Differential Retention of Pfam Domains Contributes to Long-term Evolutionary Trends.

Protein domains that emerged more recently in evolution have a higher structural disorder and greater clustering of hydrophobic residues along the primary sequence. It is hard to explain how selection acting via descent with modification could act so slowly as not to saturate over the extraordinarily long timescales over which these trends persist. Here, we hypothesize that the trends were created by a higher level of selection that differentially affects the retention probabilities of protein domains with different properties. This hypothesis predicts that loss rates should depend on disorder and clustering trait values. To test this, we inferred loss rates via maximum likelihood for animal Pfam domains, after first performing a set of stringent quality control methods to reduce annotation errors. Intermediate trait values, matching those of ancient domains, are associated with the lowest loss rates, making our results difficult to explain with reference to previously described homology detection biases. Simulations confirm that effect sizes are of the right magnitude to produce the observed long-term trends. Our results support the hypothesis that differential domain loss slowly weeds out those protein domains that have nonoptimal levels of disorder and clustering. The same preferences also shape the differential diversification of Pfam domains, thereby further impacting proteome composition.

Can laboratory HIV and infectious syphilis data inform future pre-exposure prophylaxis use in women in Ontario, Canada?

OBJECTIVES: Infectious syphilis has been proposed as an indication for HIV pre-exposure prophylaxis (PrEP) in women. We explored how many women experienced HIV seroconversion after being diagnosed with syphilis in Ontario between 20 April 2010 and 31 December 2021. METHODS: Through deterministic linkage of laboratory data at the Public Health Ontario laboratory, which conducts the vast majority of syphilis and HIV testing in Ontario, we quantified the number of females with positive syphilis diagnoses who subsequently exhibited HIV seroconversion between April 2010 and December 2021. New HIV cases were identified by diagnostic serology or HIV viral load test result of ≥20 copies/mL at least 60 days after the positive syphilis test. We report aggregate numbers of women with new laboratory evidence of HIV infection after their first positive syphilis test. RESULTS: Among 7957 women with positive syphilis tests during the study period, 6554 (82.4%) had linkable HIV serology tests and 133 (1.7%) ever tested HIV positive. With further linkage to viral load data, the number of women who ever had laboratory evidence of HIV infection increased to 184 (2.3%). However, when restricting to women whose first positive HIV test or HIV viral load occurred after their first positive syphilis test, this number decreased to 34 (0.4%). The median (IQR) time between the positive syphilis test and the first laboratory evidence of HIV was 551 (IQR=226-1159) days. CONCLUSION: Although it is clinically appropriate to recommend HIV PrEP to women with syphilis, Ontario surveillance data suggest that the population-level impact of this strategy on the HIV epidemic in Ontario would have been modest during this 11-year period. Future studies should explore additional ways of prioritising women for PrEP.

Pulmonary Nontuberculous Mycobacteria, Ontario, Canada, 2020.

We measured annual prevalence of microbiologically defined nontuberculous mycobacterial lung disease in Ontario, Canada. Mycobacterium avium prevalence was 13 cases/100,000 persons in 2020, a 2.5-fold increase from 2010, indicating a large increase in true M. avium lung disease. During the same period, M. xenopi decreased nearly 50%, to 0.84 cases/100,000 persons.

Defensive Symbiosis and the Evolution of Virulence.

AbstractA microbiome rife with enemies of the host should cause selection for defensive traits in symbionts, yet such complex environments are also predicted to select for greater symbiont virulence. Why then do we so often observe defensive mutualists that protect hosts while causing little to no damage? To address this question, we build a symbiont-centered model that incorporates the evolution of two independent symbiont traits: defense and virulence. Virulence is modeled as a continuous trait spanning parasitism (positive virulence) and mutualism (negative virulence), thus accounting for the entire range of direct effects that symbionts have on host mortality. Defense is modeled as a continuous trait that ameliorates the costs to the host associated with infection by a deleterious parasite. We show that the evolution of increased defense in one symbiont may lead to the evolution of lower virulence in both symbionts and even facilitate pathogens evolving to mutualism. However, results are context dependent, and when defensive traits are costly, the evolution of greater defense may also lead to the evolution of greater virulence, breaking the common expectation that defensive symbionts are necessarily mutualists toward the host.

Intercellular competition and the inevitability of multicellular aging.

Current theories attribute aging to a failure of selection, due to either pleiotropic constraints or declining strength of selection after the onset of reproduction. These theories implicitly leave open the possibility that if senescence-causing alleles could be identified, or if antagonistic pleiotropy could be broken, the effects of aging might be ameliorated or delayed indefinitely. These theories are built on models of selection between multicellular organisms, but a full understanding of aging also requires examining the role of somatic selection within an organism. Selection between somatic cells (i.e., intercellular competition) can delay aging by purging nonfunctioning cells. However, the fitness of a multicellular organism depends not just on how functional its individual cells are but also on how well cells work together. While intercellular competition weeds out nonfunctional cells, it may also select for cells that do not cooperate. Thus, intercellular competition creates an inescapable double bind that makes aging inevitable in multicellular organisms.

Catheter-induced acute Blalock-Taussig shunt thrombosis and bailout.

Modified Blalock-Taussig shunt thrombosis is a life-threatening event. We describe an extremely rare catheter-induced shunt thrombosis in an infant with complex CHD and its successful treatment utilising a single low dose of local recombinant tissue plasminogen activator in conjunction with balloon angioplasty.

Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors.

BACKGROUND: A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear. METHODS: In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest-volume center in the study. RESULTS: Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P<0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow-cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded. CONCLUSIONS: This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Randomized Trial to Compare Smoking Cessation Rates of Snus, With and Without Smokeless Tobacco Health-Related Information, and a Nicotine Lozenge.

Introduction: Nicotine replacement medications are moderately effective in increasing quit rates. However, some smokers reject such aids, suggesting the value of considering alternative options. Snus, a smokeless tobacco product with low nitrosamine content, could offer an alternative. This study compared smoking cessation rates for snus, with and without information about reduced risk relative to smoking, with a nicotine lozenge (without relative risk information). Methods: A randomized, open-label, multicenter clinical trial was performed with 649 smokers, aged 21 to 65, who smoked at least 10 cigarettes per day for the past year and who were motivated to quit smoking. Participants were followed for up to 12 months and were provided no counseling or support. Smoking cessation was analyzed as continuous smoking abstinence (no smoking following quit date) and repeated point prevalence abstinence (no smoking within past 7 days). Results: Abstinence rates did not differ significantly between snus and the nicotine lozenge-continuous abstinence did not differ at any time point, and point prevalence rates differed only at month 3, when the lozenge group showed higher abstinence rates (17.4%) than either of the two snus groups (snus alone: 8.7%; snus plus information: 10.1%). Large percentages of participants used the products during the treatment period. Providing relative risk information to snus users did not affect snus use. The amount of use did not predict subsequent outcome. Adverse events were reported at similar rates across the three groups. Conclusions: Smoking cessation rates were comparable between snus and a nicotine lozenge, but success rates in this trial were low. Implications: This randomized trial of the nicotine lozenge, snus, or snus plus information on the relative risks of smokeless tobacco versus smoking found comparable but low smoking cessation rates for all three groups at weeks 12, 26, and 52. The one-time provision of relative risk information did not lead to greater snus use among those provided the information, suggesting no effect for this brief intervention.

Traumatic brain injury is highly associated with self-reported childhood trauma within a juvenile offender cohort.

PRIMARY OBJECTIVE: To identify correlates of past traumatic brain injury (TBI) in a population of young offenders. RESEARCH DESIGN: Cross-sectional analyses were conducted on available data from a sample derived from the NSW Young People on Community Orders Health Survey. PROCEDURES: Study participants were administered questionnaires to collect history relating to past TBI, childhood trauma, substance abuse, and psychological/psychiatric symptoms and underwent assessments of intellectual functioning. Information on offending history was accessed through Juvenile Justice administrative records. OUTCOMES AND RESULTS: Analyses were undertaken on data from 788 young offenders (672 males and 116 females). A past TBI was reported in 39%. Symptoms of psychological distress were more prevalent in females. A history of TBI was associated with more symptoms on a Childhood Trauma Questionnaire, as well as higher psychological distress (K-10), and higher levels on standardized measures of anger/violence, post-traumatic stress, and substance abuse. CONCLUSIONS: The experience of early life trauma warrants further consideration as an antecedent to both childhood TBI and offending which might account for some of the previously observed association of mild TBI with subsequent offending behavior.

Hospital readmissions following HLA-incompatible live donor kidney transplantation: A multi-center study.

Thirty percent of kidney transplant recipients are readmitted in the first month posttransplantation. Those with donor-specific antibody requiring desensitization and incompatible live donor kidney transplantation (ILDKT) constitute a unique subpopulation that might be at higher readmission risk. Drawing on a 22-center cohort, 379 ILDKTs with Medicare primary insurance were matched to compatible transplant-matched controls and to waitlist-only matched controls on panel reactive antibody, age, blood group, renal replacement time, prior kidney transplantation, race, gender, diabetes, and transplant date/waitlisting date. Readmission risk was determined using multilevel, mixed-effects Poisson regression. In the first month, ILDKTs had a 1.28-fold higher readmission risk than compatible controls (95% confidence interval [CI] 1.13-1.46; P < .001). Risk peaked at 6-12 months (relative risk [RR] 1.67, 95% CI 1.49-1.87; P < .001), attenuating by 24-36 months (RR 1.24, 95% CI 1.10-1.40; P < .001). ILDKTs had a 5.86-fold higher readmission risk (95% CI 4.96-6.92; P < .001) in the first month compared to waitlist-only controls. At 12-24 (RR 0.85, 95% CI 0.77-0.95; P = .002) and 24-36 months (RR 0.74, 95% CI 0.66-0.84; P < .001), ILDKTs had a lower risk than waitlist-only controls. These findings of ILDKTs having a higher readmission risk than compatible controls, but a lower readmission risk after the first year than waitlist-only controls should be considered in regulatory/payment schemas and planning clinical care.

Coevolution between Mutualists and Parasites in Symbiotic Communities May Lead to the Evolution of Lower Virulence.

Most eukaryotes harbor a diverse community of parasitic, mutualistic, and commensal microbial symbionts. Although the diversity of these microbial symbiotic communities has recently drawn considerable attention, theory regarding the evolution of interactions among symbionts and with the host is still in its nascent stages. Here we evaluate the role of interactions among coinfecting symbionts in the evolution of symbiont virulence toward the host. To do so, we place the virulence-transmission trade-off into a community context and model the evolution of symbiont trophic modes along the continuum from parasitism (virulence) to mutualism (negative virulence). We establish a framework for studying multiple infections of a host by the same symbiont species and coinfection by multiple species, using a concept of shared costs, wherein the negative consequences of virulence (or harm) toward the host are shared among symbionts. Our results show that mutualism can be maintained under infection by multiple symbionts when shared costs are sufficiently low, while greater virulence and parasitism toward the host are more likely when shared costs are high. Last, for coinfection by more than one species, we show that if the presence of a mutualist ameliorates some of the costs of pathogen virulence, then the symbiotic community may more often evolve to a more commensal state and maintain mutualisms.

Influence of cigarette filter ventilation on smokers' mouth level exposure to tar and nicotine.

Cigarette filter ventilation allows air to be drawn into the filter, diluting the cigarette smoke. Although machine smoking reveals that toxicant yields are reduced, it does not predict human yields. The objective of this study was to investigate the relationship between cigarette filter ventilation and mouth level exposure (MLE) to tar and nicotine in cigarette smokers. We collated and reviewed data from 11 studies across 9 countries, in studies performed between 2005 and 2013 which contained data on MLE from 156 products with filter ventilation between 0% and 87%. MLE among 7534 participants to tar and nicotine was estimated using the part-filter analysis method from spent filter tips. For each of the countries, MLE to tar and nicotine tended to decrease as filter ventilation increased. Across countries, per-cigarette MLE to tar and nicotine decreased as filter ventilation increased from 0% to 87%. Daily MLE to tar and nicotine also decreased across the range of increasing filter ventilation. These data suggest that on average smokers of highly ventilated cigarettes are exposed to lower amounts of nicotine and tar per cigarette and per day than smokers of cigarettes with lower levels of ventilation.

Religious perspectives on the use of psychopharmaceuticals as an enhancement technology.

The use of psychopharmaceuticals as an enhancement technology has been the focus of attention in the bioethics literature. However, there has been little examination of the challenges that this practice creates for religious traditions that place importance on questions of being, authenticity, and identity. We asked expert commentators from six major world religions to consider the issues raised by psychopharmaceuticals as an enhancement technology. These commentaries reveal that in assessing the appropriate place of medical therapies, religious traditions, like secular perspectives, rely upon ideas about health and disease and about normal human behavior. But unlike secular perspectives, faith traditions explicitly concern themselves with ways in which medicine should or should not be used to live a "good life".

Beyond active learning: Using 3-Dimensional learning to create scientifically authentic, student-centered classrooms.

In recent years, much of the emphasis for transformation of introductory STEM courses has focused on "active learning", and while this approach has been shown to produce more equitable outcomes for students, the construct of "active learning" is somewhat ill-defined and is often used as a "catch-all" that can encompass a wide range of pedagogical techniques. Here we present an alternative approach for how to think about the transformation of STEM courses that focuses instead on what students should know and what they can do with that knowledge. This approach, known as three-dimensional learning (3DL), emerged from the National Academy's "A Framework for K-12 Science Education", which describes a vision for science education that centers the role of constructing productive causal accounts for phenomena. Over the past 10 years, we have collected data from introductory biology, chemistry, and physics courses to assess the impact of such a transformation on higher education courses. Here we report on an analysis of video data of class sessions that allows us to characterize these sessions as active, 3D, neither, or both 3D and active. We find that 3D classes are likely to also involve student engagement (i.e. be active), but the reverse is not necessarily true. That is, focusing on transformations involving 3DL also tends to increase student engagement, whereas focusing solely on student engagement might result in courses where students are engaged in activities that do not involve meaningful engagement with core ideas of the discipline.

Epidemiological modelling of attention-deficit/hyperactivity disorder and conduct disorder for the Global Burden of Disease Study 2010.

BACKGROUND: The most recent Global Burden of Disease Study (GBD 2010) is the first to include attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) for burden quantification. We present the epidemiological profiles of ADHD and CD across three time periods for 21 world regions. METHODS: A systematic review of global epidemiology was conducted for each disorder (based on a literature search of the Medline, PsycInfo and EMBASE databases). A Bayesian metaregression tool was used to derive prevalence estimates by age and sex in three time periods (1990, 2005 and 2010) for 21 world regions including those with little or no data. Prior expert knowledge and covariates were applied to each model to adjust suboptimal data. Final prevalence output for ADHD were adjusted to reflect an equivalent value if studies had measured point prevalence using multiple informants while final prevalence output for CD were adjusted to reflect a value equivalent to CD only. RESULTS: Prevalence was pooled for males and females aged 5-19 years with no difference found in global prevalence between the three time periods. Male prevalence of ADHD in 2010 was 2.2% (2.0-2.3) while female prevalence was 0.7% (0.6-0.7). Male prevalence of CD in 2010 was 3.6% (3.3-4.0) while female prevalence was 1.5% (1.4-1.7). ADHD and CD were estimated to be present worldwide with ADHD prevalence showing some regional variation while CD prevalence remained relatively consistent worldwide. CONCLUSIONS: We present the first prevalence estimates of both ADHD and CD globally and for all world regions. Data were sparse with large parts of the world having no estimates of either disorder. Epidemiological studies are urgently needed in certain parts of the world. Our findings directly informed burden quantification for GBD 2010. As mental disorders gained increased recognition after the first GBD study in 1990, the inclusion of ADHD and CD in GBD 2010 ensures their importance will be recognized alongside other childhood disorders.

Auditory risk assessment of college music students in jazz band-based instructional activity.

It is well-known that musicians are at risk for music-induced hearing loss, however, systematic evaluation of music exposure and its effects on the auditory system are still difficult to assess. The purpose of the study was to determine if college students in jazz band-based instructional activity are exposed to loud classroom noise and consequently exhibit acute but significant changes in basic auditory measures compared to non-music students in regular classroom sessions. For this we (1) measured and compared personal exposure levels of college students (n = 14) participating in a routine 50 min jazz ensemble-based instructional activity (experimental) to personal exposure levels of non-music students (n = 11) participating in a 50-min regular classroom activity (control), and (2) measured and compared pre- to post-auditory changes associated with these two types of classroom exposures. Results showed that the L eq (equivalent continuous noise level) generated during the 50 min jazz ensemble-based instructional activity ranged from 95 dBA to 105.8 dBA with a mean of 99.5 ± 2.5 dBA. In the regular classroom, the L eq ranged from 46.4 dBA to 67.4 dBA with a mean of 49.9 ± 10.6 dBA. Additionally, significant differences were observed in pre to post-auditory measures between the two groups. The experimental group showed a significant temporary threshold shift bilaterally at 4000 Hz (P < 0.05), and a significant decrease in the amplitude of transient-evoked otoacoustic emission response in both ears (P < 0.05) after exposure to the jazz ensemble-based instructional activity. No significant changes were found in the control group between pre- and post-exposure measures. This study quantified the noise exposure in jazz band-based practice sessions and its effects on basic auditory measures. Temporary, yet significant, auditory changes seen in music students place them at risk for hearing loss compared to their non-music cohorts.

Abuse liability of two electronic nicotine delivery systems compared with combustible cigarettes and nicotine gum from an open-label randomized crossover study.

An assessment of the likelihood of use and abuse potential for new tobacco products is an important part of tobacco product regulation in the United States and abroad. This paper reports the results of a randomized, open-label, crossover clinical study that assessed factors related to product adoption and abuse liability (AL), comparing two closed electronic nicotine delivery system (ENDS) products to combustible cigarettes and nicotine gum, high- and low-AL comparator products, respectively. During an 11-day confinement period that included multiple product familiarization sessions, healthy adult smokers participated in AL test sessions to evaluate the abuse liability of each product. During these test sessions, changes in subjective measures; speed and amount of nicotine uptake; and maximum changes in physiological effects before, during, and after use of each assigned product were assessed over 4 h. Positive subjective effects measures scores such as product-liking and overall intent to use again were highest for cigarettes, followed by the Vuse ENDS, with nicotine gum consistently having the lowest scores. The PK results (Cmax and Tmax) of the Vuse ENDS products are between UB cigarettes and nicotine gum, which correlates with the subjective effects. All nicotine uptake measures for the Vuse ENDS products were lower than that of usual brand (UB) cigarettes, including peak nicotine uptake and overall nicotine uptake, and were either similar to or lower than nicotine gum. The time course of nicotine uptake after use of the ENDS was more similar to that of combustible cigarettes than nicotine gum. The results indicate that the AL of each ENDS product is lower than that of UB cigarettes and similar to that of nicotine gum.

Changes in Biomarkers of Exposure and Potential Harm in Smokers Switched to Vuse Vibe or Vuse Ciro Electronic Nicotine Delivery Systems.

Electronic nicotine delivery systems (ENDS) have the potential to provide nicotine to tobacco consumers while reducing exposure to combustion-related toxicants. Here, we report changes in biomarkers of exposure (BoE) and biomarkers of potential harm (BoPH) in smokers who completely switched to Vuse Vibe and Vuse Ciro ENDS products, or to smoking abstinence in a randomized, controlled clinical study. Thirteen BoE (12 urinary and one blood) that indicate exposure to harmful and potentially harmful toxicants (HPHCs) were evaluated at baseline on day 5. Urinary BoPH linked to oxidative stress, platelet activation, and inflammation were also assessed at baseline, and on day 5 and day 7. Nicotine exposure was lower in Vuse Vibe and Vuse Ciro groups compared to baseline values. Urinary non-nicotine BoE decreased significantly (52.3-96.7%) in the Vuse ENDS groups, and the reductions were similar in magnitude to those observed in the abstinence group. Blood carboxyhemoglobin decreased 52.8-55.0% in all study groups. Decreases (10-50%) in BoPH were observed in all study groups. Thus, smokers who switch exclusively to Vuse Vibe or Vuse Ciro products or completely abstain from smoking are exposed to substantially lower levels of HPHCs, and experience improvements in BoPH of oxidative stress and inflammation pathways.