Hybridization in the Anthropocene - how pollution and climate change disrupt mate selection in freshwater fish.

Chemical pollutants and/or climate change have the potential to break down reproductive barriers between species and facilitate hybridization. Hybrid zones may arise in response to environmental gradients and secondary contact between formerly allopatric populations, or due to the introduction of non-native species. In freshwater ecosystems, field observations indicate that changes in water quality and chemistry, due to pollution and climate change, are correlated with an increased frequency of hybridization. Physical and chemical disturbances of water quality can alter the sensory environment, thereby affecting chemical and visual communication among fish. Moreover, multiple chemical compounds (e.g. pharmaceuticals, metals, pesticides, and industrial contaminants) may impair fish physiology, potentially affecting phenotypic traits relevant for mate selection (e.g. pheromone production, courtship, and coloration). Although warming waters have led to documented range shifts, and chemical pollution is ubiquitous in freshwater ecosystems, few studies have tested hypotheses about how these stressors may facilitate hybridization and what this means for biodiversity and species conservation. Through a systematic literature review across disciplines (i.e. ecotoxicology and evolutionary biology), we evaluate the biological interactions, toxic mechanisms, and roles of physical and chemical environmental stressors (i.e. chemical pollution and climate change) in disrupting mate preferences and inducing interspecific hybridization in freshwater fish. Our study indicates that climate change-driven changes in water quality and chemical pollution may impact visual and chemical communication crucial for mate choice and thus could facilitate hybridization among fishes in freshwater ecosystems. To inform future studies and conservation management, we emphasize the importance of further research to identify the chemical and physical stressors affecting mate choice, understand the mechanisms behind these interactions, determine the concentrations at which they occur, and assess their impact on individuals, populations, species, and biological diversity in the Anthropocene.

PASSIVE BICYCLE TRAINING STIMULATES EPIPHYSEAL BONE FORMATION AND RESTORES BONE INTEGRITY INDEPENDENT OF LOCOMOTOR RECOVERY IN A RAT SPINAL CORD INJURY MODEL.

It is unknown whether activity-based physical therapy (ABPT) modalities that mobilize the paralyzed limbs improve bone integrity at the highly fracture-prone epiphyseal regions of the distal femur and proximal tibia following severe spinal cord injury (SCI). In this study, four-months-old skeletally-mature littermate-matched male Sprague-Dawley rats received SHAM surgery or severe contusion SCI. At 1-week post-surgery, SCI rats were stratified to undergo no-ABPT or two 20-minute bouts/day of quadrupedal bodyweight-supported treadmill training (qBWSTT) or hindlimb passive-isokinetic bicycle (Cycle) training, 5-days/week for another 3-weeks. We assessed locomotor recovery and plantar flexor muscle mass, tracked cancellous and cortical bone microstructure at the distal femoral and proximal tibial epiphyses using in vivo microCT, and evaluated bone turnover at the tibial epiphysis with histomorphometry. All SCI animals displayed persistent hindlimb paralysis and pervasive muscle atrophy. Over the initial 2-weeks, which included 1-week of no exercise and 1-week of ABPT acclimation, a similar magnitude of bone loss developed in all SCI groups. Thereafter, cancellous bone loss and cortical bone decrements increased in the SCI no-ABPT group. qBWSTT attenuated this trabecular bone loss but did not prevent the ongoing cortical bone deficits. In comparison, twice-daily Cycle training increased the number and activity of osteoblasts vs other SCI groups and restored all bone microstructural parameters to SHAM levels at both epiphyseal sites. These data indicate that a novel passive-isokinetic Cycle training regimen reversed cancellous and cortical bone deterioration at key epiphyseal sites after experimental SCI, via osteoblast-mediated bone anabolic mechanisms, independent of locomotor recovery or increased muscle mass.

Intrinsically disordered sequences can tune fungal growth and the cell cycle for specific temperatures.

Temperature can impact every reaction essential to a cell. For organisms that cannot regulate their own temperature, adapting to temperatures that fluctuate unpredictably and on variable timescales is a major challenge. Extremes in the magnitude and frequency of temperature changes are increasing across the planet, raising questions as to how the biosphere will respond. To examine mechanisms of adaptation to temperature, we collected wild isolates from different climates of the fungus Ashbya gossypii, which has a compact genome of only ∼4,600 genes. We found control of the nuclear division cycle and polarized morphogenesis, both critical processes for fungal growth, were temperature sensitive and varied among the isolates. The phenotypes were associated with naturally varying sequences within the glutamine-rich region (QRR) IDR of an RNA-binding protein called Whi3. This protein regulates both nuclear division and polarized growth via its ability to form biomolecular condensates. In cells and in cell-free reconstitution assays, we found that temperature tunes the properties of Whi3-based condensates. Exchanging Whi3 sequences between isolates was sufficient to rescue temperature-sensitive phenotypes, and specifically, a heptad repeat sequence within the QRR confers temperature-sensitive behavior. Together, these data demonstrate that sequence variation in the size and composition of an IDR can promote cell adaptation to growth at specific temperature ranges. These data demonstrate the power of IDRs as tuning knobs for rapid adaptation to environmental fluctuations.

Transcranial Focused Ultrasound Targeting the Amygdala May Increase Psychophysiological and Subjective Negative Emotional Reactivity in Healthy Older Adults.

Background: The amygdala is highly implicated in an array of psychiatric disorders but is not accessible using currently available noninvasive neuromodulatory techniques. Low-intensity transcranial focused ultrasound (TFUS) is a neuromodulatory technique that has the capability of reaching subcortical regions noninvasively. Methods: We studied healthy older adult participants (N = 21, ages 48-79 years) who received TFUS targeting the right amygdala and left entorhinal cortex (active control region) using a 2-visit within-participant crossover design. Before and after TFUS, behavioral measures were collected via the State-Trait Anxiety Inventory and an emotional reactivity and regulation task utilizing neutral and negatively valenced images from the International Affective Picture System. Heart rate and self-reported emotional valence and arousal were measured during the emotional reactivity and regulation task to investigate subjective and physiological responses to the task. Results: Significant increases in both self-reported arousal in response to negative images and heart rate during emotional reactivity and regulation task intertrial intervals were observed when TFUS targeted the amygdala; these changes were not evident when the entorhinal cortex was targeted. No significant changes were found for state anxiety, self-reported valence to the negative images, cardiac response to the negative images, or emotion regulation. Conclusions: The results of this study provide preliminary evidence that a single session of TFUS targeting the amygdala may alter psychophysiological and subjective emotional responses, indicating some potential for future neuropsychiatric applications. However, more work on TFUS parameters and targeting optimization is necessary to determine how to elicit changes in a more clinically advantageous way.

Transcranial focused ultrasound (TFUS) is an emerging brain stimulation technique with the ability to noninvasively alter the activity of deep brain regions. Studying the potential for TFUS to alter behavioral response and processing, this study employed MRI-guided TFUS targeting the right amygdala in older adults. We found that TFUS targeting the right amygdala increased self-reported arousal in response to negative images, providing preliminary evidence that a single session of TFUS may be capable of affecting emotional reactivity.

Fitting Epidemic Models to Data: A Tutorial in Memory of Fred Brauer.

Fred Brauer was an eminent mathematician who studied dynamical systems, especially differential equations. He made many contributions to mathematical epidemiology, a field that is strongly connected to data, but he always chose to avoid data analysis. Nevertheless, he recognized that fitting models to data is usually necessary when attempting to apply infectious disease transmission models to real public health problems. He was curious to know how one goes about fitting dynamical models to data, and why it can be hard. Initially in response to Fred's questions, we developed a user-friendly R package, fitode, that facilitates fitting ordinary differential equations to observed time series. Here, we use this package to provide a brief tutorial introduction to fitting compartmental epidemic models to a single observed time series. We assume that, like Fred, the reader is familiar with dynamical systems from a mathematical perspective, but has limited experience with statistical methodology or optimization techniques.

Pericapsular Nerve Group Block Did Not Reduce Postoperative Pain or Opioid Use After Total Hip Arthroplasty.

BACKGROUND: The pericapsular nerve group (PENG) block is a newly developed regional anesthesia technique designed to manage postoperative hip pain following a fracture or surgery while also maintaining quadriceps strength and mobility. The goal of our study was to compare postoperative pain scores and opioid usage during the postoperative period before discharge following total hip arthroplasty (THA) using the posterior approach between patients who received a PENG block and those who did not. METHODS: We conducted a retrospective study on patients undergoing elective, posterior approach THA at a single tertiary-care academic center. The 2 groups included a study group (THA with PENG block in 2021; n = 66) and a control group (THA before PENG block implementation in 2019; n = 70). RESULTS: There were no significant differences in pain scores during postoperative minutes 0 to 59 (study group 6.8; control group 6.6; P = .81) or during postoperative minutes 60 to 119 (study group 6.2; control group 5.6; P = .40). There were no significant differences in total postoperative in-hospital morphine milliequivalent opioid consumption (study group 55.8 morphine milligram equivalents; control group 75.0 morphine milligram equivalents; P = .14). The study group was found to have a shorter length of stay (study group 17.0 hours; control group 32.6 hours; P < .0001) and faster mobilization (study group 3.0 hours; control group 4.9 hours; P < .0001) than the control group. CONCLUSIONS: Our results show that use of the PENG block did not result in lower postoperative pain scores or opioid consumption after THA using the posterior surgical approach. The study group had a shorter length of stay and time to mobilization than the control group, though this was likely due to standard hospital procedure shifting to same-day discharge for THA between 2019 and 2021 due to COVID-19.

Intelligibility of Natively and Nonnatively Produced English Speech Presented in Noise to a Large Cohort of United States Service Members.

PURPOSE: A corpus of English matrix sentences produced by 60 native and nonnative speakers of English was developed as part of a multinational coalition task group. This corpus was tested on a large cohort of U.S. Service members in order to examine the effects of talker nativeness, listener nativeness, masker type, and hearing sensitivity on speech recognition performance in this population. METHOD: A total of 1,939 U.S. Service members (ages 18-68 years) completed this closed-set listening task, including 430 women and 110 nonnative English speakers. Stimuli were produced by native and nonnative speakers of English and were presented in speech-shaped noise and multitalker babble. Keyword recognition accuracy and response times were analyzed. RESULTS: General(ized) linear mixed-effects regression models found that, on the whole, speech recognition performance was lower for listeners who identified as nonnative speakers of English and when listening to speech produced by nonnative speakers of English. Talker and listener effects were more pronounced when listening in a babble masker than in a speech-shaped noise masker. Response times varied as a function of recognition score, with longest response times found for intermediate levels of performance. CONCLUSIONS: This study found additive effects of talker and listener nonnativeness when listening to speech in background noise. These effects were present in both accuracy and response time measures. No multiplicative effects of talker and listener language background were found. There was little evidence of a negative interaction between talker nonnativeness and hearing impairment, suggesting that these factors may have redundant effects on speech recognition. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.26060191.

Molecular Recognition in Mechanochemistry: Insights from Solid-State NMR Spectroscopy.

Molecular-recognition events are highly relevant in biology and chemistry. In the present study, we investigated such processes in the solid state under mechanochemical conditions using the formation of racemic phases upon reacting enantiopure entities as example. As test systems, α-(trifluoromethyl)lactic acid (TFLA) and the amino acids serine and alanine were used. The effects of ball-milling and resonant acoustic mixing (RAM) on the formation of racemic phases were probed by using solid-state Nuclear Magnetic Resonance (NMR) spectroscopy. In a mixer mill, a highly efficient and fast racemic phase formation occurred for both TFLA and the two amino acids. RAM led to the racemic phase for TFLA also, and this process was facilitated upon employing pre-milled enantiopure entities. In contrast, under comparable conditions RAM did not result in the formation of racemic phases for serine and alanine.

Harvesting, Embedding, and Culturing Dorsal Root Ganglia in Multi-compartment Devices to Study Peripheral Neuronal Features.

The most common peripheral neuronal feature of pain is a lowered stimulation threshold or hypersensitivity of terminal nerves from the dorsal root ganglia (DRG). One proposed cause of this hypersensitivity is associated with the interaction between immune cells in the peripheral tissue and neurons. In vitro models have provided foundational knowledge in understanding how these mechanisms result in nociceptor hypersensitivity. However, in vitro models face the challenge of translating efficacy to humans. To address this challenge, a physiologically and anatomically relevant in vitro model has been developed for the culture of intact dorsal root ganglia (DRGs) in three isolated compartments in a 48-well plate. Primary DRGs are harvested from adult Sprague Dawley rats after humane euthanasia. Excess nerve roots are trimmed, and the DRG is cut into appropriate sizes for culture. DRGs are then grown in natural hydrogels, enabling robust growth in all compartments. This multi-compartment system offers anatomically relevant isolation of the DRG cell bodies from neurites, physiologically relevant cell types, and mechanical properties to study the interactions between neural and immune cells. Thus, this culture platform provides a valuable tool for investigating treatment isolation strategies, ultimately leading to an improved screening approach for predicting pain.

Effect of Jardiance on glucose uptake into astrocytomas.

PURPOSE: SGLT2, the sodium glucose cotransporter two, is expressed in human pancreatic, prostate and brain tumors, and in a mouse cancer model SGLT2 inhibitors reduce tumor glucose uptake and growth. In this study we have measured the effect of a specific SGLT2 inhibitor, Jardiance® (Empagliflozin), on glucose uptake into astrocytomas in patients. METHODS: We have used a specific SGLT glucose tracer, α-methyl-4-[18F]fluoro-4-deoxy-α-D-glucopyranoside (Me4FDG), and Positron Emission Tomography (PET) to measure glucose uptake. Four of five patients enrolled had WHO grade IV glioblastomas, and one had a low grade WHO Grade II astrocytoma. Two dynamic brain PET scans were conducted on each patient, one before and one after treatment with a single oral dose of Jardiance, a specific SGLT2 inhibitor. As a control, we also determined the effect of oral Jardiance on renal SGLT2 activity. RESULTS: In all five patients an oral dose (25 or 100 mg) of Jardiance reduced Me4FDG tumor accumulation, highly significant inhibition in four, and inhibited SGLT2 activity in the kidney. CONCLUSIONS: These initial experiments show that SGLT2 is a functional glucose transporter in astocytomas, and Jardiance inhibited glucose uptake, a drug approved by the FDA to treat type 2 diabetes mellitus (T2DM), heart failure, and renal failure. We suggest that clinical trials be initiated to determine whether Jardiance reduces astrocytoma growth in patients.

Topology Testing and Demographic Modeling Illuminate a Novel Speciation Pathway in the Greater Caribbean Sea Following the Formation of the Isthmus of Panama.

Recent genomic analyses have highlighted the prevalence of speciation with gene flow in many taxa and have underscored the importance of accounting for these reticulate evolutionary processes when constructing species trees and generating parameter estimates. This is especially important for deepening our understanding of speciation in the sea where fast moving ocean currents, expanses of deep water, and periodic episodes of sea level rise and fall act as soft and temporary allopatric barriers that facilitate both divergence and secondary contact. Under these conditions, gene flow is not expected to cease completely while contemporary distributions are expected to differ from historical ones. Here we conduct range-wide sampling for Pederson's cleaner shrimp (Ancylomenes pedersoni), a species complex from the Greater Caribbean that contains three clearly delimited mitochondrial lineages with both allopatric and sympatric distributions. Using mtDNA barcodes and a genomic ddRADseq approach, we combine classic phylogenetic analyses with extensive topology testing and demographic modeling (10 site frequency replicates x 45 evolutionary models x 50 model simulations/replicate = 22,500 simulations) to test species boundaries and reconstruct the evolutionary history of what was expected to be a simple case study. Instead, our results indicate a history of allopatric divergence, secondary contact, introgression, and endemic hybrid speciation that we hypothesize was driven by the final closure of the Isthmus of Panama and the strengthening of the Gulf Stream Current ~3.5 million years ago. The history of this species complex recovered by model-based methods that allow reticulation differs from that recovered by standard phylogenetic analyses and is unexpected given contemporary distributions. The geologically and biologically meaningful insights gained by our model selection analyses illuminate what is likely a novel pathway of species formation not previously documented that resulted from one of the most biogeographically significant events in Earth's history.

A randomized, pilot trial comparing vaginal hyaluronic acid to vaginal estrogen for the treatment of genitourinary syndrome of menopause.

OBJECTIVE: The aim of this study was to compare the efficacy of a non-hormone alternative, vaginal hyaluronic acid (HLA), to a standard-of-care therapy, vaginal estrogen, for the treatment of genitourinary syndrome of menopause (GSM). METHODS: This was a randomized, parallel arm pilot trial. Women with GSM were randomized to an HLA vaginal suppository or vaginal estrogen cream for 12 wk to compare the primary outcome, the vulvovaginal symptom questionnaire (VSQ) score. Secondary outcomes included the following: the female sexual function index (FSFI), the vaginal symptom index (VSI), visual analog scale (VAS) for dyspareunia, vaginal itching, and vaginal dryness, patient global impression of improvement (PGI-I) at follow-up, vaginal maturation index, and vaginal pH. Differences between treatment groups were estimated using the two-sided, two-sample t-test and 95% confidence intervals. RESULTS: Forty-nine women were randomized and 45 participants (vaginal estrogen = 23, vaginal HLA = 22) provided data at week 12. Baseline characteristics were similar in both groups. On the VSQ, there was no observed difference in overall scores between the HLA and vaginal estrogen groups at 12 wk (P = 0.81). Improvement was seen within both treatment groups on the VSQ after 12 wk. The VAS score, total VSI score, total FSFI score, and vaginal pH improved over time; however, improvement did not differ between study arms. Over 90% participants noted improvement on the PGI-I in both groups (P = 0.61). No treatment-related serious adverse events occurred. CONCLUSIONS: There were no clinically meaningful differences between vaginal HLA and vaginal estrogen for the treatment of GSM after 12 wk. Vaginal HLA may be a promising non-hormone therapy for GSM.

RANO 2.0 criteria: concepts applicable to the neuroradiologist's clinical practice.

PURPOSE OF REVIEW: The Response Assessment in Neuro-Oncology (RANO) 2.0 criteria aim at improving the standardization and reliability of treatment response assessment in clinical trials studying central nervous system (CNS) gliomas. This review presents the evidence supporting RANO 2.0 updates and discusses which concepts can be applicable to the clinical practice, particularly in the clinical radiographic reads. RECENT FINDINGS: Updates in RANO 2.0 were supported by recent retrospective analyses of multicenter data from recent clinical trials. As proposed in RANO 2.0, in tumors receiving radiation therapy, the post-RT MRI scan should be used as a reference baseline for the following scans, as opposed to the pre-RT scan, and radiographic findings suggesting progression within three months after radiation therapy completion should be verified with confirmatory scans. Volumetric assessments should be considered, when available, especially for low-grade gliomas, and the evaluation of nonenhancing disease should have a marginal role in glioblastoma. However, the radiographic reads in the clinical setting also benefit from aspects that lie outside RANO 2.0 criteria, such as qualitative evaluations, patient-specific clinical considerations, and advanced imaging. SUMMARY: While RANO 2.0 criteria are meant for the standardization of the response assessment in clinical trials, some concepts have the potential to improve patients' management in the clinical practice.

Partitioning of an Enzyme-Polymer Surfactant Nanocomplex into Lipid-Rich Cellular Compartments Drives In Situ Hydrolysis of Organophosphates.

Most organophosphates (OPs) are hydrophobic, and after exposure, can sequester into lipophilic regions within the body, such as adipose tissue, resulting in long term chronic effects. Consequently, there is an urgent need for therapeutic agents that can decontaminate OPs in these hydrophobic regions. Accordingly, an enzyme-polymer surfactant nanocomplex is designed and tested comprising chemically supercharged phosphotriesterase (Agrobacterium radiobacter; arPTE) electrostatically conjugated to amphiphilic polymer surfactant chains ([cat.arPTE][S-]). Experimentally-derived structural data are combined with molecular dynamics (MD) simulations to provide atomic level detail on conformational ensembles of the nanocomplex using dielectric constants relevant to aqueous and lipidic microenvironments. These show the formation of a compact admicelle pseudophase surfactant corona under aqueous conditions, which reconfigures to yield an extended conformation at a low dielectric constant, providing insight into the mechanism underpinning cell membrane binding. Significantly, it demonstrated that [cat.arPTE][S-] spontaneously binds to human mesenchymal stem cell membranes (hMSCs), resulting in on-cell OP hydrolysis. Moreover, the nanoconstruct can endocytose and partition into the intracellular fatty vacuoles of adipocytes and hydrolyze sequestered OP.

Neuronal Ceroid Lipofuscinoses Type 7 (CLN7)- A Case Series Reporting Cross Sectional and Retrospective Clinical Data to Evaluate Validity of Standardized Tools to Assess Disease Progression, Quality of Life, and Adaptive Skills.

Background: This study evaluated the clinical characteristics of neuronal ceroid lipofuscinosis type 7 or CLN7 disease spectrum to characterize the clinical, electrophysiologic and neuroimaging phenotypes. Methods: We performed a single-center cross sectional data collection along with retrospective medical chart review in patients with a genetic diagnosis of CLN7. This study received ethical approval by the University of Texas Southwestern Medical Center Institutional Review Board. A total of 8 patients were included between the ages of 4 to 6 years. All patients had a genetic diagnosis of CLN7 with homozygous or compound heterozygous mutations in the MFSD8 gene. The information collected includes patient demographics, developmental history, neurological events including seizures and neurodevelopmental regression along with further evaluation of brain magnetic resonance imaging and electrophysiological findings. The clinical phenotype is described through cross sectional and retrospective data collection and standardized tools assessing quality of life and functional skills. Conclusions: Our findings in this cohort of CLN7 patients indicated that development is initially normal with onset of clinical symptoms as early as two years of age. Language problems were noted prior to or at the onset of seizures in all cases. Gait problems were noted prior to seizure onset in 3 of 8 patients, and at or within 6 months after the onset of seizures in 5 of 8 patients. All patients followed a progressive course of language, motor, and neurocognitive deterioration. Congruent with the medical history, our patients had significantly low scores on adaptive abilities. Natural history data such as this can be used to support future clinical trial designs.

"Textbook outcome(s)" in colorectal surgery: a systematic review and meta-analysis.

BACKGROUND: Textbook outcome (TO) is a composite measure used in surgery to evaluate post operative outcomes. No review has synthesised the evidence in relation to TO regarding the elements surgeons are utilising to inform their TO composite measure and the rates of TO achieved. METHODS: Our systematic review and meta analysis was conducted in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) recommendations. PubMed, EMBASE, and Cochrane central registry of controlled trials were searched up to 8th November 2023. Pooled proportions of TO, clinical factors considered and risk factors in relation to TO are reported. RESULTS: Fifteen studies with 301,502 patients were included in our systematic review while fourteen studies comprising of 247,843 patients were included in our meta-analysis. Pooled rates of TO achieved were 55% with a 95% confidence interval (95% CI) of 54-55%. When stratified by elective versus mixed case load, rates were 56% (95% CI 49-62) and 54% (95% CI 50-58), respectively. Studies reported differing definitions of TO. Reported predictors of achieving TO include age, left sided surgery and elective nature. CONCLUSIONS: TO is achieved, on average in 55% of reported cases and it may predict short and long term post operative patient outcomes. This study did not detect a difference in rates between elective versus mixed case load TO proportions. There is no standardised definition in use of TO. Standardisation of the composite is likely required to enable meaning comparison using TO in the future and a Delphi consensus is warranted.

Computed tomography (CT) derived radiomics to predict post-operative disease recurrence in gastric cancer; a systematic review and meta-analysis.

INTRODUCTION: Radiomics offers the potential to predict oncological outcomes from pre-operative imaging in order to identify 'high risk' patients at increased risk of recurrence. The application of radiomics in predicting disease recurrence provides tailoring of therapeutic strategies. We aim to comprehensively assess the existing literature regarding the current role of radiomics as a predictor of disease recurrence in gastric cancer. METHODS: A systematic search was conducted in Medline, EMBASE, and Web of Science databases. Inclusion criteria encompassed retrospective and prospective studies investigating the use of radiomics to predict post-operative recurrence in ovarian cancer. Study quality was assessed using the QUADAS-2 and Radiomics Quality Score tools. RESULTS: Nine studies met the inclusion criteria, involving a total of 6,662 participants. Radiomic-based nomograms demonstrated consistent performance in predicting disease recurrence, as evidenced by satisfactory area under the receiver operating characteristic curve values (AUC range 0.72 - 1). The pooled AUCs calculated using the inverse-variance method for both the training and validation datasets were 0.819 and 0.789 respectively CONCLUSION: Our review provides good evidence supporting the role of radiomics as a predictor of post-operative disease recurrence in gastric cancer. Included studies noted good performance in predicting their primary outcome. Radiomics may enhance personalised medicine by tailoring treatment decision based on predicted prognosis.

Scale and rate heterogeneity in the EQ-5D-5L valuation.

OBJECTIVES: To estimate values on a quality-adjusted life year (QALY) scale using individual preference evidence, choice analyses typically include ancillary parameters, such as scale factors and discount rates. These parameters potentially differ among respondents. In this study, we investigated how allowing heterogeneity in scale and rate affects the estimation of EQ-5D-5L values. METHODS: Using the first wave of the 2016 EQ-5D-5L valuation study (N = 1017), we estimated a conditional logit (CL) model and three mixed logit models: random scale, random rate, and bivariate. Prior to the exploratory study, we hypothesized that scale and rate are correlated and that allowing heterogeneity in both parameters decreases the number of insignificant incremental effects. We confirmed the exploratory findings by re-estimating these models using paired comparison responses from a second wave (N = 1229). RESULTS: Scale and rate exhibited significant heterogeneity and were positively correlated. As hypothesized, allowing this heterogeneity improved the face validity of the EQ-5D-5L value set by reducing the number of insignificant incremental effects (from 6 to 2 p-values > 0.05; out of 20). Nevertheless, the CL and bivariate mixed logit estimates are highly correlated and concordant (Pearson correlation coefficient of 0.897, Spearman correlation coefficient of 0.888, Lin's concordance coefficient of 0.763). CONCLUSIONS: Allowing this heterogeneity adds three parameters to the estimation (two variances and a correlation) and improves the face validity of the EQ-5D-5L values. This finding may influence experimental design and choice analysis in health valuation more generally.

"Modeling Diffusive Search by Non-Adaptive Sperm: Empirical and Computational Insights".

During fertilization, mammalian sperm undergo a winnowing selection process that reduces the candidate pool of potential fertilizers from ~106-1011 cells to 101-102 cells (depending on the species). Classical sperm competition theory addresses the positive or 'stabilizing' selection that acts on sperm phenotypes within populations of organisms but does not strictly address the developmental consequences of sperm traits among individual organisms that are under purifying selection during fertilization. It is the latter that is of utmost concern for improving assisted reproductive technologies (ART) because 'low fitness' sperm may be inadvertently used for fertilization during interventions that rely heavily on artificial sperm selection, such as intracytoplasmic sperm injection (ICSI). Importantly, some form of sperm selection is used in nearly all forms of ART (e.g., differential centrifugation, swim-up, or hyaluronan binding assays, etc.). To date, there is no unifying quantitative framework (i.e., theory of sperm selection) that synthesizes causal mechanisms of selection with observed natural variation in individual sperm traits. In this report, we reframe the physiological function of sperm as a collective diffusive search process and develop multi-scale computational models to explore the causal dynamics that constrain sperm 'fitness' during fertilization. Several experimentally useful concepts are developed, including a probabilistic measure of sperm 'fitness' as well as an information theoretic measure of the magnitude of sperm selection, each of which are assessed under systematic increases in microenvironmental selective pressure acting on sperm motility patterns.