bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends of Medicare reimbursement rates for gender affirmation procedures
Authors: Siotos Charalampos , Underhill Joshua M , Sykes Jennifer , Jones Kody B , Schechter Loren , Dorafshar Amir H , Hamidian Jahromi Alireza
Published: December 2023

Background

While nearly 1 in 5 Americans receives health insurance coverage through Medicare, literature suggests that Medicare reimbursement is lagging behind inflation for many plastic surgery procedures.

Aim

This article evaluates trends in Medicare reimbursement for gender affirmation procedures.

Methods

The most common gender affirmation procedures performed at an urban academic medical center were identified in this cross-sectional study (level 4 evidence). Five nongender surgery codes were evaluated for reference. A standardized formula utilizing relative value units (RVUs) was used to calculate monetary data. Differences in reimbursement between 2014 and 2021 were calculated for each procedure.

Outcome

The main outcome was inflation-adjusted difference of charges from 2014 to 2021.

Results

Between 2014 and 2021, Medicare reimbursement for gender affirmation procedures had an inflation-unadjusted average change of –0.09% (vs +5.63% for the selected nongender codes) and an inflation-adjusted change of –10.03% (vs –5.54% for the selected nongender codes). Trends in reimbursement varied by category of gender-affirming procedure. The overall average compound annual growth rate had a change of –0.99% (vs –0.53% for the selected nongender codes). The average changes in work, facility, and malpractice RVUs were –1.05%, +9.52%, and –0.93%, respectively.

Clinical Implications

Gender surgeons and patients should be aware that the decrease in reimbursement may affect access to gender-affirming care.

Strengths and Limitations

Our study is one of the first evaluating the reimbursement rates associated with the full spectrum of gender affirmation surgery. However, our study is limited by its cross-sectional nature.

Conclusions

From 2014 to 2021, Medicare reimbursement for gender affirmation procedures lagged inflation.
Universal definition of heart failure
Authors: Coats Andrew JS , Bozkurt Biykem , Seferović Petar M
Published: December 2023

In early 2021, the Heart Failure Society of America, the Heart Failure Association of European Society of Cardiology, and the Japanese Heart Failure Society (JHFS) proposed a new universal definition of heart failure (UDHF). Four other associations endorsed the proposal: the Canadian Heart Failure Society, the Cardiac Society of Australia and New Zealand, the Heart Failure Association of India, and the Chinese Heart Failure Association. The reasons underlying the UDHF were many but importantly included the need to define heart failure (HF) easily and reproducibly as an essential step for standardization, so that accurate comparisons can be made across geographies, health systems, and timelines. A reliable UDHF will also aid in research, clinical practice, and quality and safety improvement activities. Unlike chronic kidney disease (CKD), HF cannot be defined by a numerical abnormality in any single parameter. HF is a clinical syndrome involving a commonly accepted composite of signs, symptoms, and investigative findings that are recognized as forming an identifiable disease state. This chapter reviews the history of HF definitions and outlines the advantages of the 2021 UDHF proposed by several international cardiology societies. It outlines how staging of HF can be aided by the UDHF and how the four-stage classification of the American College of Cardiology Foundation/American Heart Association can be adapted to the UDHF, and how this can aid our appreciation of the progression from risk factors for HF through early asymptomatic disease through to mildly and severely symptomatic disease. The chapter also reviews the many uses of left ventricular ejection fraction (LVEF) to subclassify HF and also its limitations, and describe four classes of HF according to ejection fraction (EF), HF with reduced EF (HFrEF), HF with mid-range EF (HFmrEF), HF with preserved EF (HFpEF), and HF with improved EF (HFimpEF). The chapter discusses the concept and usefulness of HF disease trajectories and finally outlines future uses of the UDHF in clinical practice, registries, audit, research, advocacy, and patient education.
Restrictive cardiomyopathy
Authors: Rapezzi Claudio , Aimo Alberto , Linhart Ales , Keren Andre
Published: December 2023

Restrictive cardiomyopathy (RCM) is a heterogeneous group of diseases characterized by a restrictive left ventricular physiology, that is, a rapid rise in ventricular pressure with only small increases in filling volumes because of increased myocardial stiffness. Beyond this shared haemodynamic hallmark, the phenotypic spectrum of RCM is wide. The disorders manifesting as RCM can be classified according to four main underlying disease mechanisms: (1) interstitial fibrosis or intrinsic myocardial dysfunction; (2) infiltration of extracellular spaces; (3) accumulation of storage material within cardiomyocytes; and (4) endomyocardial fibrosis. Many disorders do not show a restrictive physiology throughout their natural history, but only in the initial stage (with evolution towards a hypokinetic and dilated phenotype) or in the terminal stage (often progressing from a hypertrophic phenotype). Furthermore, elements of both hypertrophic and restrictive phenotypes may coexist in some patients, making the classification challenging. The restrictive physiology can be easily demonstrated by cardiac catheterization or Doppler echocardiography. The single conditions may usually be diagnosed based on clinical data, 12-lead electrocardiography, echocardiography, or cardiac magnetic resonance, but further investigations may be needed, including endomyocardial biopsy. The spectrum of therapies is also wide and heterogeneous, but disease-modifying treatments are available only for cardiac amyloidosis and partially for iron overload cardiomyopathy.
Prevention of heart failure
Authors: Piepoli Massimo Francesco , Matrone Maria Benedetta , Dendale Paul , Zieroth Shelley
Published: December 2023

Because of rapid ageing of the population, the incidence of heart failure is expected to increase in the coming years. Therefore, a key issue in modern medicine is prevention of the development of heart failure to reduce hospital admission rates. This chapter aims to provide practical evidence-based information to support the implementation of effective preventive measures. After reviewing the most common risk factors, potential interventions are proposed and discussed.
Molecular and cellular mechanisms
Authors: Xiao Junjie , Thum Thomas , Condorelli Gianluigi , Backs Johannes
Published: December 2023

Understanding the molecular and cellular mechanisms that control myocardial homeostasis and function is a prerequisite to establish new druggable targets for the development of innovative heart failure therapeutics. Excitation–contraction coupling, sarcomere function, autophagy, and cell–cell communication are all cardiac processes that are disturbed in heart failure patients and in several heart failure models. Numerous mediators link inherited or acquired causes of heart failure to these processes, as well as associate these processes with each other. Gene expression is altered not only in chronic disease states, but also in acute situations, and has turned out to be disease-causing. In particular, signal transduction events, transcriptional and translational regulation, epigenetic and epitranscriptomic modifications, and non-coding RNAs have emerged as druggable regulatory mediators. This chapter summarizes selected milestones in this exciting research area and discusses future directions.
Alterations in myocardial metabolism
Authors: Bertero Edoardo , Maack Christoph
Published: December 2023

The heart requires enormous amounts of energy in the form of adenosine triphosphate (ATP) that is mostly produced in mitochondria via oxidative phosphorylation. As an ‘omnivore’, the heart flexibly utilizes fatty acids, glucose, amino acids, lactate, and ketones. In patients with heart failure (HF), reduced phosphocreatine-to-ATP ratios predict adverse outcomes, coining the term of the failing heart as an ‘engine out of fuel’. However, metabolic dysfunction in HF goes far beyond a mere energetic deficit and involves alterations in substrate utilization, intermediary metabolism, and mitochondrial redox regulation that conspire to alter excitation–contraction (EC) coupling and dysregulate nutrient signalling pathways through epigenetic or post-translational control mechanisms. In contrast, defects in EC coupling and pathological cardiac workload in HF deteriorate energy supply-and-demand matching, to which the Krebs cycle with its key role in energy conversion, antioxidation, and production of metabolic intermediates is central. This chapter integrates cardiac metabolism with function and explains how this intricate relation is perturbed in the failing heart.
Alterations in renal haemodynamics and function in heart failure
Authors: Rossignol Patrick , Damman Kevin
Published: December 2023

Chronic kidney disease is a highly prevalent condition among patients with heart failure and is associated with worse clinical outcomes. Acute and chronic heart failure are inherently unstable conditions, encompassing a subtle (dis)equilibrium with kidney (dys)function within cardiorenal syndromes. Keeping in mind that lifesaving drugs (e.g. renin–angiotensin–aldosterone system inhibitors, including mineralocorticoid receptor antagonists, angiotensin receptor–neprilysin inhibitors, and/or sodium–glucose cotransporter 2 inhibitors) may alter kidney function without compromising clinical outcomes in heart failure patients with reduced ejection fraction, the practising physician must be ready to adapt the patient’s ongoing heart failure drug treatment (especially loop diuretics) at any point in time, based on the clinical status of the patient, and to accurately interpret kidney function variations.
Clinical phenotypes of heart failure with reduced ejection fraction
Authors: Halliday Brian P , Lüscher Thomas F
Published: December 2023

Following the use of left ventricular ejection fraction (LVEF) in early trials to select patients thought most likely to gain benefit from therapies, heart failure has been classified based on this measure. Indeed, more recent trials have confirmed the remarkable ability of LVEF to select patients with reduced systolic function who are most likely to benefit from pharmacological therapies. Additional classification of patients with heart failure with reduced ejection fraction (HFrEF) is often based on the presence or absence of ischaemic heart disease significant enough to cause the degree of myocardial impairment. However, both ischaemic and non-ischaemic mechanisms may also coexist. Further characterization of the phenotype is based on the clinical history, simple investigations including electrocardiography, and multimodality imaging, as well as genetic and family evaluation. While LVEF is likely to play an important ongoing role in the selection of therapy, this is likely to be complemented by in-depth phenotypic characterization, as we move into the era of precision medicine.
Heart failure with preserved ejection fraction
Authors: de Boer Rudolf A , Pieske Burkert , Borlaug Barry A
Published: December 2023

Heart failure with preserved ejection fraction (HFpEF) makes up for approximately 50% of all heart failure (HF) presentations. Current European Society of Cardiology (ESC) (and American College of Cardiology (ACC)/American Heart Association (AHA)) guidelines define HFpEF as a clinical syndrome with HF signs and/or symptoms, impaired diastolic function, and preserved systolic function (left ventricular ejection fraction ≥50%). The clinical risk factors and presentation of HFpEF are different from those of HF with (mildly) reduced ejection fraction. Generally, patients with HFpEF are older, more often female, and often have hypertension and atrial fibrillation as underlying causes, whereas HF with reduced ejection fraction more often occurs in younger males with ischaemic heart disease. Patients with multiple cardiovascular risk factors ánd HFpEF have far worse symptoms and worse outcome than those with similar cardiovascular risk burden without HFpEF, so that HFpEF cannot be regarded as an innocent complication of its associated comorbidities. In recent years, it has become increasingly evident that HFpEF is a heterogeneous disorder, with various underlying causes and precipitants, and that the diagnostic and therapeutic approach has been too simplistic. This chapter discusses the epidemiology, pathophysiology, diagnosis, and treatment options of HFpEF.
Biomarkers in diagnostic and prognostic assessment
Authors: Boer Rudolf A de , Bayes-Genis Antoni , Januzzi James L
Published: December 2023

Heart failure (HF) is a complex diagnosis, consisting of numerous syndromes with a common presentation (typically with signs and symptoms of congestion and/or low cardiac output), but with variable prognosis. Given the challenging nature that HF poses to clinicians, measurement of circulating biomarkers has been increasingly used to diagnose HF more accurately, estimate its severity, and evaluate treatment adequacy. Central to the use of biomarkers in HF patients is the understanding that biomarkers are a supplement to clinical judgement. However, biomarkers such as natriuretic peptides have revolutionized how the diagnosis of HF is regarded. Newer biomarkers such as cardiac troponins, soluble ST2, genomic markers (such as microRNA), and multi-biomarker panels developed through proteomics may provide even greater future value to better understand the complex diagnosis and management of HF.
Nuclear medicine
Authors: Neglia Danilo , Gimelli Alessia
Published: December 2023

Nuclear imaging is an evidence-based and broadly used approach for the detection and characterization of myocardial ischaemia and viability. Since coronary artery disease is still the leading cause of heart failure (HF), nuclear modalities are established for the diagnostic workup, risk stratification, and management of patients with suspected or known ischaemic cardiac dysfunction. Nuclear imaging has also an emerging role for the recognition and characterization of mechanisms or processes involved in non-ischaemic HF such as infection, inflammation, infiltration, and innervation. Nuclear modalities are advantaged by the availability of tracers able to interrogate specific molecular pathways. Imaging glucose metabolism of inflammatory cells or amyloid deposition in the myocardium, the function of sympathetic nerve endings, or myocardial receptors offers the capability of early diagnosis, risk stratification, and guide to treatment. Further developments in nuclear molecular tracers and hybrid imaging technologies will contribute to a more individualized management of patients with HF.
Computed tomography in heart failure
Authors: Achenbach Stephan , Rakisheva Amina G
Published: December 2023

Computed tomography (CT) with modern multidetector row systems offers high-resolution cross-sectional imaging of the heart. The main application remains visualization of the coronary arteries to identify and rule out coronary artery stenoses, but increasingly, CT is also used for morphological and functional imaging of the heart. In the context of heart failure, CT imaging may be applied to analyse left and right ventricular function when other methods do not suffice. It may be used for pericardial imaging if constriction is suspected, and can be highly valuable for the assessment of left ventricular assist device complications. Furthermore, CT coronary angiography may be used to rule out ischaemic cardiomyopathy, and whenever structural heart interventions are considered in patients with heart failure, CT is an indispensable tool for pre-procedural planning.
Vasodilators in heart failure
Authors: Polyzogopoulou Eftihia , Nikolaou Maria , Parissis John , Mebazaa Alexandre
Published: December 2023

Intravenous vasodilators are traditionally used agents, considered as complementary therapy to diuretics in the acute heart failure setting, in order to reduce symptoms of pulmonary and/or peripheral congestion. Current bibliography highlights primarily their beneficial impact on symptom relief and haemodynamic improvement, whereas their positive effects on short endpoints and long-term outcomes remains unproved. Moreover, oral vasodilators have been used as an alternative therapeutic approach for symptomatic improvement and reduction of death risk in chronic heart failure patients with intolerance to renin–angiotensin–aldosterone system inhibitors. This chapter summarizes the mechanism of action of vasodilators based on the pathophysiology of heart failure and emphasizes each agent’s unique characteristics. Also, it outlines the current recommendations on optimal and individualized utilization of vasodilators according to the appropriate clinical phenotype of the heart failure patient in order to achieve maximum favourable effects.
Inotropes and inodilators
Authors: Biegus Jan , Ponikowski Piotr , Maack Christoph
Published: December 2023

In patients with heart failure with reduced ejection fraction (HFrEF), defects in excitation–contraction (EC) coupling deteriorate the heart’s ability to supply the organism with sufficient amounts of blood and oxygen. For decades, drug development has aimed to increase cardiac contractility and output, especially in patients with acute, but also chronic, heart failure. However, although many approaches have succeeded in improving inotropy acutely, long-term prognosis is often adverse. Therefore, use of classical inotropes is generally limited to patients with acute heart failure and signs of hypoperfusion. More recently, compounds directly targeting sarcomeres have been developed which improve cardiac function, but also morbidity, in patients with chronic HFrEF, even when initiated during hospitalization. This chapter discusses the identification of patients requiring inotropic support, as well as the modes of action and clinical results of inotropes, to help physicians tailor treatments towards their patients’ clinical and haemodynamic situation.
Sodium–glucose cotransporter 2 inhibitors
Authors: Seferović Petar M , Cosentino Francesco , Rosano Giuseppe , Januzzi James
Published: December 2023

Sodium–glucose cotransporter 2 (SGLT2) inhibitors were initially developed as a novel therapy for type 2 diabetes mellitus (T2DM). However, several SGLT2 inhibitors demonstrated favourable effects on cardiovascular and kidney events, as well as attenuation in hospitalization for heart failure (HF), in patients with T2DM, including those with chronic kidney disease (CKD). In patients with HF with reduced ejection fraction, dapagliflozin and empagliflozin proved effective in reducing the risk of cardiovascular mortality and HF hospitalization, regardless of T2DM status or background therapy. Sotagliflozin reduced HF events and cardiovascular mortality in patients with T2DM and recent hospitalization for worsening HF. In patients with HF and preserved or mildly reduced ejection fraction, with or without T2DM, empagliflozin provided a significant reduction in cardiovascular mortality or HF hospitalization. The present chapter summarizes the mechanisms of cardiovascular protection with SGLT2 inhibitors and provides an overview of their role as cardiovascular medications essential for the prevention and treatment of HF.
Cardiac surgery (bypass surgery and remodelling surgery)
Authors: Schoenrath Felix , Neumann Franz-Josef , Uva Miguel Sousa , Falk Volkmar
Published: December 2023

Coronary artery disease is a root cause of de novo heart failure with impaired left ventricular systolic function and requires a full diagnostic workup. Despite an increased operative risk in patients with poor left ventricular function, coronary artery bypass grafting can provide not only symptomatic relief, but also a prognostic benefit in the setting of acute and chronic heart failure. Surgical ventricular reconstruction is a therapeutic option for patients with a left ventricular ejection fraction of ≤35% in combination with coronary artery bypass graft surgery or as a stand-alone procedure. The decision-making process should be guided by a specialized heart failure team, with a thorough understanding of the risks and benefits of all available medical, percutaneous, and surgical treatment options.
Cardiovascular rehabilitation and lifestyle modifications
Authors: Volterrani Maurizio , Cohen-Solal Alain , Adamopulos Stamatis , Miliopoulos Dimitris , Iellamo Ferdinando , Piepoli Massimo
Published: December 2023

Non-pharmacological management represents an important contribution to heart failure (HF) therapy. Education and counselling are instrumental in helping patients, their families, and caregivers in acquiring necessary skills for self-care and improvement in treatment adherence. Dietary sodium and fluid restrictions are important in control of congestion. Muscle wasting and cachexia are common in HF and have a significant impact on the clinical course. Nutritional advice and exercise training have proven to be effective in reducing mortality and hospitalization and improving quality of life (QoL) in cachectic patients. In addition, exercise training is highly recommended for all HF patients, regardless of the left ventricular ejection fraction. It was shown to improve functional capacity and QoL, and to reduce all-cause and HF-related mortality and hospitalization. Observational data suggest that smoking is associated with HF development and should be regarded as a modifiable risk factor. Nutritional deficiencies also need to be appropriately addressed.
Palliative care in the heart failure trajectory
Authors: Jaarsma Tiny , Fitzsimons Donna , Hjelmfors Lisa , Hill Loreena , Lambrinou Ekaterini , Strömberg Anna
Published: December 2023

Although it is generally recognized that heart failure (HF) is a serious condition and equivalent to cancer in terms of symptom burden and prognosis, only a limited number of these patients receive care that prepares them to make plans and cope through the stages of the illness. Across the course of the HF trajectory, most patients will go through several phases which can be marked by different goals for treatment and care and different issues in communication. Open and clear communication is vital to ensure good quality of care for patients, their family, and caregivers. Ethical issues include communication on difficult decisions, issues related to implantation and deactivation of devices, and deprescribing medication. There are numerous ways to organize palliative care in the HF trajectory but a coordinated interdisciplinary approach is vital.
Ventricular arrhythmias and sudden death in heart failure
Authors: Trancuccio Alessandro , Latini Alessia Chiara , Arnò Carlo , Kukavica Deni , Mazzanti Andrea , Priori Silvia G
Published: December 2023

Ventricular arrhythmias (VAs) are highly prevalent in patients with heart failure (HF) and range from isolated premature ventricular complexes (PVCs) to more severe arrhythmias such as non-sustained or sustained ventricular tachycardia (VTns and VTs, respectively) and, lastly, to ventricular fibrillation (VF). The clinical relevance of VAs, which may cause sudden cardiac death (SCD), is related to the fact that they represent an important competing cause of morbidity and mortality in patients with HF. Considering the epidemiology, progressive and degenerative nature of the disease, elevated socioeconomic costs of HF, as well overall cost-effectiveness of implantable cardioverter defibrillator (ICD), appropriate and periodic risk stratification represents a crucial moment in the management of patients with HF. This chapter reviews the current knowledge on the clinical impact of VA, most relevant arrhythmic mechanisms from the cellular level to the organ level, providing mechanistic insights for the treatment and management of VA, and highlight the state-of-the-art approaches to the prevention of the occurrence of SCD.
Diabetes, prediabetes, and heart failure
Authors: Rosano Giuseppe , Butler Javed , Seferović Petar M , Seferović Jelena , Cosentino Francesco
Published: December 2023

Type 2 diabetes mellitus (T2DM) and prediabetes confer an increased risk of developing heart failure (HF). In patients with known HF, concomitant T2DM and prediabetes are associated with worse symptoms and functional status, greater risk of complications and hospitalization for worsening HF, and greater cardiovascular and total mortality. Furthermore, patients with HF appear to be at a higher risk of developing T2DM. The underlying mechanisms of the bidirectional relationship between T2DM and HF have been intensively researched and include multiple, complex alterations at cellular, myocardial, and systemic levels. This chapter reviews the epidemiology, risk factors, and underlying mechanisms, and summarizes clinical presentation, complications, and outcomes of patients with concomitant T2DM and HF. It provides an overview of the contemporary management of HF and T2DM and highlights interventions to improve clinical outcomes in this population.
Pregnancy and heart failure
Authors: Bauersachs Johann , Hilfiker-Kleiner Denise , Sliwa Karen
Published: December 2023

Patients with pre-existing heart failure, or developing heart failure during pregnancy, are at elevated, and sometimes high, risk for adverse outcomes, including death of the mother and the child. Here we summarize the physiology and pathophysiology of the cardiovascular system and heart failure during/after pregnancy. We provide information on pre-pregnancy counselling of women at risk, or with pre-existing heart failure, and give advice for diagnosis and management of women who present with (de novo or previously unknown) heart failure during or after pregnancy. Sub-chapters include specific cardiomyopathies such as peripartum, hypertrophic dilated and restrictive cardiomyopathy, as well as left ventricular non-compaction, arrhythmogenic right ventricular cardiomyopathy, and Takotsubo syndrome. Patients in need of specific assessment and advice around pregnancy include those with adult congenital heart disease and those with a history of chemo-/radiotherapy for cancer or haematological malignancies.
First Light and Reionization Epoch Simulations (flares) – XIV. The Balmer/4000 Å breaks of distant galaxies
Authors: Wilkins Stephen M , Lovell Christopher C , Irodotou Dimitrios , Vijayan Aswin P , Vikaeus Anton , Zackrisson Erik , Caruana Joseph , Stanway Elizabeth R , Conselice Christopher J , Seeyave Louise T C , Roper William J , Chworowsky Katherine , Finkelstein Steven L
Published: December 2023

With the successful launch and commissioning of JWST we are now able to routinely spectroscopically probe the rest-frame optical emission of galaxies at z > 6 for the first time. Among the most useful spectral diagnostics used in the optical is the Balmer/4000 Å break; this is, in principle, a diagnostic of the mean ages of composite stellar populations. However, the Balmer break is also sensitive to the shape of the star formation history, the stellar (and gas) metallicity, the presence of nebular continuum emission, and dust attenuation. In this work, we explore the origin of the Balmer/4000 Å break using the synthesizer synthetic observations package. We then make predictions of the Balmer/4000 Å break using the First Light and Reionization Epoch Simulations at 5 < z < 10. We find that the average break strength weakly correlates with stellar mass and rest-frame far-ultraviolet luminosity, but that this is predominantly driven by dust attenuation. We also find that break strength provides a weak diagnostic of the age but performs better as a means to constrain star formation and stellar mass, alongside the ultraviolet and optical luminosity, respectively.
Dark-ages reionization and galaxy formation simulation – XXI. Constraining the evolution of the ionizing escape fraction
Authors: Mutch Simon J , Greig Bradley , Qin Yuxiang , Poole Gregory B , Wyithe J Stuart B
Published: December 2023

The fraction of ionizing photons that escape their host galaxies to ionize hydrogen in the intergalactic medium (IGM) is a critical parameter in analyses of the reionization era. In this paper, we use the meraxes semi-analytic galaxy formation model to infer the mean ionizing photon escape fraction and its dependence on galaxy properties through joint modelling of the observed high redshift galaxy population and existing constraints on the reionization history. Using a Bayesian framework, and under the assumption that escape fraction is primarily related to halo mass, we find that the joint constraints of the ultraviolet luminosity function, cosmic microwave background optical depth, and the Ly α forest require an escape fraction of $(18\pm 5)$ per cent for galaxies within haloes of M ≲ 109 M⊙ and $(5\pm 2)$ per cent for more massive haloes. In terms of galaxy properties, this transition in escape fraction occurs at stellar masses of M⋆ ∼ 107 M⊙, nearly independent of redshift. As a function of redshift, reionization is dominated by the smaller M⋆ ≲ 107 M⊙ galaxies with high escape fractions at z ≳ 6 and by the larger M⋆ ≳ 107 M⊙ galaxies with lower escape fractions at z ≲ 6. Galaxies with star formation rates of 10−2.5 M⊙yr−1 to 10−1.5 M⊙yr−1 provide the dominant source of ionizing photons throughout reionization. Our results are consistent with recent direct measurements of a $\sim 5~{{\ \rm per\ cent}}$ escape fraction from massive galaxies at the end of reionization and support the picture of low mass galaxies being the dominant sources of ionizing photons during reionization.
Parasitoid Serpins Evolve Novel Functions to Manipulate Host Homeostasis
Authors: Wu Zhiwei , Yuan Ruizhong , Gu Qijuan , Wu Xiaotong , Gu Licheng , Ye Xiqian , Zhou Yuenan , Huang Jianhua , Wang Zhizhi , Chen Xuexin
Published: December 2023

Parasitoids introduce various virulence factors when parasitism occurs, and some taxa generate teratocytes to manipulate the host immune system and metabolic homeostasis for the survival and development of their progeny. Host-parasitoid interactions are extremely diverse and complex, yet the evolutionary dynamics are still poorly understood. A category of serpin genes, named CvT-serpins, was discovered to be specifically expressed and secreted by the teratocytes of Cotesia vestalis, an endoparasitoid of the diamondback moth Plutella xylostella. Genomic and phylogenetic analysis indicated that the C. vestalis serpin genes are duplicated and most of them are clustered into 1 monophyletic clade. Intense positive selection was detected at the residues around the P1–P1′ cleavage sites of the Cv-serpin reactive center loop domain. Functional analyses revealed that, in addition to the conserved function of melanization inhibition (CvT-serpins 1, 16, 18, and 21), CvT-serpins exhibited novel functions, i.e. bacteriostasis (CvT-serpins 3 and 5) and nutrient metabolism regulation (CvT-serpins 8 and 10). When the host-parasitoid system is challenged with foreign bacteria, CvT-serpins act as an immune regulator to reprogram the host immune system through sustained inhibition of host melanization while simultaneously functioning as immune effectors to compensate for this suppression. In addition, we provided evidence that CvT-serpin8 and 10 participate in the regulation of host trehalose and lipid levels by affecting genes involved in these metabolic pathways. These findings illustrate an exquisite tactic by which parasitoids win out in the parasite–host evolutionary arms race by manipulating host immune and nutrition homeostasis via adaptive gene evolution and neofunctionalization.
Exonic splicing code and coordination of divalent metals in proteins
Authors: Bakhtiar Dara , Vondraskova Katarina , Pengelly Reuben J , Chivers Martin , Kralovicova Jana , Vorechovsky Igor
Published: December 2023

Exonic sequences contain both protein-coding and RNA splicing information but the interplay of the protein and splicing code is complex and poorly understood. Here, we have studied traditional and auxiliary splicing codes of human exons that encode residues coordinating two essential divalent metals at the opposite ends of the Irving–Williams series, a universal order of relative stabilities of metal–organic complexes. We show that exons encoding Zn2+-coordinating amino acids are supported much less by the auxiliary splicing motifs than exons coordinating Ca2+. The handicap of the former is compensated by stronger splice sites and uridine-richer polypyrimidine tracts, except for position –3 relative to 3′ splice junctions. However, both Ca2+ and Zn2+ exons exhibit close-to-constitutive splicing in multiple tissues, consistent with their critical importance for metalloprotein function and a relatively small fraction of expendable, alternatively spliced exons. These results indicate that constraints imposed by metal coordination spheres on RNA splicing have been efficiently overcome by the plasticity of exon–intron architecture to ensure adequate metalloprotein expression.
Dividing out quantification uncertainty allows efficient assessment of differential transcript expression with edgeR
Authors: Baldoni Pedro L , Chen Yunshun , Hediyeh-zadeh Soroor , Liao Yang , Dong Xueyi , Ritchie Matthew E , Shi Wei , Smyth Gordon K
Published: December 2023

Differential expression analysis of RNA-seq is one of the most commonly performed bioinformatics analyses. Transcript-level quantifications are inherently more uncertain than gene-level read counts because of ambiguous assignment of sequence reads to transcripts. While sequence reads can usually be assigned unambiguously to a gene, reads are very often compatible with multiple transcripts for that gene, particularly for genes with many isoforms. Software tools designed for gene-level differential expression do not perform optimally on transcript counts because the read-to-transcript ambiguity (RTA) disrupts the mean-variance relationship normally observed for gene level RNA-seq data and interferes with the efficiency of the empirical Bayes dispersion estimation procedures. The pseudoaligners kallisto and Salmon provide bootstrap samples from which quantification uncertainty can be assessed. We show that the overdispersion arising from RTA can be elegantly estimated by fitting a quasi-Poisson model to the bootstrap counts for each transcript. The technical overdispersion arising from RTA can then be divided out of the transcript counts, leading to scaled counts that can be input for analysis by established gene-level software tools with full statistical efficiency. Comprehensive simulations and test data show that an edgeR analysis of the scaled counts is more powerful and efficient than previous differential transcript expression pipelines while providing correct control of the false discovery rate. Simulations explore a wide range of scenarios including the effects of paired vs single-end reads, different read lengths and different numbers of replicates.
Risk of Severe Maternal Morbidity Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection During Pregnancy
Authors: Regan Annette K , Arah Onyebuchi A , Fell Deshayne B , Sullivan Sheena G
Published: December 2023

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy increases the risk of adverse fetal and neonatal outcomes, but the contribution to severe maternal morbidity (SMM) has been less frequently documented.

Methods

We conducted a national cohort study of 93 624 deliveries occurring between 11 March 2020 and 1 July 2021 using medical claims information from the OptumLabs Data Warehouse. SARS-CoV-2 infection was identified from diagnostic and laboratory testing claims records. We identified 21 SMM conditions using International Classification of Diseases, Tenth Revision, Clinical Modification and procedure codes and compared SMM conditions by SARS-CoV-2 status using Poisson regression with robust variance, adjusting for maternal sociodemographic and health factors, onset of labor, and week of conception.

Results

Approximately 5% of deliveries had a record of SARS-CoV-2 infection: 27.0% <7 days before delivery, 13.5% within 7–30 days of delivery, and 59.5% earlier in pregnancy. Compared to uninfected pregnancies, the adjusted risk of SMM was 2.22 times higher (95% confidence interval [CI], 1.97–2.48) among those infected <7 days before delivery and 1.66 times higher (95% CI, 1.23–2.08) among those infected 7–30 days before delivery. The highest risks were observed for acute respiratory distress syndrome (adjusted risk ratio [aRR], 13.24 [95% CI, 12.86–13.61]) and acute renal failure (aRR, 3.91 [95% CI, 3.32–4.50]).

Conclusions

COVID-19 is associated with increased rates of SMM.
A Systematic Literature Review to Identify Diagnostic Gaps in Managing Immunocompromised Patients With Cancer and Suspected Infection
Authors: Hill Joshua A , Park Sarah Y , Gajurel Kiran , Taplitz Randy
Published: December 2023

Patients with cancer are increasingly vulnerable to infections, which may be more severe than in the general population. Improvements in rapid and timely diagnosis to optimize management are needed. We conducted a systematic literature review to determine the unmet need in diagnosing acute infections in immunocompromised patients with cancer and identified 50 eligible studies from 5188 records between 1 January 2012 and 23 June 2022. There was considerable heterogeneity in study designs and parameters, laboratory methods and definitions, and assessed outcomes, with limited evaluation of diagnostic impact on clinical outcomes. Culture remains the primary diagnostic strategy. Fewer studies employing molecular technologies exist, but emerging literature suggests that pathogen-agnostic molecular tests may add to the diagnostic armamentarium. Well-designed clinical studies using standardized methodologies are needed to better evaluate performance characteristics and clinical and economic impacts of emerging diagnostic techniques to improve patient outcomes.
Increasing marsh bird abundance in coastal wetlands of the Great Lakes, 2011–2021, likely caused by increasing water levels
Authors: Tozer Douglas C , Bracey Annie M , Fiorino Giuseppe E , Gehring Thomas M , Gnass Giese Erin E , Grabas Greg P , Howe Robert W , Lawrence Gregory J , Niemi Gerald J , Wheelock Bridget A , Ethier Danielle M
Published: December 2023

Wetlands of the Laurentian Great Lakes of North America (i.e., lakes Superior, Michigan, Huron, Erie, and Ontario) provide critical habitat for marsh birds. We used 11 years (2011–2021) of data collected by the Great Lakes Coastal Wetland Monitoring Program at 1,962 point-count locations in 792 wetlands to quantify the first-ever annual abundance indices and trends of 18 marsh-breeding bird species in coastal wetlands throughout the entire Great Lakes. Nine species (50%) increased by 8–37% per year across all of the Great Lakes combined, whereas none decreased. Twelve species (67%) increased by 5–50% per year in at least 1 of the 5 Great Lakes, whereas only 3 species (17%) decreased by 2–10% per year in at least 1 of the lakes. There were more positive trends among lakes and species (n = 34, 48%) than negative trends (n = 5, 7%). These large increases are welcomed because most of the species are of conservation concern in the Great Lakes. Trends were likely caused by long-term, cyclical fluctuations in Great Lakes water levels. Lake levels increased over most of the study, which inundated vegetation and increased open water-vegetation interspersion and open water extent, all of which are known to positively influence abundance of most of the increasing species and negatively influence abundance of all of the decreasing species. Coastal wetlands may be more important for marsh birds than once thought if they provide high-lake-level-induced population pulses for species of conservation concern. Coastal wetland protection and restoration are of utmost importance to safeguard this process. Future climate projections show increases in lake levels over the coming decades, which will cause “coastal squeeze” of many wetlands if they are unable to migrate landward fast enough to keep pace. If this happens, less habitat will be available to support periodic pulses in marsh bird abundance, which appear to be important for regional population dynamics. Actions that allow landward migration of coastal wetlands during increasing lake levels by removing or preventing barriers to movement, such as shoreline hardening, will be useful for maintaining marsh bird breeding habitat in the Great Lakes.
Two ARGONAUTE proteins loaded with transposon-derived small RNAs are associated with the reproductive cell lineage in Arabidopsis
Authors: Bradamante Gabriele , Nguyen Vu Hoang , Incarbone Marco , Meir Zohar , Bente Heinrich , Donà Mattia , Lettner Nicole , Scheid Ortrun Mittelsten , Gutzat Ruben
Published: December 2023

In sexually propagating organisms, genetic, and epigenetic mutations are evolutionarily relevant only if they occur in the germline and are hence transmitted to the next generation. In contrast to most animals, plants are considered to lack an early segregating germline, implying that somatic cells can contribute genetic information to progeny. Here we demonstrate that 2 ARGONAUTE proteins, AGO5 and AGO9, mark cells associated with sexual reproduction in Arabidopsis (Arabidopsis thaliana) throughout development. Both AGOs are loaded with dynamically changing small RNA populations derived from highly methylated, pericentromeric, long transposons. Sequencing of single stem cell nuclei revealed that many of these transposons are co-expressed within an AGO5/9 expression domain in the shoot apical meristem (SAM). Co-occurrence of transposon expression and specific ARGONAUTE (AGO) expression in the SAM is reminiscent of germline features in animals and supports the existence of an early segregating germline in plants. Our results open the path to investigating transposon biology and epigenome dynamics at cellular resolution in the SAM stem cell niche.
Transcription factor OsMYB30 increases trehalose content to inhibit α-amylase and seed germination at low temperature
Authors: Yu Huihui , Teng Zhenning , Liu Bohan , Lv Jiahan , Chen Yinke , Qin Zhonge , Peng Yan , Meng Shuan , He Yuchi , Duan Meijuan , Zhang Jianhua , Ye Nenghui
Published: December 2023

Low-temperature germination (LTG) is an important agronomic trait for direct-seeding cultivation of rice (Oryza sativa). Both OsMYB30 and OsTPP1 regulate the cold stress response in rice, but the function of OsMYB30 and OsTPP1 in regulating LTG and the underlying molecular mechanism remains unknown. Employing transcriptomics and functional studies revealed a sugar signaling pathway that regulates seed germination in response to low temperature (LT). Expression of OsMYB30 and OsTPP1 was induced by LT during seed germination, and overexpressing either OsMYB30 or OsTPP1 delayed seed germination and increased sensitivity to LT during seed germination. Transcriptomics and qPCR revealed that expression of OsTPP1 was upregulated in OsMYB30-overexpressing lines but downregulated in OsMYB30-knockout lines. In vitro and in vivo experiments revealed that OsMYB30 bound to the promoter of OsTPP1 and regulated the abundance of OsTPP1 transcripts. Overaccumulation of trehalose (Tre) was found in both OsMYB30- and OsTPP1-overexpressing lines, resulting in inhibition of α-amylase 1a (OsAMY1a) gene during seed germination. Both LT and exogenous Tre treatments suppressed the expression of OsAMY1a, and the osamy1a mutant was not sensitive to exogenous Tre during seed germination. Overall, we concluded that OsMYB30 expression was induced by LT to activate the expression of OsTPP1 and increase Tre content, which thus inhibited α-amylase activity and seed germination. This study identified a phytohormone-independent pathway that integrates environmental cues with internal factors to control seed germination.
Causalized convergent cross-mapping and its approximate equivalence with directed information in causality analysis
Authors: Deng Jinxian , Sun Boxin , Scheel Norman , Renli Alina B , Zhu David C , Zhu Dajiang , Ren Jian , Li Tongtong , Zhang Rong
Published: December 2023

Convergent cross-mapping (CCM) has attracted increased attention recently due to its capability to detect causality in nonseparable systems under deterministic settings, which may not be covered by the traditional Granger causality. From an information-theoretic perspective, causality is often characterized as the directed information (DI) flowing from one side to the other. As information is essentially nondeterministic, a natural question is: does CCM measure DI flow? Here, we first causalize CCM so that it aligns with the presumption in causality analysis—the future values of one process cannot influence the past of the other, and then establish and validate the approximate equivalence of causalized CCM (cCCM) and DI under Gaussian variables through both theoretical derivations and fMRI-based brain network causality analysis. Our simulation result indicates that, in general, cCCM tends to be more robust than DI in causality detection. The underlying argument is that DI relies heavily on probability estimation, which is sensitive to data size as well as digitization procedures; cCCM, on the other hand, gets around this problem through geometric cross-mapping between the manifolds involved. Overall, our analysis demonstrates that cross-mapping provides an alternative way to evaluate DI and is potentially an effective technique for identifying both linear and nonlinear causal coupling in brain neural networks and other settings, either random or deterministic, or both.
The impacts of extreme temperature on mortality and emergency hospital admissions within East Sussex in comparison with pre-existing national trends
Authors: Jackson Kaine , Noushad Abia
Published: December 2023

Background

The impacts of heatwaves are a rapidly growing area of study; however, much of the existing research focusses on national data analysis. This article aims to add a local perspective using data from only one county, East Sussex, and comparing these with the pre-existing national data.

Methods

Population data were obtained from publicly available sources such as the Office of National Statistics, in addition to anonymized data from patients. Statistical analysis calculated excess mortality and emergency hospital admissions associated with both winter and heatwaves. Further analyses into factors associated with worse health outcomes in pre-existing data, such as the extremes of age (under 1 s and over 75 s), dementia and respiratory conditions, were conducted and their effect on excess mortality and emergency admissions was compared with national data.

Results

Excess winter mortality within East Sussex averaged 22.5%. Excess heatwave mortality averaged 17%, measuring higher than national data. The relative significance of these data is expected to increase over the next 30 years in line with the UK Health Security Agency projection of heat-related mortality tripling by 2050 in the context of global warming and increasing temperatures.

Conclusions

Although the number of residents dying or requiring emergency admission due to cold weather is larger than that of heatwaves, trends show a worsening impact of heatwaves. The results of this report are significant findings which show more action is required to mitigate the effects of extreme heat.