Generalizing Bayesian phylogenetics to infer shared evolutionary events.

Many processes of biological diversification can simultaneously affect multiple evolutionary lineages. Examples include multiple members of a gene family diverging when a region of a chromosome is duplicated, multiple viral strains diverging at a "super-spreading" event, and a geological event fragmenting whole communities of species. It is difficult to test for patterns of shared divergences predicted by such processes because all phylogenetic methods assume that lineages diverge independently. We introduce a Bayesian phylogenetic approach to relax the assumption of independent, bifurcating divergences by expanding the space of topologies to include trees with shared and multifurcating divergences. This allows us to jointly infer phylogenetic relationships, divergence times, and patterns of divergences predicted by processes of diversification that affect multiple evolutionary lineages simultaneously or lead to more than two descendant lineages. Using simulations, we find that the method accurately infers shared and multifurcating divergence events when they occur and performs as well as current phylogenetic methods when divergences are independent and bifurcating. We apply our approach to genomic data from two genera of geckos from across the Philippines to test if past changes to the islands' landscape caused bursts of speciation. Unlike previous analyses restricted to only pairs of gecko populations, we find evidence for patterns of shared divergences. By generalizing the space of phylogenetic trees in a way that is independent from the likelihood model, our approach opens many avenues for future research into processes of diversification across the life sciences.

Return on investment of fracture liaison services: a systematic review and analysis.

Fracture liaison services (FLS) have been proven clinically effective and cost-effective in preventing subsequent fractures among patients with an existing fragility fracture. Little is known about their monetary benefits such as their return on investment (ROI). This systematic review aimed to investigate the ROI of FLS and identify the FLS characteristics with better ROI. Studies on the cost-effectiveness of FLS published between January 2000 and December 2022 were searched from MEDLINE, EMBASE, PubMed, and Cochrane Central. Two independent reviewers conducted study selection and data extraction. ROI was calculated based on the difference between monetary benefits and FLS costs divided by the FLS costs. Subgroup analysis of ROI was performed across FLS types and FLS design details. A total of 23 FLS were included in this review. The majority of them were targeting patients aged over 50 years having fractures without identified sites. The mean ROI of these FLS was 10.49 (with a median ROI of 7.57), and 86.96% of FLS had positive ROI. FLS making treatment recommendations yielded the highest ROI (with a mean ROI of 18.39 and a median of 13.60). Incorporating primary care providers (with a mean ROI of 16.04 and a median of 13.20) or having them as program leaders (with a mean ROI of 12.07 and a median of 12.07) has demonstrated a high ROI. FLS for specific fracture sites had great monetary return. Intensive FLS such as type A and B FLS programs had higher ROI than non-intensive type C and D FLS. This review revealed a 10.49-fold monetary return of FLS. Identified characteristics contributing to greater economic return informed value-for-money FLS designs. Findings highlight the importance of FLS and the feasibility of expanding their contribution in mitigating the economic burden of osteoporotic fracture and are conducive to the promotion of FLS internationally.

Cytoplasmic switch of ARS2 isoforms promotes nonsense-mediated mRNA decay and arsenic sensitivity.

The life of RNA polymerase II (RNAPII) transcripts is shaped by the dynamic formation of mutually exclusive ribonucleoprotein complexes (RNPs) that direct transcript biogenesis and turnover. A key regulator of RNA metabolism in the nucleus is the scaffold protein ARS2 (arsenic resistance protein 2), bound to the cap binding complex (CBC). We report here that alternative splicing of ARS2's intron 5, generates cytoplasmic isoforms that lack 270 amino acids from the N-terminal of the protein and are functionally distinct from nuclear ARS2. Switching of ARS2 isoforms within the CBC in the cytoplasm has dramatic functional consequences, changing ARS2 from a NMD inhibitor to a NMD promoter that enhances the binding of UPF1 to NCBP1 and ERF1, favouring SURF complex formation, SMG7 recruitment and transcript degradation. ARS2 isoform exchange is also relevant during arsenic stress, where cytoplasmic ARS2 promotes a global response to arsenic in a CBC-independent manner. We propose that ARS2 isoform switching promotes the proper recruitment of RNP complexes during NMD and the cellular response to arsenic stress. The existence of non-redundant ARS2 isoforms is relevant for cell homeostasis, and stress response.

Weighing the Impact: The Influence of Body Mass Index on Facility Costs in Total Joint Arthroplasty.

BACKGROUND: Using time-driven activity-based costing (TDABC), a novel cost calculation method that more accurately reflects true resource utilization in health care, we sought to compare the total facility costs across different body mass index (BMI) groups following total joint arthroplasty (TJA). METHODS: The study consisted of 13,806 TJAs (7,340 total knee arthroplasties [TKAs] and 6,466 total hip arthroplasties [THAs]) performed between 2019 and 2023. The TDABC data from an analytics platform was employed to depict total facility costs, comprising personnel and supply costs. For the analysis, patients were stratified into four BMI categories: <30, 30 to <35, 35 to <40, and ≥40. Multivariable regression was used to determine the independent effect of BMI on facility costs. RESULTS: When indexed to patients who had BMI <30, elevated BMI categories (30 to <35, 35 to <40, and ≥40) were associated with higher total personnel costs (TKA 1.03x versus 1.07x versus 1.13x, P < .001; THA 1.00x versus 1.08x versus 1.08x, P < .001), and total supply costs (TKA 1.01x versus 1.04x versus 1.04x, P < .001; THA 1.01x versus 1.02x versus 1.03x, P = .007). Total facility costs in TJAs were significantly greater in higher BMI categories (TKA 1.02x versus 1.05x versus 1.08x, P < .001; THA 1.01x versus 1.05x versus 1.05x, P < .001). Notably, when incorporating adjustments for demographics and comorbidities, BMI values of 35, 40, and 45 relative to BMI of 25, exhibit a significant association with a 2, 3, and 5% increase in total facility cost for TKAs and a 3, 5, and 7% increase for THAs. CONCLUSIONS: Using TDABC methodology, this study found that overall facility costs of TJAs increase with BMI. The present study provides patient-level cost insights, indicating the potential need for reassessment of physician compensation models in this population. Further studies may facilitate the development of risk-adjusted procedural codes and compensation models for public and private payors. LEVEL OF EVIDENCE: Level IV, economic and decision analyses.

Revision Total Knee Arthroplasty Achieves Minimal Clinically Important Difference Faster than Primary Total Knee Arthroplasty.

INTRODUCTION: Revision total knee arthroplasty (rTKA) remains underexplored regarding patient-reported outcome measures (PROMs), particularly in terms of time to reach Minimal Clinically Important Difference (MCID). This study addresses this gap by comparing the time to achieve MCID between primary TKA (pTKA) and rTKA patients, providing valuable insights into their recovery trajectories. METHODS: A total of 8,266 TKAs (7,618 pTKA and 648 rTKA) were retrospectively studied in a multi-institutional arthroplasty registry. Patients who completed the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical, PROMIS Physical Function Short Form 10a (PF-10a), and Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form (KOOS-PS) questionnaires were identified by Current Procedural Terminology (CPT) codes. Survival curves with and without interval-censoring were utilized to evaluate the time to achieve MCID. RESULTS: Comparing the time to achieve MCID, rTKAs were significantly faster than pTKA for PROMIS Global Physical (3.5 versus 3.7 months, P = 0.004) and KOOS-PS (3.3 versus 4.2 months, P < 0.001), but similar for PROMIS PF-10a (4.4 versus 4.8 months, P = 0.057). Interval-censoring also showed similar trends with earlier times to achieve MCID for rTKAs for PROMIS Global Physical (0.6 to 0.61 versus 0.97 to 0.97 months, P = 0.009) and KOOS-PS (0.97 to 0.97 versus 1.47 to 1.47 months, P < 0.001), but not for PROMIS PF-10a (2.43 to 2.54 versus 1.90 to 1.91 months, P = 0.92). CONCLUSION: The present study revealed that the time to achieve MCID was faster in patients undergoing rTKA compared to those undergoing pTKA. These findings allow surgeons to reassure preoperative revision TKA patients that their recovery to a minimal clinically important difference postoperatively may be quicker than expected, especially when compared to their initial recovery after primary TKA.

Comparing Rates of Minimal Clinically Important Difference Between Manual and Robotic-Assisted Total Knee Arthroplasty.

BACKGROUND: Differences in patient-reported outcome measures (PROMs) between manual total knee arthroplasty (mTKA) and robotic-assisted TKA (rTKA) have not been adequately assessed. We compared the minimal clinically important difference (MCID) for improvement (MCID-I) and worsening (MCID-W) between mTKA and rTKA patients. METHODS: Patients who underwent primary TKA (874 mTKA and 439 rTKA) with complete preoperative and 1-year postoperative PROMs were retrospectively identified using a multihospital joint arthroplasty registry. Patient-Reported Outcomes Measurement Information System Physical Function Short Form 10a (PROMIS PF-10a), PROMIS Global - Physical, or Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form were collected. The MCID-I, MCID-W, and "no significant change" rates were calculated using distribution-based methods. Propensity score matching was performed to control for confounding. RESULTS: Similar 90-day pulmonary embolism (P = 0.26), deep venous thrombosis (P = 0.67), and emergency department visit (P = 0.35) rates were found. The 90-day readmission rate for mTKA was 1.7 and 3.4% for rTKA (P = 0.08), and the overall revision rates were 2.2% for mTKA and 0.7% for rTKA (P = 0.07). Revision-free survival was 99% at one and 2 years for both groups (P = 0.65 and P = 0.43, respectively). There were no differences in the proportion of patients achieving MCID-I or MCID-W for PROMIS PF-10a, PROMIS Global - Physical, or Knee Injury and Osteoarthritis Outcome Score-Physical Function Short Form. The MCID-I for PROMIS PF-10a was achieved in 65.5 and 62.2% of patients who had mTKA and rTKA, respectively (P = 0.32). CONCLUSIONS: Our study demonstrated similar complication rates and MCID-I and MCID-W attainment rates between mTKA and rTKA patients. Future studies should assess MCID attainment rates in the long term and in larger cohorts comparing mTKA and rTKA.

Low-density lipoprotein cholesterol in adolescents and young adults with type 1 diabetes: Data from the Australasian Diabetes Data Network registry.

AIM: To determine low-density lipoprotein cholesterol (LDL-C) screening frequency and levels, and factors associated with elevated LDL-C, in Australasian youth with type 1 diabetes (T1D). METHODS: Data were extracted from the Australasian Diabetes Data Network (ADDN), a prospective clinical quality registry, on all T1D healthcare visits attended by young people aged 16-25 years (with T1D duration of >1 year) between January 2011 and December 2020. The primary outcomes were elevated LDL-C > 2.6 mmol/L (100 mg/dL) and threshold for treatment: >3.4 mmol/L (130 mg/dL), according to consensus guidelines. Multivariable Generalised Estimated Equations (GEE) were used to examine factors associated with elevated LDL-C across all visits. RESULTS: A cohort of 6338 young people (52.6% men) were identified, of whom 1603 (25.3%) had ≥1 LDL-C measurement documented. At last measurement, mean age, age at T1D diagnosis and T1D duration were 18.3 ± 2.4, 8.8 ± 4.5 and 8.9 ± 4.8 years, respectively. LDL-C was elevated in 737 (46.0%) and at the treatment threshold in 250 (15.6%). In multivariable GEE elevated LDL-C continuously was associated with older age (OR = 0.07; 0.01-0.13, p = 0.02), female sex (OR = 0.31; 0.18-0.43; p < 0.001), higher HbA1c (OR = 0.04; 0.01-0.08; p = 0.01) and having an elevated BMI (OR = 0.17, 0.06-0.39, p < 0.001). CONCLUSIONS: LDL-C screening and levels are suboptimal in this cohort, increasing future cardiovascular complication risk. There is an urgent need to understand how healthcare services can support improved screening and management of dyslipidaemia in this population.

Predicting Rates of Angular Correction After Hemiepiphysiodesis in Patients With X-Linked Hypophosphatemic Rickets.

PURPOSE: Patients with X-linked hypophosphatemic rickets (XLH) often develop coronal plane knee deformities despite medical treatment. Hemiepiphysiodesis is an effective way to correct coronal plane knee deformities in skeletally immature patients, but a full understanding of the rate of angular correction after hemiepiphysiodesis in XLH patients, compared with idiopathic cases is lacking. METHODS: We retrospectively reviewed charts of 24 XLH patients and 37 control patients without metabolic bone disease who underwent hemiepiphysiodesis. All patients were treated with standard-of-care medical therapy (SOC=active vitamin D and phosphate salt supplementation) in our clinical research center and had a minimum of 2-year follow-up after hemiepiphysiodesis. Demographic data as well as complications, repeat procedures, or recurrence/overcorrection were recorded. Standing lower extremity radiographs were evaluated before the surgical intervention and at subsequent hardware removal or skeletal maturity, whichever came first. Mean axis deviation, knee zone, mechanical lateral distal femoral angle (mLDFA), and medial proximal tibial angle were measured on each radiograph. The rate of angular correction was calculated as the change in mLDFA and medial proximal tibial angle over the duration of treatment. RESULTS: The magnitude of the initial deformity of the distal femur was greater in XLH patients as compared with control for varus (XLH mLDFA 97.7 +/- 4.9 vs. Control mLDFA 92.0 +/- 2.0 degrees) and valgus (XLH mLDFA 78.7 +/- 6.2 vs. Controls mLDFA 83.6 +/- 3.2 degrees). The rate of correction was dependent on age. When correcting for age, XLH patients corrected femoral deformity at a 15% to 36% slower rate than control patients for the mLDFA (>3 y growth remaining XLH 0.71 +/- 0.46 vs. control 0.84 +/- 0.27 degrees/month, <3 y growth remaining XLH 0.37 +/- 0.33 vs. control 0.58 +/- 0.41 degrees/month). No significant differences were seen in the rate of proximal tibia correction. XLH patients were less likely to end treatment in zone 1 (55.0% XLH vs. 77.8% control). XLH patients had longer treatment times than controls (19.5 +/- 10.7 vs. 12.6 +/- 7.0 mu, P value <0.001), a higher average number of secondary procedures than controls (1.33 +/- 1.44 vs. 0.62 +/- 0.92 number of procedures), a higher rate of overcorrection than controls (29.2% vs. 5.4%), and a higher rate of subsequent corrective osteotomy than controls (37.5% vs. 8.1%). There was no significant difference in the rate of complications between groups (8.3% vs. 5.4%). CONCLUSIONS: Patients with XLH undergoing hemiepiphysiodesis have a 15% to 36% slower rate of femoral deformity correction that results in longer treatment times, a higher likelihood to undergo more secondary procedures, and a lower likelihood to reach neutral mechanical alignment. SIGNIFICANCE: This study provides important information to guide the timing and treatment of patients with XLH and coronal plane knee deformities. In addition, results from this study can be educational for families and patients with respect to anticipated treatment times, success rates of the procedure, complication rate, and likelihood of needing repeat procedures.

Gene Flow Increases Phylogenetic Structure and Inflates Cryptic Species Estimations: A Case Study on Widespread Philippine Puddle Frogs (Occidozyga laevis).

In cryptic amphibian complexes, there is a growing trend to equate high levels of genetic structure with hidden cryptic species diversity. Typically, phylogenetic structure and distance-based approaches are used to demonstrate the distinctness of clades and justify the recognition of new cryptic species. However, this approach does not account for gene flow, spatial, and environmental processes that can obfuscate phylogenetic inference and bias species delimitation. As a case study, we sequenced genome-wide exons and introns to evince the processes that underlie the diversification of Philippine Puddle Frogs-a group that is widespread, phenotypically conserved, and exhibits high levels of geographically based genetic structure. We showed that widely adopted tree- and distance-based approaches inferred up to 20 species, compared to genomic analyses that inferred an optimal number of five distinct genetic groups. Using a suite of clustering, admixture, and phylogenetic network analyses, we demonstrate extensive admixture among the five groups and elucidate two specific ways in which gene flow can cause overestimations of species diversity: 1) admixed populations can be inferred as distinct lineages characterized by long branches in phylograms; and 2) admixed lineages can appear to be genetically divergent, even from their parental populations when simple measures of genetic distance are used. We demonstrate that the relationship between mitochondrial and genome-wide nuclear $p$-distances is decoupled in admixed clades, leading to erroneous estimates of genetic distances and, consequently, species diversity. Additionally, genetic distance was also biased by spatial and environmental processes. Overall, we showed that high levels of genetic diversity in Philippine Puddle Frogs predominantly comprise metapopulation lineages that arose through complex patterns of admixture, isolation-by-distance, and isolation-by-environment as opposed to species divergence. Our findings suggest that speciation may not be the major process underlying the high levels of hidden diversity observed in many taxonomic groups and that widely adopted tree- and distance-based methods overestimate species diversity in the presence of gene flow. [Cryptic species; gene flow; introgression; isolation-by-distance; isolation-by-environment; phylogenetic network; species delimitation.].

Characterizing the Residual SCFE Deformity: Utility of the 45-degree Dunn View.

BACKGROUND: After treatment with in situ stabilization, slipped capital femoral epiphysis (SCFE) patients have variable degrees of deformity that can contribute to femoroacetabular impingement (FAI). To evaluate the severity of residual deformity most physicians currently use biplanar radiographs of an anteroposterior pelvis which profiles the lateral head-neck deformity and a frog lateral view which profiles the anterior head-neck deformity. However, the assessment of FAI morphology commonly relies on the 45-degree Dunn view to profile the anterolateral head-neck junction where FAI deformity is maximal. Therefore, the purpose of this study was to compare the magnitude of residual SCFE deformity detected on the frog lateral radiograph to the 45-degree Dunn radiograph. METHODS: A retrospective review of radiographic images of 50 hips (47 patients) diagnosed with SCFE at a single academic institution from 2014 to 2018 was performed. The group included 25 hips evaluated postoperatively after fixation (Group 1) and 25 hips presenting with residual symptomatic SCFE deformity after previous pinning (Group 2). The alpha angle was assessed on both the 45-degree Dunn and frog lateral views for comparison. The modified Southwick slip angle was assessed on the frog lateral view only as a measure of SCFE severity. RESULTS: The Dunn view showed the maximal residual SCFE deformity as measured by the alpha angle in 88% (44/50) of cases. Overall, the mean alpha angle (70.7 degree vs. 60.1 degree, P <0.001) was significantly larger on the Dunn view as compared with frog lateral. Subgroup analysis showed a larger alpha angle on Dunn view compared with frog lateral in both immediate postoperative and residual SCFE deformities as well: Group 1 (69.5 degree vs. 60.9 degree, P <0.001) and Group 2 (71.9 degree vs. 59.3 degree, P <0.001). CONCLUSION: In patients with SCFE, the maximal residual deformity of the proximal femur can typically be seen on the 45-degree Dunn view, rather than on the frog lateral view. Our findings suggest the 45-degree Dunn view may be beneficial part of the postoperative assessment of SCFEs to quantify the true maximal deformity present. LEVEL OF EVIDENCE: Level IV.

Erratum: Energy Transfer from Large to Small Scales in Turbulence by Multiscale Nonlinear Strain and Vorticity Interactions [Phys. Rev. Lett. 124, 104501 (2020)].

This corrects the article DOI: 10.1103/PhysRevLett.124.104501.

Severe Hip Dysplasia in Skeletally Mature Patients With Spastic Cerebral Palsy: The Technique and Early Outcome of Comprehensive Surgical Correction (Including the Bernese PAO).

BACKGROUND: Treatment of symptomatic hip dysplasia in skeletally mature patients with spastic cerebral palsy (CP) can be challenging. This study examines our technical experience with the Bernese periacetabular osteotomy (PAO) in combination with adjunctive procedures in the treatment of this complex hip deformity. METHODS: Sixteen consecutive patients (18 hips) with symptomatic CP hip dysplasia were treated with a PAO and variable adjunctive procedures and retrospectively reviewed. Two patient (2 hips) were excluded due to insufficient follow-up. The average age at the time of surgery was 17.7 years (range: 13 to 28 y). We compared the preoperative to postoperative changes in radiographic parameters as well as early outcomes as measured by patient assessment of hip pain and function using the modified Harris Hip Score (mHHS). RESULTS: The average time of follow-up was 3.3 years (range: 2.0 to 6.3 y). Tönnis angles decreased from a median of 30 degrees (range: 18 to 45 degrees) preoperatively to a median of 6 degrees (range: -9 to 21 degrees) postoperatively. Lateral center-edge angles increased from a median of -8 degrees (range: -28 to 15 degrees) to a median of 32 degrees (range: 19 to 38 degrees). Anterior center-edge angles increased from a median of 2 degrees (range: -22 to 39 degrees) to a median of 35 degrees (range: 22 to 47 degrees). The extrusion index decreased from a median of 57% preoperatively (range: 35% to 73%) to a median of 21% (range: 11% to 36%) postoperatively.The median mHHS was 62 (range: 37 to 81) preoperatively and 85 (range: 65 to 100) postoperatively. Notably, the pain component of the mHHS improved from 20 (range: 0 to 44) to 42 (range: 30 to 44). Tönnis osteoarthritis grade preoperatively was either 0 (11 hips) or 1 (5 hips) and remained unchanged in 11 hips and increased by 1 grade in 5 hips. CONCLUSIONS: It has been our experience that the Bernese PAO in combination with appropriate adjunctive treatments has provided a very satisfactory surgical approach in the treatment of CP hip dysplasia. In the adolescent and young adult with spastic CP, utilizing the Bernese PAO technique makes it possible to obtain redirection of often a very severe acetabular dysplasia. Adjunctive soft tissue procedures and a proximal femoral osteotomy are frequently necessary to maintain postoperative stability. A notable improvement in the quality of life and function directly attributable to our surgical treatment of their pre-existing problematic hip dysplasia has been consistently noted in early follow-up for our patients. LEVEL OF EVIDENCE: Level IV-therapeutic.

Patients With Symptomatic Sequelae of Slipped Capital Femoral Epiphysis Have Advanced Cartilage Wear at the Time of Surgical Intervention.

BACKGROUND: Slipped capital femoral epiphysis (SCFE) is a common hip problem in children. The resulting deformity can cause impingement similar to cam-type idiopathic femoroacetabular impingement (FAI). Although there are similarities between FAI and SCFE, deformity patterns, severity, and time of onset of symptoms varies, which may impact management. The purpose of this study was to describe patterns of articular cartilage damage in patients undergoing surgical hip dislocation for sequelae of SCFE in comparison to patients undergoing arthroscopic surgery for primary FAI. METHODS: Patients were identified who underwent surgical treatment for hip pain due to primary FAI (cam type) or sequelae of SCFE. Clinical data and radiographic measurements were recorded. Cartilage was assessed intraoperatively. Severity was classified using the modified Beck classification, while location was classified into 6 sectors. Statistical analysis was performed to test for differences in demographic and radiographic characteristics between the SCFE and FAI patients. χ2 or Fisher exact tests were used to evaluate trends in patterns of acetabular and femoral cartilage wear between SCFE and FAI groups. RESULTS: The SCFE group had 28 hips compared with 304 in the FAI group. SCFE patients were younger (19 vs. 32, P<0.001), had higher body mass index (30±5.9 vs. 24±4.8, P<0.001), and were more often male (61% vs. 27%, P<0.001). Deformity severity based on α-angle was higher in the SCFE group [AP 74 vs. 55 (P=0.001) and Dunn 72 vs. 58 (P<0.001)]. There were no significant differences with regards to lateral center edge angle, anterior center edge angle, or Tonnis angle. In both groups the most common locations for cartilage lesions in both groups were the anterior peripheral and superolateral peripheral regions with fewer but more widely distributed femoral head lesions. The SCFE group had higher rates of femoral head and superolateral central cartilage lesions compared with the FAI group. There was no statistical difference between high-grade femoral or acetabular cartilage lesions between groups. CONCLUSIONS: Patients with SCFE were younger at the time of surgery and presented with more severe deformity based on radiographic α-angle compared to patients with FAI. Our results suggest higher prevalence of femoral head lesions and more diffuse cartilage injury in patients with SCFE. This study can be used to support early surgical intervention in patients with symptomatic sequelae of SCFE due to risk of premature joint damage. LEVEL OF EVIDENCE: Level III-prognostic study.

Posttraumatic stress disorder and eating disorders: maintaining mechanisms and treatment targets.

Many individuals with lifetime histories of eating disorders (EDs) report exposure to interpersonal trauma and posttraumatic stress disorder (PTSD). However, this relationship is not well-understood, and there are no established, evidence-based therapies for the concurrent treatment of EDs and PTSD. This review focuses on studies of the mechanisms associating trauma exposure and/or PTSD with EDs. Possible mechanisms of the trauma-ED association identified from the literature include self-criticism, low self-worth, guilt, shame, depression, anxiety, emotion dysregulation, anger, and impulsivity/compulsivity. ED behaviors may be used as coping strategies to manage PTSD symptoms and negative affect. Avoidance of hyperarousal symptoms by engaging in binge eating, purging, and/or restriction may serve to maintain both the ED as well as the PTSD. Given the evidence of the bidirectional relationship between EDs and PTSD, we describe an integrated cognitive behavioral theory that may account for the persistence of comorbid PTSD and EDs. The integrated model is based on the theoretical models that underpin existing evidence-based treatments for PTSD and ED and incorporates many of the potential mechanisms highlighted to date. The primary aim of the model is to identify potential treatment targets as well as elucidate future directions for research.

ARS2 is required for retinal progenitor cell S-phase progression and Müller glial cell fate specification.

During a developmental period that extends postnatally in the mouse, proliferating multipotent retinal progenitor cells produce one of 7 major cell types (rod, cone, bipolar, horizontal, amacrine, ganglion, and Müller glial cells) as they exit the cell cycle in consecutive waves. Cell production in the retina is tightly regulated by intrinsic, extrinsic, spatial, and temporal cues, and is coupled to the timing of cell cycle exit. Arsenic-resistance protein 2 (ARS2, also known as SRRT) is a component of the nuclear cap-binding complex involved in RNA Polymerase II transcription, and is required for cell cycle progression. We show that postnatal retinal progenitor cells (RPCs) require ARS2 for proper progression through S phase, and ARS2 disruption leads to early exit from the cell cycle. Furthermore, we observe an increase in the proportion of cells expressing a rod photoreceptor marker, and a loss of Müller glia marker expression, indicating a role for ARS2 in regulating cell fate specification or differentiation. Knockdown of Flice Associated Huge protein (FLASH), which interacts with ARS2 and is required for cell cycle progression and 3'-end processing of replication-dependent histone transcripts, phenocopies ARS2 knockdown. These data implicate ARS2-FLASH-mediated histone mRNA processing in regulating RPC cell cycle kinetics and neuroglial cell fate specification during postnatal retinal development.

Target-capture phylogenomics provide insights on gene and species tree discordances in Old World treefrogs (Anura: Rhacophoridae).

Genome-scale data have greatly facilitated the resolution of recalcitrant nodes that Sanger-based datasets have been unable to resolve. However, phylogenomic studies continue to use traditional methods such as bootstrapping to estimate branch support; and high bootstrap values are still interpreted as providing strong support for the correct topology. Furthermore, relatively little attention has been given to assessing discordances between gene and species trees, and the underlying processes that produce phylogenetic conflict. We generated novel genomic datasets to characterize and determine the causes of discordance in Old World treefrogs (Family: Rhacophoridae)-a group that is fraught with conflicting and poorly supported topologies among major clades. Additionally, a suite of data filtering strategies and analytical methods were applied to assess their impact on phylogenetic inference. We showed that incomplete lineage sorting was detected at all nodes that exhibited high levels of discordance. Those nodes were also associated with extremely short internal branches. We also clearly demonstrate that bootstrap values do not reflect uncertainty or confidence for the correct topology and, hence, should not be used as a measure of branch support in phylogenomic datasets. Overall, we showed that phylogenetic discordances in Old World treefrogs resulted from incomplete lineage sorting and that species tree inference can be improved using a multi-faceted, total-evidence approach, which uses the most amount of data and considers results from different analytical methods and datasets.

Gene flow creates a mirage of cryptic species in a Southeast Asian spotted stream frog complex.

Most new cryptic species are described using conventional tree- and distance-based species delimitation methods (SDMs), which rely on phylogenetic arrangements and measures of genetic divergence. However, although numerous factors such as population structure and gene flow are known to confound phylogenetic inference and species delimitation, the influence of these processes is not frequently evaluated. Using large numbers of exons, introns, and ultraconserved elements obtained using the FrogCap sequence-capture protocol, we compared conventional SDMs with more robust genomic analyses that assess population structure and gene flow to characterize species boundaries in a Southeast Asian frog complex (Pulchrana picturata). Our results showed that gene flow and introgression can produce phylogenetic patterns and levels of divergence that resemble distinct species (up to 10% divergence in mitochondrial DNA). Hybrid populations were inferred as independent (singleton) clades that were highly divergent from adjacent populations (7%-10%) and unusually similar (<3%) to allopatric populations. Such anomalous patterns are not uncommon in Southeast Asian amphibians, which brings into question whether the high levels of cryptic diversity observed in other amphibian groups reflect distinct cryptic species-or, instead, highly admixed and structured metapopulation lineages. Our results also provide an alternative explanation to the conundrum of divergent (sometimes nonsister) sympatric lineages-a pattern that has been celebrated as indicative of true cryptic speciation. Based on these findings, we recommend that species delimitation of continuously distributed "cryptic" groups should not rely solely on conventional SDMs, but should necessarily examine population structure and gene flow to avoid taxonomic inflation.

Larger, unfiltered datasets are more effective at resolving phylogenetic conflict: Introns, exons, and UCEs resolve ambiguities in Golden-backed frogs (Anura: Ranidae; genus Hylarana).

Using FrogCap, a recently-developed sequence-capture protocol, we obtained >12,000 highly informative exons, introns, and ultraconserved elements (UCEs), which we used to illustrate variation in evolutionary histories of these classes of markers, and to resolve long-standing systematic problems in Southeast Asian Golden-backed frogs of the genus-complex Hylarana. We also performed a comprehensive suite of analyses to assess the relative performance of different genetic markers, data filtering strategies, tree inference methods, and different measures of branch support. To reduce gene tree estimation error, we filtered the data using different thresholds of taxon completeness (missing data) and parsimony informative sites (PIS). We then estimated species trees using concatenated datasets and Maximum Likelihood (IQ-TREE) in addition to summary (ASTRAL-III), distance-based (ASTRID), and site-based (SVDQuartets) multispecies coalescent methods. Topological congruence and branch support were examined using traditional bootstrap, local posterior probabilities, gene concordance factors, quartet frequencies, and quartet scores. Our results did not yield a single concordant topology. Instead, introns, exons, and UCEs clearly possessed different phylogenetic signals, resulting in conflicting, yet strongly-supported phylogenetic estimates. However, a combined analysis comprising the most informative introns, exons, and UCEs converged on a similar topology across all analyses, with the exception of SVDQuartets. Bootstrap values were consistently high despite high levels of incongruence and high proportions of gene trees supporting conflicting topologies. Although low bootstrap values did indicate low heuristic support, high bootstrap support did not necessarily reflect congruence or support for the correct topology. This study reiterates findings of some previous studies, which demonstrated that traditional bootstrap values can produce positively misleading measures of support in large phylogenomic datasets. We also showed a remarkably strong positive relationship between branch length and topological congruence across all datasets, implying that very short internodes remain a challenge to resolve, even with orders of magnitude more data than ever before. Overall, our results demonstrate that more data from unfiltered or combined datasets produced superior results. Although data filtering reduced gene tree incongruence, decreased amounts of data also biased phylogenetic estimation. A point of diminishing returns was evident, at which higher congruence (from more stringent filtering) at the expense of amount of data led to topological error as assessed by comparison to more complete datasets across different genomic markers. Additionally, we showed that applying a parameter-rich model to a partitioned analysis of concatenated data produces better results compared to unpartitioned, or even partitioned analysis using model selection. Despite some lingering uncertainties, a combined analysis of our genomic data and sequences supplemented from GenBank (on the basis of a few gene regions) revealed highly supported novel systematic arrangements. Based on these new findings, we transfer Amnirana nicobariensis into the genus Indosylvirana; and I. milleti and Hylarana celebensis to the genus Papurana. We also provisionally place H. attigua in the genus Papurana pending verification from positively identified (voucher substantiated) samples.

Rivers of Indochina as potential drivers of lineage diversification in the spotted flying lizard (Draco maculatus) species complex.

Southeast Asia hosts a rich concentration of biodiversity within multiple biodiversity hotspots. Indochina, a region with remarkably high levels of in situ diversification, possesses five major rivers (Ayeyarwady, Chiang Mai, Mekong, Red, and Salween), several of which coincide with phylogenetic breaks of terrestrial taxa. Draco maculatus possesses a range that stretches across Indochina, which widespread geographic distribution along with potential discrete variation within subspecies alludes to the possibility of this taxon constituting multiple divergent lineages. Using sequence data from three mitochondrial (12S, 16S, and ND2) and three nuclear (BDNF, CMOS, and PNN) genes, we provide the first estimated phylogeny of this hypothesized species complex and examine its phylogeographic architecture with maximum likelihood and Bayes factor delimitation (BFD) approaches. Our results support multiple divergent lineages with phylogenetic breaks coincident with rivers, indicating that river barriers may be contributing to the elevated levels of in situ diversification of Indochina.

Parachute geckos free fall into synonymy: Gekko phylogeny, and a new subgeneric classification, inferred from thousands of ultraconserved elements.

Recent phylogenetic studies of gekkonid lizards have revealed unexpected, widespread paraphyly and polyphyly among genera, unclear generic boundaries, and a tendency towards the nesting of taxa exhibiting specialized, apomorphic morphologies within geographically widespread "generalist" clades. This is especially true in Australasia, where monophyly of Gekko proper has been questioned with respect to phenotypically ornate flap-legged geckos of the genus Luperosaurus, the Philippine false geckos of the genus Pseudogekko, and even the elaborately "derived" parachute geckos of the genus Ptychozoon. Here we employ sequence capture targeting 5060 ultraconserved elements (UCEs) to infer phylogenomic relationships among 42 representative ingroup gekkonine lizard taxa. We analyze multiple datasets of varying degrees of completeness (10, 50, 75, 95, and 100 percent complete with 4715, 4051, 3376, 2366, and 772 UCEs, respectively) using concatenated maximum likelihood and multispecies coalescent methods. Our sampling scheme addresses four persistent systematic questions in this group: (1) Are Luperosaurus and Ptychozoon monophyletic, and are any of these named species truly nested within Gekko? (2) Are prior phylogenetic estimates of Sulawesi's L. iskandari as the sister taxon to Melanesian G. vittatus supported by our genome-scale dataset? (3) Is the high-elevation L. gulat of Palawan Island correctly placed within Gekko? (4) And, finally, where do the enigmatic taxa P. rhacophorus and L. browni fall in a higher-level gekkonid phylogeny? We resolve these issues; confirm with strong support some previously inferred findings (placement of Ptychozoon taxa within Gekko; the sister taxon relationship between L. iskandari and G. vittatus); resolve the systematic position of unplaced taxa (L. gulat, and L. browni); and transfer L. iskandari, L. gulat, L. browni, and all members of the genus Ptychozoon to the genus Gekko. Our unexpected and novel systematic inference of the placement of Ptychozoon rhacophorus suggests that this species is not grouped with Ptychozoon or even Luperosaurus (as previously expected) but may, in fact, be most closely related to several Indochinese species of Gekko. With our resolved and strongly supported phylogeny, we present a new classification emphasizing the most inclusive, original generic name (Gekko) for these ~60 taxa, arranged into seven subgenera.