bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical applications of acellular dermal matrices: A review
Authors: Petrie Kyla , Cox Cameron T , Becker Benjamin C , MacKay Brendan J
Published: January 2022

Introduction

The extracellular matrix (ECM) plays an integral role in wound healing. It provides both structure and growth factors that allow for the organised cell proliferation. Large or complex tissue defects may compromise host ECM, creating an environment that is unfavourable for the recovery of anatomical function and appearance. Acellular dermal matrices (ADMs) have been developed from a variety of sources, including human (HADM), porcine (PADM) and bovine (BADM), with multiple different processing protocols. The objective of this report is to provide an overview of current literature assessing the clinical utility of ADMs across a broad spectrum of applications.

Methods

PubMed, MEDLINE, EMBASE, Scopus, Cochrane and Web of Science were searched using keywords ‘acellular dermal matrix’, ‘acellular dermal matrices’ and brand names for commercially available ADMs. Our search was limited to English language articles published from 1999 to 2020 and focused on clinical data.

Results

A total of 2443 records underwent screening. After removing non-clinical studies and correspondence, 222 were assessed for eligibility. Of these, 170 were included in our synthesis of the literature. While the earliest ADMs were used in severe burn injuries, usage has expanded to a number of surgical subspecialties and procedures, including orthopaedic surgery (e.g. tendon and ligament reconstructions), otolaryngology, oral surgery (e.g. treating gingival recession), abdominal wall surgery (e.g. hernia repair), plastic surgery (e.g. breast reconstruction and penile augmentation), and chronic wounds (e.g. diabetic ulcers).

Conclusion

Our understanding of ADM’s clinical utility continues to evolve. More research is needed to determine which ADM has the best outcomes for each clinical scenario.

Lay Summary

Large or complex wounds present unique reconstructive and healing challenges. In normal healing, the extracellular matrix (ECM) provides both structural and growth factors that allow tissue to regenerate in an organised fashion to close the wound. In difficult or large soft-tissue defects, however, the ECM is often compromised. Acellular dermal matrix (ADM) products have been developed to mimic the benefits of host ECM, allowing for improved outcomes in a variety of clinical scenarios. This review summarises the current clinical evidence regarding commercially available ADMs in a wide variety of clinical contexts.
How Knowledgeable Are Spine Surgeons Regarding EMG-NCS for Cervical Spine Conditions? An International Aospine Survey
Authors: Joaquim Andrei Fernandes , Martins Carlos Roberto , Riew K. Daniel
Published: January 2022

Study Design

Cross-sectional, international survey.

Objectives

To evaluate the knowledge of spine surgeons regarding the use of electromyography (EMG) and nerve conduction studies (NCS) for degenerative cervical spine conditions (DCC).

Methods

All members of AO Spine International were emailed an anonymous survey to evaluate their clinical knowledge about the use of EMG and nerve conduction studies for DCC. Descriptive statistics were used to analyze the results, as well as to compare the answers among different groups of surgeons and assess demographic characteristics.

Results

A total of 402 participants answered the survey, 91.79% were men from the 5 continents. There were 221 orthopedic surgeons (55.39%) and 171 neurosurgeons (42.86%), more than a half of them with a complete spinal fellowship (56.44%). The most common reasons that surgeons obtain the test is to differentiate a radiculopathy from a peripheral nerve compression (88.06%). As a group, the responding surgeons’ knowledge regarding EMG-NCS was poor. Only 53.46% of surgeons correctly answered that EMG-NCS is unable to differentiate a C5 from a C6 radiculopathy. Only 23.47% of the surgeons knew that EMG-NCS are not able to diagnose a pre vs a post-fixed brachial plexus. Only 25% of the surgeons correctly answered a question regarding the test’s ability to diagnose other neurological diseases.

Conclusions

We found that our respondents’ knowledge regarding EMG-NCS for DCC was poor. Identifying the weak points of knowledge about EMG-NCS may help to educate surgeons on the indications for the test and the proper way to interpret the results.
Identifying the potential role of IL-1β in the molecular mechanisms of disc degeneration using gene expression profiling and bioinformatics analysis
Authors: Fan Ning , Yuan Shuo , Hai Yong , Du Peng , Li Jian , Kong Xiaochuan , Zhu Wenyi , Liu Yuzeng , Zang Lei
Published: January 2022

Purpose

We performed a bioinformatics analysis to identify the key genes that were differentially expressed between degenerative intervertebral disc (IVD) cells with and without exposure to interleukin-1β and explore the related signaling pathways and interaction networks.

Methods

The microarray data were downloaded from the Gene Expression Omnibus (27,494). Then, analyses of the gene ontology, signaling pathways, and interaction networks for the differentially expressed genes (DEGs) were conducted using tools including the Database for Annotation, Visualization, and Integrated Discovery, Metascape, Gene Set Enrichment Analysis, Search Tool for the Retrieval of Interacting Genes, Cytoscape, Venn method, and packages of the R computing language.

Results

A total of 260 DEGs were identified, including 161 upregulated and 99 downregulated genes. Gene Ontology annotation analysis showed that these DEGs were mainly associated with the extracellular region, chemotaxis, taxis, cytokine activity, and cytokine receptor binding. A Kyoto Encyclopedia of Genes and Genomes signaling pathway analysis showed that these DEGs were mainly involved in the of cytokine-cytokine receptor interaction, rheumatoid arthritis, tumor necrosis factor signaling pathway, Salmonella infection, and chemokine signaling pathway. The interaction network analysis indicated that 10 hub genes, including CXCL8, CXCL1, CCL20, CXCL2, CXCL5, CXCL3, CXCL6, C3, PF4, and GPER1 may play key roles in IVD degeneration.

Conclusions

Bioinformatic analysis showed that CXCL8 and other nine key genes may play a role in the development of disc degeneration induced by inflammatory reactions and can be used to identify potential target genes for therapeutic applications in IVD degeneration.
Choosing a Provider: What Factors Matter Most to Consumers and Patients?
Authors: Kozikowski Andrzej , Morton-Rias Dawn , Mauldin Sheila , Jeffery Colette , Kavanaugh Kasey , Barnhill Grady
Published: January 2022

Enhancing consumer and patient choice has been proposed as a means to improve care quality and reduce health-related costs. Choosing a medical provider is one of the most critical and often complex decisions patients make about their health care. We investigated the perceived importance of factors patients may consider when selecting a practitioner and if rated importance of the factors varies with their characteristics and prior experiences with different types of clinicians (physicians, physician assistants, and nurse practitioners). Participants most often identified medical license, certification, and whether the provider accepts the patients’ health insurance as important, while provider type, others’ recommendations, and online reviews were among the least important. We found wide-ranging differences based on patient characteristics. Prior experience with providers was also a strong determinant of patterns of factors patients considered valuable. Policy-makers, health systems, insurers, and providers need to take into account that patients rely on a range of factors that vary based on their distinct needs, backgrounds, and previous experiences—requiring tailored information to make more informed decisions.
“The interpreter of horrors”: The interpreter Wera Kapkajew at the First Frankfurt Auschwitz Trial (1963–1965)
Authors: Davies Peter
Published: January 2022

The three trials of SS camp personnel, held in Frankfurt am Main in the mid-1960s, represent a key moment in the development of public awareness of and attitudes towards the Holocaust in West and East Germany. The involvement of several hundred witnesses, many of whom were survivors, from across the world and collectively speaking 11 different languages, brought home the international scale of the genocide and drew attention to the individual quality of the witnesses’ voices as they told their stories. The only interpreter at the trial who attracted public attention for her work and who left a substantial trace in the archival record was the Polish-Russian-German interpreter Wera Kapkajew, who also accompanied the court on its visit to the Auschwitz complex. In contrast to the other interpreters, her work and biography attracted journalistic interest and she was singled out for praise by court personnel and witnesses: in particular, she is praised for conveying the nuances of the witness’ voices, rather than just the content of their testimony. This article explores Kapkajew’s contribution to the trial proceedings and what happens when an interpreter’s work becomes visible in a Holocaust trial.
Crystal chemistry and miscibility of chernovite-(Y), xenotime-(Y), gasparite-(Ce) and monazite-(Ce) from Mt. Cervandone, Western Alps, Italy
Authors: Pagliaro Francesco , Lotti Paolo , Guastoni Alessandro , Rotiroti Nicola , Battiston Tommaso , Gatta G. Diego
Published: January 2022

The crystal chemistry and crystal structure of the rare earth element phosphates, monazite-(Ce), Ce(PO4), and xenotime-(Y), Y(PO4), as well as the arsenates, gasparite-(Ce), Ce(AsO4), and chernovite-(Y), Y(AsO4), from the hydrothermal quartz-bearing fissures, related to pegmatites overprinted by amphibolite facies, cropping out at Mt. Cervandone, Western Alps, Piedmont, Italy, have been investigated by means of electron microprobe analysis in wavelength dispersion mode and single-crystal X-ray diffraction. The chemical data reveal the occurrence of a full solid solution among the isostructural chernovite-(Y) and xenotime-(Y) with tetragonal symmetry, whereas a wide miscibility gap is observed for the isostructural gasparite-(Ce) and monazite-(Ce) of Mt. Cervandone, with monoclinic symmetry. A significant chemical heterogeneity has been observed for several investigated samples, especially related to the Th content, which is locally enriched in ThSiO4 grains. The analysis of the refined structural models demonstrates the significant control played by the composition of the tetrahedrally-coordinated (As,P)-bearing sites on the bulk unit-cell volume, and on the size and shape of the (REE)-coordination polyhedra.
Validation of the Khorana score for predicting venous thromboembolism in 40 218 patients with cancer initiating chemotherapy
Authors: Overvad Thure Filskov , Ording Anne Gulbech , Nielsen Peter Brønnum , Skjøth Flemming , Albertsen Ida Ehlers , Noble Simon , Vistisen Anders Krog , Gade Inger Lise , Severinsen Marianne Tang , Piazza Gregory , Larsen Torben Bjerregaard
Published: January 2022

The Khorana score is recommended for guiding primary venous thromboembolism (VTE) prophylaxis in cancer patients, but its clinical utility overall and across cancer types remains debatable. Also, some previous validation studies have ignored the competing risk of death, hereby potentially overestimating VTE risk. We identified ambulatory cancer patients initiating chemotherapy without other indications for anticoagulation using Danish health registries and estimated 6-month cumulative incidence of VTE stratified by Khorana levels. Analyses were conducted with and without considering death as a competing risk using the Kaplan-Meier method vs the cumulative incidence function. Analyses were performed overall and stratified by cancer types. Of 40 218 patients, 35.4% were categorized by Khorana as low risk (score 0), 53.6% as intermediate risk (score 1 to 2), and 10.9% as high risk (score ≥3). Considering competing risk of death, the corresponding 6-month risks of VTE were 1.5% (95% confidence interval [CI], 1.3-1.7), 2.8% (95% CI, 2.6-3.1), and 4.1% (95% CI, 3.5-4.7), respectively. Among patients recommended anticoagulation by guidelines (Khorana score ≥2), the 6-month risk was 3.6% (95% CI, 3.3-3.9). Kaplan-Meier analysis overestimated incidence up to 23% compared with competing risk analyses. Using the guideline-recommended threshold of ≥2, the Khorana score did not risk-stratify patients with hepatobiliary or pancreatic cancer, lung cancer, and gynecologic cancer. In conclusion, the Khorana score was able to stratify ambulatory cancer patients according to the risk of VTE, but not for all cancer types. Absolute risks varied by methodology but were lower than in key randomized trials. Thus, although certain limitations with outcome identification using administrative registries apply, the absolute benefit of implementing routine primary thromboprophylaxis in an unselected cancer population may be smaller than seen in randomized trials.
Characterization and regulation mechanism analysis of ubiquitin-conjugating family genes in strawberry reveals a potential role in fruit ripening
Authors: Li Mengyao , Wang Liangxin , Liu Yiting , Lin Yuanxiu , Zhang Yunting , Long Yu , Luo Chuanying , Zhang Yong , Chen Qing , Chen Pinwen , Wang Yan , Wang Xiaorong , Tang Haoru , Luo Ya
Published: January 2022

Background

E2 ubiquitin-conjugating (UBC) enzymes are an integral component of the ubiquitin proteasome system that play an important role in plant development, growth, and external stress responses. Several UBC genes have been identified in various plants. However, no studies exploring the functions of UBC genes in regulating fruit of strawberry have been reported. In the present study, a systematic analysis of the entire UBC family members were conducted in the genome of strawberry (Fragaria ×ananassa) based on bioinformatics method, and the gene functioning in strawberry ripening was explored.

Results

A total of 191 UBC genes were identified in the genome of cultivated strawberry. These genes were unevenly distributed across the 28 chromosomes from the 4 subgenomes of cultivated strawberry, ranging from 3 to 11 genes per chromosome. Moreover, the expansion of FaUBC genes in strawberry was mainly driven by WGD. All the FaUBC genes were clarified into 13 groups and most of them were included in the group VI. The gene structure analysis showed that the number of exons varied from 1 to 23, and the structure of genes had few differences within the same groups but a distinction in different groups. Identification of the cis-acting elements of the promoter revealed multiple regulatory elements that responded to plant growth and development, phytohormone responsive, and abiotic and biotic stress. Data from functional annotation indicated that FaUBC genes play a role in a variety of biological processes. The RNA-seq data showed that FaUBC genes displayed different expression pattern during the fruit ripening process and clarified into 6 clusters. In particular, cluster 3 exhibiting a sudden expression increase in the turning red stage were speculated to be involved in fruit ripening. Hence, two FaUBC genes (FaUBC76 and FaUBC78) were selected for gene function analysis by transient over-expression method. The results indicated that FaUBC76 has a positive effect on the fruit development and ripening in strawberry by up-regulating accumulation of anthocyanins. Moreover, expression of some maturity-related genes were also significantly increased, further supporting a role for FaUBC76 in the regulation of fruit ripening or softening. On the contrary, the overexpression of FaUBC78 significantly increased the firmness of strawberry fruit, indicating that FaUBC78 had a positive role in inhibiting the decrease of strawberry fruit firmness.

Conclusion

Our study not only provide comprehensive information on system evolution and function on UBC genes, but also give a new insight into explore the roles of FaUBC genes in the regulation of strawberry ripening.
Nitrogen application and differences in leaf number retained after topping affect the tobacco (Nicotiana tabacum) transcriptome and metabolome
Authors: Lei Bo , Chang Wei , Zhao Huina , Zhang Kai , Yu Jing , Yu Shizhou , Cai Kai , Zhang Jie , Lu Kun
Published: January 2022

Background

Agronomic treatments such as the application of nitrogen fertilizer and topping (removal of the inflorescence and top leaves) cause substantial changes in plant metabolism. To explore these changes, we conducted comparative transcriptomic and metabolomic analyses of leaves collected from four positions along the stem on plants exposed to two nitrogen doses and with different numbers of leaves retained after topping in tobacco (Nicotiana tabacum).

Results

We identified 13,330 unique differentially expressed genes and 32 differentially abundant metabolites. Through RNA-seq and WGCNA analyze, we constructed 2 co-expression networks (green and blue) highly correlation to N application and leaf number retained, predicted a hub gene NtGER3 may play an important role in N metabolism related to amino acid (cysteine) through CK pathway in tobacco leaves, NtARFs may participated in modulating the auxin signal and N in bottom leaves and NtRAP2.12 as key gene involved in N regulation by ethylene pathway. What’s more, our data prove C/N transformation and balance affect the “source – flow - sink” redistribution and remobilization in tobacco during growth and development process.

Conclusions

Overall, this comparative transcriptomics study provides novel insight into the complex molecular mechanisms underlying plant responses to different levels of nitrogen application and the number of leaves remaining after topping in plants.
A pilot voxel-based morphometry study of older adults after the PICMOR intervention program
Authors: Sugimoto Hikaru , Otake-Matsuura Mihoko
Published: January 2022

Background

Age-related decline in cognitive function, such as executive function, is associated with structural changes in the neural substrates, such as volume reductions in the lateral prefrontal cortex. To prevent or delay age-related changes in cognitive function, cognitive intervention methods that employ social activity, including conversations, have been proposed in some intervention studies. Interestingly, previous studies have consistently reported that verbal fluency ability can be trained by conversation-based interventions in healthy older adults. However, little is known about the neural substrates that underlie the beneficial effect of conversation-based interventions on cognitive function. In this pilot study, we aimed to provide candidate brain regions that are responsible for the enhancement of cognitive function, by analyzing structural magnetic resonance imaging (MRI) data that were additionally obtained from participants in our previous intervention study.

Methods

A voxel-based morphometric analysis was applied to the structural MRI data. In the analysis, the regional brain volume was compared between the intervention group, who participated in a group conversation-based intervention program named Photo-Integrated Conversation Moderated by Robots (PICMOR), and the control group, who joined in a control program based on unstructured free conversations. Furthermore, regions whose volume was positively correlated with an increase in verbal fluency task scores throughout the intervention period were explored.

Results

Results showed that the volume of several regions, including the superior frontal gyrus, parahippocampal gyrus/hippocampus, posterior middle temporal gyrus, and postcentral gyrus, was greater in the intervention group than in the control group. In contrast, no regions showed greater volume in the control group than in the intervention group. The region whose volume showed a positive correlation with the increased task scores was identified in the inferior parietal lobule.

Conclusions

Although definitive conclusions cannot be drawn from this study due to a lack of MRI data from the pre-intervention period, it achieved the exploratory purpose by successfully identifying candidate brain regions that reflect the beneficial effect of conversation-based interventions on cognitive function, including the lateral prefrontal cortex, which plays an important role in executive functions.

Trial registration

The trial was retrospectively registered on 7 May 2019 (UMIN Clinical Trials Registry number: UMIN000036667).
The prevalence of diabetes among tuberculosis patients in Denmark
Authors: Huber Franziska Grundtvig , Kristensen Kristina Langholz , Holden Inge Kristine , Andersen Peter Henrik , Bakir Banoo , Jørgensen Anja , Lorentsson Hans Johan Niklas , Bjorn-Mortensen Karen , Johansen Isik Somuncu , Ravn Pernille
Published: January 2022

Setting

It is estimated that 25% of the world’s population are infected with Mycobacterium tuberculosis and that 463 million people are living with diabetes mellitus (DM), a number that is increasing. Patients with DM have three times the risk of developing tuberculosis (TB) and there is significant interaction between DM and TB, suggesting that DM affects not only risk of TB but also TB presentation, treatment response and outcome.

Objective

The aim was determining the prevalence of DM among TB patients in Denmark and to assess risk factors.

Design

Patient files from all notified TB cases in Denmark from 2009 to 2014 were retrospectively assessed.

Results

In total, 1912 patients were included and 5.0% had DM. Patients with DM were older, had more comorbidities, came from outside Denmark, and had a higher mortality compared to non-DM-patients. None of the patients from Greenland had DM. Patients with low socio-economic status had a low prevalence of DM. We found a higher prevalence of DM among Danish-born < 54 year and migrant ≥ 75 year compared to a Danish background population.

Conclusion

We found a higher prevalence of DM among TB patients with known risk factors, and a surprisingly low prevalence among patients with low socioeconomic status and patients from Greenland.
Revealing potential diagnostic gene biomarkers of septic shock based on machine learning analysis
Authors: Fan Yonghua , Han Qiufeng , Li Jinfeng , Ye Gaige , Zhang Xianjing , Xu Tengxiao , Li Huaqing
Published: January 2022

Background

Sepsis is an inflammatory response caused by infection with pathogenic microorganisms. The body shock caused by it is called septic shock. In view of this, we aimed to identify potential diagnostic gene biomarkers of the disease.

Material and methods

Firstly, mRNAs expression data sets of septic shock were retrieved and downloaded from the GEO (Gene Expression Omnibus) database for differential expression analysis. Functional enrichment analysis was then used to identify the biological function of DEmRNAs (differentially expressed mRNAs). Machine learning analysis was used to determine the diagnostic gene biomarkers for septic shock. Thirdly, RT-PCR (real-time polymerase chain reaction) verification was performed. Lastly, GSE65682 data set was utilized to further perform diagnostic and prognostic analysis of identified superlative diagnostic gene biomarkers.

Results

A total of 843 DEmRNAs, including 458 up-regulated and 385 down-regulated DEmRNAs were obtained in septic shock. 15 superlative diagnostic gene biomarkers (such as RAB13, KIF1B, CLEC5A, FCER1A, CACNA2D3, DUSP3, HMGN3, MGST1 and ARHGEF18) for septic shock were identified by machine learning analysis. RF (random forests), SVM (support vector machine) and DT (decision tree) models were used to construct classification models. The accuracy of the DT, SVM and RF models were very high. Interestingly, the RF model had the highest accuracy. It is worth mentioning that ARHGEF18 and FCER1A were related to survival. CACNA2D3 and DUSP3 participated in MAPK signaling pathway to regulate septic shock.

Conclusion

Identified diagnostic gene biomarkers may be helpful in the diagnosis and therapy of patients with septic shock.
Mediolateral episiotomy and risk of obstetric anal sphincter injuries and adverse neonatal outcomes during operative vaginal delivery in nulliparous women: a propensity-score analysis
Authors: Desplanches Thomas , Marchand-Martin Laetitia , Szczepanski Emilie-Denise , Ruillier Marie , Cottenet Jonathan , Semama Denis , Simon Emmanuel , Quantin Catherine , Sagot Paul
Published: January 2022

Background

The potential protective effect of mediolateral episiotomy for obstetrical anal sphincter injuries (OASIs) remains controversial during operative vaginal delivery because of the difficulties to take into account the risk factors and clinical conditions at delivery; in addition, little is known about the potential benefits of mediolateral episiotomy on neonatal outcomes.

The objectives were to investigate the associations between mediolateral episiotomy and both OASIs and neonatal outcomes, using propensity scores.

Methods

We performed a retrospective population-based observational study from a perinatal registry that includes all births in a French region between 2010 and 2017. All nulliparous women with singleton pregnancy delivering by operative vaginal deliveries at 37 weeks gestational age or later were included. Inverse-probability-of-treatment weighting with propensity scores was used to minimize indication bias. OASIs was defined as third and fourth-degree tears according to Royal College of Obstetricians and Gynecologists. Two neonatal outcomes were studied: condition at birth (5-min Apgar score less than 7 and/or umbilical artery pH less than 7.10), and admission to neonatal intensive care unit.

Results

The study population consisted of 7589 women; 2880 (38.0%) received mediolateral episiotomy. After applying propensity scores, episiotomy was associated with a lower rate of OASIs in forceps/spatula delivery (2.3 vs 6.8%, Risk Ratio (RR) 0.38, 95% Confidence Interval (CI) 0.28–0.52) and in vacuum delivery (1.3 vs 3.4%, RR 0.27, 95% CI 0.20–0.38) as compared with no episiotomy. Mediolateral episiotomy was associated with better condition at birth in case of forceps/spatula delivery (4.5 vs 8.8%, RR 0.56, 95% CI 0.39–0.81). In cases of fetal distress (40.7%), mediolateral episiotomy was associated with better condition of infant at birth in women who delivered by forceps/spatula (4.2 vs 13.5%, RR 0.52, 95% CI 0.31–0.89). No association was found with neonatal unit admission (RR 0.93, 95% CI 0.50–1.74).

Conclusions

Use of mediolateral episiotomy was associated with a lower rate of OASIs during operative vaginal delivery, and in infants it was associated with better condition at birth following forceps/spatula delivery.
Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001–2015
Authors: Reece Albert Stuart , Hulse Gary Kenneth
Published: January 2022

Background

Cannabinoids including cannabidiol have recognized genotoxic activities but their significance has not been studied broadly epidemiologically across the teratological spectrum. We examined these issues including contextual space-time relationships and formal causal inferential analysis in USA.

Methods

State congenital anomaly (CA) rate (CAR) data was taken from the annual reports of the National Birth Defects Prevention Network 2001–2005 to 2011–2015. Substance abuse rates were from the National Survey of Drug Use and Health a nationally representative longitudinal survey of the non-institutionalized US population with 74.1% response rate. Drugs examined were cigarettes, monthly and binge alcohol, monthly cannabis and analgesic and cocaine abuse. Early termination of pregnancy for abortion (ETOPFA) rates were taken from the published literature. Cannabinoid concentrations were from Drug Enforcement Agency. Ethnicity and income data were from the US Census Bureau. Inverse probability weighted (IPW) regressions and geotemporospatial regressions conducted for selected CAs.

Results

Data on 18,328,529 births from an aggregated population of 2,377,483,589 for mid-year analyses 2005–2013 comprehending 12,611 CARs for 62 CAs was assembled and ETOPFA-corrected (ETOPFACAR) where appropriate. E-Values for ETOPFACARs by substance trends were elevated for THC (40 CAs), cannabis (35 CAs), tobacco (11 CAs), cannabidiol (8 CAs), monthly alcohol (5 CAs) and binge alcohol (2 CAs) with minimum E-Values descending from 16.55, 1.55x107, 555.10, 7.53x1019, 9.30 and 32.98. Cardiovascular, gastrointestinal, chromosomal, limb reductions, urinary, face and body wall CAs particularly affected. Highest v. lowest substance use quintile CAR prevalence ratios 2.84 (95%C.I. 2.44, 3.31), 4.85 (4.08, 5.77) and 1.92 (1.63, 2.27) and attributable fraction in exposed 0.28 (0.27, 0.28), 0.57 (0.51, 0.62) and 0.47 (0.38, 0.55) for tobacco, cannabis and cannabidiol. Small intestinal stenosis or atresia and obstructive genitourinary defect were studied in detail in lagged IPW pseudo-randomized causal regressions and spatiotemporal models confirmed the causal role of cannabinoids. Spatiotemporal predictive modelling demonstrated strongly sigmoidal non-linear cannabidiol dose-response power-function relationships (P = 2.83x10−60 and 1.61x10−71 respectively).

Conclusions

Data implicate cannabinoids including cannabidiol in a diverse spectrum of heritable CAs. Sigmoidal non-linear dose-response relationships are of grave concern.

These transgenerational genotoxic, epigenotoxic, chromosomal-toxic putatively causal teratogenic effects strongly indicate tight restrictions on community cannabinoid penetration.
The effect of COVID-19 lockdown on the glycemic control of children with type 1 diabetes
Authors: Hakonen Elina , Varimo Tero , Tuomaala Anna-Kaisa , Miettinen Päivi J. , Pulkkinen Mari-Anne
Published: January 2022

Background

Between March 18th and May 13th 2020, the COVID-19 pandemic outbreak in Finland resulted in the closure of schools and the limitation of daycare (i.e. lockdown). Social distancing changed the daily routines of children with type 1 diabetes (T1D). Healthcare professionals were forced to adapt to the pandemic by replacing physical outpatient visits with virtual visits. However, the influence of the lockdown on glycemic control in these patients remained unknown.

Methods

In this retrospective register study from a pediatric diabetes outpatient clinic, we analyzed the glycemic data of T1D patients (n = 245; aged 4 to 16 years) before and under the lockdown. All the participants used continuous glucose monitoring (rtCGM or iCGM), two-thirds were on insulin pumps (CSII), and one-third on multiple daily insulin injections (MDI) therapy.

Results

In our patient cohort, time in range (TIR, n = 209) and mean glucose levels (n = 214) were similar prior to and under the lockdown (mean change 0.44% [95%CI: -1.1–2.0], p = 0.56 and -0.13 mmol/mol [95%CI: -0.3–0.1], p = 0.17, respectively). However, children treated with CSII improved their glycemic control significantly during the lockdown: TIR improved on average 2.4% [0.6–4.2] (p = 0.010) and mean blood glucose level decreased -0.3 mmol/mol [-0.6-(-0.1)] (p = 0.008). The difference was more pronounced in girls, adolescents and patients using conventional insulin pumps.

Conclusions

The glycemic control in T1D children did not deteriorate under the lockdown, and patients on CSII even improved their control, which suggests that social distancing might have allowed families to use the insulin pump more accurately as out-of-home activities were on hold.
Differential microbiological spectrum and resistance pattern in periprosthetic hip joint infections: a matched-cohort analysis comparing direct anterior versus lateral approach
Authors: Aichmair Alexander , Frank Bernhard J. H. , Singer Gabriel , Simon Sebastian , Dominkus Martin , Hofstaetter Jochen G.
Published: January 2022

Background

In recent years, total hip arthroplasty via the direct anterior approach (DAA) has become more common. Little is known on the influence of the surgical approach on the microbiological spectrum and resistance pattern in periprosthetic hip joint infections. The aim of the present study was to evaluate the microbiological spectrum and resistance pattern in periprosthetic hip joint infections comparing the direct anterior versus lateral approach in a matched-cohort analysis at a single institution.

Methods

Patients who underwent revision hip arthroplasty due to PJI following primary total hip arthroplasty with culture positive microbiology were analyzed. In all study patients, both the primary surgery and the revisions surgery were performed at the same institution. Only patients in whom primary surgery was performed via a direct anterior or lateral approach were included (n = 87). A matched cohort analysis was performed to compare the microbiological spectrum and resistance pattern in PJI following direct anterior (n = 36) versus lateral (n = 36) primary THA.

Results

We identified both a significantly different microbiological spectrum and resistance pattern in PJI comparing direct anterior versus lateral approach THA. Cutibacterium avidum was obtained more frequently in the anterior subgroup (22.2% vs. 2.8%, p = 0.028). In the subgroup of infections with Staphylococcus aureus (n = 12), methicillin resistance was detected in 3/5 cases in the direct anterior group versus 0/7 cases in the lateral group (p = 0.045). Overall, Staphylococcus epidermidis was the most common causative microorganism in both groups (direct anterior: 36.1%; lateral: 27.8%, p = 0.448).

Conclusion

The present study indicates a potential influence of the localization of the skin incision in THA on the microbiological spectrum and resistance pattern in PJI. Cutibacterium avidum seemed to be a more common causative microorganism in PJI in patients who underwent direct anterior compared to lateral approach THA.
Single-dose SARS-CoV-2 vaccinations with either BNT162b2 or AZD1222 induce disparate Th1 responses and IgA production
Authors: Müller Michael , Volzke Johann , Subin Behnam , Müller Silke , Sombetzki Martina , Reisinger Emil C. , Müller-Hilke Brigitte
Published: January 2022

Background

While vaccination programs against the severe acute respiratory syndrome virus 2 (SARS-CoV-2) are globally ongoing, disparate strategies for the deployment of spike antigen show varying effectiveness.

Methods

In order to explore this phenomenon, we sought to compare the early immune responses against AZD1222 and BNT162b2. SARS-CoV-2 seronegative participants received a single dose of either vaccine and were analyzed for immune cell, effector T cell, and antibody dynamics.

Results

AZD1222 induced transient leukopenia and major changes among innate and adaptive subpopulations. Both vaccines induced spike protein-specific effector T cells which were dominated by type 1 helper T cell responses following AZD1222 vaccination. A significant reduction of anti-inflammatory T cells upon re-stimulation was also restricted to AZD1222 vaccinees. While IgM and IgG were the dominant isotypes elicited by AZD1222, BNT162b2 led to a significant production of IgG and IgA.

Conclusions

Our results suggest that the strategy for spike protein delivery impacts on how and to what extent immune priming against the main SARS-CoV-2 antigen proceeds.
Correlation of physical and cognitive impairment in diabetic and hypertensive frail older adults
Authors: Mone Pasquale , Gambardella Jessica , Lombardi Angela , Pansini Antonella , De Gennaro Stefano , Leo Anna Luisa , Famiglietti Michele , Marro Anna , Morgante Maria , Frullone Salvatore , De Luca Antonio , Santulli Gaetano
Published: January 2022

Background

Diabetes and hypertension are common in older adults and represent established risk factors for frailty. Frailty is a multidimensional condition due to reserve loss and susceptibility to stressors with a high risk of death, hospitalizations, functional and cognitive impairment. Comorbidities such as diabetes and hypertension play a key role in increasing the risk of mortality, hospitalization, and disability. Moreover, frail patients with diabetes and hypertension are known to have an increased risk of cognitive and physical impairment. Nevertheless, no study assessed the correlation between physical and cognitive impairment in frail older adults with diabetes and hypertension.

Methods

We evaluated consecutive frail older patients with diabetes and hypertension who presented at ASL (local health unit of the Italian Ministry of Health) Avellino, Italy, from March 2021 to October 2021. The inclusion criteria were: a previous diagnosis of diabetes and hypertension with no evidence of secondary causes; age > 65 years; a frailty status; Montreal Cognitive Assessment (MoCA) score < 26.

Results

179 patients successfully completed the study. We found a strong and significant correlation between MoCA score and 5-m gait speed test (r: 0.877; p < 0.001). To further verify our results, we performed a linear multivariate analysis adjusting for potential confounding factors, with MoCA score as dependent variable, which confirmed the significant association with glycemia (p < 0.001).

Conclusions

This is the first study showing a significant correlation between 5-m gait speed test and MoCA score in frail diabetic and hypertensive older adults.
Pilot study on the value of echocardiography combined with lung ultrasound to evaluate COVID-19 pneumonia
Authors: Han Jing , Yang Xi , Xu Wei , Jin Ronghua , Liu Weiyuan , Ding Lei , Meng Sha , Zhang Yuan , Li Jin , Zheng Ying , Li Haowen , Meng Fankun
Published: January 2022

Background

This study aimed to investigate the relationship between echocardiography results and lung ultrasound score (LUS) in coronavirus disease 2019 (COVID-19) pneumonia patients and evaluate the impact of the combined application of these techniques in the evaluation of COVID-19 pneumonia.

Methods

Hospitalized COVID-19 pneumonia patients who underwent daily lung ultrasound and echocardiography were included in this study. Patients with tricuspid regurgitation within three days of admission were enrolled. Moreover, the correlation and differences between their pulmonary artery pressure (PAP) and LUS on days 3, 8, and 13 were analyzed. The inner diameter of the pulmonary artery root as well as the size of the atria and ventricles were also considered.

Results

The PAP on days 3, 8, and 13 of hospitalization was positively correlated with the LUS (r = 0.448, p = 0.003; r = 0.738, p < 0.001; r = 0.325, p = 0.036, respectively). On day 8, the values of both PAP and LUS were higher than on days 3 and 13 (p < 0.01). Similarly, PAP and LUS were significantly increased in 92.9% (39/42) and 90.5% (38/42) of patients, respectively, and at least one of these two values was positive in 97.6% (41/42) of cases. The inner diameters of the right atrium, right ventricle, and pulmonary artery also differed significantly from their corresponding values on days 3 and 13 (p < 0.05).

Conclusions

PAP is positively correlated with LUS in COVID-19 pneumonia. The two values could be combined for a more precise assessment of disease progression and recovery status.
The path to the clinic: a comprehensive review on direct KRASG12C inhibitors
Authors: Kwan Albert K. , Piazza Gary A. , Keeton Adam B. , Leite Caio A.
Published: January 2022

TheRASoncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research, in 2013, the Shokat lab achieved a seminal breakthrough by showing that the activated KRAS isozyme caused by the G12C mutation in theKRASgene can be directly inhibited via a newly unearthed switch II pocket. Building upon this groundbreaking discovery, sotorasib (AMG510) obtained approval by the United States Food and Drug Administration in 2021 to become the first therapy to directly target the KRAS oncoprotein in any KRAS-mutant cancers, particularly those harboring theKRASG12Cmutation. Adagrasib (MRTX849) and other direct KRASG12Cinhibitors are currently being investigated in multiple clinical trials. In this review, we delve into the path leading to the development of this novel KRAS inhibitor, starting with the discovery, structure, and function of the RAS family of oncoproteins. We then examine the clinical relevance of KRAS, especially the KRASG12Cmutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. Finally, we review the preclinical evidence that supported the initial development of the direct KRASG12Cinhibitors and summarize the ongoing clinical trials of all direct KRASG12Cinhibitors.
Penfluridol targets acid sphingomyelinase to inhibit TNF signaling and is therapeutic against inflammatory autoimmune diseases
Authors: Chen Yue-hong , Liu Rong-han , Cui Ya-zhou , Hettinghouse Aubryanna , Fu Wen-yu , Zhang Lei , Zhang Chen , Liu Chuan-ju
Published: January 2022

Background

Penfluridol, isolated from an FDA-approved small-molecule drug library as an inhibitor of tumor necrosis factor α (TNFα)-stimulated NF-κB activation, is clinically used to treat chronic schizophrenia and related disorders. This study is aimed to investigate the therapeutic effect of penfluridol on TNFα-stimulated inflammatory autoimmune diseases, particularly inflammatory arthritis.

Methods

Various in vitro studies to confirm the inhibitory effect of penfluridol on TNFα-induced NF-κB activity in bone marrow-derived macrophages or Raw 264.7 macrophage cell line. In vivo studies assessed the therapeutic effects of penfluridol in various disease models, including TNFα transgenic mice, collagen-induced arthritis, DSS-induced colitis, and TNBS-induced colitis. Identification and characterization of the binding of penfluridol to acid sphingomyelinase using bioinformatics and drug affinity responsive target stability assay. Acid sphingomyelinase activity assays to reveal penfluridol-mediated inhibition of acid sphingomyelinase activity. siRNA knockdown experiments to illustrate the dependence of penfluridol’s anti-TNF activity on acid sphingomyelinase.

Results

Penfluridol effectively inhibited TNFα-induced NF-κB activation in vitro and alleviated the severity of arthritis and colitis in vivo. Mechanistic studies revealed that penfluridol bound to acid sphingomyelinase and inhibited its activation. In addition, knockdown of acid sphingomyelinase largely abolished the inhibitory effects of penfluridol on TNFα-induced inflammatory cytokine production. Furthermore, penfluridol suppressed the differentiation of spleen naive CD4+T cells to TH1 and TH17 and inhibited M1 macrophage polarization.

Conclusion

This study provides the rationale for the possible innovative use of penfluridol as a newly identified small-molecule drug for TNFα-driven diseases, such as inflammatory arthritis and colitis.
Factors Influencing Retention of Transgender and Gender Nonconforming Students in Undergraduate STEM Majors
Authors: Maloy Jeffrey , Kwapisz Monika B. , Hughes Bryce E.
Published: January 2022

Science, technology, engineering, and mathematics (STEM)majors do not retain transgender and gender nonconforming (TGNC) students and cisgender students at similar rates. This article explores TGNC retention in STEM majors and describes factors that contribute to differential retention of cisgender and TGNC students.
Cannabinoids in psychiatry: they are here to stay
Authors: Woo Julia Jiyeon , van Reekum Emma , Bhattacharyya Sagnik , Samaan Zainab
Published: January 2022

Cannabinoids are commonly perceived by the public as safe and effective for improving mental health, despite limited evidence to support their use. We discuss reasons why cannabinoids may be particularly compelling for our patients and provide strategies for how psychiatrists can counsel and educate patients on the evidence regarding cannabinoids.
Phase I/II study of regorafenib (rego) and pembrolizumab (pembro) in refractory microsatellite stable colorectal cancer (MSSCRC).
Authors: Barzi Afsaneh , Azad Nilofer Saba , Yang Yan , Tsao-Wei Denice , Rehman Rabia , Fakih Marwan , Iqbal Syma , El-Khoueiry Anthony B. , Millstein Joshua , Jayachandran Priya , Zhang Wu , Lenz Heinz-Josef
Published: January 2022

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Background: Immune check point inhibitors (ICI) are ineffective in MSSCRC. Combination of ICI with targeted agents has the potential to alter the tumor microenvironment and render these tumors vulnerable to ICI. We report the results of the multicenter study of rego and pembro in a diverse patient population with advanced MSSCRC. Methods: This was an investigator-initiated study and enrolled patients (pts) who had failed/were intolerant of chemotherapy at 3 sites. A 3+3 design was used for phase I to evaluate escalating doses of rego (80,120,160, days 1-14/21) in combination with pembro (200m/q3weeks). The primary endpoint was dose limiting toxicities during the first cycle. For phase II, pts received rego at the recommended phase II dose (RP2D) with pembro. The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS) and objective response rate (ORR). The study was powered to show an improvement in PFS from 1.9 months (CORRECT data) to 2.85 months. Estimated sample size for phase II was 63 pts. Results: Study started in 7/2019 and accrual completed in 7/2021. Of 73 pts, 10 enrolled in phase I and 63 in phase II. RP2D of rego was 80 mg, days 1-14/21, and 70 pts treated at that dose. As of Sep 14, 11 pts remain on treatment. At baseline, median age was 54 years (23-81), 51% female, 53% white, 19% Asian, 12% black, and 11% Hispanic, median prior lines of therapy 2 (1-5), primary tumor location rectosigmoid/rectal 13%, KRAS mutated 68%, BRAF mutated 5%. Liver metastases was present in 78% of the pts. There was no grade 4 toxicity. The most common grade 3 toxicities were rash (20%), followed by hand-foot syndrome and HTN (7%). Dose modification was required in 14%. The most common reason for discontinuation was disease progression (85%), followed by withdrawal of consent (12%). With a median follow up of 5.3 (range:0.6-24.4) months, median PFS was 2.0 (1.8 -3.5) months, and median OS was 10.9 (5.3-NR) months. In 16 pts (23%), with non-liver metastatic disease PFS was 4.3 (1.9-8.4) months. No objective response was observed. Stable disease was observed in 49% of pts, median duration of stable disease was 2 (0.2-18.8) months. Conclusions: This is the largest trial of combination of ICI + rego in MSSCRC reported to date. The trial didn’t meet its primary endpoint, though the median OS is provocative. Analysis of biomarkers for identification of pts with longer duration of benefit is ongoing. Clinical trial information: NCT03657641.