Different transformations underlie blowhole and nasal passage development in a toothed whale (Odontoceti: Stenella attenuata) and a baleen whale (Mysticeti: Balaenoptera physalus).

Reorientation of the nasal passage away from the anteroposterior axis has evolved rarely in mammals. Unlike other mammals, cetaceans (e.g., whales, dolphins, and porpoises) have evolved a "blowhole": posteriorly repositioned nares that open dorsad. Accompanying the evolution of the blowhole, the nasal passage has rotated dorsally. Neonatal cetaceans possess a blowhole, but early in development, cetacean embryos exhibit head morphologies that resemble those of other mammals. Previous workers have proposed two developmental models for how the nasal passage reorients during prenatal ontogeny. In one model, which focused on external changes in the whole body, dorsad rotation of the head relative to the body results in dorsad rotation of the nasal passage relative to the body. A second model, based on details of the cartilaginous nasal skull, describes dorsad rotation of the nasal passage itself relative to the palate and longitudinal axis of the skull. To integrate and revise these models, we characterized both external and internal prenatal changes in a longitudinal plane that are relevant to nasal passage orientation in the body and head of the pantropical spotted dolphin (Odontoceti: Stenella attenuata). These changes were then compared to those in a prenatal series of a baleen whale, the fin whale (Mysticeti: Balaenoptera physalus), to determine if they were representative of both extant cetacean suborders. In both species, the angle between the nasal passage and the sagittal axis of the foramen magnum decreased with age. In S. attenuata, this was associated with basicranial retroflexion and midfacial lordosis: the skull appeared to fold dorsad with the presphenoid as the vertex of the angle. In contrast, in B. physalus, alignment of the nasal passage and the sagittal axis of the plane of the foramen magnum was associated with angular changes within the posterior skull (specifically, the orientations of the supraoccipital and foramen magnum relative to the posterior basicranium). With these results, we propose a new developmental model for prenatal reorientation of the odontocete nasal passage and discuss ways in which mysticetes likely deviate from this model.

The impact of large terrestrial carnivores on Pleistocene ecosystems.

Large mammalian terrestrial herbivores, such as elephants, have dramatic effects on the ecosystems they inhabit and at high population densities their environmental impacts can be devastating. Pleistocene terrestrial ecosystems included a much greater diversity of megaherbivores (e.g., mammoths, mastodons, giant ground sloths) and thus a greater potential for widespread habitat degradation if population sizes were not limited. Nevertheless, based on modern observations, it is generally believed that populations of megaherbivores (>800 kg) are largely immune to the effects of predation and this perception has been extended into the Pleistocene. However, as shown here, the species richness of big carnivores was greater in the Pleistocene and many of them were significantly larger than their modern counterparts. Fossil evidence suggests that interspecific competition among carnivores was relatively intense and reveals that some individuals specialized in consuming megaherbivores. To estimate the potential impact of Pleistocene large carnivores, we use both historic and modern data on predator-prey body mass relationships to predict size ranges of their typical and maximum prey when hunting as individuals and in groups. These prey size ranges are then compared with estimates of juvenile and subadult proboscidean body sizes derived from extant elephant growth data. Young proboscideans at their most vulnerable age fall within the predicted prey size ranges of many of the Pleistocene carnivores. Predation on juveniles can have a greater impact on megaherbivores because of their long interbirth intervals, and consequently, we argue that Pleistocene carnivores had the capacity to, and likely did, limit megaherbivore population sizes.

Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease.

Several genes have been implicated in Rett syndrome (RTT) in its typical and variant forms. We applied next-generation sequencing (NGS) to evaluate for mutations in known or new candidate genes in patients with variant forms of Rett or Rett-like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free. This missense was maternally inherited with opposite allele expression ratios in the proband and her mother. In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett-like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 encoding the potassium channel Kv 1.2 in a girl with infantile-onset seizures variant of RTT. Our study expands the genetic heterogeneity of RTT and RTT-like phenotypes. Moreover, we report the first familial case of CDKL5-related disease.

Mainland size variation informs predictive models of exceptional insular body size change in rodents.

The tendency for island populations of mammalian taxa to diverge in body size from their mainland counterparts consistently in particular directions is both impressive for its regularity and, especially among rodents, troublesome for its exceptions. However, previous studies have largely ignored mainland body size variation, treating size differences of any magnitude as equally noteworthy. Here, we use distributions of mainland population body sizes to identify island populations as 'extremely' big or small, and we compare traits of extreme populations and their islands with those of island populations more typical in body size. We find that although insular rodents vary in the directions of body size change, 'extreme' populations tend towards gigantism. With classification tree methods, we develop a predictive model, which points to resource limitations as major drivers in the few cases of insular dwarfism. Highly successful in classifying our dataset, our model also successfully predicts change in untested cases.

Tempo of trophic evolution and its impact on mammalian diversification.

Mammals are characterized by the complex adaptations of their dentition, which are an indication that diet has played a critical role in their evolutionary history. Although much attention has focused on diet and the adaptations of specific taxa, the role of diet in large-scale diversification patterns remains unresolved. Contradictory hypotheses have been proposed, making prediction of the expected relationship difficult. We show that net diversification rate (the cumulative effect of speciation and extinction), differs significantly among living mammals, depending upon trophic strategy. Herbivores diversify fastest, carnivores are intermediate, and omnivores are slowest. The tempo of transitions between the trophic strategies is also highly biased: the fastest rates occur into omnivory from herbivory and carnivory and the lowest transition rates are between herbivory and carnivory. Extant herbivore and carnivore diversity arose primarily through diversification within lineages, whereas omnivore diversity evolved by transitions into the strategy. The ability to specialize and subdivide the trophic niche allowed herbivores and carnivores to evolve greater diversity than omnivores.

Classification tree methods provide a multifactorial approach to predicting insular body size evolution in rodents.

Many hypotheses have been proposed to explain size changes in insular mammals, but no single variable suffices to explain the diversity of responses, particularly within Rodentia. Here in a data set on insular rodents, we observe strong consistency in the direction of size change within islands and within species but (outside of Heteromyidae) little consistency at broader taxonomic scales. Using traits of islands and of species in a classification tree analysis, we find the most important factor predicting direction of change to be mainland body mass (large rodents decrease, small ones increase); other variables (island climate, number of rodent species, and area) were significant, although their roles as revealed by the classification tree were context dependent. Ecological interactions appear relatively uninformative, and on any given island, the largest and smallest rodent species converged or diverged in size with equal frequency. Our approach provides a promising framework for continuing examination of insular body size evolution.

Increased Belief Instability in Psychotic Disorders Predicts Treatment Response to Metacognitive Training.

BACKGROUND AND HYPOTHESIS: In a complex world, gathering information and adjusting our beliefs about the world is of paramount importance. The literature suggests that patients with psychotic disorders display a tendency to draw early conclusions based on limited evidence, referred to as the jumping-to-conclusions bias, but few studies have examined the computational mechanisms underlying this and related belief-updating biases. Here, we employ a computational approach to understand the relationship between jumping-to-conclusions, psychotic disorders, and delusions. STUDY DESIGN: We modeled probabilistic reasoning of 261 patients with psychotic disorders and 56 healthy controls during an information sampling task-the fish task-with the Hierarchical Gaussian Filter. Subsequently, we examined the clinical utility of this computational approach by testing whether computational parameters, obtained from fitting the model to each individual's behavior, could predict treatment response to Metacognitive Training using machine learning. STUDY RESULTS: We observed differences in probabilistic reasoning between patients with psychotic disorders and healthy controls, participants with and without jumping-to-conclusions bias, but not between patients with low and high current delusions. The computational analysis suggested that belief instability was increased in patients with psychotic disorders. Jumping-to-conclusions was associated with both increased belief instability and greater prior uncertainty. Lastly, belief instability predicted treatment response to Metacognitive Training at the individual level. CONCLUSIONS: Our results point towards increased belief instability as a key computational mechanism underlying probabilistic reasoning in psychotic disorders. We provide a proof-of-concept that this computational approach may be useful to help identify suitable treatments for individual patients with psychotic disorders.

RNase 1 genes from the family Sciuridae define a novel rodent ribonuclease cluster.

The RNase A ribonucleases are a complex group of functionally diverse secretory proteins with conserved enzymatic activity. We have identified novel RNase 1 genes from four species of squirrel (order Rodentia, family Sciuridae). Squirrel RNase 1 genes encode typical RNase A ribonucleases, each with eight cysteines, a conserved CKXXNTF signature motif, and a canonical His(12)-Lys(41)-His(119) catalytic triad. Two alleles encode Callosciurus prevostii RNase 1, which include a Ser(18)<-->Pro, analogous to the sequence polymorphisms found among the RNase 1 duplications in the genome of Rattus exulans. Interestingly, although the squirrel RNase 1 genes are closely related to one another (77-95% amino acid sequence identity), the cluster as a whole is distinct and divergent from the clusters including RNase 1 genes from other rodent species. We examined the specific sites at which Sciuridae RNase 1s diverge from Muridae/Cricetidae RNase 1s and determined that the divergent sites are located on the external surface, with complete sparing of the catalytic crevice. The full significance of these findings awaits a more complete understanding of biological role of mammalian RNase 1s.

Cetacean Skull Telescoping Brings Evolution of Cranial Sutures into Focus.

Many modifications to the mammalian bauplan associated with the obligate aquatic lives of cetaceans-fusiform bodies, flukes, flippers, and blowholes-are evident at a glance. But among the most strikingly unusual and divergent features of modern cetacean anatomy are the arrangements of their cranial bones: (1) bones that are situated at opposite ends of the skull in other mammals are positioned close together, their proximity resulting from (2) these bones extensively overlapping the bones that ordinarily would separate them. The term "telescoping" is commonly used to describe the odd anatomy of modern cetacean skulls, yet its usage and the particular skull features to which it refers vary widely. Placing the term in historical and biological context, this review offers an explicit definition of telescoping that includes the two criteria enumerated above. Defining telescoping in this way draws attention to many specific biological questions that are raised by the unusual anatomy of cetacean skulls; highlights the central role of sutures as the locus for changes in the sizes, shapes, mechanical properties, and connectivity of cranial bones; and emphasizes the importance of sutures in skull development and evolution. The unusual arrangements of cranial bones and sutures referred to as telescoping are not easily explained by what is known about cranial development in more conventional mammals. Discovering the evolutionary-developmental processes that produce the extensive overlap characteristic of cetacean telescoping will give insights into both cetacean evolution and the "rules" that more generally govern mammalian skull function, development, and evolution. Anat Rec, 302:1055-1073, 2019. © 2019 Wiley Periodicals, Inc.

Hospital-acquired Clostridium difficile infection: an institutional costing analysis.

BACKGROUND: Healthcare-acquired Clostridium difficile infection (HA-CDI) is a common infection and a financial burden on the healthcare system. AIM: To estimate the hospital-based financial costs of HA-CDI by comparing time-fixed statistical models that attribute cost to the entire hospital stay to time-varying statistical models that adjust for the time between admission, diagnosis of HA-CDI, and discharge and that only attribute HA-CDI costs post diagnosis. METHODS: A retrospective cohort study was conducted (April 2008 to March 2011) using clinical and administrative costing data of inpatients (≥15 years) who were admitted to The Ottawa Hospital with stays >72 h. Two time-fixed analyses, ordinary least square regression and generalized linear regression, were contrasted with two time-dependent approaches using Kaplan-Meier survival curve. FINDINGS: A total of 49,888 admissions were included and 366 (0.73%) patients developed HA-CDI. Estimated total costs (Canadian dollars) from time-fixed models were as high as $74,928 per patient compared to $28,089 using a time-varying model, and these were 1.47-fold higher compared to a patient without HA-CDI (incremental cost $8,997 per patient). The overall annual institutional cost at The Ottawa Hospital associated with HA-CDI was as high as $10.07 million using time-fixed models and $1.62 million using time-varying models. CONCLUSION: When calculating costs associated with HA-CDI, accounting for the time between admission, diagnosis, and discharge can substantially reduce the estimated institutional costs associated with HA-CDI.

Role of spinal 5-HT2 receptor subtypes in quipazine-induced hindlimb movements after a low-thoracic spinal cord transection.

A role of serotonin receptors (5-HTRs) in spinal rhythmogenesis has been proposed several years ago based mainly upon data showing that bath-applied 5-HT could elicit locomotor-like rhythms in in vitro isolated spinal cord preparations. Such a role was partially confirmed in vivo after revealing that systemically administered 5-HTR(2) agonists, such as quipazine, could induce some locomotor-like movements (LM) in completely spinal cord-transected (Tx) rodents. However, given the limited binding selectivity of currently available 5-HTR(2) agonists, it has remained difficult to determine clearly if one receptor subtype is specifically associated with LM induction. In situ hybridization, data using tissues from L1-L2 spinal cord segments, where critical locomotor network elements have been identified in mice, revealed greater 5-HTR(2A) mRNA levels in low-thoracic Tx than non-Tx animals. This expression level remained elevated for several days, specifically in the lateral intermediate zone, where peak values were detected at 1 week post-Tx and returned to normal at 3 weeks post-Tx. Behavioral and kinematic analyses revealed quipazine-induced LM in 1-week Tx mice either non-pretreated or pretreated with selective 5-HTR(2B) and/or 5-HTR(2C) antagonists. In contrast, LM completely failed to be induced by quipazine in animals pretreated with selective 5-HTR(2A) antagonists. Altogether, these results provide strong evidence suggesting that 5-HTR(2A) are specifically associated with spinal locomotor network activation and LM generation induced by quipazine in Tx animals. These findings may contribute to design drug treatments aimed at promoting locomotor function recovery in chronic spinal cord-injured patients.

Real-time polymerase chain reaction detection of methicillin-resistant Staphylococcus aureus: impact on nosocomial transmission and costs.

OBJECTIVES: To assess the impact of real-time polymerase chain reaction (PCR) detection of methicillin-resistant Staphylococcus aureus (MRSA) on nosocomial transmission and costs. DESIGN: Monthly MRSA detection rates were measured from April 1, 2000, through December 31, 2005. Time series analysis was used to identify changes in MRSA detection rates, and decision analysis was used to compare the costs of detection by PCR and by culture.Setting. A 1,200-bed, tertiary care hospital in Canada. PATIENTS: Admitted patients at high risk for MRSA colonization. MRSA detection using culture-based screening was compared with a commercial PCR assay. RESULTS: The mean monthly incidence of nosocomial MRSA colonization or infection was 0.37 cases per 1,000 patient-days. The time-series model indicated an insignificant decrease of 0.14 cases per 1,000 patient-days per month (95% confidence interval, -0.18 to 0.46) after the introduction of PCR detection (P=.39). The mean interval from a reported positive result until contact precautions were initiated decreased from 3.8 to 1.6 days (P<.001). However, the cost of MRSA control increased from Can$605,034 to Can$771,609. Of 290 PCR-positive patients, 120 (41.4%) were placed under contact precautions unnecessarily because of low specificity of the PCR assay used in the study; these patients contributed 37% of the increased cost. The modeling study predicted that the cost per patient would be higher with detection by PCR (Can$96) than by culture (Can$67). CONCLUSION: Detection of MRSA by the PCR assay evaluated in this study was more costly than detection by culture for reducing MRSA transmission in our hospital. The cost benefit of screening by PCR varies according to incidences of MRSA colonization and infection, the predictive values of the assay used, and rates of compliance with infection control measures.

Impact and cost of infection control measures to reduce nosocomial transmission of extended-spectrum beta-lactamase-producing organisms in a non-outbreak setting.

We evaluated the impact of infection control interventions to reduce nosocomial extended-spectrum beta-lactamase (ESBL) transmission in a non-outbreak setting. This study was conducted at a tertiary 1200-bed hospital in Canada. The incidence of ESBLs was based on recovery of clinical isolates and assessed prospectively from 1999 to 2005. The incidence increased significantly from 0.28 to 0.67 per 1000 admissions during this period (P<0.001), reflecting an increase in the regional ESBL incidence from 1.32 to 9.28 per 100 000 population (P<0.001). Despite this increase, nosocomial ESBL rates increased only marginally, suggesting that infection control measures had an impact on nosocomial transmission. Infection control measures consisted of isolating all ESBL patients, as well as implementing the use of contact precautions for those with a high risk for transmission. The cost of these measures was CN$138 046.00 per year and CN$3191.83 per case admitted. A combination of control measures including active surveillance cultures, contact precautions for all colonized or infected patients and antimicrobial stewardship is required to significantly reduce the incidence of ESBLs.

Point prevalence survey for healthcare-associated infections within Canadian adult acute-care hospitals.

A survey of adult patients 19 years of age and older was conducted in February 2002 in hospitals across Canada to estimate the prevalence of healthcare-associated infections (HAIs). A total of 5750 adults were surveyed; 601 of these had 667 HAIs, giving a prevalence of 10.5% infected patients and 11.6% HAIs. Urinary tract infections (UTI) were the most frequent HAI, shown by 194 (3.4%) of the patients surveyed. Pneumonia was found in 175 (3.0%) of the patients, surgical site infections (SSI) in 146 (2.5%), bloodstream infections (BSI) in 93 (1.6%) and Clostridium difficile-associated diarrhoea (CDAD) in 59 (1%). In this first national point prevalence study in Canada, the prevalence of HAI was found to be similar to that reported by other industrialized countries.

Biodiversity and Topographic Complexity: Modern and Geohistorical Perspectives.

Topographically complex regions on land and in the oceans feature hotspots of biodiversity that reflect geological influences on ecological and evolutionary processes. Over geologic time, topographic diversity gradients wax and wane over millions of years, tracking tectonic or climatic history. Topographic diversity gradients from the present day and the past can result from the generation of species by vicariance or from the accumulation of species from dispersal into a region with strong environmental gradients. Biological and geological approaches must be integrated to test alternative models of diversification along topographic gradients. Reciprocal illumination among phylogenetic, phylogeographic, ecological, paleontological, tectonic, and climatic perspectives is an emerging frontier of biogeographic research.

Universal vs Risk Factor Screening for Methicillin-Resistant Staphylococcus aureus in a Large Multicenter Tertiary Care Facility in Canada.

OBJECTIVE To assess the clinical effectiveness of a universal screening program compared with a risk factor-based program in reducing the rates of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) among admitted patients at the Ottawa Hospital. DESIGN Quasi-experimental study. SETTING Ottawa Hospital, a multicenter tertiary care facility with 3 main campuses, approximately 47,000 admissions per year, and 1,200 beds. METHODS From January 1, 2006 through December 31, 2007 (24 months), admitted patients underwent risk factor-based MRSA screening. From January 1, 2008 through August 31, 2009 (20 months), all patients admitted underwent universal MRSA screening. To measure the effectiveness of this intervention, segmented regression modeling was used to examine monthly nosocomial MRSA incidence rates per 100,000 patient-days before and during the intervention period. To assess secular trends, nosocomial Clostridium difficile infection, mupirocin prescriptions, and regional MRSA rates were investigated as controls. RESULTS The nosocomial MRSA incidence rate was 46.79 cases per 100,000 patient-days, with no significant differences before and after intervention. The MRSA detection rate per 1,000 admissions increased from 9.8 during risk factor-based screening to 26.2 during universal screening. A total of 644 new nosocomial MRSA cases were observed in 1,448,488 patient-days, 323 during risk factor-based screening and 321 during universal screening. Secular trends in C. difficile infection rates and mupirocin prescriptions remained stable after the intervention whereas population-level MRSA rates decreased. CONCLUSION At Ottawa Hospital, the introduction of universal MRSA admission screening did not significantly affect the rates of nosocomial MRSA compared with risk factor-based screening. Infect. Control Hosp. Epidemiol. 2015;37(1):41-48.

Evaluation of N95 respirator use as a tuberculosis control measure in a resource-limited setting.

SETTING: A 150-bed public Brazilian hospital that serves as reference hospital for tuberculosis (TB) patients. OBJECTIVE: To evaluate the use of personal respiratory protection by health care workers (HCWs) as a measure to reduce TB occupational risk. DESIGN: One hundred and forty-five HCWs were randomly observed for the use of a N95 respirator when entering high-risk areas or performing high-risk procedures. RESULTS: N95 respirators were infrequently used, even for high-risk procedures such as endotracheal intubation (25%) and respiratory aspiration (12%), and in high-risk areas such as the respirology ward (69.2%), emergency department (29.5%), intensive care unit (8.8%), and TB room isolation (39.5%). Facial-seal leakage was observed in 39% of HCWs due to failure to wear the mask with a tight facial fit as directed. CONCLUSION: Respirator use as a sole control measure is inadequate in any setting and is not cost-effective in resource-limited settings. Alternative or additional measures are clearly needed in hospitals with a high incidence of active TB admissions, specially following recent recommendations from the WHO, which consider personal respiratory protection as the third line of defense for TB control, indicated when TB risk cannot be adequately reduced by administrative and engineering controls.

A multicenter evaluation of tuberculin skin test positivity and conversion among health care workers in Brazilian hospitals.

SETTING: Four general Brazilian hospitals. OBJECTIVE: To assess the occupational risk of Mycobacterium tuberculosis (TB) in participating hospitals. DESIGN: In phase one of this longitudinal study, a cross-sectional survey documented baseline tuberculin skin test (TST) positivity rates. In phase two, TST conversion rates were evaluated in participants with an initial negative two-step TST. TST conversion data were analyzed to determine risk factors for TB infection using an increase of > or = 10 mm compared to baseline TST. RESULTS: The initial TST positivity rate was 63.1%; the follow-up TST conversion rate was 10.7 per 1000 person-months (p-m). Hospital of employment, recent bacille Calmette-Guerin (BCG) vaccination, nosocomial TB exposure, and employment as a nurse were independent risk factors for TST conversion. Hospitals without TB infection control measures had higher conversion rates than those with control measures (16.0 vs. 7.8/ 1000 p-m, P < 0.001). CONCLUSIONS: This study indicates an important occupational risk of infection in health care settings with a high TB incidence. Longitudinal TST studies are a valuable tool to assess the occupational risk of TB, even in BCG-vaccinated populations, and should be used to direct limited resources for infection control.

TST reversion in a BCG-revaccinated population of nursing and medical students, São Paulo, Brazil, 1997-2000.

SETTING: A major university in São Paulo, Brazil, where vaccination against tuberculosis (TB) with bacille Calmette-Guerin (BCG) was routinely offered to first-year medical and nursing students. OBJECTIVES: To estimate the probability of negative tuberculin skin test (TST) results over a 4-year period following BCG revaccination, and to evaluate the effect of factors associated with reversion. DESIGN: Students were enrolled in 1997, initially given a two-step TST, and were retested annually or biannually for the duration of the study. Data on TB exposures and potential risk factors for TST negativity and reversion were collected through annual surveys. A linear mixture survival model was used to estimate the probability of negative TST results over time. RESULTS: Of 159 students, an estimated 20% had a negative TST result despite revaccination, and a further 31% reverted to negative over 4 years of follow-up. No cofactors significantly affected the probability of reversion. CONCLUSION: Overall, in the absence of reported exposure to Mycobacterium tuberculosis, 51% of students revaccinated upon entering nursing or medical school would have a negative TST result by the time they begin their internships. In this recently vaccinated population, reversion was common, suggesting that annual TST screening may remain a useful tool.