bluuebunny/crossref_metadata_2025 huggingface dataset:
Late olfactory bulb involvement in COVID-19
Authors: Morra Francesco , Minerva Matteo , Valeggia Silvia , Librizzi Giovanni , Tramarin Elena , Scalpelli Caterina , Bordin Anna , Ottaviano Giancarlo , Gaudioso Piergiorgio , Bertoldo Alessandra , Moretto Manuela , Miola Alessandro , Lupia Eleonora , Ceccato Riccardo , Mucignat Carla , Antonini Angelo , Manara Renzo
Published: November 2024

Transient or persistent hypo-anosmia is common in SARS‑CoV‑2 infection but olfactory pathway late-term morphometric changes are still under investigation. We evaluated late olfactory bulb (OB) imaging changes and their correlates with the olfactory function in otherwise neurologically asymptomatic COVID-19 patients. Eighty-three subjects (mean-age 43 ± 14 yr; 54 females; time-interval infection/MRI: 129±68 d) were affected by asymptomatic to mild COVID-19 in 2020 and 25 healthy controls (mean-age 40 ± 13 yr; 9 females) underwent 3T-MRI and olfactory function evaluation through anamnestic questionnaire and Sniffin’ Sticks. Exclusion criteria were intensive care treatment or neurological involvement other than olfaction. Maximal OB area was measured blindly on high-resolution coronal T2w images by 2 observers. Patients were subdivided into (i) persistently hypo/anosmic, (ii) recovered normosmic, and (iii) never complaining smell dysfunction with proven normal olfactory function. No significant differences were observed among patients’ subgroups (P = 0.76). Intraobserver and interobserver reliability were high (r = 0.96 and 0.86). Former COronaVIrus Disease 19 (COVID-19) patients had decreased mean maximal OB area than controls (6.52 ± 1.11 mm2 vs. 7.26 ± 1.17 mm2, P = 0.008) even when considering persistently hypo-anosmic (6.46 ± 0.90, P = 0.006) or normosmic patients at MRI (6.57 ± 1.25, P = 0.04). SARS-CoV-2 infection is associated with mid/late-term morphological changes in the OB, regardless of presence or persistence of olfactory dysfunction. The long-term consequences on olfactory aging need to be further investigated including possible links with neurodegenerative disorders.
The microcirculation in cardiogenic shock
Authors: Schemmelmann Mara , Kelm Malte , Jung Christian
Published: November 2024

Cardiogenic shock is a life-threatening condition characterized by inadequate cardiac output, leading to end-organ hypoperfusion and associated mortality rates ranging between 40 and 50%. The critical role of microcirculatory impairments in the progression of organ failure during shock has been highlighted in several studies. Traditional therapies have often focused on stabilizing macrocirculation, neglecting microcirculatory dysfunction, which can result in persistent tissue hypoxia and poor outcomes. This review highlights the importance of assessing microcirculation in cardiogenic shock, including parameters such as skin perfusion, sublingual microcirculation, and lactate dynamics. Integrating microcirculatory assessments into clinical practice remains challenging due to the complexity of the methods and limited therapeutic options targeting microvascular perfusion. While advances in microcirculation-guided therapies hold promise for improving outcomes in cardiogenic shock, further research is needed to establish effective protocols.
Bridging the gap: linking Torulaspora delbrueckii genotypes to fermentation phenotypes and wine aroma
Authors: Silva-Sousa Flávia , Oliveira Bruna , Franco-Duarte Ricardo , Camarasa Carole , João Sousa Maria
Published: November 2024

Climate change and consumer preferences are driving innovation in winemaking, with a growing interest in non-Saccharomyces species. Among these, Torulaspora delbrueckii (Td) has gained recognition for its ability to reduce volatile acidity and enhance aromatic complexity in wine. However, knowledge regarding its phenotypic and genomic diversity impacting alcoholic fermentation remains limited. Aiming to elucidate the metabolic differences between Td and Saccharomyces cerevisiae (Sc) and the Td intraspecies diversity, we conducted a comprehensive metabolic characterization of 15 Td strains. This analysis delved beyond standard fermentation parameters (kinetics and major metabolites production) to explore non-conventional aromas and establish genotype-phenotype links. Our findings confirmed that most Td strains produce less acetic acid and more succinate and glycerol than Sc. The overall aromatic profiles of Td strains differed from Sc, exhibiting higher levels of monoterpenes and higher alcohols, while producing less acetate esters, fatty acids, their corresponding ethyl esters, and lactones. Moreover, we identified the absence of genes responsible for specific aroma profiles, such as decreased ethyl esters production, as well as the absence of cell wall genes, which might negatively affect Td performance when compared to Sc. This work highlights the significant diversity within Td and underscores potential links between its genotype and phenotype.
Actor sensemaking and its role in implementation of the decentralized drug-resistant tuberculosis policy in South Africa
Authors: Jassat Waasila , Moshabela Mosa , Schneider Helen
Published: November 2024

South Africa has a high burden of drug-resistant tuberculosis (DR-TB). A policy to decentralize DR-TB treatment from specialized central hospitals to more accessible district facilities was introduced in 2011, but to date implementation has been suboptimal, with variable pace, coverage, and models of care emerging. This study explored multilevel policy implementation of DR-TB decentralization in two provinces of South Africa, Western Cape and KwaZulu-Natal. Applying interpretive policy analysis, this paper describes how actors across health system levels and geographies made sense of the DR-TB policy and how this shaped implementation. In an embedded qualitative case study, districts of the two provinces were compared, through data collected in 94 in-depth interviews, and analysed using Vickers’ framework of reality, value, and action judgements. Five district cases characterize variation in the pace of implementation and models of DR-TB care that emerged. Individual and collective attitudes for and against the policy were underpinned by different systems of meaning for interpreting policy problems and making decisions. These meaning systems were reflected in actor stances on whether DR-TB care needed to be specialized or generalized, nurse- or doctor-led, and institutionalized or ambulatory. Actors’ stances influenced their actions and implementation strategies adopted. Resistance to decentralized DR-TB care related to perceived threats of budget cuts to and loss of authority of central facilities, and was often justified in fears of increased transmission, poor quality of care, and inadequate resources at lower levels. New advances in diagnosis and treatment to address the growing burden of DR-TB in South Africa will have little impact unless implementation dynamics are better understood, and attention paid to the mindsets, interests, and interpretations of policy by actors tasked with implementation. Deliberative policy implementation processes will enhance the quality of discourse, communication and cross-learning between policy actors, and critical for reaching synthesis of meaning systems.
Phased T2T genome assemblies facilitate the mining of disease-resistance genes in Vitis davidii
Authors: Luo Yuanyuan , Liu Zhenya , Jin Zhongxin , Li Peng , Tan Xibei , Cao Shuo , Wang Xu , Liu Zhongqi , Shi Xiaoya , Huang Siyang , Gu Liyuan , Fan Xiucai , Jiang Jianfu , Sun Lei , Zhou Yongfeng , Liu Chonghuai , Xu Xiaodong , Ma Zhiyao , Zhang Ying
Published: November 2024

Grape is an important fruit crop, and its production faces significant threat from diseases, resulting in substantial economic loss. Wild grape relatives are valuable resources for the restoration of disease-resistance loci. However, available resistance loci in wild grape genomes remain largely unexplored. In this study, we assembled two phased genomes, including a high-resistant Chinese wild grape, Vitis davidii Föex, and a susceptible cultivar, Vitis vinifera L. cv. ‘Manicure Finger’. We detected a total of 36 688 structural variations (SVs), with the genes associated with heterozygous SVs showing an enrichment in allele-specific expression (ASE). Furthermore, we identified eight subgroups of R genes and found that 74.2% of R genes overlap with transposable elements (TEs). Among R genes, NBS-type genes exhibit higher expression profiles in the wild grape genome compared with those in the grape cultivar. Additionally, five specific NBS-type R gene clusters were identified in the wild grape genome that are absent in the cultivar. Through genetic mapping, we identified four quantitative trait loci (QTLs) associated with grape white rot resistance based on the V. davidii genome, within which six NBS-type R genes exhibit differential expression between wild and cultivated grapes. Overall, our study revealed the landscape of resistance genes in grape genomes, providing valuable genetic resources for further breeding programs.
Elucidation of the key flavonol biosynthetic pathway in golden Camellia and its application in genetic modification of tomato fruit metabolism
Authors: Jiang Lina , Han Leiqin , Zhang Wenxuan , Gao Yifei , Xu Xiaoyan , Chen Jia , Feng Shan , Fan Zhengqi , Li Jiyuan , Li Xinlei , Yin Hengfu , Fan Pengxiang
Published: November 2024

Golden Camellia refers to a group of species in the genus Camellia that display yellow petals. The secondary metabolites in these petals hold ornamental significance and potential health benefits. However, the biosynthetic mechanisms governing the synthesis of these metabolites in golden petals remain elusive, and the exploitation of their bioactive components is not fully realized. This research involved the collection and analysis of 23 species of golden Camellia, leading to the discovery that flavonols, particularly quercetin 3-O-glucoside and quercetin 7-O-glucoside, are the primary contributors to the golden flower pigmentation. Integrative transcriptomics and coexpression network analyses pinpointed CnFLS1 as a crucial gene in the biosynthetic pathway, which, in conjunction with CnCHS, CnF3’H, and CnUFGT, orchestrates the specific pathway for flower color development. The enzyme assays revealed a high affinity and catalytic efficiency of CnFLS1 for DHQ, and transient expression of CnFLS1 in tobacco was shown to enhance the biosynthesis of quercetin flavonols, highlighting the pathway specificity in golden Camellia. Moreover, strategic transformations of cultivated tomatoes with various biosynthetic genes yielded transgenic lines exhibiting yellow fruit and quercetin-enriched flesh. These modified lines not only contained distinct flavonol components characteristic of golden Camellia but also demonstrated markedly improved antioxidant capabilities and enhanced resistance. The outcomes of this study not only elucidate the metabolic processes underlying the pigmentation of golden Camellia flowers but also provide a foundation for the development of novel tomato breeds through synthetic biology.
Virus-induced gene silencing simultaneously exploits ‘attract and kill’ traits in plants and insects to manage huanglongbing
Authors: Killiny Nabil , Nehela Yasser , Hajeri Subhas , Gowda Siddarame , Stelinski Lukasz L
Published: November 2024

The vector-borne disease huanglongbing (HLB) causes severe economic losses to citrus production worldwide with no available cure. Herein, we applied virus-induced gene silencing technology to engineer citrus that preferentially attracted and specifically killed Diaphorina citri, the vector associated with HLB. We engineered the infectious citrus tristeza virus (CTV-T36) clone to carry three truncated genes. The triple construct (CTV-tAwd-tWnt-tPDS) produces small interfering RNAs (siRNAs) against phytoene desaturase, PDS, to yield a phenotype with visual, olfactory, and gustatory cues that preferentially attracted D. citri. In addition, siRNAs targeted two genes related to flight in D. citri, abnormal wing disc (DcAwd) and wingless (DcWnt), that caused wing malformations and decreased survival in psyllids that fed on plants inoculated with the engineered virus. During two successive generations, D. citri reared on CTV-tAwd-tWnt-tPDS-inoculated plants exhibited higher mortality across life stages as well as reduced fecundity and fertility as compared with those reared on noninfected plants or CTV-wt-inoculated plants. Furthermore, CTV-tAwd-tWnt-tPDS-inoculated plants shortened the lifespan of D. citri by more than 20 days. Morphological abnormalities were noted in those adults that did successfully emerge on plants inoculated with CTV-tAwd-tWnt-tPDS, including cocked wings with a bowl-shaped depression and/or a convex shape. Phloem sap from CTV-tAwd-tWnt-tPDS-inoculated plants decreased the survival of D. citri adults, confirming that siRNAs were present in the sap of these plants. Collectively, we provide proof of concept for a novel variant of the attract-and-kill method where the cultivated crop is potentially transformed into a hyper-attractive population and transmission sink for a phytopathogen vector.
Serum concentration threshold and risk factors of tigecycline-induced hypofibrinogenaemia in critically ill patients
Authors: Li Mengxue , He Jie , Dong Gaoqiu , Hu Linlin , Shao Hua
Published: November 2024

Objectives

Hypofibrinogenaemia is a serious adverse reaction associated with tigecycline (TGC) therapy and may lead to the discontinuation of the treatment. This study aimed to explore the relevant factors of TGC-induced hypofibrinogenaemia and determine the thresholds of serum concentration as a predictive indicator of TGC-induced hypofibrinogenaemia.

Methods

A retrospective single-centre study was conducted on patients with severe infection who were treated with TGC. Clinical data and serum concentration parameters were extracted from the electronic medical records of these patients. Patients were divided into the hypofibrinogenaemia group (< 2.0 g/L) and the normal fibrinogen group (≥ 2.0 g/L) in order to evaluate risk factors associated with TGC-induced hypofibrinogenaemia. Logistic regression analysis and receiver operating characteristic curves were utilized to identify the risk factors associated with TGC-induced hypofibrinogenaemia and to establish plasma concentration thresholds as predictive indicators.

Results

A total of 114 patients were enrolled in this study, with 59.6% experiencing hypofibrinogenaemia. The multivariate regression analysis indicated that baseline fibrinogen level, trough concentration (Cmin), peak concentration (Cmax), the concentration at 6 h after the dosing (C6h) and the area under the concentration–time curve over a 24-h period (AUC0–24) were significantly associated with hypofibrinogenaemia (P < 0.05). Furthermore, it was found that AUC0–24 is the optimal predictor of TGC-induced hypofibrinogenaemia. The optimal cut-off for the AUC0–24 of TGC in ICU patients was determined to be 17.03 mg h/L.

Conclusions

TGC exposure is highly predictive of TGC-induced hypofibrinogenaemia. We recommend closely monitoring plasma concentrations of TGC in patients to ensure patient efficacy and safety.
Real-life use of temocillin in the treatment of bone and joint infections due to extended spectrum β-lactamase-producing Enterobacterales
Authors: Lahouati Marin , Brousse Xavier , Dias Meireles Vasco , Rignol Laurine , Bientz Léa , Xuereb Fabien , Dauchy Frédéric-Antoine
Published: November 2024

Objectives

The aim of this study is to describe the real-life use of temocillin in bone and joint infections (BJI).

Patients and methods

We performed a monocentric retrospective study, including all patients treated by temocillin for a BJI due to extended spectrum β-lactamase-producing Enterobacterales (ESBL-E) between 1 January 2015 and 31 December 2022. Outcomes were evaluated at least 3 months after the end of antimicrobial treatment. Clinical cure was defined as the absence of recurrence of BJI during follow-up among patients who completed at least 7 days of temocillin. If the patient discontinued temocillin due to ineffectiveness, the outcome was considered to be unfavourable. Seventeen patients were treated with temocillin for ESBL-E associated BJI during the study period.

Results

Infections included osteomyelitis of the foot (7/17; 41.2%), femoral osteomyelitis (4/17; 23.5%), disco-vertebral infections (2/17; 11.8%), total knee prosthesis infections (2/17; 11.8%) and total hip prosthesis infections (2/17; 11.8%). All patients except one (n = 16) had surgical management of the infection. The main bacteria identified were the Enterobacter cloacae complex (n = 9) and Klebsiella pneumoniae (n = 5). The median daily dose was 6 g for a median duration of 42 days (IQR 14–42 days). The median duration of follow-up was 12 months (IQR 5.25–14.5). Overall, 12 patients completed at least 3 months of follow-up, and clinical cure was observed in eight of them (8/12; 66.7%).

Conclusion

So far, this is the first report of BJI successfully treated with temocillin. This suggests that temocillin may be an alternative to treat BJI involving difficult-to-treat Enterobacterales when oral therapy is not available.
Variation in the intestinal bacterial community composition under different water temperature culture conditions in largemouth bass (Micropterus salmoides)
Authors: Wei Dongdong , Zhu Libo , Wang Yibing , Liu Mingzhu , Huang Lin , Yang Hui , Wang Hao , Shi Deqiang , Wang Gaoxue , Ling Fei , Yu Qing , Li Pengfei
Published: November 2024

Aims

This study aimed to investigate the impact of temperature on the intestinal microbiota of largemouth bass using 16S rRNA gene amplicon sequencing, focusing on the under-explored role of abiotic factors in shaping the gut microbial community.

Methods and results

Five water temperature groups (20.0 ± 0.2°C, 25.0 ± 0.2°C, 28.0 ± 0.2°C, 31.0 ± 0.2°C, and 35.0 ± 0.2°C) were established, each with three replicates. Significant variations in intestinal bacterial community composition were observed across these conditions. Elevated temperatures (31.0 ± 0.2°C and 35.0 ± 0.2°C) led to an increase in opportunistic pathogens such as OTU180 Vibrio and OTU2015 Vogesella (P < 0.05). Species correlation network analysis showed a shift toward more positive relationships among intestinal microbes at higher temperatures (P < 0.05). Ecological process analysis highlighted a greater role of ecological drift in microbial community structure at 31.0 ± 0.2°C and 35.0 ± 0.2°C (P < 0.05).

Conclusions

The study suggests that higher temperatures may predispose largemouth bass to opportunistic pathogens by altering their intestinal microbiota. Effective water temperature management is crucial for largemouth bass aquaculture to mitigate pathogen risks and maintain a balanced intestinal microbiota. This research provides critical insights into the temperature–microbiota relationship and offers practical recommendations for aquaculture practices.
TV Mon – post-mass transfer Algol-type binary with δ Scuti pulsations in primary component
Authors: Kovalev Mikhail , Li Zhenwei , Xiong Jianping , Matekov Azizbek , Bo Zhang , Chen Xuefei , Han Zhanwen
Published: November 2024

We present a study of the detached eclipsing binary TV Mon using spectra from the LAMOST (Large Sky Area Multi-Object Fiber Spectroscopic Telescope) medium-resolution survey, ASAS-SN (All Sky Automated Survey for SuperNovae), and CoRoT (Convection, Rotation and planetary Transits) photometry. We apply multiple-epochs spectral fitting to derive radial velocities and spectral parameters. The analysis of eclipses in CoRoT data shows the relative sizes of the stellar components and almost edge-on circular orbit. Combining the spectral and photometrical solutions we estimate masses and radii of the components: $M_{\rm A,B}=2.063\pm 0.033({\rm stat.})\pm 0.095({\rm syst.}), \ 0.218\pm 0.004({\rm stat.})\pm 0.018({\rm syst.}) \, \mathrm{ M}_\odot$, $R_{\rm A,B}=2.394\pm 0.014, \ 2.860\pm 0.016 \, \mathrm{ R}_\odot$. Spectral energy distribution analysis and Gaia parallax allow us to get an estimation of temperatures ${T_{\rm eff}}_{\rm A,B}=7624^{+194}_{-174}, \ 5184^{+130}_{-123} \, \mathrm{ K}$ and distance $d=907\pm 11 \, \mathrm{ pc}$. We identify three $\delta$ Scuti-type pulsation frequencies in the primary component, while we also suspect TV Mon having a spot activity in the secondary component. This system experienced intensive mass transfer and mass ratio reversal in the past, but currently shows no signs of mass transfer in the spectra. The low-mass component will lose its outer envelope and shrink to the helium white dwarf, the mass and orbital period of which are in good agreement with evolutionary model predictions.
Neural bases of social facilitation and inhibition: how peer presence affects elementary eye movements
Authors: Tricoche Leslie , d’Halluin Marion Royer , Meunier Martine , Pélisson Denis
Published: November 2024

Social Facilitation/Inhibition (SFI) refers to how others’ presence influences task performance positively or negatively. Our previous study revealed that peer presence modulated saccadic eye movements, a fundamental sensorimotor activity. Pro- and anti-saccades were either facilitated or inhibited depending on trial block complexity (Tricoche et al., 2020). In the present fMRI study, we adapted our paradigm to investigate the neural basis of SFI on saccades. Considering inter- and intra-individual variabilities, we evaluated the shared and distinct neural patterns between social facilitation and inhibition. We predicted an involvement of the saccade-related and attention networks, alongside the Theory-of-Mind (ToM) network, with opposite activity changes between facilitation and inhibition. Results confirmed peer presence modulation in fronto-parietal areas related to saccades and attention, in opposite directions for facilitation and inhibition. Additionally, the ventral attention network was modulated during inhibition. Default mode regions, including ToM areas, were also modulated. Finally, pupil size, often linked to arousal, increased with peers and correlated with dorsal attention regions and anterior insula activities. These results suggest that SFI engages task-specific and domain-general networks, modulated differently based on observed social effect. Attention network seemed to play a central role at both basic (linked to arousal or vigilance) and cognitive control levels.
The Optimal Dosage and Duration of Metformin for Prevention and Treatment of Antipsychotic-Induced Weight Gain: An Updated Systematic Review and Meta-Analysis
Authors: Peng Tzu-Rong , Chen Jou-An , Lee Jen-Ai , Hsing Chih-Pin , Lee Ming-Chia , Chen Shih-Ming
Published: November 2024

Background

Weight gain and metabolic complications are substantial adverse effects associated with second-generation antipsychotics. However, comprehensive guidelines for managing antipsychotic-induced weight gain are lacking.

Methods

This review included all double-blind, placebo-controlled studies investigating metformin’s effectiveness in addressing antipsychotic-related weight gain. We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Google Scholar, and ClinicalTrials.gov for relevant studies from the inception to 2024. A random-effects model was used for the meta-analysis.

Results

This meta-analysis, including 20 studies with 1070 patients, revealed that metformin significantly surpassed placebo in attenuating weight gain in patients receiving antipsychotics. The mean weight change with metformin was −3.32 kg [95% confidence interval (CI): −4.57 to −2.07]. Additionally, metformin use resulted in a marked decrease in body mass index [−1.24 kg/m2 (95% CI: −1.70 to −0.77)]. Metformin could maintain the effects from 12 to 24 weeks.

Conclusions

This updated meta-analysis investigated the durations and dosages of metformin use in patients with schizophrenia experiencing antipsychotic-induced weight gain. The findings highlight the need for additional large-scale research to validate our findings.
The Army of Pasteurians: Militarisation of Hygiene and Hybrid Disease Control Measures in Fernand Visbecq’s 1919 Typhus Mission in French Algeria
Authors: Pouget Benoît
Published: November 2024

During mass demobilisation following the armistice of 11 November 1918, colonial troops gradually returned to their cantonments. Algeria hosted a military penal colony under French army rules to which convicts continued to converge. As a result, soldiers and convicts became the disseminators of the typhus epidemic that swept through the armies still stationed on the Western Front, before spreading to North Africa. Based on a study of the Visbecq mission against typhus in the spring and summer of 1919 in Algeria, this article examines how Visbecq’s assignment was part of a wider process of militarisation of hygiene in France as in the Empire. It promoted hybrid measures combining the implementation of new technical processes with conventional isolation measures. In fine, Visbecq’s actions were part of a set of current technopolitics which contributed to pasteurisation of the French colonial empire.
Biocompatible Naringin loaded low molecular peptide Nanogels are effective against human melanoma cells
Authors: Secerli Jülide , Karayavuz Burcu , Aksoy Rahime , Erdoğan Hakan , Bacanlı Merve Güdül
Published: November 2024

Melanoma, a type of cancer, has the ability to metastasize and can be fatal. The lack of success in the treatment of melanoma with chemotherapeutic agents and the side effects have led to the search for new agents. Moreover, developing systems that will provide reduce side effects by using biocompatible carriers, may be beneficial. Naringin (NAR), from Citrus plants, has anticancer and anti-inflammatory properties. NAR is useful in formulations where it is used with a carrier due to its low water solubility and bioavailability with few toxicity. This study aimed to evaluate the effects of NAR-loaded peptide based Fmoc-FF nanogels on human melanoma (SK-MEL-30) cells. Characterization of NAR-loaded Fmoc-FF nanogels was carried out. The biocompatibility properties of Fmoc-FF and NAR-loaded nanogels were evaluated in mouse fibroblast (L929) cells, and their cytotoxic effects were evaluated in human melanoma (SK-MEL-30) cells by the MTT method. While the DCF-DA method was used to measure the effects on reactive oxygen species (ROS) release, the changes in oxidative stress biomarkers were examined by spectrophotometric analysis, tyrosinase enzyme activity and inflammation biomarkers were investigated by ELISA method. Comet method was used to evaluate antigenotoxic effects. It has been observed that loading NAR into Fmoc peptide gels may be effective in causing cytotoxic, genotoxic, anti-inflammatory and anti-tyrosinase effects and an increase in ROS release in melanoma cells. These results indicate that NAR-loaded Fmoc-FF gels, which have the feature of easy application to the skin, may be effective in the treatment of melanoma without causing toxic effects.
A qualitative study about the public's perception of primary care providers
Authors: Gillette Chris , Ostermann Jan , Garvick Sarah , Everett Christine M. , Valente Jessica , Aguilar Aylin Aguilar , Lacci-Reilly Kandice
Published: November 2024

Objective:

With the growth of physician associates/assistants (PAs) and NPs providing primary care services, we sought to understand the public's perception of the different types of healthcare providers (HCPs) they might encounter in a clinical setting, such as primary care.

Objectives:

This study aimed to evaluate public perceptions about various types of primary care providers (PCPs), identify public preferences for PCPs in relation to experience and training, and examine public preferences for PCP credentials.

Methods:

We conducted semistructured interviews with adults, and used inductive and deductive coding and reflexive thematic analysis to analyze the data.

Results:

We reached thematic saturation after 12 completed interviews. Participants reported confusion about the types of HCPs they might encounter in a primary care setting (for example, physician, PA, NP). Participants who reported a preference for a physician valued more years in training and their role in the hierarchy of medicine; those who reported a preference for a PA or NP indicated that compassion, patience, and longer clinic visit times were most important to them.

Conclusions:

Previous reports suggested that the public might be confused by the different types of HCPs they might encounter during a primary care visit. Participants identified specific characteristics that are important when they are choosing their PCP. A direct, coordinated marketing campaign may be needed to educate the public and reduce confusion about different types of PCPs, how they contribute to safe and high-quality care, and ensure preference-concordant care.
Associations Between Vestibular Perception and Cognitive Performance in Healthy Adults
Authors: Kobel Megan J. , Wagner Andrew R. , Merfeld Daniel M.
Published: November 2024

Objectives:

A growing body of evidence has linked vestibular function to the higher-order cognitive ability in aging individuals. Past evidence has suggested unique links between vestibular function and cognition on the basis of end-organ involvement (i.e., otoliths versus canals). However, past studies have only assessed vestibular reflexes despite the diversity of vestibular pathways. Thus, this exploratory study aimed to assess associations between vestibular perception and cognition in aging adults to determine potential relationships.

Design:

Fifty adults (21 to 84 years; mean = 52.9, SD = 19.8) were included in this cross-sectional study. All participants completed a vestibular perceptual threshold test battery designed to target perception predominantly mediated by each end-organ pair and intra-vestibular integration: 1 Hz y-translation (utricle), 1 Hz z-translation (saccule), 2 Hz yaw rotation (horizontal canals), 2 Hz right anterior, left posterior (RALP), and left anterior, right posterior (LARP) tilts (vertical canals), and 0.5 Hz roll tilt (canal-otolith integration). Participants also completed standard assessments of cognition and path integration: Digit Symbol Substitution Test (DSST), Trail Making Test (TMT), and the Gait Disorientation Test (GDT). Associations were assessed using Spearman rank correlation, and multivariable regression analyses.

Results:

For correlation analyses, DSST correlated to RALP/LARP tilt, roll tilt, and z-translation. TMT-A only correlated to z-translation, and TMT-B correlated to roll tilt and z-translation after correcting for multiple comparisons. GDT correlated to RALP/LARP tilt and y-translation. In age-adjusted regression analyses, DSST and TMT-B were associated with z-translation thresholds and GDT was associated with y-translation thresholds.

Conclusions:

In this cross-sectional study, we identified associations between vestibular perceptual thresholds with otolith contributions and standard measures of cognition. These results are in line with past results suggesting unique associations between otolith function and cognitive performance.
Machine Learning–enhanced Signature of Metastasis-related T Cell Marker Genes for Predicting Overall Survival in Malignant Melanoma
Authors: Fan Chaoxin , Li Yimeng , Jiang Aimin , Zhao Rui
Published: November 2024

In this study, we aimed to investigate disparities in the tumor immune microenvironment (TME) between primary and metastatic malignant melanoma (MM) using single-cell RNA sequencing (scRNA-seq) and to identify metastasis-related T cell marker genes (MRTMGs) for predicting patient survival using machine learning techniques. We identified 6 distinct T cell clusters in 10×scRNA-seq data utilizing the Uniform Manifold Approximation and Projection (UMAP) algorithm. Four machine learning algorithms highlighted SRGN, PMEL, GPR143, EIF4A2, and DSP as pivotal MRTMGs, forming the foundation of the MRTMGs signature. A high MRTMGs signature was found to be correlated with poorer overall survival (OS) and suppression of antitumor immunity in MM patients. We developed a nomogram that combines the MRTMGs signature with the T stage and N stage, which accurately predicts 1-year, 3-year, and 5-year OS probabilities. Furthermore, in an immunotherapy cohort, a high MRTMG signature was associated with an unfavorable response to anti-programmed death 1 (PD-1) therapy. In conclusion, primary and metastatic MM display distinct TME landscapes with different T cell subsets playing crucial roles in metastasis. The MRTMGs signature, established through machine learning, holds potential as a valuable biomarker for predicting the survival of MM patients and their response to anti-PD-1 therapy.
Precision Dosing of Intravenous Tocilizumab: Development of Pharmacokinetic Model–Derived Tapering Strategies for Patients With Rheumatoid Arthritis
Authors: Hooijberg Femke , van den Berg Stefan P. H. , Layegh Zohra , Leeuw Maureen , Elkayam Ori , de Vries Annick , Nurmohamed Mike , Rispens Theo , Dorlo Thomas P. C. , Wolbink Gertjan
Published: November 2024

Background:

Tocilizumab targets the interleukin-6 receptor, and dosing is complex owing to its nonlinear clearance related to target binding. Therefore, tapering tocilizumab requires a different approach than that of tumor necrosis factor inhibitors (TNFi). This study aimed to identify these differences and enable personalized treatment of rheumatoid arthritis (RA) beyond TNFi therapy.

Methods:

A population pharmacokinetic model of intravenous tocilizumab was developed using data from a randomized controlled trial of dose tapering in patients with RA. Subsequent population-level Monte Carlo and individual Bayesian simulations were performed to create tapering strategies involving dose reduction and interval extension. The target trough concentration of tocilizumab was 5 mg/L. Finally, the drug savings were compared between the 2 methods.

Results:

The pharmacokinetic of tocilizumab was described with a 2-compartment model with parallel linear (CL 0.20 L/d) and nonlinear (VM 5.2 mg/d, KM 0.19 mg/L) elimination. The linear clearance rate and central volume of distribution increased with lean body mass, and men exhibited higher clearance rates than women. The simulated concentration–time profiles demonstrated that, owing to nonlinear clearance, drug concentrations decreased more than dose-proportionally with lower doses. Tapering based on an individual Bayesian approach emerged as the most promising strategy, yielding a 39% reduction in drug use across virtual populations.

Conclusions:

Tapering strategies were developed for intravenous tocilizumab, offering potential application in patients with RA who have reached low disease activity or remission, pending clinical validation. The developed strategies demonstrate that the tapering of tocilizumab should be approached more carefully and in smaller steps than that of TNFi.
Chronic low back pain caused by metastatic adenocarcinoma of unknown origin in a young man: a case report
Authors: Hodaifa Yara , Hodaifa Amr , Kudsi Maysoun
Published: November 2024

Introduction and importance:

Low back pain (LBP) is one of the most common complaints and sacroiliac joint dysfunction is the third cause of this chronic burden. Sacroiliitis might be a primary sign of axial spondylarthritis, although it might be found in other diseases, and malignancies, either primary tumors or metastases, meanwhile, this is a rare case that is described as sacroiliitis with adenocarcinoma of unknown origin.

Case presentation:

A 24-year-old male presented at the hospital with fever and urinary retention. He had a history of progressively worsening chronic LBP, with increased curvature in the dorsal vertebrae. Physical examination revealed fever (39°C), a dorsal kyphosis with an absence of lumbar lordosis. Strength was low in the proximal and distal muscles of the lower limbs, with hyperreflexia in the left lower limb and paresthesia limbs in the whole lower and lower region of the abdomen. Laboratory studies revealed normocytic anemia, high ESR and CRP levels, and hypercalcemia with low PTH. The radiology study showed sacroiliitis, many lytic bone lesions, and a collapse in the 4th lumbar vertebral, and increased lung density. Biopsy from a lytic lesion showed metastatic poorly differentiated adenocarcinoma of unknown origin with features suggestive of pancreatic primary. Palliative radiotherapy was started; unfortunately, he died after 4 months.

Clinical discussion:

Cancer is an additional risk factor for the development of sacroiliac joint pain and disorder. A lot of tumors and metastases can be associated with sacroiliitis. Many patients present with bone lytic metastases of unknown origin as a first manifest. The association between metastatic adenocarcinoma and sacroiliitis was reported three cases in the literature; meanwhile, this was a rare case that described sacroiliitis with adenocarcinoma of unknown origin.

Conclusion:

Low back pain is one of the most common complaints, but it may be an initial symptom of serious conditions. Awareness of clinical clues can prevent faulty or delayed diagnoses. Although sacroiliitis is usually associated with axial spondylarthritis in adult patients, it can be the first manifestation of adenocarcinoma.
Pediatric acquired demyelinating syndromes: updates in diagnosis, testing, and management
Authors: Mirchi Amytice , Hopkins Sarah
Published: November 2024

Purpose of review

To highlight the clinical presentation, diagnostic approach, and management of acquired inflammatory demyelinating syndromes in children.

Recent findings

The identification of myelin oligodendrocyte glycoprotein antibody-associated disease in 2017 and evolving evidence regarding best practices for management has had a significant impact on pediatric neuroimmunology, as has the shift in treatment of pediatric-onset multiple sclerosis, with the use of high-efficacy disease-modifying therapies early in the disease course.

With expanding awareness and growing interest in pediatric onset neuroinflammatory conditions, the number of children diagnosed with acquired demyelinating syndromes is rising. It is critical to refine our understanding of the underlying pathophysiological mechanisms in these disorders to provide the most effective care. Much of our practice continues to be modeled on adult care, and further large-scale pediatric studies are necessary to explore the natural history and assess the safety and efficacy of immunotherapies in childhood-onset demyelinating diseases.
A Pilot Study on BRCA1/2 and PI3K Mutations Across Subtypes of Triple Negative Breast Cancer in North Indian Population
Authors: Gupta Parul , Thakur Tamanna , Chadda Anjali , Irinike Santosh , Khare Siddhant , Bal Amanjit
Published: November 2024

BRCA1/2 are tumor suppressor genes which regulate the DNA repair mechanism. Mutations in BRCA1/2 may increase the risk of breast cancer in patients. In the present study frequency of BRCA1/2 mutations in triple negative breast cancer (TNBC) patients was assessed and correlated with molecular subtypes of TNBC. Blood samples from 65 confirmed cases of TNBC were collected. DNA was isolated from whole blood and libraries were prepared using a BRCA1/2 custom panel. Sequencing was done on Ion torrent S5 sequencer and ion reporter was used for data analysis. Further molecular subtyping of mutation positive TNBC cases was done using immunohistochemistry markers CK5/6; CK4/14; Vimentin and E-Cadherin and androgen receptor (AR) using tissue microarray. Twenty five of 65 patients had heterozygous pathogenic mutations, alterations with conflicting interpretation of pathogenicity, variants of uncertain significance and variants of unknown significance. Nine patients had pathogenic mutation in BRCA 1 gene only and 2 patients had pathogenic mutations in BRCA2 gene. Two patients were transheterozygous for BRCA mutations, that is, had pathogenic mutations in both BRCA1/2 genes simultaneously and 5 were compound heterozygous (involving BRCA2 gene in all the cases). Prevalent subtypes among BRCA positive cases were unclassified subtype (n=4, 33%), Basal like (n=5, 41%), and mesenchymal subtype (n=3, 25%). None of the LAR subtype showed BRCA1/2 mutations. The present study observed that the BRCA1 mutation is more frequent than BRCA2 mutation in TNBC. BRCA1/2 mutations do not correspond to BRCAness or basal phenotype. Considering high incidence of breast cancer and lack of correlation of basal morphology with BRCA1/2 mutation, the molecular methods should be used for screening for BRCA1/2 mutations. This will not only help in familial screening but also in deciding targeted therapy with PARP (poly-ADP ribose polymerase) inhibitors.
The Occipital Recess of the Sphenoidal Sinus—A Novel Anatomical Possibility
Authors: Rusu Mugurel Constantin , Toader Corneliu , Tudose Răzvan Costin , Grigoriţă Laura Octavia
Published: November 2024

There are reported here multiple rare anatomical variants of the sphenoidal sinus found in a 53-year-old male. The sinus exhibited uncommon features, including a prominent occipital recess extending bilaterally into the basilar part of the occipital bone. A narrow posterior isthmus connected the main chamber to 2 recesses: a superior postsellar recess pneumatising the dorsum sellae, and a postero-inferior occipital recess. The latter extended into the right basilar occipital bone, closely associated with the right hypoglossal canal and coursing alongside the right internal carotid artery. In addition, the sphenoidal sinus had a maxillary recess projecting above the pterygopalatine fossa and joining the right maxillary sinus and bilateral pterygoid recesses. Notably, the left vidian canal was situated superior to the pterygoid recess with no pneumatic space between it and the foramen rotundum, unlike the right side. These anatomical variants are clinically significant due to their proximity to vital neurovascular structures, increasing surgical risks. Partial ossification of the falx cerebri was also identified, potentially complicating neurosurgical procedures.
Eliminating Error in Central Line Scheduling and Placement Using Quality Improvement Methods
Authors: Roach Jonathan P , Linton Anna , Tchou Michael J , Riess Laurel , Adamson Leanne , Garrington Timothy P , Younoszai Adel , Anstett Tyler J
Published: November 2024

Background:

The Joint Commission defines a sentinel event as “surgery or other invasive procedure performed at the wrong site, on the wrong patient, or that is the wrong (unintended) procedure for a patient regardless of the type of procedure or the magnitude of the outcome.” At our institution, we observed a low but consistent rate of incorrect surgical line placement for pediatric patients with cancer.

Study Design:

Following quality improvement methodology and using the resources available on a large academic medical campus we designed and implemented a new multi-factorial process to schedule and place surgical central lines for pediatric patients with cancer. Changes included re-defining responsibilities, adding staff, and redesigning the process with workflows supported by modifications to the electronic medical record. Our primary outcome measures were incorrect central line placement or near miss event per quarter and days between these events.

Results:

After implementation the rate of incorrect line placement and near miss events was reduced to zero with 1018 days since the last incorrect line placement.

Conclusions:

As a result of our multi-factorial quality improvement initiative in the scheduling and placement of central lines, we were able to eliminate surgical line placement sentinel events and improve care for pediatric patients with cancer.
Antifungal resistance, clinical outcome and clinico-microbiological correlation in ocular infections due to common melanized fungi Curvularia lunata and Lasiodiplodia theobromae in South India
Authors: Mitra Sanchita , Garg Prashant , Murthy Somasheila , Jakati Saumya , Dave Vivek Pravin , Seba Esther
Published: November 2024

Aim. Melanized fungi were rarely studied for their antifungal resistance (AFR) or clinical outcome, despite rising incidence of melanized fungal ocular infections and AFR in general. We report the antifungal resistance patterns, clinical outcome and clinico-microbiological correlation in two commonly isolated melanized fungi from ocular infections, Curvularia lunata and Lasiodiplodia theobromae, at a tertiary eyecare centre in South India.

Gap statement. Despite melanized fungi accounting for a significant proportion of ocular fungal infections in the Indian subcontinent, and despite there being a limited selection of effective antifungal agents available for these infections, the existing data and studies on these issues remain sparse. Therefore, this study aimed to investigate the prevalence of antifungal resistance in two of the most common melanized fungal pathogens in ocular infections, Curvularia lunata and Lasiodiplodia theobromae and correlate it with the treatment given and the clinical outcome in patients.

Methodology. Electronic medical records provided the clinical data. Standard broth microdilution was performed for antifungal susceptibility testing (AFST) in 30 isolates (17 C. lunata and 13 L. theobromae) for amphotericin B and natamycin (polyenes): voriconazole, ketoconazole, posaconazole, itraconazole and fluconazole (azoles) and caspofungin (echinocandin). Multidrug resistance (MDR) was defined as resistance to more than or equal to two classes of antifungals. DNA sequencing was performed for the isolates for species confirmation. The multivariate analysis was done for determining poor prognostic factors.

Results. AFST showed highest susceptibility of study isolates for voriconazole (83.3% isolates), followed by natamycin (80%), fluconazole (80%), itraconazole (76.7%), ketoconazole (70%), posaconazole (66.7%), caspofungin (66.7%) and lastly amphotericin B (63.3%). All patients empirically received topical natamycin; additional oral ketoconazole/intraocular voriconazole was administered in select few. MDR was strongly associated with poor clinical outcome (multivariate analysis: P = 0.03, odds ratio = 7.8). All patients had microbial keratitis, one progressed to endophthalmitis. Additionally, therapeutic penetrating keratoplasty was required in 40% of cases. Globe salvage was possible in 80% patients, though good visual outcome was seen in only half of them. Both, anatomical and visual outcomes, were poor in 20% of patients. DNA sequencing showed C. lunata as the highest study species.

Conclusion.
C. lunata and L. theobromae showed varying in vitro antifungal susceptibility and clinical outcome in ocular infections. Voriconazole had significantly higher activity, while amphotericin B had lower activity in vitro for these melanized fungi. MDR isolates showed poorer clinical outcome.
Dynamics of N-genes and T-genes in cancer
Authors: Gil Gabriel , Gonzalez Augusto
Published: November 2024

The normal-tissue and tumor attractors are far apart in gene-expression space[1,2]. As a consequence, there are genes with specific gene-expression intervals characteristic only of normal tissues or tumors[3]. We call them N-genes and T-genes, respectively. They are not only perfect markers, but are also responsible of anchoring the state in the vicinity of the corresponding attractor. According to the higher degree of disorder of tumors[4,5], there are 10-times more T-genes than N-genes[3]. Carcinogenesis, which is the progressive motion from the N-attractor to the T-attractor, can also be viewed as a process of deactivating the N-genes marking and holding the normal tissue and setting new T-markers and anchors for the tumor. In prostate, for example, the process starts with around 500 activated N-genes in any healthy normal tissue that may be dramatically reduced to a few N-genes before the transition to the tumor occurs. The available gene expression data[6,7]shows that even 2 or 3 active N-genes are enough for holding the normal state condition (at least from a pathological perspective). The process is expected to evolve in the form of consecutive deregulation cascades[8], in which a few initial cascades inactivate most of the active N-genes, and a final cascade inactivates the remaining N-markers and sets the new T-markers for the tumor. The whole process shares similarities with the multistep model of cancer[9].