bluuebunny/crossref_metadata_2025 huggingface dataset:
Using linear and natural cubic splines, SITAR, and latent trajectory models to characterise nonlinear longitudinal growth trajectories in cohort studies
Authors: Elhakeem Ahmed , Hughes Rachael A. , Tilling Kate , Cousminer Diana L. , Jackowski Stefan A. , Cole Tim J. , Kwong Alex S. F. , Li Zheyuan , Grant Struan F. A. , Baxter-Jones Adam D. G. , Zemel Babette S. , Lawlor Deborah A.
Published: March 2022

Background

Longitudinal data analysis can improve our understanding of the influences on health trajectories across the life-course. There are a variety of statistical models which can be used, and their fitting and interpretation can be complex, particularly where there is a nonlinear trajectory. Our aim was to provide an accessible guide along with applied examples to using four sophisticated modelling procedures for describing nonlinear growth trajectories.

Methods

This expository paper provides an illustrative guide to summarising nonlinear growth trajectories for repeatedly measured continuous outcomes using (i) linear spline and (ii) natural cubic spline linear mixed-effects (LME) models, (iii) Super Imposition by Translation and Rotation (SITAR) nonlinear mixed effects models, and (iv) latent trajectory models. The underlying model for each approach, their similarities and differences, and their advantages and disadvantages are described. Their application and correct interpretation of their results is illustrated by analysing repeated bone mass measures to characterise bone growth patterns and their sex differences in three cohort studies from the UK, USA, and Canada comprising 8500 individuals and 37,000 measurements from ages 5–40 years. Recommendations for choosing a modelling approach are provided along with a discussion and signposting on further modelling extensions for analysing trajectory exposures and outcomes, and multiple cohorts.

Results

Linear and natural cubic spline LME models and SITAR provided similar summary of the mean bone growth trajectory and growth velocity, and the sex differences in growth patterns. Growth velocity (in grams/year) peaked during adolescence, and peaked earlier in females than males e.g., mean age at peak bone mineral content accrual from multicohort SITAR models was 12.2 years in females and 13.9 years in males. Latent trajectory models (with trajectory shapes estimated using a natural cubic spline) identified up to four subgroups of individuals with distinct trajectories throughout adolescence.

Conclusions

LME models with linear and natural cubic splines, SITAR, and latent trajectory models are useful for describing nonlinear growth trajectories, and these methods can be adapted for other complex traits. Choice of method depends on the research aims, complexity of the trajectory, and available data. Scripts and synthetic datasets are provided for readers to replicate trajectory modelling and visualisation using the R statistical computing software.
Dermoscopy use in primary care: a qualitative study with general practitioners
Authors: Fee Jonathan A. , McGrady Finbar P. , Hart Nigel D.
Published: March 2022

Background

Skin assessments constitute a significant proportion of consultations with family physicians (commonly called general practitioners or GPs in the UK), and referrals to hospital dermatology departments have risen significantly in recent years. Research has shown that dermoscopy use may help GPs to assess and triage skin lesions, including suspected skin cancers, more accurately. However, dermoscopy is used by a small minority of GPs in the UK. Previous questionnaire studies have aimed to establish in a limited way some perceptions of dermoscopy among GPs: this study aimed to explore more deeply the factors influencing the use of dermoscopy among GPs.

Methods

This was a qualitative interview study set in UK general practice. A purposive sample was taken of GPs who were established dermoscopy users, GPs who had recently adopted dermoscopy, and those who did not use dermoscopy. A total of twelve semi-structured interviews were conducted. Audio-recordings were transcribed verbatim and analysed using a thematic analysis (Braun and Clarke).

Results

GPs’ capability to use dermoscopy necessitated receiving adequate training, while previous dermatology experience and support from colleagues were also considered factors that enabled dermoscopy use. The impact of dermoscopy on patient consultations about skin complaints was generally considered to be positive, as was having an ‘in-house’ dermoscopy user within a GP practice to refer patients to. However, training in dermoscopy was not considered a priority for many GPs either due to other more pressing concerns within their practices or the perceived complexity of dermoscopy, alongside barriers such as equipment costs. Significant ethical concerns with posting patient photographs online for training and teaching purposes were also highlighted.

Conclusions

Both GPs who use dermoscopy, and those who do not, consider it to have an important role in improving skin assessments within primary care. However the need for adequate training in dermoscopy and dermatology more generally was highlighted as a key barrier to its wider use. The development of competency standards for the use of dermoscopy could allow the adequacy of training to be assessed and developed.
Correlation between hand grip strength and regional muscle mass in older Asian adults: an observational study
Authors: Chan Jessica , Lu Yi-Chien , Yao Melissa Min-Szu , Kosik Russell Oliver
Published: March 2022

Background

Previous research has demonstrated a correlation between hand grip strength (HGS) and muscle strength. This study aims to determine the relationship between HGS and muscle mass in older Asian adults.

Methods

We retrospectively reviewed the dual-energy X-ray absorptiometry (DXA) records of 907 older adults (239 (26.4%) men and 668 (73.6%) women) at one medical institution in Taipei, Taiwan, from January 2019, to December 2020. Average age was 74.80 ± 9.43 and 72.93 ± 9.09 for the males and females respectively. The inclusion criteria were: 1) aged 60 and older, 2) underwent a full-body DXA scan, and 3) performed hand grip measurements. Patients with duplicate results, incomplete records, stroke history, and other neurological diseases were excluded. Regional skeletal muscle mass was measured using DXA. HGS was measured using a Jamar handheld dynamometer.

Results

Total lean muscle mass (kg) averaged 43.63 ± 5.81 and 33.16 ± 4.32 for the males and females respectively. Average HGS (kg) was 28.81 ± 9.87 and 19.19 ± 6.17 for the males and females respectively. In both sexes, HGS and regional muscle mass consistently declined after 60 years of age. The rates of decline per decade in upper and lower extremity muscle mass and HGS were 7.06, 4.95, and 12.30%, respectively, for the males, and 3.36, 4.44, and 12.48%, respectively, for the females. In men, HGS significantly correlated with upper (r = 0.576, p < 0.001) and lower extremity muscle mass (r = 0.532, p < 0.001). In women, the correlations between HGS and upper extremity muscle mass (r = 0.262, p < 0.001) and lower extremity muscle mass (r = 0.364, p < 0.001) were less strong, though also statistically significant.

Conclusion

Muscle mass and HGS decline with advancing age in both sexes, though the correlation is stronger in men. HGS measurements are an accurate proxy for muscle mass in older Asian adults, particularly in males.
Variations in physical activity and sedentary behavior during and after hospitalization in acutely admitted older medical patients: a longitudinal study
Authors: Jawad Baker Nawfal , Petersen Janne , Andersen Ove , Pedersen Mette Merete
Published: March 2022

Background

Inactivity is frequent among older patients during hospitalization. It is unknown how patients' daily activity pattern (diurnal profile) vary between hospitalization and after discharge. This study aims to describe and compare the distribution of physical activity and sedentary behavior in acutely hospitalized older patients during hospitalization and after discharge.

Methods

We included data on 80 patients (+65 years) admitted with acute medical illness from the STAND-Cph trial. Physical activity and sedentary behavior were measured as daily number of steps, uptime (walking/standing) and sedentary behavior (lying/sitting) with an activity monitor (activPAL3, PAL Technologies Ltd). The patients wore the monitor for three periods of one week: during hospitalization, after discharge, and four weeks after discharge.

Results

The patients’ median age was 80 years [IQR: 75;88], 68% were female and the median De Morton Mobility Index (DEMMI) was 57 [IQR: 48;67]. The daily median uptime was 1.7 h [IQR: 1;2.8] during hospitalization, 4.0 h [IQR: 2.7;5.4] after discharge and 4.0 h [IQR: 2.8;5.8] four weeks after discharge. The daily median number of steps was 728 [IQR: 176;2089], 2207 [IQR: 1433;3148], and 2622 [IQR: 1714;3865], respectively, and median daily sedentary behavior was 21.4 h (IQR: 20.7;22.4), 19.5 h (IQR: 18.1;21.0) and 19.6 h (IQR: 18.0;20.8), respectively. During hospitalization, a small activity peak was observed between 9-11 AM without any notable variation after. At discharge and four weeks after discharge, a peak in physical activity was seen between 9-12 AM and at 5 PM.

Conclusion

Older hospitalized patients spend most of their time being sedentary with their highest activity between 9-11 AM. Daily activity doubles after discharge with one extra peak in the afternoon. Daily routines might be disrupted, and older patients have the potential to be more physically active during hospitalization. Interventions that encourage physical activity during hospitalization are warranted.
Response rate of anticancer drugs approved by the Food and Drug Administration based on a single-arm trial
Authors: Oda Yoshihiro , Narukawa Mamoru
Published: March 2022

Background

In recent years, an increasing number of anticancer drugs have been approved based on the results of a single-arm trial (SAT). The magnitude of the objective response rate (ORR) in SATs is important for regulatory decisions, but there has been no clear guidance specifying the degree of ORR for approval.

Methods

All anticancer drugs approved by the US Food and Drug Administration (FDA) between January 2016 and December 2019 were identified through the FDA website. From these, we selected drugs approved for solid tumors based on SATs. For each indication, one regimen was selected from the standard-of-care as the best comparison therapy (BCT), which was defined as the latest regimen for the same tumor and treatment line. We compared the ORR of the investigated product with that of the BCT.

Results

Of the 31 solid tumor indications identified, we selected BCT for 28. In 23 of the 28 indications (82.1%), the ORR of the investigated product exceeded that of the BCT, and in 16 of these (69.6%), the lower limit of the 95% confidence interval (CI) of the ORR of the investigated product exceeded the point estimate of the BCT ORR. For seven products, the lower limit of the 95% CI was below the point estimate of the BCT ORR, with differences ranging from 1.0% to 3.4%.

Conclusion

The lower limit of a 95% CI of the ORR of a new drug in an SAT exceeding the point estimate of the BCT ORR could be an important factor in obtaining regulatory approval.
Analysis of communication and logistic processes in neonatal intensive care unit
Authors: Pirrello J. , Sorin G. , Dahan S. , Michel F. , Dany L. , Tosello B.
Published: March 2022

Background

In neonatology, parents play a central role as guarantors of the new-born’s autonomy. Notifying parents about their infant’s status in neonatal critical care is an integral part of the care. However, conveying this information can be very difficult for physicians and the neonatal medical team.

The objective of this work is to assess the dimensions and dynamic processes of critical care communications in neonatal intensive care in order to enhance the development of theoretical and applied knowledge of these discussions.

Methods

This qualitative, descriptive study was conducted on critical care new-borns less than 28 days-old who were hospitalized in a neonatal intensive care unit. Verbatim communications with the parents were recorded using a dictaphone.

Results

The verbatim information had five themes: (a) critical care, (b) establishing the doctor-patient relationship, (c) assistance in decision making, (d) Socio-affective and (e) socio-symbolic dimensions. Our recordings underscored both the necessity of communication skills and the obligation to communicate effectively. Analysis of the dynamics of the communication process, according to the categories of delivering difficult information, showed few significant differences.

Conclusion

Physician training needs to include how to effectively communicate to parents to optimize their participation and cooperation in managing their care.
IRIS: Infection with RespIratory Syncytial Virus in infants—a prospective observational cohort study
Authors: Wetzke Martin , Funken Dominik , Lange Mathias , Bejo Levente , Haid Sibylle , Monteiro Joao G. Tereno , Schütz Katharina , Happle Christine , Schulz Thomas F. , Seidenberg Jürgen , Pietschmann Thomas , Hansen Gesine
Published: March 2022

Background

Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory tract infection in infants. Globally, RSV is responsible for approximately 3.2 million hospital admissions and about 60,000 in-hospital deaths per year.

Methods

Infection with RespIratory Syncytial Virus (IRIS) is an observational, multi-centre study enrolling infants with severe RSV infection and healthy controls. Inclusion criteria are age between 0 and 36 months and hospitalisation due to RSV infection at three German sites. Exclusion criteria are premature birth, congenital or acquired bronchopulmonary or cardiac diseases, and immunodeficiency. Healthy control probands are enrolled via recruitment of patients undergoing routine surgical procedures. Blood and respiratory specimens are collected upon admission, and RSV and other pathogens are analysed by multiplex polymerase chain reaction. Different biomaterials, including plasma, nasal lining fluid, blood cells, DNA, and RNA specimens, are sampled in a dedicated biobank. Detailed information on demographic characteristics and medical history is recorded, and comprehensive clinical data, including vital signs, medication, and interventions.

Discussion

The IRIS study aims to discover host and viral factors controlling RSV disease courses in infants. The approach including multi-omics characterisation in clinically well-characterized children with RSV bronchiolitis seeks to improve our understanding of the immune response against this virus. It may disclose novel diagnostic and treatment approaches for respiratory infections in infants.

Trial registration: ClinicalTrials.gov, NCT04925310. Registered 01 October 2021—Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT04925310?cond=NCT04925310&draw=2&rank=1
Circ_0000064 promotes high glucose-induced renal tubular epithelial cells injury to facilitate diabetic nephropathy progression through miR-532-3p/ROCK1 axis
Authors: Wang Huanlan , Huang Shenghua , Hu Taotao , Fei Shizhi , Zhang Huanqiao
Published: March 2022

Background

Circular RNA (circRNA) has been shown to mediate diabetic nephropathy (DN) development by regulating renal tubular epithelial cells (RTECs) injury. However, the role and mechanism of circ_0000064 in high glucose (HG)-induced RTECs injury have not been fully elucidated.

Methods

Human RTECs (HK-2) were exposed to HG to induce cell injury. Cell oxidative stress was assessed by detecting the levels of oxidative stress-markers. Moreover, cell proliferation and apoptosis were determined by CCK8 assay, EDU assay and flow cytometry. The protein levels of proliferation markers, apoptosis markers and Rho-associated coiled-coil-containing kinase 1 (ROCK1) were measured using western blot analysis. Furthermore, quantitative real-time PCR was performed to assess the expression of circ_0000064, microRNA (miR)-532-3p and ROCK1. The interaction between miR-532-3p and circ_0000064 or ROCK1 was confirmed by dual-luciferase reporter assay and RNA pull-down assay.

Results

Our results revealed that HG treatment could promote HK-2 cells oxidative stress, apoptosis, fibrosis, and inhibit proliferation. Circ_0000064 expression was increased in the serum of DN patients and HG-induced HK-2 cells, and silenced circ_0000064 could relieve HG-induced HK-2 cells injury. MiR-532-3p could be sponged by circ_0000064, and its overexpression also alleviated HG-induced HK-2 cells injury. Besides, the regulation of circ_0000064 knockdown on HG-induced HK-2 cells injury could be reversed by miR-532-3p inhibitor. Additionally, ROCK1 was a target of miR-532-3p, and its expression was inhibited by circ_0000064 knockdown. The inhibition effect of circ_0000064 knockdown on HG-induced HK-2 cells injury also could be reversed by overexpressing ROCK1.

Conclusion

In summary, circ_0000064 knockdown might alleviate HG-induced HK-2 cells injury via regulating the miR-532-3p/ROCK1 axis, which provided a new perspective for DN treatment.
Electronic medical record implementation in a large healthcare system from a leadership perspective
Authors: Arabi Yaseen M , Al Ghamdi Abdullah Ali , Al-Moamary Mohamed , Al Mutrafy Abdullah , AlHazme Raed H. , Al Knawy Bandar Abdulmohsen
Published: March 2022

Background

Information on the use of change management models to guide electronic medical records (EMR) implementation is limited. This case study describes the leadership aspects of a large-scale EMR implementation using Kotter’s change management model.

Methods

This case study presents the experience in implementing a new EMR system from the leadership perspective at King Abdulaziz Medical City, a large tertiary care hospital in Riyadh, Kingdom of Saudi Arabia. We described the process of implementation and outlined the challenges and opportunities, throughout the journey from the pre-implementation to the post-implementation phases.

Results

We described the corresponding actions to the eight domains of Kotter’s change management model: creating a sense of urgency, building the guiding team, developing a change vision and strategy, understanding and buy-in, removing obstacles, creating short-term wins, building on the change and anchoring the changes in corporate culture.

Conclusions

The case study highlights that EMR implementation is not a pure information technology project but rather is a technical-based complex social adaptive project that requires a specific set of leadership competencies that are central to its success. It demonstrates that change management models might be useful for large-scale EMR implementation.
A framework for participatory work environment interventions in home care – success factors and some challenges
Authors: Persson Johanna , Johansson Gerd , Arvidsson Inger , Östlund Britt , Holgersson Charlotte , Persson Roger , Rydenfält Christofer
Published: March 2022

Background

Home care is beset with work environment issues and high staff turnover, while research concerned with interventions to improve the work environment is sparse. Few of the existing interventions apply a participative approach, despite this being associated with more positive outcomes and sustainable change. This paper presents a framework, rooted in action research and action learning, for participatory work environment interventions in home care, and demonstrates how this framework has been implemented in four Swedish home care organizations.

Methods

The framework has three phases (pre-intervention, intervention planning and intervention implementation) and consists of cycles of action and reflection in three constellations: a group of researchers, a reference group with labour market organization representatives and home care managers, and intervention work groups in the home care organizations. The work was documented and analysed with focus on the realization of the framework and challenges that were met on the way. The interventions were evaluated using a pre-/post-test questionnaire design.

Results

Parts of the framework were successfully implemented. The pre-intervention phase and the intervention planning phase, with intervention work groups, worked well. All four groups identified one intervention relevant to their own context. However, only two of the proposed interventions were fully implemented and evaluated. The high staff and management turnover, and the high rate of organizational changes made it impossible to evaluate the interventions statistically. Yet, data from open-ended questions in the post questionnaire showed that the two implemented interventions were perceived as successful.

Conclusions

The participatory framework, presented in this paper, seems promising for work environment interventions in home care. The framework was designed to reduce the risk of known disturbances affecting the process in unstable organizations. Despite this, it proved challenging to execute the framework, and especially the interventions, due to changes happening at high speed. In the two cases where organizational changes were not dominating, the interventions were implemented successfully. While the prerequisites for participation and successful implementation could be improved somewhat, the main issue, the instability of the organizational context, is hard for researchers or the individual home care units to tackle alone.
Effect of xylazine, detomidine, medetomidine and dexmedetomidine during laparoscopic SCNT embryo transfer on pregnancy rate and some physiological variables in goats
Authors: Aghamiri Seyed Morteza , Samimi Amir Saeed , Hajian Mehdi , Samimi Amir Masoud , Oroumieh Amin
Published: March 2022

Background

The present study was conducted to determine if using α2-adrenergic agonists results in decreased stress levels (lower cortisol levels) in goats used for laparoscopic embryo [somatic cell nuclear transfer (SCNT)] transfer; and there is an effect on pregnancy rate when stress levels are lessened. Sixty healthy does aged 24 ± 4 months and weighing 30 ± 3 kg were used in experimental, prospective, randomized and blinded study. In this study, embryos were obtained by the Somatic Cell Nuclear Transfer (SCNT) method. Animals were randomly assigned to five groups: control (normal saline); xylazine (100 μg kg− 1); detomidine (50 μg kg− 1); medetomidine (20 μg kg− 1); and dexmedetomidine (5 μg kg− 1). Embryo transfer (through laparoscopic technique) began at 15 min and continued till 45 min post-treatment. Heart rate (HR), respiratory rate (RR), rectal temperature (RT), and ruminal motility were performed before (baseline) and after drug administration. Pregnancy detection was performed 38 days after embryo transfer.

Results

Compared to control, HR, RR and ruminal motility were significantly lower in α2-adrenergic agonists groups at 5–90, 15–60, and 5–120 min, respectively. Serum cortisol values significantly increased from baseline in the control group 45 min after drug administration (p = 0.001). At time points 45 and 60 min, serum cortisol concentration was significantly lower in α2-adrenergic agonists groups compared with the control. The pregnancy rate in control group (n = 4/12, 33.3%) was significantly lower than xylazine (n = 9/12, 75%; p = 0.041), detomidine (n = 10/12, 83.3%; p = 0.013), medetomidine (n = 9/12, 75%; p = 0.041) and dexmedetomidine (n = 10/12, 83.3%; p = 0.013); but no significant differences were observed among different α2-adrenergic agonists groups.

Conclusion

Alph2-adrenergic agonists were effective on increasing the pregnancy rate of recipient goats receiving cloned embryos. No significant differences were detected among different α2-adrenergic agonists.
Xylanase production by Thermobacillus xylanilyticus is impaired by population diversification but can be mitigated based on the management of cheating behavior
Authors: Bouchat Romain , Vélard Frédéric , Audonnet Sandra , Rioult Damien , Delvigne Frank , Rémond Caroline , Rakotoarivonina Harivony
Published: March 2022

Background

The microbial production of hemicellulasic cocktails is still a challenge for the biorefineries sector and agro-waste valorization. In this work, the production of hemicellulolytic enzymes by Thermobacillus xylanilyticus has been considered. This microorganism is of interest since it is able to produce an original set of thermostable hemicellulolytic enzymes, notably a xylanase GH11, Tx-xyn11. However, cell-to-cell heterogeneity impairs the production capability of the whole microbial population.

Results

Sequential cultivations of the strain on xylan as a carbon source has been considered in order to highlight and better understand this cell-to-cell heterogeneity. Successive cultivations pointed out a fast decrease of xylanase activity (loss of ~ 75%) and Tx-xyn11 gene expression after 23.5 generations. During serial cultivations on xylan, flow cytometry analyses pointed out that two subpopulations, differing at their light-scattering properties, were present. An increase of the recurrence of the subpopulation exhibiting low forward scatter (FSC) signal was correlated with a progressive loss of xylanase activity over several generations. Cell sorting and direct observation of the sorted subpopulations revealed that the low-FSC subpopulation was not sporulating, whereas the high-FSC subpopulation contained cells at the onset of the sporulation stage. The subpopulation differences (growth and xylanase activity) were assessed during independent growth. The low-FSC subpopulation exhibited a lag phase of 10 h of cultivation (and xylanase activities from 0.15 ± 0.21 to 3.89 ± 0.14 IU/mL along the cultivation) and the high-FSC subpopulation exhibited a lag phase of 5 h (and xylanase activities from 0.52 ± 0.00 to 4.43 ± 0.61 over subcultivations). Serial cultivations on glucose, followed by a switch to xylan led to a ~ 1.5-fold to ~ 15-fold improvement of xylanase activity, suggesting that alternating cultivation conditions could lead to an efficient population management strategy for the production of xylanase.

Conclusions

Taken altogether, the data from this study point out that a cheating behavior is responsible for the progressive reduction in xylanase activity during serial cultivations of T. xylanilyticus. Alternating cultivation conditions between glucose and xylan could be used as an efficient strategy for promoting population stability and higher enzymatic productivity from this bacterium.
BuFeiXiaoJiYin ameliorates the NLRP3 inflammation response and gut microbiota in mice with lung cancer companied with Qi-yin deficiency
Authors: Jiang Rui-yuan , Wang Ting , Lan Qiao-yu , Qin Yan-chun , Man Ting-ting , Sun Hua , Li Zhu-long , Zhong Xiao-ting , Mo Chun-mei , Rong Zhen
Published: March 2022

Introduction

NLRP3 inflammasome responses and gut microbiota have been shown an important role in lung cancer, however, the relationship between gut microbiota and NLRP3 inflammasome responses in lung cancer with Qi-yin deficiency remains elusive.

Methods

To investigate the effect of the traditional Chinese medicine BuFeiXiaoJiYin (BFXJY) on NLRP3 inflammasome responses and dysbiosis in lung cancer with Qi-yin deficiency, the female BALB/cA-nu mice were treated with LPS and ATP to induce inflammation, and were intragastrically treated with warm Chinese medicine and smoked with shavings to induce Qi-yin deficiency, as well as were injected with 1 × 107/ml A549 cells to simulate lung cancer. Then the three different doses of BuFeiXiaoJiYin (BFXJY) and positive control (CRID3) were used for intervention in mice for 27 consecutive days. Then, we estimated the protection effect of BFXJY on lung cancer mice with Qi-yin deficiency, through deterring tumor growth, NLRP3 inflammasome, PKC signaling, and homeostasis of gut microbiota.

Results

In this study, we found that BFXJY could inhibit the tumor growth in lung cancer with Qi-yin deficiency by reducing the production of IL-1β and IL-18 and inhibiting NLRP3 inflammasome activation, which might be associated with the inhibition of PKC signaling. Furthermore, BFXJY could promote microbial diversity and balance the microbial composition changes induced by inflammation and Qi-yin deficiency in lung cancer.

Conclusion

BuFeiXiaoJiYin ameliorates the NLRP3 inflammation response and gut microbiota in mice with lung cancer companied with Qi-yin deficiency. Our study provides a theoretical basis for the clinical development of therapeutic drugs targeting to treat lung cancer.
Prevalence of thoracoabdominal imaging findings in tuberous sclerosis complex
Authors: Ritter David M. , Fessler Bailey K. , Ebrahimi-Fakhari Daniel , Wei Jun , Franz David N. , Krueger Darcy A. , Trout Andrew T. , Towbin Alexander J.
Published: March 2022

Background

Tuberous sclerosis complex (TSC) results in neurodevelopmental phenotypes, benign tumors, and cysts throughout the body. Recent studies show numerous rare findings in TSC. Guidelines suggest routine abdominal and chest imaging to monitor these thoracoabdominal findings, but imaging is not uniformly done across centers. Thus, the prevalence of many findings is unknown. To answer this, we categorized the clinical reads of 1398 thoracoabdominal scans from 649 patients of all ages in the Cincinnati Children’s Hospital TSC Repository Database.

Results

Typical TSC findings were present in many patients: kidney cysts (72%), kidney fat-containing angiomyolipomas (51%), kidney lipid-poor angiomyolipomas (27%), liver angiomyolipomas (19%), and lung nodules thought to represent multifocal micronodular pneumocyte hyperplasia (MMPH) (18%). While many features were more common in TSC2 patients, TSC1 patients had a higher prevalence of MMPH than TSC2 patients (24% versus 13%, p = 0.05). Many rare findings (e.g., lymphatic malformations and liver masses) are more common in TSC than in the general population. Additionally, most thoracoabdominal imaging findings increased with age except kidney cysts which decreased, with the 0–10 years age group having the highest percentage (69% 0–10 years, 49% 10–21 years, 48% 21 + years, p < 0.001). Finally, in our population, no patients had renal cell carcinoma found on abdominal imaging.

Conclusions

These results show that regular thoracoabdominal scans in TSC may show several findings that should not be ignored or, conversely, over-reacted to when found in patients with TSC. Female sex, TSC2 mutation, and age are risk factors for many thoracoabdominal findings. The data suggest novel interactions of genetic mutation with pulmonary nodules and age with renal cysts. Finally, in agreement with other works, these findings indicate that several rare thoracoabdominal imaging findings occur at higher rates in the TSC population than in the general population. This work supports obtaining detailed thoracoabdominal imaging in patients with TSC.
The route of SARS-CoV-2 to brain infection: have we been barking up the wrong tree?
Authors: Butowt Rafal , von Bartheld Christopher S.
Published: March 2022

This letter draws attention to recent work supporting the notion that the SARS-CoV-2 virus may use the nervus terminalis rather than the olfactory nerve as a shortcut route from the nasal cavity to infect the brain.
LncRNA-mediated DNA methylation: an emerging mechanism in cancer and beyond
Authors: Huang Wanxu , Li Hua , Yu Qingsong , Xiao Wei , Wang Dan Ohtan
Published: March 2022

DNA methylation is one of the most important epigenetic mechanisms to regulate gene expression, which is highly dynamic during development and specifically maintained in somatic cells. Aberrant DNA methylation patterns are strongly associated with human diseases including cancer. How are the cell-specific DNA methylation patterns established or disturbed is a pivotal question in developmental biology and cancer epigenetics. Currently, compelling evidence has emerged that long non-coding RNA (lncRNA) mediates DNA methylation in both physiological and pathological conditions. In this review, we provide an overview of the current understanding of lncRNA-mediated DNA methylation, with emphasis on the roles of this mechanism in cancer, which to the best of our knowledge, has not been systematically summarized. In addition, we also discuss the potential clinical applications of this mechanism in RNA-targeting drug development.
Effect of application time of 38% silver diamine fluoride solution on arresting early childhood caries in preschool children: a randomised double-blinded controlled trial protocol
Authors: Yan Iliana Gehui , Zheng Faith Miaomiao , Gao Sherry Shiqian , Duangthip Duangporn , Lo Edward Chin Man , Chu Chun Hung
Published: March 2022

Background

To study the caries lesion activity response to topical 38% silver diamine fluoride (SDF) therapy with increasing treatment application time.

Methods/design

The design is a stratified-randomised, double-blind, active-controlled, parallel-group clinical trial with nine treatment arms. The trial will involve recruiting at least 414 3- to 5-year-old kindergarten children with caries, who will receive approximately 0.004 mL of 38% SDF (the typical amount applied per the manufacturer’s instructions) to treat each caries lesion. The children will be stratified by caries status, randomised by blocks, and allocated to nine groups of SDF application times: 3, 5, 10, 15, 30, 45, 60, 120, and 180 s. The outcome measure is caries lesion activity (active/arrest) at the tooth-surface level at 6 months post-initial treatment. A calibrated dentist will conduct the blinded clinical examinations at baseline and at the 6-month follow-up. In addition, the parents will be surveyed to examine the effects of the moderating variables, such as oral hygiene, on caries lesion activity. The hypothesis is that a monotonically increasing trend can be found between the SDF application time and the proportion of caries lesions that are arrested. The Cochran-Armitage test for trends in proportions, corrected for clustering within children, will be used to determine the relationship between the exposure to SDF (the SDF application time) and the response (proportion of lesions arrested) in children, taking into consideration the effect of the moderating variables as well as the nesting of multiple caries lesions within an individual child. An EC 80 analysis (an 80% maximal concentration) will be used to determine the exposure (the SDF application time) for 80% caries lesion arrest. Bootstrap methods will be used for clustered data and will be resampled by clustering to determine the 95% confidence interval.

Discussion

This study will help with determining the optimal application time for SDF treatment. It will provide an evidence-based protocol for the use of SDF to arrest tooth decay in the primary teeth of young children. The results will inform an evidence-based SDF protocol to arrest caries, which affects 573 million children with tooth decay worldwide.

Trial registration

ClinicalTrials.govNCT04655430. Registered on 7th December 2020.
Electro-acupuncture for protracted amphetamine abstinence syndrome: study protocol for a pragmatic randomized controlled trial
Authors: Ren Huan , Zeng Yiwei , Zhang Min , Zhang Su , Chen Zhihan , Wu Binbin , Liu Jun , Ren Yulan
Published: March 2022

Background

Protracted amphetamine abstinence syndrome is one of the primary causes of relapse for amphetamine-type drug abusers during withdrawal. However, the importance of the management of protracted amphetamine abstinence syndrome is underestimated. Electro-acupuncture may be a safe and effective alternative therapy for protracted amphetamine abstinence syndrome, but the evidence is limited.

Methods

The study is a prospective, two-center, randomized, waitlist controlled, open-label pragmatic trial. A total of 300 patients with protracted amphetamine abstinence syndrome will be recruited. All participants will be randomly assigned to an electro-acupuncture group or a waitlist group in a 1:1 ratio. Participants in the electro-acupuncture group will receive the electrical-acupuncture treatment. Waitlist group participants will not receive electro-acupuncture treatment but will be assessed at each visit. Treatments will be administered twice a week for a total of 4 consecutive weeks. The primary outcome in this study is the change in the ACSA between baseline (week 0) and the completion of treatment (week 4), and the secondary outcomes are changes in the Hamilton Depression Scale (HAMD), the visual analog scale (VAS), the Hamilton Anxiety Scale (HAMA), the Pittsburgh Sleep Quality Index (PSQI), the Montreal Cognitive Assessment (MoCA), and the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36).

Discussion

This study will assess the effectiveness of acupuncture in PAAS in real-world settings to provide support for clinical decisions and a basis for subsequent trials comparing acupuncture with other positive regimens.

Trial registration

ClinicalTrials.gov ChiCTR2000040619. Registered on 3 December 2020
Effectiveness of herb-partitioned moxibustion on the navel for pregnancy outcomes in patients with recurrent implantation failure undergoing in vitro fertilization and embryo transfer: a study protocol for a randomized controlled trial
Authors: Xia Qingchang , Gao Shuzhong , Song Jingyan , Du Dongqing , Li Chunjing , Zhou Yue , Zhang Xiaobin , Dong Zhibin , Ma Yuning , Ma Yuxia
Published: March 2022

Background

Recurrent implantation failure (RIF) in the majority of patients undergoing in vitro fertilization and embryo transfer (IVF-ET) is caused by various factors such as maternal age, embryo quality, endometrial receptivity (ER), and immunity. The incidence of RIF is usually between 5 and 10%. Previous studies have shown that herb-partitioned moxibustion on the navel is one of the treatment methods of acupuncture with a positive effect on pregnancy. However, its application in the treatment of RIF has not been reported. Therefore, this study aims to evaluate the effectiveness and safeness of herb-partitioned moxibustion on the navel in improving the outcome of frozen embryo transfer (FET) in patients with RIF.

Methods

This study conducts a randomized controlled trial (RCT). It is planned to recruit 210 patients undergoing RIF for FET from Affiliated Hospital of Shandong University of Traditional Chinese Medicine and randomly divide them into the treatment group and the control group in a ratio of 1:1. The patient of the treatment group will be treated with herb-partitioned moxibustion on the navel once a week for three consecutive menstrual cycles. No intervention will be used in the control group for 3 menstrual cycles. In the fourth menstrual cycle, all patients will undergo artificial cycle to prepare the endometrium for FET. The pregnancy outcomes will be recorded after a 3-month follow-up. Primary outcome will be assessed as the ongoing pregnancy rate compared with the control group. Secondary outcomes include the endometrial type, resistance index (RI), pulsatility index (PI) of the bilateral uterine artery, endometrial blood flow, serum estradiol (E2), progesterone (P), biochemical pregnancy rate, implantation rate, and clinical pregnancy rate.

Discussion

If the results show that the herb-partitioned moxibustion on the navel can improve IVF-ET outcomes in patients with RIF, it will be recommended in clinical practice.

Trial registration

Chinese Clinical Trial Registry (ChiCTR) ChiCTR2100043954. Registered on 8 July 2021.
Updated occurrence and bionomics of potential malaria vectors in Europe: a systematic review (2000–2021)
Authors: Bertola Michela , Mazzucato Matteo , Pombi Marco , Montarsi Fabrizio
Published: March 2022

Despite the eradication of malaria across most European countries in the 1960s and 1970s, the anopheline vectors are still present. Most of the malaria cases that have been reported in Europe up to the present time have been infections acquired in endemic areas by travelers. However, the possibility of acquiring malaria by locally infected mosquitoes has been poorly investigated in Europe, despite autochthonous malaria cases having been occasionally reported in several European countries. Here we present an update on the occurrence of potential malaria vector species in Europe. Adopting a systematic review approach, we selected 288 papers published between 2000 and 2021 for inclusion in the review based on retrieval of accurate information on the followingAnophelesspecies:An. atroparvus,An. hyrcanussensu lato (s.l.),An. labranchiae,An. maculipennissensu stricto (s.s.),An. messeae/daciae,An. sacharovi,An. superpictusandAn. plumbeus. The distribution of these potential vector species across Europe is critically reviewed in relation to areas of major presence and principal bionomic features, including vector competence toPlasmodium. Additional information, such as geographical details, sampling approaches and species identification methods, are also reported. We compare the information on each species extracted from the most recent studies to comparable information reported from studies published in the early 2000s, with particular reference to the role of each species in malaria transmission before eradication. The picture that emerges from this review is that potential vector species are still widespread in Europe, with the largest diversity in the Mediterranean area, Italy in particular. Despite information on their vectorial capacity being fragmentary, the information retrieved suggests a re-definition of the relative importance of potential vector species, indicatingAn. hyrcanuss.l.,An. labranchiae,An. plumbeusandAn. sacharovias potential vectors of higher importance, whileAn. messeae/daciaeandAn. maculipenniss.s. can be considered to be moderately important species. In contrast,An. atroparvusandAn. superpictusshould be considered as vectors of lower importance, particularly in relation to their low anthropophily. The presence of gaps in current knowledge of vectorial systems in Europe becomes evident in this review, not only in terms of vector competence but also in the definition of sampling approaches, highlighting the need for further research to adopt the appropriate surveillance system for each species.

Graphical Abstract
Susceptibility of female rats to cardiac arrhythmias following refeeding after severe food restriction
Authors: De Souza Aline M. A. , Almeida Jonathas F. Q. , Shults Nataliia , Ji Hong , Li James , Sandberg Kathryn
Published: March 2022

Background

Many studies have shown malnutrition and inadequate caloric consumption have adverse acute effects on cardiovascular structure and function.

Methods

To determine the adverse long term cardiovascular effects, we studied cardiac morphology and function in female (F) and male (M) severe food restricted rats 3 months after refeeding (sFR-Refed).

Results

Two weeks of a normal chow diet in which calories were reduced by 60% decreased body weight (BW) by approximately 15% in both sexes. Within 2 weeks of refeeding, no differences in BW were detected between CT and sFR-Refed groups. However, male rats gained almost 3 times more BW than the females over the 3-month refeeding period. Sex differences were also observed in cardiac pathology. Hearts from F-sFR-Refed rats exhibited more atrophy and less hypertrophy, while M-sFR-Refed rats predominantly exhibited hypertrophic remodeling. While there were no differences in the frequency of ventricular arrhythmias induced by ischemia/reperfusion (I/R) in the isolated heart between M-CT and M-sFR-Refed rats, I/R induced twice as many arrhythmias in the F-sFR-Refed rats compared to F-CT.

Conclusions

These findings indicate the female heart is more susceptible to the long term adverse cardiovascular effects of sFR months after refeeding. Thus, this study provides a rationale for studying sex differences in cardiovascular risk in individuals who experience sFR for voluntary (e.g., very low-calorie dieting) or involuntary (e.g., poverty) reasons earlier in life.
Decomposing compounds enables reconstruction of interaction fingerprints for structure-based drug screening
Authors: Adasme Melissa F. , Bolz Sarah Naomi , Al-Fatlawi Ali , Schroeder Michael
Published: March 2022

Background

Structure-based drug repositioning has emerged as a promising alternative to conventional drug development. Regardless of the many success stories reported over the past years and the novel breakthroughs on the AI-based system AlphaFold for structure prediction, the availability of structural data for protein–drug complexes remains very limited. Whereas the chemical libraries contain millions of drug compounds, the vast majority of them do not have structures to crystallized targets,and it is, therefore, impossible to characterize their binding to targets from a structural view. However, the concept of building blocks offers a novel perspective on the structural problem. A drug compound is considered a complex of small chemical blocks or fragments, which confer the relevant properties to the drug and have a high proportion of functional groups involved in protein binding. Based on this, we propose a novel approach to expand the scope of structure-based repositioning approaches by transferring the structural knowledge from a fragment to a compound level.

Results

We fragmented over 100,000 compounds in the Protein Data Bank (PDB) and characterized the structural binding mode of 153,000 fragments to their crystallized targets. Using the fragment’s data, we were able to artificially reconstruct the binding mode of over 7,800 complexes between ChEMBL compounds and their known targets, for which no structural data is available. We proved that the conserved binding tendency of fragments, when binding to the same targets, highly influences the drug’s binding specificity and carries the key information to reconstruct full drugs binding mode. Furthermore, our approach was able to reconstruct multiple compound-target pairs at optimal thresholds and high similarity to the actual binding mode.

Conclusions

Such reconstructions are of great value and benefit structure-based drug repositioning since they automatically enlarge the technique’s scope and allow exploring the so far ‘unexplored compounds’ from a structural perspective. In general, the transfer of structural information is a promising technique that could be applied to any chemical library, to any compound that has no crystal structure available in PDB, and even to transfer any other feature that may be relevant for the drug discovery process and that due to data limitations is not yet fully available. In that sense, the results of this work document the full potential of structure-based screening even beyond PDB.

Graphical Abstract
A multitask GNN-based interpretable model for discovery of selective JAK inhibitors
Authors: Wang Yimeng , Gu Yaxin , Lou Chaofeng , Gong Yuning , Wu Zengrui , Li Weihua , Tang Yun , Liu Guixia
Published: March 2022

The Janus kinase (JAK) family plays a pivotal role in most cytokine-mediated inflammatory and autoimmune responses via JAK/STAT signaling, and administration of JAK inhibitors is a promising therapeutic strategy for several diseases including COVID-19. However, to screen and design selective JAK inhibitors is a daunting task due to the extremely high homology among four JAK isoforms. In this study, we aimed to simultaneously predict pIC50 values of compounds for all JAK subtypes by constructing an interpretable GNN multitask regression model. The final model performance was positive, with R2 values of 0.96, 0.79 and 0.78 on the training, validation and test sets, respectively. Meanwhile, we calculated and visualized atom weights, followed by the rank sum tests and local mean comparisons to obtain key atoms and substructures that could be fine-tuned to design selective JAK inhibitors. Several successful case studies have demonstrated that our approach is feasible and our model could learn the interactions between proteins and small molecules well, which could provide practitioners with a novel way to discover and design JAK inhibitors with selectivity.

Graphical Abstract