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X-chromosome inactivation (XCI) epigenetically silences one X chromosome in every cell in female mammals. Although the majority of X-linked genes are silenced, in humans 20% or more are able to escape inactivation and continue to be expressed. Such escape genes are important contributors to sex differences in gene expression, and may impact the phenotypes of X aneuploidies; yet the mechanisms regulating escape from XCI are not understood. We have performed an enrichment analysis of transcription factor binding on the X chromosome, providing new evidence for enriched factors at the transcription start sites of escape genes. The top escape-enriched transcription factors were detected at the RPS4X promoter, a well-described human escape gene previously demonstrated to escape from XCI in a transgenic mouse model. Using a cell line model system that allows for targeted integration and inactivation of transgenes on the mouse X chromosome, we further assessed combinations of RPS4X promoter and genic elements for their ability to drive escape from XCI. We identified a small transgenic construct of only 6 kb capable of robust escape from XCI, establishing that gene-proximal elements are sufficient to permit escape, and highlighting the additive effect of multiple elements that work together in a context-specific fashion.

Secondary traumatic stress (STS), vicarious trauma (VT), and burnout (BO) are work-related outcomes commonly ascribed to mental health workers, given their exposure to clients' traumatic experiences. It is theorized that a worker's own history of trauma increases the occurrence of these outcomes, through retraumatization/activation of threat cues during client interactions and overinvolvement with a client's progress. Given the inconsistencies in the literature and the ubiquity of trauma among workers, a systematic review was conducted to examine the association of personal trauma and the 3 related, but separate, work outcomes.A systematic search strategy was used across relevant research databases (Cochrane, JSTOR, PsycINFO, PubMed) for empirical studies conducted from 2000-2021. In accordance with PRISMA guidelines, a four-phase selection process was used, resulting in 39 studies identified meeting the inclusion criteria.A clear (positive) association between personal trauma history and STS and VT were identified, whereas mostly null findings were observed in regard to BO. The majority of studies were conducted in Western countries, adopted questionnaires as the primary means of data collection, and all but one were cross-sectional in design.In addition to a lack of diversity in study design, there were conceptual limitations to the research conducted (e.g., treating victims as a unitary group, neglecting the inclusion of mechanisms). To assist in moving the field forward, five research recommendations are outlined with the goal of creating greater clarity in the work-outcomes literature and increased nuance in how personal trauma is understood. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Perception is not an independent, in-the-moment event. Instead, perceiving involves integrating prior expectations with current observations. How does this ability develop from infancy through adulthood? We examined how prior visual experience shapes visual perception in infants, children, and adults. Using an identical task across age groups, we exposed participants to pairs of colorful stimuli and measured their ability to discriminate relative saturation levels. Results showed that adult participants were biased by previously-experienced exemplars, but exhibited weakened in-the-moment discrimination between different levels of saturation. In contrast, infants and children showed less influence of memory in their perception, and they actually outperformed adults in discriminating between current levels of saturation. Our findings suggest that as humans develop, their perception relies more on prior experience and less on current observation.

Background A global stockpile of oral cholera vaccine (OCV) was established in 2013 for use in outbreak response and are licensed as two-dose regimens. Vaccine availability, however, remains limited. Previous studies have found that a single dose of OCV may provide substantial protection against cholera. Methods Using a mathematical model with two age groups paired with optimization algorithms, we determine the optimal vaccination strategy with one and two doses of vaccine to minimize cumulative overall infections, symptomatic infections, and deaths. We explore counterfactual vaccination scenarios in three distinct settings: Maela, the largest refugee camp in Thailand, with high in- and out-migration; N’Djamena, Chad, a densely populated region; and Haiti, where departments are connected by rivers and roads. Results Over the short term under limited vaccine supply, the optimal strategies for all objectives prioritize one dose to the older age group (over five years old), irrespective of setting and level of vaccination coverage. As more vaccine becomes available, it is optimal to administer a second dose for long-term protection. With enough vaccine to cover the whole population with one dose, the optimal strategies can avert up to 30% to 90% of deaths and 36% to 92% of symptomatic infections across the three settings over one year. The one-dose optimal strategies can avert 1.2 to 1.8 times as many cases and deaths compared to the standard two-dose strategy. Conclusions In an outbreak setting, speedy vaccination campaigns with a single dose of OCV is likely to avert more cases and deaths than a two-dose pro-rata campaign under a limited vaccine supply.

Most COVID-19 vaccines require two doses, however with limited vaccine supply, policymakers are considering single-dose vaccination as an alternative strategy. Using a mathematical model combined with optimization algorithms, we determined optimal allocation strategies with one and two doses of vaccine under various degrees of viral transmission. Under low transmission, we show that the optimal allocation of vaccine vitally depends on the single-dose efficacy. With high single-dose efficacy, single-dose vaccination is optimal, preventing up to 22% more deaths than a strategy prioritizing two-dose vaccination for older adults. With low or moderate single-dose efficacy, mixed vaccination campaigns with complete coverage of older adults are optimal. However, with modest or high transmission, vaccinating older adults first with two doses is best, preventing up to 41% more deaths than a single-dose vaccination given across all adult populations. Our work suggests that it is imperative to determine the efficacy and durability of single-dose vaccines, as mixed or single-dose vaccination campaigns may have the potential to contain the pandemic much more quickly., Most COVID-19 vaccines require two doses but a single dose provides partial protection, so it is unclear how best to prioritize vaccine distribution in the context of limited supply. Here, the authors show that campaigns in which some age groups receive one dose while others receive both doses may be optimal.

The optimal use of COVID-19 vaccine depends mainly on how efficacious the vaccine is and how many doses are available., Vaccines, when available, will likely become our best tool to control the COVID-19 pandemic. Even in the most optimistic scenarios, vaccine shortages will likely occur. Using an age-stratified mathematical model paired with optimization algorithms, we determined optimal vaccine allocation for four different metrics (deaths, symptomatic infections, and maximum non-ICU and ICU hospitalizations) under many scenarios. We find that a vaccine with effectiveness ≥50% would be enough to substantially mitigate the ongoing pandemic, provided that a high percentage of the population is optimally vaccinated. When minimizing deaths, we find that for low vaccine effectiveness, irrespective of vaccination coverage, it is optimal to allocate vaccine to high-risk (older) age groups first. In contrast, for higher vaccine effectiveness, there is a switch to allocate vaccine to high-transmission (younger) age groups first for high vaccination coverage. While there are other societal and ethical considerations, this work can provide an evidence-based rationale for vaccine prioritization.

Cholera is an acute, diarrheal disease caused by Vibrio cholerae O1 or 139 that is associated with a high global burden. In this review, we identify the estimated duration of immunity following cholera infection with and without clinical symptoms from available published studies. We searched Pubmed and Web of Science for studies examining the long-term infection-acquired immunity against cholera infection. We identified 22 eligible studies and categorized them as either observational, challenge, or serological. We observed in observational and challenge studies that at three years, there is strong evidence of protection. However, serological studies show that elevated humoral markers returned to baseline within one year. Although with small sample sizes, three studies found that most participants with a subclinical infection from an initial challenge with cholera had a symptomatic infection when rechallenged with a homologous biotype, suggesting that a subclinical cholera infection may confer lower protection than a clinical one. This review underscores the need to elucidate potential differences in the protection provided by clinical and subclinical cholera infections. Further, more studies are warranted to bridge the gap between the correlates of protection and cholera immunity. Understanding the duration of natural immunity to cholera can help guide control strategies and policy.

Purpose: Both facial appearance and behaviors could respectively contribute to impression formation towards an indi- vidual. However, when there is congruence between information decoded from facial appearance and behaviors which may determine impression in different ways, effect of both factors will be altered. This study aimed to investigate the discrepancy between the information carried by the face, i.e. facial trustworthiness and social description, and how these two factors influence individuals’ attitude towards a newly-met person, and their judgment with regard to warmth and competence.\ud \ud \ud Methodology: An experiment was conducted, asking participants to rate their impression in terms of warmth and compe- tence towards an individual whose facial appearance was manipulated either to be trustworthy or untrustworthy, and whose behavior was described in a short vignette.\ud \ud \ud Main Findings: The results indicated that social description had a significant influence on both warmth and competence impressions. Facial trustworthiness had no effect. It was also discovered that competence was found to be generally judged more positive than warmth, which implied judgment of warmth was made more reservedly.\ud \ud \ud Implications: The study would serve as an antecedent to further investigation on managing people’s impression towards oneself, in which such management aids in developing and maintaining positive personal relationship amongst human beings. The study will demonstrate a new vision to the researchers in cognition and perception on exploring approaches to define the mechanism involved in impression formation or attitude.\ud \ud \ud Novelty: Researchers trust that currently there is still no related research that would determine the direction and strength of effect from facial trustworthiness and social description.

The goal of this study was to isolate, screen, and characterize Arctic microbial isolates from Expedition Fjord, Axel Heiberg Island, Nunavut, Canada capable of inhibiting the growth of foodborne and clinically relevant pathogens. Arctic bacteria were isolated from twelve different high Arctic habitats pertaining to active layer permafrost soil, saline spring sediments, lake sediments, and endoliths. This was achieved using (1) the cryo-iPlate, an innovative in situ cultivation device within active layer permafrost soil and (2) bulk plating of Arctic samples by undergraduate students that applied standard culturing methods. To mitigate the possibility of identifying isolates with already-known antibacterial activities, a cell-based dereplication platform was used. Ten out of the twelve Arctic habitats tested were found to yield cold-adapted isolates with antibacterial activity. Eight cold-adapted Arctic isolates were identified with the ability to inhibit the entire dereplication platform, suggesting the possibility of new mechanisms of action. Two promising isolates, initially cultured from perennial saline spring sediments and from active layer permafrost soil (Paenibacillus sp. GHS.8.NWYW.5 and Pseudomonas sp. AALPS.10.MNAAK.13, respectively), displayed antibacterial activity against foodborne and clinically relevant pathogens. Paenibacillus sp. GHS.8.NWYW.5 was capable of inhibiting methicillin resistant and susceptible Staphylococcus aureus (MRSA and MSSA), Listeria monocytogenes, Salmonella enterica and Escherichia coli O157:H7. Pseudomonas sp. AALPS.10.MNAAK.13 was observed to have antagonistic activity against MRSA, MSSA, Acinetobacter baumanii, Enterococcus faecium, and Enterococcus faecalis. After whole genome sequencing and mining, the genome of Paenibacillus sp. GHS.8.NWYW.5 was found to contain seven putative secondary metabolite biosynthetic gene clusters that displayed low homology ( 0) to clusters identified within the genome of the type strain pertaining to the same species. These findings suggest that cold-adapted Arctic microbes may be a promising source of novel secondary metabolites for potential use in both industrial and medical settings.

Incidence of whooping cough, an infection caused by Bordetella pertussis and Bordetella parapertussis, has been on the rise since the 1980s in many countries. Immunological interactions, such as immune boosting and cross-immunity between pathogens, have been hypothesised to be important drivers of epidemiological dynamics. We present a two-pathogen model of transmission which examines how immune boosting and cross-immunity can influence the timing and severity of epidemics. We use a combination of numerical simulations and bifurcation techniques to study the dynamical properties of the system, particularly the conditions under which stable periodic solutions are present. We derive analytic expressions for the steady state of the single-pathogen model, and give a condition for the presence of periodic solutions. A key result from our two-pathogen model is that, while studies have shown that immune boosting at relatively strong levels can independently generate periodic solutions, cross-immunity allows for the presence of periodic solutions even when the level of immune boosting is weak. Asymmetric cross-immunity can produce striking increases in the incidence and period. Our study underscores the importance of developing a better understanding of the immunological interactions between pathogens in order to improve model-based interpretations of epidemiological data., 17 pages, 7 figures

The role of stray dogs in the persistence of domestic dog rabies, and whether removal of such dogs is beneficial, remain contentious issues for control programs seeking to eliminate rabies. While a community might reach the WHO vaccination target of 70% for dogs that can be handled, the stray or neighborhood dogs that are too wary of humans to be held are a more problematic population to vaccinate. So what needs to be done? Here we present a method to estimate vaccination targets for stray dogs when the dog population is made up of stray, free-roaming and confined dogs, where the latter two types are considered to have an identifiable owner. The control effort required for stray dogs is determined by the type reproduction number, T_1, the number of stray dogs infected by one rabid stray dog either directly or via any chain of infection involving owned dogs. Like the basic reproduction number R_0 for single host populations, T_1 determines the vaccination effort required to control the spread of disease when control is targeted at one host type, and there are a mix of host types. The application of T_1 to rabies in mixed populations of stray and owned dogs is novel. We show that the outcome is sensitive to the vaccination coverage in the owned dog population, such that if vaccination rates of owned dogs were too low then no control effort targeting stray dogs is able to control or eliminate rabies. The required vaccination level also depends on the composition of the dog population, where a high proportion of either stray or free-roaming dogs implies unrealistically high vaccination levels are required to prevent rabies. We find that the required control effort is less sensitive to continuous culling that increases the death rate of stray dogs than to changes in the carrying capacity of the stray dog population.

OBJECTIVE(S): In the present study, we examined whether there was an association between dopamine-β hydroxylase (DBH) promoter polymorphisms (a 5'-ins/del and a GTn repeats) and a history of suicide attempt in 223 chronic schizophrenia individuals using statistical and molecular analyses. Within the genetic association study design, we compared the statistical haplotype phase with the molecular phase produced by the amplicon size analysis. MATERIALS AND METHODS: The two DBH polymorphisms were analysed using the Applied Biosystem 3130 and the statistical analyses were carried out using UNPHASED v.3.1.5 and PHASE v.2.1.1 to determine the haplotype frequencies and infer the phase in each patient. Then, DBH polymorphisms were incorporated into the Haploscore analysis to test the association with a history of suicide attempt. RESULTS: In our sample, 62 individuals had a history of suicide attempt. There was no association between DBH polymorphisms and a history of suicide attempt across the different analytical strategies applied. There was no significant difference between the haplotype frequencies produced by the amplicon size analysis and statistical analytical strategies. However, some of the haplotype pairs inferred in the PHASE analysis were inconsistent with the molecular haplotype size measured by the ABI 3130. CONCLUSION: The amplicon size analysis proved to be the most accurate method using the haplotype as a possible genetic marker for future testing. Although the results were not significant, further molecular analyses of the DBH gene and other candidate genes can clarify the utility of the molecular phase in psychiatric genetics and personalized medicine. Language: en

Background and Purpose : Developing improved methods for analysis of the modified Rankin Scale (mRS) remains a critical issue for the stroke research community. A recently proposed permutation-based approach is assumption-free and easily interpretable but computationally intensive and does not provide confidence intervals to quantify the precision of the effect size estimate. We aimed to develop a method to overcome these limitations. Methods : We propose a procedure using generalized odds ratios to estimate the odds that a patient who received the investigational treatment will have a better outcome than a patient receiving standard treatment. This approach was validated against the permutation method using hypothetical clinical trial scenarios of neuroprotective effect, early recanalization effect, late recanalization effect, and random benefit. Results : The generalized odds ratio approach had strong agreement with the permutation approach provided sample size was >15 patients per treatment arm. Simulation established that the confidence intervals generated were accurate. Ignoring patient pairs with tied mRS scores overestimates the treatment effect compared with splitting tied mRS scores. Conclusions : In addition to all the advantages of the recently proposed permutation-based approach, our method generates confidence intervals without the need for intensive computational power. The resulting generalized odds ratios are particularly suitable for inclusion in meta-analyses and have a simple and intuitive connection with the number-needed-to-treat measure.

Worldwide, breast cancer remains as one of the most common cancer diagnosis and cause of cancer related death among women. Fortunately, nanomedicine has brought forth new potential and hope in breast cancer research. The extremely small size of nanoparticles makes it advantageous and potentially superior to use in tumor detection and imaging. One of the more extensively studied particles is quantum dots, semiconductor crystals which are capable of enhanced labeling and imaging of cancer cells. In addition, due to serious toxicity of chemotherapeutic agents, nano-formulations of breast cancer chemotherapy are under investigation and development. This may provide easier administering route and reduced frequency of drugs. With the use of nanoparticles, drug delivery can be carried out in a minimally invasive fashion and treatment regimens can be made much more targeted and specific for each patient. In this review article, we provide an overview on the role nanomedicine has played in breast cancer and mention some of the latest diagnostic and treatment modalities researched to date.

The use of engineered antigen carriers to optimize the immune response to recombinant subunit vaccines has seen great advances in recent years. Optimization can take several forms, such as facilitating stimulation of certain immune cells or amplifying the adjuvancy effect of the vaccine formulation. In this paper, we applied dose/response analysis to demonstrate the ability of outer membrane vesicle (OMV) antigen carriers derived from engineered Escherichia coli to produce strong antigen-specific immune responses to a model antigen at a significantly decreased antigen load compared to an industry standard alum-based control. Inflammopathology and histological analysis of extended studies further supported a capacity to enhance immune cell recruitment locally at the injection site while decreasing inflammation and eliminating injection site scaring. The results indicate a strong potential for OMV-based vaccines as recombinant antigen delivery vehicles, affording strong immunogenicity at low doses with a broadly applicable platform for recombinant subunit antigen inclusion.

223 Background: The Odette Cancer Centre (OCC) manages more than 24,000 chemotherapy visits annually. The delivery process is complex and patients have significant wait times for treatment. The OCC was faced with improving this process with no data infrastructure to support continuous quality improvement. Methods: An electronic scheduling manager, Chemotherapy Appointment Reservation Manager (CHARM) was designed that includes workflow communication between pharmacy and nursing. A multidisciplinary team created a value stream map of the process. Rate limiting steps and key milestones in the delivery process were identified. CHARM timestamps stages in the chemotherapy process, from nurse approval to pharmacy verification, medication processing and medications received on the chemotherapy unit. Extracted data was used to create a weekly report to monitor key performance indicators (KPIs). Results: An analysis of six months of data led to the establishment of KPIs and targets. Our baseline targets were established as pharmacy turnaround time (AR) < 1 hour, pharmacy verification (HP)< 13 minutes, medication processing (PR)