bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative assessment of enlarged perivascular spaces via deep-learning in community-based older adults reveals independent associations with vascular neuropathologies, vascular risk factors and cognition
Authors: Javierre-Petit Carles , Kontzialis Marinos , Leurgans Sue E , Bennett David A , Schneider Julie A , Arfanakis Konstantinos
Published: July 2024

Enlarged perivascular spaces (EPVS) are common in older adults, but their neuropathologic correlates are unclear mainly because most work to date has relied on visual rating scales and/or clinical cohorts. The present study first developed a deep-learning model for automatic segmentation, localization and quantification of EPVS in ex vivo brain MRI, and then used this model to investigate the neuropathologic, clinical and cognitive correlates of EPVS in 817 community-based older adults that underwent autopsy. The new method exhibited high sensitivity in detecting EPVS as small as 3 mm3, good segmentation accuracy and consistency. Most EPVS were located in the frontal lobe, but the highest density was observed in the basal ganglia. EPVS in the cerebrum and specifically in the frontal lobe were associated with infarcts independent of other neuropathologies, while temporal and occipital EPVS were associated with cerebral amyloid angiopathy. EPVS in most brain lobes were also associated with diabetes mellitus independently of neuropathologies, while basal ganglia EPVS were independently associated with hypertension, supporting the notion of independent pathways from diabetes and hypertension to EPVS. Finally, EPVS were associated with lower cognitive performance independently of neuropathologies and clinical variables, suggesting that EPVS represent additional abnormalities contributing to lower cognition.
Give-and-take of gustation: the interplay between gustatory neurons and taste buds
Authors: Landon Shannon M , Baker Kimberly , Macpherson Lindsey J
Published: July 2024

Mammalian taste buds are highly regenerative and can restore themselves after normal wear and tear of the lingual epithelium or following physical and chemical insults, including burns, chemotherapy, and nerve injury. This is due to the continual proliferation, differentiation, and maturation of taste progenitor cells, which then must reconnect with peripheral gustatory neurons to relay taste signals to the brain. The turnover and re-establishment of peripheral taste synapses are vital to maintain this complex sensory system. Over the past several decades, the signal transduction and neurotransmitter release mechanisms within taste cells have been well delineated. However, the complex dynamics between synaptic partners in the tongue (taste cell and gustatory neuron) are only partially understood. In this review, we highlight recent findings that have improved our understanding of the mechanisms governing connectivity and signaling within the taste bud and the still-unresolved questions regarding the complex interactions between taste cells and gustatory neurons.
Visioning a two-level human–machine communication framework: initiating conversations between explainable AI and communication
Authors: Xu Kun , Shi Jingyuan
Published: July 2024

Amid mounting interest in artificial intelligence (AI) technology, communication scholars have sought to understand humans’ perceptions of and attitudes toward AI’s predictions, recommendations, and decisions. Meanwhile, scholars in the nascent but growing field of explainable AI (XAI) have aimed to clarify AI’s operational mechanisms and make them interpretable, visible, and transparent. In this conceptual article, we suggest that a conversation between human–machine communication (HMC) and XAI is advantageous and necessary. Following the introduction of these two areas, we demonstrate how research on XAI can inform the HMC scholarship regarding the human-in-the-loop approach and the message production explainability. Next, we expound upon how communication scholars’ focuses on message sources, receivers, features, and effects can reciprocally benefit XAI research. At its core, this article proposes a two-level HMC framework and posits that bridging the two fields can guide future AI research and development.
The rise and future of CRISPR-based approaches for high-throughput genomics
Authors: Vercauteren Silke , Fiesack Simon , Maroc Laetitia , Verstraeten Natalie , Dewachter Liselot , Michiels Jan , Vonesch Sibylle C
Published: July 2024

Clustered regularly interspaced short palindromic repeats (CRISPR) has revolutionized the field of genome editing. To circumvent the permanent modifications made by traditional CRISPR techniques and facilitate the study of both essential and nonessential genes, CRISPR interference (CRISPRi) was developed. This gene-silencing technique employs a deactivated Cas effector protein and a guide RNA to block transcription initiation or elongation. Continuous improvements and a better understanding of the mechanism of CRISPRi have expanded its scope, facilitating genome-wide high-throughput screens to investigate the genetic basis of phenotypes. Additionally, emerging CRISPR-based alternatives have further expanded the possibilities for genetic screening. This review delves into the mechanism of CRISPRi, compares it with other high-throughput gene-perturbation techniques, and highlights its superior capacities for studying complex microbial traits. We also explore the evolution of CRISPRi, emphasizing enhancements that have increased its capabilities, including multiplexing, inducibility, titratability, predictable knockdown efficacy, and adaptability to nonmodel microorganisms. Beyond CRISPRi, we discuss CRISPR activation, RNA-targeting CRISPR systems, and single-nucleotide resolution perturbation techniques for their potential in genome-wide high-throughput screens in microorganisms. Collectively, this review gives a comprehensive overview of the general workflow of a genome-wide CRISPRi screen, with an extensive discussion of strengths and weaknesses, future directions, and potential alternatives.
DNA methylation near MAD1L1, KDM2B, and SOCS3 mediates the effect of socioeconomic status on elevated body mass index in African American adults
Authors: Glover LáShauntá , Lilly Adam G , Justice Anne E , Howard Annie Green , Staley Brooke S , Wang Yujie , Kamens Helen M , Ferrier Kendra , Bressler Jan , Loehr Laura , Raffield Laura M , Sims Mario , North Kari E , Fernández-Rhodes Lindsay
Published: July 2024

Obesity and poverty disproportionally affect African American persons. Epigenetic mechanisms could partially explain the association between socioeconomic disadvantage and body mass index (BMI). We examined the extent to which epigenetic mechanisms mediate the effect of socioeconomic status (SES) on BMI. Using data from African American adults from the Atherosclerosis Risk in Communities (ARIC) Study (n = 2664, mean age = 57 years), education, income, and occupation were used to create a composite SES score at visit 1 (1987–1989). We conducted two methylation-wide association analyses to identify associations between SES (visit 1), BMI and cytosine-phosphate-guanine (CpG) sites measured at a subsequent visit (1990–1995). We then utilized structural equation modeling (SEM) to test whether identified sites mediated the association between earlier SES and BMI in sex-stratified models adjusted for demographic and risk factor covariates. Independent replication and meta-analyses were conducted using the Jackson Heart Study (JHS, n = 874, mean age 51 years, 2000–2004). Three CpG sites near MAD1L1, KDM2B, and SOCS3 (cg05095590, cg1370865, and cg18181703) were suggestively associated (P-value < 1.3×10−5) in ARIC and at array-wide significance (P-value < 1.3×10−7) in a combined meta-analysis of ARIC with JHS. SEM of these three sites revealed significant indirect effects in females (P-value < 5.8×10−3), each mediating 7%–20% of the total effect of SES on BMI. Nominally significant indirect effects were observed for two sites near MAD1L1 and KDM2B in males (P-value < 3.4×10−2), mediating −17 and −22% of the SES-BMI effect. These results provide further evidence that epigenetic modifications may be a potential pathway through which SES may “get under the skin” and contribute to downstream health disparities.
Functional OmpA of Salmonella Typhimurium Provides Protection From Lysosomal Degradation and Inhibits Autophagic Processes in Macrophages
Authors: Roy Chowdhury Atish , Hajra Dipasree , Mukherjee Debapriya , Nair Abhilash Vijay , Chakravortty Dipshikha
Published: July 2024

Our previous study showed that OmpA-deficient Salmonella Typhimurium failed to retain LAMP-1 around the Salmonella-containing vacuoles (SCV), and escaped in to the host cell cytosol. Here we show that the cytosolic population of S. Typhimurium ΔompA sequestered autophagic markers, syntaxin17 and LC3B, in a sseL-dependent manner and initiated lysosomal fusion. Moreover, inhibition of autophagy using bafilomycinA1 restored its intracellular proliferation. Ectopic overexpression of OmpA in S. Typhimurium ΔsifA restored its vacuolar niche and increased its interaction with LAMP-1, suggesting a sifA-independent role of OmpA in maintaining an intact SCV. Mutations in the OmpA extracellular loops impaired the LAMP-1 recruitment to SCV and caused bacterial release into the cytosol of macrophages, but unlike S. Typhimurium ΔompA, they retained their outer membrane stability and did not activate the lysosomal degradation pathway, aiding in their intramacrophage survival. Finally, OmpA extracellular loop mutations protected cytosolic S. Typhimurium ΔsifA from lysosomal surveillance, revealing a unique OmpA-dependent strategy of S. Typhimurium for its intracellular survival.
Assessing how frailty and healthcare delays mediate the association between sexual and gender minority status and healthcare utilization in the All of Us Research Program
Authors: Wong Chelsea N , Smith Louisa H , Cavanaugh Robert , Kim Dae H , Streed Carl G , Kapadia Farzana , Olivieri-Mui Brianne
Published: July 2024

Objectives

To understand how frailty and healthcare delays differentially mediate the association between sexual and gender minority older adults (OSGM) status and healthcare utilization.

Materials and Methods

Data from the All of Us Research Program participants ≥50 years old were analyzed using marginal structural modelling to assess if frailty or healthcare delays mediated OSGM status and healthcare utilization. OSGM status, healthcare delays, and frailty were assessed using survey data. Electronic health record (EHR) data was used to measure the number of medical visits or mental health (MH) visit days, following 12 months from the calculated All of Us Frailty Index. Analyses adjusted for age, race and ethnicity, income, HIV, marital status ± general MH (only MH analyses).

Results

Compared to non-OSGM, OSGM adults have higher rates of medical visits (adjusted rate ratio [aRR]: 1.14; 95% CI: 1.03, 1.24) and MH visits (aRR: 1.85; 95% CI: 1.07, 2.91). Frailty mediated the association between OSGM status medical visits (Controlled direct effect [Rcde] aRR: 1.03, 95% CI [0.87, 1.22]), but not MH visits (Rcde aRR: 0.37 [95% CI: 0.06, 1.47]). Delays mediated the association between OSGM status and MH visit days (Rcde aRR: 2.27, 95% CI [1.15, 3.76]), but not medical visits (Rcde aRR: 1.06 [95% CI: 0.97, 1.17]).

Discussion

Frailty represents a need for medical care among OSGM adults, highlighting the importance of addressing it to improve health and healthcare utilization disparities. In contrast, healthcare delays are a barrier to MH care, underscoring the necessity of targeted strategies to ensure timely MH care for OSGM adults.
Civil Society and International Accountability
Authors: Chaikel Danya , Pillai Priya , Sachithanandan Pubudu
Published: July 2024

The role of Civil Society Organizations (CSOs) in pursuing accountability for atrocity crimes through international law is more diverse than ever before, and the breadth of CSO activities and the modalities of their engagement with international justice institutions has been overlooked in the scholarship to date. This article explores various CSO approaches to advancing accountability, including at the International Court of Justice (ICJ), International Criminal Court (ICC), investigative mechanisms (for Syria, Myanmar, and Iraq), and selected United Nations treaty bodies and regional human rights courts. Civil society actors take on many roles, including as advocates, documenters, analysts, victims’ representatives, and international law experts. While often described as indispensable to international justice efforts, the relationship between civil society and formal justice mechanisms remains novel and can feel incongruous with traditional and ostensibly independent and impartial legal processes. This is evolving as CSOs enter traditional international justice spaces in diverse ways. This article provides a framework to understand the modalities of CSO engagement with international legal processes, as well as critical challenges.
A review of cutaneous apocrine carcinoma: epidemiology, diagnosis, prognosis, and treatment options
Authors: Tsuruta Seiji , Ogata Dai , Namikawa Kenjiro , Nakano Eiji , Yamazaki Naoya
Published: July 2024

Cutaneous apocrine carcinoma is a rare skin cancer arising from apocrine sweat glands. Disease-specific treatments are required for cutaneous adnexal carcinomas due to their heterogeneous treatment responsiveness. This review reports on the epidemiology, diagnosis, pathological features, surgical management, and use of systemic therapies for cutaneous apocrine carcinoma. Diagnosing cutaneous apocrine carcinoma requires presenting with distinctive pathological features and excluding metastatic adenocarcinomas, particularly breast cancer. Clinical findings are essential to exclude metastatic adenocarcinomas, and immunohistochemistry can be used as an adjunctive tool to rule out other diseases. Wide local excision is the standard treatment for resectable cutaneous apocrine carcinomas. Prophylactic lymphadenectomy should be considered as a treatment option given the high incidence of lymph node metastasis. Generally, cutaneous apocrine carcinomas are resistant to chemotherapy and radiation therapy; however, adjuvant radiotherapy is recommended for high-risk patients. Radiation or systemic therapy is administered to patients with distant metastases or recurrence. The systemic therapeutic options include cytotoxic chemotherapy, hormonal therapy, targeted therapy, and immune checkpoint inhibitors. Given the lack of data on clinical prognosis and standardized treatments, further studies are needed to improve our understanding of cutaneous apocrine carcinomas.
Minocycline-rifampin–impregnated penile prosthesis surfaces retain antimicrobial activity following irrigation with 0.05% chlorhexidine gluconate and antibiotic solutions
Authors: Im Brian H , Giordano Analyse , Shah Sohan , Guillaume Samone , Evans Rachel , Hickok Noreen J , Chung Paul H
Published: July 2024

Background

0.05% Chlorhexidine gluconate (CHG; Irrisept [IrriMax]) is a commercial wound irrigation solution approved by the Food and Drug Administration that has seen recent adoption in the field of prosthetic urology; however, no study has evaluated whether 0.05% CHG is compatible with the minocycline-rifampin–impregnated surface (InhibiZone) of the AMS 700 penile prosthesis (Boston Scientific).

Aim

To evaluate whether 0.05% CHG alters the antibiotic efficacy of the minocycline-rifampin–impregnated penile prosthesis surface.

Methods

Discs (8 mm) were taken by a punch biopsy (Sklar) from sterile penile prosthesis reservoirs whose surfaces had been impregnated with rifampin and minocycline. Discs (n = 10) were suspended in 0.05% CHG, vancomycin and gentamicin, or normal saline for 2 minutes to simulate intraoperative irrigation. Discs were then rinsed in normal saline to remove any unbound solution and incubated with methicillin-sensitive Staphylococcus aureus for 48 hours. Adherent surface bacteria were suspended by shaking in a 0.3% Tween 20 solution, serially diluted, plated onto 3M PetriFilms, and counted. Kirby-Bauer disc diffusion assays were conducted to generalize findings across various organisms.

Outcomes

Outcomes included (1) bacterial adherence to the implant surface measured as bacterial counts (in colony-forming units per milliliter) and (2) bacterial growth reduction measured as zones of inhibitions (in millimeters).

Results

Incubation of implant surfaces in 0.05% CHG did not alter recovered bacterial counts as compared with normal saline and vancomycin/gentamycin. Similarly, within a single bacterial species, 0.05% CHG and vancomycin/gentamycin did not alter zone-of-inhibition measurements in Kirby-Bauer disc diffusion studies.

Clinical Translation

This study demonstrates in vitro that 0.05% CHG may be used directly on the minocycline-rifampin–impregnated surface without altering the antibiotic efficacy of the coating.

Strengths and Limitations

Strengths include that this is the first study to evaluate if 0.05% CHG affected the minocycline-rifampin–impregnated surface. Limitations include the use of in vitro studies, which serve as a proxy for in vivo practices and may not be entirely accurate or translatable in a clinical setting.

Conclusion

0.05% CHG does not alter the antimicrobial activity of the minocycline-rifampin–impregnated surface as compared with vancomycin/gentamycin and normal saline in vitro; however, its efficacy in clinical practice remains to be evaluated.
NtZIP5A/B is involved in the regulation of Zn/Cu/Fe/Mn/Cd homeostasis in tobacco
Authors: Palusińska Małgorzata , Barabasz Anna , Antosiewicz Danuta Maria
Published: July 2024

Plants grow in soils with varying concentrations of microelements, often in the presence of toxic metals e.g. Cd. To cope, they developed molecular mechanisms to regulate metal cross-homeostasis. Understanding underlying complex relationships is key to improving crop productivity. Recent research suggests that the Zn and Cd uptake protein NtZIP5A/B [Zinc-regulated, Iron-regulated transporter-like Proteins (ZIPs)] from tobacco (Nicotiana tabacum L. v. Xanthi) is involved in the regulation of a cross-talk between the two metals. Here, we support this conclusion by showing that RNAi-mediated silencing of NtZIP5A/B resulted in a reduction of Zn accumulation and that this effect was significantly enhanced by the presence of Cd. Our data also point to involvement of NtZIP5B in regulating a cross-talk between Cu, Fe, and Mn. Using yeast growth assays, Cu (but not Fe or Mn) was identified as a substrate for NtZIP5B. Furthermore, GUS-based analysis showed that the tissue-specific activity of the NtZIP5B promoter was different in each of the Zn-/Cu-/Fe-/Mn deficiencies applied with/without Cd. The results indicate that NtZIP5B is involved in maintaining multi-metal homeostasis under conditions of Zn, Cu, Fe, and Mn deficiency, and also in the presence of Cd. It was concluded that the protein regulates the delivery of Zn and Cu specifically to targeted different root cells depending on the Zn/Cu/Fe/Mn status. Importantly, in the presence of Cd, the activity of the NtZIP5B promoter is lost in meristematic cells and increased in mature root cortex cells, which can be considered a manifestation of a defense mechanism against its toxic effects.
Autoantibodies to joint-related peptides as predictive markers in early rheumatoid arthritis
Authors: Leu Agelii Monica , Sareila Outi , Lönnblom Erik , Cheng Lei , Forslind Kristina , Hafström Ingiäld , Andersson Maria L E , Kastbom Alf , Sjöwall Christopher , Jacobsson Lennart T H , Kihlberg Jan , Holmdahl Rikard , Gjertsson Inger
Published: July 2024

Objective

For better management of RA, new biomarkers are needed to predict the development of different disease courses. This study aims to identify autoantibodies against epitopes on proteins in the joints and to predict disease outcome in patients with new onset RA.

Methods

Sera from new-onset RA patients from the Swedish BARFOT (Better Anti Rheumatic PharmacOTherapy) and TIRA-2 (Swedish acronym for ‘tidiga insatser vid reumatoid artrit’) cohorts (n = 1986) were screened for autoantibodies to selected peptides (JointIDs) in a bead-based multiplex flow immunoassay. Disease outcomes included Boolean remission 1.0, swollen joint count and radiographic destruction. Multivariate logistic regression and zero-inflated negative binomial models that accounted for clinical factors were used to identify JointIDs with the strongest potential to predict prognosis.

Results

Boolean remission was predicted with 42% sensitivity and 75% specificity in male patients positive for antibodies to a non-modified collagen type II (COL2) peptide at 12 months. When antibodies to a specific citrullinated cartilage oligomeric protein (COMP) peptide were absent and the patient was in Boolean remission at 6 months, the sensitivity was 13% and the specificity 99%. Positivity for the non-modified COL2 peptide also reduced the frequency of swollen joints by 41% and 33% at 6 and 12 months, respectively. Antibodies to CCP predicted joint destruction with low specificity (58%). Positivity for a COL2 and a glucose-6-phosphate dehydrogenase peptide in citrullinated forms increased specificity (86%) at the expense of sensitivity (39%).

Conclusion

Autoantibodies against joint-related proteins at RA diagnosis predict remission with high specificity and, in combination with clinical factors, may guide future treatment decisions.
Risk-sensitive innovation: leveraging interactions between technologies to navigate technology risks
Authors: Sandbrink Jonas B , Hobbs Hamish , Swett Jacob L , Dafoe Allan , Sandberg Anders
Published: July 2024

The advancement of low-emission technologies to curb climate change demonstrates how strategically managing the timing of technological developments can mitigate negative societal outcomes. We propose that a similar approach, which we term ‘risk-sensitive innovation’, can also address risks from emerging technologies like synthetic biology and artificial intelligence. Risk-sensitive innovation (RSI) leverages interactions between technologies to reduce specific risks across a technology portfolio. For instance, it may be beneficial to delay or halt risk-increasing technologies and preferentially advance risk-reducing defensive, safety, or substitute technologies. To be of practical use, RSI requires the ability to anticipate or identify impacts and intervene in the relative timing of technological advancements. Our analysis suggests that both are sometimes viable. Consideration of RSI may inform government research funding and technology regulation, as well as philanthropic research and development funders and corporate social responsibility measures.
Novel susceptibility genes and biomarkers for obstructive sleep apnea: insights from genetic and inflammatory proteins
Authors: Zhao Yang , Jiang Yinyin , Wang Yaxi , Zhang Haiying , Zhu Jun , Jiang Xu , Shen Bo , Chen Yaning , Li Dongfeng , Pan Yang , Han Feng , Zhang Li
Published: July 2024

Study Objectives

Numerous observational studies link obstructive sleep apnea (OSA) to inflammatory proteins, yet the directionality of these associations remains ambiguous. Therefore, we aimed to clarify the potential associations of gene-predicted inflammatory proteins with OSA.

Methods

Based on genome-wide association study data, we applied Mendelian randomization (MR) to explore potential connections between circulating inflammatory proteins and OSA, primarily using the inverse-variance weighting method for robustness. Cochran’s Q test, MR‒Egger intercept test, MR-PRESSO, and leave-one-out method were used to perform sensitivity tests for pleiotropy and heterogeneity. Replication analyses and meta-analyses were performed using other independent data. Steiger tests and multivariate MR assessed the independent effects of exposure factors, and the functional mapping and annotation (FUMA) platform was used to identify key genes to enhance the understanding of genetics.

Results

Our investigation revealed 21 circulating inflammatory proteins significantly associated with OSA-related phenotypes. Notably, IL-10RA, IL-18R1, TNFSF14, CCL23, ADA, and SLAMF1 had significant effects on multiple phenotypes. After FDR correction, IL-18R1, SLAMF1, IL-10RA, and IL-17C were identified as important candidates for OSA, and multivariate MR analysis strengthened the independent heritability of 20 inflammatory factors. The FUMA platform revealed seven overlapping genes: ROBO1, PRIM1, NACA, SHBG, HSD17B6, RBMS2, and WWOX. All reverse MR analyses and sensitivity analyses confirmed the robustness of these associations.

Conclusions

Our results underscore crucial associations between inflammatory proteins and OSA pathogenesis, revealing new correlates and susceptibility genes. These findings advance biomarker identification for OSA risk and highlight the importance of genetic and inflammatory profiles in OSA management.
Circadian-informed lighting improves vigilance, sleep, and subjective sleepiness during simulated night-shift work
Authors: Scott Hannah , Guyett Alisha , Manners Jack , Stuart Nicole , Kemps Eva , Toson Barbara , Lovato Nicole , Vakulin Andrew , Lack Leon , Banks Siobhan , Dorrian Jillian , Adams Robert , Eckert Danny J , Catcheside Peter
Published: July 2024

Study Objectives

Shiftwork is associated with cognitive impairment and reduced sleep time and quality, largely due to circadian misalignment. This study tested if circadian-informed lighting could improve cognitive performance and sleep during simulated night shifts versus dim control lighting.

Methods

Nineteen healthy participants (mean ± SD 29 ± 10 years, 12 males, 7 females) were recruited to a laboratory study consisting of two counterbalanced 8-day lighting conditions (order randomized) 1-month apart: (1) control lighting condition - dim, blue-depleted and (2) circadian-informed lighting condition - blue-enriched and blue-depleted where appropriate. Participants underwent an adaptation night (22:00–07:00 hours), then four nights of simulated night work (cognitive testing battery of nine tasks, 00:00–08:00 hours), and sleep during the day (10:00–19:00 hours). Psychomotor vigilance task (PVT) lapses, Karolinska Sleepiness Scale (KSS) scores, and polysomnography-derived sleep outcomes were compared between conditions and across days using mixed models.

Results

Significant condition-by-day-by-time of task interaction effects were found for PVT lapses, median reaction time, and reaction speed, with ~50% fewer lapses by the end of simulated shift work with circadian-informed lighting versus control (mean ± SD 7.4 ± 5.0 vs. 15.6 ± 6.1). KSS was lower around the night shift midpoints on days 6 and 7 with circadian versus control lighting. Participants slept 52 minutes longer [95% CIs: 27.5, 76.5 minutes] by day 7 with circadian-informed versus control lighting, p < .001. Effects were inconsistent on other performance tasks.

Conclusions

Circadian-informed lighting improved sleep, sleepiness, and vigilance compared to control lighting. These findings support the potential for lighting interventions to improve sleep and vigilance in night shift workers chronically exposed to dim lighting.
State-Level Income Inequality as a Determinant of Suicide Mortality in the United States
Authors: Irish Andrew J
Published: July 2024

Income inequality has been increasing for decades and is now known to be related to many downstream health outcomes, where greater inequality is a predictor of poorer health. Results of investigations into the relationship between income inequality and suicidality have been mixed. This study leverages the most recent data available from the National Longitudinal Mortality Study to investigate the relationship between state-level income inequality and suicide mortality. A series of rigorously controlled logistic regression models, employing multiple measures of inequality, and various suicide mortality case-control specifications are used to investigate the phenomenon. Results indicate that the odds of suicide mortality increase with inequality, and this result is invariant across all models. A reduction in the Gini coefficient from the highest to lowest values of income inequality observed in U.S. states may reduce the odds of suicide mortality by 20 percent to 55 percent or more. Findings have application for social workers and other mental health professionals with respect to clinical assessment and treatment. Likewise, community organizers, policy advocates, and legislators should be aware that policy solutions reducing income inequality in the United States are a mechanism for alleviating the suicide mortality burden.
Cysteine‐rich 61 inhibition attenuates hepatic insulin resistance and improves lipid metabolism in high‐fat diet fed mice and HepG2 cells
Authors: Heo Yu Jung , Park Jieun , Lee Nami , Choi Sung‐E , Jeon Ja Young , Han Seung Jin , Kim Dae Jung , Lee Kwan Woo , Kim Hae Jin
Published: July 2024

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is strongly associated with insulin resistance development. Hepatic lipid accumulation and inflammation are considered the main drivers of hepatic insulin resistance in MASLD. Cysteine‐rich 61 (Cyr61 also called CCN1), a novel secretory matricellular protein, is implicated in liver inflammation, and its role in MASLD is not clearly understood. Therefore, we investigated the role of Cyr61 in hepatic insulin resistance and lipid metabolism as major factors in MASLD pathogenesis. In high‐fat diet (HFD)‐fed C57BL/6J mice, Cyr61 was downregulated or upregulated via viral transduction. Measurements of glucose homeostasis, histological assessment of liver tissues, and gene expression and signaling pathways of lipogenesis, fatty acid oxidation, and inflammation were performed using liver samples from these mice. Cyr61 levels in HepG2 cells were reduced using RNAi‐mediated gene knockdown. Inflammation and insulin resistance were evaluated using real‐time polymerase chain reaction and western blotting. HFD/AAV‐shCyr61 mice exhibited enhanced glucose tolerance via the protein kinase B pathway, reduced hepatic inflammation, decreased lipogenesis, and increased fatty acid oxidation. Notably, HFD/AAV‐shCyr61 mice showed elevated protein expression of sirtuin 6 and phosphorylated‐AMP‐activated protein kinase. In vitro experiments demonstrated that inhibition of Cyr61 downregulated pro‐inflammatory cytokines such as interleukin‐1 beta, IL‐6, and tumor necrosis factor‐alpha via the nuclear factor kappa B/c‐Jun N‐terminal kinase pathway, and alleviated insulin resistance. Cyr61 affected hepatic inflammation, lipid metabolism, and insulin resistance. Inhibition of Cyr61 reduced inflammation, recovered insulin resistance, and altered lipid metabolism in vivo and in vitro. Therefore, Cyr61 is a potential therapeutic target in MASLD.
Femoral component size in total knee replacement: a retrospective study
Authors: Al Nawaiseh Mohammad , Al-Ajlouni Jihad M. , Ibrahim Omar , Alafeef Nour , Aburajab Muawia , Raiq Neven , Halayqeh Sereen , Alfayyadh May , AlSamhori Jehad Feras , Jabaiti Mohammad S. , Alshrouf Mohammad Ali
Published: July 2024

Background:

Osteoarthrosis is the most common articular disease in the developed world. The number of people affected by knee osteoarthrosis is exponentially increasing, and with total knee replacement (TKA) demand expected to continue growing. The study establishes the relationship between femoral size components used in TKA and patients’ demographics.

Methods:

A retrospective cohort study of 385 surgeries that underwent TKA at the tertiary hospital over the period between January 2018 and December 2021 was conducted. The patients’ demographics, including height, weight, body mass index, gender, and age, and the implanted component size and type of the component (gender or not) were collected.

Results:

A significant association was found between the gender of patients and the femoral component size (P<0.001). Furthermore, height and weight had a significant correlation with femoral component size (P=0.399, P<0.001 and P=0.114, P=0.025, respectively); however, body mass index and age were not statistically correlated with femoral component size (P=0.625, 0.138, respectively). Upon ordinal logistic regression analyses, height and gender were significant predictors of the implanted femur component size (P<0.001). However, age and weight were insignificant factors in the model (P=0.640 and P=0.211, respectively).

Conclusion:

The results described will help with the pre-operative predictions of the total knee replacement femoral component size, which will decrease the operating time and implant supply chain efficiency. Further advancement of the model could be achieved with future multicenter studies with a larger sample.
Relationship between updated MELD and prognosis in alcohol-associated hepatitis: Opportunities for more efficient trial design
Authors: Al-Karaghouli Mustafa , Ventura-Cots Meritxell , Wong Yu Jun , Genesca Joan , Bosques Francisco , Brown Robert S. , Mathurin Philippe , Louvet Alexandre , Shawcross Debbie , Vargas Victor , Verna Elizabeth C. , Schnabl Bernd , Caballeria Joan , Shah Vijay J. , Kamath Patrick S. , Lucey Michael R. , Garcia-Tsao Guadalupe , Bataller Ramon , Abraldes Juan G.
Published: July 2024

Background:

Alcohol-associated hepatitis (AH) is associated with significant mortality. Model for End-Stage Liver Disease (MELD) score is used to predict short-term mortality and aid in treatment decisions. MELD is frequently updated in the course of AH. However, once the most updated MELD is known, it is uncertain if previous ones still have prognostic value, which might be relevant for transplant allocation and trial design. We aimed to investigate the predictive performance of updated MELDs in a prospectively collected cohort of patients with AH by the InTeam consortium.

Methods:

Three hundred seven patients (with 859 MELD values within 60 d of admission) fulfilled the inclusion criteria. The main endpoint was time to death or transplant up to 90 days. We used a joint model approach to assess the predictive value of updated MELDs.

Results:

Updated MELD measurements had a strong prognostic value for death/transplant (HR: 1.20, 95% CI: 1.14–1.27) (p< 0.0001). Previous MELD values did not add predictive value to the most current MELD. We also showed that MELD at day 28 (MELD28) had a significant predictive value for subsequent mortality/transplant in a landmark analysis (HR: 1.18, 95% CI: 1.12–1.23). We show that the use of an ordinal scale including death, transplant, and MELD28 as a trial outcome could substantially reduce the sample size required to demonstrate short-term benefit of an intervention.

Conclusion:

We show that updated MELDs during the trajectory of AH predict subsequent mortality or the need for transplant. MELD28 inclusion in an ordinal outcome (together with death or transplant) could increase the efficiency of randomized controlled trials.
Intereye Agreement in Dry-Eye Signs in the DREAM Study: Implications for Future Dry-Eye Trials
Authors: Zhong Anny , Augello Patrick , Asbell Penny , Ying Gui-Shuang ,   the DREAM Study Research Group
Published: July 2024

Purpose:

To investigate intereye agreement in dry-eye disease (DED) signs in the Dry Eye Assessment and Management study.

Methods:

Tear break-up time (TBUT), Schirmer test, conjunctival staining, corneal staining, meibomian gland dysfunction (MGD), and tear osmolarity were measured at baseline, 3, 6, and 12 months. Intereye agreement was assessed by intraclass correlation coefficient, weighted kappa, and percentage of participants with absolute intereye difference (AID) exceeding a clinically significant threshold (2 points for conjunctival staining and MGD, 2 seconds for TBUT, 3 points for corneal staining, 5 mm/5 minutes for Schirmer test, and 8 mOsms/L for osmolarity). The worse eye at each visit for each DED sign was determined as the eye with a sign worse than the contralateral eye by at least the clinically significant threshold.

Results:

DED signs had moderate-to-good intereye agreement with intraclass correlation coefficient ranging from 0.45 (tear osmolarity) to 0.81 (corneal staining and Schirmer test) and weighted kappa from 0.58 (plugging) to 0.69 (lid secretion). Percentage of participants exceeding threshold AID was 15% to 20% for conjunctival staining, 11% to 15% for TBUT, 17% to 21% for MGD, 13% to 18% for corneal staining, 21% to 23% for Schirmer test, and 44% to 47% for osmolarity. The eye with a worse DED sign ranged between 36% (TBUT) and 80% (osmolarity) of participants.

Conclusions:

Participants demonstrated moderate-to-good intereye agreement, yet a substantial portion showed clinically significant intereye differences in each sign. The worse eye was not the same eye in the majority during follow-up. These findings suggest considering signs from both eyes in future DED trials.
Autologous Pericranium Graft for Necrotizing Scleritis
Authors: Copete Sergio , Fagúndez-Vargas María Antonia , López-Martínez Franciso , Moreno-Martínez Almudena , García-García Jose Gregorio , Júdez Enrique , Carrilero-Ferrer María José
Published: July 2024

Purpose:

The purpose of this study was to describe the clinical outcome of scleral staphyloma secondary to necrotizing scleritis treated with autologous pericranial grafting.

Case report:

A 63-year-old woman with necrotizing scleritis and choroidal protrusion underwent homologous scleral grafting, which failed. The patient's medical management was optimized for control of her systemic inflammation, and she underwent a second surgery consisting of autologous pericranium grafted to the parietal region. A 3- × 2-cm tissue patch was harvested and sutured over the staphyloma borders with 8/0 polyglactin sutures. Complete re-epithelialization was observed at 3 weeks, the graft was well integrated, and no signs of inflammation were observed at 18 months.

Conclusions:

The pericranium offers a viable alternative for scleral thinning because of necrotizing scleritis.
Differences of Efficacy Between Tenofovir Alafenamide Fumarate and Tenofovir Disoproxil Fumarate in Pregnant Women With Different Hepatitis B Virus DNA Loads
Authors: Tao Chengjing , Zhou Guanlun , Jiang Hongxiu , Chen Chao , Ju Yuhao , Tao Xingran , Zhang Ping , Liu Shuorong , Han Guorong
Published: July 2024

Tenofovir alafenamide fumarate (TAF) has been endorsed by guidelines for blockade of mother-to-child transmission of hepatitis B virus (HBV), given that its efficacy and safety are comparable to tenofovir disoproxil fumarate (TDF). However, there is a lack of comparative studies regarding the treatment efficacy in patients with diverse viral loads. This study retrospectively analyzed 96 hepatitis B e antigen (HBeAg)–positive pregnant women with HBV DNA levels of ≥2 × 105 IU/mL. Based on viral loads (HBV DNA levels), participants in the TAF and TDF groups were stratified into three subgroups, namely, the High-G (titer ≥8 log10 IU/mL), Middle-G (7 log10 IU/mL ≤ titer < 8 log10 IU/mL) and Low-G (titer <7 log10 IU/mL) subgroups. The primary endpoint was effectiveness of TAF and TDF in patients with varying viral loads, whereas secondary endpoints were hepatitis B surface antigen (HBsAg) positivity in infants at 7 to 12 months and the safety profile for mothers and children. Compared with baseline levels, median HBV DNA levels in mothers were decreased by 4.51 and 4.09 log10 IU/mL in the TAF and TDF groups (P = 0.04) predelivery, respectively. In the High-G subgroup, the titers were significantly lower in the TAF group (P = 0.045). A higher proportion of patients experienced a virus decline of ≥4 log10 IU/mL in the TAF group compared with the TDF group, with rates of 78.26% versus 58% (P = 0.034), respectively. Moreover, the median serum phosphate levels significantly decreased from baseline to predelivery in the TDF group (P = 0.04). Finally, infants in both cohorts tested negative for HBsAg at 7–12 months after delivery. Overall, our findings indicate that TAF can be considered the preferred option for the treatment of HBeAg-positive pregnant women with HBV DNA levels of ≥8 log10 IU/mL.
Impact of Body Mass Index on Opioid Prescriptions Following Lumbar Spine Surgery
Authors: Eghrari Nafis B. , Chen Matthew , Kim Chong H.
Published: July 2024

Objective

This study aimed to evaluate the association between BMI and postoperative opioid use within two years following lumbar spine surgery using a national database.

Methods

TriNetX, a national network of de-identified patient records, was retrospectively queried from 2003 to 2021 using ICD-10, CPT, and VA codes. Propensity-score matching analysis was performed based on demographics, comorbidities, anxiety disorders, and mood disorders.

Results

21,997 total patients were included in our analysis. Patients with BMI > 30 were more likely to be prescribed opioids postoperatively (OR: 1.30; 95% CI: 1.18–1.42). Patients with BMI > 40 were more likely to be prescribed opioids when compared to patients with BMI < 30 (OR: 1.94; 95% CI: 1.48–2.56), BMI 30-34.9 (OR: 2.06; 95% CI: 1.57–2.70), BMI 35-39.9 (OR: 1.50; 95% CI: 1.13–2.00), and BMI < 40 (OR: 2.06; 95% CI: 1.57–2.70). The BMI > 40 group had an increased number of opioid prescriptions within two years following lumbar surgery compared to patients with BMI 30-34.9 (p = 0.0113) and BMI < 30 (p = 0.0018).

Conclusion

Opioid prescription following lumbar spine surgery is associated with an elevated BMI. Patients with Class III Obesity appear to be at the highest risk of increased opioid prescriptions following lumbar surgery. Physicians should consider the patient’s BMI when deciding postoperative pain management.
Effective strategies for managing trimethoprim-sulfamethoxazole and levofloxacin-resistant Stenotrophomonas maltophilia infections: bridging the gap between scientific evidence and clinical practice
Authors: Mokrani David , Luyt Charles-Edouard
Published: July 2024

Purpose of review

To discuss the therapeutic options available for the management of difficult-to-treat strains of Stenotrophomonas maltophilia (Sma), namely those resistant to trimethoprim-sulfamethoxazole and fluoroquinolones.

Recent findings

Recent pharmacological studies have highlighted the fact that current breakpoints for first-line antibiotics against Sma are too high. In light of these data, it is likely that the prevalence of difficult-to-treat (DTR) Sma is underestimated worldwide. Two promising alternatives for treating DTR strains are cefiderocol and the combination of aztreonam and an L2 inhibitor. However, clinical trials are currently very limited for these antibiotics and no comparative studies have been carried out to date. It is important to note that the clinical efficacy of cefiderocol appears to be inferior to that initially anticipated from in-vitro and animal studies. Consequently, minocycline and ceftazidime may remain viable options if they are used against strains with a low minimum inhibitory concentration. We advise against the use of intravenous polymyxins and tigecycline. Finally, recent literature does not support the systematic use of combination therapy or long-course treatments. In the coming years, phage therapy may become a promising approach against DTR Sma infections.

Overall, clinical comparative studies focused on DTR strains are required in order to provide more accurate and actionable information for therapeutic decisions.
The many faces of brucellosis: diagnostic and management approach
Authors: El Ayoubi L’Emir Wassim , Challita Caren , Kanj Souha S.
Published: July 2024

Purpose of review

This review aims to highlight the multifaceted nature of brucellosis, emphasizing the latest advancements in its diagnosis and management. Given the global prevalence and potential complications of brucellosis, understanding recent advancements in diagnostic techniques and treatment strategies is crucial for clinicians.

Recent findings

Recent literature reveals significant progress in diagnostic methods, including the application of fluorescence polarization immunoassay and time-resolved fluorescence resonance energy transfer technologies as well as the invention of artificial Brucella antigens, which offer enhanced sensitivity and specificity. Advances in molecular diagnostics and serological tests have improved early detection rates, however their interpretation remains challenging. Evolving treatment regimens such as the use of hydroxychloroquine as part of triple therapy and the use of nano-delivery systems in therapies have shown promise, in hopes of reducing relapse rates and managing chronic cases.

The findings underscore the necessity for clinicians to adopt a comprehensive approach to diagnosing and managing brucellosis. Integrating advanced diagnostic tools with tailored therapeutic strategies can significantly improve patient outcomes. Future research should focus on optimizing these diagnostic techniques and exploring novel therapeutic agents.
Strongyloides stercoralis infection in solid organ transplant recipients
Authors: Hogan John I. , Mehta Sapna A.
Published: July 2024

Purpose of review

Strongyloides stercoralis infection remains of concern due to its high associated morbidity among solid organ transplant recipients (SOTR) and the risk of donor-derived infection (DDI). We review key aspects of epidemiology to inform screening for and treatment of chronic infection among organ transplant candidates to reduce the risk of infectious complications in the posttransplant setting.

Recent findings

In this work, we offer guidance regarding the optimal management of Strongyloides hyperinfection syndrome and disseminated infection and offer recommendations regarding posttreatment surveillance and the potential need for repeat treatment during subsequent periods of augmented immunosuppression. This review also provides updated recommendations for screening of deceased and living donors as recently proposed by the Organ Procurement and Transplantation Network's Ad Hoc Disease Transmission Advisory Committee.

Risk reduction of Strongyloides infection in the SOTR population can be further enhanced by optimized treatment of infection, posttreatment surveillance during at-risk periods and recent proposed policy shifts to universal donor screening.
Memoryless chemotaxis with discrete cues
Authors: Knight Jacob , García-Galindo Paula , Pausch Johannes , Pruessner Gunnar
Published: July 2024

Biological systems such as axonal growth cones perform chemotaxis at micrometre-level length scales, where chemotactic molecules are sparse. Such systems lie outside the range of validity of existing models, which assume smoothly varying chemical gradients. We investigate the effect of introducing
discrete
chemoattractant molecules by constructing a minimal dynamical model consisting of a chemotactic cell without internal memory. Significant differences are found in the behaviour of the cell as the chemical gradient is changed from smoothly varying to discrete, including the emergence of a homing radius beyond which chemotaxis is not reliably performed.