Human Papillomavirus Perceptions, Vaccine Uptake, and Sexual Risk Factors in Students Attending a Large Public Midwestern University.

Background: It was to understand HPV vaccination patterns, uptake, perceptions, and sexual risk factors in students at a Midwest public university. Participants: Students were enrolled during the spring 2024 semester at the University of Iowa. Methods: A survey was developed and emailed to 28,095 students asking demographic, general and sexual health, and HPV-related questions. Results: The response rate was 4.9%, with 76% females and a median age of 22. The HPV vaccine uptake was 82%, with 88% recommending the vaccine. Parental preference was the main reason for being unvaccinated. The median age of sexual debut was 17 years, with a median of 2 sexual partners. Vaccination was associated with female, health science, sexually active, and COVID-19/influenza vaccinated students. Conclusions: HPV vaccine uptake at University of Iowa students is higher than the national and Iowa averages. Increased education regarding HPV vaccination is still needed, particularly in males, those not having sex, and those not receiving other vaccines.

Effect of glycocalyx-targeted therapy on vascular function in older adults: a randomized controlled trial.

Advancing age increases cardiovascular disease risk, in part, because of impaired glycocalyx thickness and endothelial dysfunction. Glycocalyx-targeted therapies, such as Endocalyx Pro, could improve both glycocalyx thickness and endothelial function in older adults; however, this has yet to be tested. We hypothesized that Endocalyx Pro supplementation would increase glycocalyx thickness and endothelial function in older adults. Twenty-three older adults aged 66 ± 7 yr (52% female) were enrolled in a randomized, double-blind, placebo-controlled, parallel-arms study to investigate the effect of 12-wk Endocalyx Pro supplementation (3,712 mg/day) on glycocalyx thickness and endothelial function. Glycocalyx thickness was assessed using the GlycoCheck, and endothelial function was determined via brachial artery flow-mediated dilation (FMD). Between-group comparisons revealed Endocalyx Pro did not increase glycocalyx thickness in microvessels 4-25 µm (P = 0.33), 4-7 µm (P = 0.07), or 10-25 µm (P = 0.47) in diameter when compared with placebo. In addition, Endocalyx Pro did not significantly improve FMD [mean ratio (95%) confidence interval [CI]) for between-group comparisons, 1.16 (0.77-1.74); P = 0.48]. However, Endocalyx Pro improved FMD normalized to shear rate (SR) area under the curve [mean ratio (95% CI) for between-group comparisons, 2.41 (1.14,4.13); P = 0.001]. Moreover, Endocalyx Pro increased capillary glycocalyx thickness more than placebo in individuals not taking antihypertensive medication [mean difference (95% CI) for between-group comparison, -0.08 (-0.15, -0.01); P = 0.02]. Our pilot study suggests that Endocalyx Pro supplementation is feasible in older adults but has no measurable effect on overall glycocalyx thickness and FMD. However, Endocalyx Pro may have select effects on capillary glycocalyx thickness and FMD normalized to shear rate among older adults, but further investigation is warranted.NEW & NOTEWORTHY Endothelial glycocalyx thickness and vascular endothelial function decline with advancing age. Endocalyx Pro is a glycocalyx-targeted therapy that may improve endothelial glycocalyx thickness and vascular endothelial function in older adults. This study demonstrated that 12-wk Endocalyx Pro supplementation did not improve overall endothelial glycocalyx thickness or flow-mediated dilation in older adults; however, Endocalyx Pro did increase capillary glycocalyx thickness in individuals not taking antihypertensive medication and improve flow-mediated dilation normalized to the shear stimulus.

Availability and use of institutional support programs for emergency department healthcare personnel during the COVID-19 pandemic.

OBJECTIVES: The COVID-19 pandemic placed health care personnel (HCP) at risk for stress, anxiety, burnout, and post-traumatic stress disorder (PTSD). To address this, hospitals developed programs to mitigate risk. The objectives of the current study were to measure the availability and use of these programs in a cohort of academic emergency departments (EDs) in the United States early in the pandemic and identify factors associated with program use. METHODS: Cross-sectional survey of ED HCP in 21 academic EDs in 15 states between June and September 2020. Site investigators provided data on the availability of 28 programs grouped into 9 categories. Individual support programs included: financial, workload mitigation, individual COVID-19 testing, emotional (e.g., mental health hotline), and instrumental (e.g., childcare) Clinical work support programs included: COVID-19 team communication (e.g., debriefing critical incident), patient-family communication facilitation, patient services (e.g., social work, ethics consultation), and system-level exposure reduction. Participants provided corresponding data on whether they used the programs. We used generalized linear mixed models clustered on site to measure the association between demographic and facility characteristics and program use. RESULTS: We received 1,541 survey responses (96% response rate) from emergency physicians or advanced practice providers, nurses, and nonclinical staff. Program availability in each of the 9 categories was high (>95% of hospitals). Program use was variable, with clinical work support programs used more frequently (28-50% of eligible HCP across categories) than individual employee support programs (6-13% of eligible HCP across categories). Fifty-seven percent of respondents reported that the COVID-19 pandemic had affected their stress and anxiety, and 12% were at elevated risk for PTSD. Program use did not significantly differ for HCP who reported symptoms of anxiety and/or stress compared to those who did not. CONCLUSIONS: Early in the pandemic, support programs were widely available to ED HCP, but program use was low. Future work will focus on identifying barriers and facilitators to use and specific programs most likely to be effective during periods of highest occupational stress.

Enhanced Spine Stability and Survival Lead to Increases in Dendritic Spine Density as an Early Response to Local Alpha-Synuclein Overexpression in Mouse Prefrontal Cortex.

Lewy Body Dementias (LBD), including Parkinson's disease dementia and Dementia with Lewy Bodies, are characterized by widespread accumulation of intracellular alpha-Synuclein protein deposits in regions beyond the brainstem, including in the cortex. However, the impact of local pathology in the cortex is unknown. To investigate this, we employed viral overexpression of human alpha-Synuclein protein targeting the mouse prefrontal cortex (PFC). We then used in vivo 2-photon microscopy to image awake head-fixed mice via an implanted chronic cranial window to assess the early consequences of alpha-Synuclein overexpression in the weeks following overexpression. We imaged apical tufts of Layer V pyramidal neurons in the PFC of Thy1-YFP transgenic mice at 1-week intervals from 1 to 2 weeks before and 9 weeks following viral overexpression, allowing analysis of dynamic changes in dendritic spines. We found an increase in the relative dendritic spine density following local overexpression of alpha-Synuclein, beginning at 5 weeks post-injection, and persisting for the remainder of the study. We found that alpha-Synuclein overexpression led to an increased percentage and longevity of newly-persistent spines, without significant changes in the total density of newly formed or eliminated spines. A follow-up study utilizing confocal microscopy revealed that the increased spine density is found in cortical cells within the alpha-Synuclein injection site, but negative for alpha-Synuclein phosphorylation at Serine-129, highlighting the potential for effects of dose and local circuits on spine survival. These findings have important implications for the physiological role and early pathological stages of alpha-Synuclein in the cortex.

Increased Maternal BMI at Time of Delivery Associated with Poor Maternal and Neonatal Outcomes.

OBJECTIVE: Current literature on the risks and outcomes of obesity in pregnancy almost exclusively utilizes prepregnancy body mass index (BMI). Given the rising obesity rate across the United States along with a paucity of available information on the relationship between delivery BMI and maternal and neonatal outcomes, our study aimed to determine the association of maternal BMI at delivery with antepartum, intrapartum, and neonatal complications at an academic referral hospital. STUDY DESIGN: This study is a secondary analysis of data collected for a prospective cohort study of Coronavirus Disease-2019 (COVID-19) in pregnancy. This analysis included all patients who delivered term singleton infants between May 1, 2020, and April 30, 2021, at the University of Iowa Hospitals and Clinics. Demographic and clinical data were obtained from the electronic medical record. The relationship between maternal BMI and maternal and neonatal characteristics of interest was assessed using logistic regression models. A statistical significance threshold of 0.05 was used for all comparisons. RESULTS: There were 1,996 women who delivered term singleton infants during the study period. The median BMI at delivery was 31.7 kg/m2 (interquartile range 27.9, 37.2), with 61.1% of women having a BMI ≥ 30.0 kg/m2. Increasing BMI was significantly associated with nonreassuring fetal status, unscheduled cesarean birth, overall cesarean birth rate, postpartum hemorrhage, prolonged postpartum stay, hypertensive diseases of pregnancy, neonatal hypoglycemia, neonatal intensive care unit admission, decreased APGAR score at 1 minute, and increasing neonatal birth weight. Even when controlling for preexisting hypertension in a multivariate model, increasing BMI was associated with gestational hypertension and preeclampsia. CONCLUSION: Increased maternal BMI at delivery was associated with adverse perinatal outcomes. These findings have implications for clinical counseling regarding risks of pregnancy and delivery for overweight and obese patients and may help inform future studies to improve safety, especially by examining reasons for high cesarean rates. KEY POINTS: · Sixty-one percent of delivering patients had a BMI330 kg/m2 at delivery.. · There was a higher cesarean rate with increasing delivery BMI.. · For every 5-unit increase in maternal BMI, neonatal weight increased by 0.47 g..

Effects of rurality and distance to care on perinatal outcomes over a 1-year period during the COVID-19 pandemic.

PURPOSE: Our aim was to investigate the roles of rurality and distance to care on adverse perinatal outcomes and COVID-19 seroprevalence at the time of delivery over a 1-year period. METHODS: Data were collected from the electronic medical record on all pregnant patients who delivered at a single, large, Midwest academic medical center over 1 year. Rurality was classified using standard Rural-Urban Commuting Area codes. Geographic Information System tools were used to map outcomes. Data were analyzed with univariate and multivariate models, controlling for Body Mass Index (BMI), insurance status, and parity. FINDINGS: A total of 2,497 patients delivered during the study period; 20% of patients were rural (n = 499), 18.6% were micropolitan (n = 466), and 61.4% were metropolitan (n = 1,532). 10.4% of patients (n = 259) were COVID-19 seropositive. Rural patients did not experience higher rates of any measured adverse outcomes than metropolitan patients; micropolitan patients had increased odds of preterm labor (OR = 1.41, P = .022) and pre-eclampsia (OR = 1.78, P<.001). Patients living 30+ miles away from the medical center had increased odds of preterm labor (OR = 1.94, P<.001), pre-eclampsia (OR = 1.73, P = .002), and infant admission to the neonatal intensive care unit (OR = 2.12, P<.001), as well as lower gestational age at delivery (ß = -9.2 days, P<.001) and birth weight (ß = -206 grams, P<.001). CONCLUSION: Distance to care, rather than rurality, was the key predictor of multiple adverse perinatal outcomes in this cohort of deliveries over a 1-year period. Our study suggests that rurality should not be used as a standalone indicator of access to care without further knowledge of the specific barriers affecting a given population.

Effect of Resveratrol on Endothelial Function in Patients with CKD and Diabetes: A Randomized Controlled Trial.

BACKGROUND: Patients with CKD and diabetes are at higher risk of developing cardiovascular disease, in part, because of impaired endothelial function. Cardioprotective compounds such as resveratrol could improve endothelial function and attenuate the cardiovascular burden in patients with CKD and diabetes. We hypothesized that resveratrol supplementation would improve endothelial function in patients with CKD and diabetes. METHODS: Twenty-eight adults aged 68±7 years (84% men) with stage 3 CKD and diabetes were enrolled in a randomized, double-blind, placebo-controlled, crossover study to investigate the effects of 6-week resveratrol supplementation (400 mg/d) on endothelial function. Endothelial function was determined through brachial artery flow-mediated dilation. RESULTS: The mean values for eGFR and hemoglobin A 1c were 40±9 ml/min per 1.73 m 2 and 7.36%±0.72%, respectively. Compared with placebo, resveratrol supplementation increased flow-mediated dilation (ratio of geometric mean changes and 95% confidence interval for between-group comparisons, 1.43 (1.15 to 1.77); P value = 0.001). eGFR, hemoglobin A 1c , BP, and nitroglycerin-mediated dilation were unchanged with resveratrol or placebo ( P = 0.15), suggesting the observed change in flow-mediated dilation was likely independent of changes in traditional cardiovascular risk factors. CONCLUSIONS: Resveratrol supplementation improved endothelial function in patients with CKD and diabetes. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Resveratrol and Vascular Function in CKD, NCT03597568 .

Enhanced spine stability and survival lead to increases in dendritic spine density as an early response to local alpha-synuclein overexpression in mouse prefrontal cortex.

Lewy Body Dementias (LBD), including Parkinson's disease dementia and Dementia with Lewy Bodies, are characterized by widespread accumulation of intracellular alpha-Synuclein protein deposits in regions beyond the brainstem, including in the cortex. Patients with LBDs develop cognitive changes, including abnormalities in executive function, attention, hallucinations, slowed processing, and cognitive fluctuations. The causes of these non-motor symptoms remain unclear; however, accumulation of alpha-Synuclein aggregates in the cortex and subsequent interference of synaptic and cellular function could contribute to psychiatric and cognitive symptoms. It is unknown how the cortex responds to local pathology in the absence of significant secondary effects of alpha-Synuclein pathology in the brainstem. To investigate this, we employed viral overexpression of human alpha-Synuclein protein targeting the mouse prefrontal cortex (PFC). We then used in vivo 2-photon microscopy to image awake head-fixed mice via an implanted chronic cranial window to assess the early consequences of alpha-Synuclein overexpression in the weeks following overexpression. We imaged apical tufts of Layer V pyramidal neurons in the PFC of Thy1-YFP transgenic mice at 1-week intervals from 1-2 weeks before and 9 weeks following viral overexpression, allowing analysis of dynamic changes in dendritic spines. We found an increase in the relative dendritic spine density following local overexpression of alpha-Synuclein, beginning at 5 weeks post-injection, and persisting for the remainder of the study. We found that alpha-Synuclein overexpression led to an increased percentage and longevity of newly-persistent spines, without significant changes in the total density of newly formed or eliminated spines. A follow up study utilizing confocal microscopy revealed that the increased spine density is found in cortical cells within the alpha-Synuclein injection site, but negative for alpha-Synuclein phosphorylation at Serine-129, highlighting the potential for effects of dose and local circuits on spine survival. These findings have important implications for the physiological role and early pathological stages of alpha-Synuclein in the cortex.

Disruption of the circadian rhythm of melatonin: A biomarker of critical illness severity.

Circadian dysrhythmias occur commonly in critically ill patients reflecting variable effects of underlying illness, ICU environment, and treatments. We retrospectively analyzed the relationship between clinical outcomes and 24-h urinary 6-sulfatoxymelatonin (aMT6s) excretion profiles in 37 critically ill patients with shock and/or respiratory failure. Nonlinear regression was used to fit a 24-h cosine curve to each patient's aMT6s profile, with rhythmicity determined by the zero-amplitude test. From these curves we determined acrophase, amplitude, phase, and night/day ratio. After assessing unadjusted relationships, we identified the optimal multivariate models for hospital survival and for discharge to home (vs. death or transfer to another facility). Normalized aMT6s rhythm amplitude was greater (p = 0.005) in patients discharged home than in those who were not, while both groups exhibited a phase delay. Patients with rhythmic aMT6s excretion were more likely to survive (OR 5.25) and be discharged home (OR 8.89; p < 0.05 for both) than patients with arrhythmic profiles, associations that persisted in multivariate modelling. In critically ill patients with shock and/or respiratory failure, arrhythmic and/or low amplitude 24-h aMT6s rhythms were associated with worse clinical outcomes, suggesting a role for the melatonin-based rhythm as a novel biomarker of critical illness severity.

Interictal respiratory variability predicts severity of hypoxemia after generalized convulsive seizures.

OBJECTIVE: Severe respiratory dysfunction induced by generalized convulsive seizures (GCS) is now thought to be a common mechanism for sudden unexpected death in epilepsy (SUDEP). In a mouse model of seizure-induced death, increased interictal respiratory variability was reported in mice that later died of respiratory arrest after GCS. We studied respiratory variability in epilepsy patients as a predictive tool for severity of postictal hypoxemia, a potential biomarker for SUDEP risk. We then explored the relationship between respiratory variability and central CO2 drive, measured by the hypercapnic ventilatory response (HCVR). METHODS: We reviewed clinical, video-electroencephalography, and respiratory (belts, airflow, pulse oximeter, and HCVR) data of epilepsy patients. Mean, SD, and coefficient of variation (CV) of interbreath interval (IBI) were calculated. Primary outcomes were: (1) nadir of capillary oxygen saturation (SpO2 ) and (2) duration of oxygen desaturation. Poincaré plots of IBI were created. Covariates were evaluated in univariate models, then, based on Akaike information criteria (AIC), multivariate regression models were created. RESULTS: Of 66 GCS recorded in 131 subjects, 30 had interpretable respiratory data. In the multivariate model with the lowest AIC value, duration of epilepsy was a significant predictor of duration of oxygen desaturation. Duration of tonic phase and CV of IBI during the third postictal minute correlated with SpO2 nadir, whereas CV of IBI during non-rapid eye movement sleep had a negative correlation. Poincaré plots showed that long-term variability was significantly greater in subjects with ≥200 s of postictal oxygen desaturation after GCS compared to those with <200 s desaturation. Finally, HCVR slope showed a negative correlation with measures of respiratory variability. SIGNIFICANCE: These results indicate that interictal respiratory variability predicts severity of postictal oxygen desaturation, suggesting its utility as a potential biomarker. They also suggest that interictal respiratory control may be abnormal in some patients with epilepsy.

The Association of Anesthesia Type and Neonatal Outcomes Following Category-1 Cesarean Delivery: A Retrospective Cohort Study.

Objectives Neuraxial anesthesia is the preferred anesthesia technique for cesarean delivery due to a decreased risk of adverse events. However, general anesthesia is often employed during emergent cesarean deliveries to achieve a shorter decision-to-delivery interval. The objective of this study was to determine if the conversion of epidural labor analgesia to surgical anesthesia for a category-1 cesarean delivery is associated with significant neonatal morbidity. Study design This was a retrospective cohort study of all intrapartum category-1 cesarean deliveries performed at an academic tertiary care institution between August 2016 and July 2021. The primary outcome was neonatal morbidity, defined as a composite of neonatal umbilical artery pH < 7.10 and/or 5-min Apgar score < 7, and/or neonatal intensive care unit admission. A multivariate regression analysis was performed to control for the presence of covariates and examine the degree to which they influenced the outcome. Results A total of 185 mother-neonate pairs qualified for inclusion, of which 23 had cesarean delivery under general anesthesia and 162 under epidural anesthesia. There was no significant difference in adverse neonatal outcomes between category-1 cesarean deliveries done under general anesthesia compared to epidural anesthesia (47% vs 35%, p = 0.3). The incidence of umbilical arterial pH < 7.10 was higher in the general anesthesia group compared to the epidural anesthesia group (35% vs 12%, p = 0.018). The multivariate regression model showed that gestational age (OR = 0.63; 95% CI = 0.51-0.75, p = <0.001) and non-reassuring fetal heart trace (OR = 0.18; 95% CI = 0.05-0.58, p = 0.005) were significant predictors of adverse neonatal outcome. Conclusion Our results suggest that the conversion of epidural analgesia to surgical anesthesia for category-1 cesarean delivery in women with a functional labor epidural catheter is not associated with poorer neonatal outcomes.

Surgeon-Specific Treatment Selection Bias and Heterogeneous Perioperative Practices in an Observational Spine Surgery Study. A Statistical Tutorial with Implications for Analysis of Observational Studies of Perioperative Interventions.

BACKGROUND: It is essential that treatment effects reported from retrospective observational studies are as reliable as possible. In a retrospective analysis of spine surgery patients, we obtained a spurious result: tranexamic acid (TXA) had no effect on intraoperative blood loss. This statistical tutorial explains how this result occurred and why statistical analyses of observational studies must consider the effects of individual surgeons. METHODS: We used an observational database of 580 elective adult spine surgery patients, supplemented with a review of perioperative medication records. We tested whether common statistical methods (multivariable regression or propensity score-based methods) could adjust for surgeons' selection bias in TXA administration. RESULTS: Because TXA administration (frequency, timing, and dose) and surgeon were linked (collinear), estimating and testing the independent effect of TXA on outcome using multivariable regression without including surgeon as a variable would provide biased (spurious) results. Likewise, because of surgeon/TXA linkage, assumptions of propensity score-based analysis were violated, statistical methods to improve comparability between groups failed, and spurious blood loss results were worsened. Others numerous differences among surgeons existed in intraoperative and postoperative practices and outcomes. CONCLUSIONS: In observational studies in which individual surgeons determine whether their patients receive the treatment of interest, consideration must be given to inclusion of surgeon as an independent variable in all analyses. Failure to include the surgeon in an analysis of observational data carries a substantial risk of obtaining spurious results, either creating a spurious treatment effect or failing to detect a true treatment effect.

Selective Serotonin Reuptake Inhibitors and 5-HT2 Receptor Agonists Have Distinct, Sleep-state Dependent Effects on Postictal Breathing in Amygdala Kindled Mice.

Seizures can cause profound breathing disruptions. Seizures arising from sleep cause greater breathing impairment than those emerging from wakefulness and more often result in sudden unexpected death in epilepsy (SUDEP). The neurotransmitter serotonin (5-HT) plays a major role in respiration and sleep-wake regulation. 5-HT modulates seizure susceptibility and severity and is dysregulated by seizures. Thus, the impact of seizures on breathing dysregulation may be due to impaired 5-HT neurotransmission. We examined whether pharmacologically increasing 5-HT neurotransmission prior to seizures improves postictal breathing and how sleep-state during seizure induction contributes to these effects. We assessed breathing with whole-body plethysmography in 84 amygdala-kindled mice pre-treated with selective serotonin reuptake inhibitors (SSRI) or 5-HT2 receptor agonists. SSRIs and 5-HT2 agonists increased postictal breathing frequency (fR), tidal volume (VT), and minute ventilation (VE) at different timepoints following seizures induced during wakefulness. These effects were not observed following seizures induced during NREM sleep. SSRIs suppressed ictal and postictal apnea regardless of sleep state. The SSRI citalopram and the 5-HT2 agonists TCB-2 and MK-212 decreased breathing variability following wake-occurring seizures at different postictal timepoints. Only MK-212 decreased breathing variability when seizures were induced during NREM sleep. The 5-HT2A antagonist MDL-11939 reduced the effect of citalopram on fR, VT, and VE, and enhanced its effect on breathing variability in the initial period following a seizure. These results suggest that 5-HT mechanisms that are dependent on or independent from the 5-HT2 family of receptors impact breathing on different timescales during the recovery of eupnea, and that certain serotonergic treatments may be less effective at facilitating postictal breathing following seizures emerging from sleep.

Thromboprophylaxis for children hospitalized with COVID-19 and MIS-C.

Background: Limited data exist about effective regimens for pharmacological thromboprophylaxis in children with acute coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C). Objectives: Study the outcomes of institutional thromboprophylaxis protocol for primary venous thromboembolism (VTE) prevention in children hospitalized with acute COVID-19/MIS-C. Methods: This single-center retrospective cohort study included consecutive children (aged less than 21 years) with COVID-19/MIS-C who received tailored intensity thromboprophylaxis, primarily with low-molecular-weight heparin, from April 2020 through October 2021. Thromboprophylaxis was given to those with moderate to severe disease based on the World Health Organization scale and exposure to two or more VTE risk factors. Therapeutic intensity was considered for severe illness. Clinical recovery along with D-dimer improvement determined thromboprophylaxis duration. Outcomes were incident VTEs, bleeding, and mortality. Results: Among 211 hospitalizations, 45 (21.3%) received thromboprophylaxis (COVID-19, 16; MIS-C, 29). Median age was 14.8 years (interquartile range [IQR], 8.9-16.1). Among 35 (77.8%) with severe illness, 27 (60.0%) required respiratory support, and 19 (42.2%) required an intensive care unit stay. Median hospitalization was 6 days (IQR, 5.0-10.5). Median thromboprophylaxis duration was 19 days (IQR, 6.0-31.0) with therapeutic intensity in 24 (53.3%) and prophylactic in 21 (46.7%). Outcomes were as follows: VTE, 1 (2.2%); death, 1 (2.2%, unrelated to bleeding/thrombosis); major/clinically relevant nonmajor bleeding, 0; and minor bleeding, 7 (15.5%). D-dimer was elevated in a majority at diagnosis (median, 2.3; IQR, 1.2-3.3 mg/ml fibrinogen-equivalent units) and was noninformative in assessing disease severity. D-dimer normalized at thromboprophylaxis discontinuation. Conclusions: Our experience of using clinically directed thromboprophylaxis with tailored intensity approach for children hospitalized with COVID-19 and MIS-C favors its inclusion in current standard of care. The role of D-dimer in directing thromboprophylaxis management deserves further evaluation.

The megaherbivore gap after the non-avian dinosaur extinctions modified trait evolution and diversification of tropical palms.

The Cretaceous-Palaeogene (K-Pg) extinction of the non-avian dinosaurs (66 Ma) led to a 25 million year gap of megaherbivores (>1000 kg) before the evolution of megaherbivorous mammals in the Late Eocene (40 Ma). The botanical consequences of this 'Palaeocene megaherbivore gap' (PMHG) remain poorly explored. We hypothesize that the absence of megaherbivores should result in changes in the diversification and trait evolution of associated plant lineages. We used phylogenetic time- and trait-dependent diversification models with palms (Arecaceae) and show that the PMHG was characterized by speciation slowdowns, decreased evolution of armature and increased evolution of megafaunal (≥4 cm) fruits. This suggests that the absence of browsing by megaherbivores during the PMHG may have led to a loss of defence traits, but the absence of megaherbivorous seed dispersers did not lead to a loss of megafaunal fruits. Instead, increases in PMHG fruit sizes may be explained by simultaneously rising temperatures, rainforest expansion, and the subsequent radiation of seed-dispersing birds and mammals. We show that the profound impact of the PMHG on plant diversification can be detected even with the overwriting of adaptations by the subsequent Late Eocene opening up of megaherbivore-associated ecological opportunities. Our study provides a quantitative, comparative framework to assess diversification and adaptation during one of the most enigmatic periods in angiosperm history.

The evolution of flowering phenology: an example from the wind-pollinated African Restionaceae.

BACKGROUND AND AIMS: Flowering phenology is arguably the most striking angiosperm phenophase. Although the response of species to climate change and the environmental correlates of the communities have received much attention, the interspecific evolution of flowering phenology has hardly been investigated. I explored this in the wind-pollinated dioecious Restionaceae (restios) of the hyperdiverse Cape flora, to disentangle the effects of phylogeny, traits, and biotic and abiotic environments on flowering time shifts. METHODS: I recorded the flowering times of 347 of the 351 species, mapped these over a 98 % complete phylogeny and inferred the evolutionary pattern and abiotic correlates of flowering time shifts. The patterns and biotic/abiotic correlates of restio community mean flowering time were explored using 934 plots. KEY RESULTS: Restios flower throughout the year, with large spring and smaller autumn peaks. Species flowering time is evolutionarily labile, poorly explained by either the environment or traits of the species, with half of all sister species allochronic. Community mean flowering time is related to elevation, temperature and rainfall. CONCLUSIONS: Flowering time shifts may result from assortative mating and allochronic speciation, possibly leading to non-adaptive radiation. However, community mean flowering time may be environmentally selected. Diversification of flowering time may be non-adaptive, but species could be filtered through survival in suitable communities.

Diversification in evolutionary arenas-Assessment and synthesis.

Understanding how and why rates of evolutionary diversification vary is a key issue in evolutionary biology, ecology, and biogeography. Evolutionary rates are the net result of interacting processes summarized under concepts such as adaptive radiation and evolutionary stasis. Here, we review the central concepts in the evolutionary diversification literature and synthesize these into a simple, general framework for studying rates of diversification and quantifying their underlying dynamics, which can be applied across clades and regions, and across spatial and temporal scales. Our framework describes the diversification rate (d) as a function of the abiotic environment (a), the biotic environment (b), and clade-specific phenotypes or traits (c); thus, d ~ a,b,c. We refer to the four components (a-d) and their interactions collectively as the "Evolutionary Arena." We outline analytical approaches to this framework and present a case study on conifers, for which we parameterize the general model. We also discuss three conceptual examples: the Lupinus radiation in the Andes in the context of emerging ecological opportunity and fluctuating connectivity due to climatic oscillations; oceanic island radiations in the context of island formation and erosion; and biotically driven radiations of the Mediterranean orchid genus Ophrys. The results of the conifer case study are consistent with the long-standing scenario that low competition and high rates of niche evolution promote diversification. The conceptual examples illustrate how using the synthetic Evolutionary Arena framework helps to identify and structure future directions for research on evolutionary radiations. In this way, the Evolutionary Arena framework promotes a more general understanding of variation in evolutionary rates by making quantitative results comparable between case studies, thereby allowing new syntheses of evolutionary and ecological processes to emerge.

The genetics of evolutionary radiations.

With the realization that much of the biological diversity on Earth has been generated by discrete evolutionary radiations, there has been a rapid increase in research into the biotic (key innovations) and abiotic (key environments) circumstances in which such radiations took place. Here we focus on the potential importance of population genetic structure and trait genetic architecture in explaining radiations. We propose a verbal model describing the stages of an evolutionary radiation: first invading a suitable adaptive zone and expanding both spatially and ecologically through this zone; secondly, diverging genetically into numerous distinct populations; and, finally, speciating. There are numerous examples of the first stage; the difficulty, however, is explaining how genetic diversification can take place from the establishment of a, presumably, genetically depauperate population in a new adaptive zone. We explore the potential roles of epigenetics and transposable elements (TEs), of neutral process such as genetic drift in combination with trait genetic architecture, of gene flow limitation through isolation by distance (IBD), isolation by ecology and isolation by colonization, the possible role of intra-specific competition, and that of admixture and hybridization in increasing the genetic diversity of the founding populations. We show that many of the predictions of this model are corroborated. Most radiations occur in complex adaptive zones, which facilitate the establishment of many small populations exposed to genetic drift and divergent selection. We also show that many radiations (especially those resulting from long-distance dispersal) were established by polyploid lineages, and that many radiating lineages have small genome sizes. However, there are several other predictions which are not (yet) possible to test: that epigenetics has played a role in radiations, that radiations occur more frequently in clades with small gene flow distances, or that the ancestors of radiations had large fundamental niches. At least some of these may be testable in the future as more genome and epigenome data become available. The implication of this model is that many radiations may be hard polytomies because the genetic divergence leading to speciation happens within a very short time, and that the divergence history may be further obscured by hybridization. Furthermore, it suggests that only lineages with the appropriate genetic architecture will be able to radiate, and that such a radiation will happen in a meta-population environment. Understanding the genetic architecture of a lineage may be an essential part of accounting for why some lineages radiate, and some do not.

Unexpected diversity and evolutionary lability in root architectural ecomorphs in the rushes of the hyperdiverse Cape flora.

Plants use roots to access soil resources, so differences in root traits and their ecological consequences could be a mechanism of species coexistence and niche divergence. Current views of the evolution of root diversity are informed by large-scale evolutionary analyses based on taxonomically coarse sampling and led to the 'root trait phylogenetic conservatism hypothesis'. Here we test this hypothesised conservatism among closely related species, and whether root variation plays an ecological role. We collected root architectural traits for the species-rich Cape rushes (Restionaceae) in the field and from herbaria. We used machine learning to interpolate missing data. Using model-based clustering we classified root syndromes. We modelled the proportion of the syndromes along environmental gradients using assemblages and environmental data of 735 plots. We fitted trait evolutionary models to test for the conservatism hypothesis. We recognised five root syndromes. Responses to environmental gradients are syndrome specific and thus these represent ecomorphs. Trait evolutionary models reveal an evolutionary lability in these ecomorphs. This could present the mechanistic underpinning of the taxonomic radiation of this group which has been linked to repeated habitat shifts. Our results challenge the perspective of strong phylogenetic conservatism and root trait evolution may more generally drive diversification.

Ecophysiological strategy switch through development in heteroblastic species of mediterranean ecosystems - an example in the African Restionaceae.

BACKGROUND AND AIMS: Heteroblasty is a non-reversible morphological change associated with life stage change and has been linked to predictable environmental variation. It is present in several clades from mediterranean-type climates, such as African Restionaceae (restios). These have heteroblastic shoots: juvenile shoots are thin, branched and sterile (sterile shoots); adult shoots are thicker and less branched, and bear inflorescences (reproductive shoots). Ten per cent of the restios retain juvenile-like, sterile shoots as adults (neoteny). We hypothesize (1) that the two shoot types differ in ecophysiological attributes, and (2) that these shoot types (and the neoteny) are associated with different environments. METHODS: We measured shoot mass per surface area (SMA), maximum photosynthetic capacity per biomass (Amass) and chlorenchyma to ground tissue ratio (CGR) of both shoot types in 14 restio species. We also calculated environmental niche overlap between neotenous and non-neotenous species using an improved multidimensional overlap function based on occurrence data, and linked shoot types with environments using a phylogenetic generalized linear model. KEY RESULTS: Sterile shoots showed higher Amass, lower SMA and higher CGR than reproductive shoots. Neotenous and non-neotenous species overlapped ecologically less than expected by chance: neotenous species favoured more mesic, non-seasonal conditions. CONCLUSIONS: We associate sterile shoot morphology with acquisitive ecophysiological strategies and reproductive shoots with conservative strategies. The heteroblastic switch optimizes carbon efficiency in the juvenile phase (by sterile shoots) in the mesic post-fire conditions. The adult shoots present a compromise between a more conservative strategy favourable under harsher conditions and reproductive success. Heteroblasty in seasonally arid, oligotrophic ecosystems with predictable, fire-driven shifts in water and nutrient availability might play a role in the success of restios and other species-rich lineages in mediterranean-type ecosystems. It may represent a previously unrecognized adaptation in mediterranean clades sharing similar conditions, contributing to their ecological and taxonomic dominance.