Psoriasis is a chronic immune-mediated inflammatory disease associated with systemic comorbidities, including gastrointestinal disorders. Emerging evidence supports a bidirectional gut-skin axis, with shared immunologic pathways involving the interleukin (IL)-23/IL-17 axis. Irritable bowel syndrome (IBS), traditionally considered a functional disorder, has also been linked to low-grade inflammation and cytokine dysregulation. We report a case of a 67-year-old man with moderate plaque and inverse psoriasis and longstanding IBS with diarrhea (IBS-D) who experienced complete resolution of gastrointestinal symptoms following treatment with risankizumab, an IL-23 inhibitor. Improvement in IBS symptoms began within weeks of therapy initiation and was sustained at follow-up, alongside complete skin clearance. No other changes in medications or lifestyle were identified. This case highlights a potential role of IL-23-mediated inflammation in IBS pathophysiology and suggests that targeted inhibition of the IL-23/IL-17 axis may benefit select patients with concurrent dermatologic and gastrointestinal disease.
Congenital melanocytic naevi (CMN) and arteriovenous malformations (AVM) are rare, severe and incurable birthmark conditions associated with lifelong visible difference and complex medical needs. Despite the importance of early health care experiences for parental and child adjustment in general, these remain unexplored in this context. This study aimed to explore parental experiences of raising a child with rare severe birthmarks, the role of specialist care in parental adjustment, and to develop recommendations for clinical care. Reflective thematic analysis (RTA) was used to analyse semi-structured narrative-style interviews conducted with 23 parents of children aged ≤12 years recruited sequentially from a specialized NHSE Rare Disease Collaborative Network (RDCN) outpatient clinic in London, UK. Interviews were conducted virtually via telephone or Zoom and analysed using RTA using NVivo software (version 13). Reflexivity was achieved through the keeping of a reflexive journal and debriefing with the research team. Through RTA, three themes were generated which highlight the challenges faced by parents of children with rare birthmarks. Firstly, parents' experiences before coming to the first appointment, secondly 'learning to belong' in the health care system and thirdly 'making room' for the condition. These themes and respective subthemes provide new insights into the importance of specialist centres in relation to parental adjustment to rare birthmarks. Findings underscore the pivotal role of specialist care in parental adjustment to rare, appearance-altering conditions. Practical care recommendations are presented to support families across care pathways.
Atopic dermatitis (AD) and alopecia areata (AA) are chronic immune-mediated disorders that frequently coexist in the same patient, an observation noted in both pediatric and adult populations. The clinical implications of a patient experiencing both disease states simultaneously underscores the need for a deeper understanding of pathophysiology of both disease states, how to optimally utilize specific therapeutic options to achieve synergistic outcomes, suggest simplified rational approaches to treatment selection, how to integrate care with other specialists when needed, and hopefully reach the ultimate goal of clinicians incorporating more personalized treatment selection through immunophenotype-guided therapy. This article , based primarily on emerging case reports and off-label data, reviews all the above implications when encountering a patient with both AD and AA. Continued research and real-world clinical evidence are needed in this important area that affects many individuals that clinicians encounter in their practice, including within the pediatric population.
In chronic myeloid leukemia in chronic phase (CML-CP), BCR::ABL1T315I commonly leads to treatment resistance, worse patient outcomes, and limited subsequent treatment options. By targeting the ABL1 myristoyl pocket, asciminib maintains activity against BCR::ABL1T315I. We report final long-term safety, tolerability, and efficacy results with asciminib in 48 patients with T315I-mutated CML-CP who received asciminib 200 mg twice daily in the phase 1, nonrandomized trial (NCT02081378). After a median exposure of 3.5 years, 52.1% of patients continued to receive asciminib via posttrial access. Of 45 evaluable patients, 24 (53.3%) achieved major molecular response (MMR); 20 of 24 maintained or deepened their response by the cutoff. The Kaplan-Meier estimated proportion of patients maintaining their first MMR for at least 144 weeks (2.8 years) was 86% (95% CI: 71.9-100.0%). The safety profile showed no new or worsening safety signals. With 1.4 years' additional exposure since the previous analysis, the incidence of grade ≥3 adverse events (AEs) (60.4%) did not increase. Four patients (8.3%) discontinued due to AEs. The exposure-adjusted incidence rate of first all-grade AOEs was 4.4 cases per 100 patient-years. With up to approximately 6 years of exposure, this final analysis confirms asciminib as a treatment option for patients with T315I-mutated CML-CP.
Apathy, defined as a significant and sustained reduction in goal-directed behavior associated with impaired daily functioning, is a common and clinically important syndrome in mild and major neurocognitive disorders (NCDs) and is associated with poorer outcomes for patients and carers. Despite growing research, important gaps in knowledge continue to hinder accurate recognition and effective treatment. This International Psychogeriatric Association (IPA) white paper summarizes key scientific and clinical insights from a multidisciplinary Apathy Task Force, with the aim of providing a narrative overview of current knowledge on nomenclature, biomarkers, treatments, and prevention, and of identifying gaps to inform global priorities in research and clinical care, and inform policy. The IPA convened a multidisciplinary task force of apathy researchers during the 2024 and 2025 IPA Congress meetings. Through structured discussions informed by targeted literature review, the group identified key themes and critical gaps across domains relevant to apathy in NCDs. Apathy is highly prevalent across NCDs and evidence demonstrates that it has substantial functional, emotional, and societal impact. Although diagnostic criteria have recently been refined, clinical identification remains challenging. Multiple scales exist to assess apathy, yet inconsistent use across settings and misalignment with updated diagnostic criteria limit comparability. Neuroimaging studies consistently implicate fronto-subcortical network involvement, but no reliable peripheral biomarkers have been established. While select non-pharmacological, pharmacological and neuromodulatory interventions show promising evidence, non-pharmacological are considered central to current management. Clinical guidelines and policy efforts remain limited despite the substantial burden of apathy. Emerging evidence highlights opportunities to improve diagnosis, deepen mechanistic understanding, and develop more treatments that are targeted and scalable. Key priorities identified include increasing awareness of and education around apathy, incorporating apathy into national dementia strategies, improving implementation of effective non-pharmacological interventions, and advancing the development of interventions and biomarkers aligned with contemporary diagnostic criteria. By integrating evidence across clinical, biological, and care domains, this white paper provides a structured framework to guide future research, clinical practice, and policy.
The molecular mechanisms by which mutant huntingtin (mHTT) drives pathogenesis in Huntington's disease (HD) remain incompletely defined. Here we show that neurogenesis is disrupted at multiple stages of lineage progression in both rodent and human neural stem cell (NSC) models of HD. We identify a previously unrecognized phenotype characterized by aberrant expansion of early multipotent progenitors coupled to a profound defect in astrogliogenesis, whereby HD astrocytes fail to express glial fibrillary acidic protein (GFAP). Mechanistically, this defect arises from dysregulation of an epigenetic regulatory axis involving EZH2 and LIN28 upregulation together with reduced expression of the mature let-7g microRNA. Epigenetic pharmacological interventions, targeting this pathway at distinct nodes-through EZH2 modulation, let-7g restoration, or LIN28 inhibition-rescued astroglial differentiation in human HD cells and improved motor function in a Drosophila HD model. Our findings suggest that mHTT might trigger a dual-phase astroglial failure: an early developmental impairment followed by a collapse of regenerative gliogenesis. This bimodal mechanism proposes astrocytic dysfunction as a central driver of HD pathogenesis. Finally, we identify a panel of clinically relevant epigenetic compounds that, by converging on distinct targets within this axis, hold promise for stage-spanning therapeutic strategies capable of modifying disease trajectory.
Melanoma has an excellent prognosis when detected at a localized stage, but when patients present with regional or distant metastases, 5-year survival decreases to approximately 76% and 35%, respectively. Although recent advances in systemic therapies have improved outcomes for patients with advanced melanoma, these treatments are often not curative, and many patients ultimately develop disease progression requiring subsequent lines of therapy. This study aimed to characterize real-world treatment patterns among patients in the USA with advanced cutaneous melanoma who transitioned from first-line (1L) to second-line (2L) systemic therapy. This retrospective, observational study used administrative claims data from a large US managed care database. Adult patients with metastatic melanoma who initiated 1L systemic therapy between January 2023 and December 2025 and subsequently received 2L therapy were included. Claims-based algorithms identified treatment regimens by line of therapy. Sankey diagrams illustrate treatment transitions overall and by BRAF V600 mutation status. Of 1772 patients who met study criteria, 680 (38.4%) were classified as presumed BRAF V600-mutated (BRAFmut) on the basis of treatment exposure, and 1092 (61.6%) were classified as presumed BRAF wild-type (BRAFwt). Immune checkpoint inhibitor (ICI)-based regimens were the most common first-line (1L) therapies (78.5%), while BRAF + MEK inhibitors accounted for 14.4%. In second-line (2L) therapy, sequencing patterns were diverse, with no dominant 2L pathway observed. BRAF + MEK inhibitors were the most frequently used 2L therapy (27.5%). In patients with BRAFmut, targeted therapy predominated in 2L (71.8%), whereas ICI-based regimens remained dominant in patients with BRAFwt (84.9%). 1L therapy was significantly associated with 2L treatment selection (p < 0.001). Treatment distributions differed across index years for both 1L (p = 0.001) and 2L (p = 0.005) therapies. Over time, use of PD-1 monotherapy decreased, while use of nivolumab plus ipilimumab increased; use of BRAF + MEK therapy remained stable. Although treatment practices for advanced melanoma continue to evolve in response to emerging clinical evidence, substantial uncertainty remains regarding optimal treatment sequencing after 1L progression. These findings highlight the need for prospective sequencing studies and more effective therapeutic options following disease progression.
Loneliness and social isolation are important public health concerns due to their associations with a range of health outcomes. However, it is difficult to ascertain whether any effects are biased by confounding and reverse causation. We use a triangulation approach combining observational, sibling control, and Mendelian Randomisation analyses (a genetically informed analysis), to draw robust conclusions about these relationships. Using a combination of UK Biobank data (N = 8,004 to 414,432) and genome-wide association studies (N = 17,526 to 2,083,151), we examine relationships between loneliness and social isolation and outcomes related to physical health, mental health and wellbeing and general health (e.g., multimorbidity capturing both mental and physical health). We find evidence for effects of loneliness and social isolation on poorer mental health and wellbeing and of loneliness on poorer general health. We do not find evidence of effects on specific physical health outcomes; however, these effects cannot definitively be ruled out.
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In a phase 2 trial (NCT04308681), treatment with admilparant (BMS-986278), an oral lysophosphatidic acid receptor 1 (LPA1) antagonist, reduced lung function decline in patients with idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). In this exploratory analysis, we evaluated post-treatment changes in circulating biomarkers of lung fibrosis to elucidate mechanisms of admilparant action. Patients with IPF or PPF were randomized 1:1:1 to receive twice-daily admilparant (30 or 60 mg) or placebo for 26 weeks; background antifibrotics were allowed. The IPF and PPF cohorts were analyzed separately. Changes from baseline (CfB) in serum proteins associated with epithelial injury, inflammation, and fibrosis were measured by quantitative immunoassays at 4, 12, and 26 weeks, and compared between patients who received admilparant versus placebo. Pharmacodynamic biomarker changes were evaluated by clinical response status at week 26. Plasma samples from patients with IPF were assessed post hoc by SomaScan v4.1 proteomics assay. Statistical evaluations used linear mixed-effects models. In the IPF cohort (n=276), nine serum proteins showed significant CfB (p<0.05) at week 26 in patients treated with 60-mg admilparant versus placebo, including increased adiponectin, MMIF, CD163, CEA, and ENRAGE, and decreased markers of epithelial injury and fibrosis (CA-125/MUC16, MMP-7, TN-C, PRO-FIB). In the PPF cohort (n=116), significant differences at week 26 (p<0.05) were observed for 11 serum proteins, including increased CEA and decreased periostin, IL6Rβ, CD163, KIM-1, multiple inflammatory markers (YKL-40, VCAM-1, PECAM-1, ferritin), and collagen degradation markers (C3M and C4M). Two serum proteins, CA-125 and TN-C, showed significantly greater CfB (p<0.05) in responders compared with non-responders in the IPF cohort. Plasma proteomic analysis identified differential expression (adjusted p<0.1) of adiponectin, CKMT1A, ANGPTL3, PDCD1LG2, and IGFBP6 at week 26 in patients with IPF treated with 60-mg admilparant versus placebo. Treatment with 60-mg admilparant improved circulating biomarkers associated with epithelial injury and fibrosis in IPF, and with inflammation, fibrosis, and collagen degradation in PPF. Proteomic analysis identified additional biomarkers associated with mitochondrial and metabolic pathways in IPF. These findings expand our understanding of potential mechanisms of LPA1 antagonism with admilparant and identify biomarkers that may help evaluate treatment response and disease activity.
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Modern biopharmaceutical manufacturing requires purification platforms capable of processing structurally and functionally diverse products while addressing the challenge of removing persistent and high-risk host cell proteins (HCPs). Current purification processes utilize adsorbents that operate in bind-and-elute mode, which limits productivity, and often struggle to remove critical impurities. Addressing these limitations, our team developed a flow-through pseudo-affinity chromatography platform that utilizes size-exclusion resins (Monomix Core 500) functionalized with mixed-mode peptide ligands (AviGuard) to remove process-related impurities while maximizing productivity and product integrity. This study evaluates this technology across three therapeutic modalities: two bi-specific monoclonal antibodies (bsAbs) and an Fc-fusion protein from Chinese hamster ovary (CHO) cell culture fluids, and adeno-associated virus serotypes 2 and 9 (AAV2 and AAV9) from HEK293 cell lysates. For the CHO-derived proteins, the platform comprised a pre-capture step with LigaGuard-Monomix Core 500 resin (LGMC500), a Protein A-based capture step, and a polishing step using a single-use size-exclusion mixed-mode (SEMM) resin. This configuration achieved global product yields exceeding 70%, final product pool concentration > 15 mg/mL, monomeric purity ~99%, and excellent cumulative HCP clearance (LRV > 4.5) to residual levels of 60-165 ng/mL (4-11 ppm). For AAV purification, the process utilized a mixed-bed adsorbent comprising dextran-coated charcoal and LGMC500 for removing HCPs, cell metabolites, and media components, followed by a capture step using either CaptureSelect AAVX resin or Natrix CH membranes. The optimization of the charcoal-to-resin volume ratio (1:3) and load volume (~ 1014 vp per mL of resin) yielded ~50% AAV recovery with a residual HCP level of 350 ng/mL, representing < 100 ng per dose, in compliance with regulatory guidelines. Process productivity ranged from 19 to 23 g/L·hr for CHO-derived proteins and ~7 × 1014 vp/L·hr for AAV9, positioning this technology in the optimal operating space for modern bioprocessing.
Cancer Variant Interpretation Group UK (CanVIG-UK) was established in 2017 in response to the publication of the 2015 American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) v3 guidance for the interpretation of sequence variants. Its initial purpose was to ensure consistency in the UK clinical-laboratory community implementation of ACMG/AMP v3 guidance for cancer susceptibility genes (CSGs). Still convening for monthly national meetings, the remit of CanVIG-UK now encompasses additional activities delivered under the following objectives: (1) creation of a national multidisciplinary professional network and regular forum, (2) delivery of training and education, (3) establishment of a consensus approach to the fundamentals of variant interpretation in CSGs, (4) development and ratification of gene-specific frameworks for variant interpretation for CSGs, (5) development and maintenance of an online platform to facilitate information sharing and variant interpretation within the UK clinical-laboratory community and (6) facilitation of UK contribution to international variant interpretation endeavours. A survey of CanVIG-UK members evaluating the impact of these activities conducted in November 2025 had 163 responses, including 113 clinical scientists/trainees and 27 Clinical Genetics consultants/trainees. The utility of the CanVIG-UK consensus recommendations for variant interpretation in CSGs was highly rated, with 89/145 (61.4%) of survey respondents reporting using the guidance at least weekly (≥4 times/month) and 124/128 (96.9%) rating it as extremely/very useful. The usage frequency and perceived utility reported for the gene-specific guidance by survey respondents were similar. Both qualitative and quantitative survey responses clearly demonstrate the value of the CanVIG-UK activities to the clinical-diagnostic community.
Parasitism has independently evolved hundreds of times among metazoans. Nonetheless, parasites have explored only a limited range of ecologies, and they display frequent convergence in morphological, behavioral, and life-history traits. Although gene loss in particular parasitic species has been documented, it is not known if gene loss converges along the same lines as these other traits. To test for convergent gene loss, we characterized the housekeeping, regulatory, and DNA-repair complements of 48 bilaterian species, including 20 parasites belonging to six different bilaterian phyla. We found that different parasitic strategies do not display characteristic tempos or modes of gene loss. Further, the accelerated rates of gene loss seen in some parasites were almost always shared with their free-living relatives, indicating that the increased rate of loss preceded the rise of parasitism. Therefore, the convergent ecological strategies and adaptations that have arisen in distantly related parasitic lineages overlay contingent gene losses which largely reflect their phylogenetic history. These results have important implications for how ecologists and evolutionary biologists should model the acquisition of parasitism, especially regarding the long-held assumption that reversion from a parasitic to a free-living state is impossible.
Mitral (MR) and tricuspid regurgitation (TR) are common valvular disorders that may progress over time. Atrial fibrillation (AF) affects atrial structure and may contribute to the progression of MR or TR. However, longitudinal data quantifying progression rates are limited. We aimed to assess MR and TR progression in patients with and without AF. A total of 412 patients with and without AF from the Swiss-AF and BEAT-AF cohorts between 2010 and 2023 were studied. MR and TR severity were graded using the first and last available transthoracic echocardiogram (TTE). The primary endpoint was any progression. Clinically relevant progression additionally required at least moderate severity on the second TTE. Multivariable logistic regression analyses were performed to examine the association between AF and progression of MR or TR. Median age at first TTE was 74 years (IQR: 69-81, 26% female). Incidence rates of any MR progression were 7.3 vs. 15.0 and of clinically relevant progression 3.3 vs. 3.9 per 100 person-years in AF vs. non-AF patients. For TR, incidence rates were 9.9 vs. 8.9 and 5.2 vs. 2.1 per 100 person-years, respectively. In multivariable analyses, AF was independently associated with both a higher likelihood of any TR progression and clinically relevant TR progression, but not with MR progression. AF was associated with higher rates of progression of TR severity, including clinically relevant progression. However, AF was not associated with higher rates of progression of MR.Clinical Trial Registration: clinicaltrial.gov, identifier NCT02105844.
Real-world evidence studies provide valuable information on clinical multi-kinase inhibitor (MKI) treatment approaches. Reported real-world (rw) progression-free-survival (rwPFS) and overall-survival (rwOS), and prognostic factors show considerable variability. We aimed to characterise clinicopathological features and identify prognostic factors of rwPFS and rwOS in patients with unresectable or metastatic radioactive iodine-refractory differentiated thyroid carcinoma (RAI-R DTC) treated with MKIs as part of routine clinical care across three medical centres in southeastern Spain. Multicentre retrospective observational study based on real-world data. We analysed rwPFS, rwOS, objective response rate (ORR), disease control rate (DCR), adverse events (AEs) and adjusted risk factors. Statistical analysis comprised descriptive statistics, Kaplan-Meier curves, log-rank tests and multivariable Cox regression. Cohort of 58 patients. Median age at DTC diagnosis was 62.0 years, at metastasis diagnosis 67 years, and 55.2% were female. First-line MKIs comprised mostly sorafenib 55.2%, and lenvatinib 34.5%. Median follow-up was 37.13 (0.49-165.82) months. Median rwPFS and rwOS were 32.66 and 55.66 months, respectively. ORR, DCR and AEs grade (3-4) rate were 41.2%, 88.2%, and 25.9%, respectively. Age ≥ 67 years at metastasis diagnosis, AEs grade (3-4), and objective response were independent factors significantly associated with improved rwPFS whereas neutrophil-to-lymphocyte ratio (NLR) ≥ 3.5 was independently associated with shorter rwPFS and, in adjusted analysis, with shorter rwOS. NLR ≥ 3.5 was independently associated with poorer rwPFS and, in adjusted analysis, with poorer rwOS, representing a low-cost candidate marker with potential utility to guide MKI therapy and patient selection that warrants prospective validation.
Small-cell lung cancer (SCLC) is an aggressive malignancy accounting for approximately 15% of all lung cancers, with over 70% of patients diagnosed at the extensive stage (ES). Phase III studies have shown significantly improved overall survival (OS) with the addition of PD-(L)1 inhibitors to platinum-based chemotherapy (CT), establishing chemoimmunotherapy (CIT) as the new first-line standard. This study investigates the real-world efficacy of CIT compared to alternative first-line regimens in patients with ES SCLC. In this retrospective study, we analyzed 904 patients with newly diagnosed ES SCLC treated at a specialized thoracic cancer center between 2010 and 2022. The primary endpoints were OS and progression-free survival (PFS). Secondary endpoints included the impact of baseline brain metastases (BM), brain and thoracic radiotherapy (RT), and immune-related adverse events (irAEs). CIT (n = 203) resulted in longer OS than both platinum-based CT (n = 530) and nonplatinum CT (n = 171; median OS 10.2 vs. 9.4 vs. 3.6 months, P < .001). PFS under CIT and platinum-based CT was significantly longer compared to nonplatinum CT (median PFS 5.3 vs. 5.6 vs. 2.6 months, P < .001). Compared to platinum-based CT, CIT significantly reduced the risk of death or progression (OS HR 0.73, 95% CI, 0.62-0.87; P < .001; PFS HR 0.79, 95% CI, 0.67-0.93; P = .006), whereas nonplatinum CT was associated with a 2x higher risk (OS HR 2.19, 95% CI, 1.84-2.61; PFS HR 2.28, 95% CI, 1.91-2.72; both P < .001). Thoracic RT was an independent predictor of longer survival across the entire cohort (OS HR 0.57, 95% CI, 0.48-0.69; P < .001 in multivariable analysis [MVA] including sex, age, ECOG performance status, type of systemic treatment, and presence of baseline BM). While the presence of BM at diagnosis was prognostically neutral, brain RT among patients with baseline BM was also associated with longer survival (OS HR 0.47, 95% CI, 0.35-0.65; P < .001 in MVA). Immune-related adverse events (iAEs) were associated with longer OS and PFS (OS HR 0.67, 95% CI, 0.46-0.97; P = .032; PFS HR 0.68, 95% 0.47-0.97; P = .035 in MVA), while treatment discontinuation due to irAEs did not compromise survival. Chemoimmunotherapy confers a clear OS advantage over conventional chemotherapy in real-world ES-SCLC. Local radiotherapy is associated with additional survival improvement, while the occurrence of irAEs may correlate with treatment efficacy.
β-thalassemia is a globally distributed hereditary red blood cell disorder. Up to now, clinical management of transfusion-dependent β-thalassemia (TDT) patients is still based on chronic transfusion combined with iron chelation therapy. Allogeneic hematopoietic cell transplantation potentially provides a cure, but few patients have an HLA-identical sibling, and optimal results are reported in patients ≤ 14 years. The European Hematology Association (EHA), through the EHA Scientific Working Group on Red Cells/Iron and the European Bone Marrow Transplantation (EBMT) group, has updated a 2021 EHA decision-making algorithm on evidence and expert consensus with the aim of identifying which patients with TDT could benefit from gene therapy (GT). Indeed, it is important to establish the patient setting for whom it is a priority, particularly in the early phase of real-world use outside experimental trials. Moreover, actual price, limited availability, and resource disposal constitute a further indication of a rational and progressive approach to this innovative treatment. In this expert consensus document, different clinical scenarios have been considered and analyzed for the possible impact on treatment outcome. This expert opinion provides dynamic, updatable, priority-based guidance for physicians taking care of TDT patients.
Transcatheter closure is becoming the standard of care for definitive closure of patent ductus arteriosus (PDA) in premature infants. To avoid risks associated with the transportation of a fragile neonate, the intervention can be performed as a bedside procedure within the neonatal intensive care unit, even in extremely low birth weight (ELBW) infants. Limited evidence-based guidelines are available for transcatheter PDA closure in premature infants in general and for bedside PDA closure specifically. This framework represents an expert consensus regarding bedside PDA closure in ELBW infants and guidance for procedural implementation. Recommendations for patient eligibility, pre-procedural planning, staff requirements, procedural aspects, imaging and follow-up and a stepwise implementation plan for a bedside PDA closure program are presented. IMPACT: Extremely low birth weight (ELBW) infants with a patent ductus arteriosus (PDA) may be considered for transcatheter PDA closure. An expert consensus is provided on bedside transcatheter PDA closure performed within the neonatology intensive care unit, thereby mitigating the risks associated with transportation of these highly vulnerable infants outside of the neonatology intensive care unit. Guidance is provided regarding procedural aspects, including staff requirements, planning, setting, and imaging, and implementation of a bedside transcatheter PDA closure program.
Teeth define mammalian evolution, and one of many adaptive dental breakthroughs in crown mammals is the tribosphenic molar: a tooth with a dual shearing-crushing function, often considered a key adaptation in crown mammals. However, we do not know how potential trade-offs between these antagonistic functions may influence the macroevolutionary outcomes of mammalian lineages. Here, we show that predatory mammals evolved dichotomized performance in their tribosphenic carnassial teeth, with slicing constrained to a narrow set of optimal phenotypes and crushing exhibiting redundant solutions. Less than 1% of predators evolved optimized shearing and crushing. The fundamental trade-off in functions of the tribosphenic architecture promoted divergent macroevolutionary specializations rather than functional duality. These results highlight how key innovations can drive early evolutionary success while simultaneously constraining subsequent diversification.