bluuebunny/crossref_metadata_2025 huggingface dataset:
Bidirectional rotating direct-current triboelectric nanogenerator with self-adaptive mechanical switching for harvesting reciprocating motion
Authors: Lee Donghan , Chae Joonmin , Cho Sumin , Kim Jong Woo , Ahmad Awais , Karim Mohammad Rezaul , La Moonwoo , Park Sung Jea , Choi Dongwhi
Published: April 2024

Amid the growing interest in triboelectric nanogenerators (TENGs) as novel energy-harvesting devices, several studies have focused on direct current (DC) TENGs to generate a stable DC output for operating electronic devices. However, owing to the working mechanisms of conventional DC TENGs, generating a stable DC output from reciprocating motion remains a challenge. Accordingly, we propose a bidirectional rotating DC TENG (BiR-TENG), which can generate DC outputs, regardless of the direction of rotation, from reciprocating motions. The distinct design of the BiR-TENG enables the mechanical rectification of the alternating current output into a rotational-direction-dependent DC output. Furthermore, it allows the conversion of the rotational-direction-dependent DC output into a unidirectional DC output by adapting the configurations depending on the rotational direction. Owing to these tailored design strategies and subsequent optimizations, the BiR-TENG could generate an effective unidirectional DC output. Applications of the BiR-TENG for the reciprocating motions of swinging doors and waves were demonstrated by harnessing this output. This study demonstrates the potential of the BiR-TENG design strategy as an effective and versatile solution for energy harvesting from reciprocating motions, highlighting the suitability of DC outputs as an energy source for electronic devices.
Part 1 of Martin’s Conjecture for order-preserving and measure-preserving functions
Authors: Lutz Patrick , Siskind Benjamin
Published: April 2024

Martin’s Conjecture is a proposed classification of the definable functions on the Turing degrees. It is usually divided into two parts, the first of which classifies functions which are not above the identity and the second of which classifies functions which are above the identity. Slaman and Steel proved the second part of the conjecture for Borel functions which are order-preserving (i.e. which preserve Turing reducibility). We prove the first part of the conjecture for all order-preserving functions. We do this by introducing a class of functions on the Turing degrees which we call “measure-preserving” and proving that part 1 of Martin’s Conjecture holds for all measure-preserving functions and also that all nontrivial order-preserving functions are measure-preserving. Our result on measure-preserving functions has several other consequences for Martin’s Conjecture, including an equivalence between part 1 of the conjecture and a statement about the structure of the Rudin-Keisler order on ultrafilters on the Turing degrees.
Deep partially linear cox model for current status data
Authors: Wu Qiang , Tong Xingwei , Zhao Xingqiu
Published: April 2024

Deep learning has continuously attained huge success in diverse fields, while its application to survival data analysis remains limited and deserves further exploration. For the analysis of current status data, a deep partially linear Cox model is proposed to circumvent the curse of dimensionality. Modeling flexibility is attained by using deep neural networks (DNNs) to accommodate nonlinear covariate effects and monotone splines to approximate the baseline cumulative hazard function. We establish the convergence rate of the proposed maximum likelihood estimators. Moreover, we derive that the finite-dimensional estimator for treatment covariate effects is $\sqrt{n}$-consistent, asymptotically normal, and attains semiparametric efficiency. Finally, we demonstrate the performance of our procedures through extensive simulation studies and application to real-world data on news popularity.
The Public’s Attitudes towards Social Workers: The Role of Values, Opinions of Others and Personal Experience
Authors: Tartakovsky Eugene
Published: April 2024

The present study investigates the psychological factors affecting the public’s attitudes towards social workers. The study was based on the theory of human values and aimed to investigate the role of personal motivational goals reflected in values on attitudes towards social workers. In addition, we tested the contact hypothesis in the context of social work. The study was conducted in Israel using a stratified representative sample that included individuals who had no contact with social workers during the last 3 years (n = 303) and those with such contact (n = 220). In the inexperienced population, values affected the perception of social workers indirectly through the opinions of others. In the experienced population, personal experience with social workers affected their perception and support of their struggle. Finally, a higher preference for self-transcendence vs. self-enhancement values was associated with stronger support of the social workers’ struggle to improve their working conditions in both the experienced and inexperienced populations. The results of the present study advance the theory of human values and the contact hypothesis in the context of social work. In addition, they have important implications for social work practice, permitting social workers to understand their clients better.
A data browsing application for accessing gene and module-level blood transcriptome profiles of healthy pregnant women from high- and low-resource settings
Authors: Rinchai Darawan , Brummaier Tobias , A Marr Alexandra , Habib Tanwir , Toufiq Mohammed , Kino Tomoshigue , Nosten François , Al Khodor Souhaila , Terranegra Annalisa , McGready Rose , Kabeer Basirudeen Syed Ahamed , Chaussabel Damien
Published: April 2024

Transcriptome profiling data, generated via RNA sequencing, are commonly deposited in public repositories. However, these data may not be easily accessible or usable by many researchers. To enhance data reuse, we present well-annotated, partially analyzed data via a user-friendly web application. This project involved transcriptome profiling of blood samples from 15 healthy pregnant women in a low-resource setting, taken at 6 consecutive time points beginning from the first trimester. Additional blood transcriptome profiles were retrieved from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) public repository, representing a cohort of healthy pregnant women from a high-resource setting. We analyzed these datasets using the fixed BloodGen3 module repertoire. We deployed a web application, accessible at https://thejacksonlaboratory.shinyapps.io/BloodGen3_Pregnancy/which displays the module-level analysis results from both original and public pregnancy blood transcriptome datasets. Users can create custom fingerprint grid and heatmap representations via various navigation options, useful for reports and manuscript preparation. The web application serves as a standalone resource for exploring blood transcript abundance changes during pregnancy. Alternatively, users can integrate it with similar applications developed for earlier publications to analyze transcript abundance changes of a given BloodGen3 signature across a range of disease cohorts.

Database URL: https://thejacksonlaboratory.shinyapps.io/BloodGen3_Pregnancy/
Daylight saving time was not associated with a change in suicide rates in Austria, Switzerland and Sweden
Authors: Plöderl Martin , Pichler Eva-Maria , Westerlund Joakim , Niederseer David , Fartacek Clemens
Published: April 2024

Background

Some studies have reported an increase in suicides after the start of daylight saving time (DST), but the evidence is mixed and more research about proposed mechanisms (disrupted sleep, changing light exposure) is needed.

Methods

In our preregistered study, we analyzed change in suicide rates in the 2 weeks before/after DST, based on data between 1980 and 2022 from Austria, Switzerland and Sweden, using Poisson regression models and changepoint analyses. To explore the impact of disrupted sleep, we repeated the analysis for retired people who are likely less bound to DST, and for younger people. To explore the effect of changed daylight exposure, we repeated the analysis for northern and southern regions because twilight and daylight exposure varies by latitude.

Results

Suicide rates did not significantly increase after the start of DST (adjusted incidence rate ratio IRR = 0.98, 95% CI 0.91–1.06, P = 0.66, n = 13 362 suicides) or after DST ended (adjusted IRR = 0.99, 95% CI 0.91–1.07, P = 0.76, n = 12 319 suicides). There were no statistically significant findings among younger or older subgroups and also not in Sweden and Austria/Switzerland. No changepoints were detected.

Conclusions

There were no significant changes in suicide rates associated with DST and no clear evidence to support proposed mechanisms (light exposure, disruption of sleep). Our study is one of the largest and was adequately powered. Nonetheless, even larger studies to detect smaller effects could be important to inform the debate about harms and benefits of DST.
Childlessness, Social Network Profiles in Midlife and Late Adulthood, and Their Implications for Subjective Well-Being
Authors: Teerawichitchainan Bussarawan , Kim Dahye , Ho Christine
Published: April 2024

Objectives

Despite the rising prevalence of individuals reaching advanced age without children, little is known about the diversity of support networks within childless populations. We examine the network profiles of childless adults aged 50+ in Singapore, which observes high childlessness rates despite societal emphasis on familism.

Methods

We employ latent class analysis to derive network typology based on a 2022 nationwide survey in Singapore. Additionally, we use logistic regression analyses to investigate the sociodemographic correlates of childless individuals’ network types and the associations between these network types and subjective well-being.

Results

Childless Singaporeans form a heterogeneous group characterized by different support networks. Evidence suggests the centrality of parents in the childless’ social networks and the continuity of parent–child support exchanges that extend into the child’s midlife and late adulthood. When parents are absent, siblings/extended kin serve as their support sources. Age, sibship size, and socioeconomic status are key correlates of network types. Membership in diverse networks is beneficial to the subjective well-being of childless individuals. Although one-fifth of childless individuals in restricted networks demonstrate significantly poorer well-being, the remaining four-fifths show comparable, if not better, well-being than the non-childless.

Discussion

Results underscore the importance of differentiating network types among the childless, particularly when assessing their well-being. Contrary to the notion of associating later-life childlessness with social isolation and vulnerabilities, many childless Singaporeans manage to construct non-child-based networks equipped with various supportive relations that cater to their needs. Nevertheless, persistent vulnerabilities among restricted network members deserve policymakers’ attention.
Adaptive regulation of miRNAs/milRNAs in tissue-specific interaction between apple and Valsa mali
Authors: Gao Chengyu , Zhao Binsen , Zhang Jian , Du Xuan , Wang Jie , Guo Yan , He Yanting , Feng Hao , Huang Lili
Published: April 2024

In plant-pathogen interactions, pathogens display tissue specificity, infecting and causing disease in particular tissues. However, the involvement of microRNAs/microRNA-like RNAs (miRNAs/milRNAs) in tissue-specific regulation during plant-pathogen interactions remains largely unexplored. This study investigates the differential expression of miRNAs/milRNAs, as well as their corresponding target genes, in interactions between Valsa mali (Vm) and different apple tissues. The results demonstrated that both apple miRNAs and Vm milRNAs exhibited distinct expression profiles when Vm infected bark and leaves, with functionally diverse corresponding target genes. Furthermore, one apple miRNA (Mdo-miR482a) and one Vm milRNA (Vm-milR57) were identified as exhibiting tissue-specific expression in interactions between Vm and apple bark or leaves. Mdo-miR482a was exclusively up-regulated in response to Vm infection in bark and target a nucleotide-binding leucine-rich repeat (NLR) gene of apple. When Mdo-miR482a was transiently over-expressed or silenced, the resistance was significantly reduced or improved. Similarly, transient expression of the NLR gene also showed an increase in resistance. Vm-milR57 could target two essential pathogenicity-related genes of Vm. During Vm infection in bark, the expression of Vm-milR57 was down-regulated to enhance the expression of the corresponding target gene to improve the pathogenicity. The study is the first to reveal tissue-specific characteristics of apple miRNAs and Vm milRNAs in interactions between Vm and different apple tissues, providing new insights into adaptive regulation in tissue-specific interactions between plants and fungi.
Decorated Discrete Conformal Maps and Convex Polyhedral Cusps
Authors: Bobenko Alexander I , Lutz Carl O R
Published: April 2024

We discuss a notion of discrete conformal equivalence for decorated piecewise Euclidean surfaces (PE-surface), that is, PE-surfaces with a choice of circle about each vertex. It is closely related to inversive distance and hyperideal circle patterns. Under the assumption that the circles are non-intersecting, we prove the corresponding discrete uniformization theorem. The uniformization theorem for discrete conformal maps corresponds to the special case that all circles degenerate to points. Our proof relies on an intimate relationship between decorated PE-surfaces, canonical tessellations of hyperbolic surfaces and convex hyperbolic polyhedra. It is based on a concave variational principle, which also provides a method for the computation of decorated discrete conformal maps.
Health literacy and household financial loss on malaria treatment for children under five in Ghana: a patients’ perspective
Authors: Ofori Boateng Millicent , Asuman Derek , Kugbey Nuworza , Amoah Padmore Adusei , Agyei-Baffour Peter , Enemark Ulrika
Published: April 2024

Background

Inadequate health literacy increases medical costs and leads to poor health outcomes. However, there is a paucity of empirical evidence of such associations in sub-Saharan Africa. This study investigates how the household cost of malaria in children under five in Ghana varies based on different levels of health literacy.

Methods

A cross-sectional survey involving 1270 caregivers of children under five was conducted. The survey included health literacy questionnaire and several pieces of sociodemographic and behavioural variables.

Results

We created seven caregiver health literacy profiles by scoring nine dimensions. The mean total cost for managing malaria among respondents was US$20.29 per episode. The total household cost for caregivers with high health literacy (Profile 1) (US$24.77) was higher than all other profiles, with the lowest cost (US$17.93) among the low health literacy profile (Profile 6). Compared with Profile 4, caregivers with high health literacy (Profile 1) spent more on managing malaria in children, while those with the lowest health literacy (Profile 7) spent less.

Conclusion

The current study presents a snapshot of malaria treatment costs, and argues that low health literacy may lead to increased costs due to possible reinfections from delayed healthcare use. There is a need for longitudinal studies to understand causal relationship between health literacy and household expenses on malaria treatment to inform policy development and interventions.

Lay Summary

This study explores the impact of caregiver health literacy levels on the cost of managing malaria incidents in children under five in Ghana. High health-literate caregivers incurred the highest total household cost at US$24.77, with US$17.93 incurred by lower health-literate caregivers per malaria episode.
Effect of rainfall on White Rhino calf survival depends on home range choice of the mother
Authors: de Lange Christoffel J , Bonnet Olivier , Shrader Adrian M
Published: April 2024

Within African savannas, seasonal rainfall influences the survival of mammalian grazers by determining the availability and quality of food. The strength of these effects may, however, vary depending on the availability of reserve and buffer resources within the home range of an individual. From 1999 to 2019, 24% of the white rhino (Ceratotherium simum simum) calves born in Ithala Game Reserve died without a known cause. To explore this, we investigated the impacts of seasonal rainfall on calf survival, and whether these relationships were modified by the availability of woodlands (i.e., reserve resources) and bunch grasslands (i.e., buffer resources) within the home ranges established by the mothers. We found that nearly all of the deceased calves died during their first dry season after weaning had commenced. The likelihood of a calf surviving this period was positively influenced by rainfall during the dry season and negatively influenced by its duration. However, these effects were more pronounced when the availability of woodlands within the home range of the mother was high. Ultimately, calf deaths were caused by a combination of low dry season rainfall, long dry seasons, and the selection of home ranges with insufficient bunch grasslands by some mothers. With climate change models predicting increased dry season durations and a reduction in dry season rainfall, our results highlight future challenges for the conservation of white rhinos and other large herbivores.
A framework of African Continental Free Trade Area dispute settlement mechanism: legal challenges
Authors: Demamu Alemayehu Yismaw
Published: April 2024

African countries have recently signed an ambitious and progressive trade pact titled the African Continental Free Trade Area (AfCFTA) agreement. The agreement establishes a free trade area, which also includes a dispute settlement mechanism (DSM). African countries further agreed on the Protocol on Rules and Procedures on the Settlement of Disputes to establish and regulate the process of the DSM. The Dispute Settlement Body formally launched its business on 26 April 2021. The Agreement and the Protocol are the first of the kind in the continent and are on the verge of implementation. Given that, the article examines the AfCFTA Agreement and the Protocol on Rules and Procedures on the Settlement of Disputes. Accordingly, the article finds that the Agreement and the Protocol involve some legal challenges that will constrain the efficacy of the DSM in the continent.
Huge mesenchymal hamartoma in a young adult: a case report
Authors: Pinelli Domenico , Guerci Claudio , Cammarata Francesco , Cirelli Riccardo , Scatigno Agnese , Colledan Michele
Published: April 2024

Mesenchymal hamartoma of the liver (MHL) is rare. Less than 50 adult cases have been described. Due to their potential degeneration or recurrence, a complete surgical resection must be performed. We describe a case of a 26-year-old with a palpable solid lesion, which displaced abdominal organs. Percutaneous needle biopsies suggested the diagnosis of MHL. A right hemi-hepatectomy without segment 1 was performed; the post-operative course was uneventful. The mesenchymal component of the tumour was reactive to desmin and smooth muscle actin. Low proliferation index was confirmed (MIB1). Genetic counselling: the sequencing analysis of DICER1 and CDKN1C gene was negative, DNA methylation analysis on the chromosome 11p15 region was normal. After 42 months, there was no recurrence. In conclusion, clinicians should consider MHL in the differential diagnosis. The dimension and the need of radicality impose major liver resections or liver transplantations, which should be performed in referral centres.
Vaginal vault dehiscence with small bowel evisceration, bowel necrosis, and intra-abdominal haemorrhage: a case report
Authors: Lim Ee Thong , Stylianides Nicholas , Craciunas Laurentiu , Tsampras Nikolaos
Published: April 2024

Vaginal vault dehiscence with evisceration is a rare but a potentially life-threatening complication of total hysterectomy that requires prompt recognition, diagnosis, and management. The overall incidence of vaginal vault dehiscence is 0.53%. The mortality rate increases to 5.6% when bowel evisceration is present. We report a case of vaginal vault dehiscence with small bowel evisceration complicated by bowel necrosis and intra-abdominal haemorrhage in a 48-year-old woman following her first sexual intercourse 4 months after her total abdominal hysterectomy.
Sigmoid carcinoma contained within a scrotal hernia in an octogenarian: case report
Authors: Cotter Aine , Joyce William
Published: April 2024

Scrotal hernias are common in the general population. Patients often present acutely reporting pain or sometimes with more severe symptoms if the hernia is strangulated or incarcerated. An 81-year-old man presented with left-sided iliac fossa pain with no other associated symptoms. On clinical exam, a left-sided non-reducible inguinoscrotal hernia was detected with no evidence to suggest strangulation. Imaging revealed a probable colorectal cancer with likely liver metastases. The patient went on to have open surgery to excise the tumour with clear oncological margins. Colorectal cancers contained within scrotal hernias are very rare occurrences. In this case, the surgeon had the advantage of preoperative images that identified the cancer. In some cases, this cohort of patients do not have such scans prior to surgery and the surgical team can be faced with a much more complex operation than anticipated.
Changing the logic without changing the subject: the case of computability
Authors: MartÍnez-Aviña Francisco N
Published: April 2024

In this paper, I argue against the thesis that the meaning of ‘computability’ is logic-dependent. I do this from a category-theoretic perspective. Applying a method due to Mortensen and Lavers [26], I show that we can dualize the internal logic of the effective topos, in order to obtain a model of paraconsistent computability theory. Since the dualization leaves the structural properties of universal constructions in the topos unchanged, in particular the properties of the natural numbers object, I conclude that, at least in this case, changing the logic does not change our characterization of computability.
Incidence and Mortality of COVID-19-Associated Invasive Fungal Infections Among Critically Ill Intubated Patients: A Multicenter Retrospective Cohort Analysis
Authors: Zuniga-Moya Julio C , Papadopoulos Benjamin , Mansoor Armaghan-E-Rehman , Mazi Patrick B , Rauseo Adriana M , Spec Andrej
Published: April 2024

Background

An association between coronavirus disease 2019 (COVID-19)–associated invasive fungal infections (CAIFIs) and high mortality among intubated patients has been suggested in previous research. However, some of the current evidence was derived from small case series and multicenter studies conducted during different waves of the COVID-19 pandemic. We examined the incidence of CAIFIs and their associated mortality using a large, multicenter COVID-19 database built throughout the pandemic.

Methods

We conducted a retrospective analysis of the National COVID Cohort Collaborative (N3C) database collected from 76 medical centers in the United States between January 2020 and August 2022. Patients were 18 years or older and intubated after severe acute respiratory syndrome coronavirus 2 infection. The primary outcomes were incidence and all-cause mortality at 90 days. To assess all-cause mortality, we fitted Cox proportional hazard models after adjusting for confounders via inverse probability weighting.

Results

Out of the 4 916 229 patients with COVID-19 diagnosed during the study period, 68 383 (1.4%) met our cohort definition. The overall incidence of CAIFI was 2.80% (n = 1934/68 383). Aspergillus (48.2%; n = 933/1934) and Candida (41.0%; n = 793/1934) were the most common causative organisms. The incidence of CAIFIs associated with Aspergillus among patients who underwent BAL was 6.2% (n = 83/1328). Following inverse probability weighting, CAIFIs caused by Aspergillus (hazard ratio [HR], 2.0; 95% CI, 1.8–2.2) and Candida (HR, 1.7; 95% CI, 1.5–1.9) were associated with increased all-cause mortality. Systemic antifungals reduced mortality in 17% of patients with CAIFI with Aspergillus and 24% of patients with CAIFI with Candida.

Conclusions

The incidence of CAIFI was modest but associated with higher 90-day all-cause mortality among intubated patients. Systemic antifungals modified mortality.
Outpatient Parenteral Antimicrobial Therapy in a Safety Net Hospital: Opportunities for Improvement
Authors: Bouzigard Rory , Arnold Mark , Msibi Sithembiso S , Player Jacob K , Mang Norman , Hall Brenton , Su Joseph , Lane Michael A , Perl Trish M , Castellino Laila M
Published: April 2024

Background

Outpatient parenteral antimicrobial therapy (OPAT) is a safe and cost-effective transitional care approach administered via different delivery models. No standards exist for appropriate OPAT program staffing. We examined outcomes of patients receiving OPAT via different care models to identify strategies to improve safety while reducing health care overuse.

Methods

Retrospective demographic, clinical, and outcome data of patients discharged with OPAT were reviewed in 2 periods (April–June 2021 and January–March 2022; ie, when staffing changed) and stratified by care model: self-administered OPAT, health care OPAT, and skilled nursing facility OPAT.

Results

Of 342 patients, 186 (54%) received OPAT in 2021 and 156 (46%) in 2022. Hospital length of stay rose from 12.4 days to 14.3 in 2022. In a Cox proportional hazards regression model, visits to the emergency department (ED) within 30 days of OPAT initiation (hazard ratio, 1.76; 95% CI, 1.13–2.73; P = .01) and readmissions (hazard ratio, 2.34; 95% CI, 1.22–4.49; P = .01) increased in 2022 vs 2021, corresponding to decreases in OPAT team staffing. Higher readmissions in the 2022 cohort were for reasons unrelated to OPAT (P = .01) while readmissions related to OPAT did not increase (P = .08).

Conclusions

In a well-established OPAT program, greater health care utilization—length of stay, ED visits, and readmissions—were seen during periods of higher staff turnover and attrition. Rather than blunt metrics such as ED visits and readmissions, which are influenced by multiple factors besides OPAT, our findings suggest the need to develop OPAT-specific outcome measures as a quality assessment tool and to establish optimal OPAT program staffing ratios.
In-vitro assessment of cutaneous immune responses to aedes mosquito salivary gland extract and dengue virus in Cambodian individuals
Authors: Guerrero David , Lay Sokchea , Piv Eakpor , Chhin Chansophea , Leng Sokkeang , Meng Ratana , Mam Kim Eng , Pean Polidy , Vantaux Amelie , Boyer Sebastien , Missé Dorothée , Cantaert Tineke
Published: April 2024

Dengue virus (DENV) poses a global health threat, affecting millions individuals annually with no specific therapy and limited vaccines. Mosquitoes, mainly Aedes aegypti and Aedes albopictus worldwide, transmit DENV through their saliva during blood meals. In this study, we aimed to understand how Aedes mosquito saliva modulate skin immune responses during DENV infection in individuals living in mosquito-endemic regions. To accomplish this, we dissociated skin cells from Cambodian volunteers and incubated them with salivary gland extract (SGE) from three different mosquito strains: Ae. aegypti USDA strain, Ae. aegypti and Ae. albopictus wild type (WT) in the presence/absence of DENV. We observed notable alterations in skin immune cell phenotypes subsequent to exposure to Aedes salivary gland extract (SGE). Specifically, exposure lead to an increase in the frequency of macrophages expressing chemokine receptor CCR2, and neutrophils expressing CD69. Additionally, we noted a substantial increase in the percentage of macrophages that became infected with DENV in the presence of Aedes SGE. Differences in cellular responses were observed when Aedes SGE of three distinct mosquito strains were compared. Our findings deepen the understanding of mosquito saliva's role in DENV infection and skin immune responses in individuals regularly exposed to mosquito bites. This study provides insights into skin immune cell dynamics that could guide strategies to mitigate DENV transmission and other arbovirus diseases.
Size Discount and Size Penalty: Trading Costs in Bond Markets
Authors: Pinter Gabor , Wang Chaojun , Zou Junyuan
Published: April 2024

We show that larger trades incur lower trading costs in government bond markets (“size discount”), but costs increase in trade size after controlling for client identity (“size penalty”). The size discount is driven by the cross-client variation of larger traders obtaining better prices, consistent with theories of trading with imperfect competition. The size penalty, driven by the within-client variation, is larger for corporate bonds, during major macroeconomic surprises and during COVID-19. These differences are larger among more sophisticated clients, consistent with information-based theories.
Stem cell dynamics and cellular heterogeneity across lineage subtypes of castrate-resistant prostate cancer
Authors: Beshiri Michael L , Capaldo Brian J , Lake Ross , Ku Anson T , Burner Danielle , Tice Caitlin M , Tran Crystal , Kostas Julianna , Alilin Aian Neil , Yin JuanJuan , Agarwal Supreet , Morris Samantha A , Karzai Fatima H , Lotan Tamara L , Dahut William L , Sowalsky Adam G , Kelly Kathleen
Published: April 2024

To resist lineage-dependent therapies such as androgen receptor inhibition, prostate luminal epithelial adenocarcinoma cells often adopt a stem-like state resulting in lineage plasticity and phenotypic heterogeneity. Castrate-resistant prostate adenocarcinoma can transition to neuroendocrine (NE) and occasionally to amphicrine, co-expressed luminal and NE, phenotypes. We developed castrate-resistant prostate cancer (CRPC) patient-derived organoid models that preserve heterogeneity of the originating tumor, including an amphicrine model displaying a range of luminal and NE phenotypes. To gain biological insight and to identify potential treatment targets within heterogeneous tumor cell populations, we assessed the lineage hierarchy and molecular characteristics of various CRPC tumor subpopulations. Transcriptionally similar stem/progenitor (St/Pr) cells were identified for all lineage populations. Lineage tracing in amphicrine CRPC showed that heterogeneity originated from distinct subclones of infrequent St/Pr cells that produced mainly quiescent differentiated amphicrine progeny. By contrast, adenocarcinoma CRPC progeny originated from St/Pr cells and self-renewing differentiated luminal cells. Neuroendocrine prostate cancer (NEPC) was composed almost exclusively of self-renewing St/Pr cells. Amphicrine subpopulations were enriched for secretory luminal, mesenchymal, and enzalutamide treatment persistent signatures that characterize clinical progression. Finally, the amphicrine St/Pr subpopulation was specifically depleted with an AURKA inhibitor, which blocked tumor growth. These data illuminate distinct stem cell (SC) characteristics for subtype-specific CRPC in addition to demonstrating a context for targeting differentiation-competent prostate SCs.
The Unidroit Principles and the inflexibility of code as law: reconciling smart contracts with general clauses
Authors: Meyer Olaf , Ortolani Pietro
Published: April 2024

Smart contracts are a set of digital technologies enabling the automation of certain aspects of contractual performance and/or remedies. These technologies follow a deterministic, if/then logic that is often difficult to reconcile with the inherent malleability of contract law. This article scrutinizes this tension, with specific reference to the International Institute for the Unification of Private Law’s (Unidroit) Principles of International Commercial Contracts (PICC). The article argues that some recurring PICC general clauses (such as good faith and reasonableness) play a crucial role in ensuring fairness. Therefore, their operation should not be constrained by smart contracts. To the contrary, the parties to an international commercial contract should use technology to empower arbitrators to make full use of the flexibility inherent to the PICC and issue (partially) self-enforcing awards.
Availability in ECMO Reduces the Failure to Rescue in Patients With Pulmonary Embolism After Major Surgery: A Nationwide Analysis of 2.4 Million Cases
Authors: Diers Johannes , Baumann Nikolas , Baum Philip , Uttinger Konstantin L. , Wagner Johanna C. , Kranke Peter , Meybohm Patrick , Germer Christoph-Thomas , Wiegering Armin
Published: April 2024

Objective:

Postoperative pulmonary embolism (PE) is a rare but potentially life-threatening complication, which can be treated with extracorporeal membrane oxygenation (ECMO) therapy, a novel therapy option for acute cardiorespiratory failure. We postulate that hospitals with ECMO availability have more experienced staff, technical capabilities, and expertise in treating cardiorespiratory failure.

Design:

A retrospective analysis of surgical procedures in Germany between 2012 and 2019 was performed using hospital billing data. High-risk surgical procedures for postoperative PE were analyzed according to the availability of and expertise in ECMO therapy and its effect on outcome, regardless of whether ECMO was used in patients with PE.

Methods:

Descriptive, univariate, and multivariate analyses were applied to identify possible associations and correct for confounding factors (complications, complication management, and mortality).

Results:

A total of 13,976,606 surgical procedures were analyzed, of which 2,407,805 were defined as high-risk surgeries. The overall failure to rescue (FtR) rate was 24.4% and increased significantly with patient age, as well as type of surgery. The availability of and experience in ECMO therapy (defined as at least 20 ECMO applications per year; ECMO centers) are associated with a significantly reduced FtR in patients with PE after high-risk surgical procedures. In a multivariate analysis, the odds ratio (OR) for FtR after postoperative PE was significantly lower in ECMO centers (OR, 0.75 [0.70–0.81], P < 0.001).

Conclusions:

The availability of and expertise in ECMO therapy lead to a significantly reduced FtR rate of postoperative PE. This improved outcome is independent of the use of ECMO in these patients.
Trauma-Informed Care as a Universal Precaution: A Brief, Case-Based, Educational Primer Featuring Role-Playing and Individual Self-Reflection Exercises
Authors: Kopstick Avi J. , Aly Aly M. , Zientek Emily , Williams Cydni N. , Hall Trevor A. , Macauley Robert C. , Duffee James H.
Published: April 2024

Despite its growing popularity, the implementation of Trauma-Informed Care (TIC) in standard medical practices remains insufficient. A workshop, featuring role-playing scenarios and individual self-reflection exercises, was developed to enhance compassion among health care providers. The workshop was created by a multidisciplinary team of community pediatricians, pediatric intensivists, psychologists, and palliative care physicians, was structured around key elements and principles of TIC, and was based on actual patient encounters. The 90-minute session included didactics, role-playing, writing and self-reflection exercises, and large-group debriefings, and it was presented at two academic meetings. It is currently available as an open-sourced, freely accessible website. The workshop was attended by individuals with varying levels of training and experience. Of approximated 80 participants, 39 responded to surveys about baseline knowledge and workshop satisfaction, and 24 completed self-perceived pre- and postknowledge surveys. Nearly 90% had limited prior exposure to TIC. All rated the workshop highly, with no significant differences based on workshop facilitation. Nearly 95% felt that they learned something that would impact their day-to-day practices. Self-perceived pre–post knowledge showed statistically significant improvements. This workshop is feasible and can potentially increase health care professionals' capacity to care, decrease moral injury, and alleviate burnout from difficult cases.
Activation of mGlu2/3 receptors with the orthosteric agonist LY-404,039 alleviates dyskinesia in experimental parkinsonism
Authors: Kang Woojin , Frouni Imane , Kwan Cynthia , Desbiens Louis , Hamadjida Adjia , Huot Philippe
Published: April 2024

LY-404,039 is an orthosteric agonist at metabotropic glutamate 2 and 3 (mGlu2/3) receptors, with a possible additional agonist effect at dopamine D2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously been tested in clinical trials for psychiatric indications and could therefore be repurposed if they were shown to be efficacious in other conditions. We have recently demonstrated that the mGlu2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat without hampering the anti-parkinsonian action of L-DOPA. Here, we seek to take advantage of a possible additional D2-agonist effect of LY-404,039 and see if an anti-parkinsonian benefit might be achieved in addition to the antidyskinetic effect of mGlu2/3 activation. To this end, we have administered LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg) to 6-OHDA-lesioned rats, after which the severity of axial, limbs and oro-lingual (ALO) AIMs was assessed. The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of ALO AIMs over 60–100 min (54%, P < 0.05). In addition, LY-404,039 significantly enhanced the antiparkinsonian effect of L-DOPA, assessed through the cylinder test (76%, P < 0.01). These results provide further evidence that mGlu2/3 orthosteric stimulation may alleviate dyskinesia in PD and, in the specific case of LY-404,039, a possible D2-agonist effect might also make it attractive to address motor fluctuations. Because LY-404,039 and its pro-drug have been administered to humans, they could possibly be advanced to Phase IIa trials rapidly for the treatment of motor complications in PD.
Design of OASIS 1 and 2: phase 3 clinical trials assessing the efficacy and safety of elinzanetant for the treatment of vasomotor symptoms associated with menopause
Authors: Pinkerton JoAnn V. , Simon James , Panay Nick , Seitz Christian , Parke Susanne , Caetano Cecilia , Mellinger Uwe , Haseli Mashhadi Nazanin , Haberland Claudia , Atanackovic Gordana , Holz Cornelia , Mao Guangping , Morrison Marina , Nisius Sven , Schaefers Matthias , Zuurman Lineke
Published: April 2024

Objective

Elinzanetant is a selective neurokinin-1,3 receptor antagonist in development for the treatment of vasomotor symptoms (VMS) associated with menopause. The pivotal, double-blind, randomized, placebo-controlled phase 3 studies Overall Assessment of efficacy and Safety of elinzanetant In patients with vasomotor Symptoms (OASIS) 1 and 2 will assess the efficacy and safety of elinzanetant in women with VMS.

Methods

The OASIS 1 and 2 pivotal studies are designed in accordance with regulatory guidance. Postmenopausal women with moderate/severe VMS are randomized to receive 120 mg elinzanetant or placebo once daily for 12 weeks, followed by a 14-week active treatment extension. Primary endpoints are the mean change in frequency and severity of moderate/severe VMS from baseline to weeks 4 and 12. Key secondary endpoints will assess the onset of action and effects on sleep disturbance and menopause-related quality of life. Primary and key secondary endpoints will be analyzed using a mixed model with repeated measures. Feedback from postmenopausal women with VMS was used during protocol development.

Results

Women confirmed the relevance of endpoints that assess the impact of VMS, sleep disturbance, and mood changes, and the need for new nonhormone treatments. Educational materials around study design, conduct and expected assessments and procedures were developed based on questions and concerns raised by women.

Conclusions

The OASIS 1 and 2 pivotal phase 3 studies will enable assessment of the efficacy and safety of elinzanetant as a treatment for VMS, together with its effect on sleep disturbances, depressive symptoms, and menopause-related quality of life. Feedback from postmenopausal women with VMS was used to maximize patient centricity in the trials.
Conserved long noncoding RNA TILAM promotes liver fibrosis through interaction with PML in HSCs
Authors: Sun Cheng , Zhou Chan , Daneshvar Kaveh , Ben Saad Amel , Kratkiewicz Arcadia J. , Toles Benjamin J. , Arghiani Nahid , Hess Anja , Chen Jennifer Y. , Pondick Joshua V. , York Samuel R. , Li Wenyang , Moran Sean P. , Gentile Stefan D. , Rahman Raza Ur , Li Zixiu , Zhou Peng , Sparks Robert P. , Habboub Tim , Kim Byeong-Moo , Choi Michael Y. , Affo Silvia , Schwabe Robert F. , Popov Yury V. , Mullen Alan C.
Published: April 2024

Background and Aims:

Fibrosis is the common end point for all forms of chronic liver injury, and the progression of fibrosis leads to the development of end-stage liver disease. Activation of HSCs and their transdifferentiation into myofibroblasts results in the accumulation of extracellular matrix proteins that form the fibrotic scar. Long noncoding RNAs regulate the activity of HSCs and provide targets for fibrotic therapies.

Approach and Results:

We identified long noncoding RNA TILAM located near COL1A1, expressed in HSCs, and induced with liver fibrosis in humans and mice. Loss-of-function studies in human HSCs and human liver organoids revealed that TILAM regulates the expression of COL1A1 and other extracellular matrix genes. To determine the role of TILAM in vivo, we annotated the mouse ortholog (Tilam), generated Tilam-deficient green fluorescent protein-reporter mice, and challenged these mice in 2 different models of liver fibrosis. Single-cell data and analysis of single-data and analysis of Tilam-deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Tilam-deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Furthermore, loss of Tilam expression attenuated the development of fibrosis in the setting of in vivo liver injury. Finally, we found that TILAM interacts with promyelocytic leukemia nuclear body scaffold protein to regulate a feedback loop by which TGF-β2 reinforces TILAM expression and nuclear localization of promyelocytic leukemia nuclear body scaffold protein to promote the fibrotic activity of HSCs.

Conclusions:

TILAM is activated in HSCs with liver injury and interacts with promyelocytic leukemia nuclear body scaffold protein to drive the development of fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end-stage liver disease.
Reverse 4-Flanged Technique for Intrascleral Fixation of a Foldable Hydrophobic Intraocular Lens in the Absence of Capsular Support Through a 2.2-mm Corneal Incision
Authors: Romero-Valero Daniel , Martínez Toldos Jose Juan
Published: April 2024

Purpose:

The purpose of this study was to describe a modified technique for sutureless intrascleral intraocular lens fixation in patients without capsular support: the reverse 4-flanged technique.

Methods:

A 2.2-mm corneal incision was made for aphakic patients. The 6-0 polypropylene sutures were threaded through a 30-gauge needle outside the eye. An MDJ injector was employed to insert the intraocular lens into the eye. A suture-needle snare with 7-0 polypropylene was used to exteriorize the superior end of the sutures through the sclerotomy. The 6-0 polypropylene was heated with a cautery to create the flanges.

Results:

Nine eyes of nine patients underwent the reverse 4-flanged technique. The median follow-up time was 182 days (range 174–195). Best-corrected distance visual acuity improved from 20/400 [hand movement—20/33] to 20/120 [20/400–20/21]. No vitreous hemorrhage, retinal detachment, endophthalmitis, intraocular lens luxation, or flange exposure was recorded during the follow-up.

Conclusion:

The reverse 4-flanged technique maintains the advantages of the original 4-flanged technique in terms of intraocular lens stability while reducing the incision size and surgical maneuvers performed inside the eye. This modification promises to be a reliable, safe, and relatively simple technique to correct aphakia in the absence of capsular support.
Directional Optical Coherence Tomography Imaging of Macular Pathology
Authors: Lujan Brandon J. , Griffin Shane , Makhijani Vikram S. , Antony Bhavna J. , Chew Emily Y. , Roorda Austin , McDonald H. Richard
Published: April 2024

Purpose:

To survey the impact of directional reflectivity on structures within optical coherence tomography (OCT) images in retinal pathology.

Methods:

Sets of commercial OCT images taken from multiple pupil positions were analyzed. These Directional OCT (D-OCT) sets revealed directionally reflective structures within the retina. After ensuring sufficient image quality, resulting hybrid and composite images were characterized by assessing the Henle Fiber Layer (HFL), Outer Nuclear Layer (ONL), Ellipsoid Zone (EZ), and Interdigitation Zone (IZ). Additionally, hybrid images were reviewed for novel directionally reflective pathological features.

Results:

Cross-sectional D-OCT image sets were obtained in 75 eyes of 58 subjects having a broad range of retinal pathologies. All cases showed improved visualization of the ONL/Henle fiber layer interface, and ONL thinning was therefore more apparent in several cases. The EZ and IZ also demonstrated attenuation where a geometric impact of underlying pathology affected their orientation. Misdirected photoreceptors were also noted as a consistent direction-dependent change in EZ reflectivity between regions of normal and absent EZ.

Conclusion:

D-OCT enhances the understanding of retinal anatomy and pathology. This optical contrast yields more accurate identification of retinal structures and possible imaging biomarkers for photoreceptor-related pathology.
FOVEAL AVASCULAR ZONE IN ADULTS BORN PRETERM WITH AND WITHOUT RETINOPATHY OF PREMATURITY
Authors: Fieß Achim , Zange Maria , Gißler Sandra , Mildenberger Eva , Urschitz Michael S. , Laspas Panagiotis , Stoffelns Bernhard , Pfeiffer Norbert , Schuster Alexander K.
Published: April 2024

Purpose:

To examine potential changes in the foveal avascular zone (FAZ) during adulthood due to prematurity and retinopathy of prematurity (ROP), as assessed by measurements of the FAZ area and circularity.

Methods:

The Gutenberg Prematurity Eye Study is a retrospective German cohort study with a prospective ophthalmologic examination of adults aged 18 years to 52 years, born either preterm or full-term, using spectral-domain optical coherence tomography angiography. Participants were categorized into groups based on gestational age and postnatal ROP status. The study conducted multivariable linear regression analyses to explore associations with the FAZ.

Results:

The study cohort comprised 380 right eyes from individuals born both preterm and full-term, with an average age of 28.4 years ± 8.6 years, including 214 women. The FAZ area decreased as gestational age decreased: FAZ was 0.28 mm2 ± 0.12 mm2 in the control group, 0.21 ± 0.10 mm2 at GA 33 weeks to 36 weeks, 0.18 mm2 ± 0.10 mm2 at GA 29 weeks to 32 weeks, 0.11 mm2 ± 0.10 mm2 at GA ≤28 weeks, 0.11 mm2 ± 0.10 mm2 in ROP without treatment, and 0.11 mm2 ± 0.10 mm2 in those requiring ROP treatment. In the multivariable analyses, smaller FAZ was independently associated with gestational age (P < 0.05), increased foveal retinal thickness (P < 0.05), and foveal hypoplasia (P < 0.05). Moreover, no association was seen between visual acuity and FAZ.

Conclusion:

The main perinatal factor associated with a smaller FAZ in this German cohort is preterm birth, while ROP, ROP treatment, or other perinatal factors do not affect FAZ observed in adulthood. A smaller FAZ shape in preterm individuals might be an indicator of foveal hypoplasia.