bluuebunny/crossref_metadata_2025 huggingface dataset:
Fall injuries in Sub-Saharan Africa: analysis of prospective injury registry from 23 health facilities in Malawi and Tanzania
Authors: Sawe Hendry R. , Mulwafu Wakisa , Chokotho Linda , Croke Kevin , Chamanga Rachel , Mohammed Meyhar , Bertfelt Jonna , Ndumwa Harrieth P. , Mfinanga Juma A. , Milusheva Sveta
Published: April 2023

Background

Low-and middle-income countries account for over 80% of fall-related fatalities globally. However there is little emphasis on the issue and limited high quality data to understand the burden, and to inform preventive and management strategies. We characterise the burden of fall injuries in Malawi and Tanzania.

Methods

This multi-centre prospective descriptive study utilized trauma registry data from 10 hospitals in Malawi and 13 hospitals in Tanzania. The study included twelve months of data in Tanzania (October 2019 to September 2020), and eighteen months of data from Malawi (September 2018 to March 2020). We describe patient demographics, the causes, location, and nature of injuries, timing of arrival to hospital, and final disposition. Regression analyses were performed to determine risk factors for serious injuries.

Results

There were 93,178 trauma patients in the registries of both countries, of which 44,609 (47.9%) had fall related complaints. Fall injuries accounted for 55.3% and 17.4% of all trauma cases in Malawi and Tanzania respectively. Overall the median age was 16 years (Interquartile range (IQR) 8–31 years), and 62.8% were male. Most fall injuries (69.9%) occurred at home, were unintentional (98.1%), and were due to a ground level fall (74.9%). Nearly half of patients (47.9%) arrived at a facility using public transport, with median arrival time of 10 h (IQR 8–13 h) from initial injury. Extremities (87.0%) were the most commonly injured region, followed by head and neck (4.4%). Overall 3275 (7.4%) patients had potentially serious injuries. Age > 60 years was associated with two times odds of having serious injuries than those < 5 years, and those sustaining injury at work (adjusted Odds Ratio (aOR) 1.95 95% CI; 1.56–2.43) or recreational areas (aOR 3.47 95% CI; 2.93–4.10) had higher odds of serious injuries compared to those injured at home.

Conclusions

In these facilities in Sub-Saharan Africa, fall injuries accounted for a substantial fraction of all injuries. While most common in younger males, those aged 5–13 and over 60 years were more likely to have serious injuries. Most falls occurred at home, but serious injuries were more likely to occur at recreational and work areas. Future efforts should focus on preventive strategies to mitigate these injuries.
Computer-based cognitive tests and cerebral pathology among Japanese older adults
Authors: Shimada Hiroyuki , Makino Keitaro , Kato Takashi , Ito Kengo
Published: April 2023

Background

This study aimed to identify the appropriate computer-based cognitive tests and cut-off values for estimating amyloid burden in preclinical Alzheimer’s disease drug trials.

Methods

Data from 103 older individuals, who underwent 18F-florbetapir positron emission tomography and cognitive testing, were analyzed. Cognitive tests evaluated word list memory (immediate recognition and delayed recall), attention (Trail Making Test-part A), executive function (Trail Making Test-Part B), and processing speed (Digit Symbol Substitution Test [DSST]).

Results

The Aβ burden was significantly associated with word list memory (odds ratio [OR] = 0.42, 95% confidence interval [CI], 0.19–0.91) and DSST (OR = 0.35; 95% CI, 0.14–0.85). Positive predictive value and number needed to screen at a cut-off of 1.5 SD were better for word list memory and DSST among predictive values.

Conclusions

The computer-based memory and processing speed tests have the potential to reduce failure rates while screening individuals with Aβ accumulation in community settings.
Guided Self-rehabilitation Contract vs conventional therapy in chronic peripheral facial paresis: VISAGE, a multicenter randomized controlled trial
Authors: Baude Marjolaine , Guihard Marina , Gault-Colas Caroline , Bénichou Ludovic , Coste André , Méningaud Jean-Paul , Schmitz David , Natella Pierre-André , Audureau Etienne , Gracies Jean-Michel
Published: April 2023

Background

One year after persistent peripheral facial paresis (PFP), prescriptions of conventional rehabilitation are often downgraded into maintenance rehabilitation or discontinued, the patient entering what is seen as a chronic stage. This therapeutic choice is not consistent with current knowledge about behavior-induced plasticity, which is available all life long and may allow intense sensorimotor rehabilitation to remain effective. This prospective, randomized, multicenter single-blind study in subjects with chronic unilateral PFP evaluates changes in facial motor function with a Guided Self-rehabilitation Contract (GSC)vs.conventional therapy alone, carried out for six months.

Methods

Eighty-two adult subjects with chronic unilateral PFP (> 1 year since facial nerve injury) will be included in four tertiary, maxillofacial surgery (2), otolaryngology (1) and rehabilitation (1) centers to be randomized into two rehabilitation groups. In the experimental group, the PM&R specialist will implement the GSC method, which for PFP involves intensive series of motor strengthening performed daily on three facial key muscle groups,i.e.Frontalis, Orbicularis oculi and Zygomatici. The GSC strategy involves: i) prescription of a daily self-rehabilitation program, ii) teaching of the techniques involved in the program, iii) encouragement and guidance of the patient over time, in particular by requesting a quantified diary of the work achieved to be returned by the patient at each visit. In the control group, participants will benefit from community-based conventional therapy only, according to their physician’s prescription. The primary outcome measure is the composite score of Sunnybrook Facial Grading System. Secondary outcome measures include clinical and biomechanical facial motor function quantifications (Créteil Scale and 3D facial motion analysis through the Cara system), quality of life (Facial Clinimetric Evaluation and Short-Form 12), aesthetic considerations (FACE-Q scale) and mood representations (Hospital Anxiety and Depression scale). Participants will be evaluated every three months by a blinded investigator, in addition to four phone calls (D30/D60/D120/D150) to monitor compliance and tolerance to treatment.

Discussion

This study will increase the level of knowledge on the effects of intense facial motor streng-          Facial paralysisthening prescribed through a GSC in patients with chronic peripheral facial paresis.

Trial registration

ClinicalTrials.gov,NCT04074018. Registered 29 August 2019.

Protocol version

Version N°4.0—04/02/2021.
A prospective cohort study on active surveillance after neoadjuvant chemoradiotherapy for esophageal cancer: protocol of Surgery As Needed for Oesophageal cancer-2
Authors: van der Zijden Charlène J. , Lagarde Sjoerd M. , Hermus Merel , Kranenburg Leonieke W. , van Lanschot J. Jan B. , Mostert Bianca , Nuyttens Joost J. M. E. , Oudijk Lindsey , van der Sluis Pieter C. , Spaander Manon C. W. , Valkema Maria J. , Valkema Roelf , Wijnhoven Bas P. L. ,   SANO-2 study group, Dekker Jan Willem T. , Fiets Willem E. , Hartgrink Hendrik H. , Hazen Wouter L. , Kouwenhoven Ewout A. , Nieuwenhuijzen Grard A. P. , Rosman Camiel , van Sandick Johanna W. , Sosef Meindert N. , van der Zaag Edwin S.
Published: April 2023

Background

Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is a standard treatment for potentially curable esophageal cancer. Active surveillance in patients with a clinically complete response (cCR) 12 weeks after nCRT is regarded as possible alternative to standard surgery. The aim of this study is to monitor the safety, adherence and effectiveness of active surveillance in patients outside a randomized trial.

Methods

This nationwide prospective cohort study aims to accrue operable patients with non-metastatic histologically proven adenocarcinoma or squamous cell carcinoma of the esophagus or esophagogastric junction. Patients receive nCRT and response evaluation consists of upper endoscopy with bite-on-bite biopsies, endoscopic ultrasonography plus fine-needle aspiration of suspicious lymph nodes and 18F-fluorodeoxyglucose positron emission tomography/computed tomography scan. When residue or regrowth of tumor in the absence of distant metastases is detected, surgical resection is advised. Patients with cCR after nCRT are suitable to undergo active surveillance. Patients can consult an independent physician or psychologist to support decision-making. Primary endpoint is the number and severity of adverse events in patients with cCR undergoing active surveillance, defined as complications from response evaluations, delayed surgery and the development of distant metastases. Secondary endpoints include timing and quality of diagnostic modalities, overall survival, progression-free survival, fear of cancer recurrence and decisional regret.

Discussion

Active surveillance after nCRT may be an alternative to standard surgery in patients with esophageal cancer. Similar to organ-sparing approaches applied in other cancer types, the safety and efficacy of active surveillance needs monitoring before data from randomized trials are available.

Trial registration

The SANO-2 study has been registered at ClinicalTrials.gov as NCT04886635 (May 14, 2021) – Retrospectively registered.
HOXA9 gene promotor methylation and copy number variation of SOX2 and HV2 genes in cell free DNA: A potential diagnostic panel for non-small cell lung cancer
Authors: Abou-Zeid Abla , Hashad Doaa , Baess Ayman , Mosaad Mai , Tayae Eman
Published: April 2023

Background

Most cases of lung cancer are diagnosed at advanced stage. Detection of genetic and epigenetic markers in cell-free DNA (cfDNA) is a promising tool for the diagnosis of lung cancer at an early stage. The aim of this study was to identify non-invasive diagnostic markers in cell free DNA (cfDNA) for non-small cell lung cancer (NSCLC) as it is the most common type of lung cancer.

Methods

We investigated the cfDNA HOXA9 gene promotor methylation by pyrosequencing. Copy number variation of SOX2 and HV2 genes were detected by real-time PCR in cfDNA extracted from plasma samples of 25 newly diagnosed NSCLC patients and 25 age and sex matched controls.

Results

Methylation level of HOXA9 was significantly higher in NSCLC patients than controls (p > 0.001). SOX2 showed significantly higher CNV and HV2 showed lower CNV in patients than controls (p > 0.001, p = 0.001 respectively). Receiver Operating Characteristic (ROC) curve analysis for HOXA9 methylation, SOX2 CNV and HV2 CNV showed a discrimination power of 79.4%, 80% and 77.5% respectively and the area under the curve for the combined analysis of the three genes was 0.958 with 88% sensitivity and 100% specificity.

Conclusions

In this study, we suggest a potentially diagnostic panel that may help in detection of lung cancer with high sensitivity and specificity using cell free DNA. This Panel included HOXA9 gene methylation and the CNV of SOX2 and HV2 genes.
Adverse childhood experiences as a risk factor for non-suicidal self-injury and suicide attempts in forensic psychiatric patients
Authors: Laporte Natalie , Ozolins Andrejs , Westling Sofie , Westrin Åsa , Wallinius Märta
Published: April 2023

Background

Exposure to adverse childhood experiences (ACE) have been found to have profound negative consequences on an individuals’ health. Non-suicidal self-injury (NSSI) is a clinically complex and serious global health issue and is closely related to suicide attempts. Previous research has found associations between ACE and NSSI and suicide attempts in clinical samples. However, this association has to our knowledge not been studied to this extent in a sample of forensic psychiatric patients. The aim of this study was therefore to describe the prevalence of adverse childhood experiences (ACE) and their associations with non-suicidal self-injury (NSSI) and/or suicide attempts in forensic psychiatric patients.

Methods

The current study is a cross-sectional study of a consecutive cohort of 98 forensic psychiatric patients (86.7% male) in Sweden. We invited 184 patients with a predicted stay of > 8 weeks who had been cleared for participation by their treating psychiatrist. Of these, 83 declined and 98 eligible patients provided informed consent. Information on ACE, NSSI, and suicide attempts derived from files, self-reports (Childhood Trauma Questionnaire-Short Form; CTQ-SF), and interviews were compared separately among participants with and without NSSI or suicide attempts using t-tests. The dose–response association between ACE and NSSI/suicide attempts was analysed using binary logistic regression.

Results

In file reviews, 57.2% of participants reported physical abuse, 20% sexual abuse, and 43% repeated bullying by peers during childhood. NSSI and suicide attempts were associated significantly with CTQ-SF total scores, with medium effect sizes (d = .60 to .63, p < .01), and strongly with several CTQ-SF subscales. Parental substance abuse was also associated with NSSI (p = .006, OR = 3.23; 95% confidence interval [CI] = 1.36 to 7.66) and suicide attempts (p = .018, OR = 2.75; 95% CI = 1.18 to 6.42). Each additional ACE factor predicted an increased probability of NSSI (p = .016, OR = 1.29; CI = 1.04 to 1.59) but not of suicide attempts. When anxiety and depressive disorders were included in the model, ACE remained a significant predictor of NSSI.

Conclusions

We report extensive ACE, from both files and self-reports. When comparing groups, correlations were found between ACE and NSSI, and ACE and suicide attempts among forensic psychiatric patients. ACE seem to predict NSSI but not suicide attempts in this group, even when controlling for affective and anxiety disorders. Early ACE among forensic psychiatric patients, especially physical and emotional abuse and parental substance abuse, have important impacts on self-harming behaviours that must be acknowledged both by the institutions that meet them as children and in their later assessment and treatment.
Dynamic ultrasound reveals the specific behavior of the medial meniscus extrusion in patients with knee osteoarthritis
Authors: Ishii Yosuke , Ishikawa Masakazu , Nakashima Yuko , Hashizume Takato , Okamoto Saeko , Iwamoto Yoshitaka , Okada Kaoru , Takagi Kazuya , Takahashi Makoto , Adachi Nobuo
Published: April 2023

Background

In the dynamic condition, knee osteoarthritis (OA) usually presents with pain. In the weight-bearing condition, a medial meniscus extrusion (MME) may cause severe symptoms and pathological progression. However, the correlation between a dynamic MME and pain has not been elucidated. Now, an MME can be evaluated under dynamic conditions and reflect the characteristics of symptomatic knee OA. This study investigated MMEs during walking and their correlation with knee pain.

Methods

Thirty-two symptomatic patients with knee OA (mean age, 60.5 ± 9.9 years) were enrolled in this study. The medial meniscus was evaluated using ultrasonograms during walking, and in the static supine and unipedal standing positions, as dynamic and static conditions, respectively. The ΔMME (the difference between the maximum and minimum MMEs) was obtained in each condition. The intensity of the knee pain during walking was measured by the visual analog scale (VAS).

Results

The ΔMME in the dynamic condition was significantly higher than that in the static condition (P < 0.01). There was a significant correlation between VAS and ΔMME only in the dynamic condition.

Conclusions

The dynamic evaluation is a valid tool for understanding the mechanisms of knee pain and the behavior of the medial meniscus in symptomatic knee OA.
Attitudes toward depression among rural primary healthcare providers in hunan areas, China: a cross sectional study
Authors: Xie Jianfei , Liu Min , Ding Siqing , Zhong Zhuqing , Zeng Sainan , Liu Aizhong , He Shiwen , Zhou Jianda
Published: April 2023

Background

Mental health services are not sufficient for depression patients in rural areas of China, training in mental health knowledge for primary healthcare providers has been encouraged, but the effect of this encouragement has rarely been reported.

Methods

A cross-sectional survey was conducted in primary healthcare facilities that sought to include all the primary healthcare providers (registered physicians and nurses) in two cities in Hunan province, China by administering questionnaires that covered depression symptoms, typical depression cases, and the Revised Depression Attitude Questionnaire.

Results

In total, 315 primary healthcare providers agreed to participate in the study and finished the questionnaires, of which 12.1% had training in depression. In addition, 62.9% of the rural primary healthcare providers were able to recognize most general depression symptoms, and 8.3% were able to recognize all general depression symptoms. The primary healthcare providers in the survey held a neutral to slightly negative attitude towards depression as indicated by their professional confidence (mean scores 16.51 ± 4.30), therapeutic optimism/pessimism (mean scores 29.02 ± 5.98), and general perspective (mean scores 18.12 ± 3.12) scores. Fewer rural primary healthcare providers knew (28.3%) or applied (2.9%) psychological intervention in the clinic.

Conclusions

Our study indicated that primary healthcare providers knew about general depression symptoms, but lacked psychological intervention skills and held low confidence in and pessimistic attitudes toward depression care. We therefore speculate that existing psychological training for primary healthcare providers is insufficient in quantity and quality, making the need to explore more effective types of training urgently.
Evaluating a novel intervention in undergraduate medicine: an MBBS Curriculum Map
Authors: Wardle Katie , Chakrabarti Rima , Wright Tor , Bennie Taylor , Ntuiabane Daniel , Gishen Faye
Published: April 2023

Background

Following student feedback, a Curriculum Map (CM) was commissioned in 2018 at UCL Medical School (UCLMS). After exploring key requirements of a CM, the second phase focused on building a prototype before its launch. This study evaluates this novel pedagogical intervention following its implementation, from the perspective of its primary users, UCL medical students.

Methods

This multi-method study was conducted two months after the CM’s launch in 2019. Quantitative and qualitative data was gathered via a survey and focus groups across four domains: usefulness, satisfaction, appearance, and content. Reflective Thematic Analysis was used to analyse the qualitative data to build themes.

Results

One hundred ninety five participants (195/1347, 14%) responded to the survey and two focus groups were held. Higher rates of satisfaction were seen among later years compared to early years students. Five key themes emerged on the CM as a: UCLMS textbook; learning aid for assessments; tool for capturing scientific content; modern learning technology and tool for ‘levelling the playing field’. Key findings suggest that while students welcomed a centralised resource to create transparency, there were clear differences between early and later years students, with the former preferring a more prescriptive approach. Learning was assessment-driven across all years and students highlighted their desire for greater clarity on the importance of curricular content for summative assessments.

Conclusion

A CM provides a benchmark for medical educators on the undergraduate curriculum, which must be balanced with its limitations; a CM cannot provide an exhaustive syllabus and needs to be supplemented with self-directed learning and clinical preparation for practice.
A randomized controlled trial of a nurse-led psychological pain solution-focused intervention for depressed inpatients: study protocol
Authors: Chen Shu-Yan , Bian Cheng , Cheng Yin , Zhao Wei-Wei , Yan Shi-Rui , Zhang Yan-Hong
Published: April 2023

Background

Depressed patients commonly experience psychological pain. Research pointed to positive psychological interventions as an effective means of ameliorating psychological pain, although the exact effect is unclear. Based on the hope theory and solution-focused brief therapy (SFBT), this study combines hope theory with solution-focused brief therapy to develop a nurse-led psychological pain solution-focused (PPSF) intervention in depressed patients.

Methods

This is an assessor-blinded randomized controlled trial following the SPIRIT guidance. A total of 84 depressed patients will be recruited from the inpatient wards of a psychiatric hospital and randomly assigned to the control and experimental groups. Patients in the control group will be treated as usual. In contrast, patients in the experimental group will receive 6 sessions of the PPSF intervention for two weeks on top of the routine care. Primary outcomes are psychological pain, hope, cognitive distortions. Secondary outcomes are depression and suicidal ideation. Data will be collected at 5-time points: baseline, 1 and 2 weeks (post-intervention), 1 month (follow up), and 6 months after baseline. Generalized equation evaluation will be used to assess the effectiveness of the PPSF intervention.

Discussion

From a positive psychology perspective, there remains much room for developing psychological pain interventions in depressed patients. SFBT and hope theory are both based on positive psychology. With hope theory as the general framework and SFBT questions as the practical guide, the PPSF intervention program is designed that nursing staff can implement. If the intervention is effective, it will advance the development of psychological pain interventions for patients with depression.

Trial registration

ChiCTR2100048223
Transformative dimensions of resilience and brittleness during health systems’ collapse: a case study in Brazil using the Functional Resonance Analysis Method
Authors: de Carvalho Paulo Victor Rodrigues , Bellas Hugo , Viana Jaqueline , de Castro Nunes Paula , Arcuri Rodrigo , da Silva Fonseca Valéria , Carneiro Ana Paula Morgado , Jatobá Alessandro
Published: April 2023

Background

As health systems struggle to tackle the spread of Covid-19, resilience becomes an especially relevant attribute and research topic. More than strength or preparedness, to perform resiliently to emerging shocks, health systems must develop specific abilities that aim to increase their potential to adapt to extraordinary situations while maintaining their regular functioning.

Brazil has been one of the most affected countries during the pandemic. In January 2021, the Amazonas state's health system collapsed, especially in the city of Manaus, where acute Covid-19 patients died due to scarcity of medical supplies for respiratory therapy.

Methods

This paper explores the case of the health system's collapse in Manaus to uncover the elements that prevented the system from performing resiliently to the pandemic, by carrying out a grounded-based systems analysis of the performance of health authorities in Brazil using the Functional Resonance Analysis Method. The major source of information for this study was the reports from the congressional investigation carried out to unveil the Brazilian response to the pandemic.

Results

Poor cohesion between the different levels of government disrupted essential functions for managing the pandemic. Moreover, the political agenda interfered in the abilities of the system to monitor, respond, anticipate, and learn, essential aspects of resilient performance.

Conclusions

Through a systems analysis approach, this study describes the implicit strategy of "living with Covid-19", and an in-depth view of the measures that hampered the resilience of the Brazilian health system to the spread of Covid-19.
Phylogenomics revealed migration routes and adaptive radiation timing of Holarctic malaria mosquito species of the Maculipennis Group
Authors: Yurchenko Andrey A. , Naumenko Anastasia N. , Artemov Gleb N. , Karagodin Dmitry A. , Hodge James M. , Velichevskaya Alena I. , Kokhanenko Alina A. , Bondarenko Semen M. , Abai Mohammad R. , Kamali Maryam , Gordeev Mikhail I. , Moskaev Anton V. , Caputo Beniamino , Aghayan Sargis A. , Baricheva Elina M. , Stegniy Vladimir N. , Sharakhova Maria V. , Sharakhov Igor V.
Published: April 2023

Background

Phylogenetic analyses of closely related species of mosquitoes are important for better understanding the evolution of traits contributing to transmission of vector-borne diseases. Six out of 41 dominant malaria vectors of the genusAnophelesin the world belong to the Maculipennis Group, which is subdivided into two Nearctic subgroups (Freeborni and Quadrimaculatus) and one Palearctic (Maculipennis) subgroup. Although previous studies considered the Nearctic subgroups as ancestral, details about their relationship with the Palearctic subgroup, and their migration times and routes from North America to Eurasia remain controversial. The Palearctic speciesAn. beklemisheviis currently included in the Nearctic Quadrimaculatus subgroup adding to the uncertainties in mosquito systematics.

Results

To reconstruct historic relationships in the Maculipennis Group, we conducted a phylogenomic analysis of 11 Palearctic and 2 Nearctic species based on sequences of 1271 orthologous genes. The analysis indicated that the Palearctic speciesAn. beklemisheviclusters together with other Eurasian species and represents a basal lineage among them. Also,An. beklemisheviis related more closely toAn. freeborni, which inhabits the Western United States, rather than toAn. quadrimaculatus, a species from the Eastern United States. The time-calibrated tree suggests a migration of mosquitoes in the Maculipennis Group from North America to Eurasia about 20–25 million years ago through the Bering Land Bridge. A Hybridcheck analysis demonstrated highly significant signatures of introgression events between allopatric speciesAn. labranchiaeandAn. beklemishevi. The analysis also identified ancestral introgression events betweenAn. sacharoviand its Nearctic relativeAn. freebornidespite their current geographic isolation. The reconstructed phylogeny suggests that vector competence and the ability to enter complete diapause during winter evolved independently in different lineages of the Maculipennis Group.

Conclusions

Our phylogenomic analyses reveal migration routes and adaptive radiation timing of Holarctic malaria vectors and strongly support the inclusion ofAn. beklemisheviinto the Maculipennis Subgroup. Detailed knowledge of the evolutionary history of the Maculipennis Subgroup provides a framework for examining the genomic changes related to ecological adaptation and susceptibility to human pathogens. These genomic variations may inform researchers about similar changes in the future providing insights into the patterns of disease transmission in Eurasia.
The relationship between sphingosine-1-phosphate receptor 2 and epidermal growth factor in migration and invasion of oral squamous cell carcinoma
Authors: Wongviriya Adjabhak , Shelton Richard M. , Cooper Paul R. , Milward Michael R. , Landini Gabriel
Published: April 2023

Sphingosine-1-phosphate (S1P) is a lipid mediator and its binding to the S1P receptor 2 (S1PR2) is reported to regulate cytoskeletal organization. Epidermal growth factor (EGF) has been shown to induce migration and invasion in tumour cells. Since binding of S1P to S1PR2 and EGF to the EGF receptors exhibit some overlapping functionality, this study aimed to determine whether S1PR2 was involved in EGF-induced migration and invasion of oral squamous cell carcinoma (OSCC) lines and to identify any potential crosstalk between the two pathways. Migration was investigated using the scratch wound assay while invasion was studied using the transwell invasion and multicellular tumour spheroid (MCTS) assays. Activity of Rac1, a RhoGTPase, was measured using G-LISA (small GTPase activation assays) while S1P production was indirectly measured via the expression of sphingosine kinase (Sphk). S1PR2 inhibition with 10 µM JTE013 reduced EGF-induced migration, invasion and Rac1 activity, however, stimulation of S1PR2 with 10 µM CYM5478 did not enhance the effect of EGF on migration, invasion or Rac1 activity. The data demonstrated a crosstalk between EGF/EGFR and S1P/S1PR2 pathways at the metabolic level. S1PR2 was not involved in EGF production, but EGF promoted S1P production through the upregulation of Sphk1. In conclusion, OSCC lines could not migrate and invade without S1PR2 regulation, even with EGF stimulation. EGF also activated S1PR2 by stimulating S1P production via Sphk1. The potential for S1PR2 to control cellular motility may lead to promising treatments for OSCC patients and potentially prevent or reduce metastasis.
Genome-wide association testing in malaria studies in the presence of overdominance
Authors: Akoth Morine , Odhiambo John , Omolo Bernard
Published: April 2023

Background

In human genetics, heterozygote advantage (heterosis) has been detected in studies that focused on specific genes but not in genome-wide association studies (GWAS). For example, heterosis is believed to confer resistance to certain strains of malaria in patients heterozygous for the sickle-cell gene, haemoglobin S (HbS). Yet the power of allelic tests can be substantially diminished by heterosis. Since GWAS (and haplotype-associations) also utilize allelic tests, it is unclear to what degree GWAS could underachieve because heterosis is ignored.

Methods

In this study, a two-step approach to genetic association testing in malaria studies in a GWAS setting that may enhance the power of the tests was proposed, by identifying the underlying genetic model first before applying the association tests. Generalized linear models for dominant, recessive, additive, and heterotic effects were fitted and model selection was performed. This was achieved via tests of significance using the MAX and allelic tests, noting the minimump-values across all the models and the proportion of tests that a given genetic model was deemed the best. An example dataset, based on 17 SNPs, from a robust genetic association study and simulated genotype datasets, were used to illustrate the method. Case–control genotype data on malaria from Kenya and Gambia were used for validation.

Results and conclusion

Results showed that the allelic test returned some false negatives under the heterosis model, suggesting reduced power in testing genetic association. Disparities were observed for some chromosomes in the Kenyan and Gambian datasets, including the sex chromosomes. Thus, GWAS and haplotype associations should be treated with caution, unless the underlying genetic model had been determined.
Super-enhancer-driven TOX2 mediates oncogenesis in Natural Killer/T Cell Lymphoma
Authors: Zhou Jianbiao , Toh Sabrina Hui-Min , Tan Tze King , Balan Kalpnaa , Lim Jing Quan , Tan Tuan Zea , Xiong Sinan , Jia Yunlu , Ng Siok-Bian , Peng Yanfen , Jeyasekharan Anand D. , Fan Shuangyi , Lim Soon Thye , Ong Chin-Ann Johnny , Ong Choon Kiat , Sanda Takaomi , Chng Wee-Joo
Published: April 2023

Background

Extranodal natural killer/T-cell lymphoma (NKTL) is an aggressive type of non-Hodgkin lymphoma with dismal outcome. A better understanding of disease biology and key oncogenic process is necessary for the development of targeted therapy. Super-enhancers (SEs) have been shown to drive pivotal oncogenes in various malignancies. However, the landscape of SEs and SE-associated oncogenes remain elusive in NKTL.

Methods

We used Nano-ChIP-seq of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs NKTL primary tumor samples. Integrative analysis of RNA-seq and survival data further pinned down high value, novel SE oncogenes. We utilized shRNA knockdown, CRISPR-dCas9, luciferase reporter assay, ChIP-PCR to investigate the regulation of transcription factor (TF) on SE oncogenes. Multi-color immunofluorescence (mIF) staining was performed on an independent cohort of clinical samples. Various function experiments were performed to evaluate the effects of TOX2 on the malignancy of NKTL in vitro and in vivo.

Results

SE landscape was substantially different in NKTL samples in comparison with normal tonsils. Several SEs at key transcriptional factor (TF) genes, including TOX2, TBX21(T-bet), EOMES, RUNX2, and ID2, were identified. We confirmed that TOX2 was aberrantly overexpressed in NKTL relative to normal NK cells and high expression of TOX2 was associated with worse survival. Modulation of TOX2 expression by shRNA, CRISPR-dCas9 interference of SE function impacted on cell proliferation, survival and colony formation ability of NKTL cells. Mechanistically, we found that RUNX3 regulates TOX2 transcription by binding to the active elements of its SE. Silencing TOX2 also impaired tumor formation of NKTL cells in vivo. Metastasis-associated phosphatase PRL-3 has been identified and validated as a key downstream effector of TOX2-mediated oncogenesis.

Conclusions

Our integrative SE profiling strategy revealed the landscape of SEs, novel targets and insights into molecular pathogenesis of NKTL. The RUNX3-TOX2-SE-TOX2-PRL-3 regulatory pathway may represent a hallmark of NKTL biology. Targeting TOX2 could be a valuable therapeutic intervene for NKTL patients and warrants further study in clinic.
The cervical lymph node contributes to peripheral inflammation related to Parkinson’s disease
Authors: Liu Zongran , Huang Yang , Wang Xuejing , Li Jia-Yi , Zhang Can , Yang Ying , Zhang Jing
Published: April 2023

Background

Peripheral inflammation is an important feature of Parkinson’s disease (PD). However, if and how CNS pathology is involved in the peripheral inflammation in PD remains to be fully investigated. Recently, the existence of meningeal lymphatics and its involvement in draining cerebral spinal fluid (CSF) to the cervical lymph node has been discovered. It is known that meningeal lymphatic dysfunction exists in idiopathic PD. The deep cervical lymph node (dCLN) substantially contributes to the drainage of the meningeal lymphatics. In addition, one of the lymphatics draining components, CSF, contains abundant α-synuclein (α-syn), a protein critically involved in PD pathogenesis and neuroinflammation. Thus, we began with exploring the possible structural and functional alterations of the dCLN in a PD mouse model (A53T mice) and investigated the role of pathological α-syn in peripheral inflammation and its potential underlying molecular mechanisms.

Methods

In this study, the transgenic mice (prnp-SNCA*A53T) which specifically overexpressed A53T mutant α-syn in CNS were employed as the PD animal model. Immunofluorescent and Hematoxylin and eosin staining were used to evaluate structure of dCLN. Inflammation in dCLNs as well as in bone-marrow-derived macrophages (BMDMs) was assessed quantitatively by measuring the mRNA and protein levels of typical inflammatory cytokines (including IL-1β, IL-6 and TNF-α). Intra-cisterna magna injection, flow cytometric sorting and electrochemiluminescence immunoassays were applied to investigate the lymphatic drainage of α-syn from the CNS. RNA-seq and Western blot were used to explore how pathological α-syn mediated the inflammation in PD mice.

Results

The results unequivocally revealed substantially enlarged dCLNs, along with slow lymphatic flow, and increased inflammation in the dCLNs of A53T mice. Oligomeric α-syn drained from CSF potently activated macrophages in the dCLN via endoplasmic reticulum (ER) stress. Notably, inhibition of ER stress effectively suppressed peripheral inflammation in PD mice.

Conclusions

Our findings indicate that lymph node enlargement is closely related to macrophage activation, induced by meningeal lymphatics draining oligomeric α-syn, and contributes to the peripheral inflammation in PD. In addition, ER stress is a potential therapeutic target to ameliorate PD pathogenesis.
Offspring thermal demands and parental brooding efficiency differ for precocial birds living in contrasting climates
Authors: Kolešková Veronika , Šálek Miroslav E. , Brynychová Kateřina , Chajma Petr , Pešková Lucie , Elhassan Esmat , Petrusová Vozabulová Eva , Janatová Veronika , Almuhery Aisha , Sládeček Martin
Published: April 2023

Background

Chicks of precocial birds hatch well-developed and can search actively for food but their homeothermy develops gradually during growth. This makes them dependent on heat provided by parents (“brooding”), which is then traded off against other activities, mainly foraging. Although brooding has been documented in many precocial birds, little is known about the differences in the amount and efficiency of brooding care, brooding diel rhythmicity, and impact on the chick’s growth, particularly between species living in different climatic conditions.

Results

We used multisensory dataloggers to evaluate brooding patterns in two congeneric species inhabiting contrasting climate zones: temperate Northern lapwing (Vanellus vanellus) and desert Red-wattled lapwing (Vanellus indicus). In accordance with our expectation, the adult desert lapwings brooded the chicks slightly less compared to the adult temperate lapwings. However, the desert lapwings brooded their chicks in higher ambient temperatures and less efficiently (i.e. they could not reach the same brooding temperature as the temperate lapwings), which are new and hitherto unknown brooding patterns in precocial birds. In both species, night brooding prevailed even during warm nights, suggesting a general brooding rule among birds. Although the high rates of brooding can reduce the time spent by foraging, we found no negative effect of the high brooding rate on the growth rate in either species.

Conclusions

Our data suggest that the chicks of species breeding in colder climates may reduce their thermal demands, while their parents may increase the efficiency of parental brooding care. More research is however needed to confirm this as a rule across species.
The effect of temperature and invasive alien predator on genetic and phenotypic variation in the damselfly Ischnura elegans: cross-latitude comparison
Authors: Wos Guillaume , Palomar Gemma , Marszałek Marzena , Babik Wiesław , Sniegula Szymon
Published: April 2023

Background

Understanding and predicting how organisms respond to human-caused environmental changes has become a major concern in conservation biology. Here, we linked gene expression and phenotypic data to identify candidate genes underlying existing phenotypic trait differentiation under individual and combined environmental variables. For this purpose, we used the damselflyIschnura elegans. Egg clutches from replicated high- (southern Sweden) and central-latitude (southern Poland) populations facing different degrees of seasonal time constraints were collected. Damselfly larvae were exposed to experimental treatments: current and mild warming temperatures crossed with the presence or absence of an invasive alien predator cue released by the spiny-cheek crayfish,Faxonius limosus, which is only present in Poland to date. We measured the following traits: larval development time, body size, mass and growth rate, and used the larvae for gene expression analysis by RNA-seq. Data were analysed using a multivariate approach.

Results

We showed latitudinal differences in coping with mild warming and predator cues. When exposed to an increased temperature and a predator cue, central-latitude individuals had the shortest development and the fastest growth compared to high-latitude individuals. There was a general effect of predator cues regarding mass and growth rate reduction independent of latitude. Transcriptome analysis revealed that metabolic pathways related to larval anatomy and development tended to be upregulated in response to mild warming but only in fast-growing central-latitude individuals. Metabolic pathways linked to oxidative stress tended to be downregulated in response to a predator cue, especially in central-latitude individuals.

Conclusion

Different phenotypic and transcriptomic responses to environmental factors might be attributed to the variability inI. eleganslife history strategies between the two latitudes caused by seasonal time constraints and to its coexistence with the invasive alien predator in nature. By providing insights into how organisms may respond to future anthropogenic changes, our results may be of particular interest in conservation biology.
Modifiable factors associated with a consistently high acute pain trajectory after surgical treatment of traumatic fractures in Ethiopia: a multi-center prospective cohort study
Authors: Getachew Mestawet , Lerdal Anners , Småstuen Milada Cvancarova , Eshete Million Tesfaye , Desta Tilahun , Lindberg Maren Falch
Published: April 2023

Background

In Ethiopia, little is known about postoperative pain trajectories and possible predictive factors associated with them in patients undergoing surgery following traumatic fractures.

Methods

This multi-center prospective observational cohort study included surgical candidates for traumatic fractures (n = 218). Worst pain intensity was measured with an 11-point numeric rating scale on the first 4 postoperative days and day of hospital discharge. Growth mixture modeling was used to identify subgroups of patients based on their pain trajectories, and logistic regression models to quantify associations between pain trajectories and demographic, clinical, psychological, and life style factors.

Results

Two postoperative pain trajectory subgroups were identified: rapid pain relief (48% of included individuals) and consistently high pain (52% of included individuals). Sub-analysis stratified by cause of injury demonstrated that higher preoperative pain was an independent risk factor for consistently high postoperative pain regardless of the patient’s injury type: traffic accident (OR = 1.48, 95% CI 1.23–1.79), machine/tool injury or conflict (OR = 1.58, 95% CI 1.11–2.26), or fall (OR = 1.47, 95% CI 1.08–1.99). Moreover, longer surgical time was a risk factor for consistently high postoperative pain among patients who had a fall-related injury (OR = 1.02, 95% CI 1.00–1.03). In contrast, among patients with a traffic-related injury, receiving a nerve block was a protective factor (OR = 0.19, 95% CI 0.04–0.87) compared with general anesthesia.

Conclusion

Higher preoperative pain and longer surgical time were associated with a consistently high acute postoperative pain trajectory. Clinicians may use these potentially modifiable factors to identify patients at risk for consistently high pain during the early postoperative period.
Adverse effects associated with acupuncture therapies: An evidence mapping from 535 systematic reviews
Authors: Xu Meng , Yang Chaoqun , Nian Tao , Tian Chen , Zhou Liying , Wu Yanan , Li Yanfei , Deng Xinxin , Li Xiuxia , Yang Kehu
Published: April 2023

Background and Objective

Considering that physicians and patients widely use acupuncture, it is necessary to explore its adverse effects during treatment. Herein, an evidence map was generated based on published studies to identify acupuncture-induced adverse effects and assess their severity, with the overarching goal of providing references for safe and effective implementation.

Methods

A comprehensive literature search was performed in four public databases (PubMed, Embase, Web of science, and the Cochrane Library) to identify relevant studies published up to 15th June 2022. In addition, relevant studies were explored in the Epistemonikos database and reference lists were retrieved as a supplement. A MeaSurement Tool to Assess systematic Reviews, Version 2 (AMSTAR-2) quality assessment tool was applied to determine the methodological quality of included systematic reviews (SRs) and/or meta-analysis (MAs), whereas Microsoft Excel 2019 tool was used for data extraction and coding. Heatmaps were generated to display disease type, countries of origin for the first authors, and the sample sizes of original studies. Moreover, bubble charts comprehensively presented intervention categories, adverse reaction types, and evidence levels.

Results

A total of 535 SRs involving 33 adverse reactions were included. Among them, 22 studies were rated as high quality, 28 as moderate, 106 as low, and the rest were of critically-low quality. Numerous adverse effects were described in the studies, including syncope (86 SRs), organ or tissue injury (233 SRs), systemic reactions (113 SRs), infection (19 SRs), and other adverse events (373 SRs). Importantly, these adverse reactions were mainly associated with 19 acupuncture techniques, including electroacupuncture (n = 67), manual acupuncture (n = 47) and acupoint catgut embedding (n = 41). Furthermore, the 535 SRs described 23 diseases, among which symptoms, signs or clinical findings (83 SRs), mental, behavioral or neurodevelopmental disorders (67 SRs), and diseases of the nervous system (66 SRs) had the highest incidence.

Conclusion

This evidence mapping explores the adverse effects of acupuncture, showing that there are multiple types of adverse reactions to acupuncture, with milder symptoms. The methodological assessment revealed that most of the included studies were of low- or critically low-quality. Therefore, there is a need for future randomized controlled trials and SRs to comprehensively analyze acupuncture-related adverse events in order to provide reliable and credible evidence.
The intracranial compartmental syndrome: a proposed model for acute brain injury monitoring and management
Authors: Godoy Daniel Agustín , Brasil Sérgio , Iaccarino Corrado , Paiva Wellingson , Rubiano Andres M.
Published: April 2023

For decades, one of the main targets in the management of severe acute brain injury (ABI) has been intracranial hypertension (IH) control. However, the determination of IH has suffered variations in its thresholds over time without clear evidence for it. Meanwhile, progress in the understanding of intracranial content (brain, blood and cerebrospinal fluid) dynamics and recent development in monitoring techniques suggest that targeting intracranial compliance (ICC) could be a more reliable approach rather than guiding actions by predetermined intracranial pressure values. It is known that ICC impairment forecasts IH, as intracranial volume may rapidly increase inside the skull, a closed bony box with derisory expansibility. Therefore, an intracranial compartmental syndrome (ICCS) can occur with deleterious brain effects, precipitating a reduction in brain perfusion, thereby inducing brain ischemia. The present perspective review aims to discuss the ICCS concept and suggest an integrative model for the combination of modern invasive and noninvasive techniques for IH and ICC assessment. The theory and logic suggest that the combination of multiple ancillary methods may enhance ICC impairment prediction, pointing proactive actions and improving patient outcomes.