bluuebunny/crossref_metadata_2025 huggingface dataset:
Perinatal, metabolic, and reproductive features inPPARG-related lipodystrophy
Authors: Gosseaume Camille , Fournier Thierry , Jéru Isabelle , Vignaud Marie-Léone , Missotte Isabelle , Archambeaud Françoise , Debussche Xavier , Droumaguet Céline , Fève Bruno , Grillot Sophie , Guerci Bruno , Hieronimus Sylvie , Horsmans Yves , Nobécourt Estelle , Pienkowski Catherine , Poitou Christine , Thissen Jean-Paul , Lascols Olivier , Degrelle Séverine , Tsatsaris Vassilis , Vigouroux Corinne , Vatier Camille
Published: February 2023

Objective

The adipogenic PPARG-encoded PPARγ nuclear receptor also displays essential placental functions. We evaluated the metabolic, reproductive, and perinatal features of patients with PPARG-related lipodystrophy.

Methods

Current and retrospective data were collected in patients referred to a National Rare Diseases Reference Centre.

Results

26 patients from 15 unrelated families were studied (18 women, median age 43 years). They carried monoallelic PPARG variants except a homozygous patient with congenital generalized lipodystrophy. Among heterozygous patients aged 16 or more (n = 24), 92% had diabetes, 96% partial lipodystrophy (median age at diagnosis 24 and 37 years), 78% hypertriglyceridaemia, 71% liver steatosis, and 58% hypertension. The mean BMI was 26 ± 5.0 kg/m2. Women (n = 16) were frequently affected by acute pancreatitis (n = 6) and/or polycystic ovary syndrome (n = 12). Eleven women obtained one or several pregnancies, all complicated by diabetes (n = 8), hypertension (n = 4), and/or hypertriglyceridaemia (n = 10). We analysed perinatal data of patients according to the presence (n = 8) or absence (n = 9) of a maternal dysmetabolic environment. The median gestational age at birth was low in both groups (37 and 36 weeks of amenorrhea, respectively). As expected, the birth weight was higher in patients exposed to a foetal dysmetabolic environment of maternal origin. In contrast, 85.7% of non-exposed patients, in whom the variant is, or is very likely to be, paternally-inherited, were small for gestational age.

Conclusions

Lipodystrophy-related PPARG variants induce early metabolic complications. Our results suggest that placental expression of PPARG pathogenic variants carried by affected foetuses could impair prenatal growth and parturition. This justifies careful pregnancy monitoring in affected families.
Lipoprotein(a) is linked to atherothrombosis and aortic valve stenosis independent of C-reactive protein
Authors: Thomas Peter E , Vedel-Krogh Signe , Kamstrup Pia R , Nordestgaard Børge G
Published: February 2023

Aims

Recent evidence suggest that the lipoprotein(a)-associated risk of atherosclerotic cardiovascular disease (ASCVD) may be observed only in individuals with low-grade systemic inflammation. It was hypothesized that high lipoprotein(a) is a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis irrespective of C-reactive protein levels.

Methods and results

A total of 68 090 individuals from the Copenhagen General Population Study, a prospective cohort study, were included. During a median follow-up of 8.1 years, 5104 individuals developed ASCVD, 2432 myocardial infarction, and 1220 aortic valve stenosis. The risk of ASCVD, myocardial infarction, and aortic valve stenosis increased with higher values of both lipoprotein(a) and C-reactive protein. For individuals with lipoprotein(a) in the 91st–100th percentiles (≥70 mg/dl, ≥147 nmol/l) vs. the 1st–33rd percentiles (≤6 mg/dl, ≤9 nmol/l), the multivariable-adjusted hazard ratio for ASCVD was 1.61 (95% confidence interval 1.43–1.81) for those with C-reactive protein <2 mg/l and 1.57 (1.36–1.82) for those with C-reactive protein ≥2 mg/l (P for interaction = 0.87). The corresponding values were 2.08 (1.76–2.45) and 1.65 (1.34–2.04) for myocardial infarction, and 2.01 (1.59–2.55) and 1.73 (1.31–2.27) for aortic valve stenosis, respectively (P for interaction = 0.15 and = 0.18). The highest absolute 10-year risks were found in men aged 70–79 years with lipoprotein(a) levels in the 91st–100th percentiles and C-reactive protein ≥2 mg/l, with 34% for ASCVD, 19% for myocardial infarction, and 13% for aortic valve stenosis. The corresponding values in women were 20%, 10%, and 8%, respectively.

Conclusion

High lipoprotein(a) was a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis independent of C-reactive protein levels.
Chinese expert consensus on standardized treatment for presacral cysts
Authors: Wang Gangcheng , Miao Chengli
Published: February 2023

Presacral cysts are cystic or cyst–solid lesions between the sacrum and rectum, almost involving adjacent pelvic floorstructures including sacrococcygeal fascia, rectum, and anal sphincter. Presacral cysts are usually benign, currently believed to arise from aberrant embryogenesis. Presacral cysts are clinically rare and the true incidence is unknown. Surgical resection remains the major treatment for presacral cysts. Unless the cysts are completely resected, recurrence is unavoidable. Recurrent cysts or hard-to-heal sinuses in the sacrococcyx cause patients extreme pain. However, the current knowledge of presacral cysts is insufficient. They are occasionally confused with other diseases such as ovarian cysts and perianal abscesses. Moreover, lack of the correct surgical concept and skills leads to palliative treatment for complex presacral cysts and serious complications such as impairing the function of the anal sphincter or important blood vessels and nerves. The consensus summarizes the opinions and experiences of multidisciplinary experts in presacral cysts and aims to provide clinicians with a more defined concept of the treatment, standardize the surgical approach, and improve the efficacy of presacral cysts.
Association of Sensory Impairment With Institutional Care Willingness Among Older Adults in Urban and Rural China: An Observational Study
Authors: Zhang Shimin , Wang Qiong , Zhao Dan , Fu Peipei , Qi Kaili , Wang Xiyuan , Zhou Yanxin , Li Peilong , Sun Jingjie , Zhou Chengchao
Published: February 2023

Background and Objectives

An aging population has contributed to increasing rates of sensory impairment (SI) among older adults and a boom in institutional elder care. However, little is known regarding the association between SI and institutional care willingness. This study identified the association between SI and institutional care willingness among older adults living both in urban and rural China.

Research Design and Methods

This was an observational study using the sixth National Health Service Survey of Shandong Province, China, in 2018. A total of 8 583 individuals aged ≥60 years were included. The primary outcome was institutional care willingness. Self-reported SI was categorized as vision impairment (VI), hearing impairment (HI), and dual sensory impairment (DSI). We used multivariable logistic regression models to estimate the association between SI and institutional care willingness, stratified by the place of residence.

Results

The overall proportion of older adults with institutional care willingness was 7.8%. In fully adjusted models, older adults with HI only (odds ratio [OR] = 1.57, 95% confidence interval [CI]: 1.12–2.20) or DSI (OR = 1.68, 95% CI: 1.14–2.49) were more likely to show institutional care willingness than those without SI in urban areas, but no significant associations between VI only (OR = 0.95, 95% CI: 0.68–1.31), HI only (OR = 0.99, 95% CI: 0.73–1.34), or DSI (OR = 0.95, 95% CI: 0.68–1.31) and institutional care willingness were observed among rural older adults.

Discussion and Implications

Our results underscore that the relationship between SI and institutional care willingness varied by place of residence, and provide a reference for making targeted and appropriate endowment policies. Improving the quality of institutional elder care is vital for urban older adults with SI, whereas community-based care might be more appropriate for rural older adults with SI.
Seasonal activity and depth distribution of resident yellow-phase American eels (Anguilla rostrata) in a large fluvial ecosystem
Authors: Burliuk Colleen M M , Casselman John M
Published: February 2023

The American eel (Anguilla rostrata) is a catadromous species occupying diverse habitats, but little is known about the specific activities of this elusive nocturnal fish. Mobile radio and acoustic telemetry were used to locate 33 transmitter-implanted resident yellow eels (729 ± 22 mm TL), acquiring 1613 locations from 2014 to 2017 in a 21-km2 slow-flowing section of the upper St. Lawrence River. Measurements of distance moved, water depth, and temperature were used to study activity, homing, and site fidelity. Movement was greatest in spring, late April (422 m, median semi-monthly), after emergence from winter dormancy, from their deepest habitat (3.71 ± 0.06 m) to their shallowest (1.74 ± 0.17 m). Activity was low in early summer and early fall (69 m). As temperature reached a maximum during midsummer (24.3 ± 0.29°C), most eels became more active (106 m) and moved deeper (2.46 ± 0.28 m), probably following prey fish. Activity increased in mid-to-late fall (277 m), decreased considerably at ≲8°C when settling into their winter habitat, and ceased at ≲4°C. Temperatures of ≃10°C (8.1–11.1°C) corresponded with the greatest seasonal activity and spring/fall commercial hoop-net catches. These spatial and temporal habitat insights can help focus sampling and assessment procedures, as well as habitat suitability modelling.
Costly Commitments “Under His Eye”: Reconceptualizing the Costly Signaling Theory of Religion
Authors: Potz Maciej
Published: February 2023

Costly signaling theory of religion has been proposed to explain the evolutionary adaptiveness of religion in general and, specifically, its prosocial effects, including the relative longevity of religious communes vis-à-vis their secular counterparts. This article focuses on two crucial aspects of this relationship: the features and functions of signals and the mechanism through which signaling translates into enhanced prosociality. It identifies some of the key factors of the costliness of behavior and distinguishes between religious and secular signals, arguing that only the latter serve to broadcast commitment. The role of religious signals, instead, might be to stimulate the supernatural watching (“Under His Eye”) mechanism: enhancing supernatural sanctions beliefs and providing a setting in which implicit prosocial responses are triggered. The relative absence of this mechanism in secular communities may explain their shorter life spans. A link is thus established between the costly signaling and supernatural punishment theories of religious behavior.
Low self-reported penicillin allergy in South Africa—implications for global public health response
Authors: Day Cascia , Mendelson Marc , Peter Jonny ,   ADvISE study group, Deetlefs Maria , O’Brien Andrew , Smith Jenna , Boyd Michael , Embling Nicky , Patel Sabiha , Moody Kirsten , Ramabele Tokoloho , Budge Andrea , Tarwa Tapiwa , Jim Odwa , Maharaj Tiara , Pandy Saabira , Abrahams Jean-Michel , Panieri Angelica , Verhage S , van der Merwe Matthew , Geragotellis Alexander , Amanjee Waheed , Joseph Cameron , Zhao Ziqi , Moosa Salmaan , Bunting Megan , Pulani Yanelisa , Mukhari Phumzile , Paiva Melissa de , Deyi Gcobisa , Wonkam Ramses Peigou , Mancotywa Nqaba , Dunge Andiswa , Msimanga Tumi , Singh Ashmika , Monnaruri Ofentse , Molale Bokamoso , Butler Thomas Alexander Gugile , Browde Kate , Muller Chantal , Van Der Walt Janet , Whitelaw Richard , Cronwright Daniel , Sinha Suniti , Binase Uvile , Francis Innocent , Boakye Darleen , Dlamini Sipho
Published: February 2023

Objectives

In high-income countries, up to 25% of inpatients have a self-reported penicillin allergy (PA). After testing, 95% of these self-reported PAs are incorrect. These incorrectly labelled PAs increase the use of broad-spectrum antibiotics, and drive bacterial resistance. The epidemiology of PA in low- and middle-income countries is unknown. We aimed to describe the epidemiology and delabelling outcomes of self-reported PA in South African (SA) inpatients.

Methods

We conducted point prevalence surveys between April 2019 and June 2021 at seven hospitals in Cape Town, South Africa. A team trained in the PEN-FAST allergy decision tool conducted in-person interviews, and reviewed patient notes to identify and risk stratify inpatients with a self-reported PA. These patients were referred to the Groote Schuur Hospital (GSH) allergy clinic for delabelling.

Results

A total of 1486 hospital inpatients were surveyed and 3.2% (n = 48) carried a PA label. Importantly, 64.6% (n = 31) were classified by PEN-FAST as low risk for true penicillin hypersensitivity. Overall, 25% of the self-reported PAs received a β-lactam antibiotic in hospital and were directly delabelled. Delabelling attrition was very high, with 6.3% (3/48) of the self-reported PAs attending the GSH allergy clinic, and only one patient proceeding to a negative oral penicillin challenge.

Conclusions

Inpatient self-reported PA was lower in South Africa hospitals compared with other upper-middle-income countries, and the majority of patients carried a low-risk PA label. Linkage for delabelling with the allergy clinic was very poor, and thus strategies to improve access and delivery of delabelling remains an urgent public health issue.
Occurrence of potential virulence determinants inAeromonasspp. isolated from different aquatic environments
Authors: Majeed Sana , De Silva Liyana Arachchilage Dinithi Sandunika , Kumarage Prasanga Madhushani , Heo Gang-Joon
Published: February 2023

Aeromonas species are bacterial pathogens that cause significant economic losses in the aquaculture industry worldwide. They are widely distributed in aquatic environments and cause several diseases in both humans and aquatic animals. The presence of various virulent Aeromonas spp. in aquatic environments predisposes infections in aquatic animals and humans. Concern about the transfer of pathogens from fish to humans also increased with the substantial increase in seafood consumption. Aeromonas spp. are also primary human pathogens that cause local and systemic infections, both in immunologically compromised and immunologically competent hosts. The most common Aeromonas spp. causing infections in aquatic animals and humans are A. hydrophila, A. salmonicida, A. caviae, and A. veronii biotype sobria. The ability of Aeromonas spp. to produce a variety of virulence factors enhances their pathogenic ability. Literature has supplied evidence for the presence of various virulence factors, including proteases, enterotoxins, hemolysin, and toxin genes of Aeromonas spp. in aquatic environments. The high prevalence of Aeromonas spp. in the aquatic environment is also a threat to public health. Because the Aeromonas spp. infections in humans are generally the result of ingestion or exposure to contaminated food and water. This review summarizes the recently published information on various virulence factors and virulence genes of Aeromonas spp. isolated from various aquatic environments, including seawater, freshwater, wastewater, and drinking water. It is also intended to highlight the risks associated with Aeromonas species’ virulence properties for both aquaculture and public health.
Ongoing Impact of COVID-19 on Breast Radiologists’ Wellness
Authors: Dodelzon Katerina , Grimm Lars J , Plimpton S Reed , Markovic Daniela , Milch Hannah S
Published: February 2023

Objective

Assess the ongoing impact of COVID-19 on mental well-being of breast radiologists nationwide two years after the start of the pandemic and compared to early in the pandemic.

Methods

A 27-question survey was distributed from December 2021 to January 2022 to physician members of the Society of Breast Imaging. Psychological distress and anxiety scores were calculated, and factors associated with them were identified with a multivariate logistic model.

Results

A total of 550 surveys were completed (23% response rate); the mean respondent age was 50 +/− 10 years. Fifty percent (265/526) of respondents reported two or more psychological distress symptoms, down from 58% in 2020 (P = 0.002), whereas 70% (362/526) of respondents reported increased anxiety, down from 82% in 2020 (P < 0.001). As in 2020, reporting financial strain and childcare adversely affecting job ability were associated with worse psychological distress scores (OR 3.6, 95% CI: 1.6–8.3, P = 0.02 and OR 6.0, 95% CI: 2.5–14.4, P = 0.002, respectively). Less time spent consulting, educating, and discussing results with patients was associated with higher psychological distress (OR 5.3, 95% CI: 2.1–13.2, P = 0.036) and anxiety (OR 6.4, 95% CI: 2.3–17.5, P < 0.001). Diminished research collaboration was associated with higher anxiety (OR 1.8, 95% CI: 1.1–2.9, P = 0.019).

Conclusion

The COVID-19 pandemic continues to cause mental health symptoms in breast radiologists, especially for those with pandemic-specific childcare needs and financial distress. Pandemic-related decreased opportunities to connect with patients and colleagues negatively impacts radiologists’ mental health.
Childhood Send-Down Experience and Old-Age Support to Parents: The Twins Experiment in China
Authors: Zhang Hongliang , Zhang Junsen , Zhang Ning
Published: February 2023

In the mass movement of sending urban youth to the countryside during China’s Cultural Revolution, many families with multiple age-eligible children were forced to make a send-down choice among the siblings. We exploit this rare social experiment and employ data on urban twins in China to investigate the effect of childhood send-down experience on children’s old-age support to parents. We find that compared with their twin siblings who had stayed in the city, send-downs were less likely to make a monetary transfer to parents and also tended to transfer less. We show that the inferior transfer behavior of send-downs was not due to any income disadvantage or selection of family’s send-down choice in terms of children’s altruism endowment. After ruling out the income and selection channel explanations, we posit that the inferior transfer behavior of send-downs is driven by the adverse effect of childhood send-down experience on children’s willingness to provide old-age support to parents, which could work through both pure altruism and warm glow.
Histories of Medieval Plague in Renaissance Italy
Authors: Martin Craig
Published: February 2023

During the sixteenth century, Italian scholars revised their conception of the field of history so that its purposes went beyond providing political and morally edifying narratives. These scholars contended that history must also account for culture and nature in an encyclopedic fashion. In the same years, numerous newly available texts from antiquity, the Byzantine empire, and the Middle Ages provided insight into the character of earlier outbreaks of plague. Italian physicians, embracing new visions of the field of history, the culture of humanism, and an inductivist epistemology, used these texts to argue that there were continuities among ancient, medieval, and Renaissance epidemics. They catalogued plague and formed historical categories based on severity and perceived origins, leading to the rejection of the conclusions of fourteenth-century western Europeans who viewed the plague of 1347-1353 as unprecedented. These erudite physicians saw medieval plague to be one example of the extreme epidemics that have regularly occurred throughout history.
— Yiqtol as Evidential Strategy in Biblical Hebrew
Authors: Olivero Vladimir
Published: February 2023

The goal of this study is to argue that the — yiqtol construction has an evidential meaning when employed with reference to the past. The yiqtol functions in these situations as an evidential strategy and is used to express the source of information. For instance, Exod. 15:1, which famously begins with , should be understood as ‘then (as reported / as they say) Moses sang’. The words added between brackets refer to the source of information. In most biblical passages where this rare and puzzling construction is attested the evidential yiqtol appears with deictic markers that tie the world of the narrative to that of the authors and of the audience. Interestingly, paratextual elements and redactional observations support the idea that we are dealing with evidential strategies. Finally, the Hebrew Bible seems to contain additional instances of the evidential yiqtol in a similar construction ( — yiqtol).
Considerations for developing a targeted amino acid supplement for people with Parkinson’s disease that promotes health while accounting for pathophysiology and medication interference
Authors: Earp Jacob E , Colon-Semenza Cristina , LoBuono Dara L
Published: February 2023

For individuals with Parkinson’s disease (PD), dietary habits affect disease symptoms, progression, and overall health. Protein consumption is of great interest because of the direct and indirect effects of specific amino acids (AAs) on disease progression and interference with levodopa medication. Proteins comprise 20 distinct AAs with varying effects on overall health, disease progression, and medication interference. Therefore, it is important to consider both the potential beneficial and detrimental effects of each AA when considering supplementation for an individual with PD. Such consideration is of particular importance because PD pathophysiology, altered dietary patterns associated with PD, and competitive absorption with levodopa have been shown to result in characteristically altered AA profiles (eg, some AAs are stored in excess while others are deficient). To address this problem, considerations for the development of a precision nutritional supplement that targets AAs specific to the needs of people with PD are discussed. The objective of this review is to provide a theoretical framework for such a supplement, detailing the current state of knowledge relating relevant evidence to such a supplement, and highlighting areas of future research. Specifically, the general need for such a supplement is discussed before a systematic examination is provided of the potential benefits and risks of dietary supplementation of each AA in people with PD. As a part of this discussion, evidence-based recommendations are provided regarding the inclusion or exclusion of each AA for such a supplement for people with PD, and areas are highlighted where additional research is needed.
Commentary: When applying dietary therapies for gastrointestinal conditions, family values, culture, and social challenges matter
Authors: Iacovou Marina , Lewis James D
Published: February 2023

Some gastrointestinal conditions now have diet as a cornerstone to therapy. Three examples include the low-fermentable, oligosaccharide, disaccharide, monosaccharide, and polyol diet for irritable bowel syndrome, a gluten-free diet for celiac disease, and a hypoallergenic diet for eosinophilic esophagitis. All have been shown to be effective in Western or highly industrialized countries. However, these gastrointestinal conditions occur worldwide. Less is known regarding the effectiveness of dietary therapies in cultures and regions of dense religious and traditional practices where food is a central focus. This includes South Asia, the Mediterranean region, Africa, the Middle East, South America, and within Indigenous communities. Hence, there is a need to reproduce dietary intervention studies within cultures of dense traditional dietary practices to understand the applicability and acceptability of dietary therapy to establish generalizability. Furthermore, there is a need for nutrition experts to have a deep understanding of various cultural cuisines, practices, values, and customs. To achieve this, increasing the diversity of students in the sciences and having a diverse workforce of nutrition experts and health professionals that reflects the patient population will allow for more personalized care. In addition, there are social challenges, including a lack of medical insurance coverage, the cost of dietary interventions, and inconsistent nutrition messaging. Although there are many cultural considerations and social challenges to implementing effective dietary interventions around the world, these barriers are addressable through research methodologies that address culture and society challenges, and enhanced training of dietitians.
Plant organellar RNA maturation
Authors: Small Ian , Melonek Joanna , Bohne Alexandra-Viola , Nickelsen Jörg , Schmitz-Linneweber Christian
Published: February 2023

Plant organellar RNA metabolism is run by a multitude of nucleus-encoded RNA-binding proteins (RBPs) that control RNA stability, processing, and degradation. In chloroplasts and mitochondria, these post-transcriptional processes are vital for the production of a small number of essential components of the photosynthetic and respiratory machinery—and consequently for organellar biogenesis and plant survival. Many organellar RBPs have been functionally assigned to individual steps in RNA maturation, often specific to selected transcripts. While the catalog of factors identified is ever-growing, our knowledge of how they achieve their functions mechanistically is far from complete. This review summarizes the current knowledge of plant organellar RNA metabolism taking an RBP-centric approach and focusing on mechanistic aspects of RBP functions and the kinetics of the processes they are involved in.
O‐glycan structures in apo(a) subunit of human lipoprotein(a) suppresses the pro‐angiogenic activity of galectin‐1 on human umbilical vein endothelial cells
Authors: Kalaivani Vasantha , Krishna Mahesh S. , Kumar Asokan Aneesh , Satheesh Gopika , Jaleel Abdul
Published: February 2023

Apolipoprotein(a) [apo(a)] is a highly polymorphic O‐glycoprotein circulating in human plasma as lipoprotein(a) [Lp(a)]. The O‐glycan structures of apo(a) subunit of Lp(a) serve as strong ligands of galectin‐1, an O‐glycan binding pro‐angiogenic lectin abundantly expressed in placental vascular tissues. But the pathophysiological significance of apo(a)‐galectin‐1 binding is not yet been revealed. Carbohydrate‐dependent binding of galectin‐1 to another O‐glycoprotein, neuropilin‐1 (NRP‐1) on endothelial cells activates vascular endothelial growth factor receptor 2 (VEGFR2) and mitogen‐activated protein kinase (MAPK) signaling. Using apo(a), isolated from human plasma, we demonstrated the potential of the O‐glycan structures of apo(a) in Lp(a) to inhibit angiogenic properties such as proliferation, migration, and tube‐formation in human umbilical vein endothelial cells (HUVECs) as well as neovascularization in chick chorioallantoic membrane. Further, in vitro protein‐protein interaction studies have confirmed apo(a) as a superior ligand to NRP‐1 for galectin‐1 binding. We also demonstrated that the protein levels of galectin‐1, NRP‐1, VEGFR2, and downstream proteins in MAPK signaling were reduced in HUVECs in the presence of apo(a) with intact O‐glycan structures compared to that of de‐O‐glycosylated apo(a). In conclusion, our study shows that apo(a)‐linked O‐glycans prevent the binding of galectin‐1 to NRP‐1 leading to the inhibition of galectin‐1/neuropilin‐1/VEGFR2/MAPK‐mediated angiogenic signaling pathway in endothelial cells. As higher plasma Lp(a) level in women is an independent risk factor for pre‐eclamsia, a pregnancy‐associated vascular complication, we propose that apo(a) O‐glycans‐mediated inhibition of the pro‐angiogenic activity of galectin‐1 may be one of the underlying molecular mechanism of pathogenesis of Lp(a) in pre‐eclampsia.
X‐ray structure and function of fibronectin domains two and three of the neural cell adhesion molecule L1
Authors: Guédez Gabriela , Loers Gabriele , Jeffries Cy M. , Kozak Sandra , Meijers Rob , Svergun Dmitri I. , Schachner Melitta , Löw Christian
Published: February 2023

The cell adhesion molecule L1 (L1CAM, L1 in short) plays crucial roles during neural development, regeneration after injury, synapse formation, synaptic plasticity and tumor cell migration. L1 belongs to the immunoglobulin superfamily and comprises in its extracellular part six immunoglobulin (Ig)‐like domains and five fibronectin type III homologous repeats (FNs). The second Ig‐like domain has been validated for self‐ (so‐called homophilic) binding between cells. Antibodies against this domain inhibit neuronal migration in vitro and in vivo. The fibronectin type III homologous repeats FN2 and FN3 bind small molecule agonistic L1 mimetics and contribute to signal transduction. FN3 has a stretch of 25 amino acids that can be triggered with a monoclonal antibody, or the L1 mimetics, to enhance neurite outgrowth and neuronal cell migration in vitro and in vivo. To correlate the structural features of these FNs with function, we determined a high‐resolution crystal structure of a FN2FN3 fragment, which is functionally active in cerebellar granule cells and binds several mimetics. The structure illustrates that both domains are connected by a short linker sequence allowing a flexible and largely independent organization of both domains. This becomes further evident by comparing the X‐ray crystal structure with models derived from Small‐Angle X‐ray Scattering (SAXS) data for FN2FN3 in solution. Based on the X‐ray crystal structure, we identified five glycosylation sites which we believe are crucial for folding and stability of these domains. Our study signifies an advance in the understanding of structure–functional relationships of L1.
Involvement of eNAMPT/TLR4 inflammatory signaling in progression of non‐alcoholic fatty liver disease, steatohepatitis, and fibrosis
Authors: Sun Belinda L. , Sun Xiaoguang , Kempf Carrie L. , Song Jin H. , Casanova Nancy G. , Camp Sara M. , Reyes Hernon Vivian , Fallon Michael , Bime Christian , Martin Diego R. , Travelli Cristina , Zhang Donna D. , Garcia Joe G. N.
Published: February 2023

Although the progression of non‐alcoholic fatty liver disease (NAFLD) from steatosis to steatohepatitis (NASH) and cirrhosis remains poorly understood, a critical role for dysregulated innate immunity has emerged. We examined the utility of ALT‐100, a monoclonal antibody (mAb), in reducing NAFLD severity and progression to NASH/hepatic fibrosis. ALT‐100 neutralizes eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel damage‐associated molecular pattern protein (DAMP) and Toll‐like receptor 4 (TLR4) ligand. Histologic and biochemical markers were measured in liver tissues and plasma from human NAFLD subjects and NAFLD mice (streptozotocin/high‐fat diet—STZ/HFD, 12 weeks). Human NAFLD subjects (n = 5) exhibited significantly increased NAMPT hepatic expression and significantly elevated plasma levels of eNAMPT, IL‐6, Ang‐2, and IL‐1RA compared to healthy controls, with IL‐6 and Ang‐2 levels significantly increased in NASH non‐survivors. Untreated STZ/HFD‐exposed mice displayed significant increases in NAFLD activity scores, liver triglycerides, NAMPT hepatic expression, plasma cytokine levels (eNAMPT, IL‐6, and TNFα), and histologic evidence of hepatocyte ballooning and hepatic fibrosis. Mice receiving the eNAMPT‐neutralizing ALT‐100 mAb (0.4 mg/kg/week, IP, weeks 9 to 12) exhibited marked attenuation of each index of NASH progression/severity. Thus, activation of the eNAMPT/TLR4 inflammatory pathway contributes to NAFLD severity and NASH/hepatic fibrosis. ALT‐100 is potentially an effective therapeutic approach to address this unmet NAFLD need.
Independent Associations of Neighborhood Deprivation and Patient-Level Social Determinants of Health With Textbook Outcomes After Inpatient Surgery
Authors: Schmidt Susanne , Kim Jeongsoo , Jacobs Michael A. , Hall Daniel E. , Stitzenberg Karyn B. , Kao Lillian S. , Brimhall Bradley B. , Wang Chen-Pin , Manuel Laura S. , Su Hoah-Der , Silverstein Jonathan C. , Shireman Paula K.
Published: February 2023

Objective:

Assess associations of social determinants of health (SDoH) using area deprivation index (ADI), race/ethnicity and insurance type with textbook outcomes (TO).

Background:

Individual- and contextual-level SDoH affect health outcomes, but only one SDoH level is usually included.

Methods:

Three healthcare system cohort study using National Surgical Quality Improvement Program (2013–2019) linked with ADI risk-adjusted for frailty, case status, and operative stress examining TO/TO components (unplanned reoperations, complications, mortality, emergency department/observation stays, and readmissions).

Results:

Cohort (34,251 cases) mean age 58.3 [SD = 16.0], 54.8% females, 14.1% Hispanics, 11.6% Non-Hispanic Blacks, 21.6% with ADI >85, and 81.8% TO. Racial and ethnic minorities, non-private insurance, and ADI >85 patients had increased odds of urgent/emergent surgeries (adjusted odds ratios [aORs] range: 1.17–2.83, all P < 0.001). Non-Hispanic Black patients, ADI >85 and non-Private insurances had lower TO odds (aORs range: 0.55–0.93, all P < 0.04), but ADI >85 lost significance after including case status. Urgent/emergent versus elective had lower TO odds (aOR = 0.51, P < 0.001). ADI >85 patients had higher complication and mortality odds. Estimated reduction in TO probability was 9.9% (95% confidence interval [CI] = 7.2%–12.6%) for urgent/emergent cases, 7.0% (95% CI = 4.6%–9.3%) for Medicaid, and 1.6% (95% CI = 0.2%–3.0%) for non-Hispanic Black patients. TO probability difference for lowest-risk (White-Private-ADI <85-elective) to highest-risk (Black-Medicaid-ADI >85-urgent/emergent) was 29.8% for very frail patients.

Conclusion:

Multilevel SDoH had independent effects on TO, predominately affecting outcomes through increased rates/odds of urgent/emergent surgeries driving complications and worse outcomes. Lowest-risk versus highest-risk scenarios demonstrated the magnitude of intersecting SDoH variables. Combination of insurance type and ADI should be used to identify high-risk patients to redesign care pathways to improve outcomes. Risk adjustment including contextual neighborhood deprivation and patient-level SDoH could reduce unintended consequences of value-based programs.
Pembrolizumab-Induced Acral Vasculitis
Authors: Yohannan Binoy , Truly Tate , Kala Jaya , Jafri Syed Hasan
Published: February 2023

Immune checkpoint inhibitors (ICIs) have emerged as groundbreaking new therapies for a variety of solid tumors. ICIs stimulate the host immune system to attack cancer cells. However, this nonspecific immune activation can cause autoimmunity across multiple organ systems—this is referred to as an immune-related adverse event. Vasculitis secondary to ICI administration is an extremely rare event seen in <1% of cases. We identified 2 cases of pembrolizumab-induced acral vasculitis at our institution. The first patient, with stage IV adenocarcinoma of the lung, developed antinuclear antibody–positive vasculitis 4 months after initiation of treatment with pembrolizumab. The second patient had stage IV oropharyngeal cancer and presented with acral vasculitis 7 months after starting pembrolizumab. Unfortunately, both cases resulted in dry gangrene and poor outcomes. Here, we discuss the incidence, pathophysiology, clinical features, treatment, and prognosis of patients with ICI-induced vasculitis with the intention of raising awareness about this rare and potentially fatal immune-related adverse event. Early diagnosis and discontinuation of ICIs are critical for improving clinical outcomes in this situation.
Honokiol attenuates mitochondrial fission and cell apoptosis by activating Sirt3 in intracerebral hemorrhage
Authors: Zheng Xue cheng , Gao Jun ling , Zhao Man man , Han Ling ling , Zhang De xin , Wang Kai jie , Cui Jian zhong
Published: February 2023

Background:

Sirtuin-3 (Sirt3) has been documented to protect against mitochondrial dysfunction and apoptosis. Honokiol (HKL) is a Sirt3 pharmacological activator with reported neuroprotective effects in multiple neurological disorders. The present study aimed to explore the neuroprotective effects of HKL and the role of Sirt3 following intracerebral hemorrhage (ICH).

Methods:

An in vivo ICH model in rats was established by injecting autologous blood into the right basal ganglia. PC12 cells were stimulated with hemin. For the in vivo investigation, the modified Neurological Severity Scores and the Morris water maze test were performed to assess neurological deficits. Hematoxylin–Eosin and Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining were employed to evaluate the histopathology and apoptosis. Immunohistochemical staining was used to investigate the expression of Sirt3. Adenosine triphosphate (ATP) levels were quantified to assess mitochondrial dysfunction. Cell counting kit-8, lactate dehydrogenase assay, and flow cytometry were used to analyze cell vitality and apoptosis in vitro. Immunofluorescence staining was performed to observe mitochondrial morphology and dynamin-related protein 1 (Drp1) localization to mitochondria. Western blot was applied to quantify the expression of Sirt3, Bax, Bcl-2, cleaved-caspase-3, Drp1, phosphorylation of Drp1 at serine-616, and phosphorylation of Drp1 at serine-637 in vivo and in vitro.

Results:

HKL treatment alleviated neurological deficits, attenuated the histopathological damage and cell apoptosis, and restored the decreased ATP levels in ICH rats. HKL improved cell survival rate, reduced cell apoptosis, and inhibited mitochondrial fission in PC12 cells. Moreover, both in vivo and in vitro models showed increased phosphorylation of Drp1 at Ser616, and reduced phosphorylation of Drp1 at Ser637. Meanwhile, immunofluorescence co-localization analysis revealed that hemin increased the overlap of Drp1 and mitochondria in PC12 cells. The phosphorylation and mitochondrial translocation of Drp1 were effectively reversed by HKL treatment. Importantly, the selective Sirt3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine suppressed these effects.

Conclusion:

Our findings demonstrated that HKL ameliorated ICH-induced apoptosis and mitochondrial fission by Sirt3, suggesting that HKL has immense prospects for the treatment of ICH.
Impact of vaccination against COVID-19 on the outcomes of in vitro fertilization–embryo transfer: a retrospective cohort study
Authors: Yin Jingwen , Wang Yang , Tao Liyuan , Chen Lixue , Liu Ping , Li Rong
Published: February 2023

Background:

Vaccination against coronavirus disease 2019 (COVID-19) has become the primary approach in the fight against the spread of COVID-19. Studies have shown that vaccination against COVID-19 has adverse effects, particularly on human reproductive health, despite the fact that vaccination rates are still on the rise. However, few studies have reported whether vaccination affects the outcome of in vitro fertilization–embryo transfer (IVF–ET) or not. In this study, we compared the outcome of IVF–ET and the development of follicles and embryos between vaccinated and unvaccinated groups.

Methods:

A single-center retrospective cohort study of 10,541 in vitro fertilization (IVF) cycles was conducted from June 2020 to August 2021. 835 IVF cycles with a history of vaccination against COVID-19 and 1670 IVF cycles that served as negative controls were selected and analyzed utilizing the Matchlt package of R software (http://www.R-project.org/) and the nearest neighbor matching algorithm for propensity-matched analysis at a 1:2 ratio.

Results:

The number of oocytes collected in the vaccinated group and the unvaccinated group were 8.00 (0, 40.00) and 9.00 (0, 77.00) (P = 0.073) and the good-quality embryo rates of the two groups were 0.56±0.32 and 0.56±0.31 averagely (P = 0.964). Clinical pregnancy rates for the vaccinated group and unvaccinated group were 42.4% (155/366) and 40.2% (328/816) (P = 0.486) and biochemical pregnancy rates were 7.1% (26/366) and 8.7% (71/816) (P = 0.355). Two other factors were analyzed in this study; vaccination among different genders and different types (inactivated vaccine or recombinant adenovirus vaccine) showed no statistically significant effect on the above outcomes.

Conclusions:

In our findings, vaccination against COVID-19 showed no statistically significant effect on the outcomes of IVF-ET and the development of follicles and embryos, nor did the gender of the vaccinated person or the formulation of vaccines showed significant effects.
Pseudolymphoma to Lymphoma: A Case of Chronic Reactive Lymphoid Hyperplasia Transforming to Primary Cutaneous Marginal Zone Lymphoma
Authors: Singh Neha , Fagan Kiley K. , Patel Riya T. , Grider Douglas J.
Published: February 2023

Primary cutaneous marginal zone lymphoma (PCMZL) is a low-grade malignant B-cell lymphoma that originates from the skin. It often presents as erythematous solitary or multiple papules, nodules, and/or plaques. It is one of the 3 main subtypes of primary cutaneous B-cell lymphomas. PCMZLs are believed to develop from chronic antigenic stimulation such as from tick-borne bacteria, vaccines, tattoo pigment, or other foreign body. In addition, cutaneous lymphoid hyperplasia, a documented precursor to malignant PCMZL, often presents in response to areas of chronic inflammation. Cutaneous lymphoid hyperplasia and PCMZL share several clinical and histological similarities that require clinicopathologic suspicion, immunohistochemical ancillary studies, and histopathologic analysis to accurately differentiate the 2 entities. Although gene rearrangement studies have historically been of limited value in the diagnosis of PCMZL, recent studies investigating molecular markers have identified the presence of multiple genetic abnormalities that have helped to better characterize the disease and aid in diagnosis. In addition, newer studies have found associations between PCMZL and gastrointestinal disorders, including Helicobacter pylori and inflammatory bowel disorders. In this article, we describe a case of a 56-year-old patient with a history of ulcerative colitis presenting with chronic reactive lymphoid hyperplasia that transformed to primary cutaneous marginal zone lymphoma.
Clinical considerations for menopause and associated symptoms in women with HIV
Authors: Looby Sara E.
Published: February 2023

Worldwide, more women with HIV are aging and entering menopause. Although a limited number of evidenced-based care recommendations are published, formal guidelines for the management of menopause in women with HIV are not available. Many women with HIV receive primary care from HIV infectious disease specialists, without any detailed assessment of menopause. Women’s healthcare professionals specializing in menopause may have limited knowledge regarding the care of women with HIV. Clinical considerations for menopausal women with HIV include distinguishing menopause from amenorrhea because of other etiologies, early assessment of symptoms, and recognizing unique clinical, social, and behavioral comorbidities to facilitate care management.
Impact of setanaxib on quality of life outcomes in primary biliary cholangitis in a phase 2 randomized controlled trial
Authors: Jones David , Carbone Marco , Invernizzi Pietro , Little Nicola , Nevens Frederik , Swain Mark G. , Wiesel Philippe , Levy Cynthia
Published: February 2023

Background:

There is a real unmet need for primary biliary cholangitis (PBC) treatments that can improve quality of life impacting symptoms. In this post hoc analysis, we evaluated potential effects of the NADP oxidase 1/4 inhibitor, setanaxib, on patient-reported quality of life from a phase 2 trial in PBC.

Patients and Methods:

The underpinning double-blind, randomized, placebo-controlled trial (NCT03226067) recruited 111 patients with PBC and inadequate response/intolerance to ursodeoxycholic acid. Patients self-administered oral placebo (n=37), setanaxib 400 mg once daily (OD; n=38), or setanaxib 400 mg twice daily (BID; n=36), in addition to ursodeoxycholic acid for 24 weeks. Quality of life outcomes were assessed using the validated PBC-40 questionnaire. Patients were stratified post hoc by baseline fatigue severity.

Results:

At week 24, patients treated with setanaxib 400 mg BID reported greater mean (SE) absolute reductions from baseline in PBC-40 fatigue domain score [–3.6 (1.3)] versus those receiving setanaxib 400 mg OD [–0.8 (1.0)]) or placebo [0.6 (0.9)]. Similar observations were made across all PBC-40 domains except itch. In the setanaxib 400 mg BID arm, patients with moderate-to-severe fatigue at baseline had a greater reduction in mean fatigue score at week 24 [–5.8 (2.1)] versus those with mild fatigue [–0.6 (0.9)]; results were similar across all domains. Reduced fatigue was correlated with emotional, social, symptom, and cognitive improvements.

Conclusions:

These results support further investigation of setanaxib as a treatment for patients with PBC, particularly for those with clinically significant fatigue.
Hepatotoxicity of immune checkpoint inhibitors: What is Currently Known
Authors: Zheng Caiyun , Huang Shunmin , Lin Meimei , Hong Baohui , Ni Ruping , Dai Hengfen , Lin Xiuqin , Yang Jing
Published: February 2023

Background:

This systematic review and network meta-analysis aimed to provide a complete hepatotoxicity profile, hepatotoxicity spectrum, and safety ranking of immune checkpoint inhibitor drugs for cancer treatment.

Methods:

PubMed, Embase, Scopus, CINAHL, Web of Science, psycINFO, Cochrane Library, and ClinicalTrials.gov. websites were searched, and a manual search of relevant reviews and trials up to January 1, 2022, was undertaken. Head-to-head III randomized controlled trials comparing any 2 or 3 of the following treatments or different doses of the same immune checkpoint inhibitor drug were included: programmed death 1 (PD-1), programmed death ligand 1, and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitors and conventional therapy. We included 106 randomized trials (n=164,782) containing 17 treatment arms.

Results:

The overall incidence of hepatotoxicity was 4.06%. The rate of fatal liver adverse events was 0.07%. The programmed death ligand 1 inhibitor+targeted therapy drug+chemotherapy group had the highest risk of treatment-related increases in all-grade alanine aminotransferase and aspartate aminotransferase levels, and the differences were significant. For immune-related hepatotoxicity, no significant difference was found between PD-1 and CTLA-4 inhibitors for all-grade hepatotoxicity; however, CTLA-4 inhibitors were associated with a higher risk of grade 3–5 hepatotoxicity than PD-1 inhibitors.

Conclusions:

The highest incidence of hepatotoxicity and fatality was observed with triple therapy. The overall incidence of hepatotoxicity was similar between different dual regimens. For immune checkpoint inhibitor monotherapy, the overall risk of immune-mediated hepatotoxicity related to CTLA-4 inhibitors did not differ significantly from that of PD-1 inhibitors. There was no direct relationship between the risk of liver injury and drug dose, whether monotherapy or combination therapy was used.