bluuebunny/crossref_metadata_2025 huggingface dataset:
Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome: protocol for a series of randomized, placebo-controlled N-of-1 trials
Authors: Müller A. R. , den Hollander B. , van de Ven P. M. , Roes K. C. B. , Geertjens L. , Bruining H. , van Karnebeek C. D. M. , Jansen F. E. , de Wit M. C. Y. , ten Hoopen L. W. , Rietman A. B. , Dierckx B. , Wijburg F. A. , Boot E. , Brands M. M. G. , van Eeghen A. M.
Published: January 2024

Background

Many rare genetic neurodevelopmental disorders (RGNDs) are characterized by intellectual disability (ID), severe cognitive and behavioral impairments, potentially diagnosed as a comorbid autism spectrum disorder or attention-deficit hyperactivity disorder. Quality of life is often impaired due to irritability, aggression and self-injurious behavior, generally refractory to standard therapies. There are indications from previous (case) studies and patient reporting that cannabidiol (CBD) may be an effective treatment for severe behavioral manifestations in RGNDs. However, clear evidence is lacking and interventional research is challenging due to the rarity as well as the heterogeneity within and between disease groups and interindividual differences in treatment response. Our objective is to examine the effectiveness of CBD on severe behavioral manifestations in three RGNDs, including Tuberous Sclerosis Complex (TSC), mucopolysaccharidosis type III (MPS III), and Fragile X syndrome (FXS), using an innovative trial design.

Methods

We aim to conduct placebo-controlled, double-blind, block-randomized, multiple crossover N-of-1 studies with oral CBD (twice daily) in 30 patients (aged ≥ 6 years) with confirmed TSC, MPS III or FXS and severe behavioral manifestations. The treatment is oral CBD up to a maximum of 25 mg/kg/day, twice daily. The primary outcome measure is the subscale irritability of the Aberrant Behavior Checklist. Secondary outcome measures include (personalized) patient-reported outcome measures with regard to behavioral and psychiatric outcomes, disease-specific outcome measures, parental stress, seizure frequency, and adverse effects of CBD. Questionnaires will be completed and study medication will be taken at the participants’ natural setting. Individual treatment effects will be determined based on summary statistics. A mixed model analysis will be applied for analyzing the effectiveness of the intervention per disorder and across disorders combining data from the individual N-of-1 trials.

Discussion

These N-of-1 trials address an unmet medical need and will provide information on the effectiveness of CBD for severe behavioral manifestations in RGNDs, potentially generating generalizable knowledge at an individual-, disorder- and RGND population level.

Trial registration

EudraCT: 2021-003250-23, registered 25 August 2022, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-003250-23/NL.
Dental service utilization and the COVID-19 pandemic, a micro-data analysis
Authors: akbari Amir , khami Mohammad Reza , Beymouri Amine , Akbari Solmaz
Published: January 2024

Background

Global crises and disease pandemics, such as COVID-19, negatively affect dental care utilization by several factors, such as infection anxiety, disrupted supply chains, economic contraction, and household income reduction. Exploring the pattern of this effect can help policy makers to be prepared for future crises. The present study aimed to investigate the financial impact of COVID‐19 disruptions on dental service utilization.

Methods

Data on the number of dental services offered in Dental School Clinics of Tehran University of Medical Sciences was collected over a period of two years, before and after the initial COVID-19 outbreak in Iran. School of Dentistry operates two clinics; one with competitive service fees and one with subsidies. Regression analyses were performed to determine the effect of the pandemic on the number of dental services divided by dental treatment groups and these clinics. The analyses were adjusted for seasonal patterns and the capacity of the clinics.

Results

There was a significant drop in dental services offered in both clinics across all dental groups in the post-COVID period (on average, 77 (39.44%) fewer services per day). The majority of the procedure loss happened in the Private clinic. Adjusting for seasonal patterns and the service capacity, regression results documented 54% and 12% service loss in Private and Subsidized clinics following the pandemic, respectively. Difference-in-difference analysis documented that the Subsidized clinic performed 40% more treatments than the Private clinic in the post-COVID period.

Conclusions

Pandemic –reduction in dental care utilization could have long-term ramifications for the oral health of the population, and policymakers need to provide supportive packages to the affected segments of the economy to reverse this trend.
Role of finite element analysis for selection of single point fixation in zygomaticomaxillary complex fracture
Authors: Refahee Shaimaa Mohsen , Khalifa Mahmoud Elsayed , Askar Mohamed Gamal , Breshah Maram N.
Published: January 2024

Background

One-point fixation was superior to the two and three-points fixation in minimally displaced zygomaticomaxillary complex (ZMC) fracture regarding the cost, invasiveness, scaring, number of wounds, and operation time. Accordingly, this study aimed to predict which one-point fixation is the most stable in managing minimally displaced ZMC fracture.

Material & methods

This study simulated the different one-point fixation approaches on three ZMC models after fracture reduction and application of all forces exerted on the fractured area. The findings were represented as stress impact on the ZMC fracture and plating system as well as the inter-fragments micro-motion.

Results

The von misses stresses of plates for the zygomaticofrontal, infra-orbital rim, and zygomaticomaxillary buttress model were (66.508, 1.285, and1.16 MPa) respectively. While the screws’ von misses for the infraorbital rim, zygomaticofrontal, and zygomaticomaxillary buttress models were (13.8, 4.05, and 1.60 MPa) respectively. Whereas, the maximum principles stress at zygomaticofrontal, zygomaticomaxillary buttress, and infraorbital rim models were (37.03, 37.01, and 34.46 MPa) respectively. In addition, the inter-fragment micro-motion for zygomaticomaxillary buttress, infraorbital rim, and zygomaticofrontal models were (0.26, 0.25, and 0.15 mm) respectively.

Conclusion

One-point fixation at zygomaticomaxillary buttress is the preferred point because it is exposed to low stresses, and the inter-fragment micro-motion is within the approved limit with the elements in the same direction of fixation which indicates the rigid fixation. In addition, it is less palpable and scarless.

Trial registration

clinical trial.gov (NCT05819372) at 19/04/2023.
The state of health professions students’ self-directed learning ability during online study and the factors that influence it
Authors: Xu Xiaoyue , Li Ziyi , Mackay Louisa , Li Na , Zhang Yaheng , Wu Yujie , Zhang Yang
Published: January 2024

Background

Universities have widely switched from traditional face-to-face classes to online instruction as a result of the epidemic. Self-directed learning is becoming the new norm for university students’ learning styles. The ability of health professions students to learn independently during online study directly impacts the effectiveness of online medical education. The ability to learn on their own initiative may be affected by health professions students’ professional identities, defined as their positive perceptions, evaluations, emotional experiences, and identity as professionals related to medicine. This study aimed to look into the current status and the factors that influence health professions students’ self-directed learning ability (SDLA) during online study and its relationship with professional identity.

Methods

This study was conducted from September to November 2022 at a medical school in East China. An online questionnaire was used to collect participants’ status of online learning, self-directed learning ability (SDLA), and professional identity.

Results

One thousand two hundred ninety-eight health professions students demonstrated intermediate self-directed learning ability during online study. In terms of teacher-student interaction (F = 14.778, P < 0.001), student–student interaction (F = 15.713, P < 0.001), and learning concentration (F = 13.424, P < 0.001), there were significant differences in health professions students’ self-directed learning ability. Professional identity and self-directed learning ability positively correlated (r = 0.589–0.802, P < 0.01). Academic atmosphere and professional identity were significant predictors.

Conclusions

The self-directed learning ability of health professions students while receiving instruction online is at an intermediate level and is influenced by several factors. Developing health professions students’ professional identities can enhance their ability for self-directed learning.
Symbolic access: medical students’ awareness of institutional culture and its influence on learning, a phenomenographic study
Authors: Lulua Dina-Ruth , Moch Shirra
Published: January 2024

Background

The discussion of access in medical education has its focus largely on physical and epistemological access, leaving a qualitative gap regarding sociocultural factors which enable access in this context. This study introduces and defines symbolic access, a concept with a specific lens on sociocultural inclusion, and the influence it has on student learning within the South African medical education landscape.

Methods

A phenomenographic design was used to explore students’ conceptions of symbolic access and its impact on learning. One-on-one exploratory interviews were conducted with fifteen final year medical students at the University of Witwatersrand in Johannesburg. Interviews were analysed using Sjöström and Dahlgren‘s seven-step phenomenography model.

Results

Four categories of description were induced, which described students’ understanding of symbolic access, these were rejection, disregard, invalidation, and actualization. Four dimensions of variation were discovered expressing the diversity of events which informed the collectives’ understanding of the phenomenon. These dimensions were; interactions with educators, peer relationships, educational environment, and race. Categories of description and dimensions of variation formed the Outcome Space, a visual representation of the student experience of symbolic access. The outcome space had a double narrative related to symbolic access; exclusion (major) and actualization (minor). Medical student’s chief experience within the medical community was exclusion, however clinical immersion, meaningful participation, peer-relationships, and clinical skills lessons facilitated community enculturation, and impacted learning.

Conclusion

Despite deeply exclusionary experiences throughout their programme, medical students articulated a paradox of both awareness and no awareness of symbolic access. The awareness of symbolic access was predominantly influenced by clinical experiences and clinical immersion during the pre-clinical and clinical years of study. Further, descriptions of valuable learning experiences were connected to clinical events and the involvement with patient care. This study suggests that the actualization of symbolic access and description of meaningful learning experiences are linked. Medical educationalists should design undergraduate curricula with early clinical immersion at the fore and explore symbolic concepts pertaining to access, as they are linked to transformative learning experiences for the medical student.
Effect of virtual reality training to enhance laparoscopic assistance skills
Authors: Chen Xiuwen , Liao Peng , Liu Shiqing , Zhu Jianxi , Abdullah Abdullah Sultan , Xiao Yao
Published: January 2024

Background

While laparoscopic assistance is often entrusted to less experienced individuals, such as residents, medical students, and operating room nurses, it is important to note that they typically receive little to no formal laparoscopic training. This deficiency can lead to poor visibility during minimally invasive surgery, thus increasing the risk of errors. Moreover, operating room nurses and medical students are currently not included as key users in structured laparoscopic training programs.

Objectives

The aim of this study is to evaluate the laparoscopic skills of OR nurses, clinical medical postgraduate students, and residents before and after undergoing virtual reality training. Additionally, it aimed to compare the differences in the laparoscopic skills among different groups (OR nurses/Students/Residents) both before and after virtual reality training.

Methods

Operating room nurses, clinical medical postgraduate students and residents from a tertiary Grade A hospital in China in March 2022 were selected as participants. All participants were required to complete a laparoscopic simulation training course in 6 consecutive weeks. One task from each of the four training modules was selected as an evaluation indicator. A before-and-after self-control study was used to compare the basic laparoscopic skills of participants, and laparoscopic skill competency was compared between the groups of operating room nurses, clinical medical postgraduate students, and residents.

Results

Twenty-seven operating room nurses, 31 clinical medical postgraduate students, and 16 residents were included. The training course scores for the navigation training module, task training module, coordination training module, and surgical skills training module between different groups (operating room nurses/clinical medical postgraduate/residents) before laparoscopic simulation training was statistically significant (p < 0.05). After laparoscopic simulation training, there was no statistically significant difference in the training course scores between the different groups. The surgical level scores before and after the training course were compared between the operating room nurses, clinical medical postgraduate students, and residents and showed significant increases (p < 0.05).

Conclusion

Our findings show a significant improvement in laparoscopic skills following virtual surgery simulation training across all participant groups. The integration of virtual surgery simulation technology in surgical training holds promise for bridging the gap in laparoscopic skill development among health care professionals.
Effects of glucagon-like peptide-1 receptor agonists on liver-related and cardiovascular mortality in patients with type 2 diabetes
Authors: Yen Fu-Shun , Hou Ming-Chih , Wei James Cheng-Chung , Shih Ying-Hsiu , Hwu Chii-Min , Hsu Chih-Cheng
Published: January 2024

Background

Patients with type 2 diabetes (T2D) tend to have nonalcoholic fatty liver disease (NAFLD) with poorer prognosis. We performed this research to compare the risks of cardiovascular diseases, cirrhosis, liver-related mortality, and cardiovascular mortality between glucagon-like peptide-1 receptor agonist (GLP-1 RA) use and no-use in patients with T2D without viral hepatitis.

Methods

From January 1, 2008, to December 31, 2018, we used propensity-score matching to identify 31,183 pairs of GLP-1 RA users and nonusers from Taiwan’s National Health Insurance Research Database. Multivariable-adjusted Cox proportional hazards models were used to examine the outcomes between the study and control groups.

Results

The median (Q1, Q3) follow-up time for GLP-1 RA users and nonusers were 2.19 (1.35, 3.52) and 2.14 (1.19, 3.68) years, respectively. The all-cause mortality incidence rate was 5.67 and 13.06 per 1000 person-years for GLP-1 RA users and nonusers, respectively. Multivariable-adjusted analysis showed that GLP-1 RA use had significantly lower risks of all-cause mortality (aHR 0.48, 95%CI 0.43–0.53), cardiovascular events (aHR 0.92, 95%CI 0.86–0.99), cardiovascular death (aHR 0.57, 95%CI 0.45–0.72), and liver-related death (aHR 0.32, 95%CI 0.13–0.75). However, there was no significant difference in the risk of liver cirrhosis development, hepatic failure, and hepatocellular carcinoma compared to GLP-1 RA no-use.

Conclusions

This nationwide cohort study showed that GLP-1 RA use was associated with a significantly lower risk of all-cause mortality, cardiovascular events, and cardiovascular death in patients with T2D among Taiwan population. More prospective studies are warranted to verify our results.
Hospitalisation patterns in interstitial lung diseases: data from the EXCITING-ILD registry
Authors: Buschulte Katharina , Kabitz Hans-Joachim , Hagmeyer Lars , Hammerl Peter , Esselmann Albert , Wiederhold Conrad , Skowasch Dirk , Stolpe Christoph , Joest Marcus , Veitshans Stefan , Höffgen Marc , Maqhuzu Phillen , Schwarzkopf Larissa , Hellmann Andreas , Pfeifer Michael , Behr Jürgen , Karpavicius Rainer , Günther Andreas , Polke Markus , Höger Philipp , Somogyi Vivien , Lederer Christoph , Markart Philipp , Kreuter Michael
Published: January 2024

Background

Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with more than 200 entities and relevant differences in disease course and prognosis. Little data is available on hospitalisation patterns in ILD.

Methods

The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for hospitalisations. Reasons for hospitalisation were classified as all cause, ILD-related and respiratory hospitalisations, and patients were analysed for frequency of hospitalisations, time to first non-elective hospitalisation, mortality and progression-free survival. Additionally, the risk for hospitalisation according to GAP index and ILD subtype was calculated by Cox proportional-hazard models as well as influencing factors on prediction of hospitalisation by logistic regression with forward selection.

Results

In total, 601 patients were included. 1210 hospitalisations were recorded during the 6 months prior to registry inclusion until the last study visit. 800 (66.1%) were ILD-related, 59.3% of admissions were registered in the first year after inclusion. Mortality was associated with all cause, ILD-related and respiratory-related hospitalisation. Risk factors for hospitalisation were advanced disease (GAP Index stages II and III) and CTD (connective tissue disease)-ILDs. All cause hospitalisations were associated with pulmonary hypertension (OR 2.53, p = 0.005). ILD-related hospitalisations were associated with unclassifiable ILD and concomitant emphysema (OR = 2.133, p = 0.001) as well as with other granulomatous ILDs and a positive smoking status (OR = 3.082, p = 0.005).

Conclusion

Our results represent a crucial contribution in understanding predisposing factors for hospitalisation in ILD and its major impact on mortality. Further studies to characterize the most vulnerable patient group as well as approaches to prevent hospitalisations are warranted.
Complete microbial synthesis of crocetin and crocins from glycerol in Escherichia coli
Authors: Lee Jun Ho , Lee Seong-Rae , Lee Sang Yup , Lee Pyung Cheon
Published: January 2024

Background

Crocin, a glycosylated apocarotenoid pigment predominantly found in saffron, has garnered significant interest in the field of biotechnology for its bioactive properties. Traditional production of crocins and their aglycone, crocetin, typically involves extraction from crocin-producing plants. This study aimed to develop an alternative biosynthetic method for these compounds by engineering the metabolic pathways of zeaxanthin, crocetin, and crocin in Escherichia coli strains.

Results

Employing a series of genetic modifications and the strategic overexpression of key enzymes, we successfully established a complete microbial pathway for synthesizing crocetin and four glycosylated derivatives of crocetin, utilizing glycerol as the primary carbon source. The overexpression of zeaxanthin cleavage dioxygenase and a novel variant of crocetin dialdehyde dehydrogenase resulted in a notable yield of crocetin (34.77 ± 1.03 mg/L). Further optimization involved the overexpression of new types of crocetin and crocin-2 glycosyltransferases, facilitating the production of crocin-1 (6.29 ± 0.19 mg/L), crocin-2 (5.29 ± 0.24 mg/L), crocin-3 (1.48 ± 0.10 mg/L), and crocin-4 (2.72 ± 0.13 mg/L).

Conclusions

This investigation introduces a pioneering and integrated microbial synthesis method for generating crocin and its derivatives, employing glycerol as a sustainable carbon feedstock. The substantial yields achieved highlight the commercial potential of microbial-derived crocins as an eco-friendly alternative to plant extraction methods. The development of these microbial processes not only broadens the scope for crocin production but also suggests significant implications for the exploitation of bioengineered compounds in pharmaceutical and food industries.
Combining pathological risk factors and T, N staging to optimize the assessment for risk stratification and prognostication in low-risk stage III colon cancer
Authors: Xian Zhen-Yu , Song Yi-Wen , Zhang Zong-Jin , Gan Ying-Guo , Chen Yong-Le , Hu Tuo , Wen Xiao-Feng , Mo Tai-Wei , He Xiao-Wen
Published: January 2024

Background

This study aimed to investigate the combined pathological risk factors (PRFs) to stratify low-risk (pT1-3N1) stage III colon cancer (CC), providing a basis for individualized treatment in the future.

Patients and methods

PRFs for low-risk stage III CC were identified using COX model. Low-risk stage III CC was risk-grouped combining with PRFs, and survival analysis were performed using Kaplan–Meier. The Surveillance, Epidemiology, and End Results (SEER) databases was used for external validation.

Results

Nine hundred sixty-two stage III CC patients were included with 634 (65.9%) as low risk and 328 (34.1%) as high risk. Poor differentiation (OS: P = 0.048; DFS: P = 0.011), perineural invasion (OS: P = 0.003; DFS: P < 0.001) and tumor deposits (OS: P = 0.012; DFS: P = 0.003) were identified as PRFs. The prognosis of low-risk CC combined with 2 PRFs (OS: HR = 3.871, 95%CI, 2.004–7.479, P < 0.001; DFS: HR = 3.479, 95%CI, 2.158–5.610, P < 0.001) or 3 PRFs (OS: HR = 5.915, 95%CI, 1.953–17.420, P = 0.002; DFS: HR = 5.915, 95%CI, 2.623–13.335, P < 0.001) was similar to that of high-risk CC (OS: HR = 3.927, 95%CI, 2.317–6.656, P < 0.001; DFS: HR = 4.132, 95%CI, 2.858–5.974, P < 0.001). In the SEER database, 18,547 CC patients were enrolled with 10,023 (54.0%) as low risk and 8524 (46.0%) as high risk. Low-risk CC combined with 2 PRFs (OS: HR = 1.857, 95%CI, 1.613–2.139, P < 0.001) was similar to that of high-risk CC without PRFs (HR = 1.876, 95%CI, 1.731–2.033, P < 0.001).

Conclusion

Combined PRFs improved the risk stratification of low-risk stage III CC, which could reduce the incidence of undertreatment and guide adjuvant chemotherapy.
Learning health systems and evidence ecosystems: a perspective on the future of evidence-based medicine and evidence-based guideline development
Authors: Rajit D. , Johnson A. , Callander E. , Teede H. , Enticott J.
Published: January 2024

Despite forming the cornerstone of modern clinical practice for decades, implementation of evidence-based medicine at scale remains a crucial challenge for health systems. As a result, there has been a growing need for conceptual models to better contextualise and pragmatize the use of evidence-based medicine, particularly in tandem with patient-centred care. In this commentary, we highlight the emergence of the learning health system as one such model and analyse its potential role in pragmatizing both evidence-based medicine and patient-centred care. We apply the learning health system lens to contextualise the key activity of evidence-based guideline development and implementation, and highlight how current inefficiencies and bottlenecks in the evidence synthesis phase of evidence-based guideline development threaten downstream adherence. Lastly, we introduce the evidence ecosystem as a complementary model to learning health systems, and propose how innovative developments from the evidence ecosystem may be integrated with learning health systems to better enable health impact at speed and scale.
Investing in midwifery for sustainable development goals in low- and middle-income countries: a cost-benefit analysis
Authors: Boukhalfa Chakib , Ouakhzan Brahim , Masbah Hanane , Acharai Leila , Zbiri Saad
Published: January 2024

Background

Maternal and neonatal mortality in low- and middle-income countries is frequently caused by inadequate management of obstetric and neonatal complications and a shortage of skilled health workers. The availability of these workers is essential for effective and high-quality healthcare. To meet the needs of sexual, reproductive, maternal, new-born, child, and adolescent health by 2030, more than one million health workers, including 900 000 midwives, are required globally. Despite this, uncertainty persists regarding the return on investment in the health workforce.

Methods

The objective of this research was to determine the cost-benefit ratio of increasing investment in midwifery in Morocco from 2021 to 2030. A comparative analysis was conducted between scenarios “with” and “without” the additional investment. The costs and benefits were estimated using relevant data from national and international sources.

Results

Following the International Confederation of Midwives’ recommendations, it is advised that Morocco recruit 760 midwives annually to achieve 95% of universal health coverage. This increase in midwifery could result in saving 120 593 lives by 2030, including reducing maternal deaths by 3 201, stillbirths by 48 399, and neonatal deaths by 68 993. The estimated economic benefit of investing in midwives was US$ 10 152 287 749, while the total cost was US$ 638 288 820. Consequently, the cost-benefit ratio was calculated as 15.91, indicating that investing in midwifery would provide 16 times more benefits than costs.

Conclusion

Increasing investment in midwifery appears to be an efficient strategy for achieving comprehensive maternal and child health coverage in low- and middle-income countries.
Racial differences in length of stay and readmission for asthma in the all of us research program
Authors: Correa-Agudelo Esteban , Gautam Yadu , Mendy Angelico , Mersha Tesfaye B.
Published: January 2024

Background

This study addresses the limited research on racial disparities in asthma hospitalization outcomes, specifically length of stay (LOS) and readmission, across the U.S.

Methods

We analyzed in-patient and emergency department visits from the All of Us Research Program, identifying various risk factors (demographic, comorbid, temporal, and place-based) associated with asthma LOS and 30-day readmission using Bayesian mixed-effects models.

Results

Of 17,233 patients (48.0% White, 30.7% Black, 19.7% Hispanic/Latino, 1.3% Asian, and 0.3% Middle Eastern and North African) with 82,188 asthma visits, Black participants had 20% shorter LOS and 12% higher odds of readmission, compared to White participants in multivariate analyses. Public-insured patients had 14% longer LOS and 39% higher readmission odds than commercially insured patients. Weekend admissions resulted in a 12% shorter LOS but 10% higher readmission odds. Asthmatics with chronic diseases had a longer LOS (range: 6–39%) and higher readmission odds (range: 9–32%) except for those with allergic rhinitis, who had a 23% shorter LOS.

Conclusions

A comprehensive understanding of the factors influencing asthma hospitalization, in conjunction with diverse datasets and clinical-community partnerships, can help physicians and policymakers to systematically address racial disparities, healthcare utilization and equitable outcomes in asthma care.
On the use of receiver operating characteristic curve analysis to determine the most appropriate p value significance threshold
Authors: Habibzadeh Farrokh
Published: January 2024

Background

p value is the most common statistic reported in scientific research articles. Choosing the conventional threshold of 0.05 commonly used for the p value in research articles, is unfounded. Many researchers have tried to provide a reasonable threshold for the p value; some proposed a lower threshold, eg, 0.005. However, none of the proposals has gained universal acceptance. Using the analogy between the diagnostic tests with continuous results and statistical inference tests of hypothesis, I wish to present a method to calculate the most appropriate p value significance threshold using the receiver operating characteristic curve (ROC) analysis.

Results

As with diagnostic tests where the most appropriate cut-off values are different depending on the situation, there is no unique cut-off for the p significance threshold. Unlike the previous proposals, which mostly suggest lowering the threshold to a fixed value (eg, from 0.05 to 0.005), the most appropriate p significance threshold proposed here, in most instances, is much less than the conventional cut-off of 0.05 and varies from study to study and from statistical test to test, even within a single study. The proposed method provides the minimum weighted sum of type I and type II errors.

Conclusions

Given the perplexity involved in using the frequentist statistics in a correct way (dealing with different p significance thresholds, even in a single study), it seems that the p value is no longer a proper statistic to be used in our research; it should be replaced by alternative methods, eg, Bayesian methods.
Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice
Authors: Zhu Ya-Jing , Huang Jing , Chen Ru , Zhang Yu , He Xin , Duan Wen-Xin , Zou Yuan-Lei , Sun Meng-Mei , Sun Hui-Li , Cheng Si-Min , Wang Hao-Chuan , Zhang Hao , Wu Wen-Ning
Published: January 2024

Background

Major depressive disorder (MDD) is a common but severe psychiatric illness characterized by depressive mood and diminished interest. Both nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 1 (NLRP1) inflammasome and autophagy have been reported to implicate in the pathological processes of depression. However, the mechanistic interplay between NLRP1 inflammasome, autophagy, and depression is still poorly known.

Methods

Animal model of depression was established by chronic social defeat stress (CSDS). Depressive-like behaviors were determined by social interaction test (SIT), sucrose preference test (SPT), open field test (OFT), forced swim test (FST), and tail-suspension test (TST). The protein expression levels of NLRP1 inflammasome complexes, pro-inflammatory cytokines, phosphorylated-phosphatidylinositol 3-kinase (p-PI3K)/PI3K, phosphorylated-AKT (p-AKT)/AKT, phosphorylated-mechanistic target of rapamycin (p-mTOR)/mTOR, brain-derived neurotrophic factor (BDNF), phosphorylated-tyrosine kinase receptor B (p-TrkB)/TrkB, Bcl-2-associated X protein (Bax)/B-cell lymphoma-2 (Bcl2) and cleaved cysteinyl aspartate-specific proteinase-3 (caspase-3) were examined by western blotting. The mRNA expression levels of pro-inflammatory cytokines were tested by quantitative real-time PCR. The interaction between proteins was detected by immunofluorescence and coimmunoprecipitation. Neuronal injury was assessed by Nissl staining. The autophagosomes were visualized by transmission electron microscopy.Nlrp1aknockdown was performed using an adeno-associated virus (AAV) vector containingNlrp1a–shRNA–eGFP infusion.

Results

CSDS exposure caused a bidirectional change in hippocampal autophagy function, which was activated in the initial period but impaired at the later stage. In addition, CSDS exposure increased the expression levels of hippocampal NLRP1 inflammasome complexes, pro-inflammatory cytokines, p-PI3K, p-AKT and p-mTOR in a time-dependent manner. Interestingly, NLRP1 is immunoprecipitated with mTOR but not PI3K/AKT and CSDS exposure facilitated the immunoprecipitation between them. HippocampalNlrp1aknockdown inhibited the activity of PI3K/AKT/mTOR signaling, rescued the impaired autophagy and ameliorated depressive-like behavior induced by CSDS. In addition, rapamycin, an autophagy inducer, abolished NLRP1 inflammasome-driven inflammatory reactions, alleviated depressive-like behavior and exerted a neuroprotective effect.

Conclusions

Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behavior in mice and the regulation of autophagy could be a valuable therapeutic strategy for the management of depression.
Cholinergic signaling via the α7 nicotinic acetylcholine receptor regulates the migration of monocyte-derived macrophages during acute inflammation
Authors: Keever Kasey R. , Cui Kui , Casteel Jared L. , Singh Sanjay , Hoover Donald B. , Williams David L. , Pavlov Valentin A. , Yakubenko Valentin P.
Published: January 2024

Background

The involvement of the autonomic nervous system in the regulation of inflammation is an emerging concept with significant potential for clinical applications. Recent studies demonstrate that stimulating the vagus nerve activates the cholinergic anti-inflammatory pathway that inhibits pro-inflammatory cytokines and controls inflammation. The α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages plays a key role in mediating cholinergic anti-inflammatory effects through a downstream intracellular mechanism involving inhibition of NF-κB signaling, which results in suppression of pro-inflammatory cytokine production. However, the role of the α7nAChR in the regulation of other aspects of the immune response, including the recruitment of monocytes/macrophages to the site of inflammation remained poorly understood.

Results

We observed an increased mortality in α7nAChR-deficient mice (compared with wild-type controls) in mice with endotoxemia, which was paralleled with a significant reduction in the number of monocyte-derived macrophages in the lungs. Corroborating these results, fluorescently labeled α7nAChR-deficient monocytes adoptively transferred to WT mice showed significantly diminished recruitment to the inflamed tissue. α7nAChR deficiency did not affect monocyte 2D transmigration across an endothelial monolayer, but it significantly decreased the migration of macrophages in a 3D fibrin matrix. In vitro analysis of major adhesive receptors (L-selectin, β1 and β2 integrins) and chemokine receptors (CCR2 and CCR5) revealed reduced expression of integrin αM and αX on α7nAChR-deficient macrophages. Decreased expression of αMβ2 was confirmed on fluorescently labeled, adoptively transferred α7nAChR-deficient macrophages in the lungs of endotoxemic mice, indicating a potential mechanism for α7nAChR-mediated migration.

Conclusions

We demonstrate a novel role for the α7nAChR in mediating macrophage recruitment to inflamed tissue, which indicates an important new aspect of the cholinergic regulation of immune responses and inflammation.
Doxycycline for transgene control disrupts gut microbiome diversity without compromising acute neuroinflammatory response
Authors: Koller Emily J. , Wood Caleb A. , Lai Zoe , Borgenheimer Ella , Hoffman Kristi L. , Jankowsky Joanna L.
Published: January 2024

The tetracycline transactivator (tTA) system provides controllable transgene expression through oral administration of the broad-spectrum antibiotic doxycycline. Antibiotic treatment for transgene control in mouse models of disease might have undesirable systemic effects resulting from changes in the gut microbiome. Here we assessed the impact of doxycycline on gut microbiome diversity in a tTA-controlled model of Alzheimer’s disease and then examined neuroimmune effects of these microbiome alterations following acute LPS challenge. We show that doxycycline decreased microbiome diversity in both transgenic and wild-type mice and that these changes persisted long after drug withdrawal. Despite the change in microbiome composition, doxycycline treatment had minimal effect on basal transcriptional signatures of inflammation the brain or on the neuroimmune response to LPS challenge. Our findings suggest that central neuroimmune responses may be less affected by doxycycline at doses needed for transgene control than by antibiotic cocktails at doses used for experimental microbiome disruption.
Perspectives on menstrual policymaking and community-based actions in Catalonia (Spain): a qualitative study
Authors: García-Egea Andrea , Holst Anna Sofie , Jacques-Aviñó Constanza , Martínez-Bueno Cristina , Berenguera Anna , Vicente-Hernández María Mercedes , Valls-Llobet Carme , Pinzón-Sanabria Diana , Pujolar-Díaz Georgina , Medina-Perucha Laura
Published: January 2024

Background

Menstrual research and policymaking have become imperative worldwide. It is necessary that these are informed by women and people who menstruate (PWM) alongside expert professionals and activists.

Methods

The main aim of this study was to identify and propose policies and community-based actions to address menstrual inequity and promote menstrual health in Catalonia (Spain). This study consisted of two qualitative studies: (a) 34 individual photoelicitation interviews with women and PWM, (b) a World Café study with 22 professionals and activists. Sampling for both studies was purposive and selective. Recruitment was conducted through healthcare centres, social media, key contacts, and snowball sampling techniques. Data were collected in December 2020-September 2022, and analysed using Framework Analysis.

Results

Participants considered the implementation of menstrual policies that address the taboo and stigma of menstruation to be crucial. They stressed the need for menstrual education, which should be integrated into formal education curricula. Participants, and especially women and PWM, highlighted the need to improve the access and quality of healthcare services, so that the menstrual cycle and menstruation are seen as health indicators. Health professionals should encourage agentic informed decisions, hence why both participant groups considered menstrual health education amongst health professionals to be pivotal. Taking action to improve the access and affordability of menstrual products was also imperative for participants, especially for socioeconomically vulnerable populations. Participants agreed on guaranteeing fully equipped menstrual management facilities, and and professionals discussed gender-neutral and sex-segregated bathrooms. Workplace menstrual policies to accommodate and ensure menstrual self-care were also suggested.

Conclusions

Our study highlights the need for multi-dimensional menstrual policies. These should include actions to address menstrual taboo and stigma, to promote menstrual education that goes beyond the hegemonic biomedical prism, to improve the access and quality of menstrual health services, along with policies ensuring adequate menstrual management facilities in public spaces and the access to menstrual products. Policymaking should also focus on how to ensure menstrual management and care in workplaces. Menstrual policies and community-based actions should be framed within intersectionality, to consider how societal structures of power and oppression influence menstrual experiences.
Integrated analysis of miRNA-mRNA expression of newly emerging swine H3N2 influenza virus cross-species infection with tree shrews
Authors: Wang Qihui , Liu Zihe , Zeng Xia , Zheng Yu , Lan Li , Wang Xinhang , Lai Zhenping , Hou Xiaoqiong , Gao Lingxi , Liang Liang , Tang Shen , Zhang Zengfeng , Leng Jing , Fan Xiaohui
Published: January 2024

Background

Cross-species transmission of zoonotic IAVs to humans is potentially widespread and lethal, posing a great threat to human health, and their cross-species transmission mechanism has attracted much attention. miRNAs have been shown to be involved in the regulation of IAVs infection and immunity, however, few studies have focused on the molecular mechanisms underlying miRNAs and mRNAs expression after IAVs cross-species infection.

Methods

We used tree shrews, a close relative of primates, as a model and used RNA-Seq and bioinformatics tools to analyze the expression profiles of DEMs and DEGs in the nasal turbinate tissue at different time points after the newly emerged swine influenza A virus SW2783 cross-species infection with tree shrews, and miRNA-mRNA interaction maps were constructed and verified by RT-qPCR, miRNA transfection and luciferase reporter assay.

Results

14 DEMs were screened based on functional analysis and interaction map, miR-760-3p, miR-449b-2, miR-30e-3p, and miR-429 were involved in the signal transduction process of replication and proliferation after infection, miR-324-3p, miR-1301-1, miR-103-1, miR-134-5p, miR-29a, miR-31, miR-16b, miR-34a, and miR-125b participate in negative feedback regulation of genes related to the immune function of the body to activate the antiviral immune response, and miR-106b-3p may be related to the cross-species infection potential of SW2783, and the expression level of these miRNAs varies in different days after infection.

Conclusions

The miRNA regulatory networks were constructed and 14 DEMs were identified, some of them can affect the replication and proliferation of viruses by regulating signal transduction, while others can play an antiviral role by regulating the immune response. It indicates that abnormal expression of miRNAs plays a crucial role in the regulation of cross-species IAVs infection, which lays a solid foundation for further exploration of the molecular regulatory mechanism of miRNAs in IAVs cross-species infection and anti-influenza virus targets.
Estrogen receptor-negative/progesterone receptor-positive breast cancer has distinct characteristics and pathologic complete response rate after neoadjuvant chemotherapy
Authors: Dou He , Li Fucheng , Wang Youyu , Chen Xingyan , Yu Pingyang , Jia Siyuan , Ba Yuling , Luo Danli , Gao Tian , Li Zhaoting , Xiao Min
Published: January 2024

Purpose

The status of hormone receptors (HR) is an independent factor affecting survival and chemotherapy sensitivity in breast cancer (BC) patients, with estrogen receptor (ER) and progesterone receptor (PR) having the most significant effects. The ER-/PR + phenotype has been controversial in BC, and experts will face many challenges in determining treatment strategies. Herein, we systematically analyzed the clinicopathological characteristics of the ER-/PR + phenotype in BC patients and the response to chemotherapy.

Patients and methods

We included two cohorts. The first cohort counted the relationship between clinicopathologic data and survival outcomes for 72,666 female patients in the Surveillance, Epidemiology, and End Results (SEER) database. The second cohort analyzed the relationship between clinicopathological data and pathologic complete response (pCR) rate in 879 patients at the Harbin Medical University Cancer Hospital. The classification data were compared by the chi-square test and Fister's exact test of the Logistic regression model, and predictor variables with P < 0.05 in the univariate analysis were included in the multivariate regression analysis. The Kaplan–Meier method evaluated breast cancer-specific survival (BCSS) and overall survival (OS) to investigate the relationship between different HR typing and survival and pCR.

Results

In the two cohorts, 704 (0.9%) and 11 (1.3%) patients had the ER-/PR + phenotype, respectively. The clinicopathologic features of patients with the ER-/PR + phenotype are more similar to those of the ER-/PR- phenotype. The ER-/PR + phenotype is more common in younger and premenopausal women, and most ER-/PR + phenotypes exhibit higher histological grades. Survival analysis showed that there were significant differences in OS and BCSS among patients with different HR states (P < 0.001). The survival results of patients with the ER + /PR + phenotype were the best. The prognosis of the ER-/PR + phenotype was similar to that of the ER-/PR- phenotype. On the other hand, we found that HR status was also an independent predictor of post-NAC pCR rate in BC patients. The ER + /PR- and ER-/PR- phenotypes were more sensitive to chemotherapy than the ER + /PR + phenotypes.

Conclusion

HR status is the main factor affecting BC's survival outcome and pCR rate. Patients with the ER-/PR + phenotype possess more aggressive biological factors and can benefit significantly from chemotherapy. We need to pay more attention to this group and achieve individualized treatment, which will help us treat BC better and provide new targets and blueprints for our clinical treatment.
Local and traditional knowledge systems, resistance, and socioenvironmental justice
Authors: Hanazaki Natalia
Published: January 2024

In this essay, for the debate series of Journal of Ethnobiology and Ethnomedicine, I argue against the oversimplified causal argument that the maintenance of local and traditional knowledge systems is related to less advantaged circumstances. This statement is based on a colonialist perspective of what a less advantageous circumstance is, which is being questioned by several authors. It also ignores the struggles and resistance of traditional knowledge holders and the urgent call for socioenvironmental justice. As an ethnobiologist, I argue that we must face this reality to build science with justice and inclusiveness.
Magnitude and determinants of early initiation and exclusive breastfeeding at six weeks postpartum: evidence from the PMA Ethiopia longitudinal survey
Authors: Armdie Addisalem Zebene , Ejigu Bedilu Alamirie , Seme Assefa , Desta Selamawit , Yihdego Mahari , Shiferaw Solomon
Published: January 2024

Background

Early initiation and exclusive breastfeeding are crucial in preventing child morbidity and mortality. Despite the importance of these practices, rates of timely initiation of breastfeeding and exclusive breastfeeding remain suboptimal in many sub-Saharan countries, including Ethiopia. This paper aimed to estimate the prevalence and identify determinants of breastfeeding initiation within the first hour after birth and exclusive breastfeeding in Ethiopia.

Methods

Data from the Performance Monitoring for Action Ethiopia project, a national survey conducted from August 2019 to September 2020, were used. The analytical sample comprises 2564 postpartum women and their children; data reported at baseline during enrollment and six weeks postpartum were used in this analysis. A multi-level binary logistic regression model was employed to identify determinant factors linked with initiation breastfeeding and exclusive breastfeeding.

Results

Of the 2564 mothers, 77.8% of infants breastfed within the first hour of birth and 68.4% of women practiced exclusive breastfeeding at six weeks postpartum with significant variation across regions. In the multivariate analysis, mothers who had cesarean delivery were less likely to initiate early breastfeeding as compared to mothers with vaginal delivery (AOR 0.27; 95% CI 0.17, 0.41). The odds of early initiation of breastfeeding were higher for mothers whose baby cried immediately after birth (AOR 3.31; 95% CI 1.95, 5.62) and who had skilled assisted delivery (AOR 2.13; 95% CI 1.01, 4.48). Other factors that were significantly associated with early initiation of breastfeeding were obstetric complication(s), parity, immediate mother-to-baby skin-to-skin contact, immediate postnatal care and the region. Similarly, mothers whose babies had a good neonatal birth status (AOR 1.81; 95% CI 1.09, 2.99) were more likely to exclusively breastfeed their child at six weeks postpartum.

Conclusions

Early initiation of breastfeeding and exclusive breastfeeding is sub-optimal in Ethiopia. Nutrition programmers should consider regional variations in designing intervention programs to enhance breastfeeding practices. Healthcare providers should give special attention to women at risk such as those giving birth through cesarean section and having obstetric complications during delivery.