bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating Efficacy of Statutory Disclaimers of Mutual Funds on Novice and Seasoned Investors
Authors: Kulkarni Medha , Dam Leena B. , Pathan Feeroj Nasirkhan , Vasundekar Vaibhav V.
Published: March 2023

The purpose of the present study was to empirically examine the efficacy of statutory disclosures in the Indian mutual fund industry. Whether the disclaimers aid investors in their decision-making process was investigated. The study made a distinction between type of investors (novice and seasoned investors) as disclaimers affect differently on investor’s belief, attitude and ability to take informed decision. Survey was conducted using a structured questionnaire to evaluate the responses of 388 investors, consisting of 243 novice and 145 seasoned investors. Data was analyzed using mean comparison, independent t-test, and logistic regression model. Results revealed that statutory disclaimers were less effective on seasoned investors compared to novice investors. This suggests seasoned investors process the disclaimer information differently. Novice investors systematically process the disclaimers of mutual fund advertising, and their investment decision was meaningfully affected by the disclaimers. The study offers specific suggestions for stakeholders working in the area of behavioral finance, highlighting the importance of considering the dual process theory of information processing. To the best of authors knowledge, this study is the first of its kind to evaluate the efficacy of mandatory disclaimers in the Indian mutual fund industry, providing unique insights for future research in the field.
Randomized Controlled Trial Comparing the Clinical Effectiveness of Collagenase Injection (Xiaflex®) and Palmar Fasciectomy in the Management of Dupuytren's Contracture
Authors: Thoma Achilles , Murphy Jessica , Gallo Lucas , Ayeni Bimpe , Thabane Lehana
Published: March 2023

Introduction: Limited palmar fasciectomy (LPF) and collagenase injection (CI) are the most common procedures to manage symptoms of Dupuytren's Disease. This randomized controlled trial (RCT) aimed to directly compare patient outcomes 12 months following CI and LPF. Methods: Twenty-two patients with Dupuytren's Disease were randomized to either LPF or CI. The primary outcome was health state measured by the Michigan Hand Questionnaire. Secondary outcomes were health status (The Health Utility Index-3), function (The Unité Rhumatologique des Affections de la Main and The Southampton Dupuytren's Scoring Scheme), and range of motion (ROM) of treated digits. Measurements were collected at baseline and 1-, 3-, 6-, and 12-months post-procedure. Results: Thirteen patients were randomized to the LPF and eight patients to the CI group. Most patients (85.7%) were male; the average age of the sample was 65.3 years. No statistically significant difference in the MHQ (mean difference [MD]: −12.4 (95% confidence interval [CI]: −30.0, 5.2)), SDSS (.9 (−4.0, 5.8)), URAM (−.9 (−14.4, 12.6)) or HUI-3 (−.04, −.2, .2)) was found between groups 12-months post-operatively. There was no statistically significant difference in 12-month loss of extension between groups at the MCP (−16.9 (−35.4, 1.7) or PIP (−2.9 (−22.9, 17.1) joints. Three CI patients and 1 LPF patient developed a contracture in the same digit requiring surgery. Conclusion: Results should be interpreted with caution given the small sample size. Available data suggests both techniques are reasonable for managing Dupuytren's Disease. Considerations for future RCTs are provided.
Velocity and thermal slips impact on boundary layer flow of micropolar nanofluid over a vertical nonlinear stretched Riga sheet
Authors: Abbas Nadeem , Shatanawi Wasfi , Rehman Khalil Ur , Shatnawi Taqi AM
Published: March 2023

In the present analysis, heat and mass transfer of micropolar nanofluid flow over vertical nonlinear Riga stretching sheet is considered. Effects of velocity slip, thermal slip, Joule heating, thermal radiations, variable thermal conductivity, and heat generation are examined. Thermophoresis and Brownian motion effects are highlighted in current study. The mathematical model is developed under flow assumptions, the partial differential equations are formed by implementing the boundary layer approximations. The partial differential equations are further reduced in form of ordinary differential equations by means of suitable transformations. The ordinary differential equations are solved through numerical procedure. The effects physical parameters presented through tables and graphs for the both case of suction/injection. Velocity function declined due to higher values of micropolar parameter. The velocity function declined due to increasing the values of velocity slip. The concentration function declined due to larger values of Brownian motion. The positive values of velocity slip increases the Sherwood number and Nusselt number. The Nusselt number and Sherwood number declined for higher values of thermal slip [Formula: see text]. The values of Sherwood number and Nusselt number declined for higher values of Eckert number [Formula: see text].
Passive Dynamic Ankle Foot Orthoses Use in Civilian Patients with Arthritic Conditions of the Foot and Ankle
Authors: Feng Jing , Weiss Jason , Thompson Austin , Meeker James E.
Published: March 2023

Background:

Nonsurgical interventions such as bracing with ankle foot orthoses (AFOs) aim to assist, restore, and redirect weightbearing forces to address difficulty with mobilization. We identified a custom carbon fiber passive dynamic ankle foot orthosis (PDAFO) that was designed to meet the needs of military combat veterans. We sought to evaluate the off-loading properties of one model of PDAFO (ExoSym) in a civilian population.

Methods:

Civilian patients 18 years or older were prescribed a PDAFO by a single surgeon. Pedobarographic data were obtained using the Tekscan F-Scan system. With the insole, participants were instructed to walk at a self-selected pace along a 20 m walkway under 3 conditions: (1) insole placed in between the brace and foot (over); (2) insole placed between the brace and insole of the shoe (under); (3) without the brace, the insole was placed in between the foot and insole of the shoe in both limbs (without). For assessment, forefoot and heel areas were evaluated with respect to maximal force, force*time integral (FTI), maximal contact area, maximal contact pressure, pressure*time integral (PTI), center of force (COF) excursion.

Results:

Six patients with arthritic foot and ankle conditions completed pedobarographic assessment for analysis. The brace reduced forefoot maximal force and contact pressures by 66% and 49%, respectively (538 ± 236 to 185 ± 130 N [ P < .001], and 99 ± 38 to 50 ± 24 P < .002). Additionally, participants were observed to load the forefoot portion of the brace with double the maximum contact pressures compared to the unbraced foot (204 ± 57 to 99 ± 38 kPa, P < .001).

Conclusion:

The results of this study showed that the PDAFO unloaded substantial force and pressure experienced by the forefoot. Participants loaded the brace to a greater extent than when going unbraced. ADAFO can provide measurable pressure relief for patients with arthritic conditions.

Level of Evidence:

Level IV, case series.
The Probable Protective Effect of Photobiomodulation on the Immunologic Factor’s mRNA Expression Level in the Lung: An Extended COVID-19 Preclinical and Clinical Meta-analysis
Authors: Arjmand Babak , Rahim Fakher
Published: March 2023

Background:

Different expression of cytokine genes in the body determines the type of immune response (Th1 or Th2), which can play an important role in the pathogenesis of the COVID-19 disease.

Aims:

This meta-analysis was conducted to evaluate the probable effect of photobiomodulation (PBMT) therapy on the cytokine’s mRNA expression in the lung.

Methods:

We systematically searched indexing databases, including PubMed/Medline, ISI web of science, Scopus, EMBASE, and Cochrane central, using standard terms without language, study region or type restrictions. Studies on using PBM in lung injury modeling with samples collected from lung tissue to observe IL-1β, TNF-α, IL-10, and IL-6 mRNA expression were included. RevMan 5.3 software was used for data analysis and standardized mean difference as effect size.

Results:

Of the 438 studies found through initial searches, 17 met the inclusion criteria. The main properties of 13 articles on 384 animals included in this meta-analysis with a wide range of species include rats (n = 10) and rabbits (n = 3). The analysis revealed that PBMT reduced the mRNA expression of TNFα (SMD: −3.70, 95% CI: −6.29, −1.11, P = .005, I2 = 71%) and IL-1β (SMD: −5.85, 95% CI: −8.01, −3.69, P < .00001, I2 = 37%) significantly, but no statistically significant reduction in IL-6 (SMD: −2.89, 95% CI: −5.79, 0.01, P = .05, I2 = 88%) was observed compared with the model controls. Also, PBMT increased IL-10 mRNA expression significantly compared with the model controls (SMD: 1.04, 95% CI: 0.43, 1.64, P = .0008, I2 = 17%).

Conclusion:

This meta-analysis revealed that the PBMT utilizes beneficial anti-inflammatory effects and modulation of the immune system on lung damage in animal models and clinical studies. However, animal models and clinical studies appear limited considering the evidence’s quality; therefore, large clinical trials are still required.
Comparative Performance Evaluation of Personal Protective Measures and Antiviral Agents Against SARS-CoV-2 Variants: A Narrative Review
Authors: Haque Md Anamul , Tanbir Md , Ahamed Bulbul , Hossain Md Jamal , Roy Arpita , Shahriar Mohammad , Bhuiyan Mohiuddin Ahmed , Islam Md Rabiul
Published: March 2023

Scientists identified SARS-CoV-2 in December 2019 in Wuhan city of China. Soon after its identification, Covid-19 spreads almost everywhere. The World Health Organization (WHO) declared the Covid-19 outbreak as a pandemic on March 11, 2020. Countries are facing multiple waves due to the different variants of the coronavirus. Personal preventive measures, vaccines, and antiviral drugs are the approaches to control Covid-19. However, these approaches are being implemented in different countries at different levels because of the availability of personal protective measures and antiviral agents. The objective of this study was to evaluate the effectiveness of practicing measures to fight the Covid-19 pandemic. Here we searched relevant literature from PubMed and Scopus using the keywords such as personal protective measures, antiviral agents, and vaccine effectiveness. According to the present findings, protective measures were found comparatively less effective. Nevertheless, these measures can be used to limit the spreading of Covid-19. Antiviral agents can reduce the hospitalization rate and are more effective than personal protective measures. The most effective strategy against Covid-19 is early vaccination or multiple vaccination dose. The respective authorities should ensure equal distribution of vaccines, free availability of antiviral drugs, and personal protective measure in poor and developing countries. We recommend more studies to describe the effectiveness of practicing preventive measures and antiviral agents against recent variants of the coronavirus.
Women and Care: Reflections on the Lived Experience of COVID-19 Sufferers
Authors: Romulo Sheilalaine G. , Urbano Ryan C.
Published: March 2023

Women play a crucial role in the care and response to the COVID-19 pandemic, whether in paid or unpaid work. This article looks into the lived experience of some of these women infected by COVID-19 while doing their job as care providers. We selected nine women from Cebu City, Philippines. We presented their lived experience through van Manen’s phenomenology of practice. Themes of the lived experience reveal pain and separation, suffering and caring, stigma of discrimination, caring response, and supportive relationship in the midst of a health crisis. Our reflections reveal that even in serious vulnerability and sustained domestic burden, women remained steadfast in their caring character. Their caring attitude has turned the quarantine facility into a liveable space where empathy, reciprocity, and relationality dwell and thus help everyone survive the COVID-19 ordeal.
Easing Into Jazz Improvisation With the Blues
Authors: Williams Sarin
Published: March 2023

Although there is a consensus that it is important to teach jazz and the skill of improvisation inherent within it, many feel unprepared to do so. This article presents a simple way for beginners to improvise through the blues scale and harmonic progression at any present skill level in kindergarten through high school general music coursework. This practical method addresses the Creating pillar of the 2014 Music Standards while enhancing students’ and instructors’ musical skills and leadership skills, and presenting an avenue for live performance. Teachers and students alike can feel empowered to learn jazz improvisation with the “correct notes” provided through these friendly steps that I have been using in my own teaching for over 15 years.
Crack Fault Diagnosis and Location Method for a Dual-Disk Hollow Shaft Rotor System Based on the Radial Basis Function Network and Pattern Recognition Neural Network
Authors: Jin Yuhong , Hou Lei , Lu Zhenyong , Chen Yushu
Published: March 2023

The crack fault is one of the most common faults in the rotor system, and researchers have paid close attention to its fault diagnosis. However, most studies focus on discussing the dynamic response characteristics caused by the crack rather than estimating the crack depth and position based on the obtained vibration signals. In this paper, a novel crack fault diagnosis and location method for a dual-disk hollow shaft rotor system based on the Radial basis function (RBF) network and Pattern recognition neural network (PRNN) is presented. Firstly, a rotor system model with a breathing crack suitable for a short-thick hollow shaft rotor is established based on the finite element method, where the crack’s periodic opening and closing pattern and different degrees of crack depth are considered. Then, the dynamic response is obtained by the harmonic balance method. By adjusting the crack parameters, the dynamic characteristics related to the crack depth and position are analyzed through the amplitude-frequency responses and waterfall plots. The analysis results show that the first critical speed, first subcritical speed, first critical speed amplitude, and super-harmonic resonance peak at the first subcritical speed can be utilized for the crack fault diagnosis. Based on this, the RBF network and PRNN are adopted to determine the depth and approximate location of the crack respectively by taking the above dynamic characteristics as input. Test results show that the proposed method has high fault diagnosis accuracy. This research proposes a crack detection method adequate for the hollow shaft rotor system, where the crack depth and position are both unknown.
DADOS: A Cloud-based Data-driven Design Optimization System
Authors: Song Xueguan , Wang Shuo , Zhao Yonggang , Liu Yin , Li Kunpeng
Published: March 2023

This paper presents a cloud-based data-driven design optimization system, named DADOS, to help engineers and researchers improve a design or product easily and efficiently. DADOS has nearly 30 key algorithms, including the design of experiments, surrogate models, model validation and selection, prediction, optimization, and sensitivity analysis. Moreover, it also includes an exclusive ensemble surrogate modeling technique, the extended hybrid adaptive function, which can make use of the advantages of each surrogate and eliminate the effort of selecting the appropriate individual surrogate. To improve ease of use, DADOS provides a user-friendly graphical user interface and employed flow-based programming so that users can conduct design optimization just by dragging, dropping, and connecting algorithm blocks into a workflow instead of writing massive code. In addition, DADOS allows users to visualize the results to gain more insights into the design problems, allows multi-person collaborating on a project at the same time, and supports multi-disciplinary optimization. This paper also details the architecture and the user interface of DADOS. Two examples were employed to demonstrate how to use DADOS to conduct data-driven design optimization. Since DADOS is a cloud-based system, anyone can access DADOS atwww.dados.com.cnusing their web browser without the need for installation or powerful hardware.
Bayesian optimization of hydrogen plasma treatment in silicon quantum dot multilayer and application to solar cells
Authors: Kumagai Fuga , Gotoh Kazuhiro , Miyamoto Satoru , Kato Shinya , Kutsukake Kentaro , Usami Noritaka , Kurokawa Yasuyoshi
Published: March 2023

Silicon quantum dot multilayer (Si-QDML) is a promising material for a light absorber of all silicon tandem solar cells due to tunable bandgap energy in a wide range depending on the silicon quantum dot (Si-QD) size, which is possible to overcome the Shockley–Queisser limit. Since solar cell performance is degenerated by carrier recombination through dangling bonds (DBs) in Si-QDML, hydrogen termination of DBs is crucial. Hydrogen plasma treatment (HPT) is one of the methods to introduce hydrogen into Si-QDML. However, HPT has a large number of process parameters. In this study, we employed Bayesian optimization (BO) for the efficient survey of HPT process parameters. Photosensitivity (PS) was adopted as the indicator to be maximized in BO. PS (σp/σd) was calculated as the ratio of photoconductivity (σp) and dark conductivity (σd) of Si-QDML, which allowed the evaluation of important electrical characteristics in solar cells easily without fabricating process-intensive devices. 40-period layers for Si-QDML were prepared by plasma-enhanced chemical vapor deposition method and post-annealing onto quartz substrates. Ten samples were prepared by HPT under random conditions as initial data for BO. By repeating calculations and experiments, the PS was successfully improved from 22.7 to 347.2 with a small number of experiments. In addition, Si-QD solar cells were fabricated with optimized HPT process parameters; open-circuit voltage (VOC) and fill factor (FF) values of 689 mV and 0.67, respectively, were achieved. These values are the highest for this type of device, which were achieved through an unprecedented attempt to combine HPT and BO. These results prove that BO is effective in accelerating the optimization of practical process parameters in a multidimensional parameter space, even for novel indicators such as PS.
Long read isoform sequencing reveals hidden transcriptional complexity between cattle subspecies
Authors: Ren Yan , Tseng Elizabeth , Smith Timothy P. L. , Hiendleder Stefan , Williams John L. , Low Wai Yee
Published: March 2023

The Iso-Seq method of full-length cDNA sequencing is suitable to quantify differentially expressed genes (DEGs), transcripts (DETs) and transcript usage (DTU). However, the higher cost of Iso-Seq relative to RNA-seq has limited the comparison of both methods. Transcript abundance estimated by RNA-seq and deep Iso-Seq data for fetal liver from two cattle subspecies were compared to evaluate concordance. Inter-sample correlation of gene- and transcript-level abundance was higher within technology than between technologies. Identification of DEGs between the cattle subspecies depended on sequencing method with only 44 genes identified by both that included 6 novel genes annotated by Iso-Seq. There was a pronounced difference between Iso-Seq and RNA-seq results at transcript-level wherein Iso-Seq revealed several magnitudes more transcript abundance and usage differences between subspecies. Factors influencing DEG identification included size selection during Iso-Seq library preparation, average transcript abundance, multi-mapping of RNA-seq reads to the reference genome, and overlapping coordinates of genes. Some DEGs called by RNA-seq alone appear to be sequence duplication artifacts. Among the 44 DEGs identified by both technologies some play a role in immune system, thyroid function and cell growth. Iso-Seq revealed hidden transcriptional complexity in DEGs, DETs and DTU genes between cattle subspecies previously missed by RNA-seq.
Safety and tolerability of Sacubitril/Valsartan in heart failure patient with reduced ejection fraction
Authors: Khan Muhammad Nauman , Soomro Najia Aslam , Naseeb Khalid , Bhatti Usman Hanif , Rauf Rubina , Balouch Iram Jehan , Moazzam Ali , Bashir Sonia , Ashraf Tariq , Karim Musa
Published: March 2023

Background

Angiotensin receptor blocker and a neprilysin inhibitor (ARNI) has emerged as an innovative therapy for patients of heart failure with reduced ejection fraction (HFrEF). The purpose of this study was to assess the safety and tolerability of Sacubitril/Valsartan in patient with HFrEF in Pakistani population.

Methods

This proof-of-concept, open label non-randomized clinical trial was conducted at a tertiary care cardiac center of Karachi, Pakistan. Patients with HFrEF were prescribed with Sacubitril/Valsartan and followed for 12 weeks for the assessment of safety and tolerability. Safety measures included incidence of hypotension, renal dysfunction, hyperkalemia, and angioedema.

Results

Among the 120 HFrEF patients, majority were male (79.2%) with means age of 52.73 ± 12.23 years. At the end of 12 weeks, four (3.3%) patients died and eight (6.7%) dropped out of the study. In the remaining 108 patients, 80.6% (87) of the patients were tolerant to the prescribed dose. Functional class improved gradually with 75.0% (81) in class I and 24.1% (26) in class II, and only one (0.9%) patient in class III at the end of 12 weeks. Hyperkalemia remains the main safety concern with incidence rate of 21.3% (23) followed by hypotension in 19.4% (21), and renal dysfunction in 3.7% (4) of the patients.

Conclusions

Sacubitril/Valsartan therapy in HFrEF patients is safe and moderately tolerated among the Pakistani population. It can be used as first line of treatment for these patients.

Trial registration

NCT05387967. Registered 24 May 2022—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05387967
Data collection systems for active safety surveillance of vaccines during pregnancy in low- and middle-income countries: developing and piloting an assessment tool (VPASS)
Authors: Belizán Maria , Rodriguez Cairoli Federico , Mazzoni Agustina , Goucher Erin , Zaraa Sabra , Matthews Sarah , Pingray Verónica , Stergachis Andy , Xiong Xu , Berrueta Mabel , Buekens Pierre
Published: March 2023

Background

There is an urgent need for active safety surveillance to monitor vaccine exposure during pregnancy in low- and middle-income countries (LMICs). Existing maternal, newborn, and child health (MNCH) data collection systems could serve as platforms for post-marketing active surveillance of maternal immunization safety. To identify sites using existing systems, a thorough assessment should be conducted. Therefore, this study had the objectives to first develop an assessment tool and then to pilot this tool in sites using MNCH data collection systems through virtual informant interviews.

Methods

We conducted a rapid review of the literature to identify frameworks on population health or post-marketing drug surveillance. Four frameworks that met the eligibility criteria were identified and served to develop an assessment tool capable of evaluating sites that could support active monitoring of vaccine safety during pregnancy. We conducted semi-structured interviews in six geographical sites using MNCH data collection systems (DHIS2, INDEPTH, and GNMNHR) to pilot domains included in the assessment tool.

Results

We developed and piloted the “VPASS (Vaccines during Pregnancy – sites supporting Active Safety Surveillance) assessment tool” through interviews with nine stakeholders, including central-level systems key informants and site-level managers from DHIS2 and GNMNHR; DHIS2 in Kampala (Uganda) and Kigali (Rwanda); GNMNHR from Belagavi (India) and Lusaka (Zambia); and INDEPTH from Nanoro (Burkina Faso) and Manhica (Mozambique). The tool includes different domains such as the system’s purpose, the scale of implementation, data capture and confidentiality, type of data collected, the capability of integration with other platforms, data management policies and data quality monitoring. Similarities among sites were found regarding some domains, such as data confidentiality, data management policies, and data quality monitoring. Four of the six sites met some domains to be eligible as potential sites for active surveillance of vaccinations during pregnancy, such as a routine collection of MNCH individual data and the capability of electronically integrating individual MNCH outcomes with information related to vaccine exposure during pregnancy. Those sites were: Rwanda (DHIS2), Manhica (IN-DEPTH), Lusaka (GNMNHR), and Belagavi (GNMNHR).

Conclusion

This study's findings should inform the successful implementation of active safety surveillance of vaccines during pregnancy by identifying and using active individual MNCH data collection systems in LMICs.
Rural job preferences of graduate class medical students in Ethiopia—a discrete choice experiment (DCE)
Authors: Engidaw Mamo , Alemu Melaku Birhanu , Muche Getasew Amare , Yitayal Mezgebu
Published: March 2023

Background

Human resource is one of the health system’s building blocks, which ultimately leads to improved health status, equity, and efficiency. However, human resources in the health sector are characterized by high attrition, distributional imbalance, and geographic inequalities in urban and rural settings.

Methods

An discrete choice experiment (DCE) with 16 choice tasks with two blocks containing five attributes (salary, housing, drug and medical equipment, year of experience before study leave, management support, and workload) were conducted. A latent class and mixed logit model were fitted to estimate the rural job preferences and heterogeneity. Furthermore, the relative importance, willingness to accept and marginal choice probabilities were calculated. Finally, the interaction of preference with age and sex was tested.

Results

A total of 352 (5632 observations) final-year medical students completed the choice tasks. On average, respondents prefer to work with a higher salary with a superior housing allowance In addition, respondents prefer a health facility with a stock of drug and medical equipment which provide education opportunities after one year of service with supportive management with a normal workload. Young medical students prefer lower service years more than older students. Besides age and service year, we do not find an interaction between age/sex and rural job preference attributes.

A three-class latent class model best fits the data. The salary was the most important attribute in classes 1 and 3. Contrary to the other classes, respondents in class 2 do not have a significant preference for salary. Respondents were willing to accept an additional 4271 ETB (104.2 USD), 1998 ETB (48.7 USD), 1896 ETB (46.2 USD), 1869 (45.6 USD), and 1175 ETB (28.7 USD) per month for the inadequate drug and medical supply, mandatory two years of service, heavy workload, unsupportive management, and basic housing, respectively.

Conclusion

Rural job uptake by medical students was influenced by all the attributes, and there was individual and group-level heterogeneity in preference. Policymakers should account for the job preferences and heterogeneity to incentivize medical graduates to work in rural settings and minimize attrition.
An artificial intelligence approach for predicting death or organ failure after hospitalization for COVID-19: development of a novel risk prediction tool and comparisons with ISARIC-4C, CURB-65, qSOFA, and MEWS scoring systems
Authors: Kwok Stephen Wai Hang , Wang Guanjin , Sohel Ferdous , Kashani Kianoush B. , Zhu Ye , Wang Zhen , Antpack Eduardo , Khandelwal Kanika , Pagali Sandeep R. , Nanda Sanjeev , Abdalrhim Ahmed D. , Sharma Umesh M. , Bhagra Sumit , Dugani Sagar , Takahashi Paul Y. , Murad Mohammad H. , Yousufuddin Mohammed
Published: March 2023

Background

We applied machine learning (ML) algorithms to generate a risk prediction tool [Collaboration for Risk Evaluation in COVID-19 (CORE-COVID-19)] for predicting the composite of 30-day endotracheal intubation, intravenous administration of vasopressors, or death after COVID-19 hospitalization and compared it with the existing risk scores.

Methods

This is a retrospective study of adults hospitalized with COVID-19 from March 2020 to February 2021. Patients, each with 92 variables, and one composite outcome underwent feature selection process to identify the most predictive variables. Selected variables were modeled to build four ML algorithms (artificial neural network, support vector machine, gradient boosting machine, and Logistic regression) and an ensemble model to generate a CORE-COVID-19 model to predict the composite outcome and compared with existing risk prediction scores. The net benefit for clinical use of each model was assessed by decision curve analysis.

Results

Of 1796 patients, 278 (15%) patients reached primary outcome. Six most predictive features were identified. Four ML algorithms achieved comparable discrimination (P > 0.827) with c-statistics ranged 0.849–0.856, calibration slopes 0.911–1.173, and Hosmer–Lemeshow P > 0.141 in validation dataset. These 6-variable fitted CORE-COVID-19 model revealed a c-statistic of 0.880, which was significantly (P < 0.04) higher than ISARIC-4C (0.751), CURB-65 (0.735), qSOFA (0.676), and MEWS (0.674) for outcome prediction. The net benefit of the CORE-COVID-19 model was greater than that of the existing risk scores.

Conclusion

The CORE-COVID-19 model accurately assigned 88% of patients who potentially progressed to 30-day composite events and revealed improved performance over existing risk scores, indicating its potential utility in clinical practice.
Neutral effects of SGLT2 inhibitors in acute coronary syndromes, peripheral arterial occlusive disease, or ischemic stroke: a meta-analysis of randomized controlled trials
Authors: Tsai Pei-Chien , Chuang Wei-Jung , Ko Albert Min-Shan , Chen Jui-Shuan , Chiu Cheng-Hsun , Chen Chun-Han , Yeh Yung-Hsin
Published: March 2023

Background

Patients with type 2 diabetes are at increased risk for cardiovascular diseases. Sodium-glucose transport 2 inhibitors (SGLT2i) have been shown to enhance cardiovascular health since their debut as a second-line therapy for diabetes. Acute coronary syndrome (ACS), peripheral arterial occlusive disease (PAOD), and ischemic stroke (IS) are types of atherosclerotic cardiovascular disease (ASCVD), although the benefits of treating these disorders have not been shown consistently.

Methods

We searched four databases (PubMed, Embase, the Cochrane library, and clinicaltrial.gov) for randomized clinical trials (RCTs) until November of 2022. Comparisons were made between SGLT2i-treated and control individuals with type 2 diabetes. Primary outcomes were ACS, PAOD, and IS; secondary outcomes included cardiovascular mortality and all-cause mortality. Risk ratio (RR) and 95% confidence intervals (CI) were determined using a fixed effects model. Cochrane's risk-of-bias (RoB2) instrument was used to assess the validity of each study that met the inclusion criteria.

Results

We enrolled 79,504 patients with type 2 diabetes from 43 RCTs. There was no difference in the risk of ACS (RR = 0.97, 95% CI 0.89–1.05), PAOD (RR = 0.98, 95% CI 0.78–1.24), or IS (RR = 0.95, 95% CI 0.79–1.14) among patients who took an SGLT2i compared to those who took a placebo or oral hypoglycemic drugs. Subgroup analysis revealed that none of the SGLT2i treatments (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) significantly altered outcomes when analyzed separately. Consistent with prior findings, SGLT2i reduced the risk of cardiovascular mortality (RR = 0.85, 95% CI 0.77–0.93) and all-cause mortality (RR = 0.88, 95% CI 0.82–0.94).

Conclusion

Our results appear to contradict the mainstream concepts regarding the cardiovascular effects of SGLT2i since we found no significant therapeutic benefits in SGLT2i to reduce the incidence of ACS, PAOD, or IS when compared to placebo or oral hypoglycemic drugs.
Enhancement of herbicolin A production by integrated fermentation optimization and strain engineering in Pantoea agglomerans ZJU23
Authors: Wang Hongkai , Zhou Yaqi , Xu Sunde , Zhang Boyan , Cernava Tomislav , Ma Zhonghua , Chen Yun
Published: March 2023

Background

The lipopeptide herbicolin A (HA) secreted by the biocontrol agent Pantoea agglomerans ZJU23 is a promising antifungal drug to combat fungal pathogens by targeting lipid rafts, both in agricultural and clinical settings. Improvement of HA production would be of great significance in promoting its commercialization. This study aims to enhance the HA production in ZJU23 by combining fermentation optimization and strain engineering.

Results

Based on the results in the single-factor experiments, corn steep liquor, temperature and initial pH were identified as the significant affecting factors by the Plackett–Burman design. The fermentation medium and conditions were further optimized using the Box-Behnken response surface method, and the HA production of the wild type strain ZJU23 was improved from ~ 87 mg/mL in King’s B medium to ~ 211 mg/mL in HA induction (HAI) medium. A transposon library was constructed in ZJU23 to screen for mutants with higher HA production, and two transcriptional repressors for HA biosynthesis, LrhA and PurR, were identified. Disruption of the LrhA gene led to increased mRNA expression of HA biosynthetic genes, and subsequently improved about twofold HA production. Finally, the HA production reached ~ 471 mg/mL in the ΔLrhA mutant under optimized fermentation conditions, which is about 5.4 times higher than before (~ 87 mg/mL). The bacterial suspension of the ΔLrhA mutant fermented in HAI medium significantly enhanced its biocontrol efficacy against gray mold disease and Fusarium crown rot of wheat, showing equivalent control efficacies as the chemical fungicides used in this study. Furthermore, HA was effective against fungicide resistant Botrytis cinerea. Increased HA production substantially improved the control efficacy against gray mold disease caused by a pyrimethanil resistant strain.

Conclusions

This study reveals that the transcriptional repressor LrhA negatively regulates HA biosynthesis and the defined HAI medium is suitable for HA production. These findings provide an extended basis for large-scale production of HA and promote biofungicide development based on ZJU23 and HA in the future.

Graphical Abstract
Cu-doped TiO2 nanoparticles improve local antitumor immune activation and optimize dendritic cell vaccine strategies
Authors: Hesemans Evelien , Saffarzadeh Neshat , Maksoudian Christy , Izci Mukaddes , Chu Tianjiao , Rios Luci Carla , Wang Yuqing , Naatz Hendrik , Thieme Sebastian , Richter Cornelia , Manshian Bella B. , Pokhrel Suman , Mädler Lutz , Soenen Stefaan J.
Published: March 2023

Nanoparticle-mediated cancer immunotherapy holds great promise, but more efforts are needed to obtain nanoformulations that result in a full scale activation of innate and adaptive immune components that specifically target the tumors. We generated a series of copper-doped TiO2 nanoparticles in order to tune the kinetics and full extent of Cu2+ ion release from the remnant TiO2 nanocrystals. Fine-tuning nanoparticle properties resulted in a formulation of 33% Cu-doped TiO2 which enabled short-lived hyperactivation of dendritic cells and hereby promoted immunotherapy. The nanoparticles result in highly efficient activation of dendritic cells ex vivo, which upon transplantation in tumor bearing mice, exceeded the therapeutic outcomes obtained with classically stimulated dendritic cells. Efficacious but simple nanomaterials that can promote dendritic cancer cell vaccination strategies open up new avenues for improved immunotherapy and human health.

Graphical Abstract
Eukaryotic Initiation Factor 5A2 localizes to actively translating ribosomes to promote cancer cell protrusions and invasive capacity
Authors: Martínez-Férriz Arantxa , Gandía Carolina , Pardo-Sánchez José Miguel , Fathinajafabadi Alihamze , Ferrando Alejandro , Farràs Rosa
Published: March 2023

Background

Eukaryotic Initiation Factor 5A (eIF-5A), an essential translation factor, is post-translationally activated by the polyamine spermidine. Two human genes encode eIF-5A, being eIF5-A1 constitutively expressed whereas eIF5-A2 is frequently found overexpressed in human tumours. The contribution of both isoforms with regard to cellular proliferation and invasion in non-small cell lung cancer remains to be characterized.

Methods

We have evaluated the use of eIF-5A2 gene as prognosis marker in lung adenocarcinoma (LUAD) patients and validated in immunocompromised mice. We have used cell migration and cell proliferation assays in LUAD lines after silencing each eIF-5A isoform to monitor their contribution to both phenotypes. Cytoskeleton alterations were analysed in the same cells by rhodamine-phalloidin staining and fluorescence microscopy. Polysome profiles were used to monitor the effect of eIF-5A2 overexpression on translation. Western blotting was used to study the levels of eIF-5A2 client proteins involved in migration upon TGFB1 stimulation. Finally, we have co-localized eIF-5A2 with puromycin to visualize the subcellular pattern of actively translating ribosomes.

Results

We describe the differential functions of both eIF-5A isoforms, to show that eIF5-A2 properties on cell proliferation and migration are coincident with its features as a poor prognosis marker. Silencing of eIF-5A2 leads to more dramatic consequences of cellular proliferation and migration compared to eIF-5A1. Overexpression of eIF-5A2 leads to enhanced global translation. We also show that TGFβ signalling enhances the expression and activity of eIF-5A2 which promotes the translation of polyproline rich proteins involved in cytoskeleton and motility features as it is the case of Fibronectin, SNAI1, Ezrin and FHOD1. With the use of puromycin labelling we have co-localized active ribosomes with eIF-5A2 not only in cytosol but also in areas of cellular protrusion. We have shown the bulk invasive capacity of cells overexpressing eIF-5A2 in mice.

Conclusions

We propose the existence of a coordinated temporal and positional interaction between TFGB and eIF-5A2 pathways to promote cell migration in NSCLC. We suggest that the co-localization of actively translating ribosomes with hypusinated eIF-5A2 facilitates the translation of key proteins not only in the cytosol but also in areas of cellular protrusion.
IL-1β and TNF-α play an important role in modulating the risk of periodontitis and Alzheimer’s disease
Authors: Wang Rachel Pei-Hsuan , Huang Jianpan , Chan Kannie Wai Yan , Leung Wai Keung , Goto Tetsuya , Ho Yuen-Shan , Chang Raymond Chuen-Chung
Published: March 2023

Background

Systemic activation of the immune system can exert detrimental effects on the central nervous system. Periodontitis, a chronic disease of the oral cavity, is a common source of systemic inflammation. Neuroinflammation might be a result of this to accelerate progressive deterioration of neuronal functions during aging or exacerbate pre-existing neurodegenerative diseases, such as Alzheimer’s disease. With advancing age, the progressive increase in the body’s pro-inflammatory status favors the state of vulnerability to both periodontitis and Alzheimer’s disease. In the present study, we sought to delineate the roles of cytokines in the pathogenesis of both diseases.

Methods

To examine the impacts of periodontitis on the onset and progression of Alzheimer’s disease, 6-month-old female 3 × Tg-AD mice and their age-matched non-transgenic mice were employed. Periodontitis was induced using two different experimental models: heat-killed bacterial-induced periodontitis and ligature-induced periodontitis. To delineate the roles of pro-inflammatory cytokines in the pathogenesis of periodontitis and Alzheimer’s disease, interleukin 1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) were also injected into the buccal mandibular vestibule of mice.

Results

Here, we show that IL-1β and TNF-α were two of the most important and earliest cytokines upregulated upon periodontal infection. The systemic upregulation of these two cytokines promoted a pro-inflammatory environment in the brain contributing to the development of Alzheimer’s disease-like pathology and cognitive dysfunctions. Periodontitis-induced systemic inflammation also enhanced brain inflammatory responses and subsequently exacerbated Alzheimer’s disease pathology and cognitive impairment in 3 × Tg-AD mice. The role of inflammation in connecting periodontitis to Alzheimer’s disease was further affirmed in the conventional magnetization transfer experiment in which increased glial responses resulting from periodontitis led to decreased magnetization transfer ratios in the brain of 3 × Tg-AD mice.

Conclusions

Systemic inflammation resulting from periodontitis contributed to the development of Alzheimer’s disease tau pathology and subsequently led to cognitive decline in non-transgenic mice. It also potentiated Alzheimer’s disease pathological features and exacerbated impairment of cognitive function in 3 × Tg-AD mice. Taken together, this study provides convincing evidence that systemic inflammation serves as a connecting link between periodontitis and Alzheimer’s disease.
TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization: a specialized Tau perspective
Authors: Kapoor Mahima , Chinnathambi Subashchandrabose
Published: March 2023

Microtubule-associated protein, Tau has been implicated in Alzheimer's disease for its detachment from microtubules and formation of insoluble intracellular aggregates within the neurons. Recent findings have suggested the expulsion of Tau seeds in the extracellular domain and their prion-like propagation between neurons. Transforming Growth Factor-β1 (TGF-β1) is a ubiquitously occurring cytokine reported to carry out immunomodulation and neuroprotection in the brain. TGF-β-mediated regulation occurs at the level of neuronal survival and differentiation, glial activation (astrocyte and microglia), amyloid production–distribution–clearance and neurofibrillary tangle formation, all of which contributes to Alzheimer's pathophysiology. Its role in the reorganization of cytoskeletal architecture and remodelling of extracellular matrix to facilitate cellular migration has been well-documented. Microglia are the resident immune sentinels of the brain responsible for surveying the local microenvironment, migrating towards the beacon of pertinent damage and phagocytosing the cellular debris or patho-protein deposits at the site of insult. Channelizing microglia to target extracellular Tau could be a good strategy to combat the prion-like transmission and seeding problem in Alzheimer's disease. The current review focuses on reaffirming the role of TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization and considers utilizing the approach of TGF-β-triggered microglia-mediated targeting of extracellular patho-protein, Tau, as a possible potential strategy to combat Alzheimer's disease.
Blood glucose trajectories and incidence of diabetes mellitus in Ugandan people living with HIV initiated on dolutegravir
Authors: Mulindwa Frank , Castelnuovo Barbara , Brusselaers Nele , Bollinger Robert , Rhein Joshua , Edrisa Mutebi , Buzibye Allan , Amutuhaire Willington , Yendewa George , Nabaggala Sarah , Odongpiny Eva Laker Agnes , Kiguba Ronald , Nakawooza Aisha , Dujanga Simon , Nabwana Martin , Schwarz Jean-Marc
Published: March 2023

Background

Following reports of anti-retroviral therapy (ART) experienced Ugandan people living with HIV (PLHIV) presenting with diabetic ketoacidosis weeks to months following a switch to dolutegravir (DTG), the Uganda Ministry of Health recommended withholding DTG in both ART naïve and experienced PLHIV with diabetes mellitus (T2DM), as well as 3-monthly blood glucose monitoring for patients with T2DM risk factors. We sought to determine if the risk of T2DM is indeed heightened in nondiabetic ART naïve Ugandan PLHIV over the first 48 weeks on DTG.

Methods

Between January and October 2021, 243 PLHIV without T2DM were initiated on DTG based ART for 48 weeks. Two-hour oral glucose tolerance tests (2-h OGTT) were performed at baseline, 12, and 36 weeks; fasting blood glucose (FBG) was measured at 24 and 48 weeks. The primary outcome was the incidence of T2DM. Secondary outcomes included: incidence of pre-Diabetes Mellitus (pre-DM), median change in FBG from baseline to week 48 and 2-h blood glucose (2hBG) from baseline to week 36. Linear regression models were used to determine adjusted differences in FBG and 2hBG from baseline to weeks 48 and 36 respectively.

Results

The incidence of T2DM was 4 cases per 1000 PY (1/243) and pre-DM, 240 cases per 1000 person years (PY) (54/243). There was a significant increase in FBG from baseline to week 48 [median change from baseline (FBG): 3.6 mg/dl, interquartile range (IQR): − 3.6, 7.2, p-value (p) = 0.005] and significant reduction in 2hBG (2hBG: − 7.26 mg/dl, IQR: − 21.6, 14.4, p = 0.024) at week 36. A high CD4 count and increased waist circumference were associated with 2hBG increase at week 36.

Conclusion

We demonstrated a low incidence of T2DM in Ugandan ART-naïve patients receiving DTG. We also demonstrated that longitudinal changes in BG were independent of conventional risk factors of T2DM in the first 48 weeks of therapy. Restricting the use of dolutegravir in Ugandan ART naïve patients perceived to be high risk for diabetes mellitus may be unwarranted.
High-demand tasks show that ACL reconstruction is not the only factor in controlling range of tibial rotation: a preliminary investigation
Authors: Zee Mark , Keizer Michele , van Raaij Jos , Hijmans Juha , van den Akker-Scheek Inge , Diercks Ron
Published: March 2023

Background

Excessive range of tibial rotation (rTR) may be a reason why athletes cannot return to sports after ACL reconstruction (ACLR). After ACLR, rTR is smaller in reconstructed knees compared to contralateral knees when measured during low-to-moderate-demand tasks. This may not be representative of the amount of rotational laxity during sports activities. The purpose of this study is to determine whether rTR is increased after ACL injury compared to the contralateral knee and whether it returns to normal after ACLR when assessed during high-demand hoptests, with the contralateral knee as a reference.

Methods

Ten ACL injured subjects were tested within three months after injury and one year after reconstruction. Kinematic motion analysis was conducted, analysing both knees. Subjects performed a level-walking task, a single-leg hop for distance and a side jump. A paired t-test was used to detect a difference between mean kinematic variables before and after ACL reconstruction, and between the ACL-affected knees and contralateral knees before and after reconstruction.

Results

RTR was greater during high-demand tasks compared to low-demand tasks. Pre-operative, rTR was smaller in the ACL-deficient knees compared to the contralateral knees during all tests. After ACLR, a greater rTR was seen in ACL-reconstructed knees compared to pre-operative, but a smaller rTR compared to the contralateral knees, even during high-demand tasks.

Conclusion

The smaller rTR, compared to the contralateral knee, seen after a subacute ACL tear may be attributed to altered landing technique, neuromuscular adaptation and fear of re-injury. The continued reduction in rTR one year after ACLR may be a combination of this neuromuscular adaptation and the biomechanical impact of the reconstruction.

Trial registration: The trial was registered in the Dutch Trial Register (NTR: www.trialregister.nl, registration ID NL7686).