Primary infection with human cytomegalovirus (HCMV) results in a lifelong infection due to its ability to establish latent infection, with one characterized viral reservoir being hematopoietic cells. ...Although reactivation from latency causes serious disease in immunocompromised individuals, our molecular understanding of latency is limited. Here, we delineate viral gene expression during natural HCMV persistent infection by analyzing the massive transcriptome RNA sequencing (RNA-seq) atlas generated by the Genotype-Tissue Expression (GTEx) project. This systematic analysis reveals that HCMV persistence
is prevalent in diverse tissues. Notably, we find only viral transcripts that resemble gene expression during various stages of lytic infection with no evidence of any highly restricted latency-associated viral gene expression program. To further define the transcriptional landscape during HCMV latent infection, we also used single-cell RNA-seq and a tractable experimental latency model. In contrast to some current views on latency, we also find no evidence for any highly restricted latency-associated viral gene expression program. Instead, we reveal that latency-associated gene expression largely mirrors a late lytic viral program, albeit at much lower levels of expression. Overall, our work has the potential to revolutionize our understanding of HCMV persistence and suggests that latency is governed mainly by quantitative changes, with a limited number of qualitative changes, in viral gene expression.
Human cytomegalovirus is a prevalent pathogen, infecting most of the population worldwide and establishing lifelong latency in its hosts. Although reactivation from latency causes significant morbidity and mortality in immunocompromised hosts, our molecular understanding of the latent state remains limited. Here, we examine the viral gene expression during natural and experimental latent HCMV infection on a transcriptome-wide level. In contrast to the classical views on herpesvirus latency, we find no evidence for a restricted latency-associated viral gene expression program. Instead, we reveal that latency gene expression largely resembles a late lytic viral profile, albeit at much lower levels of expression. Taken together, our data transform the current view of HCMV persistence and suggest that latency is mainly governed by quantitative rather than qualitative changes in viral gene expression.
Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation-amelogenesis
. Amelogenesis depends on multiple ameloblast-derived proteins that ...function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta
. Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency
, and in patients diagnosed with coeliac disease
. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.
Variations in speech intonation are known to be associated with changes in mental state over time. Behavioral vocal analysis is an algorithmic method of determining individuals' behavioral and ...emotional characteristics from their vocal patterns. It can provide biomarkers for use in psychiatric assessment and monitoring, especially when remote assessment is needed, such as in the COVID-19 pandemic.
The objective of this study was to design and validate an effective prototype of automatic speech analysis based on algorithms for classifying the speech features related to MDD using a remote assessment system combining a mobile app for speech recording and central cloud processing for the prosodic vocal patterns.
Machine learning compared the vocal patterns of 40 patients diagnosed with MDD to the patterns of 104 non-clinical participants. The vocal patterns of 40 patients in the acute phase were also compared to 14 of these patients in the remission phase of MDD.
A vocal depression predictive model was successfully generated. The vocal depression scores of MDD patients were significantly higher than the scores of the non-patient participants (p < 0.0001). The vocal depression scores of the MDD patients in the acute phase were significantly higher than in remission (p < 0.02).
The main limitation of this study is its relatively small sample size, since machine learning validity improves with big data.
The computerized analysis of prosodic changes may be used to generate biomarkers for the early detection of MDD, remote monitoring, and the evaluation of responses to treatment.
•Variations in speech intonation may be biomarkers for psychiatric assessment and monitoring.•Prosodic vocal patterns analysis is based on mobile speech recording and central cloud processing.•A vocal depression predictive model based on machine learning was successfully generated.•Computerized analysis of prosodic changes may be used to generate biomarkers for MDD.
This article deals with the question of which kinds of deceptions vitiate consent to sexual relations. More specifically, it addresses the question of which characteristics of the perpetrator (e.g. ...their identity, wealth, or marital status), of their relations with the victim (e.g. marriage, long-term intentions), or of the sexual act itself (e.g. protected) vitiate consent when deception is involved. In this proposal, we offer our view on how this question should be answered: the criminalisation of deceptive sex should be cautiously extended to include deception regarding any characteristic of the deceiver or the relationship on which the deceived's consent was conditional, where the deceiver was aware of this conditionality. To support our proposal, we examine the different definitions of "deceptive sex" and diverse legal approaches taken to its criminalisation in the United Kingdom, Germany, and Israel, and discuss their respective merits and shortcomings. Surprisingly, different jurisdictions take strikingly different stances on these matters. This diversity ranges from the narrow definition of traditional English law (and its more opaque contemporary version in England, Canada, and Israel) to the minimalist approach of the German system. To counter the risk of over-criminalisation inherent in our proposal, we also propose using an offence lighter than rape and criminalising only those deceivers who actively lied and whose actual knowledge of the victim's hypothetical refusal can be proven beyond reasonable doubt. Overall, while our proposal would cautiously extend the criminalisation of deceptive sex to some types of cases that are currently not criminalised, it would also significantly limit the criminalisation of deceptive sex by enhancing the requirements regarding both the accused's actus reus and their mens rea.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The purpose of this study was to examine associations of serum phosphate levels with mortality, target organ damage and length of hospital stay in adults with infectious diseases hospitalized outside ...of the intensive care unit.
This nationwide retrospective cohort study comprised patients admitted with infections, to medical and surgical departments in eight tertiary hospitals during 2001-2020. The main exposure variable was the first serum phosphate levels at admission (up to 1 week). The analysis included multivariable logistic regression models and quantile regression.
Of 126,088 patients (49% males, mean age: 69.3 years), 24,809 (19.7%) had decreased phosphate levels, 92,730 (73.5%) normal phosphate levels, and 8,549 (6.8%) elevated phosphate levels on admission. Overall- and in-hospital mortality rates were highest among those with hyperphosphatemia (74.5 and 16.4%, respectively), followed by those with normophosphatemia (57.0 and 6.6%), and lastly the hypophosphatemia group (48.7 and 5.6%);
< 0.001 for all. After adjusting for confounders, the lowest predicted mortality rate was observed in the normophosphatemia group. In the multivariable model, hyperphosphatemia conferred a higher probability of target organ damage (OR 95% CI: 2.43 2.06-2.86), while moderate hypophosphatemia conferred a lower probability (OR 95% CI: 0.73 0.65-0.82), compared to normal phosphate levels and extreme hypophosphatemia showed a non-significant association (OR 95% CI: 0.87 0.57-1.28). The associations were independent of renal failure. In a multivariable model, hyperphosphatemia was associated with a slight increase of 0.33 days in length of stay compared to normal phosphate levels.
A J-shaped relation was found between phosphate levels and prognosis in patients hospitalized with infectious diseases, regardless of their renal function.
Traumatic brain injury (TBI) affects millions of people worldwide, many of whom are affected with post-TBI mood disorders or behavioral changes, including aggression or social withdrawal. Diminished ...functionality can persist for decades after TBI and delay rehabilitation and resumption of employment. It has been established that there is a relationship between these mental disorders and brain injury. However, the etiology and causal relationships behind these conditions are poorly understood. Rodent models provide a helpful tool for researching mood disorders and social impairment due to their natural tendencies to form social hierarchies. Here, we present a rat model of mental complications after TBI using a suite of behavioral tests to examine the causal relationships between changes in social behavior, including aggressive, hierarchical, depressive, and anxious behavior. For this purpose, we used multivariate analysis to identify causal relationships between the above post-TBI psychiatric sequelae. We performed statistical analysis using principal component analysis, discriminant analysis, and correlation analysis, and built a model to predict dominant-submissive behavior based on the behavioral tests. This model displayed a predictive accuracy of 93.3% for determining dominant-submissive behavior in experimental groups. Machine learning algorithms determined that in rats, aggression is not a principal prognostic factor for dominant-submissive behavior. Alternatively, dominant-submissive behavior is determined solely by the rats' depressive-anxious state and exploratory activity. We expect the causal approach used in this study will guide future studies into mood conditions and behavioral changes following TBI.
Background : Critically ill patients with sepsis often require packed cell transfusions (PCTs). Packed cell transfusion causes changes in body's core temperature. Objective : To trace the course and ...amplitude of body core temperature after PCT in adults with sepsis. Methods : We conducted a population-based retrospective cohort study of patients with sepsis who received one unit of PCT during their hospitalization in a general intensive care unit during 2000-2019. A control group was established by matching each of these patients to a patient who did not receive PCT. We calculated the mean values of urinary bladder temperature for the 24 h before and 24 h after PCT. To evaluate the effect of PCT on body core temperature, multivariable analyses using a mixed linear regression model were performed. Results : The study comprised 1,100 patients who received one unit of PCT and 1,100 matched patients. The mean temperature before PCT was 37.3°C. Immediately from initiation of PCT, body temperature decreased, to a minimum of 37.0°C. During the 24 subsequent hours, the temperature increased gradually and consistently, until a peak temperature of 37.4°C. In a linear regression model, body core temperature increased by a mean 0.06°C in the first 24 h after PCT and decreased by a mean 0.65°C for every 1.0°C increase before PCT. Conclusions : Among critically ill patients with sepsis, PCT itself causes only mild and clinically insignificant temperature changes. Thus, significant changes in core temperature during the 24 h after PCT may indicate an unusual clinical event that requires clinicians' immediate attention.
Abstract
Background
Critically ill patients with sepsis often require packed cell transfusions (PCT). PCT causes changes in body's core temperature.
Objective
To trace the course and amplitude of ...body core temperature following PCT in adults with sepsis.
Methods
We conducted a population-based retrospective cohort study of patients with sepsis who received one unit of PCT during their hospitalization in a general intensive care unit during 2000-2019. A control group was established by matching each of these patients to a patient who did not receive PCT. We calculated the mean values of urinary bladder temperature for the 24 hours before, and 24 hours after PCT. To evaluate the effect of PCT on body core temperature, multivariable analyses using a mixed linear regression model were performed.
Results
The study comprised 1100 patients who received one unit of PCT, and 1100 matched patients. The mean temperature before PCT was 37.3 °C. Immediately from initiation of PCT, body temperature decreased, to a minimum of 37.0 °C. During the 24 subsequent hours, the temperature increased gradually and consistently, until a peak temperature of 37.4 °C. In a linear regression model, body core temperature increased by a mean 0.06 °C in the first 24 hours following PCT, and decreased by a mean 0.65 °C for every 1.0 °C increase before PCT.
Conclusions
Among critically ill patients with sepsis, PCT itself causes only mild and clinically insignificant temperature changes. Thus, significant changes in core temperature during the 24 hours following PCT may indicate an unusual clinical event that requires clinicians' immediate attention.
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