The Role of Strength-Related Factors on Psychological Readiness for Return to Sport Following Anterior Cruciate Ligament (ACL) Reconstruction.

Psychological readiness following anterior cruciate ligament reconstruction (ACLR) correlates with different return to sport outcomes. However, the relationship between strength and power and psychological readiness remains unexplored. The aim of this study was to investigate the relationship between anterior cruciate ligament return to sport after injury (ACL-RSI) scores and various hamstrings and quadriceps strength and power variables. Twelve participants (20.7 ± 2.5 years old; 174.2 ± 7.5 cm; 70.2 ± 8.5 kg; 18.2 ± 8.3% of body fat) who had an ACLR nine months or more before the study completed the ACL-RSI questionnaire and isokinetic strength testing of the hamstrings and quadriceps (60°·s-1 and 180°·s-1). Based on ACL-RSI scores, they were divided into "cases" and "controls", deemed not psychologically ready and psychologically ready to return to previous sport performance (PILOS), respectively. The main findings are that quadriceps' and hamstrings' rate of torque development (RTD) and time since surgery were determinants of psychological readiness following ACLR. Furthermore, compared to controls, cases showed significantly lower quadriceps torque at angles close to full knee extension (40 deg and 30 deg from extension). They also showed lower RTD than controls, but no difference in peak torque. These results suggest that physiotherapists should facilitate athletes' return to sport (RTS) by focusing on the restoration of RTD and strength at angles close to full knee extension.

Anxiety attenuates learning advantages conferred by statistical stability and induces loss of volatility-attuning in brain activity.

Anxiety can alter an individual's perception of their external sensory environment. Previous studies suggest that anxiety can increase the magnitude of neural responses to unexpected (or surprising) stimuli. Additionally, surprise responses are reported to be boosted during stable compared to volatile environments. Few studies, however, have examined how learning is impacted by both threat and volatility. To investigate these effects, we used threat-of-shock to transiently increase subjective anxiety in healthy adults while they performed an auditory oddball task under stable and volatile environments and while undergoing functional Magnetic Resonance Imaging (fMRI) scanning. We then used Bayesian Model Selection (BMS) mapping to identify the brain areas where different models of anxiety displayed the highest evidence. Behaviourally, we found that threat-of-shock eliminated the accuracy advantage conferred by environmental stability over volatility. Neurally, we found that threat-of-shock led to attenuation and loss of volatility-attuning of brain activity evoked by surprising sounds across most subcortical and limbic regions including the thalamus, basal ganglia, claustrum, insula, anterior cingulate, hippocampal gyrus and the superior temporal gyrus. Taken together, our findings suggest that threat eliminates learning advantages conferred by statistical stability compared to volatility. Thus, we propose that anxiety disrupts behavioural adaptation to environmental statistics, and that multiple subcortical and limbic regions are implicated in this process.

Long-term Small Population Size, Deleterious Variation, and Altitude Adaptation in the Ethiopian Wolf, a Severely Endangered Canid.

Ethiopian wolves, a canid species endemic to the Ethiopian Highlands, have been steadily declining in numbers for decades. Currently, out of 35 extant species, it is now one of the world's most endangered canids. Most conservation efforts have focused on preventing disease, monitoring movements and behavior, and assessing the geographic ranges of sub-populations. Here, we add an essential layer by determining the Ethiopian wolf's demographic and evolutionary history using high-coverage (∼40×) whole-genome sequencing from 10 Ethiopian wolves from the Bale Mountains. We observe exceptionally low diversity and enrichment of weakly deleterious variants in the Ethiopian wolves in comparison with two North American gray wolf populations and four dog breeds. These patterns are consequences of long-term small population size, rather than recent inbreeding. We infer the demographic history of the Ethiopian wolf and find it to be concordant with historic records and previous genetic analyses, suggesting Ethiopian wolves experienced a series of both ancient and recent bottlenecks, resulting in a census population size of fewer than 500 individuals and an estimated effective population size of approximately 100 individuals. Additionally, long-term small population size may have limited the accumulation of strongly deleterious recessive mutations. Finally, as the Ethiopian wolves have inhabited high-altitude areas for thousands of years, we searched for evidence of high-altitude adaptation, finding evidence of positive selection at a transcription factor in a hypoxia-response pathway [CREB-binding protein (CREBBP)]. Our findings are pertinent to continuing conservation efforts and understanding how demography influences the persistence of deleterious variation in small populations.

Aeroallergen-related Diseases Predate the Diagnosis of Inflammatory Bowel Disease.

OBJECTIVE: This study aimed to determine whether having a diagnosis of asthma or allergic rhinitis (AR) increased the risk of being diagnosed with inflammatory bowel disease (IBD) and whether there was increased incidence of these diseases after a diagnosis of IBD. DESIGN: This is a retrospective, historical cohort-based study. We used the administrative data of Manitoba Health and the population-based University of Manitoba IBD Epidemiology Database. We used numbers of prescriptions for drugs used to treat asthma and to treat AR to identify diagnoses of asthma and AR, respectively.We calculated relative risks (RRs) to assess incidence of IBD compared with matched controls after diagnoses of asthma and AR and hazard ratios to determine the incidence of asthma and AR after IBD diagnosis. RESULTS: Compared with controls, a diagnosis of asthma or AR preceding a diagnosis of IBD was increased in cases (RR, 1.62; 95% confidence interval [CI], 1.50-1.75; and RR, 2.10; 95% CI, 1.97-2.24) with a similar outcome by subtype of IBD (Crohn's disease vs ulcerative colitis) and by sex. On sensitivity analysis, diagnoses of asthma or AR were comparable when considering at least 5, 10, 15 or 20 drug prescriptions. Persons with IBD were more likely to develop asthma or AR than controls after being diagnosed with IBD (hazard ratio for asthma, 1.31, 95% CI, 1.18-1.45; and hazard ratio for AR, 2.62, 95% CI, 2.45-2.80). CONCLUSIONS: The association between asthma, AR, and IBD suggest the possibility that whatever triggers the onset of these atopic diseases may trigger the onset of IBD as well, and aeroallergens are plausible culprits.

This study demonstrates that a preexisting diagnosis of asthma or allergic rhinitis is associated with an increased risk of subsequently developing IBD. These data reinforce the importance of considering that gastrointestinal complaints in patients with asthma and allergic rhinitis may reflect a possible diagnosis of IBD. It also raises the possibility that aeroallergens may be environmental cause(s) of IBD.

Prospective study of beginner running groups: psychological predictors and outcomes of participation.

Running is an example of vigorous activity that leads to important health benefits if maintained. Beginner running groups provide supportive training programs to help people progress from walking to sustained running. This study explored the characteristics of individuals joining beginner running groups and the outcomes they achieve. New members of beginner running groups (n = 141; mean age 43 years, 122 female) completed online assessments at the start of their group program with 63 participants (45%) also completing a follow-up assessment at the end of the program. Validated scales were used to assess exercise behavior, mental wellbeing, self-efficacy, running identity and social physique anxiety. The majority of participants had low exercise levels at the start of the program (63%, n = 89). By the program end, 47 participants (75% of those completing the follow-up assessment) reported meeting the training goal (running for 30 minutes continuously) with self-efficacy, program adherence and younger age representing significant predictors of success. Significant improvements in exercise levels, mental wellbeing, self-efficacy, running identity and social physique anxiety were observed by the end of the program. In conclusion, beginner running programs attract low active individuals and may lead to improved levels of exercise and psychological outcomes. Additional research is needed to examine the extent to which improvements are sustained longer term.

Decision tree-based rules outperform risk scores for childhood asthma prognosis.

BACKGROUND: There are no widely accepted prognostic tools for childhood asthma; this is in part due to the multifactorial and time-dependent nature of mechanisms and risk factors that contribute to asthma development. Our study objective was to develop and evaluate the prognostic performance of conditional inference decision tree-based rules using the Pediatric Asthma Risk Score (PARS) predictors as an alternative to the existing logistic regression-based risk score for childhood asthma prediction at 7 years in a high-risk population. METHODS: The Canadian Asthma Primary Prevention Study data were used to develop, compare, and contrast the prognostic performance (area under the curve [AUC], sensitivity, and specificity) of conditional inference tree-based decision rules to the pediatric asthma risk score for the prediction of childhood asthma at 7 years. RESULTS: Conditional inference decision tree-based rules have higher prognostic performance (AUC: 0.85; 95% CI: 0.81, 0.88; sensitivity = 47%; specificity = 93%) than the pediatric asthma risk score at an optimal cutoff of ≥6 (AUC: 0.71; 95% CI: 0.67, 0.76; sensitivity = 60%; specificity = 74%). Moreover, the pediatric asthma risk score is not linearly related to asthma risk, and at any given pediatric asthma risk score value, different combinations of its pediatric asthma risk score clinical variables differentially predict asthma risk. CONCLUSION: Conditional inference tree-based decision rules could be a useful childhood asthma prognostic tool, providing an alternative way to identify unique subgroups of at-risk children, and insights into associations and effect mechanisms that are suggestive of appropriate tailored preventive interventions. However, the feasibility and effectiveness of such decision rules in clinical practice is warranted.

Statistical Learning and Inference Is Impaired in the Nonclinical Continuum of Psychosis.

Our perceptions result from the brain's ability to make inferences, or predictive models, of sensory information. Recently, it has been proposed that psychotic traits may be linked to impaired predictive processes. Here, we examine the brain dynamics underlying statistical learning and inference in stable and volatile environments, in a population of healthy human individuals (N = 75; 36 males, 39 females) with a range of psychotic-like experiences. We measured prediction error responses to sound sequences with electroencephalography, gauged sensory inference explicitly by behaviorally recording sensory statistical learning errors, and used dynamic causal modeling to tap into the underlying neural circuitry. We discuss the findings that were robust to replication across the two experiments (Discovery dataset, N = 31; Validation dataset, N = 44). First, we found that during stable conditions, participants demonstrated greater precision in their predictive model, reflected in a larger prediction error response to unexpected sounds, and decreased statistical learning errors. Moreover, individuals with attenuated prediction errors in stable conditions were found to make greater incorrect predictions about sensory information. Critically, we show that greater errors in statistical learning and inference are related to increased psychotic-like experiences. These findings link neurophysiology to behavior during statistical learning and prediction formation, as well as providing further evidence for the idea of a continuum of psychosis in the healthy, nonclinical population.SIGNIFICANCE STATEMENT While perceiving the world, we make inferences by learning the statistics present in the sensory environment. It has been argued that psychosis may emerge because of a failure to learn sensory statistics, resulting in an impaired representation of the world. Recently, it has been proposed that psychosis exists on a continuum; however, there is conflicting evidence on whether sensory learning deficits align on the nonclinical end of the psychosis continuum. We found that statistical learning of sensory events is associated with the magnitude of mismatch negativity and, critically, is impaired in healthy people who report more psychotic-like experiences. We replicated these findings in an independent sample, demonstrating strengthened credibility to support the continuum of psychosis that extends into the nonclinical population.

Total Synthesis of Micrococcin P1 through Scalable Thiazole Forming Reactions of Cysteine Derivatives and Nitriles.

Thiopeptides are a class of natural products with untapped therapeutic potential. To expand the methods available for the scaled production of these antibiotics, we report the laboratory synthesis of micrococcin P1 showcasing thiazole forming reactions of cysteine derivatives and nitriles followed by oxidation. In most instances, this thiazole forming sequence does not require chromatography and proved scalable. Using this approach, 199 mg of micrococcin P1 was generated in a single synthetic sequence.

Morphological development of Pleurochrysis carterae coccoliths examined by cryo-electron tomography.

Coccolithophores are single-celled marine algae that produce calcified scales called coccoliths. Each scale is composed of anvil-shaped single crystals of calcite that are mechanically interlocked, constituting a remarkable example of the multi-level construction of mineralized structures. Coccolith formation starts with the nucleation of rhombohedral crystals on an organic substrate called base plate. The crystals then grow preferentially along specific directions to generate the mature structure, which is then transported to the outside of the cells. Here, we extracted forming coccoliths from Pleurochrysis carterae cells and used cryo-electron tomography to characterize, in their native, hydrated state, the three-dimensional morphology and arrangement of the crystals. Comparing the crystal morphology across three different stages of coccolith formation, we show that competition for space between adjacent crystals contributes significantly to regulation of morphology by constraining growth in certain directions. We further demonstrate that crystals within a coccolith ring develop at different rates and that each crystalline unit rests directly in contact with the base plate and overgrow the rim of the organic substrate during development.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2.

Building on our previously-reported novel tricyclic topoisomerase inhibitors (NTTIs), we disclose the discovery of REDX07965, which has an MIC90 of 0.5 µg mL-1 against Staphylococcus aureus, favourable in vitro pharmacokinetic properties, selectivity versus human topoisomerase II and an acceptable toxicity profile. The results herein validate a rational design approach to address the urgent unmet medical need for novel antibiotics.

Psychomotor Performance Decrements following a Successful Physical Activity Intervention for Insomnia.

Objectives: Evidence supports the view that reductions in cognitive hyperarousal contribute substantially to improved sleep outcomes following cognitive and behavioral interventions for insomnia disorder. Assuming an inverted-u relationship between arousal and performance, a theoretical possibility, supported by limited empirical data, is that the same mediating processes could negatively impact aspects of psychomotor performance, reducing speed on tests of reaction time. Participants: Sedentary participants (mean age = 59.8; SD = 9.46) meeting research diagnostic criteria for insomnia were randomized to either an exercise intervention of ≥150 min of moderate-intensity activity per week (n = 20), or a wait-list control group (n = 21). Of these, n = 17 intervention and n = 18 control participants completed 6-month follow-up assessments. Methods: Digit span, and simple and complex vigilance task performance was assessed using a computerized protocol at baseline and 6-month follow-up. Dependent variables included digit span, simple reaction time (SRT), complex reaction time (CRT), false positive responses, number of lapses, and SRT/CRT ratio (indicative of the magnitude of difference between simple and complex RT performance). The primary clinical outcome was Insomnia Severity Index (ISI) score. Results: In comparisons of baseline to follow-up change, ISI scores showed clinically significant improvement in the intervention group at 6-month follow-up (F (8,26) = 5.16; P = 0.03). Baseline vigilance performance was equivalent in both groups. At 6-month follow-up, however, the intervention group showed significantly slower simple reaction time F(4,30) = 10.25, p < 0.01, and a significantly decreased SRT/CRT ratio (F(4,30) = 13.22, p < 0.01). Conclusions: Among people meeting diagnostic criteria for insomnia, beneficial sleep outcomes following successful behavioral interventions may, under some circumstances, come at the cost of slower psychomotor performance.

Three-dimensional architecture and surface functionality of coccolith base plates.

Coccolithophores are marine phytoplankton that are among the most prolific calcifiers widespread in Earth's oceans, playing a crucial role in the carbon cycle and in the transport of organic matter to the deep sea. These organisms produce highly complex mineralized scales that are composed of hierarchical assemblies of nano-crystals of calcium carbonate in the form of calcite. Coccolith formation in vivo occurs within compartmentalized mineralisation vesicles derived from the Golgi body, which contain coccolith-associated polysaccharides ('CAPs') providing polymorph selection and mediating crystal growth kinetics, and oval organic mineralisation templates, also known as base plates, which promote heterogenous nucleation and further mechanical interlocking of calcite single crystals. Although the function of coccolith base plates in controlling crystal nucleation have been widely studied, their 3D spatial organization and the chemical functional groups present on the crystal nucleation sites, which are two crucial features impacting biomineralization, remain unsolved. Utilising cryo-electron tomography we show that base plates derived from an exemplary coccolithophore Pleurochrysis carterae (Pcar) in their native hydrated state have a complex 3-layered structure. We further demonstrate, for the first time, the edge and rim of the base plate - where the crystals nucleate - are rich in primary amine functionalities that provide binding targets for negatively charged complexes composed of synthetic macromolecules and Ca2+ ions. Our results indicate that electrostatic interactions between the negatively charged biogenic CAPs and the positively charged rim of the base plate are sufficient to mediate the transport of Ca2+ cations to the mineralization sites.

Understanding the Hidden Complexity of Latin American Population Isolates.

Most population isolates examined to date were founded from a single ancestral population. Consequently, there is limited knowledge about the demographic history of admixed population isolates. Here we investigate genomic diversity of recently admixed population isolates from Costa Rica and Colombia and compare their diversity to a benchmark population isolate, the Finnish. These Latin American isolates originated during the 16th century from admixture between a few hundred European males and Amerindian females, with a limited contribution from African founders. We examine whole-genome sequence data from 449 individuals, ascertained as families to build mutigenerational pedigrees, with a mean sequencing depth of coverage of approximately 36×. We find that Latin American isolates have increased genetic diversity relative to the Finnish. However, there is an increase in the amount of identity by descent (IBD) segments in the Latin American isolates relative to the Finnish. The increase in IBD segments is likely a consequence of a very recent and severe population bottleneck during the founding of the admixed population isolates. Furthermore, the proportion of the genome that falls within a long run of homozygosity (ROH) in Costa Rican and Colombian individuals is significantly greater than that in the Finnish, suggesting more recent consanguinity in the Latin American isolates relative to that seen in the Finnish. Lastly, we find that recent consanguinity increased the number of deleterious variants found in the homozygous state, which is relevant if deleterious variants are recessive. Our study suggests that there is no single genetic signature of a population isolate.

Bayesian Model Selection Maps for Group Studies Using M/EEG Data.

Predictive coding postulates that we make (top-down) predictions about the world and that we continuously compare incoming (bottom-up) sensory information with these predictions, in order to update our models and perception so as to better reflect reality. That is, our so-called "Bayesian brains" continuously create and update generative models of the world, inferring (hidden) causes from (sensory) consequences. Neuroimaging datasets enable the detailed investigation of such modeling and updating processes, and these datasets can themselves be analyzed with Bayesian approaches. These offer methodological advantages over classical statistics. Specifically, any number of models can be compared, the models need not be nested, and the "null model" can be accepted (rather than only failing to be rejected as in frequentist inference). This methodological paper explains how to construct posterior probability maps (PPMs) for Bayesian Model Selection (BMS) at the group level using electroencephalography (EEG) or magnetoencephalography (MEG) data. The method has only recently been used for EEG data, after originally being developed and applied in the context of functional magnetic resonance imaging (fMRI) analysis. Here, we describe how this method can be adapted for EEG using the Statistical Parametric Mapping (SPM) software package for MATLAB. The method enables the comparison of an arbitrary number of hypotheses (or explanations for observed responses), at each and every voxel in the brain (source level) and/or in the scalp-time volume (scalp level), both within participants and at the group level. The method is illustrated here using mismatch negativity (MMN) data from a group of participants performing an audio-spatial oddball attention task. All data and code are provided in keeping with the Open Science movement. In doing so, we hope to enable others in the field of M/EEG to implement our methods so as to address their own questions of interest.

Using Scipion for stream image processing at Cryo-EM facilities.

Three dimensional electron microscopy is becoming a very data-intensive field in which vast amounts of experimental images are acquired at high speed. To manage such large-scale projects, we had previously developed a modular workflow system called Scipion (de la Rosa-Trevín et al., 2016). We present here a major extension of Scipion that allows processing of EM images while the data is being acquired. This approach helps to detect problems at early stages, saves computing time and provides users with a detailed evaluation of the data quality before the acquisition is finished. At present, Scipion has been deployed and is in production mode in seven Cryo-EM facilities throughout the world.

Reassessing access to intensive care using an estimate of the population incidence of critical illness.

BACKGROUND: The consistently observed male predominance of patients in intensive care units (ICUs) has raised concerns about gender-based disparities in ICU access. Comparing rates of ICU admission requires choosing a normalizing factor (denominator), and the denominator usually used to compare such rates between subpopulations is the size of those subpopulations. However, the appropriate denominator is the number of people whose medical condition warranted ICU care. We devised an estimate of the number of critically ill people in the general population, and used it to compare rates of ICU admission by gender and income. METHODS: This population-based, retrospective analysis included all adults in the Canadian province of Manitoba, 2004-2015. We created an estimate for the number of critically ill people who warrant ICU care, and used it as the denominator to generate critical illness-normalized rates of ICU admission. These were compared to the usual population-normalized rates of ICU care. RESULTS: Men outnumbered women in ICUs for all age groups; population-normalized male:female rate ratios significantly exceed 0 for every age group, ranging from 1.15 to 2.10. Using critical-illness normalized rates, this male predominance largely disappeared; critically ill men and women aged 45-74 years were admitted in equivalent proportions (critical-illness normalized rate ratios 0.96-1.01). While population-normalized rates of ICU care were higher in lower income strata (p < 0.001), the gradient for critical illness-based rates was reversed (p < 0.001). CONCLUSIONS: Across a 30-year adult age span, the male predominance of ICU patients was accounted for by higher estimated rates of critical illness among men. People in lower income strata had lower critical-illness normalized rates of ICU admission. Our methods highlight that correct inferences about access to healthcare require calculating rates using denominators appropriate for this purpose.

Assessing Symptoms, Concerns, and Quality of Life in Noncancer Patients at End of Life: How Concordant Are Patients and Family Proxy Members?

CONTEXT: It has become commonplace to use family caregivers as proxy responders where patients are unable to provide information about their symptoms and concerns to health care providers. OBJECTIVES: The objective of this study was to determine the degree of concordance between patients' and family members' reports of patient symptoms and concerns at end of life. METHODS: Sample dyads included a mix of patients residing at home, in a nursing home, in a long-term care facility, or in hospice. Diagnoses included patients with amyotrophic lateral sclerosis (n = 75), chronic obstructive pulmonary disease (n = 52), end-stage renal disease (n = 42), and institutionalized, cognitively intact frail elderly (n = 49). Dyads completed the Patient Dignity Inventory (PDI), the modified Structured Interview Assessment of Symptoms and Concerns in Palliative Care, and Graham and Longman's two-item Quality of Life Scale. RESULTS: Concordance was less than 70% for seven of the 25 PDI items, with the lowest concordance (65.1%) for the item "not being able to continue with my usual routines." For all but one PDI item, discordance was in the direction of family members reporting that the patient was worse off than the patient had indicated. Where discordance was observed on the Structured Interview Assessment of Symptoms and Concerns in Palliative Care and Quality of Life Scales, the trend toward family members overreporting patient distress and poor quality of life continued. CONCLUSION: Understanding discordance between patients and family member reports of symptoms and concerns is a valuable step toward minimizing patient and family burden at end of life.

Targeted Suppression and Knockout of ASCT2 or LAT1 in Epithelial and Mesenchymal Human Liver Cancer Cells Fail to Inhibit Growth.

Amino acid transporters alanine-serine-cysteine transporter 2 (ASCT2) and L-Type Amino Acid Transporter 1 (LAT1) are coordinately enhanced in human cancers where among other roles, they are thought to drive mechanistic target-of-rapamycin (mTOR) growth signaling. To assess ASCT2 and LAT1 as therapeutic targets, nine unique short hairpin RNA (shRNA) vectors were used to stably suppress transporter expression in human epithelial (Hep3B) and mesenchymal (SK-Hep1) hepatocellular carcinoma (HCC) cell lines. In addition, six unique CRISPR-Cas9 vectors were used to edit the ASCT2 (SLC1A5) and LAT1 (SLC7A5) genes in epithelial (HUH7) and mesenchymal (SK-Hep1) HCC cells. Both approaches successfully diminished glutamine (ASCT2) and leucine (LAT1) initial-rate transport proportional to transporter protein suppression. In spite of profoundly reduced glutamine or leucine transport (up to 90%), transporter suppression or knockout failed to substantially affect cellular proliferation or basal and amino acid-stimulated mTORC1 growth signaling in either HCC cell type. Only LAT1 knockout in HUH7 slightly reduced growth rate. However, intracellular accumulation of radiolabeled glutamine and leucine over longer time periods largely recovered to control levels in ASCT2 and LAT1 knockout cells, respectively, which partially explains the lack of an impaired growth phenotype. These data collectively establish that in an in vitro context, human epithelial and mesenchymal HCC cell lines adapt to ASCT2 or LAT1 knockout. These results comport with an emerging model of amino acid exchangers like ASCT2 and LAT1 as "harmonizers", not drivers, of amino acid accumulation and signaling, despite their long-established dominant role in initial-rate amino acid transport.