bluuebunny/crossref_metadata_2025 huggingface dataset:
The Species Membership Approach
Authors: Fasel Raffael N
Published: February 2024

This chapter makes the case for the Species Membership Approach (SMA). The SMA is the unorthodox proposal that, criticism of speciesism notwithstanding, we should rehabilitate the species criterion in law to achieve a middle ground between the Aristocratic and Meritocratic conceptions. According to the SMA, fundamental legal rights and similar entitlements should be extended to animals based on their species, not their individual capacities. Section 2 sheds light on the pragmatic and political reasons for using species membership instead of individual capacities as a criterion for extending legal rights. Section 3 demonstrates the usefulness of the SMA by applying it to three test cases: Sesha the human being, Minnie the elephant, and Knuckles the chimpanzee. Finally, Section 4 explores how the SMA can be operationalized in practice.
Conclusion
Authors: Fasel Raffael N
Published: February 2024

This concluding chapter draws the book to a close in three ways. First, it recapitulates the historical, analytical, and practical ground covered in the previous chapters and the Species Membership Approach (SMA) which emerged from those discussions. Second, it points to four fruitful areas of future research that will help shed light on operational aspects of the SMA which the book could not explore. Lastly, it reflects on the contributions made in the book and how they carry on the conversation started by the trailblazing research of Christopher Stone.
Minimization of preventable drug waste through use of a vial combination calculator tool
Authors: Song Ju Young , Wysocki Mark , Chen Franklin , Martinez Dylcia , Cabie Eric
Published: February 2024

Purpose

This project aimed to determine whether a supportive calculator that automates the vial selection process might offer a practical and efficient method of reducing pharmaceutical expenditures through minimizing preventable drug waste in outpatient pharmacy settings.

Drug waste is a substantial target of cost-saving efforts in the areas of oncology and autoimmune therapy, which involve use of a vast number of high-cost medications packaged in single-dose vials of varying strength. To facilitate selection of the optimal combination of medication vials and thereby minimize preventable drug waste, a Microsoft Excel–based calculator was developed for use by staff of a large oncology pharmacy network. Twenty-three high-cost chemotherapy and monoclonal antibody medications were identified as initial targets for the drug waste prevention initiative. After dissemination and implementation of the calculator and provision of monthly pharmacy staff education, the dollar value of preventable drug waste and the number of suboptimal vial combination selections were reduced by 51% ($412,300) and 54% (315 selections), respectively, in fiscal year 2022 and further reduced by 46% ($183,400) and 27% (71 selections), respectively, in fiscal year 2023.

Conclusion

After implementation of an automated vial selection tool, preventable drug waste and the quantity of suboptimal vial combination selections were markedly reduced across 11 outpatient compounding pharmacies.
Law reform: the institutional perspective
Authors: van Haersolte-van Hof Jacomijn J
Published: February 2024

The Law Commission was tasked with reviewing the Arbitration Act 1996, to determine whether any amendments to the Act were needed to ensure that the Act remains fit for purpose and continues to promote England and Wales as a leading destination for commercial arbitration. As part of that process, the Law Commission engaged with many different stakeholders across the arbitration community. The London Court of International Arbitration was one of those stakeholders. Accordingly, this article seeks to offer readers an insight into the perspective of an arbitral institution on the topic of reform of the Act. While this article does not address comprehensively all of the Law Commission’s proposals, it provides an insight into the London Court of Arbitration (LCIA)’s responses to the Law Commission’s consultation and the competing considerations that are at play with respect to the duty of confidentiality, the duties of impartiality, independence and disclosure, discrimination, section 67 of the Act, and the law applicable to the arbitration agreement.
Exploring Superselective Intraarterial Thrombolysis for Autologous Fat Injection–Induced Vision Loss
Authors: Wu Qian , Zhou Guiwen , Xu Xiao , Liu Bing , Fu Qiang , Zhang Jie , Zhang Peixuan , Bai Ruiqi , Meng Fanting , Chen Minliang
Published: February 2024

Background

Intravascular injection represents the most severe complication in fat transplantation procedures. Currently, the prognosis for patients who suffer from blindness due to fat transplantation–induced ocular vascular occlusion is far from optimistic.

Objectives

The aim of this study was to explore and evaluate the efficacy and safety of arterial thrombolysis in the treatment of ocular vascular occlusion caused by fat transplantation.

Methods

We analyzed the data of 12 patients who underwent intraarterial thrombolysis and conservative treatments for facial autologous fat grafting–associated ocular vascular occlusion. Among the cases, there were 6 instances of ophthalmic artery embolism and 6 cases of central retinal artery occlusion. All patients suffered with sudden blindness, sometimes accompanied by eye pain, ptosis, strabismus, skin necrosis at the injection site, or cerebral microinfarction. They received symptomatic conservative treatments and intraarterial thrombolysis, encompassing mechanical vessel recanalization, vessel dilation, and dissolution of thrombus constituents.

Results

Following intraarterial thrombolysis, a noteworthy improvement in the blood flow of both the main trunk and peripheral branches of the ophthalmic artery was observed in the majority of patients when contrasted with their pretreatment status. One patient experienced a headache intraoperatively, while no significant discomfort was reported by the remaining patients. After conservative treatments and intraarterial thrombolysis, all patients experienced improvement in ocular symptoms, skin necrosis, and cerebral infarction. Three patients demonstrated improvement in visual acuity. These patients had surpassed the recommended time window for treatment, yet the occlusion of the ophthalmic artery was not complete.

Conclusions

Intraarterial thrombolysis combined with conservative treatments achieves early perfusion and is expected to promote visual recovery. Hospitals that possess the necessary treatment capabilities are encouraged to establish this therapeutic pathway.
Reinforcement of the stapled duodenal stump during laparoscopic gastrectomy
Authors: Liu Wenwu , Chen Xiaojiang , Zhou Zhiwei , Chen Yongming
Published: February 2024

Reinforcement of the duodenal stump during laparoscopic gastrectomy can be technically challenging. This study reports a surgical technique, called the cabbage suture, for laparoscopic reinforcement of the duodenal stump.
Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development
Authors: Ahmed Hazem , Wang Yuqin , Griffiths William J , Levey Allan I , Pikuleva Irina , Liang Steven H , Haider Ahmed
Published: February 2024

Cholesterol homeostasis is impaired in Alzheimer's disease; however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date.

Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of Alzheimer's disease. Indeed, neuronal cholesterol was linked to the formation of amyloid-β and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies. Furthermore, remarkable advances in translational molecular imaging have now made it possible to probe cholesterol metabolism in the living human brain with PET, which is an important prerequisite for future clinical trials that target the brain cholesterol machinery in Alzheimer's disease patients—with the ultimate aim being to develop disease-modifying treatments.

This work summarizes current concepts of how the biosynthesis, transport and clearance of brain cholesterol are affected in Alzheimer's disease. Further, current strategies to reverse these alterations by pharmacotherapy are critically discussed in the wake of emerging translational research tools that support the assessment of brain cholesterol biology not only in animal models but also in patients with Alzheimer's disease.
Obesity is associated with alterations in anatomical connectivity of frontal-corpus callosum
Authors: Hu Yang , Li Guanya , Zhang Wenchao , Wang Jia , Ji Weibin , Yu Juan , Han Yu , Cui Guangbin , Wang Haoyi , Manza Peter , Volkow Nora , Ji Gang , Wang Gene-Jack , Zhang Yi
Published: February 2024

Obesity has been linked to abnormal frontal function, including the white matter fibers of anterior portion of the corpus callosum, which is crucial for information exchange within frontal cortex. However, alterations in white matter anatomical connectivity between corpus callosum and cortical regions in patients with obesity have not yet been investigated. Thus, we enrolled 72 obese and 60 age-/gender-matched normal weight participants who underwent clinical measurements and diffusion tensor imaging. Probabilistic tractography with connectivity-based classification was performed to segment the corpus callosum and quantify white matter anatomical connectivity between subregions of corpus callosum and cortical regions, and associations between corpus callosum–cortex white matter anatomical connectivity and clinical behaviors were also assessed. Relative to normal weight individuals, individuals with obesity exhibited significantly greater white matter anatomical connectivity of corpus callosum–orbitofrontal cortex, which was positively correlated with body mass index and self-reported disinhibition of eating behavior, and lower white matter anatomical connectivity of corpus callosum–prefrontal cortex, which was significantly negatively correlated with craving for high-calorie food cues. The findings show that alterations in white matter anatomical connectivity between corpus callosum and frontal regions involved in reward and executive control are associated with abnormal eating behaviors.
A radiomics-based brain network in T1 images: construction, attributes, and applications
Authors: Liu Han , Ma Zhe , Wei Lijiang , Chen Zhenpeng , Peng Yun , Jiao Zhicheng , Bai Harrison , Jing Bin
Published: February 2024

T1 image is a widely collected imaging sequence in various neuroimaging datasets, but it is rarely used to construct an individual-level brain network. In this study, a novel individualized radiomics-based structural similarity network was proposed from T1 images. In detail, it used voxel-based morphometry to obtain the preprocessed gray matter images, and radiomic features were then extracted on each region of interest in Brainnetome atlas, and an individualized radiomics-based structural similarity network was finally built using the correlational values of radiomic features between any pair of regions of interest. After that, the network characteristics of individualized radiomics-based structural similarity network were assessed, including graph theory attributes, test–retest reliability, and individual identification ability (fingerprinting). At last, two representative applications for individualized radiomics-based structural similarity network, namely mild cognitive impairment subtype discrimination and fluid intelligence prediction, were exemplified and compared with some other networks on large open-source datasets. The results revealed that the individualized radiomics-based structural similarity network displays remarkable network characteristics and exhibits advantageous performances in mild cognitive impairment subtype discrimination and fluid intelligence prediction. In summary, the individualized radiomics-based structural similarity network provides a distinctive, reliable, and informative individualized structural brain network, which can be combined with other networks such as resting-state functional connectivity for various phenotypic and clinical applications.
Exebacase in Addition to Standard-of-Care Antibiotics for Staphylococcus aureus Bloodstream Infections and Right-Sided Infective Endocarditis: A Phase 3, Superiority-Design, Placebo-Controlled, Randomized Clinical Trial (DISRUPT)
Authors: Fowler Vance G , Das Anita F , Lipka-Diamond Joy , Ambler Jane E , Schuch Raymond , Pomerantz Roger , Cassino Cara , Jáuregui-Peredo Luis , Moran Gregory J , Rupp Mark E , Lachiewicz Anne M , Kuti Joseph L , Wise Robert A , Kaye Keith S , Zervos Marcus J , Nichols W Garrett
Published: February 2024

Background

Novel treatments are needed for Staphylococcus aureus bacteremia, particularly for methicillin-resistant S. aureus (MRSA). Exebacase is a first-in-class antistaphylococcal lysin that is rapidly bactericidal and synergizes with antibiotics.

Methods

In Direct Lysis of Staph Aureus Resistant Pathogen Trial of Exebacase (DISRUPT), a superiority-design phase 3 study, patients with S. aureus bacteremia/endocarditis were randomly assigned to receive a single dose of intravenous exebacase or placebo in addition to standard-of-care antibiotics. The primary efficacy outcome was clinical response at day 14 in the MRSA population.

Results

A total of 259 patients were randomized before the study was stopped for futility based on the recommendation of the unblinded Data Safety Monitoring Board. Clinical response rates at day 14 in the MRSA population (n = 97) were 50.0% (exebacase + antibiotics; 32/64) versus 60.6% (antibiotics alone; 20/33) (P = .392). Overall, rates of adverse events were similar across groups. No adverse events of hypersensitivity related to exebacase were reported.

Conclusions

Exebacase + antibiotics failed to improve clinical response at day 14 in patients with MRSA bacteremia/endocarditis. This result was unexpected based on phase 2 data that established proof-of-concept for exebacase + antibiotics in patients with MRSA bacteremia/endocarditis. In the antibiotics-alone group, the clinical response rate was higher than that seen in phase 2. Heterogeneity within the study population and a relatively small sample size in either the phase 2 or phase 3 studies may have increased the probability of imbalances in the multiple components of day 14 clinical outcome. This study provides lessons for future superiority studies in S. aureus bacteremia/endocarditis.

Clinical Trials Registration.NCT04160468
The association of off-hour vs. on-hour intensive care unit admission time with mortality in patients with cardiogenic shock: a retrospective multi-centre analysis
Authors: Naumann Dominik , Fischer Julius , Gmeiner Jonas , Lüsebrink Enzo , Beer Benedikt N , Grieger Maximilian , Giousouf Atakan , Schrage Benedikt , Stremmel Christopher , Massberg Steffen , Orban Martin , Scherer Clemens
Published: February 2024

Aims

Studies have shown a so-called off-hour effect for many different diseases, but data are scarce concerning cardiogenic shock. We therefore assessed the association of off-hour vs. on-hour intensive care unit admission with 30-day mortality in patients with cardiogenic shock.

Methods and results

In total, 1720 cardiogenic shock patients (666 admitted during off-hours) from two large university hospitals in Germany were included in retrospect. An admission during off-hours was associated with increased 30-day mortality compared to an admission during on-hours [crude mortality 48% vs. 41%, HR 1.17 (1.03–1.33), P = 0.017]. This effect remained significant after propensity score matching (P = 0.023). Neither patients with a combined SCAI stage D and E (P = 0.088) or C (P = 0.548) nor those requiring cardiopulmonary resuscitation (P = 0.114) had a higher mortality at off-hour admission. In contrast, those without veno-arterial extracorporeal membrane oxygenation [HR 1.17 (1.00–1.36), P = 0.049], without acute myocardial infarction [HR 1.27 (1.02–1.56), P = 0.029] or a with combined SCAI stage A and B [HR 2.23 (1.08–4.57), P = 0.025] had an increased mortality at off-hour admission.

Conclusion

Our study showed an increased mortality in patients with cardiogenic shock admitted during off-hours, especially in those with a milder onset of disease. This stresses the importance of a thorough workup of each patient, especially at times of limited resources, the menace of underestimating the severity of cardiogenic shock, and the need for an improved 24×7 available risk stratification.
The Laws of Rollo as a Primitive Constitution for Normandy: Writing and Rewriting Legal History in France during the Seventeenth and Eighteenth Centuries
Authors: Davy Gilduin
Published: February 2024

The laws of Rollo are regularly evoked in seventeenth- and eighteenth-century Norman historiography. As a result of a renaissance of interest in, and the study of, medieval Norman sources, notably the gestae of Dudo of Saint-Quentin and Guillaume of Jumièges, early modern jurists and historians located the legal particularism of Normandy in Rollo’s laws. They exploited these sources in order to preserve Norman rights and liberties and to use the history of their medieval origins to justify ongoing legal provincialism. But as the Revolution approached, the memory of Rollo’s laws also became an essential issue in emerging political and ideological debates, because they served as much to defend absolute monarchy as to challenge it.
Association between cardiovascular disease and risk of female sexual dysfunction: a systematic review and meta-analysis
Authors: Dilixiati Diliyaer , Cao Ruotong , Mao Yishen , Li Yuting , Dilimulati Daniyaer , Azhati Baihetiya , Rexiati Mulati
Published: February 2024

Aims

Female sexual dysfunction (FSD) is a considerably underestimated condition. It has been repeatedly reported that patients with cardiovascular diseases (CVD) may suffer from an increased risk of FSD. However, there is still a lack of comprehensive and systematic evaluation of various CVD and FSD. We aimed to elucidate the association between CVD and FSD through a comprehensive literature review and meta-analysis.

Methods and results

The PubMed, Scopus, Embase, and Cochrane Library databases were systematically searched from inception to 28 February 2023. We identified all relevant studies reporting the risk of FSD in subjects with or without CVD. The associations between CVD and the risk of FSD were assessed by calculating pooled odds ratios (ORs) (cross-sectional studies) and risk ratios (RRs) (longitudinal studies) with 95% CIs. We employed random-effects models to account for potential heterogeneity, and the quality of the included studies was assessed using the Newcastle–Ottawa Scale. Fifty-four articles with 148 946 individuals were included in our meta-analysis. Compared with control subjects, subjects with CVD had a 1.51-fold increased risk of FSD (OR 1.51 95% CI, 1.34–1.69, P < 0.001, heterogeneity I2 = 91.4%, P < 0.001). Subgroup analyses indicated that the association between CVD and FSD remained significant in longitudinal studies (RR 1.50 95% CI, 1.21–1.86, P < 0.001, heterogeneity I2 = 86.7%, P < 0.001). Particularly, hypertension (OR 1.41 95% CI, 1.23–1.62, P < 0.001, heterogeneity I2 = 82.7%, P < 0.001), stroke (OR 1.81 95% CI, 1.54–2.12, P < 0.001, heterogeneity I2 = 0%, P < 0.423), and myocardial infarction (OR 2.07 95% CI, 1.60–2.67, P < 0.001 heterogeneity I2 = 82.4%, P < 0.001) were significantly associated with FSD. Meta-regression revealed that the primary sources of heterogeneity in FSD are attributable to adjustments for covariates, study design, and study population.

Conclusion

Our meta-analysis indicated that patients with CVD suffer from a greater risk of developing FSD. Meanwhile, we validated these findings in longitudinal queues. Notably, conditions such as hypertension, stroke, and myocardial infarction demonstrated a significant association with the incidence of FSD.
Role of electroanatomical mapping–guided superior vena cava isolation in paroxysmal atrial fibrillation patients without provoked superior vena cava triggers: a randomized controlled study
Authors: Dong Yan , Zhao Dongsheng , Chen Xinguang , Shi Linshen , Chen Qiushi , Zhang Haiyan , Yu Yue , Ullah Inam , Kojodjojo Pipin , Zhang Fengxiang
Published: February 2024

Aims

Data about whether empirical superior vena cava (SVC) isolation (SVCI) improves the success rate of paroxysmal atrial fibrillation (PAF) are conflicting. This study sought to first investigate the characteristics of SVC-triggered atrial fibrillation and secondly investigate the impact of electroanatomical mapping–guided SVCI, in addition to circumferential pulmonary vein isolation (CPVI), on the outcome of PAF ablation in the absence of provoked SVC triggers.

Methods and results

A total of 130 patients undergoing PAF ablation underwent electrophysiological studies before ablation. In patients for whom SVC triggers were identified, SVCI was performed in addition to CPVI. Patients without provoked SVC triggers were randomized in a 1:1 ratio to CPVI plus SVCI or CPVI only. The primary endpoint was freedom from any documented atrial tachyarrhythmias lasting over 30 s after a 3-month blanking period without anti-arrhythmic drugs at 12 months after ablation. Superior vena cava triggers were identified in 30 (23.1%) patients with PAF. At 12 months, 93.3% of those with provoked SVC triggers who underwent CPVI plus SVCI were free from atrial tachyarrhythmias. In patients without provoked SVC triggers, SVCI, in addition to CPVI, did not increase freedom from atrial tachyarrhythmias (87.9 vs. 79.6%, log-rank P = 0.28).

Conclusion

Electroanatomical mapping–guided SVCI, in addition to CPVI, did not increase the success rate of PAF ablation in patients who had no identifiable SVC triggers.

Registration

ChineseClinicalTrials.gov: ChiCTR2000034532
Temporal dynamics of microbial transcription in wetted hyperarid desert soils
Authors: León-Sobrino Carlos , Ramond Jean-Baptiste , Coclet Clément , Kapitango Ritha-Meriam , Maggs-Kölling Gillian , Cowan Don A
Published: February 2024

Rainfall is rare in hyperarid deserts but, when it occurs, it triggers large biological responses essential for the long-term maintenance of the ecosystem. In drylands, microbes play major roles in nutrient cycling, but their responses to short-lived opportunity windows are poorly understood. Due to its ephemeral nature, mRNA is ideally suited to study microbiome dynamics upon abrupt changes in the environment. We analyzed microbial community transcriptomes after simulated rainfall in a Namib Desert soil over 7 days. Using total mRNA from dry and watered plots we infer short-term functional responses in the microbiome. A rapid two-phase cycle of activation and return to basal state was completed in a short period. Motility systems activated immediately, whereas competition–toxicity increased in parallel to predator taxa and the drying of soils. Carbon fixation systems were downregulated, and reactivated upon return to a near-dry state. The chaperone HSP20 was markedly regulated by watering across all major bacteria, suggesting a particularly important role in adaptation to desiccated ecosystems. We show that transcriptomes provide consistent and high resolution information on microbiome processes in a low-biomass environment, revealing shared patterns across taxa. We propose a structured dispersal–predation dynamic as a central driver of desert microbial responses to rainfall.
Genome assembly and annotation of the mermithid nematode Mermis nigrescens
Authors: Bhattarai Upendra R , Poulin Robert , Gemmell Neil J , Dowle Eddy
Published: February 2024

Genetic studies of nematodes have been dominated by Caenorhabditis elegans as a model species. A lack of genomic resources has limited the expansion of genetic research to other groups of nematodes. Here, we report a draft genome assembly of a mermithid nematode, Mermis nigrescens. Mermithidae are insect parasitic nematodes with hosts including a wide range of terrestrial arthropods. We sequenced, assembled, and annotated the whole genome of M. nigrescens using nanopore long reads and 10X Chromium link reads. The assembly is 524 Mb in size consisting of 867 scaffolds. The N50 value is 2.42 Mb, and half of the assembly is in the 30 longest scaffolds. The assembly BUSCO score from the eukaryotic database (eukaryota_odb10) indicates that the genome is 86.7% complete and 5.1% partial. The genome has a high level of heterozygosity (6.6%) with a repeat content of 83.98%. mRNA-seq reads from different sized nematodes (≤2 cm, 3.5–7 cm, and >7 cm body length) representing different developmental stages were also generated and used for the genome annotation. Using ab initio and evidence-based gene model predictions, 12,313 protein-coding genes and 24,186 mRNAs were annotated. These genomic resources will help researchers investigate the various aspects of the biology and host–parasite interactions of mermithid nematodes.
GRUR Taskforce IGC: The WIPO Draft International Legal Instrument Relating to Intellectual Property, Genetic Resources and Traditional Knowledge Associated with Genetic Resources – Overview and Analysis
Authors: Würtenberger Gert , Freischem Stephan
Published: February 2024

The German Association for the Protection of Intellectual Property (Deutsche Vereinigung für gewerblichen Rechtsschutz und Urheberrecht e.V., or GRUR) is a non-profit scientific association of professional groups and organisations working in the field of industrial property and copyright. Its members include, in particular, academics, judges, lawyers, patent attorneys and representatives of associations and private companies.

The GRUR Taskforce IGC has been observing the negotiations of the World Intellectual Property Organization’s (WIPO) Intergovernmental Committee on Intellectual Property and Genetic Resources, Traditional Knowledge and Folklore since 2022. This opinion summarises the results of the discussions of the GRUR Taskforce IGC on the WIPO negotiations on a convention on the protection of genetic resources and associated traditional knowledge and on the draft text of a convention.
The role of constraints and information gaps in driving risky medicine purchasing practices in four African countries
Authors: Wagnild Janelle M , Akhter Nasima , Lee Diana , Jayeola Babatunde , Darko Delese Mimi , Adeyeye Moji Christianah , Komeh James P , Nahamya David , Kasim Adetayo , Hampshire Kate
Published: February 2024

Substandard and falsified (SF) medical products pose a major threat to public health and socioeconomic development, particularly in low- and middle-income countries. In response, public education campaigns have been developed to alert consumers about the risks of SF medicines and provide guidance on ‘safer’ practices, along with other demand- and supply-side measures. However, little is currently known about the potential effectiveness of such campaigns while structural constraints to accessing quality-assured medicines persist. This paper analyses survey data on medicine purchasing practices, information and constraints from four African countries (Ghana, Nigeria, Sierra Leone and Uganda; n > 1000 per country). Using multivariate regression and structural equation modelling, we present what we believe to be the first attempt to tease apart, statistically, the effects of an information gap vs structural constraints in driving potential public exposure to SF medicines. The analysis confirms that less privileged groups (including, variously, those in rural settlements, with low levels of formal education, not in paid employment, often women and households with a disability or long-term sickness) are disproportionately potentially exposed to SF medicines; these same demographic groups also tend to have lower levels of awareness and experience greater levels of constraint. Despite the constraints, our models suggest that public health education may have an important role to play in modifying some (but not all) risky practices. Appropriately targeted public messaging can thus be a useful part of the toolbox in the fight against SF medicines, but it can only work effectively in combination with wider-reaching reforms to address higher-level vulnerabilities in pharmaceutical supply chains in Africa and expand access to quality-assured public-sector health services.
Bipedalism and the dawn of uterine fibroids
Authors: Vilos George A , Vilos Angelos G , Burbank Fred
Published: February 2024

The high prevalence and burden of uterine fibroids in women raises questions about the origin of these benign growths. Here, we propose that fibroids should be understood in the context of human evolution, specifically the advent of bipedal locomotion in the hominin lineage. Over the ≥7 million years since our arboreal ancestors left their trees, skeletal adaptations ensued, affecting the pelvis, limbs, hands, and feet. By 3.2 million years ago, our ancestors were fully bipedal. A key evolutionary advantage of bipedalism was the freedom to use hands to carry and prepare food and create and use tools which, in turn, led to further evolutionary changes such as brain enlargement (encephalization), including a dramatic increase in the size of the neocortex. Pelvic realignment resulted in narrowing and transformation of the birth canal from a simple cylinder to a convoluted structure with misaligned pelvic inlet, mid-pelvis, and pelvic outlet planes. Neonatal head circumference has increased, greatly complicating parturition in early and modern humans, up to and including our own species. To overcome the so-called obstetric dilemma provoked by bipedal locomotion and encephalization, various compensatory adaptations have occurred affecting human neonatal development. These include adaptations limiting neonatal size, namely altricial birth (delivery of infants at an early neurodevelopmental stage, relative to other primates) and mid-gestation skeletal growth deceleration. Another key adaptation was hyperplasia of the myometrium, specifically the neomyometrium (the outer two-thirds of the myometrium, corresponding to 90% of the uterine musculature), allowing the uterus to more forcefully push the baby through the pelvis during a lengthy parturition. We propose that this hyperplasia of smooth muscle tissue set the stage for highly prevalent uterine fibroids. These fibroids are therefore a consequence of the obstetric dilemma and, ultimately, of the evolution of bipedalism in our hominin ancestors.
The Purine Biosynthesis Repressor, PurR, Contributes to Vancomycin Susceptibility of Methicillin-resistant Staphylococcus aureus in Experimental Endocarditis
Authors: Xiong Yan Q , Li Yi , Goncheva Mariya I , Elsayed Ahmed M , Zhu Fengli , Li Liang , Abdelhady Wessam , Flannagan Ronald S , Yeaman Michael R , Bayer Arnold S , Heinrichs David E
Published: February 2024

Background

Staphylococcus aureus is the most common cause of life-threatening endovascular infections, including infective endocarditis (IE). These infections, especially when caused by methicillin-resistant strains (MRSA), feature limited therapeutic options and high morbidity and mortality rates.

Methods

Herein, we investigated the role of the purine biosynthesis repressor, PurR, in virulence factor expression and vancomycin (VAN) treatment outcomes in experimental IE due to MRSA.

Results

The PurR-mediated repression of purine biosynthesis was confirmed by enhanced purF expression and production of an intermediate purine metabolite in purR mutant strain. In addition, enhanced expression of the transcriptional regulators, sigB and sarA, and their key downstream virulence genes (eg, fnbA, and hla) was demonstrated in the purR mutant in vitro and within infected cardiac vegetations. Furthermore, purR deficiency enhanced fnbA/fnbB transcription, translating to increased fibronectin adhesion versus the wild type and purR-complemented strains. Notably, the purR mutant was refractory to significant reduction in target tissues MRSA burden following VAN treatment in the IE model.

Conclusions

These findings suggest that the purine biosynthetic pathway intersects the coordination of virulence factor expression and in vivo persistence during VAN treatment, and may represent an avenue for novel antimicrobial development targeting MRSA.
Emergency Myelopoiesis Distinguishes Multisystem Inflammatory Syndrome in Children From Pediatric Severe Coronavirus Disease 2019
Authors: Roznik Katerina , Andargie Temesgen E , Johnston T Scott , Gordon Oren , Wang Yi , Akindele Nadine Peart , Persaud Deborah , Antar Annukka A R , Manabe Yukari C , Zhou Weiqiang , Ji Hongkai , Agbor-Enoh Sean , Karaba Andrew H , Thompson Elizabeth A , Cox Andrea L
Published: February 2024

Background

Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition caused by recent infection with severe acute respiratory syndrome coronavirus 2, but the underlying immunological mechanisms driving this distinct syndrome are unknown.

Methods

We utilized high-dimensional flow cytometry, cell-free (cf) DNA, and cytokine and chemokine profiling to identify mechanisms of critical illness distinguishing MIS-C from severe acute coronavirus disease 2019 (SAC).

Results

Compared to SAC, MIS-C patients demonstrated profound innate immune cell death and features of emergency myelopoiesis (EM), an understudied phenomenon observed in severe inflammation. EM signatures were characterized by fewer mature myeloid cells in the periphery and decreased expression of HLA-DR and CD86 on antigen-presenting cells. Interleukin 27 (IL-27), a cytokine known to drive hematopoietic stem cells toward EM, was increased in MIS-C, and correlated with immature cell signatures in MIS-C. Upon recovery, EM signatures decreased and IL-27 plasma levels returned to normal levels. Despite profound lymphopenia, we report a lack of cfDNA released by adaptive immune cells and increased CCR7 expression on T cells indicative of egress out of peripheral blood.

Conclusions

Immune cell signatures of EM combined with elevated innate immune cell-derived cfDNA levels distinguish MIS-C from SAC in children and provide mechanistic insight into dysregulated immunity contributing toward MIS-C, offering potential diagnostic and therapeutic targets.
Cytotoxic Lymphocyte-Monocyte Complex Reflects the Dynamics of Coronavirus Disease 2019 Systemic Immune Response
Authors: Lin Jiajia , Bai Shiyu , He Liheng , Yang Ye , Li Xiyue , Luo Liulin , Wang Ying , Chen Ying-ying , Qin Jinhong , Zhong Yi
Published: February 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes a variety of clinical manifestations, many of which originate from altered immune responses, either locally or systemically. Immune cell cross-talk occurs mainly in lymphoid organs. However, systemic cell interaction specific to coronavirus disease 2019 has not been well characterized. Here, by employing single-cell RNA sequencing and imaging flow cytometry analysis, we unraveled, in peripheral blood, a heterogeneous group of cell complexes formed by the adherence of CD14+ monocytes to different cytotoxic lymphocytes, including SARS-CoV-2–specific CD8+ T cells, γδ T cells, and natural killer T cells. These lymphocytes attached to CD14+ monocytes that showed enhanced inflammasome activation and pyroptosis-induced cell death in progression stage; in contrast, in the convalescent phase, CD14+ monocytes with elevated antigen presentation potential were targeted by cytotoxic lymphocytes, thereby restricting the excessive immune activation. Collectively, our study reports previously unrecognized cell–cell interplay in the SARS-CoV-2–specific immune response, providing new insight into the intricacy of dynamic immune cell interaction representing antiviral defense.
Plasmodium falciparum Glutamic Acid-Rich Protein-Independent Polyclonal Antibodies Inhibit Malaria Parasite Growth in Human Erythrocytes
Authors: Schwake Christopher J , Krueger Rachel M , Hanada Toshihiko , Chishti Athar H
Published: February 2024

Plasmodium falciparum glutamic acid-rich protein (PfGARP) is a recently characterized cell surface antigen encoded by Plasmodium falciparum, the causative agent of severe human malaria pathophysiology. Previously, we reported that the human erythrocyte band 3 (SLC4A1) serves as a host receptor for PfGARP. Antibodies against PfGARP did not affect parasite invasion and growth. We surmised that PfGARP may play a role in the rosetting and adhesion of malaria. Another study reported that antibodies targeting PfGARP exhibit potent inhibition of parasite growth. This inhibition occurred without the presence of any immune or complement components, suggesting the activation of an inherent density-dependent regulatory system. Here, we used polyclonal antibodies against PfGARP and a monoclonal antibody mAb7899 to demonstrate that anti-PfGARP polyclonal antibodies, but not mAb7899, exerted potent inhibition of parasite growth in infected erythrocytes independent of PfGARP. These findings suggest that an unknown malaria protein(s) is the target of growth arrest by polyclonal antibodies raised against PfGARP.
Biotic interactions between benthic infauna and aerobic methanotrophs mediate methane fluxes from coastal sediments
Authors: Broman Elias , Olsson Markus , Maciute Adele , Donald Daniel , Humborg Christoph , Norkko Alf , Jilbert Tom , Bonaglia Stefano , Nascimento Francisco J A
Published: February 2024

Coastal ecosystems dominate oceanic methane (CH4) emissions. However, there is limited knowledge about how biotic interactions between infauna and aerobic methanotrophs (i.e. CH4 oxidizing bacteria) drive the spatial–temporal dynamics of these emissions. Here, we investigated the role of meio- and macrofauna in mediating CH4 sediment–water fluxes and aerobic methanotrophic activity that can oxidize significant portions of CH4. We show that macrofauna increases CH4 fluxes by enhancing vertical solute transport through bioturbation, but this effect is somewhat offset by high meiofauna abundance. The increase in CH4 flux reduces CH4 pore-water availability, resulting in lower abundance and activity of aerobic methanotrophs, an effect that counterbalances the potential stimulation of these bacteria by higher oxygen flux to the sediment via bioturbation. These findings indicate that a larger than previously thought portion of CH4 emissions from coastal ecosystems is due to faunal activity and multiple complex interactions with methanotrophs.
The profile of HIV-1 drug resistance in Shanghai, China: a retrospective study from 2017 to 2021
Authors: Zhang Min , Ma Yingying , Wang Gang , Wang Zhenyan , Wang Qianying , Li Xin , Lin Feng , Qiu Jianping , Chen Daihong , Shen Yinzhong , Zhang Chiyu , Lu Hongzhou
Published: February 2024

Background

HIV-1 drug resistance is a huge challenge in the era of ART.

Objectives

To investigate the prevalence and characteristics of acquired HIV-1 drug resistance (ADR) in Shanghai, China.

Methods

An epidemiological study was performed among people living with human immunodeficiency virus (PLWH) receiving ART in Shanghai from January 2017 to December 2021. A total of 8669 PLWH were tested for drug resistance by genotypic resistance testing. Drug resistance mutations (DRMs) were identified using the Stanford University HIV Drug Resistance Database program.

Results

Ten HIV-1 subtypes/circulating recombinant forms (CRFs) were identified, mainly including CRF01_AE (46.8%), CRF07_BC (35.7%), B (6.4%), CRF55_01B (2.8%) and CRF08_BC (2.4%). The prevalence of ADR was 48% (389/811). Three NRTI-associated mutations (M184V/I/L, S68G/N/R and K65R/N) and four NNRTI-associated mutations (V179D/E/T/L, K103N/R/S/T, V106M/I/A and G190A/S/T/C/D/E/Q) were the most common DRMs. These DRMs caused high-level resistance to lamivudine, emtricitabine, efavirenz and nevirapine. The DRM profiles appeared to be significantly different among different subtypes.

Conclusions

We revealed HIV-1 subtype characteristics and the DRM profile in Shanghai, which provide crucial guidance for clinical treatment and management of PLWH.
Declaration of the Town Square: The Urgency of Speaking as One
Authors: Agudelo-Hernández Felipe , Cardona Porras Luisa Fernanda , Giraldo Álvarez Ana Belén
Published: February 2024

Ethics in biomedical research in mental health plays a central role. Historically the principles of autonomy, beneficence, non-maleficence and justice have been violated in individuals with mental disorders. This article aims to analyse the perceptions of individuals involved in research ethics advocacy in Aranzazu-Colombia, from the Declaration of the Town Square to current research practices and community empowerment initiatives. For this, a qualitative study was conducted in the municipality of Aranzazu as part of a Community-Based Rehabilitation strategy in Mental Health. Two focus groups were conducted with a total of 30 participants, including community representatives, institutional members, and healthcare personnel. The themes that emerged were ‘The urgency of speaking as one’, ‘Our research questions’ and ‘Human rights for recovery’. The process of adoption of community protection measures that guided the investigative processes with the town of Aranzazu is presented. A discussion is raised around the instrumentalization of people in the investigation and the claim of human rights by communities, as a mechanism to strengthen community recovery actions. It is concluded that mental health research should help to affirm dignity, reduce stigma, improve access to psychosocial recovery and achieve real participation in building the well-being of communities.
Chronic traumatic encephalopathy and aging-related tau astrogliopathy in community-dwelling older persons with and without moderate-to-severe traumatic brain injury
Authors: Agrawal Sonal , Leurgans Sue E , Barnes Lisa L , Dams-O’Connor Kristen , Mez Jesse , Bennett David A , Schneider Julie A
Published: February 2024

This study examined the frequency of chronic traumatic encephalopathy-neuropathologic change (CTE-NC) and aging-related tau astrogliopathy (ARTAG) in community-dwelling older adults and tested the hypothesis that these tau pathologies are associated with a history of moderate-to-severe traumatic brain injury (msTBI), defined as a TBI with loss of consciousness >30 minutes. We evaluated CTE-NC, ARTAG, and Alzheimer disease pathologies in 94 participants with msTBI and 94 participants without TBI matched by age, sex, education, and dementia status TBI from the Rush community-based cohorts. Six (3%) of brains showed the pathognomonic lesion of CTE-NC; only 3 of these had a history of msTBI. In contrast, ARTAG was common in older brains (gray matter ARTAG = 77%; white matter ARTAG = 54%; subpial ARTAG = 51%); there were no differences in severity, type, or distribution of ARTAG pathology with respect to history of msTBI. Furthermore, those with msTBI did not have higher levels of PHF-tau tangles density but had higher levels of amyloid-β load (Estimate = 0.339, SE = 0.164, p = 0.040). These findings suggest that CTE-NC is infrequent while ARTAG is common in the community and that both pathologies are unrelated to msTBI. The association of msTBI with amyloid-β, rather than with tauopathies suggests differential mechanisms of neurodegeneration in msTBI.
Successful closure of a refractory giant (15 sq mm) macular hole with amniotic membrane graft
Authors: Chalam Kakarla Venkata , Akanda Marib , Subramanian Meenakshi
Published: February 2024

The management of macular hole defects has undergone a significant transformation with the advent of advanced diagnostic tools and surgical techniques. These developments have enabled the effective treatment of macular holes that were previously considered untreatable. Although the majority of patients exhibit a positive response to initial treatment, a subset of patients may develop refractory macular holes that necessitate multiple surgeries for closure. In these instances, the utilization of amniotic membrane grafts to aid in the closure of large retinal holes presents a promising alternative. This report details the successful closure of a refractory giant macular hole (15 sq. mm) in a patient using an amniotic membrane graft, with improvement in visual acuity.
Motherhood, Mental Incompetence, and the Denial of Reproductive Autonomy in the Early Years of Israeli Statehood
Authors: Di Giulio Marco
Published: February 2024

As the State of Israel defined citizenship rights for its Jewish population after independence in 1948, it also began to articulate the rights of those affected by disabilities of the mind—i.e., psychiatric, cognitive, and learning disabilities—by issuing, for example, the “Law for the Management of Institutes” (1952) and the “Law for the Treatment of the Mentally Ill” (1955). Due to haphazard state-building and insufficient funding, however, this process was slow and uneven. In the meantime, people with mental and cognitive disabilities often remained vulnerable to abuse and sexual violence in domestic and institutional spaces and suffered from a lack of proper care and accommodation. Operating on the assumption that disability of the mind could be transmitted from generation to generation, some medical professionals contemplated sterilization as a way to prevent the reproduction of mental disability in the children of affected parents, but the lingering trauma caused by the Holocaust and Nazi racial hygiene hindered their plan. This article examines a 1954 case involving a cognitively disabled woman who was brought to court for neglecting her children. Due to her delinquent parenting, she was slated to undergo sterilization, but her legal incompetence raised a host of ethical questions that tested the psychiatrists’ and judicial authorities’ assumptions about cognitive competence, civic fitness, and reproductive autonomy. By examining contemporary press reports of the legal proceedings, their larger context, and their consequences, this article shows how the woman remained hostage to male-dominated power structures that devalued her dual status as a mother and as a cognitively impaired citizen. While this case study shows how easily overridden were the liberties and protections of those affected by disabilities of the mind, it can also be viewed as a situation that impelled the Israeli public to contemplate the rights of the cognitively disabled, foreshadowing later movements aimed at expanding the boundaries of society to include members of many degrees of ability.
SPECT and PET Instrumentation
Authors: Galt James R. , Garcia Ernest V. , Chen Ji
Published: February 2024

Imaging instrumentation for nuclear cardiology is designed for imaging radionuclides that emit gamma rays (single photons) and radionuclides that emit positrons. SPECT uses mechanical devices, called collimators, to determine the direction of travel of detected photons. The most common collimators are parallel-hole designs that eliminate all photons that are not perpendicular to the detector face. Photons that pass through the collimator encounter a scintillation crystal; scintillation produces a flash of light with brightness proportional to the photon’s energy. This flash is detected by an array of devices called photomultiplier tubes (PMTs). Determining the location and brightness of the scintillation allows formation of a planar projection. Acquiring planar projections at several positions around the patient provides the information necessary to reconstruct tomographic images. Advanced SPECT system use unique designs to improve sensitivity. PET does not image positrons directly but uses a ring of scintillation detectors to detect the annihilation photon pairs that are emitted in opposite directions when a positron (antimatter) and an electron (matter) meet, and their mass is converted to energy. By only accepting photon pairs that occur in coincidence, the line between the two detectors gives the direction of travel of the photons (electrical collimation). Improved PET designs utilize the difference in arrival time of the photon pair to estimate the location of the annihilation and lengthen the axial FOV (along the table) to improve sensitivity. Some improved SPECT and PET designs have replaced PMTs with solid-state detectors.