Cas9 vectors in Vero cells drastically suppressed HSV-1 replication. In addition, we productively infected COs with HSV-1, characterized the viral replication kinetics, and established a viral latency model. Finally, we discovered that ICP0- or ICP27-targeting AAV2-CRISPR-Cas9 vector significantly reduced viral rebound in the COs that were latently infected with HSV-1. In summary, our results suggest that CRISPR-Cas9 gene editing of HSV-1 is an efficient therapeutic approach to eliminate the latent viral reservoir and treat HSV-1-associated complications.

Time-Dependent Effects of Altered Prebedtime Light Exposure in Enclosed Spaces on Sleep Performance Associated with Human States.

Purpose: Exposure to artificial light influences human performance, which is essential for maintaining healthy work and sleep. However, existing research has not explored the intrinsic links between sleep performance and human states over time under prebedtime light exposure interventions (LEIs). Methods: To investigate the time-dependent effects of altered prebedtime light exposure, four LEI groupings (#L1 - #L4) and a Time factor (D8, D9, and D10) were chosen for sleep experiments in enclosed spaces. Forty-eight young adults recruited were available for data analysis. Subjective alertness (SA), negative affect (NA), subjective sleep, and objective sleep were measured via the Karolinska Sleepiness Scale, Positive and Negative Affect Schedule, Next-day Self-assessment Sleep Quality, and joint assessment of wrist actigraphy and sleep diaries, respectively. Statistical analysis was used for the effects of light exposure on the human states (corresponding to the SA and NA) and sleep performance, while the process model helped construct the associations between the two. Results: The statistical effects revealed that the Time had a significant main effect on subjective sleep and changes in prebedtime alertness; the LEI had a significant main effect only on sleep onset latency (SOL). After undergoing altered prebedtime light exposure, the mean SA increased at prebedtime of D9 (p = 0.022) and D10 (p = 0.044); No significant effect on the NA was observed; Mean subjective sleep had a significant increase from D8 to D10. Moreover, five actigraphy-estimated sleep parameters were interrelated. In light of this, a chained pathway relationship was identified. The SOL played a mediating predictor between prebedtime state and objective sleep, which was linked to the awakening state through subjective sleep. Conclusion: Our study suggests that time-dependent effects of altered prebedtime light exposure on sleep performance are associated with human states at prebedtime and awakening, with implications for its prediction of sleep health.

Specific Cytokines Analysis Incorporating Latency-Associated Antigens Differentiates Mycobacterium tuberculosis Infection Status: An Exploratory Study.

Introduction: Current immunologic methods cannot distinguish Mycobacterium tuberculosis (Mtb) infection statuses, especially to discriminate active tuberculosis (ATB) from latent tuberculosis infection (LTBI). This study explored the potential of latency-associated antigens (Rv1733cSLP and Rv2028c) and multifactorial cytokine detection to distinguish tuberculosis infection states. Methods: ATB patients (20), LTBI healthcare workers (25), fever patients (11), and healthy controls (10) were enrolled. Cytokine levels (IFN-γ, TNF-α, IL-2, IL-6, IP-10, IL-1Ra, CXCL-1, and MCP-1) were measured using Luminex with/without MTB-specific virulence factor and latency-associated antigens stimulation. Results: Without antigen stimulation, IL-6, IP-10, MCP-1, and IL-1Ra were higher in the ATB group than in the LTBI group (p<0.05), but no significant differences between the ATB group and the fever group. Stimulated with the four antigens, respectively, the cytokines, including IP-10Esat-6, IP-10CFP-10, IFN-γRv1733cSLP, IFN-γRv2028c, IL-6Esat-6, IL-6Rv1733cSLP, IL-6Rv2028c, IL-2Rv1733cSLP, IL-2 Rv2028c, IL-1RaEsat-6, IL-1RaCFP-10, IL-1RaRv2028c, CXCL-1Esat-6, CXCL-1CFP-10, CXCL-1Rv1733cSLP, CXCL-1Rv2028c, MCP-1Esat-6 and MCP-1CFP-10, demonstrated accurate discrimination between ATB and LTBI (p<0.05). Additive concentrations demonstrated significant secretion differences of IFN-γ, IP-10 and IL-2, primarily by virulence factors in ATB and latency-associated antigens in LTBI. Latency-associated antigens synergized with virulence factors, enhancing TH1-type cytokine diagnostic efficacy for discriminating ATB from LTBI, the AUC for TNF-α increased from 0.696 to 0.820 (p=0.038), IFN-γ increased from 0.806 to 0.962 (p=0.025), and IL-2 increased from 0.565 to 0.868 (p=0.007). Model selected by forward likelihood method indicated combined detection of IFN-γCFP-10, IFN-γRv1733cSLP, IP-10Rv1733cSLP, and CXCL-1Rv1733cSLP achieved ATB diagnosis (AUC=0.996) and ATB-LTBI differentiation (AUC=0.992). Combined detection of IFN-γCFP-10 and IFN-γRv1733cSLP achieved tuberculosis infection diagnosis (AUC=0.943). Conclusion: Latency-associated antigens enhance multiple cytokine discriminatory ability, particularly TH1-type cytokines, for differentiating Mtb infection statuses.

Association of sleep timing, sleep duration, and sleep latency with metabolic syndrome in middle-aged adults in Korea: A cross-sectional and longitudinal study.

OBJECTIVE: Sleep is a potential risk factor for metabolic syndrome. We investigated the associations of various sleep characteristics with the status and incidence of metabolic syndrome in middle-aged Koreans. METHODS: Using data from a community-based Korean Medicine Daejeon Citizen Cohort study on participants aged 30-50years, cross-sectional (n = 1984) and longitudinal (n = 1216, median follow-up: 2.1years) analyses were performed. To study the association of metabolic syndrome and five components with various sleep characteristics, measured using the Pittsburgh Sleep Quality Index, we used Poisson and logistic regression and Cox proportional hazard regression analyses, adjusting for covariates. RESULTS: Of 1984 participants, 66%, 19%, and 15% belonged to the non-metabolic syndrome, pre-metabolic syndrome, and metabolic syndrome groups, respectively. After covariate adjustments, the pre-metabolic syndrome group was associated with late mid-sleep time (≥5:00; prevalence ratios 1.61, 95% confidence interval 1.01-2.54) and late bedtime (≥2:00; prevalence ratios 1.55, 95% confidence interval 1.03-2.34), and the metabolic syndrome group was associated with long sleep latency (prevalence ratios 1.33, 95% confidence interval 1.03-1.73), poor sleep quality (prevalence ratios 1.38, 95% confidence interval 1.07-1.78), and early wake time (<6:00; prevalence ratios 1.29, 95% confidence interval 1.01-1.63). Longitudinal analysis of participants without metabolic syndrome at baseline indicated a significant increase in metabolic syndrome risk associated with very short sleep duration (<6 hours; hazard ratio 1.72, 95% confidence interval 1.06-2.79), long sleep latency (>30 minutes; hazard ratio 1.86, 95% confidence interval 1.1-3.12), and early wake time (<6:00 o'clock; hazard ratio 1.73, 95% confidence interval 1.01-2.97). CONCLUSION: Sleep characteristics, such as short duration, long latency, and early wake time, were associated with an increased risk of metabolic syndrome in middle-aged adults.

Evaluating speech latencies during structured psychiatric interviews as an automated objective measure of psychomotor slowing.

We sought to derive an objective measure of psychomotor slowing from speech analytics during a psychiatric interview to avoid potential burden of dedicated neurophysiological testing. Speech latency, which reflects response time between speakers, shows promise from the literature. Speech data was obtained from 274 subjects with a diagnosis of bipolar I depression enrolled in a randomized, doubleblind, 6-week phase 2 clinical trial. Audio recordings of structured Montgomery-Åsberg Depression Rating Scale (MADRS) interviews at 6 time points were examined (k = 1,352). We evaluated speech latencies, and other aspects of speech, for temporal stability, convergent validity, sensitivity/responsivity to clinical change, and generalization across seven socio-linguistically diverse countries. Speech latency was minimally associated with demographic features, and explained nearly a third of the variance in depression (categorically defined). Speech latency significantly decreased as depression symptoms improved over time, explaining nearly 20 % of variance in depression remission. Classification for differentiating people with versus without concurrent depression was high (AUCs > 0.85) both cross-sectionally and longitudinally. Results replicated across countries. Other speech features offered modest incremental contribution. Neurophysiological speech parameters with face validity can be derived from psychiatric interviews without the added patient burden of additional testing.

Binaural interaction in human auditory brainstem and middle-latency responses affected by sound frequency band, lateralization predictability, and attended modality.

The binaural interaction component (BIC) of the auditory evoked potential is the difference between the waveforms of the binaural response and the sum of left and right monaural responses. This investigation examined BICs of the auditory brainstem (ABR) and middle-latency (MLR) responses concerning three objectives: 1) the level of the auditory system at which low-frequency dominance in BIC amplitudes begins when the binaural temporal fine structure is more influential with lower- than higher-frequency content; 2) how BICs vary as a function of frequency and lateralization predictability, as could relate to the improved lateralization of high-frequency sounds; 3) how attention affects BICs. Sixteen right-handed participants were presented with either low-passed (< 1000 Hz) or high-passed (> 2000 Hz) clicks at 30 dB SL with a 38 dB (A) masking noise, at a stimulus onset asynchrony of 180 ms. Further, this repeated-measures design manipulated stimulus presentation (binaural, left monaural, right monaural), lateralization predictability (unpredictable, predictable), and attended modality (either auditory or visual). For the objectives, respectively, the results were: 1) whereas low-frequency dominance in BIC amplitudes began during, and continued after, the Na-BIC, binaural (center) as well as summed monaural (left and right) amplitudes revealed low-frequency dominance only after the Na wave; 2) with a predictable position that was fixed, no BIC exhibited equivalent amplitudes between low- and high-passed clicks; 3) whether clicks were low- or high-passed, selective attention affected the ABR-BIC yet not MLR-BICs. These findings indicate that low-frequency dominance in lateralization begins at the Na latency, being independent of the efferent cortico-collicular pathway's influence.

Causal diagrams for disease latency bias.

BACKGROUND: Disease latency is defined as the time from disease initiation to disease diagnosis. Disease latency bias (DLB) can arise in epidemiological studies that examine latent outcomes, since the exact timing of the disease inception is unknown and might occur before exposure initiation, potentially leading to bias. Although DLB can affect epidemiological studies that examine different types of chronic disease (e.g. Alzheimer's disease, cancer etc), the manner by which DLB can introduce bias into these studies has not been previously elucidated. Information on the specific types of bias, and their structure, that can arise secondary to DLB is critical for researchers, to enable better understanding and control for DLB. DEVELOPMENT: Here we describe four scenarios by which DLB can introduce bias (through different structures) into epidemiological studies that address latent outcomes, using directed acyclic graphs (DAGs). We also discuss potential strategies to better understand, examine and control for DLB in these studies. APPLICATION: Using causal diagrams, we show that disease latency bias can affect results of epidemiological studies through: (i) unmeasured confounding; (ii) reverse causality; (iii) selection bias; (iv) bias through a mediator. CONCLUSION: Disease latency bias is an important bias that can affect a number of epidemiological studies that address latent outcomes. Causal diagrams can assist researchers better identify and control for this bias.

Erratum: Neuromodulatory effects of high-definition theta transcranial alternating current stimulation on the parietal cortex: a pilot study of healthy males.

[This corrects the article DOI: 10.3389/fnins.2023.1255124.].

Enrichment using speech latencies improves treatment effect size in a clinical trial of bipolar depression.

Clinical trials in depression lack objective measures. Speech latencies are an objective measure of psychomotor slowing with face validity and empirical support. 'Turn latency' is the response time between speakers. Retrospective analysis was carried-out on the utility of turn latencies as an enrichment tool in a clinical trial of bipolar I depression. Speech data was obtained from 274 participants during 1,352 Montgomery-Åsberg Depression Rating Scale (MADRS) recordings in a randomized, placebo controlled, 6-week clinical trial of SEP-4199 (200 mg or 400 mg). Post-randomization turn latencies were compared between patients with moderate to severe depression and patients whose depression had remitted. A cutoff was determined and applied to turn latencies pre-randomization to classify individuals into two groups: Speech Latencies Slow (SL-Slow) and Speech Latencies Normal (SL-Normal). At week 6, SL-Slow (N = 172) showed significant separation in MADRS scores between placebo and treatment arms. SL-Normal (N = 102) showed larger MADRS improvements and no significant separation between placebo and treatment arms. Excluding SL-Normal increased primary outcome effect size by 52 % and 100 % for the treatment arms. Turn latencies are an objective measure available from standard clinical assessments and may assess the severity of symptoms more accurately and screen out placebo responders.

The patient-perceived intravaginal ejaculation latency time cut-off for lifelong premature ejaculation.

BACKGROUND: The current cutoff values of intravaginal ejaculation latency time for diagnosing lifelong premature ejaculation do not always match clinical practice, and the inconsistency in the cutoff values of intravaginal ejaculation latency time among different definitions has also posed challenges to both clinical management and research of premature ejaculation. OBJECTIVES: To re-evaluate the intravaginal ejaculation latency time and to find evidence-based cut-off values for diagnosing lifelong premature ejaculation that can be widely accepted and match clinical practice. MATERIALS AND METHODS: We addressed the flaws of previous studies. Lifelong premature ejaculation was diagnosed based on both patient self-report of premature ejaculation status and scores on the Premature Ejaculation Diagnostic Tool, with a control group consisting of non-premature ejaculation individuals included for comparison. Utilizing receiver operating characteristic curve analysis, the optimal self-estimated cutoff value for intravaginal ejaculation latency time in diagnosing lifelong premature ejaculation was determined. RESULTS: A total of 307 heterosexual participants (mean age = 30.7 ± 6.4) were included, comprising 187 lifelong premature ejaculation patients (mean age = 28.0 ± 4.6) and 120 non-premature ejaculation individuals (mean age = 35.0 ± 6.5). 2.7% of lifelong premature ejaculation patients experienced anteportal ejaculation. 59.9%, 92%, and 97.9% of lifelong premature ejaculation patients displayed intravaginal ejaculation latency times within 1, 2, and 3 min, respectively. The receiver-operating characteristic curve's area under the curve was 0.996 with a 95% confidence interval of 0.991-1.000 (p < 0.0001). The perceived intravaginal ejaculation latency time cut-off at 3.5 (sensitivity = 97.9%, specificity = 99.2%) showed the highest Youden index compared with other options. DISCUSSION: Although we found that 92.0% of lifelong premature ejaculation patients had a perceived intravaginal ejaculation latency time within 2 min, a perceived intravaginal ejaculation latency time cutoff value of less than 3.5 min for diagnosing lifelong premature ejaculation could encompass a larger proportion (97.9%) of patients seeking medical help for complaints of PE, and increasing the perceived intravaginal ejaculation latency time cutoff value to 3.5 min would not significantly increase the false-positive rate. CONCLUSION: The perceived intravaginal ejaculation latency time cutoff value for diagnosing lifelong premature ejaculation within a clinical practice context is 3.5 min.

Comparison of Regression Methods to Predict the First Spike Latency in Response to an External Stimulus in Intracellular Recordings for Cerebellar Cells.

The significance of intracellular recording in neurophysiology is emphasized in this article, with considering the functions of neurons, particularly the role of first spike latency in response to external stimuli. The study employs advanced machine learning techniques to predict first spike latency from whole cell patch recording data. Experiments were conducted on Control (Salin) and Experiment (Harmaline) groups, generating a dataset for developing predictive models. Because the dataset has a limited number of samples, we utilized models that are effective with small datasets. Among different groups of regression models (linear, ensemble, and tree models), the ensemble models, specifically the LGB method, can achieve better performance. The results demonstrate accurate prediction of first spike latency, with an average mean squared error of 0.0002 and mean absolute error of 0.01 in 10-fold cross-validation. The research suggests the potential of machine learning in forecasting the first spike latency, allowing reliable estimation without the need for extensive animal testing. This intelligent predictive system facilitates efficient analysis of first spike latency changes in both healthy and unhealthy brain cells, streamlining experimentation and providing more detailed insights into the captured signals.

Analysis of the effect of HDAC inhibitors on the formation of the HIV reservoir.

The HIV reservoir is more dynamic than previously thought with around 70% of the latent reservoir originating from viruses circulating within 1 year of the initiation of antiretroviral therapy (ART). In an ex vivo model system of HIV latency, it was reported that early exposure to class I histone deacetylase (HDAC) inhibitors might prevent these more recently infected cells from entering a state of stable viral latency. This finding raises the possibility that co-administration of HDAC inhibitors at the time of ART initiation may prevent the establishment of much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and panobinostat co-administered at the time of ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. As previously shown, SAHA and panobinostat were well tolerated in humanized mice. Unexpectedly, co-administration of SAHA resulted in an increase in the frequency of CD4+ cells carrying HIV DNA but did not alter the frequency of cell-associated HIV RNA in HIV-infected, ART-treated humanized mice. Co-administration of panobinostat did not alter levels of cell-associated HIV DNA or RNA. Our in vivo findings indicate that co-administration of HDAC inhibitors initiated at the same time of ART treatment does not prevent recently infected cells from entering latency.IMPORTANCECurrent antiretroviral therapy (ART) does not eradicate cells harboring replication-competent HIV reservoir. Withdrawal of ART inevitably results in a rapid viremia rebound. The HIV reservoir is more dynamic than previously thought. Early exposure to class I histone deacetylase (HDAC) inhibitors inhibit these more recently infected cells from entering a state of stable viral latency in an ex vivo model of latency, raising the possibility that co-administration of HDAC inhibitors at the time of ART initiation may reduce much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid or panobinostat during ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. Our in vivo study indicates that in contrast to in vitro observations, the co-administration of HDAC inhibitors at the same time of ART initiation does not prevent recently infected cells from entering latency.

Allowing ad libitum sleep during overnight polysomnography impacts Multiple Sleep Latency Test results in patients being assessed for hypersomnolence.

STUDY OBJECTIVES: The Multiple Sleep Latency Test (MSLT) is a key diagnostic component in the diagnosis of central disorders of hypersomnolence. Due to time constraints, it is common practice to wake patients at a standard time from overnight polysomnography (PSG) prior to the MSLT. This has the potential to influence MSLT results due to sleep deprivation. We describe the impact of allowing ad libitum sleep on the night prior to the MSLT in patients being assessed for hypersomnolence. METHODS: 580 consecutive patients undergoing PSG/MSLT for assessment of hypersomnolence were analyzed: 290 either side of a change in laboratory protocol which allowed patients ad libitum sleep during the PSG, rather than being woken at a pre-specified time. Baseline characteristics, PSG and MSLT results were compared between the groups. RESULTS: Groups were similar at baseline, other than there being more females in the ad libitum group. After adjusting for confounding variables, ad libitum patients had later sleep offset time (+58.7 minutes; p<0.001), longer PSG total sleep time (+47.8 minutes; p<0.001), longer MSLT mean sleep latency (+1.3 minutes; p=0.002) and 23% fewer MSLT with mean sleep latency less than 8 minutes (p=0.004) when compared with patients who were woken at a standard time. CONCLUSIONS: The common practice of waking patients from their PSG at a standard time has the potential to curtail sleep and impact MSLT results by reducing mean sleep latency. Patients being assessed for hypersomnolence should be allowed ad libitum sleep during the PSG on the night prior to their MSLT.

HIV-1 control in vivo is related to the number but not the fraction of infected cells with viral unspliced RNA.

In the absence of antiretroviral therapy (ART), a subset of individuals, termed HIV controllers, have levels of plasma viremia that are orders of magnitude lower than non-controllers (NC) who are at higher risk for HIV disease progression. In addition to having fewer infected cells resulting in fewer cells with HIV RNA, it is possible that lower levels of plasma viremia in controllers are due to a lower fraction of the infected cells having HIV-1 unspliced RNA (HIV usRNA) compared with NC. To directly test this possibility, we used sensitive and quantitative single-cell sequencing methods to compare the fraction of infected cells that contain one or more copies of HIV usRNA in peripheral blood mononuclear cells (PBMC) obtained from controllers and NC. The fraction of infected cells containing HIV usRNA did not differ between the two groups. Rather, the levels of viremia were strongly associated with the total number of infected cells that had HIV usRNA, as reported by others, with controllers having 34-fold fewer infected cells per million PBMC. These results reveal that viremic control is not associated with a lower fraction of proviruses expressing HIV usRNA, unlike what is reported for elite controllers, but is only related to having fewer infected cells overall, maybe reflecting greater immune clearance of infected cells. Our findings show that proviral silencing is not a key mechanism for viremic control and will help to refine strategies toward achieving HIV remission without ART.

[Primary premature ejaculation of kidney deficiency and liver stagnation treated with warm acupuncture of large-quantity moxibustion: a randomized controlled trial].

OBJECTIVE: To explore the clinical effect of warm acupuncture with large-quantity moxibustion on primary premature ejaculation (kidney deficiency and liver stagnation). METHODS: A total of 240 patients with primary premature ejaculation (kidney deficiency and liver stagnation) were randomly divided into a warm acupuncture group (80 cases, 5 cases dropped out), an acupuncture group (80 cases, 4 cases dropped out) and a western medication group (80 cases, 6 cases dropped out). In the warm acupuncture group, a large quantity of moxibustion was delivered after acupuncture at Baihui (GV 20), Qihai (CV 6), Guanyuan (CV 4) and Zhongji (CV 3), as well as bilateral Fengchi (GB 20), lateral line 3 of forehead (MS 4), neishengzhiqi (TF2), Ganshu (BL 18), Shenshu (BL 23), and etc. One treatment with warm acupuncture took 40 min, once daily; five treatments were given per week and 4 weeks of treatment was required. In the acupuncture group, moxibustion was not delivered, and the rest operation of acupuncture was same as the warm acupuncture group. In the western medication group, dapoxetine hydrochloride tablets were administered orally, 30 mg each time, taken with warm water 1 h to 3 h before sexual intercourse. Medication was administered at most once within 24 h, twice per week, and 6 times within 4 weeks. Before and after treatment, the score of TCM symptoms, the score of premature ejaculation diagnostic tool (PEDT), intravaginal ejaculation latency time (IELT) and the serum sex hormone content (testosterone [T], luteinizing hormone [LH] and follicule stimulating hormone [FSH]) were observed and the clinical effect was evaluated in the three groups. RESULTS: After treatment, the scores for less duration of intercourse (<1 min), post-ejaculation fatigue, low spirit and decreased libido, and the total scores of TCM symptoms, as well as PEDT scores were reduced when compared with those before treatment in each group (P<0.01, P<0.05), and IELT was prolonged (P<0.01) in the three groups. The serum T content was increased when compared with that before treatment in the warm acupuncture group (P<0.05). After treatment, in comparison with the acupuncture group and the western medication group, the scores for post-ejaculation fatigue, soreness and weakness in the lumbar region and knee joints, decreased libido, insomnia, dream-disturbed sleep and frequent nocturnal enuresis, as well as the total score of TCM symptoms were lower (P<0.05, P<0.01) and the serum T content was increased (P<0.05) in the warm acupuncture group. When compared with the acupuncture group, PEDT scores were lower and IELT prolonged in the warm acupuncture group and the western medication group (P<0.05, P<0.01). The total effective rate was 82.7% (62/75) in the warm acupuncture group, higher than that of the acupuncture group (68.4%, 52/76) and the western medication group (64.9%, 48/74, P<0.05) respectively. CONCLUSION: Warm acupuncture with large-quantity moxibustion ameliorates the clinical symptoms and increases intravaginal ejaculation latency time and the levels of sex hormone in the patients with primary premature ejaculation (kidney deficiency and liver stagnation).