bluuebunny/crossref_metadata_2025 huggingface dataset:
Whipple’s Disease – delay of diagnosis by immunosuppressive therapy; a case-series report
Authors: Obst Wilfried , Hoffmann Armin , Weigt Jochen , Canbay Ali , Malfertheiner Peter , Arnim Ulrike von
Published: March 2023

Background Risk factors for the development of Whipple's disease
(WD) are largely unknown. Case reports, case series, and reviews suggest immunosuppressive
therapy as a potential triggering factor in WD. The low incidence of WD and non-specific
symptoms at disease onset contribute to the frequent delay of diagnosis. We describe our
centre´s experience on differences in the clinical presentation of patients with classic WD
compared to patients with “masked” WD because of immunosuppressive therapy.

Methods In this retrospective case series, 8 patients were
included. Diagnosis of WD was confirmed by histological staining of duodenal biopsies
revealing T. whipplei within foamy macrophages or by PCR- based
detection of specific T. whipplei DNA. Clinical manifestations,
laboratory data, and medication have been recorded over a period of 19 years. Subgroup
analyses for the two different variants of WD were performed.

Results Seven of eight patients were initially diagnosed with
rheumatic disease (polyarthritis, polymyalgia rheumatica). One patient was correctly diagnosed
at the beginning without any medication. Three patients were on immunosuppressive therapy and
being treated with disease-modifying drugs (DMARDs), three patients were receiving low-dose
cortisone in combination with non-steroidal anti- inflammatory drugs (NSAIDs), and one patient
was receiving NSAIDs only. All patients presented with increased parameters of inflammation
and with clinical and/or laboratory signs of a malabsorption. From the onset of first
symptoms, diagnosis of WD took a median of 36 months (range: 6–120 months). The time between
onset of joint complaints and onset of gastrointestinal symptoms was 36 months (range: 0–117
months). WD patients receiving immunosuppressive therapy, compared to those not receiving it,
had a longer duration of gastrointestinal symptoms (12 months versus 6 months) and reported a
greater weight loss (20,3 kg versus 7,8 kg) up to diagnosis of WD.

Conclusions Immunosuppressive drugs may delay the diagnosis of WD
and prolong the course of T. whipplei infection with deterioration
of clinical symptoms. If a patient with rheumatic complaints develops gastrointestinal
symptoms, diagnosis of WD should be considered and proper diagnostic investigation carried
out.
Long-COVID und Post-COVID-Syndrom
Authors: Schütz Burkhard , Crecelius Meike
Published: March 2023

Unter dem Post-COVID-Syndrom (PCS) versteht man eine länger als 12 Wochen
anhaltende Symptomatik mit Fatigue, Kurzatmigkeit, eingeschränkter
Leistungsfähigkeit u. a., die bei rund 15% der Patienten
nach einer akuten Infektion mit SARS-CoV-2 auftritt. Als Ursache werden
Veränderungen im Mikrobiom und Störungen des
Tryptophanstoffwechsels diskutiert, welche zu einer vermehrten Umwandlung von
Tryptophan in prooxidativ und proinflammatorisch wirkende Abbauprodukte
führen. Nach aktuellen Studien können infolge der Infektion
latente Viren wie Epstein-Barr-, Cytomegalie- und Varizella-Zoster-Virus
reaktiviert werden und PCS-typische Symptome auslösen. Eine
überschießende Entzündungsreaktion bei COVID-19
führt zur Bildung von Autoantikörpern, die durch
Einschränkung der Immunantwort die Virusbekämpfung erschweren.
Therapeutisch kann eine Supplementierung von Mikronährstoffen wie
Vitamin C, D, E, B6, B12, ω-3-Fettsäuren
und Coenzym Q10 sinnvoll sein.
Autoimmunerkrankungen und Vitamin D
Authors: Gröber Uwe , Holick Michael F.
Published: March 2023

Die biologisch aktive Form von Vitamin D, das Secosteroidhormon
1,25(OH)2D, moduliert zahlreiche Gene des angeborenen und
adaptiven Immunsystems über Regulation seines Transkriptionsfaktors
Vitamin-D-Rezeptor (VDR). Der Beitrag stellt den Einfluss des Prohormons auf das
Epigenom vor und den aktuellen Stellenwert in der Therapie von
Autoimmunerkrankungen, z. B. Multiple Sklerose, sowie bei einer
Vitamin-D-Resistenz.
Coimbra-Protokoll
Authors: Didier Rainer
Published: March 2023

Das Coimbra-Protokoll ist eine Vitamin-D3-Therapie. Sie wurde von Prof. Coimbra,
Dozent an der Universität in Sao Paulo entwickelt und seit Jahren
erfolgreich, u. a. bei der Behandlung Multipler Sklerose (MS)
eingesetzt. Auch die langjährigen Erfahrungen in der eigenen Praxis zur
Therapie u. a. verschiedener Autoimmunerkrankungen sind positiv. Zwei
Patienten mit MS schildern ihre Erfahrungen.
Lenition alternation in West Gyalrongic and its implications for Southeast Asian panchronic phonology
Authors: Lai Yunfan
Published: March 2023

Based on internal reconstruction, this paper resolves a long-standing problem observed in Khroskyabs, a West Gyalrongic language (Sino-Tibetan), that seems to sporadically have lenited voiceless stops, resulting in irregular correspondences with East Gyalrongic. Two major sound changes are involved: intervocalic lenition and post-stress intersyllabic compression. It turns out that the processes proposed here are one probable solution to monosyllabicization in languages of Southeast Asia, explaining a pathway from polysyllables or sesquisyllables toward monosyllables. Through examining potential problems of previous reconstructions in various languages, this paper shows that the Khroskyabs case provides a plausible direction in the solution of relevant unresolved problems from a panchronic perspective.
What’s in a mime?
Authors: Sibierska Marta , Boruta-Żywiczyńska Monika , Żywiczyński Przemysław , Wacewicz Sławomir
Published: March 2023

Several lines of research within developmental psychology, experimental semiotics and language origins studies have recently converged in their interest in pantomime as a system of bodily communication distinct from both language (spoken or signed) and nonlinguistic gesticulation. These approaches underscore the effectiveness of pantomime, which despite lack of semiotic conventions is capable of communicating complex meanings. However, very little research is available on the structural underpinnings of this effectiveness, that is, the specific properties of pantomime that determine its communicative success. To help fill in this gap, we conducted an exploratory rating study aimed at identifying those properties of pantomime that facilitate its understanding. We analysed an existing corpus of 602 recordings of whole-body re-enactments of short transitive events, coding each of them for 6 properties, and found out that the presence of salient elements (conspicuous objects in a specific semantic space), image mapping (representing the physical orientation of the object), and gender markers (distinguishing between the represented characters) increased the guessability of pantomimes.
Yogesh Kulathu: Decoding complex intracellular messages
Authors: Morgado-Palacin Lucia
Published: March 2023

Yogesh Kulathu studies signaling mechanisms with a focus on ubiquitin and other post-translational modifications such as UFMylation.
Investigation on the micro-structure and magnetic properties of LMZBS-Bi2O3 doped low-temperature sintered NiCuZn ferrites
Authors: Wang Yang , Yang Changlong , Kong Qingjiang , Wu Xinglin , Zhang Zhongrui
Published: March 2023

NiCuZn ferrites were widely used in communication and electronic information fields because of the high frequency, high impedance, wide band and low power loss. In this work, it reports that the (Ni0.2Cu0.2Zn0.6O)1.03(Fe2O3)0.97 ferrites were synthesized based on the solid-state reaction method and LMZBS (Li2CO3-MgO-ZnO-B2O3-SiO2)-Bi2O3 were also used as the dopant to regulate the micro-structure and magnetic properties. The crystal phase and micro-structure of the LMZBS-Bi2O3 doped NiCuZn ferrites were characterized by x-ray diffraction (XRD) and scanning electron microscopy (SEM), respectively. The magnetic properties including saturation magnetization (Ms), coercive force (Hc), Q-factor and permeability as well as the power loss (Pcv) were investigated and analyzed in detail. The results showed that LMZBS (0.2wt%)-Bi2O3 (0.3wt%) doped NiCuZn ferrites exhibited a uniform and dense microstructure, and possessed the highest Ms, Q factor and magnetic permeability as well as the lowest Hc and Pcv. Overall, LMZBS-Bi2O3 doped NiCuZn ferrites possessed the outstanding micro-structure and magnetic properties, which make it promising for a series of applications.
Mechanical properties and strengthening mechanism of V-containing weathering steel
Authors: Bo Wang , Hua Zhang , Bo Zhang , Cheng-bao Liu , Hui Li
Published: March 2023

In order to insure atmospheric resistance and weldability, the carbon content of weathering steel was decreased. At the same time, increases in Mn content and V-N micro-alloying were adopted to increase the strength of weathering steel in this paper. The results indicate that when the mass fraction of Mn is 1.36%, the yield strength increases to 435 MPa, and the contribution of fine grain strengthening and dislocation strengthening to the yield strength is 59.8%. When the yield strength reaches 555 MPa, V-N alloyed weathering steel has good precipitation strengthening and fine grain strengthening effects, and the sum of the two mechanisms contributes more than 70% of the yield strength of the two groups of V-N alloyed weathering steel.
The Grushin hemisphere as a Ricci limit space with curvature ≥1
Authors: Pan Jiayin
Published: March 2023

The Grushin sphere is an almost-Riemannian manifold that degenerates along its equator. We construct a sequence of Riemannian metrics on a sphere

S

m
+
n

S^{m+n}

with

R
i
c
≥
1

Ric\ge 1

such that its Gromov-Hausdorff limit is the

n
n

-dimensional Grushin hemisphere.
Counterpoint: Preprints and the Future of Scientific Publishing—In Favor of Relevance
Authors: Glymour M Maria , Charpignon Marie-Laure , Chen Yea-Hung , Kiang Mathew V
Published: March 2023

Peer-reviewed journals provide an invaluable but inadequate vehicle for scientific communication. Preprints are now an essential complement to peer-reviewed publications. Eschewing preprints will slow scientific progress and reduce the public health impact of epidemiologic research. The coronavirus disease 2019 (COVID-19) pandemic highlighted long-standing limitations of the peer-review process. Preprint servers, such as bioRxiv and medRxiv, served as crucial venues to rapidly disseminate research and provide detailed backup to sound-bite science that is often communicated through the popular press or social media. The major criticisms of preprints arise from an unjustified optimism about peer review. Peer review provides highly imperfect sorting and curation of research and only modest improvements in research conduct or presentation for most individual papers. The advantages of peer review come at the expense of months to years of delay in sharing research methods or results. For time-sensitive evidence, these delays can lead to important missteps and ill-advised policies. Even with research that is not intrinsically urgent, preprints expedite debate, expand engagement, and accelerate progress. The risk that poor-quality papers will have undue influence because they are posted on a preprint server is low. If epidemiology aims to deliver evidence relevant for public health, we need to embrace strategic uses of preprint servers.
Rationale and design of CONTINUITY: a Phase 4 randomized controlled trial of continued post-discharge sodium zirconium cyclosilicate treatment versus standard of care for hyperkalemia in chronic kidney disease
Authors: Burton James O , Allum Alaster M , Amin Alpesh , Linde Cecilia , Lesén Eva , Mellström Carl , Eudicone James M , Sood Manish M
Published: March 2023

Background

Individuals with chronic kidney disease (CKD) hospitalized with hyperkalemia are at risk of hyperkalemia recurrence and re-hospitalization. We present the rationale and design of CONTINUITY, a study to examine the efficacy of continuing sodium zirconium cyclosilicate (SZC)—an oral, highly selective potassium (K+) binder—compared with standard of care (SoC) on maintaining normokalemia and reducing re-hospitalization and resource utilization among participants with CKD hospitalized with hyperkalemia.

Methods

This Phase 4, randomized, open-label, multicenter study will enroll adults with Stage 3b–5 CKD and/or estimated glomerular filtration rate <45 mL/min/1.73 m2, within 3 months of eligibility screening, hospitalized with a serum potassium (sK+) level of >5.0–≤6.5 mmol/L, without ongoing K+ binder treatment. The study will include an in-hospital phase, where participants receive SZC for 2–21 days, and an outpatient (post-discharge) phase. At discharge, participants with sK+ 3.5–5.0 mmol/L will be randomized (1:1) to SZC or SoC and monitored for 180 days. The primary endpoint is the occurrence of normokalemia at 180 days. Secondary outcomes include incidence and number of hospital admissions or emergency department visits both with hyperkalemia as a contributing factor, and renin–angiotensin–aldosterone system inhibitor down-titration. The safety and tolerability of SZC will be evaluated.

Ethics approval has been received from all relevant ethics committees. Enrollment started March 2022 and the estimated study end date is December 2023.

Conclusions

This study will assess the potential of SZC versus SoC in managing people with CKD and hyperkalemia post-discharge.

Trial registration

ClinicalTrials.gov identifier: NCT05347693; EudraCT: 2021-003527-14, registered on 19 October 2021.
Job satisfaction among community drug distributors in the Mass Drug Administration programme in Nigeria: a cross-sectional study
Authors: Kevin Diltokka Gideon , Lawong Bernsah Damian , Dixon Ruth , Woode Maame Esi , Agboraw Efundem , Ozano Kim , Dean Laura , Forrer Armelle , Isiyaku Sunday , Thomson Rachael , Worrall Eve
Published: March 2023

Background

Despite having one of the largest human resources for health in Africa, the delivery of neglected tropical disease (NTD) health interventions in Nigeria has been hampered by health worker shortages. This study assessed factors associated with job satisfaction among community drug distributors (CDDs) supporting the Nigerian NTD programme, with the goal of identifying opportunities to improve job satisfaction in support of NTD control and elimination efforts in Nigeria.

Methods

A health facility-based cross-sectional survey was conducted in 2019 among CDDs in two states with sharply contrasting NTD programme support, Kaduna and Ogun. A multivariate logistic regression model was used to determine the association between respondent characteristics, programme delivery modalities and job satisfaction.

Results

Overall, 75.3% and 74.0% of CDDs were categorised as being satisfied with their job in Kaduna and Ogun states, respectively. The component with the highest reported satisfaction was motivation, where 98.9% and 98.6% of CDDs were satisfied, in Kaduna and Ogun, respectively. Participants were least satisfied with remuneration, communication, supplies and materials, as well as workload. Location (rural/urban) and state, years of experience, who delivers training and reimbursement of transport fare during medicine distribution were significantly associated with job satisfaction.

Conclusions

Including multiple health staff and NTD programme cadres in CDD training and providing remuneration to cover transport fares spent during MDA delivery may improve CDDs’ job satisfaction both in Ogun and Kaduna states. Given these two states are at opposite ends of the programme support spectrum, such adaptative measures might help improve CDD job satisfaction in the wider Nigerian NTD programme context.
A mixed methods evaluation of an integrated training package for skin neglected tropical diseases in Kaduna and Ogun, Nigeria
Authors: Lar Luret A , Chowdhury Shahreen , Umunnakwe Cynthia , Yahemba Dupe , David Adekunle , Omitola Olaitan O , Haruna Stephen , Lawal Sefiat , Isiyaku Sunday , Shuaibu Joy , Albarka Jehoshaphat , Thomson Rachael , Dean Laura
Published: March 2023

Background

The overall burden of neglected tropical diseases (NTDs) affecting the skin is undetermined. Skin conditions are among the top 10 causes of disability worldwide. Affected persons seek treatment at advanced stages of the disease, resulting in morbidity and disability. We developed and evaluated an integrated training intervention for early case detection, referral and management of skin NTDs in two states in Nigeria.

Methods

This was a mixed-methods study using participatory approaches to develop specific skin algorithms and training packages for community and primary level health workers. This supported the identification, referral and clinical diagnosis of suspected cases. We used Kirkpatrick's model to evaluate the training package.

Results

Participants’ knowledge improved after the 2-months intervention. Across both states, knowledge retention appeared more robust for cadres at all levels: state, local government area and primary healthcare. All (100%) participants mentioned that the training assisted them in detecting, referring and managing skin NTDs. Training was understood by participants and training materials were easy to understand. Materials were also effective in educating community members about the symptoms of NTDs and supported referral to facilities for appropriate management.

Conclusions

Community implementers can be trained and supervised to detect people affected by skin NTDs and support appropriate management within the existing patient care pathway.
EU antitrust in support of the Green Deal. Why better is not good enough
Authors: Loozen Edith
Published: March 2023

The European Union (EU) Commission proposes to ‘green up’ its enforcement of Article 101(3) TFEU to allow producers to collectively overcome so-called first mover disadvantages that would result from inefficient market regulation. The Commission's reboot focuses on the last three exemption conditions. First, the consumer benefit condition is customized to use collective consumer benefits to determine whether consumers receive a ‘fair share’ of the benefits established under the efficiency condition. Here, the Commission bypasses the Dutch proposition to also take account of non-consumer benefits when investigating whether consumers are compensated for anticompetitive harm. Second, the indispensability condition is tasked to filter out greenwashing. Third, the residual competition condition is trusted to allow private collective action insofar it does not eliminate competition on price and/or innovation. Discussing both EU and Dutch proposals, this article finds that greening up Article 101(3) brings competition policy outside the limiting principles that define objective and effective competition enforcement in terms of voluntary exchange.
A home-based low-intensity resistance exercise programme with supervision for secondary sarcopenia in a patient with established rheumatoid arthritis: A case report
Authors: Hishikawa Norikazu , Toyama Shogo , Shimahara Noriyoshi , Taira Kazuaki , Kawasaki Takashi , Ohashi Suzuyo , Sawada Koshiro , Mikami Yasuo
Published: March 2023

Patients with established rheumatoid arthritis (RA) are at risk of developing secondary sarcopenia. Both pharmacological and exercise interventions are essential for treatment. However, for such patients, exercise loads may lead to the progression of joint destruction and worsening of pain. The purpose of this report was to assess the feasibility of a home-based, low-intensity resistance exercise programme. The case was a 70-year-old female patient with sarcopenia secondary to RA. She was diagnosed with RA at 57 years of age and began medication, maintaining remission of disease activity. However, she did not exercise habitually and was relatively inactive in her daily life. Furthermore, she had kinesiophobia associated with her RA-related symptoms. We suggested implementing a home-based low-intensity resistance exercise programme >3 months, with the goal of exercising the lower extremities daily. The patient was asked to self-monitor using an exercise diary and attend monthly outpatient visits for repeat counselling and feedback. As a result, she was able to perform the exercise programme safely with high compliance, improving her kinesiophobia as well as physical inactivity, although her skeletal muscle mass did not change. Regular exercise and increased physical activity may help prevent the onset of sarcopenia. These results demonstrate the feasibility of implementing our exercise programme and support its potential for preventing the progression of sarcopenia. While questions remain in terms of treating sarcopenia, we believe that our findings will lead to the establishment of an exercise programme for patients with sarcopenia secondary to established rheumatoid arthritis.
High Seroprevalence of Kaposi Sarcoma–Associated Herpesvirus in Men Who Have Sex With Men With HIV in the Southern United States
Authors: Knights Sheena M , Salyards Maverick , Kendall Noelle , Lazarte Susana M , Kainthla Radhika , Miley Wendell , Marshall Vickie , Labo Nazzarena , Whitby Denise , Chiao Elizabeth Y , Nijhawan Ank E
Published: March 2023

Background

Disparities in mortality in human immunodeficiency virus (HIV)–associated Kaposi sarcoma have been described, particularly in Black men in the southern United States. It is unclear if there are racial/ethnic differences in the seroprevalence of Kaposi sarcoma–associated herpesvirus (KSHV) that may be contributing.

Methods

This is a cross-sectional study of men who have sex with men (MSM) and transgender women with HIV. Participants were recruited from an outpatient HIV clinic in Dallas, Texas, for a 1-time study visit and were excluded from analysis if they had any history of KSHV disease. Plasma was tested for antibodies to KSHV K8.1 or ORF73 antigens, and KSHV DNA was measured in oral fluids and blood by polymerase chain reaction. KSHV seroprevalence and viral shedding in blood and oral fluids were calculated. Additionally, independent risk factors for KSHV seropositivity were assessed by multivariable logistic regression analysis.

Results

Two hundred five participants were included in our analysis. Overall, KSHV seroprevalence was high (68%) with no significant difference between racial/ethnic groups. Among seropositive participants, KSHV DNA was detected in 28.6% of oral fluids and 10.9% of peripheral blood specimens, respectively. The factors most strongly associated with KSHV seropositivity were oral–anal sex (odds ratio [OR], 3.02), oral–penile sex (OR, 4.63), and methamphetamine use (OR, 4.67).

Conclusions

High local seroprevalence of KSHV is likely a key driver of the high burden of KSHV-associated diseases regionally, though it does not explain the observed disparities in KSHV-associated disease prevalence among racial/ethnic groups. Our findings support that KSHV is primarily transmitted via exchange of oral fluids.
C-Reactive protein rise in rheumatology patients following COVID-19 vaccination
Authors: Gor Shivani , Kim Sung-Hee , Yein Khin , Michael Jessica , Price Elizabeth
Published: March 2023

Objective

The aim was to determine the proportion of patients with inflammatory arthritis who have a flare of their rheumatological disease within 4 weeks of receiving a coronavirus disease 2019 (COVID-19) vaccine, using CRP as a surrogate marker.

Methods

A retrospective review was conducted of notes for patients with inflammatory arthritis within 30 days of their COVID-19 vaccine. An electronic database (DAWN) was used to identify all patients who were currently on a DMARD or biologic therapy. This was then correlated with vaccine data from the National Immunisation and Vaccination System (NIVS) and CRP within 30 days of their vaccination.

Results

From the DAWN database, 1620 adults were identified (mean age 61 years, 64% female). Three types of vaccinations were administered: AstraZeneca (AZ), BioNTech-Pfizer or Moderna. Vaccine uptake was 1542 of 1620 (95.2% for the first dose), 1550 of 1620 (95.7% for the second dose) and 1437 of 1620 (88.7% for the third dose). One hundred and ninety-two of 1542 patients (12.5%) had a CRP rise of >10 mg/l within 30 days of their vaccine, which was higher than the baseline flare rate of 8.6% (P = 0.0004).

Conclusion

Patients with inflammatory arthritis and on DMARDs have a high uptake of COVID-19 vaccine (95%), which is greater than the national average. A CRP rise >10 mg/l within 30 days of vaccination was observed in ∼1 in 10 patients in our study population after all three doses. There might be a slight increase in disease flare in patients with inflammatory arthritis after COVID-19 vaccinations, and additional research is required to assess this association further.
Growing up with chronic pain: a systematic review of the evidence in transitional care for young people with chronic pain
Authors: Huckerby Lauren , McDonagh Janet E , Lee Rebecca Rachael
Published: March 2023

Objective

Paediatric chronic pain presents a significant individual and societal burden, with an estimated prevalence of 11–38%. A large proportion of adolescents with chronic pain will have unresolved pain that continues into adulthood and thus requires transitional care. The aim of this review was to investigate the current evidence for the core components of effective transitional care interventions designed for young people with chronic pain.

Methods

Studies were identified by searching the Embase, MEDLINE, CINAHL and PsycINFO databases. A search strategy using terms such as ‘Adolescent’, ‘Persistent long-term pain’ and ‘Transition’ (or variations of such words) was implemented. Inclusion criteria were sample population age 10–24 years, a confirmed diagnosis of a condition characterized by chronic pain, any healthcare setting, any service provider, published peer reviewed and English language.

Results

Ninety-eight articles were identified by the search and 14 were selected after abstract screening. Two independent reviewers screened the articles, followed by a senior reviewer. Of the 14 articles, full-text review found that none of the articles looked specifically at evidence with respect to core components of effective transitional care designed for young people with chronic pain.

Conclusion

Chronic pain is a feature of many long-term health conditions. It remains unknown as to whether there are any pain-specific aspects of transitional care. How pain management is addressed in existing transitional care provision and the relationship of pain to outcomes needs further research. If effective interventions can be provided during these crucial years, the trajectory of these young people can potentially be improved into adulthood.
Zonal interdependence in the temporomandibular joint cartilage
Authors: Xu Xiaojie , Zhang Yuejiao , Zhang Jing , Wang Dongmei , Yang Hongxu , Liu Qian , Zhou Peng , Wang Yazhou , Yang Liu , Wang Meiqing
Published: March 2023

The temporomandibular joint (TMJ) cartilage is biomechanical sensitive. Cells in TMJ cartilage are zonally arranged, earlier differentiated in the super zone and late differentiated in the deep zone. The purpose was to detect the zonal interdependence in TMJ cartilage under dental biomechanical stimulations. Here, we obtained the Sox9CreER; Rosa26tdTomato and Col10CreER; Rosa26tdTomato mice to label super zone Sox9‐expressing (Sox9+) or deep zone Col10‐expressing (Col10+) cells by tdTomato (TdT), and Sox9CreER; Rosa26DTA and Col10CreER; Rosa26DTA mice to ablate Sox9+ or Col10+ cells selectively. These mice were subjected to unilateral anterior crossbite (UAC) or bilateral anterior elevation (BAE) dental stimulation, which promoted terminal differentiation or proliferation of TMJ chondrocytes, respectively. In both UAC and BAE models, the Sox9‐TdT+ cells performed as proliferation and mature differentiation, showing as expressing Ki67 and Col‐X, respectively; while the Col10‐TdT+ cells performed as terminal differentiation, showing as expressing osteocalcin (OCN). In both Sox9+‐ and Col10+‐cells ablation groups, there were reductions in cell number, cartilage thickness and matrix amount, subchondral bone loss, and condylar deformation. The UAC‐promoted terminal differentiation was enhanced, and the BAE‐promoted cellular proliferation was ruined. Impressively, when Col10+ cells were ablated, the UAC‐promoted DAP3 expression, an anoikis marker, was further increased, while the BAE‐suppressed DAP3 expression was instead greatly increased. These findings demonstrated that the cartilage zones function interdependently. The super zone harbors the cells that undergo differentiation to deep zone cells, the deep zone contains load‐bearing matrix which is structural essential for the cells located inside or superficial.
Epigenetic cues regulating airway development in human lung organoids: Polycomb repressive complex 2 and altered chromatin accessibility determine cell fate
Authors: Shirvaliloo Milad , Akhavan‐Sigari Reza
Published: March 2023

Today, human organoids are becoming an integrated part of genomics and epigenomics, as they provide a platform that can be used for the definite study of molecular and cellular mechanisms occurring at different stages of development, particularly organogenesis, within the human body. Airway development is a complex process heavily influenced by epigenetic regulatory mechanisms in response to environmental changes, and as such, human lung organoids are an indispensable asset for further exploration of these mechanisms as a mode of transition from human in vitro to human ex vivo studies. Cultured primarily in compounds mimicking the extracellular matrix, such as Matrigel, these lung organoids have helped us to come to a better understanding of the role of polycomb repressive complex 2 (PRC2) and enhancer of zeste homolog 2 (EZH2) in lung epithelial cell differentiation and airway development, which was first reported in the FASEB journal in 2019. The following is an extended account of how the histone methylation‐regulating PRC2 comes to play in the molding of the human bronchial tree, along with further epigenetic insights based on more recently developed human lung organoids.
Medical Therapy to Prevent or Slow Progression of Aortic Stenosis: Current Evidence and Future Directions
Authors: Chong Travis , Lan Nick S. R. , Courtney William , He Albert , Strange Geoff , Playford David , Dwivedi Girish , Hillis Graham S. , Ihdayhid Abdul Rahman
Published: March 2023

Degenerative aortic stenosis is a growing clinical problem owing to the high incidence in an aging population and its significant morbidity and mortality. Currently, aortic valve replacement remains the only treatment. Despite promising observational data, pharmacological management to slow or halt progression of aortic stenosis has remained elusive. Nevertheless, with a greater understanding of the mechanisms which underpin aortic stenosis, research has begun to explore novel treatment strategies. This review will explore the historical agents used to manage aortic stenosis and the emerging agents that are currently under investigation.
Exploring the molecular mechanism of Ling-Gui-Zhu-Gan decoction for the treatment of type 2 diabetes mellitus based on network pharmacology and molecular docking: A review
Authors: Long Feng , Zhang Zhe , Luo Chunxiu , Lei Xiao , Guo Jinlian , An Lin
Published: March 2023

To investigate the mechanism of action of the classical formula Ling-Gui-Zhu-Gan (LGZG) decoction in treating type 2 diabetes mellitus based on network pharmacology and molecular docking. The active ingredients and targets of LGZG decoction were collected by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database and mapped using Cytoscape software to show their interrelationships. GeneCards, Pharmacogenomics Knowledge Base, OMIM, Therapeutic Target Database, and Drugbank databases were used to obtain targets related to type 2 diabetes; protein-protein interaction networks were established with the help of the STRING platform. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed on selected core targets with the help of the Metascape platform. Finally, the AutoDock platform was used to perform molecular docking and display the results by Pymol software. One hundred twenty-one active ingredients, 216 effective target genes, 11,277 type 2 diabetes mellitus-related genes, 210 crossover genes, and 18 core genes were obtained for LGZG decoction. The results obtained by Kyoto Encyclopedia of Genes and Genomes indicated that the advanced glycosylation end products-receptor of advanced glycosylation end products signaling pathway, the phosphatidylinositol 3 kinase-Akt signaling pathway, and HIF-1 signaling pathway might be the key signaling pathways. Molecular docking showed that the binding energy of quercetin, kaempferol, naringenin, and licorice chalcone A to the core target genes were all <5.0 kJ-mol−1, with good affinity. In this study, the potential active ingredients and mechanisms of action of LGZG decoction in the treatment of type 2 diabetes were initially investigated, which provided a basis for the in-depth study of its drug basis and mechanisms of action.
Case report: Mild leukoencephalopathy caused by a new mutation of NOTCH3 gene
Authors: Qi Yuxiang , Li Hairong , Yu Ling
Published: March 2023

Background:

Cerebral autosomal dominant arteriosis with subcortical infarction and leukoencephalopathy (CADASIL) is a single-gene small-vessel disease of the brain characterized by migraine, recurrent ischemic stroke, psychiatric disorders, progressive cognitive decline, and occasional intracerebral hemorrhage.[1]
NOTCH3 was identified as a pathogenic gene for CADASIL.[2] The NOTCH3 gene encodes a membrane-bound receptor protein, and to date, several different NOTCH3 gene mutations have been identified.[3] Here, we report a case of CADASIL with a heterozygous mutation c.931T > G (thymine > guanine) on the exon region of the NOTCH3 gene, resulting in an amino acid change p.C311G (cysteine > glycine).

Case report:

We report a case of a female patient with CADASIL whose genetic sequencing revealed a mutation in the NOTCH3 gene. However, this patient did not exhibit any of the typical clinical findings of CADASIL but the patient’s cerebral magnetic resonance imaging was consistent with the characteristic findings of CADASIL.

Conclusions:

This case reminds us that mutations caused by different mutation sites present different clinical symptoms.
Solitary bone plasmacytoma of the tibia presenting as chronic osteomyelitis: A rare case report and literature review
Authors: Yang Xiao-Wei , Zhou Gui-Chao , Long Zhi-Sheng , Gong Fei-Peng , Chen Gang
Published: March 2023

Rationale:

Plasmacytoma is a rare plasma cell dyscrasia that grows within the axial skeleton or soft tissue structures as solitary or multiple masses. The primary types are solitary plasmacytoma, including solitary bone plasmacytoma (SBP) and solitary extramedullary plasmacytoma, and multiple solitary plasmacytomas. SBP is characterized by localized proliferation of monoclonal plasma cells and is rare. However, SBP with chronic osteomyelitis is even rarer.

Patient concerns:

A 47-year-old man previously diagnosed with chronic osteomyelitis presented with repeated discharge and ulceration in the front of his right tibia.

Diagnosis, interventions and outcomes:

Lower extremity magnetic resonance imaging (MRI) and computed tomography (CT) examinations showed dead bone formation and surrounding inflammatory edema. Thus, the patient underwent dead bone excision and fenestration of the bone marrow cavity. The histopathologic examination results indicated plasmacytoma. Therefore, we administered radiotherapy with satisfactory results.

Lessons:

Physicians should pay close attention to chronic osteomyelitis because it may be accompanied by plasmacytoma. Postoperative pathological and immunohistochemical examinations are crucial, and surgical resection of the lesion and local radiotherapy are effective treatment methods.
Risk of Staphylococcus aureus Bacteremia Before and After Solid Organ Transplantation
Authors: Inagaki Kengo , Weinberg Jason B. , Kaul Daniel R.
Published: March 2023

Background.

Solid organ transplant recipients are at high risk forStaphylococcus aureusbacteremia, but the risks before and after transplantation require further research.

Methods.

We performed a population-based retrospective self-controlled study using the State Inpatient Database from 10 states in the United States. Adult and pediatric patients who had solid organ transplantation from 2004 to 2018 were tracked longitudinally for 1 y before and after transplantation outside of the immediate peritransplant periods. The exposure of interest was solid organ transplantation, and the outcome of interest was hospitalization withS. aureusbacteremia.

Results.

Of 75 549 patients, 581 (0.77%) and 239 (0.32%) were hospitalized withS. aureusbacteremia in the pretransplant and posttransplant periods, respectively (P< 0.001). Overall, the odds of hospitalization withS. aureusbacteremia increased from 7 to 12 mo to 1 to 6 mo before transplantation (odds ratio, 1.24; 95% confidence interval, 1.05-1.46) and then decreased following transplantation (odds ratio, 0.35; 95% confidence interval, 0.28-0.45; 7–12 mo after transplantation). The decreased rate after transplantation was driven by the cases associated with central line-associated bloodstream infections and endocarditis among kidney and heart transplant recipients. Odds of hospitalization withS. aureusbacteremia did not change after liver transplantation, whereas they increased after lung transplantation.

Conclusions.

In addition to immunosuppression, the reversal of organ failure and associated requirements for organ support following transplantation may play an important role in the risk ofS. aureusbacteremia in solid organ transplant recipients. These results can guide infection prevention approaches and future research onS. aureusinfections in transplant patients.
Differences in Implicit Attitudes in West and East Germans as Measured by the Go/NoGo Association Task and Event-related EEG Potentials
Authors: Wagner-Altendorf Tobias A. , van der Lugt Arie H. , Kroeber Anna , Cirkel Anna , Heldmann Marcus , Münte Thomas F.
Published: March 2023

Background and Objective:

Implicit social cognition refers to attitudes and stereotypes that may reside outside conscious awareness and control but that still affect human behavior. In particular, the implicit favoritism of an ingroup, to which an individual belongs, as opposed to an outgroup, to which the individual does not belong, characterized as ingroup bias, is of interest and is investigated here.

Method:

We used a Go/NoGo association task (GNAT) and behavioral and electroencephalographic (event-related EEG potential [ERP] analysis) measures to investigate the implicit bias toward cities in East Germany, West Germany, and Europe, in 16 individuals each from West and East Germany (mixed gender, Mage = 24). The GNAT assesses an individual’s Go and NoGo responses for a given association between a target category and either pole (positive or negative) of an evaluative dimension.

Results:

Behavioral measures revealed slightly faster reaction times to the combination of European city names and negative, as compared with positive, evaluative words in both groups. ERP analysis showed an increased negativity at 400–800 ms poststimulus in the incongruent conditions of East German city/positive word pairings (in West Germans) and West German city/positive word pairings (in East Germans).

Conclusion:

An implicitly moderately negative evaluation of Europe by both groups was exhibited based on the behavioral data, and an increased level of conflict arising from the “incongruent” pairings (ie, as manifestation of an implicitly negative attitude toward East Germany in West Germans, and toward West Germany in East Germans) was exhibited based on the electrophysiological data.
Age or age of onset: which is the best criterion to classify late-life depression?
Authors: Olgiati Paolo , Fanelli Giuseppe , Serretti Alessandro
Published: March 2023

In late-life depression (LLD), several differences between patients whose first episode is reported after age 65 (late-onset depression, LOD) and those with early-onset depression (EOD) might reflect the effects of brain ageing. To test this hypothesis, we analysed the impact of current age and age at illness onset on a number of clinical and cognitive manifestations in 438 outpatients with major depressive disorder aged >60 years, treated with venlafaxine for 12 weeks. When compared to the EOD group, patients with LOD were older (P < 0.00001) and associated with lower depression severity (P = 0.0029), lower global cognitive functioning [Mini-Mental State Examination (MMSE): P = 0.0001; Repeatable Battery for the Assessment of Neuropsychological Status: immediate memory, P = 0.0009, and delayed memory, P < 0.00001; Delis-Kaplan Executive Function System measuring executive functions: Trail-Making Test (TMT) – P = 0.0004 and Colour-Word Interference Test, Inhibition – P = 0.0063], and more dyskinesias (Abnormal Involuntary Movement Scale: P = 0.0006). After controlling for its interactions with age of onset, current age was inversely correlated with Montgomery Åsberg Depression Rating Scale scores at baseline (P < 0.00001) and week 12 (P = 0.0066), MMSE (P < 0.00001), delayed memory (P < 0.00001), and TMT (P = 0.0021). Age of onset predicted impairment in immediate (P = 0.023) and delayed memory (P = 0.0181), and dyskinesias (P = 0.0006). Although most features of LLD are related to ageing rather than to late-onset, LOD is a possible separate diagnostic entity characterised by memory dysfunction and increased liability to movement disorders.
Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cancer
Authors: Levallet Jérôme , Biojout Tiphaine , Bazille Céline , Douyère Manon , Dubois Fatéméh , Leite Ferreira Dimitri , Taylor Jasmine , Teulier Sylvain , Toutain Jérôme , Bernaudin Myriam , Valable Samuel , Bergot Emmanuel , Levallet Guénaëlle
Published: March 2023

The molecular mechanisms induced by hypoxia are misunderstood in non-small cell lung cancer (NSCLC), and above all the hypoxia and RASSF1A/Hippo signaling relationship.

We confirmed that human NSCLC (n=45) as their brain metastases (BM) counterpart are hypoxic since positive with CAIX-antibody (target gene of Hypoxia-inducible factor (HIF)). A severe and prolonged hypoxia (0.2% O2, 48h) activated YAP (but not TAZ) in Human Bronchial Epithelial Cells (HBEC) lines by downregulating RASSF1A/kinases Hippo (except for NDR2) regardless their promoter methylation status. Subsequently, the NDR2-overactived HBEC cells exacerbated a HIF-1A, YAP and C-Jun-dependent-amoeboid migration, and mainly, support BM formation. Indeed, NDR2 is more expressed in human tumour of metastatic NSCLC than in human localized NSCLC while NDR2 silencing in HBEC lines (by shRNA) prevented the xenograft formation and growth in a lung cancer-derived BM model in mice.

Collectively, our results indicated that NDR2 kinase is over-active in NSCLC by hypoxia and supports BM formation. NDR2 expression is thus a useful biomarker to predict the metastases risk in patients with NSCLC, easily measurable routinely by immunohistochemistry on tumour specimens.
FLONE: fully Lorentz network embedding for inferring novel drug targets
Authors: Yue Yang , McDonald David , Hao Luoying , Lei Huangshu , Butler Mark S. , He Shan
Published: March 2023

Motivation: To predict novel drug targets, graph-based machine learning methods have been widely used to capture the relationships between drug, target, and disease entities in heterogeneous biological networks. However, most of the existing methods cannot explicitly consider disease types when predicting targets. More importantly, drug-disease-target (DDT) networks could exhibit multi-relational hierarchical sub-structures with the information of biological interactive functions, but these methods, especially those based on Euclidean space embedding cannot fully utilize such topology information, which might lead to sub-optimal prediction results. We hypothesized that, by properly importing hyperbolic space embedding specifically for modeling hierarchical DDT networks, graph-based machine learning algorithms could better capture the relationships between aforementioned entities, which ultimately improves the target prediction performance. Results: To test our hypothesis, we formulated the drug target prediction problem as a knowledge graph triple completion task explicitly considering disease types. To solve this problem, we proposed FLONE, a novel hyperbolic Lorentz space embedding-based method to capture the hierarchical structural information in the DDT network when inferring drug targets. We evaluated it on two different DDT networks, our experimental results showed that by introducing Lorentz space, one of the isomorphic models of hyperbolic space, FLONE generates more accurate candidate target predictions given the drug and disease than the Euclidean translation-based counterparts, which supports our hypothesis. Beyond these experiments, we also devised the hyperbolic encoders to fuse drug and target similarity information into FLONE, to make it capable to handle triples corresponding to previously unseen drugs and targets for more challenging prediction scenarios.
Gene conversion limits the cost of asexuality in somatically immortal worms
Authors: Kershenbaum Simon , Espejo Manuel Jara , Griffin Asheligh , Aboobaker Aziz
Published: March 2023

Most multicellular organisms reproduce sexually despite the costs associated with sexuality. This has been explained as the result of selection favouring the ability to recombine the genome. The lack of recombination in asexual species constrains their adaptability and leads to the accumulation of deleterious mutations, ultimately increasing their risk of extinction. Nonetheless, successful asexual life histories persist among multicellular organisms, and explanatory mechanisms which may help limit the cost of asexuality remain enigmatic. In search of these mechanisms, we looked at that the molecular evolutionary changes in sexual and obligate asexual strains of the planarian flatworm, Schmidtea mediterranea. We find that the accumulation of deleterious mutations in highly conserved genes is largely avoided in the asexual strain. We find evidence that this is achieved by somatic gene conversion in stem cells allowing for the restoration of fit alleles and the purification of deleterious mutations. Our analyses provide a potential mechanism for the maintenance of asexuality in a metazoan. Taken together, these findings suggest that gene conversion may be used by asexual lineages to unlink loci, counteracting some of the key challenges facing obligate asexual species.