bluuebunny/crossref_metadata_2025 huggingface dataset:
Tenapanor in Chinese ESRD patients with hyperphosphatemia on haemodialysis: a randomised, phase 3 trial
Authors: Gan Liangying , Xing Li , Xu Yan , Zhou Linghui , Jiang Hong , Sun Xiuli , Guan Tianjun , Luo Ping , Wang Junxia , Sun Fuyun , Guo Zhiyong , Guo Minghao , Gao Ju , Wei Gang , Zhong Wen , Zhou Yongchun , Zuo Li
Published: October 2023

Background

The efficacy and safety of tenapanor has not been confirmed in Chinese end-stage renal disease (ESRD) patients with hyperphosphatemia on haemodialysis (HD).

Methods

This was a randomised, double blind, phase 3 trial conducted at 26 dialysis facilities in China (https://www.chictr.org.cn/index.aspx; CTR20202588). After a 3-week washout, adults with ESRD on HD with hyperphosphatemia were randomised (1:1) using an interactive web response system to oral tenapanor 30 mg twice a day or placebo for 4 weeks. The primary endpoint was the change in mean serum phosphorous level from baseline to the endpoint visit (day 29 or last serum phosphorus measurement). Efficacy was analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drug.

Results

Between 5 March 2021 and 8 June 2022, 77 patients received tenapanor and 73 received placebo. Tenapanor treatment (n = 75) resulted in a significantly greater least squares (LS) mean reduction in serum phosphate at the endpoint visit versus placebo (n = 72): LS mean difference −1.17 mg/dl (95% CI −1.694 to −0.654, P < .001). More patients receiving tenapanor achieved a serum phosphorous level <5.5 mg/dl at the endpoint visit (44.6% versus 10.1%). The most common treatment-related adverse event was diarrhoea [tenapanor 28.6% (22/77), placebo 2.7% (2/73)], which was mostly mild and led to treatment discontinuation in two patients receiving tenapanor.

Conclusions

Tenapanor significantly reduced the serum phosphorous level versus placebo in Chinese ESRD patients on HD and was generally well tolerated.
‘The words of a nation worn down by cares’: classical wisdom and modern crisis in Lin Shu’s Aesop’s Fables
Authors: Porteous Benjamin
Published: October 2023

This article analyses the remarkable translation of Aesop’s Fables produced by the Chinese literatus-turned-cultural-impresario Lin Shu [林紓; 1852–1924] at the turn of the twentieth century. Collaborating with colleagues proficient in English, which he himself was not, Lin translated the Fables into elegant Classical Chinese. This article examines the preface to the translation, which uses Aesop’s status as an enduring classical figure in Western education to argue for the continuing relevance of Classical Chinese in newly constituted school curricula. More importantly though, this article probes at the voluminous epimythia Lin composed for most of the fables in the collection. Written immediately after the humiliating Boxer Protocol, these present a feisty critique of Western imperialism in China. They range in topic from China’s lack of cultural self-confidence to comparative reflection on the status of enslaved Africans in the antebellum USA. Lin was a confident and wilful reader of texts; in his hands, the Fables become a foil for razor-edged polemic. His translation is surely one of the most culturally significant in the Fables’ long and murky textual history, and represents an overlooked monument of classical reception in an East Asia teetering on the violent edge of modernity.
Host-plant phenology mediates facultative ant mutualism in the rare butterfly, Celastrina humulus (Lepidoptera: Lycaenidae)
Authors: Mooney Emily H , Fahland Audrey C , Nolan Hailee A , Swift Abbey M , Schorr Robert
Published: October 2023

Host-plant phenology can directly and indirectly mediate the abundance of insect herbivores. Our objective was to determine how host-plant flowering phenology shapes a facultative ant–lycaenid mutualism. The focus of our research was the hops azure, Celastrina humulus Scott & D. Wright, a rare species whose larvae feed on the pollen-bearing inflorescences of Humulus lupulus var. neomexicanus. We used several approaches to evaluate the role of host-plant flowering phenology in this system. First, we monitored larvae over three study years (2020–2022) to parse the role of host-plant flowering phenology and other factors in shaping the likelihood of ant tending. Second, we tested larval performance at various phenological stages of the host plant. We also quantified variation in soluble proteins and secondary metabolites among inflorescences at varying phenological stages. Lastly, we treated artificial sugar–protein baits with extracts from different phenological stages of the host plant; this allowed us to assess how chemical variation among stages could impact ant recruitment. Monitoring results revealed that the likelihood of ant tending was lowest for larvae on host plants with early-stage inflorescences. These floral stages had the greatest concentrations of both soluble proteins and α-acids (humulone and cohumulone), and in the feeding trial, early-stage flowers enabled greater weight gain for larvae. However, extracts from early-stage flowers reduced ant recruitment to sugar–protein baits. Altogether, these results suggest that early-stage inflorescences enhance larval growth while also reducing the recruitment of mutualist ants. This shows an indirect mechanism whereby changing host-plant phenology can mediate herbivore populations through interactions with ants.
Developing a universal and reliable temporomandibular joint reference system for quantifying morphological and positional changes
Authors: Feng Bin , Wu Qinxin , Wang Jun , Jiang Yun , Liu Zi’ang , Lu Mengting , Liu Zuozhu , Yu Mengfei , Zhu Fudong
Published: October 2023

Objectives

This study aimed to provide a universal and reliable reference system quantifying temporomandibular joint (TMJ) morphological and positional changes.

Methods

Large field-of-view (FOV) cone-beam computed tomography (CBCT) images (20 TMJs) from 10 preorthognathic surgery patients and limited FOV CBCT images (40 TMJs) from 20 splint therapy-treated patients with temporomandibular disorders were collected. TMJ-specific reference system including a TMJ horizontal reference plane (TMJHP) and a local coordinate system (TMJCS) was constructed with landmarks on cranial base. Its application for TMJ measurements and its spatial relationship to common Frankfort horizontal plane (FHP) and maxillofacial coordinate system (MFCS) were evaluated.

Results

Five relevant landmarks were selected to optimally construct TMJ-specific reference system. General parallelism between TMJHP and FHP was demonstrated by minimal angular and constant distance deviation (1.714 ± 0.811º; 2.925 ± 0.817 mm). Additionally, tiny axial orientational deviations (0.181 ± 6.805º) suggested TMJCS rivaled MFCS. Moreover, small deviations in orientations and distances (1.232 ± 0.609º; 0.310 ± 0.202 mm) indicated considerable reliability for TMJCS construction, with intraclass correlation coefficients (ICCs) ranging from 0.999 to 1.000. Lastly, slight discrepancies in translations and rotations revealed high reliability for condylar positional and morphological measurements (ICC, 0.918–0.999).

Limitations

TMJ-specific reference system was merely tested in two representative FOVs.

Conclusions

This study provides a universal and reliable reference system for TMJ assessment that is applicable to both limited and large FOV CBCT. It would improve comparability among diverse studies and enable comprehensive evaluations of TMJ positional and morphological changes during TMJ-related treatment follow-up such as splint therapy and disease progression.
A novel synthesis of light transmission from upcycled polyethylene terephthalate polymer and low-density polyethylene for greenhouse design in tropical climate
Authors: Wongwatcharapaiboon Jitiporn , Chankasem Chanikarn , Lertwattanarak Pusit , Riffat Saffa
Published: October 2023

To support the circular economy in Thai’s agriculture, the main interviewed challenges point to knowledge and knowhow for greenhouse structure and system boosting up productivities. One popular material that possibly affected productivity is transparent polymer film, which can be recycled based on material property and blowing machine condition. This paper investigates the light transmittance performance of transparent polyethylene terephthalate polymer (PET) and low-density polyethylene (LDPE) sheets for use in low-energy greenhouses in tropical climates. The aim of the study is to optimize the thermal performance and light transmittance of these materials to support plant growth and human comfort. The study focuses on seven stages of plant growth, each of which requires different light characteristics including 1) seed, 2) germinating, 3) young seedling, 4) older vine, 5) flowering, 6) fruit bearing and 7) harvesting and drying. Each stage requires different light characteristics, e.g. light intensity, red light, blue light, white light and ultraviolet (UV) and pulsed light (PL). The methodology involves selecting PET and LDPE materials, preparing samples for thermal property and lighting laboratory tests and analysing the results based on suitable criteria. The findings show that LDPE sheets have 28.78% lower light transmittance than PET sheets, making them suitable for supporting the seedling stage and older vines of plant growth. PET sheets, on the other hand, deliver a high intensity of red light, making them suitable for stimulating photosynthesis in older vines and during the harvesting process. The study highlights the importance of considering both thermal performance and light transmittance when selecting materials for low-energy greenhouses in tropical climates.
Observer-based controller design for switched systems with stable and unstable subsystems
Authors: Xie Donglei , Chen Yantao , Qiao Ying
Published: October 2023

This paper studies the problems of both state estimation and observer-based control for a class of switched linear systems with stable and unstable subsystems. By combining slow switching and fast switching mechanism, the observer design and observer-based controller are presented. Firstly, a state observer is developed to estimate the states of switched system by designing admissible edge-dependent switching signal, and a multiple discontinuous Lyapunov function is also constructed to obtain the existence condition of observer. Secondly, based on the stability characteristics of subsystem and the estimated state information, an observer-based feedback controller is proposed. The stability of the closed-loop system is also guaranteed by Lyapunov stability theory. Finally, the feasibility of the proposed method is verified by simulation.
Systematic review on cumulative HIV viraemia among people living with HIV receiving antiretroviral treatment and its association with mortality and morbidity
Authors: Mesic Anita , Decroo Tom , Florence Eric , Ritmeijer Koert , van Olmen Josefien , Lynen Lutgarde
Published: October 2023

Background

We performed a systematic review to generate evidence on the association between cumulative human immunodeficiency virus (HIV) viraemia and health outcomes.

Methods

Quantitative studies reporting on HIV cumulative viraemia (CV) and its association with health outcomes among people living with HIV (PLHIV) on antiretroviral treatment (ART) were included. We searched MEDLINE via PubMed, Embase, Scopus and Web of Science and conference abstracts from 1 January 2008 to 1 August 2022.

Results

The systematic review included 26 studies. The association between CV and mortality depended on the study population, methods used to calculate CV and its level. Higher CV was not consistently associated with greater risk of acquire immunodeficiency syndrome–defining clinical conditions. However, four studies present a strong relationship between CV and cardiovascular disease. The risk was not confirmed in relation of increased hazards of stroke. Studies that assessed the effect of CV on the risk of cancer reported a positive association between CV and malignancy, although the effect may differ for different types of cancer.

Conclusions

CV is associated with adverse health outcomes in PLHIV on ART, especially at higher levels. However, its role in clinical and programmatic monitoring and management of PLHIV on ART is yet to be established.
Innovative UV Protocols Based on Straightforward Mathematical Filtration for Concurrent Estimation of Two Antidiabetic Drugs in Their Brand-New Combination: A Comparative Study
Authors: Nour Israa M , Mohamed Ahmed R , Badrawy Mohamed
Published: October 2023

Background

In 2019, the U.S. Food and Drug Administration approved a brand-new combination of linagliptin and empagliflozin in a formulation called Glyxambi® tablets for managing type 2 diabetes mellitus. Nowadays, spectrophotometric techniques occupy the first place among their peers in terms of ease of application, friendliness to the environment, and low costs.

Objective

This research discusses the development of two very simple spectrophotometric protocols based on zero-order spectra for the determination of linagliptin and empagliflozin.

Methods

The developed protocols were the induced dual-wavelength and absorption correction protocols. Linagliptin could be determined directly at 305 nm, at which the empagliflozin spectrum was zero-crossing. Empagliflozin was determined using the two developed protocols. The induced dual-wavelength technique was developed by calculating the equality factor of linagliptin to cancel its interference. The absorption correction technique was developed by measuring the correction absorption factor.

Results

The concentration ranges of linagliptin and empagliflozin were 1–10 µg/mL and 3–30 µg/mL, respectively. Excellent recovery results were found in bulk, dosage form, and synthetic mixtures. Low LOD and LOQ values were obtained, indicating the high sensitivity of the protocols. The statistical Student’s t-test was performed to compare the results of the applied and reported protocols, indicating no difference between them.

Conclusion

The proposed protocols have the advantages of being straightforward, affordable, and requiring no sophisticated manipulations, just simple mathematical calculations. The proposed protocols are acceptable for routine usage in QC laboratories and in future research applications.

Highlights

Two novel univariate methods were developed for quantitative analysis of linagliptin and empagliflozin in their pharmaceutical and laboratory mixtures, and produced satisfactory results.
Evaluation of identification methods for cryptic Bactrocera dorsalis (Diptera: Tephritidae) specimens: combining morphological and molecular techniques
Authors: Charbonnel Emeline , Chapuis Marie-Pierre , Taddei Andrea , Schutze Mark K , Starkie Melissa L , Benoit Laure , Mouttet Raphaëlle , Ouvrard David
Published: October 2023

The potential for population genomics to elucidate invasion pathways of a species is limited by taxonomic identification issues. The Oriental fruit fly pest, Bactrocera dorsalis (Hendel) belongs to a complex in which several sympatric species are attracted to the same lure used in trapping and are morphologically cryptic and/or reported to hybridize. In this study, we evaluated the taxonomic ambiguity between B. dorsalis and 2 major cryptic species, based on morphological expertise and 289 target specimens sampled across the whole distribution range. Specimens were then subjected to DNA sequence analyses of the COI mitochondrial barcode and the EIF3L nuclear marker to evaluate the potential for molecular identification, in particular for specimens for which morphological identification was inconclusive. To this aim, we produced reference datasets with DNA sequences from target specimens whose morphological identification was unambiguous, which we complemented with 56 new DNA sequences from closest relatives and 76 published and curated DNA sequences of different species in the complex. After the necessary morphological observation, about 3.5% of the target dataset and 47.6% of the specimens from Southeast Asian islands displayed ambiguous character states shared with B. carambolae and/or B. occipitalis. Critical interpretation of DNA sequence data solved morphological ambiguities only when combining both mitochondrial and nuclear markers. COI discriminated B. dorsalis from 5 species; EIF3L and ITS from another species. We recommend this procedure to ensure correct identification of B. dorsalis specimens in population genetics studies and surveillance programs.
New Work on Biosignatures
Authors: Cowie Christopher
Published: October 2023

The search for extraterrestrial life centres on the search for ‘biosignatures’. Yet there is little agreement within the scientific community with respect to what exactly it is for something to be a biosignature. Existing accounts are presented and criticised. An alternative is provided that resolves problems with existing accounts by distinguishing clearly between types and tokens.
HOOKLESS1 acetylates AUTOPHAGY-RELATED PROTEIN18a to promote autophagy during nutrient starvation in Arabidopsis
Authors: Huang Li , Wen Xing , Jin Lian , Han Huihui , Guo Hongwei
Published: October 2023

Acetylation is an important posttranslational modification (PTM) that regulates almost all core processes of autophagy in yeast and mammals. However, the role of protein acetylation in plant autophagy and the underlying regulatory mechanisms remain unclear. Here, we show the essential role of the putative acetyltransferase HOOKLESS1 (HLS1) in acetylation of the autophagy-related protein ATG18a, a key autophagy component that regulates autophagosome formation in Arabidopsis (Arabidopsis thaliana). Loss of HLS1 function suppressed starvation-induced autophagy and increased plant susceptibility to nutrient deprivation. We discovered that HLS1 physically interacts with and directly acetylates ATG18a both in vitro and in vivo. In contrast, mutating putative active sites in HLS1 inhibited ATG18a acetylation and suppressed autophagy upon nutrient deprivation. Accordingly, overexpression of ATG18a mutant variants with lower acetylation levels inhibited the binding activity of ATG18a to PtdIns(3)P and autophagosome formation under starvation conditions. Moreover, HLS1-modulated autophagy was uncoupled from its function in hook development. Taken together, these findings shed light on a key regulator of autophagy and further elucidate the importance of PTMs in modulating autophagy in plants.
Barley MLA3 recognizes the host-specificity effector Pwl2 from Magnaporthe oryzae
Authors: Brabham Helen J , Gómez De La Cruz Diana , Were Vincent , Shimizu Motoki , Saitoh Hiromasa , Hernández-Pinzón Inmaculada , Green Phon , Lorang Jennifer , Fujisaki Koki , Sato Kazuhiro , Molnár István , Šimková Hana , Doležel Jaroslav , Russell James , Taylor Jodie , Smoker Matthew , Gupta Yogesh Kumar , Wolpert Tom , Talbot Nicholas J , Terauchi Ryohei , Moscou Matthew J
Published: October 2023

Plant nucleotide-binding leucine-rich repeat (NLRs) immune receptors directly or indirectly recognize pathogen-secreted effector molecules to initiate plant defense. Recognition of multiple pathogens by a single NLR is rare and usually occurs via monitoring for changes to host proteins; few characterized NLRs have been shown to recognize multiple effectors. The barley (Hordeum vulgare) NLR gene Mildew locus a (Mla) has undergone functional diversification, and the proteins encoded by different Mla alleles recognize host-adapted isolates of barley powdery mildew (Blumeria graminis f. sp. hordei [Bgh]). Here, we show that Mla3 also confers resistance to the rice blast fungus Magnaporthe oryzae in a dosage-dependent manner. Using a forward genetic screen, we discovered that the recognized effector from M. oryzae is Pathogenicity toward Weeping Lovegrass 2 (Pwl2), a host range determinant factor that prevents M. oryzae from infecting weeping lovegrass (Eragrostis curvula). Mla3 has therefore convergently evolved the capacity to recognize effectors from diverse pathogens.
Moving to Smart Specialization for sustainability: the implications on the design of monitoring indicators
Authors: Moujaes Ghinwa
Published: October 2023

Smart Specialization policy, Europe’s place-based innovation policy, is transitioning into an innovation policy for sustainability inspired by academic debate and the urgency of societal challenges. The implications in terms of policy design remain underexplored. This paper studies the policy implications of this transition on the design of monitoring indicators. First, a theoretical framework based on the literature is created. Then, monitoring indicators used in the first policy phase are summarized into categories and themes through inductive and deductive document analysis. The indicators’ strengths and limitations are discussed. By highlighting how monitoring indicators need to adjust to the policy transition, this paper contributes to the literature on innovation policy and Smart Specialization. It also provides guidance to policymakers by developing a framework on indicator design and providing practical recommendations on aspects that need to be considered, captured, and analysed through the indicators.
Delayed melatonin circadian timing, lower melatonin output, and sleep disruptions in myopic, or short-sighted, children
Authors: Chakraborty Ranjay , Seby Chris , Scott Hannah , Tang Victoria , Kemps Eva , Anstice Nicola , Juers Emilia , Lovato Nicole , Taranath Deepa A , Mills Richard A , Lack Leon C
Published: October 2023

Study Objectives

This study investigated the differences in melatonin circadian timing and output, sleep characteristics, and cognitive function in myopic and non-myopic (or emmetropic) children, aged 8–15 years.

Methods

Twenty-six myopes (refractive error [mean ± standard error mean] −2.06 ± 0.23 diopters) and 19 emmetropes (−0.06 ± 0.04 diopters), aged 11.74 ± 2.31 years were recruited. Circadian timing was assessed using salivary dim-light melatonin onset (DLMO), collected half-hourly for 7 hours, beginning 5 hours before and finishing 2 hours after individual average sleep onset in a sleep laboratory. Nocturnal melatonin output was assessed via aMT6s levels from urine voids collected from 05:30 pm to 8:00 am the following morning. Actigraphy-derived objective sleep timing were acquired for a week prior to the sleep laboratory visit. Cognitive assessments of sustained attention (using psychomotor vigilance task [PVT]) and working memory (using digit spans) were performed on the night of sleep laboratory.

Results

Myopic children (9:07 pm ± 14 minutes) exhibited a DLMO phase-delay of 1 hour 8 minutes compared to emmetropes (7:59 pm ± 13 minutes), p = 0.002. aMT6s melatonin levels were significantly lower among myopes (18.70 ± 2.38) than emmetropes (32.35 ± 6.93, p = 0.001). Myopes also exhibited significantly delayed sleep onset, delayed wake-up time, poor and reduced sleep, and more evening-type diurnal preference than emmetropes (all p < 0.05). Finally, myopes showed a slower reaction time in the PVT (p < 0.05), but not digit span tasks at night.

Conclusions

These findings suggest a potential association between circadian rhythm dysfunction and myopia in children.
Harvest for health in survivors of chronic disease: A demonstration project in the Alabama Black Belt and Mississippi Delta Region
Authors: Bail Jennifer R , Wilson Jeff , Tipre Meghan , Duck Angela , Hall Katherine , Akinyele Oluseun , Bowman Tara , Hardy Claudia , Garner Marcus , Demark-Wahnefried Wendy , Baskin Monica
Published: October 2023

This demonstration project expands upon the Harvest for Health vegetable gardening intervention for cancer survivors by: (i) including survivors of other chronic diseases (i.e. heart disease and diabetes); and (ii) targeting an area with known health inequities (Alabama Black Belt and Mississippi Delta Region). To assess: (i) gardening acceptability (engagement, satisfaction, sustainability, and safety); and (ii) changes over time in health behaviors (fruit and vegetable [F&V] intake, and physical activity) and outcomes (physical performance and anthropometrics). Chronic disease survivors (CDS) were recruited across 15 counties in Alabama and Mississippi and provided with gardening supplies and paired with a master gardener (MG). MGs mentored participants in planning, planting, and maintaining a vegetable garden over a 3-month period. Data collection consisted of an electronic survey (baseline, post-intervention, 6-month follow-up) and community-based physical assessments (baseline and post-intervention). Participants (n = 137; 92% African American; Mage = 65) included individuals with a history of diabetes (56%), heart disease (29%), and cancer (26%). Seventy-five percent of participants engaged in gardening ≥3 times a week. Significant improvements in F&V intake (+0.73, P = .04), physical activity (+49.6, P < .01), and 4 of 7 physical performance measures were observed, while positive trends were seen in others. Eighteen participants withdrew (13% attrition rate). No adverse events occurred. Participants were satisfied with their gardening experience (90%) and were still gardening at 6-month follow-up (85%). Seventy-two percent of participants expanded, or planned on expanding, their garden at 6-month follow-up. Harvest for Health was acceptable and associated with improved health behaviors and outcomes.
Unexpected Diversity of Pseudomonads Associated with Bacterial Leaf Spot of Cucurbits in the Southeastern United States
Authors: Fullem Kiersten R. , Pena Michelle M. , Potnis Neha , Goss Erica M. , Minsavage Gerald V. , Iriarte Fanny B. , Holland Auston , Jones Jeffrey B. , Paret Mathews L.
Published: October 2023

Bacterial leaf spot of cucurbits (BLS) is an emerging disease in the southeastern United States that is capable of causing widespread outbreaks under conducive conditions. Historically attributed solely to the bacterium Pseudomonas syringae pv. lachrymans, recent studies have identified additional P. syringae pathovars as causal agents of the disease. To further investigate the identity and diversity of P. syringae strains associated with BLS in the southeastern United States, 47 bacterial isolates were recovered from symptomatic cucurbits from Florida, Alabama, and Georgia. Strains were characterized using the LOPAT testing scheme, fluorescence, and pathogenicity to watermelon and squash seedlings. Thirty-eight fluorescent isolates underwent whole-genome sequencing and were further characterized with 16S rRNA, four gene multilocus sequence analysis (MLSA) phylogeny, and average nucleotide identity analysis. Thirty-four isolates were identified as members of the P. syringae species complex, including P. syringae sensu stricto (12), P. alliivorans (12), P. capsici (nine), and P. viridiflava (one). An additional four isolates were found to belong to the Pseudomonas genus outside of the syringae species complex, though they did not share 95% or greater average nucleotide identity to any validly published species and are believed to belong to three novel Pseudomonas species. These results reveal an unpredicted level of diversity of Pseudomonas strains associated with BLS in the region and show the benefits of whole-genome sequencing for strain identification. Identification of P. capsici, which is capable of causing disease at higher temperatures than P. syringae, as a causal agent of BLS may also affect management strategies in the future.
TRPV4‐mediated Ca2+ deregulation causes mitochondrial dysfunction via the AKT/α‐synuclein pathway in dopaminergic neurons
Authors: Sun Xiao , Kong Jun , Dong Shuangshan , Kato Hiroki , Sato Hiroshi , Hirofuji Yuta , Ito Yosuke , Wang Lu , Kato Takahiro A. , Torio Michiko , Sakai Yasunari , Ohga Shouichi , Fukumoto Satoshi , Masuda Keiji
Published: October 2023

Mutations in the gene encoding the transient receptor potential vanilloid member 4 (TRPV4), a Ca2+ permeable nonselective cation channel, cause TRPV4‐related disorders. TRPV4 is widely expressed in the brain; however, the pathogenesis underlying TRPV4‐mediated Ca2+ deregulation in neurodevelopment remains unresolved and an effective therapeutic strategy remains to be established. These issues were addressed by isolating mutant dental pulp stem cells from a tooth donated by a child diagnosed with metatropic dysplasia with neurodevelopmental comorbidities caused by a gain‐of‐function TRPV4 mutation, c.1855C > T (p.L619F). The mutation was repaired using CRISPR/Cas9 to generate corrected isogenic stem cells. These stem cells were differentiated into dopaminergic neurons and the pharmacological effects of folic acid were examined. In mutant neurons, constitutively elevated cytosolic Ca2+ augmented AKT‐mediated α‐synuclein (α‐syn) induction, resulting in mitochondrial Ca2+ accumulation and dysfunction. The TRPV4 antagonist, AKT inhibitor, or α‐syn knockdown, normalizes the mitochondrial Ca2+ levels in mutant neurons, suggesting the importance of mutant TRPV4/Ca2+/AKT‐induced α‐syn in mitochondrial Ca2+ accumulation. Folic acid was effective in normalizing mitochondrial Ca2+ levels via the transcriptional repression of α‐syn and improving mitochondrial reactive oxygen species levels, adenosine triphosphate synthesis, and neurite outgrowth of mutant neurons. This study provides new insights into the neuropathological mechanisms underlying TRPV4‐related disorders and related therapeutic strategies.
Human bone marrow mesenchymal stem cell‐derived extracellular vesicles restore Th17/Treg homeostasis in periodontitis via miR‐1246
Authors: Xia Yuxing , Cheng Tianfan , Zhang Chengfei , Zhou Min , Hu Zhekai , Kang Feiwu , Liao Chongshan
Published: October 2023

T‐cell‐mediated immunity is crucial in the immunopathology of periodontitis. The restoration of the homeostasis between the T helper cell 17 (Th17) and regulatory T cell (Treg) subsets by extracellular vesicles (EVs) obtained from human bone marrow stem cells (hBMSCs) promotes new bone formation and suppresses inflammation. Uncovering the functions of hBMSC‐derived EVs in the immune microenvironment of periodontal tissue and their underlying regulatory mechanisms may shed new light on developing potential cell‐free immunotherapies for periodontal regeneration. Here, we reported that the Th17/Treg ratio elevated in peripheral blood from periodontitis patients. Furthermore, we found that hBMSC‐derived EVs could reduce the Th17/Treg ratio in CD4+ T cells from periodontitis patients in vitro and ameliorate conditions of experimental periodontitis in mice. Additionally, by investigating the differentially expressed miRNAs and target genes in EVs from hBMSCs stimulated with Porphyromonas gingivalis LPS using miRNA sequencing, we found that EV‐miR‐1246 is highly effective at downregulating the ratio of Th17/Treg in vitro. Mechanistically, EV‐miR‐1246 suppressed expression of its potential target angiotensin‐converting enzyme 2 (ACE2) and increased the p‐Yes‐associated protein (YAP)1/YAP1 ratio in CD4+ T cells. Our results indicated that hBMSC‐derived EVs improve periodontitis via miR‐1246, consequently downregulating Th17/Treg ratio, and represented a promising therapeutic target for precision treatment in periodontitis.
The Reset Neurotomy within a Nonidentifiable Zone of Injury after Trauma
Authors: Schnack Lauren L. , Rodriguez-Collazo Edgardo R. , Oexeman Stephanie A. , Costa Andrew J.
Published: October 2023

Recent reconstructive approaches to peripheral nerve surgery have been directed toward active approaches; one such approach is nerve grafting the injured nerve segment. Addressing a nerve injury proximal to the zone of injury has demonstrated reproducible results in preventing symptomatic neuroma formation. A 53-year-old woman with a history of an ankle fracture presented with neuritic symptoms that interfered with her activities of daily living. Her intractable pain was significantly but temporarily relieved with in-office nerve blocks to the superficial peroneal nerve and sural nerve. There were no identifiable zones of injury in the nerve conduction study. Orthopedic etiology was ruled out. Nerve allografts, each 3 cm in length, were utilized with conduits and placed at the location proximal to the zone of maximum tenderness. Once the neurotomy was performed, the nerve allografts and conduits were coapted to each nerve. The patient’s intractable neuritic pain was relieved even 15 months postoperatively. The visual analog scale went from eight of 10 preoperatively to two of 10 postoperatively. Additional nerve conduction studies were not needed, and the patient returned to daily activities once the skin incisions healed. The reset neurotomy is an option for the microsurgical surgeon to have for patients with a nonidentifiable zone of injury or no identifiable neuroma but presents with intractable nerve pain relieved by local anesthetic nerve blocks.
Complete correction of murine phenylketonuria by selection-enhanced hepatocyte transplantation
Authors: Vonada Anne , Wakefield Leslie , Martinez Michael , Harding Cary O. , Grompe Markus , Tiyaboonchai Amita
Published: October 2023

Background and Aims:

Hepatocyte transplantation for genetic liver diseases has several potential advantages over gene therapy. However, the low efficiency of cell engraftment has limited its clinical implementation. This problem could be overcome by selectively expanding transplanted donor cells until they replace enough of the liver mass to achieve therapeutic benefit. We previously described a gene therapy method to selectively expand hepatocytes deficient in cytochrome p450 reductase (Cypor) using acetaminophen (APAP). Because Cypor is required for the transformation of APAP to a hepatotoxic metabolite, Cypor-deficient cells are protected from toxicity and are able to expand following APAP-induced liver injury. Here, we apply this selection system to correct a mouse model of phenylketonuria by cell transplantation.

Approach and Results:

Hepatocytes from a wild-type donor animal were edited in vitro to create Cypor deficiency and then transplanted into phenylketonuric animals. Following selection with APAP, blood phenylalanine concentrations were fully normalized and remained stable following APAP withdrawal. Cypor-deficient hepatocytes expanded from < 1% to ~14% in corrected animals, and they showed no abnormalities in blood chemistries, liver histology, or drug metabolism.

Conclusions:

We conclude that APAP-mediated selection of transplanted hepatocytes is a potential therapeutic for phenylketonuria with long-term efficacy and a favorable safety profile.
Pigment epithelial detachment thickness and variability impacts visual outcomes in patients with neovascular age-related macular degeneration
Authors: Sarraf David , Khanani Arshad M. , Sadda SriniVas R. , Chang Andrew , Wong David T. , Kempf Anne-Sophie , Saffar Insaf , Tang Shuhan , Tadayoni Ramin
Published: October 2023

Purpose:

To evaluate the impact of pigment epithelial detachment (PED) thickness (i.e. height) and thickness variability on best corrected visual acuity (BCVA) outcomes in patients with neovascular age-related macular degeneration (nAMD) in the Phase 3 HAWK and HARRIER trials.

Methods:

Optical coherence tomography images from the pooled brolucizumab 6mg and aflibercept 2mg arms were analysed for the maximum PED thickness across the macula at baseline through to Week 96. BCVA outcomes were compared in patients with different PED thickness and variability cut-off thresholds.

Results:

Greater PED thickness at baseline or at Week 12 was associated with lower mean BCVA gain from baseline to Week 96 (baseline PED ≥200 µm: +4.6 letters; <200 µm: +7.0 letters; Week 12 PED ≥100 µm: +5.6 letters; <100 µm: +6.6 letters). Eyes with the largest PED thickness variability from Week 12 through Week 96 gained fewer letters from baseline at Week 96 (≥33 µm: +3.3 letters; <9 µm: +6.2 letters). Furthermore, increased PED thickness at Week 48 was associated with higher prevalence of intraretinal and subretinal fluid.

Conclusions:

In this treatment-agnostic analysis, greater PED thickness and PED thickness variability were associated with poorer visual outcomes in patients with nAMD and greater neovascular activity.
A combination of clot formation abnormalities in thromboelastometry has a high prognostic value in patients with acute-on-chronic liver failure
Authors: Kampelos George , Alexopoulos Theodoros , Vasilieva Larisa , Mani Iliana , Hadziyannis Emilia , Giannouli Stavroula , Manioudaki Sofia , Nomikou Efrosyni , Alexopoulou Alexandra
Published: October 2023

Background

Global coagulation tests offer a better tool to assess procoagulant and anticoagulant pathways, fibrinolysis and clot firmness and evaluate more accurately coagulation defects compared to conventional coagulation tests. Their prognostic role in acute-on-chronic liver disease (ACLF) or acute decompensation (AD) has not been well established.

Aims

To assess the properties and prognostic value of the coagulation profile measured by rotational thromboelastometry (ROTEM) in ACLF and AD.

Methods

84 consecutive patients (35 ACLF and 49 AD) were prospectively studied. Twenty healthy persons matched for age and gender were used as controls. ‘Hypocoagulable’ or ‘hypercoagulable’ profiles on admission were assessed based on nine ROTEM parameters and mortality was recorded at 30 and 90 days.

Results

Individual ROTEM parameters denoted significantly more hypocoagulability in patients compared to controls. ‘Hypocoagulable’ profile (defined as a composite of 4 or more ROTEM parameters outside the range) was associated with more severe liver disease assessed either as MELD or Child-Pugh scores (P < 0.001 for both) and higher 30-day mortality (Log-rank P = 0.012). ‘Hypocoagulable’ profile (HR 3.160, 95% CI 1.003–9.957, P = 0.049) and ACLF status (HR 23.786, 95% CI 3.115–181.614, P = 0.002) were independent predictors of 30-day mortality, in multivariate model. A higher early mortality rate was shown in ACLF patients with ‘hypocoagulable’ phenotype compared to those without (Log-rank P = 0.017). ‘Hypocoagulable’ profile was not associated with mortality in AD.

Conclusion

‘Hypocoagulable’ profile was associated with more advanced liver disease and higher short-term mortality in patients with ACLF.
Relevance of GLP-1 receptor agonists or SGLT-2 inhibitors on the recruitment for clinical studies in patients with NAFLD
Authors: Holzhey Michael , Petroff David , Wirkner Kerstin , Engel Christoph , Baber Ronny , Tönjes Anke , Zeynalova Samira , Yahiaoui-Doktor Maryam , Berg Thomas , Karlas Thomas , Wiegand Johannes
Published: October 2023

Introduction

Guidelines increasingly recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose co-transporter-2 inhibitors (SGLT2i) to prevent cardiovascular and cardiorenal endpoints. Both drugs also show beneficial effects in nonalcoholic fatty liver disease (NAFLD). Preexisting GLP-1 RA and SGLT2i therapies are frequently defined as exclusion criterion in clinical studies to avoid confounding effects. We therefore investigated how this might limit recruitment and design of NAFLD studies.

Methods

GLP-1 RA and SGLT2i prescriptions were analyzed in NAFLD patients with diabetes mellitus recruited at a tertiary referral center and from the population-based LIFE-Adult-Study. Individuals were stratified according to noninvasive parameters of liver fibrosis based on vibration-controlled transient elastography (VCTE).

Results

97 individuals were recruited at tertiary care and 473 from the LIFE-Adult-Study. VCTE was available in 97/97 and 147/473 cases.

GLP-1 RA or SGLT2i were used in 11.9% of the population-based cohort (LSM < 8 kPa), but in 32.0% with LSM ≥ 8 kPa. In the tertiary clinic, it was 30.9% overall, independent of LSM, and 36.8% in patients with medium and high risk for fibrotic NASH (FAST score > 0.35). At baseline, 3.1% of the patients in tertiary care were taking GLP-1 RA and 4.1% SGLT2i. Four years later, the numbers had increased to 15.5% and 21.6%.

Conclusion

GLP-1 RA and SGLT2i are frequently and increasingly prescribed. In candidates for liver biopsy for NASH studies (VCTE ≥ 8 kPa) the use of them exceeds 30%, which needs careful consideration when designing NASH trials.
Optimizing the pediatric transplant candidate
Authors: Squires James E. , Raghu Vikram K. , Mazariegos George V.
Published: October 2023

Purpose of review

Advances in pediatric transplant parallel those in adult populations; however, there remain critical unique considerations and differences that require specialized knowledge and a specific skill set to optimize care afforded to the pediatric transplant candidate. We introduce general themes regarding optimization of the transplant candidate that are unique to children.

Recent findings

The pathologies leading to pediatric organ transplant candidacy differ from adults and a precise understanding of the physiologies and natural histories of such diseases is critical for optimized care. Regardless of etiology, comorbidities including malnutrition, sarcopenia, and developmental delay are seen and often require disease and organ specific approaches to management. Additionally, an understanding of the concepts of developmental immunology and their relevance to transplant is critical.

When looking to optimize pretransplant care, awareness of the pediatric-specific challenges by the transplant community in addition to organ- and age-specific management strategies enable the best outcomes for children awaiting solid organ transplantation.
Examining the Nurse Manager Practice Environment Effects on Burnout
Authors: Miller Rebecca , Zanville Noah , Hasse Adam
Published: October 2023

OBJECTIVE

This study examined the relationships between the dimensions of the nurse manager (NM) practice environment (PE) and burnout.

BACKGROUND

NMs are critical to the success of their unit(s). Understanding the degree to which their PE characteristics impact their level of burnout is important to NM retention.

METHOD

A cross-sectional research design using a 71-item questionnaire was used to measure NM characteristics, hospital characteristics, NM PE, and burnout. There were 110 completed respondents across 22 hospitals in the United States.

RESULTS

Moderate inverse relationships exist between the NM PE and 2 of the 3 (work and personal) dimensions of burnout. NM age and tenure also showed an inverse relationship with burnout.

CONCLUSIONS

This study added evidence showing a statistically significant relationship between NM PE and the work and personal dimensions of burnout. These results also suggest the relationships NMs have with the patients on their unit(s) do not add to their level of burnout.
Patient-Reported Experiences Filling Expedited Partner Therapy Prescriptions for Chlamydia, Including Recommendations for Mitigating Encountered Obstacles, New York City, 2019 to 2020
Authors: Gary Danielle E. , Klingler Ellen J. , Slutsker Jennifer Sanderson
Published: October 2023

Background

Expedited partner therapy (EPT) is commonly provided by prescription. Multiple barriers to prescription-EPT have been described, although information on patient experiences with this practice is limited.

Methods

We conducted telephone interviews from July 2019 to January 2020, with women aged 15 to 24 years who were reported to the New York City Department of Health with chlamydia and for whom a health care provider report indicated provision of prescription-EPT (patients). A standard questionnaire was used to explore patients' experiences with filling an EPT prescription for their most recent sex partner and included questions about factors that would make it easier to obtain EPT medication.

Results

A total of 425 young women were reported with chlamydia and indicated to have received prescription-EPT. We completed interviews with 245 of these patients (57.6%), of whom 204 affirmed receiving prescription-EPT (83.3%). Nearly all patients (193 of 204 [94.6%]) took actions to fill the EPT prescription (visited the pharmacy themselves (139 of 193 [72.0%]) or directed their partner to fill the prescription (54 of 193 [28.0%]). Among these patients, most reported obtaining medication (173 of 193 [89.6%]). A small number of patients reported ways to enhance EPT practices, including 22, 19, and 12 who reported factors related to payment, health care providers, and the pharmacy, respectively, that would make it easier to obtain medication. Patients highlighted the importance of reducing cost and increasing convenience.

Conclusions

Most interviewed patients successfully filled EPT prescriptions. However, some patients encountered barriers during the process. Approaches to streamline EPT practices, such as provision of medication-EPT at the point of care, are critical.
Smartphone App PACOM to Provide Advice Regarding Self-Triage for the Acute Primary Care Needs of Children
Authors: Navion Anouk , Segretin Pierre , Bailhache Marion
Published: October 2023

Background

We developed a phone app, PACOM (Parents Application Conseils et Orientation Médicale), to provide medical advice to caregivers based on several algorithms and a series of binary questions related to children's symptoms. We compared the recommendations of the PACOM algorithms and clinicians for children visiting the emergency department (ED).

Methods

Between January and February 2022, we prospectively recruited French-speaking parents of children without any chronic disease who presented to the pediatric ED with any complaint except for mental health problems or trauma. Isolated head trauma was included. They completed questionnaires and the various PACOM algorithms. The first algorithm, called “Quick Look,” was developed to identify children with life-threatening emergencies. The standard reference was the advice of the ED clinicians who were blinded to the parental responses to the PACOM algorithm questions. The recommendations included “call urgent medical support,” “visit the ED,” “visit your general practitioner within 24 hours,” and “visit your general practitioner in the next days.”

Results

The study included 269 parents. The response rate was 75%. The median age of the children was 3 years with interquartile range: 1 to 7 years. In total, 268 children completed the “Quick Look,” 141 “fever,” 83 “abdominal pain,” 72 “cough,” 70 “vomiting,” 130 questionnaires relative to other proposed symptoms, and 70 “other symptom” questionnaires. The PACOM recommendations were “call urgent medical assistant” for 98 children, “ED visit” for 131, “visit general practitioner within 24 hours” for 13, and “visit general practitioner during the next days” for 24. The sensitivity and specificity of the PACOM recommendation to “call urgent medical support or visit the ED” were 98.1% (95% confidence interval, 95.5–100.00) and 22.1% (95% confidence interval, 15.3–28.8), respectively.

Conclusions

The PACOM algorithms has high sensitivity but low specificity for reducing ED visits and calls for urgent medical support.
Child and Caregiver Beliefs of Importance of Physical Function and Quality of Life in Juvenile Idiopathic Arthritis: A Survey Study
Authors: Woolnough Leandra U. , Lentini Logan , Bhavsar Prachi H. , Thomas Maren F. , Casella Zachery M. , Vincent Heather K.
Published: October 2023

Purpose:

To evaluate patient-caregiver beliefs of relative importance across 4 domains while living with juvenile idiopathic arthritis (JIA).

Methods:

This was a cross-sectional, anonymous survey study conducted in an academic medical center. Participants with JIA and caregivers (N = 151) completed a Likert-style survey to rate items by importance of knowledge about 4 domains: medications, physical activity, routine measures, and quality of life.

Results:

Knowledge of medication issues ranked higher than the remaining 3 domains (4.2 ± 0.7 points vs 4.0 ± 0.7, 4.1 ± 0.8, and 4.0 ± 0.9 points, respectively; P = .026; P = .026). Compared with caregivers, participants rated importance lower for all 4 domains.

Conclusions:

Gait and physical activity and well-being are not uniformly measured as part of routine clinical care and disease tracking in JIA. Both participants and caregivers ranked knowledge of physical activity similarly to routine office measures and quality of life. Inclusion of these measures in routine care could improve people centeredness and inform treatment plans.