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Objective: Melphalan flufenamide (melflufen) plus dexamethasone is fully approved in Europe for patients with relapsed/refractory multiple myeloma (RRMM) with ≥ 3 prior lines of therapy. We analyzed the efficacy and safety of melflufen in the real-world setting., Methods: In this retrospective analysis, we examined baseline features, efficacy, and safety outcomes with melflufen plus dexamethasone in a cohort of 12 patients with heavily pre-treated RRMM at the Dana-Farber Cancer Institute, USA., Results: Patients had received a median of 5.5 prior lines of therapy. Three patients (25%) had extramedullary disease, three (25%) cytogenetically high-risk features, and five (42%) had received prior autologous stem cell transplantation. The overall response rate was 55% (complete response: three [27%], very good partial response: one [9%], partial response: two [18%] patients). Five patients (42%) had stable disease; one was non-evaluable. Adverse events (AEs) were mostly hematologic and proved manageable; two patients had Grade 2 infections. Reasons for melflufen discontinuation were progressive disease (42%), drug withdrawal from the United States market (33%), AEs (17%), and sudden death (8%) unrelated to treatment., Conclusions: Consistent with clinical trial data, melflufen had an expected safety profile with manageable toxicity and clinically meaningful efficacy in patients with RRMM treated in the real-world setting., (© 2025 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Objective: To analyze the approach to cardiovascular care and long-term outcomes in infants undergoing hypothermia for neonatal encephalopathy (NE)., Study Design: This is a retrospective cohort study of 152 infants with NE [SickKids Hospital (Center A, n = 74) or Semmelweis University (Center B, n = 78)], who developed hypotension and underwent neonatal follow-up. Primary outcome was defined as death or neurodevelopmental impairment (<70 on Bayley-II or <85 points on Bayley-III test)., Result: The presence of hypoxic injury in the brain MRI increased the odds of adverse outcome by 10.5 fold. In addition, for every 24 h increase in the duration of cardiovascular support the odds of adverse outcome increased by 12%. In a subgroup of patients with detailed echocardiography evaluation lower tricuspid annulus plane systolic excursion was noted in the non-survivors., Conclusion: Hypoxic brain injury and longer cardiovascular therapy are independently associated with the adverse long-term outcome in patients with NE., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Rationale: The impact of respiratory exacerbation on chronic obstructive pulmonary disease (COPD) is well established. The effects of respiratory exacerbations in people with cigarette smoking but normal spirometry are unknown., Objective: To assess the association of respiratory exacerbations with lung function decline and mortality in people with normal spirometry and current or former cigarette smoking history., Methods: We analyzed data from COPDGene participants with ≥10 pack-years cigarette smoking and normal spirometry at enrollment (Visit 1) defined as post-bronchodilator forced expiratory volume in 1 second (FEV 1 )/forced vital capacity (FVC) ≥lower limit of normal (LLN) and FEV 1 ≥LLN. We examined whether respiratory exacerbations occurring between Visits 1 and the 5-year follow-up visit (Visit 2) were associated with FEV 1 decline, and all-cause mortality., Measurements and Main Results: Among 2,939 participants with cigarette smoking history and normal lung function at Visit 1, each additional exacerbation between visit 1 and 2 was associated with a 2.96 ml/year FEV 1 decline (95%CI 1.81 to 4.12; P<0.001) at Visit 2. Experiencing ≥1 severe exacerbation between Visits 1 and 2 was associated with 14.6 ml/year FEV 1 decline relative to those with no severe exacerbations (95% CI 8.56 to 20.6; P<0.001). Individuals with ≥1 severe exacerbation between Visits 1 and 2 had increased mortality compared to those with no severe exacerbations (17.1% vs. 9.8%; adjusted hazard ratio 1.97;95% CI 1.40 to 2.77; P<0.001)., Conclusions: Respiratory exacerbations in people with cigarette smoking but normal spirometry were associated lung function decline. Experiencing a severe respiratory exacerbation was associated with increased mortality.

Classically, pyramidal cells of the hippocampus are viewed as flexibly representing spatial and non-spatial information. Recent work has illustrated distinct types of hippocampal excitatory neurons, suggesting that hippocampal representations and functions may be constrained and interpreted by these underlying cell-type identities. In mice, here we reveal a non-pyramidal excitatory neuron type - the "ovoid" neuron - that is spatially adjacent to subiculum pyramidal cells but differs in gene expression, electrophysiology, morphology, and connectivity. Functionally, novel object encounters drive sustained ovoid neuron activity, whereas familiar objects fail to drive activity even months after single-trial learning. Silencing ovoid neurons prevents non-spatial object learning but leaves spatial learning intact, and activating ovoid neurons toggles novel-object seeking to familiar-object seeking. Such function is doubly dissociable from pyramidal neurons, wherein manipulation of pyramidal cells affects spatial assays but not non-spatial learning. Ovoid neurons of the subiculum thus illustrate selective cell-type-specific control of non-spatial memory and behavioral preference., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Juniperus spp. are keystone shrubs in western North America and important climatic indicators in paleo-records. However, a lack of taxonomic resolution among fossil species limits our ability to track past environmental changes. Plant macrofossils at Rancho La Brea (RLB) allow for reconstructions of juniper occurrence to species across 60 000 yr. We use microscopy, image analysis, species distribution modeling (SDM), and radiocarbon dating to identify an unknown Juniperus species at RLB and put it into chronological context with fossil Juniperus californica at the site to infer past environmental conditions. We identify the unknown taxon as Juniperus scopulorum Sargent, 1897. The Pleistocene occurrence of this species in California expands its known distribution and documents its extirpation. Temporal ranges of the two fossil junipers alternate, revealing a pattern of differential climatic sensitivity throughout the end of the Pleistocene. Occurrence patterns suggest sensitivity to temperature, moisture availability, and the presence of two mega-droughts at c. 48-44.5 ka and c. 29.3-25.2 ka. Extirpation of both taxa by c. 13 ka is likely driven by climate, megafaunal extinction, and increasing fire. The extirpation of fossil junipers during these past climatic events demonstrates vulnerability of juniper species in the face of global change., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Background and Aims: Anti-tumor necrosis factor (anti-TNF) therapies are commonly prescribed treatments for Crohn's disease (CD) and ulcerative colitis (UC). Many patients treated with anti-TNF therapy eventually develop anti-drug antibodies (ADAs). Understanding the factors associated with immunogenicity in anti-TNF-treated patients can help guide treatment. The Humira SERENE studies were Phase 3 trials investigating adalimumab induction regimens in CD and UC patients., Methods: We imputed alleles for 7 HLA genes in 1100 patients from the SERENE CD and SERENE UC trials. We then tested these alleles for association with time to immunogenicity. Subsequently, we tested loci significantly associated with immunogenicity for their association with patients who had consistently low drug serum concentrations., Results: This study replicated the association of HLA-DQA1*05 with time to immunogenicity (hazard ratio [HR] 1.42, p = 2.22E-06). Specifically, HLA-DQA1*05:05 was strongly associated (HR 1.76, p = 2.02E-10) and we detected a novel association represented by HLA-DRB1*01:02 (HR 3.16, p = 2.92E-07). Carriage of HLA-DQA1*05:05 and HLA-DRB1*01:02 was associated with patients who experienced consistently low adalimumab trough concentrations (HLA-DQA1*05:05: odds ratio [OR] 1.98, p = 0.0049; HLA DRB1*01:02: OR 7.06, p = 7.44E-05)., Conclusions: We found a significant association between alleles at genes in the human HLA locus and the formation of adalimumab immunogenicity and low adalimumab drug serum concentrations in large clinical studies of CD and UC patients. This work extends previous findings in CD to UC and directly shows a genetic association in patients with low drug concentrations. This work builds on existing literature to suggest that genetic screening could be a useful tool for clinicians concerned with patient anti-TNF immunogenicity., Clinical Trial Registration Numbers: SERENE CD (NCT02065570), SERENE UC (NCT02065622)., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Objective: To investigate the current state of clinical practice and training regarding the use of cardiac point of care ultrasound (cPOCUS) in neonatal intensive care units., Study Design: An online survey was disseminated through the Association of Academic Directors of Neonatology to appraise clinical usage, infrastructure, and training for cPOCUS. A single response per center was obtained., Results: Overall survey response rate was 51% (48/94). Of respondents [40/48 (83%)] who reported having a POCUS program, 19/40 (47%) reported performing cPOCUS. In 74% of centers, <10 cPOCUS studies are performed monthly. Only 16% (3/19) of centers had standardized imaging protocols. The most common indication for cPOCUS was central line evaluation. Only 9 (19%) programs reported cPOCUS training, of whom 4 had a formalized process of ongoing competency assessment., Conclusion: Although use of cPOCUS is increasing, program infrastructure and governance, training, and evaluation vary markedly between institutions and are missing in many. There is an urgent need to develop consensus standards regarding clinical practice and training., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: To compare the prevalence of physical morbidities between older aged patients with bipolar disorder (OABD) and non-psychiatric comparisons (NC), and to analyze sex differences in prevalence., Methods: OABD was defined as bipolar disorder among adults aged ≥50 years. Outcomes analyzed were the prevalence of diseases affecting the cardiovascular, respiratory, gastrointestinal, genitourinary, renal, musculoskeletal, and endocrine systems. The analysis used cross-sectional data of OABD participants (n = 878; mean age 60.9 ± 8.0 years, n = 496 (56%) women) from the collaborative Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) dataset and NC participants recruited at the same sites (n = 355; mean age 64.4 ± 9.7 years, n = 215 (61%) women)., Results: After controlling for sex, age, education, and smoking history, the OABD group had more cardiovascular (odds ratio [95% confidence interval]: 2.12 [1.38-3.30]), renal (5.97 [1.31-43.16]), musculoskeletal (2.09 [1.30-3.43]) and endocrine (1.90 [1.20-3.05]) diseases than NC. Women with OABD had more gastrointestinal (1.56 [0.99-2.49]), genitourinary (1.72 [1.02-2.92]), musculoskeletal (2.64 [1.66-4.37]) and endocrine (1.71 [1.08-2.73]) comorbidities than men with OABD, when age, education, smoking history, and study site were controlled., Conclusions: This replication GAGE-BD study confirms previous findings indicating that OABD present more physical morbidities than matched comparison participants, and that this health burden is significantly greater among women., Competing Interests: Declaration of competing interest VB-M has received honoraria from Angelini, unrelated to the present work. JBL has received grant funding from NIH, AHA, and Merck. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Johnson & Johnson, Lundbeck, Medincell, Merck, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Low muscle mass is associated with numerous adverse outcomes independent of other associated comorbid diseases. We aimed to predict and understand an individual's risk for developing low muscle mass using proteomics and machine learning. We identified eight biomarkers associated with low pectoralis muscle area (PMA). We built three random forest classification models that used either clinical measures, feature selected biomarkers, or both to predict development of low PMA. The area under the receiver operating characteristic curve for each model was: clinical-only = 0.646, biomarker-only = 0.740, and combined = 0.744. We displayed the heterogenetic nature of an individual's risk for developing low PMA and identified two distinct subtypes of participants who developed low PMA. While additional validation is required, our methods for identifying and understanding individual and group risk for low muscle mass could be used to enable developments in the personalized prevention of low muscle mass., (© 2024. The Author(s).)

Background: Treatment resistant depression (TRD) is a subset of major depressive disorder (MDD) in which symptoms do not respond to front line therapies. In older adults, the assessment and treatment of TRD is complicated by psychosocial risk factors unique to this population, as well as a relative paucity of research., Methods: Narrative review aimed at (1) defining TRLLD for clinical practice and research; (2) describing psychosocial risk factors; (3) reviewing psychological and non-pharmacological treatments; (4) discussing the role of clinical phenotyping for personalized treatment; and (5) outlining research priorities., Results: Our definition of TRLLD centers on response to medication and neuromodulation in primary depressive disorders. Psychosocial risk factors include trauma and early life adversity, chronic physical illness, social isolation, personality, and barriers to care. Promising non-pharmacological treatments include cognitive training, psychotherapy, and lifestyle interventions. The utility of clinical phenotyping is highlighted by studies examining the impact of comorbidities, symptom dimensions (e.g., apathy), and structural/functional brain changes., Limitations: There is a relative paucity of TRLLD research. This limits the scope of empirical data from which to derive reliable patterns and complicates efforts to evaluate the literature quantitatively., Conclusions: TRLLD is a complex disorder that demands further investigation given our aging population. While this review highlights the promising breadth of TRLLD research to date, more research is needed to help elucidate, for example, the optimal timing for implementing risk mitigation strategies, the value of collaborative care approaches, specific treatment components associated with more robust response, and phenotyping to help inform treatment decisions., Competing Interests: Declaration of competing interest Regan E. Patrick, PhD: Partial salary support from NIH/NIA, Rogers Family Foundation, and Biogen, Inc. Rebecca A. Dickinson, BSc, BA: No disclosures or conflicts. Melanie T. Gentry, MD: No disclosures or conflicts. Joseph U. Kim, PhD: No disclosures or conflicts. Lauren E. Oberlin, PhD: No disclosures or conflicts. Soohyun Park, PhD: Grant support from Pope-Hintz Fellowship (Hintz Family Foundation) and Alzheimer's Association Research Fellowship. Jessica L. Principe, MD, MS: No disclosures or conflicts. Antonio L. Teixeira, MD, PhD: No disclosures or conflicts. Sara L. Weisenbach, PhD: NIH grant support as PI (R01MH116033); ADHD Expert Consortium Member for Qbtech., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Hemodynamically significant patent ductus arteriosus (hsPDA) shunt may predispose infants to retinopathy of prematurity (ROP) because of its higher preductal cardiac output and blood oxygen content, which may augment ocular oxygen delivery., Methods: A retrospective cohort study of preterm infants, born at <27 weeks' gestation and admitted at <24h postnatal age to a large quaternary referral was conducted. The primary composite outcome was death at <32 weeks or moderate-to-severe ROP (≥stage 2 or requiring treatment) in either eye. Secondary outcomes included ROP requiring treatment, and any ROP. Univariate analysis of patient characteristics and outcomes was performed as well as logistic regression. A receiver operating characteristics curve was generated for the outcome of ROP ≥stage 2 or requiring treatment., Results: A total of 91 patients were screened, of whom 86 (54 hsPDA, 32 controls) were eligible for inclusion. hsPDA patients were younger and lighter at birth and had a higher burden of hyperglycemia and respiratory illness. The rates of the composite outcome (death <32 weeks or moderate-to-severe ROP) and of any ROP were more frequent in the hsPDA group. hsPDA shunt exposure was independently associated with development of any ROP among survivors to assessment (P = 0.006). PDA cumulative exposure score of 78 (clinical equivalent = 7 days high-volume shunt exposure) predicts moderate-to-severe ROP with 80% sensitivity and 78% specificity., Conclusions: Among infants <27 weeks, hsPDA shunt is associated with increased risks of a composite outcome of death or moderate-to-severe ROP, as well as ROP of any stage. Shunt modulation as a strategy to reduce ROP represents a biologically plausible avenue for investigation., (Copyright © 2024 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Objective: To develop an individualized method for detecting cognitive adverse events (CAEs) in the context of an ongoing trial of electroconvulsive therapy for refractory agitation and aggression for advanced dementia (ECT-AD study)., Methods: Literature search aimed at identifying (a) cognitive measures appropriate for patients with advanced dementia, (b) functional scales to use as a proxy for cognitive status in patients with floor effects on baseline cognitive testing, and (c) statistical approaches for defining a CAE, to develop CAEs monitoring plan specifically for the ECT-AD study., Results: Using the Severe Impairment Battery-8 (SIB-8), baseline floor effects are defined as a score of ≤5/16. For patients without floor effects, a decline of ≥6 points is considered a CAE. For patients with floor effects, a decline of ≥30 points from baseline on the Barthel Index is considered a CAE. These values were derived using the standard deviation index (SDI) approach to measuring reliable change., Conclusions: The proposed plan accounts for practical and statistical challenges in detecting CAEs in patients with advanced dementia. While this protocol was developed in the context of the ECT-AD study, the general approach can potentially be applied to other interventional neuropsychiatric studies that carry the risk of CAEs in patients with advanced dementia., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Transition metal dichalcogenide-based moiré superlattices exhibit strong electron-electron correlations, thus giving rise to strongly correlated quantum phenomena such as generalized Wigner crystal states. Evidence of Wigner crystals in transition metal dichalcogenide moire superlattices has been widely reported from various optical spectroscopy and electrical conductivity measurements, while their microscopic nature has been limited to the basic lattice structure. Theoretical studies predict that unusual quasiparticle excitations across the correlated gap between upper and lower Hubbard bands can arise due to long-range Coulomb interactions in generalized Wigner crystal states. However, the microscopic proof of such quasiparticle excitations is challenging because of the low excitation energy of the Wigner crystal. Here we describe a scanning single-electron charging spectroscopy technique with nanometre spatial resolution and single-electron charge resolution that enables us to directly image electron and hole wavefunctions and to determine the thermodynamic gap of generalized Wigner crystal states in twisted WS 2 moiré heterostructures. High-resolution scanning single-electron charging spectroscopy combines scanning tunnelling microscopy with a monolayer graphene sensing layer, thus enabling the generation of individual electron and hole quasiparticles in generalized Wigner crystals. We show that electron and hole quasiparticles have complementary wavefunction distributions and that thermodynamic gaps of ∼50 meV exist for the 1/3 and 2/3 generalized Wigner crystal states in twisted WS 2 ., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The competitive success of ferns has been foundational to hypotheses about terrestrial recolonization following biotic upheaval, from wildfires to the Cretaceous-Paleogene asteroid impact (66 million years ago). Rapid fern recolonization in primary successional environments has been hypothesized to be driven by ferns' high spore production and wind dispersal, with an emphasis on their competitive advantages as so-called disaster taxa. We propose that a competition-based view of ferns is outdated and in need of reexamination in light of growing research documenting the importance of positive interactions (i.e., facilitation) between ferns and other species. Here, we integrate fossil and modern perspectives on fern ecology to propose that ferns act as facilitators of community assemblage following biotic upheaval by stabilizing substrates, enhancing soil properties, and mediating competition. Our reframing of ferns as facilitators has broad implications for both community ecology and ecosystem recovery dynamics, because of ferns' global distribution and habitat diversity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Institute of Biological Sciences.)

Low muscle mass is associated with numerous adverse outcomes independent of other associated comorbid diseases. We aimed to predict and understand an individual's risk for developing low muscle mass using proteomics and machine learning. We identified 8 biomarkers associated with low pectoralis muscle area (PMA). We built 3 random forest classification models that used either clinical measures, feature selected biomarkers, or both to predict development of low PMA. The area under the receiver operating characteristic curve for each model was: clinical-only = 0.646, biomarker-only = 0.740, and combined = 0.744. We displayed the heterogenetic nature of an individual's risk for developing low PMA and identified 2 distinct subtypes of participants who developed low PMA. While additional validation is required, our methods for identifying and understanding individual and group risk for low muscle mass could be used to enable developments in the personalized prevention of low muscle mass., Competing Interests: Competing interests Mr. Enzer reports no conflicts of interest. Dr. Mason reports employment by Sarepta Therapeutics, outside of this current work, and grant funding from the National Institutes of Health (NIH), related to this current work. Dr. Chiles reports grant funding from the NIH. Dr. McDonald reports no conflicts of interest. Dr. Shirahata reports no conflicts of interest. Ms. Yuan reports no conflicts of interest. Mr. Castro reports no conflicts of interest. Dr. Choi reports consulting fees from Quantitative Imaging Solutions, outside of this current work. Dr. Diaz reports no conflicts of interest. Dr Washko reports ownership/dividend from Quantitative Imaging Solutions, outside of this current work. Dr. Estepar reports ownership/dividend from Quantitative Imaging Solutions, outside of this current work. Dr. Ash reports ownership/dividend from Quantitative Imaging Solutions, outside of this current work, and grant funding from the National Institutes of Health (NIH), related to this current work.

Objective: To assess clinical and echocardiography predictors of acetaminophen response for the treatment of patent ductus arteriosus (PDA) in preterm neonates., Study Design: Retrospective cohort study of preterm infants born <30 weeks, with a diagnosis of hemodynamically significant PDA, who received 1 st line treatment with intravenous acetaminophen during the first 2 postnatal weeks. Response was defined by PDA closure or improvement in PDA score of >50%., Results: A total of 100 infants were included whose median weight and gestational age at birth were 663 grams and 24.6 weeks respectively. In total, 66 infants were classified as responders and were more likely to have intrauterine growth restriction, exposure to maternal hypertension and chorioamnionitis. Non-response was more common among infants with thrombocytopenia and anemia., Conclusion: Responders were more likely to be IUGR with echocardiography indices of lower preload. Response to 1 st line intravenous acetaminophen therapy is comparable to non-steroidal drugs in preterm infants. Relationship of response to acetaminophen to perinatal characteristics requires further characterization., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: The Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project pools archival datasets on older age bipolar disorder (OABD). An initial Wave 1 (W1; n = 1369) analysis found both manic and depressive symptoms reduced among older patients. To replicate this finding, we gathered an independent Wave 2 (W2; n = 1232, mean ± standard deviation age 47.2 ± 13.5, 65% women, 49% aged over 50) dataset., Design/methods: Using mixed models with random effects for cohort, we examined associations between BD symptoms, somatic burden and age and the contribution of these to functioning in W2 and the combined W1 + W2 sample (n = 2601)., Results: Compared to W1, the W2 sample was younger (p < 0.001), less educated (p < 0.001), more symptomatic (p < 0.001), lower functioning (p < 0.001) and had fewer somatic conditions (p < 0.001). In the full W2, older individuals had reduced manic symptom severity, but age was not associated with depression severity. Age was not associated with functioning in W2. More severe BD symptoms (mania p ≤ 0.001, depression p ≤ 0.001) were associated with worse functioning. Older age was significantly associated with higher somatic burden in the W2 and the W1 + W2 samples, but this burden was not associated with poorer functioning., Conclusions: In a large, independent sample, older age was associated with less severe mania and more somatic burden (consistent with previous findings), but there was no association of depression with age (different from previous findings). Similar to previous findings, worse BD symptom severity was associated with worse functioning, emphasizing the need for symptom relief in OABD to promote better functioning., (© 2024 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Objectives: To characterize pulmonary artery Doppler flow profile (PAFP) patterns among infants receiving care in neonatal intensive care units and to examine the association of PAFP patterns with pulmonary and right ventricular (RV) hemodynamics., Study Design: This is a retrospective study at 2 tertiary intensive care units over 4 years that included neonates who demonstrated a complete tricuspid regurgitation envelope on targeted neonatal echocardiography. Separate personnel reviewed TNEs to characterize PAFP patterns, divide cohort into PAFP groups, and measure quantitative indices of RV hemodynamics (RV systolic pressure, pulmonary artery acceleration time and its ratio with RV ejection time, tricuspid annular plane systolic excursion, and RV output), for intergroup comparisons., Results: We evaluated TNEs from 186 neonates with median gestational age of 28.5 weeks (IQR, 25.9-35.9 weeks). Four distinct PAFP patterns were identified (A) near-isosceles triangle (22%), (B) right-angled triangle (29%), (C) notching (40%), and (D) low peak velocity (<0.4 m/s; 9%). Groups A-C demonstrated a stepwise worsening in all indices of PH, whereas pattern D was associated with lower tricuspid annular plane systolic excursion and RV output. Using common definitions of pulmonary hypertension (PH), pattern A performed best to rule out PH (sensitivity range, 81%-90%) and pattern C for diagnosing PH (specificity range, 63%-78%)., Conclusions: Inspection of PAFP is a simple bedside echocardiography measure that provides clinically meaningful information on underlying RV hemodynamics and may aid in screening and monitoring of patients for PH in intensive care units., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest. This project is conducted as a part of AJ's “Improving Management of Pulmonary hypertension and Right heart function In NeonaTes (IMPRINT)” research program, supported by funding from the Heart & Stroke Foundation of Canada (HSFC)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Premise: Leaf epidermal cell morphology is closely tied to the evolutionary history of plants and their growth environments and is therefore of interest to many plant biologists. However, cell measurement can be time consuming and restrictive with current methods. CuticleTrace is a suite of Fiji and R-based functions that streamlines and automates the segmentation and measurement of epidermal pavement cells across a wide range of cell morphologies and image qualities., Methods and Results: We evaluated CuticleTrace-generated measurements against those from alternate automated methods and expert and undergraduate hand tracings across a taxonomically diverse 50-image data set of variable image qualities. We observed ~93% statistical agreement between CuticleTrace and expert hand-traced measurements, outperforming alternate methods., Conclusions: CuticleTrace is a broadly applicable, modular, and customizable tool that integrates data visualization and cell shape measurement with image segmentation, lowering the barrier to high-throughput studies of epidermal morphology by vastly decreasing the labor investment required to generate high-quality cell shape data sets., (© 2024 The Authors. Applications in Plant Sciences published by Wiley Periodicals LLC on behalf of Botanical Society of America.)

Background: The survival of smaller and more immature premature infants has been associated with lifelong cardiorespiratory comorbidities. Infants with bronchopulmonary dysplasia (BPD) undergo routine screening echocardiography to evaluate for development of chronic pulmonary hypertension, a late manifestation of pulmonary vascular disease., Methods: Our aim was to evaluate left ventricular (LV) performance in infants with BPD and pulmonary vascular disease who developed systemic hypertension. We hypothesized that infants with hypertension were more likely to have impaired LV performance. We present a single-center cross-sectional study of premature infants born at less than 28 0/7 weeks' gestational age with a clinical diagnosis of BPD. Infants were categorized by the systolic arterial pressure (SAP) at time of echocardiography as hypertensive (SAP ≥90 mm Hg) or normotensive (SAP <90 mm Hg). Sixty-four patients were included., Results: Infants with hypertension showed altered LV diastolic function with prolonged tissue Doppler imaging-derived isovolumic relaxation time (54.2 ± 5.1 vs 42.9 ± 8.2, P < .001), lower E:A, and higher E:e'. Indices of left heart volume/pressure loading (left atrium:aorta and LV end-diastolic volume [6.1 ± 2 vs 4.2 ± 1.2, P < .001]) were also higher in the hypertensive group. Finally, infants in the hypertensive group had higher pulmonary vascular resistance index (4.42 ± 1.1 vs 3.69 ± 0.8, P = .004)., Conclusions: We conclude that extremely preterm infants with BPD who develop systemic hypertension are at risk of abnormal LV diastolic dysfunction. Increased pulmonary vascular resistance index in the hypertensive group may relate to pulmonary venous hypertension secondary to LV dysfunction. This is an important consideration in this cohort when selecting the physiologically most appropriate treatment., (Copyright © 2023 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Emotion regulation (ER), or the ability to modulate the experience and expression of emotion, is critical to adaptive functioning and is a key feature of mood disorders. At the same time, normal aging is associated with changes in ER, though the interaction of aging with the presence of a mood disorder are unclear. Here, we review what is known about ER and its underlying neural mechanisms in late life mood disorders, specifically late life depression and bipolar disorder. We also review behavioral and neuromodulation therapies that seek to reduce negative affect and improve positive affect. We conclude with recommendations for future research into the nature and mechanisms of ER and interventions targeting ER in older adults with mood disorders., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Coupled two-dimensional electron-hole bilayers provide a unique platform to study strongly correlated Bose-Fermi mixtures in condensed matter. Electrons and holes in spatially separated layers can bind to form interlayer excitons, composite Bosons expected to support high-temperature exciton condensates. The interlayer excitons can also interact strongly with excess charge carriers when electron and hole densities are unequal. Here, we use optical spectroscopy to quantitatively probe the local thermodynamic properties of strongly correlated electron-hole fluids in MoSe 2 /hBN/WSe 2 heterostructures. We observe a discontinuity in the electron and hole chemical potentials at matched electron and hole densities, a definitive signature of an excitonic insulator ground state. The excitonic insulator is stable up to a Mott density of ~0.8 × 10 12 cm -2 and has a thermal ionization temperature of ~70 K. The density dependence of the electron, hole, and exciton chemical potentials reveals strong correlation effects across the phase diagram. Compared with a non-interacting uniform charge distribution, the correlation effects lead to significant attractive exciton-exciton and exciton-charge interactions in the electron-hole fluid. Our work highlights the unique quantum behavior that can emerge in strongly correlated electron-hole systems., (© 2023. The Author(s).)

Objective: The current literature on employment in older adults with bipolar disorder (OABD) is limited. Using the Global Aging and Geriatric Experiments in Bipolar Disorder Database (GAGE-BD), we examined the relationship of occupational status in OABD to other demographic and clinical characteristics., Methods: Seven hundred and thirty-eight participants from 11 international samples with data on educational level and occupational status were included. Employment status was dichotomized as employed versus unemployed. Generalized linear mixed models with random intercepts for the study cohort were used to examine the relationship between baseline characteristics and employment. Predictors in the models included baseline demographics, education, psychiatric symptom severity, psychiatric comorbidity, somatic comorbidity, and prior psychiatric hospitalizations., Results: In the sample, 23.6% (n = 174) were employed, while 76.4% were unemployed (n = 564). In multivariable logistic regression models, less education, older age, a history of both anxiety and substance/alcohol use disorders, more prior psychiatric hospitalizations, and higher levels of BD depression severity were associated with greater odds of unemployment. In the subsample of individuals less than 65 years of age, findings were similar. No significant association between manic symptoms, gender, age of onset, or employment status was observed., Conclusion: Results suggest an association between educational level, age, psychiatric severity and comorbidity in relation to employment in OABD. Implications include the need for management of psychiatric symptoms and comorbidity across the lifespan, as well as improving educational access for people with BD and skills training or other support for those with work-life breaks to re-enter employment and optimize the overall outcome., (© 2023 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Purpose: Lip prints are unique and have potential for use as a human identifier. The purpose of this study was to observe possible cheiloscopy differences of individuals with and without parafunctional oral habits such as smoking, vaping, playing a wind instrument or using an asthma inhaler., Methods: This IRB approved blinded cross-sectional observation pilot study collected lip prints from 66 individuals, three of which were excluded. Participants cleansed their lips, then lipstick was applied to the vermillion zones of the upper and lower lips. Adhesive tape was applied to the lips and prints were transferred to white bond paper for viewing purposes. Each set of included lip prints was divided into quadrants and dichotomized into a group of those with an oral parafunctional habit or with no such habits. Each quadrant sample was then manually analysed and classed according to the gold standard Suzuki and Tsuchihashi system., Results: A total of 252 dichotomized lip print quadrants (with habits n = 76, 30.2%, and without habits n = 176, 69.8%) were analysed. Type II patterns were the most common for examined quadrant samples; however, no statistically significant differences (Pearson's chi-squared test, p = 0.366) were observed between pattern classifications of samples with and without parafunctional oral habits., Conclusions: There is no statistically significant difference of lip print patterns between individuals with and without parafunctional oral habits. Further research on populational variations is needed for cheiloscopy to aid in human identifications., (© 2023 The Authors. International Journal of Dental Hygiene published by John Wiley & Sons Ltd.)

Background: People with coronary heart disease are at an increased risk of morbidity and mortality even if they attend cardiac rehabilitation. High sedentary behavior levels potentially contribute to this morbidity. Smartphone apps may be feasible to facilitate sedentary behavior reductions and lead to reduced health care use., Objective: We aimed to test the effect of a sedentary behavior change smartphone app (Vire app and ToDo-CR program) as an adjunct to cardiac rehabilitation on hospital admissions and emergency department (ED) presentations over 12 months., Methods: A multicenter, randomized controlled trial was conducted with 120 participants recruited from 3 cardiac rehabilitation programs. Participants were randomized 1:1 to cardiac rehabilitation plus the fully automated 6-month Vire app and ToDo-CR program (intervention) or usual care (control). The primary outcome was nonelective hospital admissions and ED presentations over 12 months. Secondary outcomes including accelerometer-measured sedentary behavior, BMI, waist circumference, and quality of life were recorded at baseline and 6 and 12 months. Logistic regression models were used to analyze the primary outcome, and linear mixed-effects models were used to analyze secondary outcomes. Data on intervention and hospital admission costs were collected, and the incremental cost-effectiveness ratios (ICERs) were calculated., Results: Participants were, on average, aged 62 (SD 10) years, and the majority were male (93/120, 77.5%). The intervention group were more likely to experience all-cause (odds ratio [OR] 1.54, 95% CI 0.58-4.10; P=.39) and cardiac-related (OR 3.26, 95% CI 0.84-12.55; P=.09) hospital admissions and ED presentations (OR 2.07, 95% CI 0.89-4.77; P=.09) than the control group. Despite this, cardiac-related hospital admission costs were lower in the intervention group over 12 months (Aus $252.40 vs Aus $859.38; P=.24; a currency exchange rate of Aus $1=US $0.69 is applicable). There were no significant between-group differences in sedentary behavior minutes per day over 12 months, although the intervention group completed 22 minutes less than the control group (95% CI -22.80 to 66.69; P=.33; Cohen d=0.21). The intervention group had a lower BMI (β=1.62; P=.05), waist circumference (β=5.81; P=.01), waist-to-hip ratio (β=.03, P=.03), and quality of life (β=3.30; P=.05) than the control group. The intervention was more effective but more costly in reducing sedentary behavior (ICER Aus $351.77) and anxiety (ICER Aus $10,987.71) at 12 months. The intervention was also more effective yet costly in increasing quality of life (ICER Aus $93,395.50) at 12 months., Conclusions: The Vire app and ToDo-CR program was not an outcome-effective or cost-effective solution to reduce all-cause hospital admissions or ED presentations in cardiac rehabilitation compared with usual care. Smartphone apps that target sedentary behavior alone may not be an effective solution for cardiac rehabilitation participants to reduce hospital admissions and sedentary behavior., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12619001223123; https://australianclinicaltrials.gov.au/anzctr/trial/ACTRN12619001223123., International Registered Report Identifier (irrid): RR2-10.1136/bmjopen-2020-040479., (©Kacie Patterson, Rachel Davey, Richard Keegan, Theo Niyonsenga, Itismita Mohanty, Sarah Bowen, Elizabeth Regan, Michelle Lander, Sander van Berlo, Nicole Freene. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 03.10.2023.)

Objective: Using targeted neonatal echocardiography (TNE) to examine cardiopulmonary physiological impact of diuretics in preterm infants with chronic pulmonary hypertension (cPH)., Study Design: Retrospective study comparing TNE indices pre- and ≤2 weeks (post) of initiating diuretic therapy in infants born <32 weeks gestational age with cPH., Results: Twenty-seven neonates with mean gestational age, birthweight and interval between pre-post diuretic TNE of 27.0 ± 2.8 weeks, 859 ± 294 grams, and 7.8 ± 3.0 days respectively were studied. Diuretics was associated with improvement in pulmonary vascular resistance [pulmonary artery acceleration time (PAAT); 34.27(9.76) vs. 40.24(11.10)ms, p = 0.01), right ventricular (RV) ejection time:PAAT ratio [5.92(1.66) vs. 4.83(1.14), p < 0.01)], RV fractional area change [41.6(9.8) vs. 46.4(6.5%), p = 0.03)] and left ventricular myocardial performance index [0.55(0.09) vs. 0.41(0.23), p < 0.01)]. Post-treatment, frequency of bidirectional/right-to-left inter-atrial shunts decreased significantly (24% vs. 4%, p = 0.05)., Conclusion: Primary diuretic treatment in neonates with cPH may result in improvement in PVR, RV and LV function and compliance., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To determine the clinical/echocardiography (ECHO) phenotype of patients with hypoxic respiratory failure (HRF) and response to late surfactant, according to patent ductus arteriosus (PDA) status., Study Design: This retrospective study included infants ≤26 +6 weeks gestation who received ≥1 surfactant dose after 6 postnatal days and where PDA status was available by ECHO. Response to surfactant was appraised based on change in respiratory severity score over 48 h. The relationship between PDA status and response to surfactant was evaluated via univariate analysis., Result: We studied late surfactant (n = 71 doses) administration in 35 preterm infants born at a mean weight and GA at birth were 595 g (508, 696) and 23.3 (22.7, 25) weeks, respectively of whom 16 (46%) had a diagnosis of PDA. Positive response to late surfactant treatment was independently associated with absence of PDA [OR 26 (2, 334), p = 0.01] whereas presence of PDA was independently associated with negative response [OR 12 (1.1, 126), p = 0.04]., Conclusions: In neonates ≤26 +6 weeks gestation, with HRF, response to surfactant after postnatal day 6 is influenced by PDA status. Future trials should consider PDA status which may enhance diagnostic precision and refine patient selection for late surfactant treatment., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The cause, or causes, of the Pleistocene megafaunal extinctions have been difficult to establish, in part because poor spatiotemporal resolution in the fossil record hinders alignment of species disappearances with archeological and environmental data. We obtained 172 new radiocarbon dates on megafauna from Rancho La Brea in California spanning 15.6 to 10.0 thousand calendar years before present (ka). Seven species of extinct megafauna disappeared by 12.9 ka, before the onset of the Younger Dryas. Comparison with high-resolution regional datasets revealed that these disappearances coincided with an ecological state shift that followed aridification and vegetation changes during the Bølling-Allerød (14.69 to 12.89 ka). Time-series modeling implicates large-scale fires as the primary cause of the extirpations, and the catalyst of this state shift may have been mounting human impacts in a drying, warming, and increasingly fire-prone ecosystem.

Rationale: Increasing survival of extremely preterm infants with a stable rate of severe intraventricular hemorrhage represents a growing health risk for neonates. Objectives: To evaluate the role of early hemodynamic screening (HS) on the risk of death or severe intraventricular hemorrhage. Methods: All eligible patients 22-26 +6 weeks' gestation born and/or admitted <24 hours postnatal age were included. As compared with standard neonatal care for control subjects (January 2010-December 2017), patients admitted in the second epoch (October 2018-April 2022) were exposed to HS using targeted neonatal echocardiography at 12-18 hours. Measurements and Main Results: A primary composite outcome of death or severe intraventricular hemorrhage was decided a priori using a 10% reduction in baseline rate to calculate sample size. A total of 423 control subjects and 191 screening patients were recruited with a mean gestation and birth weight of 24.7 ± 1.5 weeks and 699 ± 191 g, respectively. Infants born at 22-23 weeks represented 41% ( n  = 78) of the HS epoch versus 32% ( n  = 137) of the control subjects ( P  = 0.004). An increase in perinatal optimization (e.g., antepartum steroids) but with a decline in maternal health (e.g., increased obesity) was seen in the HS versus control epoch. A reduction in the primary outcome and each of severe intraventricular hemorrhage, death, death in the first postnatal week, necrotizing enterocolitis, and severe bronchopulmonary dysplasia was seen in the screening era. After adjustment for perinatal confounders and time, screening was independently associated with survival free of severe intraventricular hemorrhage (OR 2.09, 95% CI [1.19, 3.66]). Conclusions: Early HS and physiology-guided care may be an avenue to further improve neonatal outcomes; further evaluation is warranted.

Objective: An alternative therapy for preterm infants with a hemodynamically significant patent ductus arteriosus (hsPDA) is needed when cyclooxygenase inhibitors fail or where treatment is contraindicated due to coexisting renal failure, necrotizing enterocolitis, and/or intestinal perforation. No studies have evaluated the efficacy of per rectum (PR) acetaminophen. The study aimed to evaluate the efficacy of PR acetaminophen in modulating the risk of PDA ligation., Study Design: A retrospective matched case-control study was conducted to compare neonates born <29 weeks' gestation with evidence of hsDA, in an era when rescue rectal acetaminophen was used (January 2014-March 2018) as a treatment strategy, versus historical controls (July 2006-August 2012). All patients underwent comprehensive echocardiography assessment of ductal shunt volume according to a standardized protocol. Acetaminophen treated neonates were matched according to demographics, gestation, preintervention echocardiography features, and comorbidities. Control patients were selected when an echocardiography was performed at an equivalent postnatal age. Infants with a genetic syndrome, severe congenital malformation, or major forms of congenital heart disease excluding small atrial septal defect or ventricular septal defect, PDA, or patent formale ovale were excluded. The primary outcome was surgical ligation of the PDA. Secondary outcomes included echocardiography indices of hemodynamic significance, the composite of death, or severe BPD (defined by ventilator dependence at 36 weeks postmenstrual age). Descriptive statistics and univariate ( t -tests, Fisher's exact test, and Mann-Whitney U test) analyses were used to evaluate clinical and echocardiography characteristics of the groups and compare outcomes., Results: Forty infants (20 cases and 20 controls), with similar demographic and echocardiography features, were compared. Cases received 6.8 ± 0.7 days (60 mg/kg/day) of PR acetaminophen. Responders ( n  = 12, 60%) had echocardiography evidence of reduced ductal diameter (2.2 mm [1.9-2.6] to 1.1 mm [0-1.7], p  = 0.002), left ventricular output (363 ± 108-249 ± 61 mL/min/kg; p  = 0.002) and left atrium to aortic root ratio (1.7 ± 0.3-1.3 ± 0.2; p  = 0.002) following treatment. The rate of PDA ligation was 50% lower ( p  = 0.02) and composite outcome of death or severe bronchopulmonary dysplasia was reduced ( p  = 0.04) in the acetaminophen group., Conclusion: Rectal acetaminophen was associated with improvement in echocardiography indices of PDA shunt volume, a 50% reduction in PDA ligation rates and a reduction in the composite outcome of death or severe BPD. Pharmacologic and further prospective clinical studies are needed., Key Points: · Many preterm infants encounter the clinical consequences of a hemodynamically significant PDA.. · The merits and optimal timing of PDA ligation remains an area of controversy amongst neonatologists.. · Cyclooxygenase inhibitors are associated with adverse events or are often contraindicated.., Competing Interests: None declared., (Thieme. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The diagnosis, prognostication, and differentiation of phenotypes of COPD can be facilitated by CT scan imaging of the chest. CT scan imaging of the chest is a prerequisite for lung volume reduction surgery and lung transplantation. Quantitative analysis can be used to evaluate extent of disease progression. Evolving imaging techniques include micro-CT scan, ultra-high-resolution and photon-counting CT scan imaging, and MRI. Potential advantages of these newer techniques include improved resolution, prediction of reversibility, and obviation of radiation exposure. This article discusses important emerging techniques in imaging patients with COPD. The clinical usefulness of these emerging techniques as they stand today are tabulated for the benefit of the practicing pulmonologist., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Definitive closure of the patent ductus arteriosus (PDA) is associated with significant changes in the loading conditions of the left ventricle (LV), which may lead to cardiovascular and respiratory instability. The objective of the study was to evaluate targeted neonatal echocardiography (TnECHO) characteristics and the clinical course of preterm infants ≤2 kg undergoing percutaneous PDA closure., Methods: Retrospective cohort study of prospectively acquired pre- and post-closure TnECHOs to assess hemodynamic changes. Cardiorespiratory parameters in the first 24 h following PDA closure were also evaluated., Results: Fifty patients were included with a mean age of 30.6 ± 9.6 days and weight of 1188 ± 280 g. LV global longitudinal strain decreased from -20.6 ± 2.6 to -14.9 ± 2.9% (p < 0.001) after 1 h. There was a decrease in LV volume loading, left ventricular output, LV systolic and diastolic parameters. Cardiorespiratory instability occurred in 24 (48%) [oxygenation failure in 44%] but systolic hypotension and/or need for cardiovascular medications was only seen in 6 (12%). Patients with instability had worse baseline respiratory severity score and lower post-closure early diastolic strain rates., Conclusions: Percutaneous PDA closure leads to a reduction in echocardiography markers of LV systolic/diastolic function. Post-closure cardiorespiratory instability is characterized primarily by oxygenation failure and may relate to impaired diastolic performance., Impact: Percutaneous patent ductus arteriosus closure leads to a reduction in echocardiography markers of left ventricular volume loading, cardiac output, and left ventricular systolic/diastolic function. Post-procedural cardiorespiratory instability is characterized primarily by oxygenation failure. Post-procedural cardiorespiratory instability may relate to impaired diastolic performance., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

COPD is a condition characterized by chronic airflow obstruction resulting from chronic bronchitis, emphysema, or both. The clinical picture is usually progressive with respiratory symptoms such as exertional dyspnea and chronic cough. For many years, spirometry was used to establish a diagnosis of COPD. Recent advancements in imaging techniques allow quantitative and qualitative analysis of the lung parenchyma as well as related airways and vascular and extrapulmonary manifestations of COPD. These imaging methods may allow prognostication of disease and shed light on the efficacy of pharmacologic and nonpharmacologic interventions. This is the first of a two-part series of articles on the usefulness of imaging methods in COPD, and it highlights useful information that clinicians can obtain from these imaging studies to make more accurate diagnosis and therapeutic decisions., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Recent research has increased focus and interest in characterizing the physiology of the transition circulation using echocardiography. Critique of published normative neonatal echocardiography data among healthy term neonates has not been performed. We have performed a comprehensive literature review using the key terms: cardiac adaptation, hemodynamics, neonatal transition, term newborns. Studies were included if they had reported echocardiography indices of cardiovascular function in the presence of maternal diabetes, intrauterine growth restricted newborns and prematurity and had a comparison group of healthy term newborns within first seven postnatal days. Sixteen published studies evaluating transitional circulation in healthy newborns were included. There was marked heterogeneity in the methodologies used; specifically, inconsistency in time of evaluation and imaging techniques used makes it challenging to determine specific trends of expected physiologic changes. Some studies revealed nomograms for echocardiography indices, though limitations persist in terms of sample size, number of reported parameters and consistency of measurement technique. A comprehensive standardized echocardiography framework which includes consistent techniques for assessment dimensions, function, blood flow, pulmonary/systemic vascular resistance, and shunts pattern is warranted to ensure consistency in the use of echocardiography to guide care of healthy and sick newborns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Suciu, Prelipcean, Făgărășan, Giesinger and McNamara.)

The effects of riociguat, an oral-soluble guanylate-cyclase stimulator, were studied in 10 infants with chronic pulmonary arterial hypertension. Respiratory status (n = 8/10), right heart dilation (n = 7/10), function (n = 9/10), and chronic pulmonary arterial hypertension (n = 8/10) improved. Median decrement in systolic (12 [4, 14]), diastolic (14 [7, 20]), and mean arterial (14 [10, 17]) pressures were noted; no critical hypotension or hypoxemia occurred., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The significance of biophysical modulators of the epithelial to mesenchymal transition (EMT) is demonstrated by experiments that document full EMT on stiff, nano-patterned substrates in the absence of biochemical induction. Yet, current models focus on biochemical triggers of EMT without addressing its mechanosensitive nature. Here, we built a Boolean model of EMT triggered by mechanosensing - mitogen crosstalk. Our model reproduces epithelial, hybrid E/M and mesenchymal phenotypes, the role of autocrine TGFβ signaling in maintaining mesenchymal cells in the absence of external drivers, inhibition of proliferation by TGFβ, and its apoptotic effects on soft ECM. We offer testable predictions on the density-dependence of partial EMT, its molecular drivers, and the conflict between mitosis and hybrid E/M stability. Our model opens the door to modeling the effects of the biomechanical environment on cancer cell stemness linked to the hybrid E/M state, as well as the mutually inhibitory crosstalk between EMT and senescence., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Introduction: Recent evidence suggests a high prevalence of undiagnosed chronic obstructive pulmonary disease (COPD). These individuals are at risk of exacerbations and delayed treatment. We analyzed an at-risk population for the prevalence of abnormal spirometry to provide clarity into who should undergo early spirometry., Methods: We analyzed data from the COPDGene study. Participants with ≥10 pack-years of smoking were included. Individuals with self-reported or physician-diagnosed COPD, asthma, chronic bronchitis, emphysema and/or were on inhalers were excluded. Parsimonious multivariable logistic regression models identified factors associated with abnormal spirometry, defined as either airflow obstruction (AFO) or preserved ratio impaired spirometry. Variables were selected for the final model using a stepwise backward variable elimination process which minimized Akaike information criterion (AIC). Similarly, during the 5-year follow-up period, we assessed factors associated with incident diagnosis of COPD., Results: Of 5055 individuals, 1064 (21%) had undiagnosed AFO. Age, pack-years, current smoking and a history of acute bronchitis were associated with AFO while body mass index, female sex, and Black race were inversely associated. Among 2800 participants with 5-year follow-up, 532 (19%) had an incident diagnosis of COPD. Associated risk factors included mMRC ≥2, chronic productive cough, respiratory exacerbations during the follow-up period, and abnormal spirometry. Age was inversely associated., Conclusions: The prevalence of undiagnosed COPD is high in at-risk populations. We found multiple factors associated with undiagnosed COPD and incident diagnosis of COPD at follow up. These results can be used to identify those at risk for undiagnosed COPD to facilitate earlier diagnosis and treatment., Competing Interests: Declaration of competing interest Alejandro Comellas has consulted for GSK and VIDA Diagnostics. Arianne K. Baldomero is supported by the NIHNational Center for Advancing Translational Sciences Grants KL2TR002492 and UL1TR002494. Jeffrey L. Curtis is supported by R01 HL144718, R01 HL144849, U01 HL137880, and I01 CX001969 and has consulted for AstraZeneca PLC, Novartis AG, and CSL Behring LLC. Richard Casaburi has received consultant fees or honoraria from Boehringer Ingelheim, Glaxo Smith Kline and Inogen. Victor Kim has consulted for Boehringer Ingelheim, Gala Therapeutics and AstraZeneca and received personal fees from American Board of Internal Medicine. Alejandro A. Diaz is supported by NIH grants R01-HL133137, R01-HL14986; has reported speaker fees from Boehringer Ingelheim, outside the submitted work. Edwin K. Silverman has received grant support from GlaxoSmithKline and Bayer. Surya P. Bhatt is supported by NIH Grants R01HL151421, R21EB027891, and UG3HL155806 and he has served on advisory boards for Boehringer Ingelheim and Sanofi/Regeneron. Spyridon Fortis has received grants from American Thoracic Society and Fisher &Paykel and served as a consultant for Genentech. The rest of the authors have no relevant conflicts to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the outcomes of extremely premature infants who received inhaled nitric oxide(iNO) for hypoxic respiratory failure(HRF)., Study Design: Retrospective analysis of 107 infants born 22-26 weeks gestation who received iNO for HRF at a single institution. Infants were categorized as positive, negative, or no responders based on change in FiO 2 or OI. Underlying physiology was determined using Echocardiography/Radiography/Biochemistry., Results: 63% of infants had a positive response; they received iNO earlier and were more likely to have acute pulmonary hypertension(PH). Positive response correlated with decreased incidence of death or grade 3 BPD at 36 weeks postmenstrual age, as compared to a negative response., Conclusions: Extremely premature infants have a positive response rate to iNO comparable to term infants when used for PH in the transitional period. Infants with a negative response to iNO had worse outcomes, necessitating the determination of the underlying physiology of HRF prior to iNO initiation., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Thrombotic microangiopathy (TMA) has been reported to occur in multiple myeloma (MM) patients in association with treatment with carfilzomib, an irreversible proteasome inhibitor (PI). The hallmark of TMA is vascular endothelial damage leading to microangiopathic hemolytic anemia, platelet consumption, fibrin deposition and small-vessel thrombosis with resultant tissue ischemia. The molecular mechanisms underlying carfilzomib-associated TMA are not known. Germline mutations in the complement alternative pathway have been recently shown to portend increased risk for the development of atypical hemolytic uremic syndrome (aHUS) and TMA in the setting of allogeneic stem cell transplant in pediatric patients. We hypothesized that germline mutations in the complement alternative pathway may similarly predispose MM patients to carfilzomib-associated TMA. We identified 10 MM patients with a clinical diagnosis of TMA in the context of carfilzomib treatment and assessed for the presence of germline mutations in the complement alternative pathway. Ten, matched MM patients exposed to carfilzomib but without clinical TMA were used as negative controls. We identified a frequency of deletions in the complement Factor H genes 3 and 1 (delCFHR3-CFHR1) and genes 1 and 4 (delCFHR1-CFHR4) in MM patients with carfilzomib-associated TMA that was higher as compared to the general population and matched controls. Our data suggest that complement alternative pathway dysregulation may confer susceptibility to vascular endothelial injury in MM patients and predispose to development of carfilzomib-associated TMA. Larger, retrospective studies are needed to evaluate whether screening for complement mutations may be indicated to properly counsel patients about TMA risk with carfilzomib use., (© 2023. The Author(s).)

Objectives: The distinction between bipolar I disorder (BD-I) and bipolar II disorder (BD-II) has been a topic of long-lasting debate. This study examined differences between BD-I and BD-II in a large, global sample of OABD, focusing on general functioning, cognition and somatic burden as these domains are often affected in OABD., Methods: Cross-sectional analyses were conducted with data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database. The sample included 963 participants aged ≥50 years (714 BD-I, 249 BD-II). Sociodemographic and clinical factors were compared between BD subtypes including adjustment for study cohort. Multivariable analyses were conducted with generalized linear mixed models (GLMMs) and estimated associations between BD subtype and (1) general functioning (GAF), (2) cognitive performance (g-score) and (3) somatic burden, with study cohort as random intercept., Results: After adjustment for study cohort, BD-II patients more often had a late onset ≥50 years (p = 0.008) and more current severe depression (p = 0.041). BD-I patients were more likely to have a history of psychiatric hospitalization (p < 0.001) and current use of anti-psychotics (p = 0.003). Multivariable analyses showed that BD subtype was not related to GAF, cognitive g-score or somatic burden., Conclusion: BD-I and BD-II patients did not differ in terms of general functioning, cognitive impairment or somatic burden. Some clinical differences were observed between the groups, which could be the consequence of diagnostic definitions. The distinction between BD-I and BD-II is not the best way to subtype OABD patients. Future research should investigate other disease specifiers in this population., (© 2022 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Objectives: To study changes in heart function and hemodynamics during the transitional period in small for gestational (SGA) infants and appropriate (AGA) healthier counterparts., Design: A hospital based prospective observational study was performed at a perinatal center. Echocardiograms were performed on the first postnatal day and again at 48 h age. Term SGA infants were compared with those AGA newborns matched for the GA and mode of delivery., Results: Eighteen SGA infants were compared with 18 AGA infants [gestation 38 ± 1.5 vs. 38 ± 1.2 weeks, p  > 0.05 and birthweight 2331 ± 345 vs. 3332 ± 405 grams, p  < 0.05, respectively]. Maternal weight and body mass index was higher among non-affected pregnancies, 61% infants were born vaginally, and no differences in cord blood pH at birth were noted. SGA infants had higher systolic and mean blood pressure at both time points, lower indices of right ventricular (RV) performance [TAPSE (tricuspid annular peak systolic excursion) 7.4 ± 2.8 vs. 9.3 ± 0.7 on day 1, 7.2 ± 2.8 vs. 9.2 ± 0.5 on day 2, p  = 0.001], lower pulmonary acceleration time (PAAT) suggestive of elevated pulmonary vascular resistance [56.4 ± 10.5 vs. 65.7 ± 13.2 on day 1, 61.4 ± 12.5 vs. 71.5 ± 15.7 on day 2, p  = 0.01] and higher left ventricular (LV) ejection fraction [62.1 ± 7.8 vs. 54.9 ± 5.5 on day 1, 61.9 ± 7.6 vs. 55.8 ± 4.9 on day 2, p  = 0.003]., Conclusions: SGA infants had evidence of higher pulmonary vascular resistance, and lower RV performance during the postnatal transition. The relevance and impact of these changes to hemodynamic disease states during the postnatal transition requires prospective investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Suciu, Giesinger, Mărginean, Muntean, Cucerea, Făgărășan and McNamara.)

Rationale: Chronic obstructive pulmonary disease (COPD) mortality risk is often estimated using the BODE (body mass index, obstruction, dyspnea, exercise capacity) index, including body mass index, forced expiratory volume in 1 second, dyspnea score, and 6-minute walk distance. Diffusing capacity of the lung for carbon monoxide (Dl CO ) is a potential predictor of mortality that reflects physiology distinct from that in the BODE index. Objectives: This study evaluated Dl CO as a predictor of mortality using participants from the COPDGene study. Methods: We performed time-to-event analyses of individuals with COPD (former or current smokers with forced expiratory volume in 1 second/forced vital capacity < 0.7) and Dl CO measurements from the COPDGene phase 2 visit. Cox proportional hazard methods were used to model survival, adjusting for age, sex, pack-years, smoking status, BODE index, computed tomography (CT) percent emphysema (low attenuation areas below -950 Hounsfield units), CT airway wall thickness, and history of cardiovascular or kidney diseases. C statistics for models with Dl CO and BODE scores were used to compare discriminative accuracy. Results: Of 2,329 participants, 393 (16.8%) died during the follow-up period (median = 4.9 yr). In adjusted analyses, for every 10% decrease in Dl CO percent predicted, mortality increased by 28% (hazard ratio = 1.28; 95% confidence interval, 1.17-1.41, P  < 0.001). When compared with other clinical predictors, Dl CO percent predicted performed similarly to BODE (C statistic Dl CO  = 0.68; BODE = 0.70), and the addition of Dl CO to BODE improved its discriminative accuracy (C statistic = 0.71). Conclusions: Diffusing capacity, a measure of gas transfer, strongly predicted all-cause mortality in individuals with COPD, independent of BODE index and CT evidence of emphysema and airway wall thickness. These findings support inclusion of Dl CO in prognostic models for COPD.

Group A streptococcus (GAS) is a Gram-positive human bacterial pathogen responsible for more than 700 million infections annually worldwide. Beta-lactam antibiotics are the primary agents used to treat GAS infections. Naturally occurring GAS clinical isolates with decreased susceptibility to beta-lactam antibiotics attributed to mutations in PBP2X have recently been documented. This prompted us to perform a genome-wide screen to identify GAS genes that alter beta-lactam susceptibility in vitro . Using saturated transposon mutagenesis, we screened for GAS gene mutations conferring altered in vitro susceptibility to penicillin G and/or ceftriaxone, two beta-lactam antibiotics commonly used to treat GAS infections. In the aggregate, we found that inactivating mutations in 150 GAS genes are associated with altered susceptibility to penicillin G and/or ceftriaxone. Many of the genes identified were previously not known to alter beta-lactam susceptibility or affect cell wall biosynthesis. Using isogenic mutant strains, we confirmed that inactivation of clpX (Clp protease ATP-binding subunit) or cppA (CppA proteinase) resulted in decreased in vitro susceptibility to penicillin G and ceftriaxone. Deletion of murA1 (UDP- N- acetylglucosamine 1-carboxyvinyltransferase) conferred increased susceptibility to ceftriaxone. Our results provide new information about the GAS genes affecting susceptibility to beta-lactam antibiotics. IMPORTANCE Beta-lactam antibiotics are the primary drugs prescribed to treat infections caused by group A streptococcus (GAS), an important human pathogen. However, the molecular mechanisms of GAS interactions with beta-lactam antibiotics are not fully understood. In this study, we performed a genome-wide mutagenesis screen to identify GAS mutations conferring altered susceptibility to beta-lactam antibiotics. In the aggregate, we discovered that mutations in 150 GAS genes were associated with altered beta-lactam susceptibility. Many identified genes were previously not known to alter beta-lactam susceptibility or affect cell wall biosynthesis. Our results provide new information about the molecular mechanisms of GAS interaction with beta-lactam antibiotics.

Objective: To analyze the association between cardiovascular care and adverse outcome in infants undergoing therapeutic hypothermia for neonatal encephalopathy (NE)., Study Design: This was a retrospective cohort study of 176 infants with NE and hypotension, admitted to the SickKids Hospital (Center A, n = 86) or Semmelweis University (Center B, n = 90)., Result: The lowest systolic/diastolic blood pressures were comparable amongst centers; however, proportion of cardiovascular support was lower in Center A (51% vs 97% in Center B). Overall rate of death or abnormal MRI (adverse outcome) were comparable between centers, although pattern differed with more basal ganglia injury in Center B. A 24-hour longer duration of cardiovascular support increased the odds for adverse outcome by 14%., Conclusion: We demonstrated that management of hemodynamic instability in infants with NE was markedly different in two high-volume NICUs and showed that longer duration of cardiovascular medication is an independent risk factor for adverse outcome., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Harmonizing different depression severity scales often requires creation of categorical variables that may decrease the sensitivity of the measure. Our aim was to compare the associations between categorical and continuous and harmonized measures of depression and global functioning in a large dataset of older age patients with bipolar disorder (OABD)., Method: In the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) the 17-item Hamilton Depression scale (HAM-D), Montgomery Asberg Depression Rating Scale (MADRS) or the Center for Epidemiological Studies Depression scales (CES-D) was used to assess current depressive symptoms, while the Global Assessment of Functioning (GAF) assessed functional status. Data were harmonized from 8 OABD studies (n = 582). In each subsample, the relationship of depression severity as a continuous and categorical measure was compared to GAF. In the total sample, harmonized ordinal depression categories were compared to GAF., Results: Effect size and variance explained by the model for the categorical measure in the total sample was higher than both the categorical and continuous measure in the CES-D subsample, higher than the categorical but lower than the continuous measure in the HAM-D subsample, and lower than both the categorical and continuous measures in the MADRS subsample., Limitations: All included studies have different inclusion and exclusion criteria, study designs, and differ in aspects of sociodemographic variables., Conclusions: Associations were only slightly larger for the continuous vs categorical measures of depression scales. Harmonizing different depression scales into ordinal categories for analyses is feasible without losing statistical power., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Some individuals with bipolar disorder (BD) experience manic and depressive symptoms concurrently, but data are limited on symptom mixity in older age bipolar disorder (OABD). Using the Global Aging & Geriatric Experiments in Bipolar Disorder Database, we characterized mixity in OABD and associations with everyday function., Methods: The sample (n = 805), from 12 international studies, included cases with both mania and depression severity ratings at a single timepoint. Four mixity groups were created: asymptomatic (A), mixed (Mix), depressed only (Dep), and manic only (Man). Generalized linear mixed models used mixity group as the predictor variable; cohort was included as a random intercept. Everyday function was assessed with the Global Assessment of Functioning score., Results: Group proportions were Mix (69.6%; n = 560), followed by Dep (18.4%; n = 148), then A (7.8%; n = 63), then Man (4.2%; n= 34); levels of depression and mania were similar in Mix compared to Dep and Man, respectively. Everyday function was lowest in Mix, highest in A, and intermediate in Man and Dep. Within Mix, severity of depression was the main driver of worse functioning. Groups differed in years of education, with A higher than all others, but did not differ by age, gender, employment status, BD subtype, or age of onset., Conclusions: Mixed features predominate in a cross-sectional, global OABD sample and are associated with worse everyday function. Among those with mixed symptoms, functional status relates strongly to current depression severity. Future studies should include cognitive and other biological variables as well as longitudinal designs to allow for evaluation of causal effects., (Published by Elsevier Inc.)