bluuebunny/crossref_metadata_2025 huggingface dataset:
Foucault and the Task of Philosophy
Authors: Oksala Johanna
Published: July 2024

The chapter assesses Michel Foucault’s position in the tradition of modern French philosophy by focusing on his most influential philosophical ideas concerning power and the subject. The chapter situates these ideas in the context of the French philosophy of his time, particularly in their relation to existential phenomenology and Marxist philosophy, which had been the dominant philosophical frameworks in France during Foucault’s formative years, that is, during the 1950s and 1960s. A key contention of this chapter is that phenomenology and Marxist philosophy provide an essential backdrop for bringing into relief the philosophical novelty of Foucault’s philosophical innovations about power and the subject.
French Phenomenology after 1961
Authors: Dastur Françoise
Published: July 2024

French philosophy opened up to German philosophy in the 1930s and to Husserlian and Heideggerian phenomenology during the Second World War. Existentialism was the main philosophical current until 1961, a year marked by Merleau-Ponty’s death. During the following twenty years, French philosophical life was dominated by what has been called ‘French structuralism’. This article shows how it was only at the beginning of the 1980s that, with structuralism losing its hegemony, a kind of renaissance of phenomenology took place, and how it came to be dominated by what has been called the ‘theological turn of French phenomenology’ in the work of Emmanuel Levinas, Michel Henry, and Jean-Luc Marion. In the last twenty years the proliferation of phenomenological works by young philosophers and the opening of phenomenology to the fields of art, anthropology, sociology, and psychiatry attest to the vitality of the French phenomenological movement.
Heidegger in Modern French Philosophy
Authors: Raffoul François
Published: July 2024

It would be hard to underestimate the impact that Heidegger’s thought has had on twentieth-century French philosophy. Heidegger influenced a wide range of philosophical movements, and, after him, French thought has to a large extent constituted itself in dialogue with his thought, whether by embracing it, rejecting it, or misunderstanding it. The French reception of Heidegger has been everything but passive; it has given rise to all kinds of interpretations, appropriations, or misappropriations, not to mention misunderstandings, even if these were brilliant and inventive, as in the case of Sartre. This chapter explores the forms that this reception has taken in the work of Sartre, Levinas, and Derrida.
Aesthetics in Modern French Philosophy
Authors: Talon-Hugon Carole
Published: July 2024

In French philosophy during the nineteenth and twentieth centuries, philosophical reflection on the topics of beauty, art, and aesthetic values took on extremely varied forms. These reflections do not only include very different theses on such topics, but also opposed methodological approaches to them. Moreover, these opposed methodological approaches implied very different definitions of aesthetics itself. In surveying this work, this chapter addresses the philosophical delimitation of these topics and methods, and, in consequence, the question of whether aesthetics is a branch of philosophy, a science that ought to gain autonomy in relation to philosophy, or a mixed discipline that presupposes a collaboration between philosophy and other disciplines.
Desire in Modern French Philosophy
Authors: de Beistegui Miguel
Published: July 2024

This chapter focuses on a fifty-year period (1933–1984), during which the question of desire took centre stage. At the heart of it lies the effort to question the Cartesian cogito as the root of human subjectivity, and to explore desire as a deeper layer of human experience. This crucial shift from the ‘I think’ to the ‘I desire’, which began with Maine de Biran and Ravaisson, took two fundamental and ultimately incompatible forms: a transcendent one, for which desire signals the presence of a lack, an absence, or something that is always to come; and an immanent one, which recognizes the essentially productive nature of desire, or its power of subjectivation, for better or for worse.
Reason and Analysis in Modern French Philosophy
Authors: Engel Pascal
Published: July 2024

French philosophy since 1800 has not been dominated by rationalism, but, instead, by various forms of rejection of reason inspired by spiritualism. Nonetheless, a small group of thinkers have defended various versions of what one may call intellectualist rationalism, promoting the primacy of concepts and scientific reason over that of life and emotion. This chapter describes this small and somewhat neglected tradition, starting from Cournot to Couturat, furthered by Nicod, Cavaillès, Granger, Vuillemin, and Bouveresse. Although these developments look to what later became analytic philosophy in the twentieth century, I explain that they constitute a distinctive brand of French rationalism.
Vacherot and His Circle
Authors: Yuva Ayşe
Published: July 2024

This chapter deals with some of the spiritualist heirs to Cousin, Vacherot, and Saisset, and the reactions they provoked among Catholic authors on the one hand, and those in thrall to the positive sciences, like Renan, on the other. Vacherot and Saisset argue, against both these groups, that reason is capable of ascending to metaphysical truths, and that philosophy is not thereby subordinated to either religion or the positive sciences. Although the discussion focuses on the relationship between God and the world, what is at stake is the capacity of philosophy to take on intellectual and political authority, even when that authority is democratic in Vacherot’s case.
Agriculture, Food Systems, and the Environment
Authors: Lokhandwala Zainab
Published: July 2024

Despite extensive environmental impacts such as soil degradation, land use changes, biodiversity loss, water resource depletion, chemical and toxic release, and pollution, environmental law has remained virtually silent about agriculture and food systems. As a result, environmental law’s prescriptive, administrative, and adjudicatory capacities to tackle environmental impacts of agriculture remain underdeveloped. India’s agriculture and food systems continue to tread towards greater environmental damage owing to the combination of passive silences and active protections of the law. This chapter shows that since the 1960 Green Revolution, agricultural development in India idealises ‘success’ based on growth and productivism, technological and input intensity, and the ability to cater to a globalized commodity market. This chapter further explores a blend of interventions within environmental law, agricultural law, and other legal domains, along with a reimagination of agriculture and food systems that may prevent future environmental impacts.
Forest Rights and the Forest Rights Act
Authors: Khanna Shomona
Published: July 2024

The enactment of the Scheduled Tribes and Other Traditional Forest Dwellers (Recognition of Forest Rights) Act, 2006 (the FRA) advances international best practice in forest conservation, recognising that indigenous and local forest dwelling communities play a vital role in forest ecosystems, and their active involvement in forest governance is integral to climate change mitigation. It recognises the land rights of indigenous peoples and other local communities who depend on forest resources for their livelihoods and food security. The FRA necessarily sets about re-calibrating the forest law architecture and forest bureaucracy. While the FRA has been in force for more than sixteen years, it continues to be a site of fierce contestation. This chapter analyses these contestations from a legal perspective.
Air Quality Regulation
Authors: Ghosh Shibani
Published: July 2024

This chapter unpacks the key components of air quality regulation in India. It provides an overview of the regulatory and institutional framework that governs some of the major sources of air pollution in the country, focusing primarily on national laws and policies. It identifies four main challenges in regulating air quality: weaknesses in regulatory design; capacity and capability constraints in regulatory institutions; flawed policy-making; and the inadequacy of hard regulation in delivering cleaner air. The chapter concludes by suggesting certain pathways for reform: through legal amendments, institutional strengthening, and development of technical capacity for sound policy-making.
Climate Change
Authors: Dubash Navroz Kersi , Pillai Aditya Valiathan , Sridhar Anirudh
Published: July 2024

Transforming towards a low-carbon, climate-resilient society will require reimagining existing governance arrangements. This chapter documents how India’s policies, institutions, and legal structures have changed in response to climate change. These developments have been opportunistic in character, with policy changes preceding institutional development. Policies are many and widespread, therefore, but lack strategic coherence. A more deliberate approach would bring with it enhanced governance requirements, including new structures for coordination, deliberation, and strategy-setting. This chapter pays attention to the prospects for climate law in India in this context, discussing different approaches to constructing firmer legal foundations for climate action.
The security of politicians: towards a research agenda
Authors: Matthews Neil , Haughey Sean
Published: July 2024

Members of Parliament (MPs) are increasingly experimenting with a variety of measures to protect their personal security. This trend is particularly evident at the local level, with MPs adjusting their constituency service on security grounds in ways that likely affect how they interact with constituents. Despite potentially significant representative implications, these enhanced security measures have yet to be problematized in detail. This article calls for a new research agenda to address this deficit. Exploring some of the anecdotal evidence, we highlight potential trade-offs arising from a more securitized constituency service experience, noting, in particular, costs pertaining to (1) accessibility, (2) symbolism, and (3) resources. We conclude by sketching out the broad parameters of a multi-method, multi-level, and multi-disciplinary research agenda on the security of politicians.
Jim Crow and Black Economic Progress after Slavery
Authors: Althoff Lukas , Reichardt Hugo
Published: July 2024

This article studies the long-run effects of slavery and restrictive Jim Crow institutions on Black Americans’ economic outcomes. We track individual-level census records of each Black family from 1850 to 1940 and extend our analysis to neighborhood-level outcomes in 2000 and surname-based outcomes in 2023. We show that Black families whose ancestors were enslaved until the Civil War have considerably lower education, income, and wealth than Black families whose ancestors were free before the Civil War. The disparities between the two groups have persisted substantially because most families enslaved until the Civil War lived in states with strict Jim Crow regimes after slavery ended. In a regression discontinuity design based on ancestors’ enslavement locations, we show that Jim Crow institutions sharply reduced Black families’ economic progress in the long run.
Religious rebound, political backlash, and the youngest cohort: understanding religious change in Turkey
Authors: Atac Ibrahim Enes , Adler Jr Gary J
Published: July 2024

We distinguish two streams of theory that dominate explanations of religious change: cohort-based cumulative decline theory, which emphasizes small and ongoing declines in individual religiosity accruing across generations; and political backlash theory, which emphasizes period- and identity-based changes due to the politicized meaning of religion. Notably, Muslim countries have largely been excluded from a recent wave of quantitative research on individual-level religious change, implicitly continuing an assumption that Islamic societies require different theoretical concepts. We deploy both theories to examine religious identity and behavior over multiple decades in Turkey, a Muslim-majority country with recent social conflict over religion. Utilizing age-period-cohort interaction models, our results suggest minimal evidence for a cohort-based process in Turkey, in contrast to that observed in Western countries. Rather, a political transformation—the politicization of religion through the rise of Turkey’s AKP (Justice and Development Party) and President Erdogan—is most salient to Turkish religious change. We introduce two concepts to backlash theory—identity updating and performance signaling—to show how different dimensions of individual religiosity respond to different politicized contexts. These findings extend our understanding of religious change beyond the Western context, with further implications for theorizing political backlash and cohort-based processes.
Understanding Species Boundaries that Arise from Complex Histories: Gene Flow Across the Speciation Continuum in the Spotted Whiptail Lizards
Authors: Barley Anthony J , Nieto-Montes de Oca Adrián , Manríquez-Morán Norma L , Thomson Robert C
Published: July 2024

—Gene flow between diverging lineages challenges the resolution of species boundaries and the understanding of evolutionary history in recent radiations. Here, we integrate phylogenetic and coalescent tools to resolve reticulate patterns of diversification and use a perspective focused on evolutionary mechanisms to distinguish interspecific and intraspecific taxonomic variation. We use this approach to resolve the systematics for one of the most intensively studied but difficult to understand groups of reptiles: the spotted whiptail lizards of the genus Aspidoscelis (A. gularis complex). Whiptails contain the largest number of unisexual species known within any vertebrate group and the spotted whiptail complex has played a key role in the generation of this diversity through hybrid speciation. Understanding lineage boundaries and the evolutionary history of divergence and reticulation within this group is therefore key to understanding the generation of unisexual diversity in whiptails. Despite this importance, long-standing confusion about their systematics has impeded understanding of which gonochoristic species have contributed to the formation of unisexual lineages. Using reduced representation genomic data, we resolve patterns of divergence and gene flow within the spotted whiptails and clarify patterns of hybrid speciation. We find evidence that biogeographically structured ecological and environmental variation has been important in morphological and genetic diversification, as well as the maintenance of species boundaries in this system. Our study elucidates how gene flow among lineages and the continuous nature of speciation can bias the practice of species delimitation and lead taxonomists operating under different frameworks to different conclusions (here we propose that a 2 species arrangement best reflects our current understanding). In doing so, this study provides conceptual and methodological insights into approaches to resolving diversification patterns and species boundaries in rapid radiations with complex histories, as well as long-standing taxonomic challenges in the field of systematic biology.
Method for Testing Etiologic Heterogeneity Among Noncompeting Diagnoses, Applied to Impact of Perinatal Exposures on Autism and Attention Deficit Hyperactivity Disorder
Authors: Kalkbrenner Amy E. , Zheng Cheng , Yu Justin , Jenson Tara E. , Kuhlwein Thomas , Ladd-Acosta Christine , Grove Jakob , Schendel Diana
Published: July 2024

Background:

Testing etiologic heterogeneity, whether a disorder subtype is more or less impacted by a risk factor, is important for understanding causal pathways and optimizing statistical power. The study of mental health disorders especially benefits from strategic subcategorization because these disorders are heterogeneous and frequently co-occur. Existing methods to quantify etiologic heterogeneity are not appropriate for noncompeting events in an open cohort of variable-length follow-up. Thus, we developed a new method.

Methods:

We estimated risks from urban residence, maternal smoking during pregnancy, and parental psychiatric history, with subtypes defined by the presence or absence of a codiagnosis: autism alone, attention deficit hyperactivity disorder (ADHD) alone, and joint diagnoses of autism + ADHD. To calculate the risk of a single diagnosis (e.g., autism alone), we subtracted the risk for autism + ADHD from the risk for autism overall. We tested the equivalency of average risk ratios over time, using a Wald-type test and bootstrapped standard errors.

Results:

Urban residence was most strongly linked with autism + ADHD and least with ADHD only; maternal smoking was associated with ADHD only but not autism only; and parental psychiatric history exhibited similar associations with all subgroups.

Conclusion:

Our method allowed the calculation of appropriate P values to test the strength of association, informing etiologic heterogeneity wherein two of these three risk factors exhibited different impacts across diagnostic subtypes. The method used all available data, avoided neurodevelopmental outcome misclassification, exhibited robust statistical precision, and is applicable to similar heterogeneous complex conditions using common diagnostic data with variable follow-up.
Estimating the Effect of Bariatric Surgery on Cardiovascular Events Using Observational Data?
Authors: Madenci Arin L. , Kurgansky Katherine E. , Dickerman Barbra A. , Gerlovin Hanna , Wanis Kerollos Nashat , Smith Ann D. , Trinquart Ludovic , Gagnon David R. , Cho Kelly , Gaziano J. Michael , Casas Juan P. , Robins James M. , Hernán Miguel A.
Published: July 2024

Background:

Observational studies have reported strongly protective effects of bariatric surgery on cardiovascular disease, but with oversimplified definitions of the intervention, eligibility criteria, and follow-up, which deviate from those in a randomized trial. We describe an attempt to estimate the effect of bariatric surgery on cardiovascular disease without introducing these sources of bias, which may not be entirely possible with existing observational data.

Methods:

We propose two target trials among persons with diabetes: (1) bariatric operation (vs. no operation) among individuals who have undergone preoperative preparation (lifestyle modifications and screening) and (2) preoperative preparation and a bariatric operation (vs. neither preoperative nor operative component). We emulated both target trials using observational data of US veterans.

Results:

Comparing bariatric surgery with no surgery (target trial #1; 8,087 individuals), the 7-year cardiovascular risk was 18.0% (95% CI = 6.9, 32.7) in the surgery group and 18.9% (95% CI = 17.7, 20.1) in the no-surgery group (risk difference −0.9, 95% CI = −12.0, 14.0). Comparing preoperative components plus surgery vs. neither (target trial #2; 10,065 individuals), the 7-year cardiovascular risk was 17.4% (95% CI = 13.6, 22.0) in the surgery group and 18.8% (95% CI = 17.8, 19.9) in the no-surgery group (risk difference −1.4, 95% CI = −5.1, 3.2). Body mass index and hemoglobin A1c were reduced with bariatric interventions in both emulations.

Conclusions:

Within limitations of available observational data, our estimates do not provide evidence that bariatric surgery reduces cardiovascular disease and support equipoise for a randomized trial of bariatric surgery for cardiovascular disease prevention.
Coadministration of Voriconazole and Rifabutin Can Increase the Risk of Adverse Drug Reactions in Patients with Multiple Infections
Authors: Kim Yoonjin , Bae Sungyeun , Huh Ki Young , Joo Jong Sun , Lee Jikyo , Song Sang Hoon , Yu Kyung-Sang , Jang In-Jin , Oh Jaeseong
Published: July 2024

Background:

Coinfection of tuberculosis or nontuberculous mycobacteria and Aspergillus presents a challenge in medication selection because of the pharmacokinetic interactions between rifampin and voriconazole. Some researchers have suggested the use of rifabutin as an alternative to rifampin because of its lower hepatic cytochrome P450 enzyme induction potency despite its contraindication to drug labels. This study presents clinical cases of voriconazole and rifabutin coadministration and their potential risks.

Methods:

This retrospective study was conducted using clinical data from patients who met the following criteria: (1) admitted to Seoul National University Hospital between July 2014 and August 2023 and (2) concurrently administered rifabutin and voriconazole for more than 5 days.

Results:

Among the 6 patients analyzed, 4 experienced adverse drug reactions (ADRs). Three patients experienced visual and auditory hallucinations, lower extremity numbness, or delirious behavior. Two patients had prolonged the time from the start of the Q wave to the end of the T wave intervals, and 1 had elevated aspartate aminotransferase and alanine aminotransferase levels. In addition, 2 patients experienced severe nausea, poor oral intake, and weight loss. Despite receiving 1.81-fold the recommended voriconazole dosage, a therapeutic concentration (1.0–5.5 mg/L) was not achieved because of cytochrome P450 induction by rifabutin. However, during septic shock, the voriconazole concentration increased by 13.7- to 36-fold.

Conclusions:

Concurrent use of rifabutin and voriconazole was associated with ADRs, including the time from the start of the Q wave to the end of the T wave prolongation, hallucinations, and severe nausea. Moreover, initially, there was a significant decrease in voriconazole concentrations; however, these concentrations substantially increased during septic shock. Therefore, it is essential to monitor drug concentrations and ADRs during concurrent use of voriconazole and rifabutin.
Modeling Fallout from Nuclear Weapon Detonations: Efficient Activity and Dose Calculation of Radionuclides and Their Progeny
Authors: van Dijk Arjan , de Bode Michiel , Kloosterman Astrid , van der Linden Marte , Tomas Jasper M.
Published: July 2024

The purpose of this paper is to present a practical method for quick determination of potential radiological doses and contaminations by fallout from nuclear detonations, or other releases, that includes the contributions from all nuclides. We precalculate individual (total) activities of all radionuclides from any initial cocktail and all their ingrowing progeny at a set of pinpoints in time with a logarithmic time-spacing. This is combined with the set of dose conversion factors (DCC) for any exposure pathway to obtain a time-dependent cocktail for the whole release as if it is one substance. An atmospheric dispersion model then provides the thinning coefficient of the released material to give local concentrations and dose rates. Progeny ingrowth is illustrated for pure 238U and for a nuclear reactor that has been shut down. Efficient dose assessment is demonstrated for fallout from nuclear detonations and compared with the traditional approach of preselecting nuclides for specific endpoints and periods-of-interest. The compound cocktail DCC reduces the assessment of contaminations and potential dose-effects from fallout after a nuclear detonation to (the atmospheric dispersion of) only one tracer substance, representing any cocktail of nuclides and their progeny. This removes the need to follow all separate nuclides or an endpoint-specific preselection of “most important nuclides.” As the cocktail DCCs can be precalculated and the atmospheric dispersion of only one tracer substance has to be modelled, our method is fast. The model for calculating cocktail DCCs is freely available, easily coupled to any regular atmospheric dispersion model, and therefore ready for operational use by others.
Risk of Traumatic Brain Injury in Deployment and Nondeployment Settings Among Members of the Millennium Cohort Study
Authors: Jannace Kalyn C. , Pompeii Lisa , Gimeno Ruiz de Porras David , Perkison William Brett , Yamal Jose-Miguel , Trone Daniel W. , Rull Rudolph P.
Published: July 2024

Objective:

To describe and quantify the prevalence and risk of deployment and nondeployment service-related traumatic brain injury (TBI) among participants of the Millennium Cohort Study.

Setting:

Survey data.

Participants:

28 759 Millennium Cohort Study participants who were active duty, Reserves, or National Guard at the time of the survey.

Design:

Cross-sectional secondary data analysis.

Main Measures:

Estimates of prevalence and rates of TBI were calculated. Multivariable Poisson regression estimated rate ratios of TBI overall and stratified by deployment and nondeployment settings.

Results:

The rate of TBI over the 362 535 person-years (PY) was 2.95 p/100 PY. the nondeployment rate was 2.15 p/100 PY, with a significantly higher rate (11.38 p/100 PY) in deployment settings. Bullets/blasts were the most common TBI mechanisms in deployed settings, while sports/physical training and military training were common in nondeployed settings.

Conclusions:

The risk of TBI as well as its mechanism varies by deployment and nondeployment, suggesting that targeted prevention strategies are needed to reduce the risk for TBI among military personnel based on their deployment status.
Disease X and COVID-19: turning lessons from India and the world into policy recommendations
Authors: Bardhan Mainak , Ray Ishita , Roy Shubhajeet , Roy Priyanka , Thanneeru Priya , Twayana Anu Radha , Prasad Sakshi , Bardhan Mayukh , Anand Ayush
Published: July 2024

Disease X is caused by pathogen X, an unknown infectious agent that can potentially trigger an epidemic or pandemic. Pathogen X might be any pathogen, including bacteria, viruses, parasites, fungi, and prions. WHO uses the term ‘Disease X’ for any new emerging disease caused by an unknown pathogen X. Disease X stands for any possible future pandemic in WHO’s shortlist of high-priority diseases. This review looks at the manifestations of the recent COVID-19 epidemic as the first Disease X to evaluate what has happened and to learn from what went wrong in India and worldwide. To this end, a summary is presented of response measures by governments, often lacking flows of information, discrepancies in the views of experts and decisions of policymakers, and undesirable variations in individual and collective behavior and their consequences. The elements of combating Disease X in a world with considerable inequalities in relevant knowledge, expertise, information, quality of governance, and financial possibilities are discussed. Based on this, recommendations are given for an innovative global pandemic preparedness system.
Morphomolecular Correlation and Clinicopathologic Analysis in Endometrial Carcinoma
Authors: Bülbül Göksenil , Aktaş Tekincan Çağri , Aysal Ağalar Anil , Aktaş Safiye , Kurt Sefa , Saatli Bahadir , Ulukuş Emine Çağnur
Published: July 2024

Research groups have identified 4 groups [polymerase epsilon (POLE) mutant, mismatch repair-deficient, p53-abnormal, and no specific molecular profile)] reflecting the Tumor Cancer Genomic Atlas Research Network subgroups in endometrial carcinomas, improving the clinical applicability of molecular classification. We have analyzed the histopathologic and prognostic characteristics of our cases based on the ProMisE classification, supported by growing data on recommended treatment regimens. The study included 118 cases of endometrial carcinoma diagnosed between 2016 and 2020, which underwent mismatch repair and p53 immunohistochemistry. Next-generation sequencing was performed for POLE mutation analysis, dividing the cases into 4 subgroups. The histopathologic and clinical characteristics of these groups were then analyzed statistically. Four cases(3.4%) were classified as POLE mutant, 31 (26.3%) as mismatch repair-deficient, 22 (18.6%) as p53 mutant, and 61 (51.7%) as no specific molecular profile. We categorized 118 patients with endometrial carcinoma into low (n=43), intermediate (n=28), high-intermediate (n=21), high (n=22), and advanced metastatic (n=4) risk groups regardless of the molecular subtypes of their disease. When we reclassified all cases according to the molecular subtypes of endometrial carcinoma only the risk group of 3 (2.5%) cases changed. Using the new algorithm we designed, after narrowing down the number of patients, the microcystic, elongated, and fragmented pattern of invasion was revealed as an independent prognostic factor that reduces overall survival time (hazard ratio: 16.395, 95% CI: 2.140–125.606, P=0.007). In conclusion, using the new algorithm we have designed, and by identifying patients for whom molecular classification could alter risk groups, we observed that molecular tests can be utilized more efficiently in populations with limited economic resources and, in doing so, we discovered a new morphologic marker with prognostic significance.
Lymphaticovenous and Lymph Node–to-Vein Anastomosis to Improve Milroy Disease–Related Chylothorax and Lymphedema
Authors: Alshomer Feras , Cho Jeongmok , Noh Hyungjoo , Pak Changsik John , Suh Hyunsuk Peter , Hong Joon Pio
Published: July 2024

Background:

Primary lymphedema is characterized by lymphatic dysplasia in which one variant is Milroy disease. The association with congenital chylothorax is even rarer, with poor outcome. This is the first report to use peripheral lymphovenous anastomosis (LVA) and lymph node–to-vein anastomosis (LNVA) for the management of such condition.

Methods:

A retrospective chart review of patients with Milroy disease with complication of chylothorax between 2019 until 2023 was performed. Clinical assessment and radiologic investigations were reviewed.

Results:

Six patients with a mean age of 12 ± 3.9 years and disease duration of 10.5 ± 2.8 years were reviewed. Three had International Society of Lymphology stage 3 disease, and the others had stage 2 (late) disease. All had bilateral lower extremity lymphedema and chylothorax with history of chest tube drainage. After LVA and LNVA, significant reduction in extremity volume (P = 0.028) along with nearly complete resolution of chylothorax were noted during the long-term follow-up (32 ± 17.9 months).

Conclusions:

Milroy disease complicated with chylothorax remains challenging. This is the first report using peripheral bypass (LVA and LNVA), which resulted in improvement of both lower extremity lymphedema and chylothorax. The utility of this approach represents a promising modality in the management of this devastating condition.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Elevated stress-responsive biomarkers are associated with HIV acquisition in young women in rural South Africa
Authors: Stoner Marie C.D. , Kelly Nicole K. , Gomez-Olive F. Xavier , Mall Sumaya , Wagner Danielle , Aiello Allison E. , Bhushan Nivedita , Kahn Kathleen , Pettifor Audrey E.
Published: July 2024

Objective:

Biological markers of stress have been associated with HIV progression and pathogenesis but not with HIV incidence. We sought to determine if elevated stress-responsive biomarkers would be associated with incident HIV among adolescent girls and young women (AGYW).

Design:

We conducted a case-cohort study within the HIV Prevention Trials Network (HPTN) 068 study among 949 AGYW in South Africa. Cases were AGYW who tested HIV-positive during the eight-year follow-up. Unmatched controls were randomly selected from the HIV-negative population at enrollment.

Methods:

Dried blood spots from cases and controls were tested from enrollment (2011–2012) for C-reactive protein (CRP), herpes simplex virus type-1 (HSV-1) antibody titers, and cytomegalovirus (CMV) antibody titers. Cox proportional hazards models estimated the association between each biomarker and time to incident HIV.

Results:

Compared to AGYW with the lowest CRP levels, those with medium and high CRP levels had a higher hazard ratio (HR) of incident HIV [HR: 1.45, 95% confidence interval (CI): 0.95, 2.21; HR: 1.50, 95% CI: 0.98, 2.30, respectively], although not statistically significant. The relative hazard of incident HIV was also higher among AGYW who were CMV seropositive vs. seronegative (low antibodies HR: 2.18, 95% CI: 1.2, 3.87; medium HR: 2.25, 95% CI: 1.28, 3.95; high HR: 1.78, 95% CI: 0.99, 3.21). Those with the highest HSV-1 antibody levels experienced an increased hazard of HIV compared to those who were HSV-1 seronegative (HR: 1.58, 95% CI: 1.03, 2.44).

Conclusions:

Biological stress may increase AGYW's susceptibility to HIV acquisition through changes in immune function, viral infection, and increased biological vulnerability to disease.
Modeling Alternative Conformational States of Pseudo-Symmetric Solute Carrier Transporters using Methods from Deep Learning
Authors: Swapna G.V.T. , Dube Namita , Roth Monica J. , Montelione Gaetano T.
Published: July 2024

The Solute Carrier (SLC) superfamily of integral membrane proteins function to transport a wide array of small molecules across plasma and organelle membranes. SLC proteins also function as important drug transporters and as viral receptors. Despite being classified as a single superfamily, SLC proteins do not share a single common fold classification; however, most belong to multi-pass transmembrane helical protein fold families. SLC proteins populate different conformational states during the solute transport process, including outward-open, intermediate (occluded), and inward-open conformational states. For some SLC fold families this structural “flipping” corresponds to swapping between conformations of their N-terminal and C-terminal symmetry-related sub-structures. Conventional AlphaFold2, AlphaFold3, or Evolutionary Scale Modeling methods typically generate models for only one of these multiple conformational states of SLC proteins. Several modifications of these AI-based protocols for modeling multiple conformational states of proteins have been described recently. These methods are often impacted by “memorization” of one of the alternative conformational states, and do not always provide both the inward and outward facing conformations of SLC proteins. Here we describe a combined ESM – template-based-modeling process, based on a previously described template-based modeling method that relies on the internal pseudo-symmetry of many SLC proteins, to consistently model alternate conformational states of SLC proteins. We further demonstrate how the resulting multi-state models can be validated experimentally by comparison with sequence-based evolutionary co-variance data (ECs) that encode information about contacts present in the various conformational states adopted by the protein. This simple, rapid, and robust approach for modeling conformational landscapes of pseudo-symmetric SLC proteins is demonstrated for several integral membrane protein transporters, including SLC35F2 the receptor of a feline leukemia virus envelope protein required for viral entry into eukaryotic cells.
Simulations of the infant gut microbiota suggest that complex ecological interactions regulate effects of human milk oligosaccharides on microbial mucin consumption
Authors: Versluis David M. , Wijtkamp Clair , Looijesteijn Ellen , Geurts Jan M. W. , Merks Roeland M. H.
Published: July 2024

Intestinal mucin acts as a barrier protecting the infant gut wall against diseases such as colitis and rotavirus.In vitroexperiments have shown that the gut microbiota of breastfed infants consumes less mucin than the microbiota of non-breastfed infants, but the mechanisms are incompletely understood. The main difference between human milk and most infant formulas is the presence of human milk oligosaccharides (HMOs) in human milk. We hypothesize that HMOs protect mucin by stimulating non-mucin consuming bacteria. To understand the un-derlying mechanisms we developed a computational model that describes the metabolism and ecology of the infant gut microbiota. Model simulations suggest that extracellular digestion of the HMO 2’-fucosyllactose by the mucin-consumerBifidobacterium bifidummay make this species vulnerable to competitors. The digestion products of HMOs become ‘public goods’ that can be consumed by competing species such asBacteroides vulgatusinstead.Bifidobacterium longum, which does not consume mucin or produce public goods, can then become dominant, despite growing less efficiently on HMOs in monocultures thanB. bifidum. In conclusion, our model simulations suggest that, through complex ecological interactions, HMOs may help lower mucin consumption by stimulating the non-mucin consumerB. longumat the expense of the mucin consumerB. bifidum.
Automated Skin Lesion Detection and Prevalence Estimation in Tamanend’s Bottlenose Dolphins
Authors: Murphy Colin J. , Collier Melissa A. , Jacoby Ann-Marie , Patterson Eric M. , Wallen Megan M. , Mann Janet , Bansal Shweta
Published: July 2024

Anthropogenic global change is occurring at alarming rates, leading to increased urgency in the ability to monitor wildlife health in real time. Monitoring sentinel marine species, such as bottlenose dolphins, is particularly important due to extensive anthropogenic modifications to their habitats. The most common non-invasive method of monitoring cetacean health is documentation of skin lesions, often associated with poor health or disease, but the current methodology is inefficient and imprecise. Recent advancements in technology, such as machine learning, can provide researchers with more efficient ecological monitoring methods to address health questions at both the population and the individual levels. Our work develops a machine learning model to classify skin lesions on the understudied Tamanend’s bottlenose dolphins (Tursiops erebennus) of the Chesapeake Bay, using manual estimates of lesion presence in photographs. We assess the model’s performance and find that our best model performs with a high mean average precision (65.6%-86.8%), and generally increased accuracy with improved photo quality. We also demonstrate the model’s ability to address ecological questions across scales by generating model-based estimates of lesion prevalence and testing the effect of gregariousness on health status. At the population level, our model accurately estimates a prevalence of 72.1% spot and 27.3% fringe ring lesions, with a slight underprediction compared to manual estimates (82.2% and 32.1%). On the other hand, we find that individual-level analyses from the model predictions may be more sensitive to data quality, and thus, some individual scale questions may not be feasible to address if data quality is inconsistent. Manually, we do find that lesion presence in individuals suggests a positive relationship between lesion presence and gregariousness. This work demonstrates that object detection models on photographic data are reasonably successful, highly efficient, and provide initial estimates on the health status of understudied populations of bottlenose dolphins.
Effect of Voltage-Gated K+Channel Inhibition by 4-aminopyridine in Spinal Cord Injury Recovery in Zebrafish
Authors: Hoffman Payge M. , Mruk Karen
Published: July 2024

Spinal cord injury (SCI) affects between 250,000 to 500,000 individuals annually. After the initial injury, a delayed secondary cascade of cellular responses occurs causing progressive degeneration and permanent disability. One part of this secondary process is disturbance of ionic homeostasis. The K+channel blocker, 4-aminopyridine (4-AP), is used clinically to alleviate symptoms of multiple sclerosis (MS). Several ongoing studies are being conducted to explore additional areas where 4-AP may have an effect, including stroke, traumatic brain injury, and nervous system recovery after SCI. The goal of our study was to determine whether 4-AP affects recovery from SCI in zebrafish (Danio rerio). Using the transgenic lineTg(gfap:EGFP), we created a spinal transection and tracked swim recovery. We found that constant treatment with 10 µM 4-AP increases swimming distance 40%. Live imaging demonstrated that treatment with 4-AP increases radial glial cells bridging at the site of injury in the presence of 4-AP. We conclude that 10 µM 4-AP is pro-regenerative after SCI.

Significance Statement

In this study, we found that 4-AP can enhance locomotor recovery in zebrafish after spinal cord injury. Our findings indicate that inhibition of K+channels with 4-AP may promote glial remodeling that is pro-regenerative.
Resistance to age-related hearing loss in the echolocating big brown bat (Eptesicus fuscus)
Authors: Capshaw Grace , Diebold Clarice A. , Adams Danielle M. , Rayner Jack , Wilkinson Gerald S. , Moss Cynthia F. , Lauer Amanda M.
Published: July 2024

Hearing mediates many behaviors critical for survival in echolocating bats, including foraging and navigation. Most mammals are susceptible to progressive age-related hearing loss; however, the evolution of biosonar, which requires the ability to hear low-intensity echoes from outgoing sonar signals, may have selected against the development of hearing deficits in echolocating bats. Although many echolocating bats exhibit exceptional longevity and rely on acoustic behaviors for survival to old age, relatively little is known about the aging bat auditory system. In this study, we used DNA methylation to estimate the ages of wild-caught big brown bats (Eptesicus fuscus) and measured hearing sensitivity in young and aging bats using auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). We found no evidence for hearing deficits in aging bats, demonstrated by comparable thresholds and similar ABR wave and DPOAE amplitudes across age groups. We additionally found no significant histological evidence for cochlear aging, with similar hair cell counts, afferent, and efferent innervation patterns in young and aging bats. Here we demonstrate that big brown bats show minimal evidence for age-related loss of peripheral hearing sensitivity and therefore represent informative models for investigating mechanisms that may preserve hearing function over a long lifetime.
The Neurobiology of Cognitive Fatigue and Its Influence on Effort-Based Choice
Authors: Steward Grace , Chib Vikram S.
Published: July 2024

Feelings of cognitive fatigue emerge through repeated mental exertion and are ubiquitous in our daily lives. However, there is a limited understanding of the neurobiological mechanisms underlying the influence of cognitive fatigue on decisions to exert. We use functional magnetic resonance imaging to examine brain activity while participants make choices to exert effort for reward, before and after bouts of fatiguing cognitive exertion. We found that when participants became cognitively fatigued, they were more likely to choose to forgo higher levels of reward that required more effort. We describe a mechanism by which signals related to cognitive exertion in dlPFC influence effort value computations, instantiated by the insula, thereby influencing an individual’s decisions to exert while fatigued. Our results suggest that cognitive fatigue plays a critical role in decisions to exert effort and provides a mechanistic link through which information about cognitive state shapes effort-based choice.
Mathematical model of transcription loss due to accumulated DNA damage
Authors: Raseta Marko , Dealy Shannon , Grint Jacinta van de , Chang Jiang , Hoeijmakers Jan , Pothof Joris
Published: July 2024

We offer a simple mathematical model of gene transcription loss due to accumulated DNA damage in time based on widely agreed biological axioms. Closed form formulae characterizing the distribution of the underlying stochastic processes representing the transcription loss upon specified number of DNA damages are obtained. Moreover, the asymptotic behavior of the stochastic process was analyzed. Finally, the distribution of the first hitting time of transcription loss to specified biologically relevant levels was studied both analytically and computationally on mice data.
State dependent motor cortex stimulation reveals distinct mechanisms for corticospinal excitability and cortical responses
Authors: Perera Nipun D , Wischnewski Miles , Alekseichuk Ivan , Shirinpour Sina , Opitz Alexander
Published: July 2024

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method which can modulate brain activity by inducing electric fields in the brain. It is a popular tool to study causal brain-behavior relationships. However, brain states vary over time and affect the response of TMS. Neural oscillations can track the current brain state and are a promising marker to guide stimulation timing. Real-time, state-dependent brain stimulation has shown that neural oscillation phase modulates corticospinal excitability reflecting the connection from the primary motor cortex to a target muscle. However, such motor-evoked potentials (MEPs) only indirectly reflect motor cortex activation and are unavailable at other brain regions of interest. The direct and secondary cortical effects of phase-dependent brain stimulation remain an open question. In this study, we recorded the cortical responses during single-pulse transcranial magnetic stimulation (TMS) using electroencephalography (EEG) concurrently with the MEP measurements. TMS was delivered at peak, rising, trough, and falling phases of mu (8-13 Hz) and beta (14-30 Hz) oscillations in the motor cortex. The cortical responses were quantified through TMS-evoked potential components N15, P50, and N100 as peak-to-peak amplitudes (P50-N15 and P50-N100). We further analyzed whether the pre-stimulus frequency band power was predictive of the motor cortical responses. We found a significant main effect of neural oscillation phase on early evoked component (P50-N15). Furthermore, we found an interaction effect of oscillation phase and frequency on both early and late (P50-N100) components. Next, we compared the direct EEG response to the corticospinal excitability reflected by MEP amplitude. Interestingly, the preferred phase of the mu rhythm showed a 900phase shift between the early TEP components and MEPs. The late component showed the same phase preference between EEG and MEPs. However, such a well-defined relationship did not exist for either of the components during beta phase specific stimulation. In addition, pre-TMS mu oscillatory power and phase significantly predicted both early and late cortical EEG responses when mu rhythm was targeted, indicating the independent causal effects of phase and power. However, only pre-TMS beta power significantly predicted the early and late TEP components when beta rhythm was targeted. Further analysis indicated that both pre-TMS mu and beta power jointly affect early cortical responses. In contrast, the late cortical responses were only influenced by pre-TMS mu power. These findings provide insight to mechanistic understanding of neural oscillation states in cortical and corticospinal activation in humans.