bluuebunny/crossref_metadata_2025 huggingface dataset:
Rotenone Modulates Caenorhabditis elegans Immunometabolism and Pathogen Susceptibility
Authors: Mello Danielle F. , Bergemann Christina M. , Fisher Kinsey , Chitrakar Rojin , Bijwadia Shefali R. , Wang Yang , Caldwell Alexis , Baugh Larry Ryan , Meyer Joel N.
Published: February 2022

Mitochondria are central players in host immunometabolism as they function not only as metabolic hubs but also as signaling platforms regulating innate immunity. Environmental exposures to mitochondrial toxicants occur widely and are increasingly frequent. Exposures to these mitotoxicants may pose a serious threat to organismal health and the onset of diseases by disrupting immunometabolic pathways. In this study, we investigated whether the Complex I inhibitor rotenone could alter C. elegans immunometabolism and disease susceptibility. C. elegans embryos were exposed to rotenone (0.5 µM) or DMSO (0.125%) until they reached the L4 larval stage. Inhibition of mitochondrial respiration by rotenone and disruption of mitochondrial metabolism were evidenced by rotenone-induced detrimental effects on mitochondrial efficiency and nematode growth and development. Next, through transcriptomic analysis, we investigated if this specific but mild mitochondrial stress that we detected would lead to the modulation of immunometabolic pathways. We found 179 differentially expressed genes (DEG), which were mostly involved in detoxification, energy metabolism, and pathogen defense. Interestingly, among the down-regulated DEG, most of the known genes were involved in immune defense, and most of these were identified as commonly upregulated during P. aeruginosa infection. Furthermore, rotenone increased susceptibility to the pathogen Pseudomonas aeruginosa (PA14). However, it increased resistance to Salmonella enterica (SL1344). To shed light on potential mechanisms related to these divergent effects on pathogen resistance, we assessed the activation of the mitochondrial unfolded protein response (UPRmt), a well-known immunometabolic pathway in C. elegans which links mitochondria and immunity and provides resistance to pathogen infection. The UPRmt pathway was activated in rotenone-treated nematodes further exposed for 24 h to the pathogenic bacteria P. aeruginosa and S. enterica or the common bacterial food source Escherichia coli (OP50). However, P. aeruginosa alone suppressed UPRmt activation and rotenone treatment rescued its activation only to the level of DMSO-exposed nematodes fed with E. coli. Module-weighted annotation bioinformatics analysis was also consistent with UPRmt activation in rotenone-exposed nematodes consistent with the UPR being involved in the increased resistance to S. enterica. Together, our results demonstrate that the mitotoxicant rotenone can disrupt C. elegans immunometabolism in ways likely protective against some pathogen species but sensitizing against others.
Ozoralizumab, a Humanized Anti-TNFα NANOBODY® Compound, Exhibits Efficacy Not Only at the Onset of Arthritis in a Human TNF Transgenic Mouse but Also During Secondary Failure of Administration of an Anti-TNFα IgG
Authors: Ishiwatari-Ogata Chihiro , Kyuuma Masanao , Ogata Hitoshi , Yamakawa Machi , Iwata Katsuya , Ochi Motoki , Hori Miyuki , Miyata Noriyuki , Fujii Yasuyuki
Published: February 2022

Although the introduction of tumor necrosis factor (TNF) inhibitors represented a significant advance in the treatment of rheumatoid arthritis (RA), traditional anti-TNFα antibodies are somewhat immunogenic, and their use results in the formation of anti-drug antibodies (ADAs) and loss of efficacy (secondary failure). Ozoralizumab is a trivalent, bispecific NANOBODY® compound that differs structurally from IgGs. In this study we investigated the suppressant effect of ozoralizumab and adalimumab, an anti-TNFα IgG, on arthritis and induction of ADAs in human TNF transgenic mice. Ozoralizumab markedly suppressed arthritis progression and did not induce ADAs during long-term administration. We also developed an animal model of secondary failure by repeatedly administering adalimumab and found that switching from adalimumab to ozoralizumab was followed by superior anti-arthritis efficacy in the secondary-failure animal model. Moreover, ozoralizumab did not form large immune complexes that might lead to ADA formation. The results of our studies suggest that ozoralizumab, which exhibited low immunogenicity in the animal model used and has a different antibody structure from that of IgGs, is a promising candidate for the treatment of RA patients not only at the onset of RA but also during secondary failure of anti-TNFα treatment.
Electroactive Scaffolds to Improve Neural Stem Cell Therapy for Spinal Cord Injury
Authors: Mutepfa Anthea R. , Hardy John G. , Adams Christopher F.
Published: February 2022

Spinal cord injury (SCI) is a serious condition caused by damage to the spinal cord through trauma or disease, often with permanent debilitating effects. Globally, the prevalence of SCI is estimated between 40 to 80 cases per million people per year. Patients with SCI can experience devastating health and socioeconomic consequences from paralysis, which is a loss of motor, sensory and autonomic nerve function below the level of the injury that often accompanies SCI. SCI carries a high mortality and increased risk of premature death due to secondary complications. The health, social and economic consequences of SCI are significant, and therefore elucidation of the complex molecular processes that occur in SCI and development of novel effective treatments is critical. Despite advances in medicine for the SCI patient such as surgery and anaesthesiology, imaging, rehabilitation and drug discovery, there have been no definitive findings toward complete functional neurologic recovery. However, the advent of neural stem cell therapy and the engineering of functionalized biomaterials to facilitate cell transplantation and promote regeneration of damaged spinal cord tissue presents a potential avenue to advance SCI research. This review will explore this emerging field and identify new lines of research.
Computational Approaches Integrated in a Digital Ecosystem Platform for a Rare Disease
Authors: Visibelli Anna , Cicaloni Vittoria , Spiga Ottavia , Santucci Annalisa
Published: February 2022

Alkaptonuria (AKU) is an ultra-rare autosomal recessive disease caused by a mutation in the homogentisate 1,2-dioxygenase gene. One of the main obstacles in studying AKU and other ultra-rare diseases, is the lack of a standardized methodology to assess disease severity or response to treatment. Based on that, a multi-purpose digital platform, called ApreciseKUre, was implemented to facilitate data collection, integration and analysis for patients affected by AKU. It includes genetic, biochemical, histopathological, clinical, therapeutic resources and Quality of Life (QoL) scores that can be shared among registered researchers and clinicians to create a Precision Medicine Ecosystem. The combination of machine learning applications to analyse and re-interpret data available in the ApreciseKUre clearly indicated the potential direct benefits to achieve patients’ stratification and the consequent tailoring of care and treatments to a specific subgroup of patients. In order to generate a comprehensive patient profile, computational modeling and database construction support the identification of potential new biomarkers, paving the way for more personalized therapy to maximize the benefit-risk ratio. In this work, different Machine Learning implemented approaches were described:
Talimogene Laherparepvec: Moving From First-In-Class to Best-In-Class
Authors: Kaufman Howard L. , Shalhout Sophia Z. , Iodice Gail
Published: February 2022

Talimogene laherparepvec (T-VEC) is a modified oncolytic herpes Simplex virus, type 1 (HSV-1) encoding granulocyte-macrophage colony stimulating factor (GM-CSF). T-VEC is adapted for selective replication in melanoma cells and GM-CSF was expressed to augment host anti-tumor immunity. T-VEC is indicated for the local treatment of melanoma recurrent after primary surgery and is the first-in-class oncolytic virus to achieve approval by the FDA in 2015. This review will describe the progress made in advancing T-VEC to the most appropriate melanoma patients, expansion to patients with non-melanoma cancers and clinical trial results of T-VEC combination studies. Further, strategies to identify predictive biomarkers of therapeutic response to T-VEC will be discussed. Finally, a brief outline of high-priority future directions for investigation of T-VEC and other promising oncolytic viruses will set the stage for a best-in-class oncolytic virus to bring the maximum benefit of this emerging class of anti-cancer agents to patients with cancer.
Effects of Anosognosia on Static and Dynamic Amplitudes of Low-Frequency Fluctuation in Mild Cognitive Impairment
Authors: Fu Yanv , Luo Xiao , Zeng Qingze , Li Kaicheng , Zhang Tianyi , Li Zheyu , Xu Xiaopei , Hong Luwei , Chen Yanxing , Zhang Minming , Liu Zhirong
Published: February 2022

Background: Anosognosia is a significant symptom in patients with mild cognitive impairment (MCI) while the underlying neurological mechanism behind it is still unclear.

Methods: A total of 121 subjects were included and classified into three groups, including 39 normal controls (NCs), 42 individuals with MCI without anosognosia (MCI-NA), and 40 individuals with MCI with anosognosia (MCI-A), based on their everyday cognition (ECog) questionnaire (discrepancy score). Resting-state functional MRIs were acquired from all the subjects, and the static amplitudes of low-frequency fluctuation (sALFF) and dynamic ALFF (dALFF) variance were investigated to evaluate the intrinsic functional network strength and stability, respectively, and both were corrected by age, sex, education, and gray matter volume. Eventually, correlation analyses were conducted to explore the relationship between brain activity changes and cognitive status in all the subjects.

Results: No significant difference was found between MCI-A and MCI-NA (P > 0.05) in cognitive ability. Regarding intrinsic brain activity, MCI-A had increased sALFF and dALFF variance in the anterior cingulate cortex (ACC) relative to MCI-NA, as well as decreased sALFF and dALFF variance in the precuneus relative to MCI-NA and controls. Moreover, MCI-A had decreased sALFF in the inferior temporal gyrus (ITG) and paracentral lobule (PCL) compared to MCI-NA. Among all the subjects, correlation analyses showed that the sALFF and dALFF variance in the precuneus was related to the Ecog discrepancy score (r = 0.232 and 0.235, respectively), immediate story recall (r = 0.200 and 0.277, respectively), and delayed story recall (r = 0.255 and 0.298, respectively).

Conclusion: Alterations of intrinsic brain activation in the ACC and precuneus seem to be associated with the anosognosia symptom in patients with MCI.
Classification of Alzheimer’s Disease Based on Abnormal Hippocampal Functional Connectivity and Machine Learning
Authors: Zhu Qixiao , Wang Yonghui , Zhuo Chuanjun , Xu Qunxing , Yao Yuan , Liu Zhuyun , Li Yi , Sun Zhao , Wang Jian , Lv Ming , Wu Qiang , Wang Dawei
Published: February 2022

Objective

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive deterioration of memory and cognition. Mild cognitive impairment (MCI) has been implicated as a prodromal phase of AD. Although abnormal functional connectivity (FC) has been demonstrated in AD and MCI, the clinical differentiation of AD, MCI, and normal aging remains difficult, and the distinction between MCI and normal aging is especially problematic. We hypothesized that FC between the hippocampus and other brain structures is altered in AD and MCI, and that measurement of abnormal FC could have diagnostic utility for the classification of different AD stages.

Methods

Elderly adults aged 60–85 years were assigned to AD, MCI, or normal control (NC) groups based on clinical criteria. Functional magnetic resonance scanning was completed by 119 subjects. Five dimension reduction/classification methods were applied, using hippocampus-derived FC strengths as input features. Classification performance of the five dimensionality reduction methods was compared between AD, MCI, and NC groups.

Results

FCs between the hippocampus and left insula, left thalamus, cerebellum, right lingual gyrus, posterior cingulate cortex, and precuneus were significantly reduced in AD and MCI. Support vector machine learning coupled with sparse principal component analysis demonstrated the best discriminative performance, yielding classification accuracies of 82.02% (AD vs. NC), 81.33% (MCI vs. NC), and 81.08% (AD vs. MCI).

Conclusion

Hippocampus-seed-based FCs were significantly different between AD, MCI, and NC groups. FC assessment combined with widely used machine learning methods can improve AD differential diagnosis, and may be especially useful to distinguish MCI from normal aging.
Case Report: Successful Mechanical Thrombectomy in a Newborn With Basilar Artery Occlusion
Authors: Stracke Christian Paul , Meyer Lukas , Schwindt Wolfram , Ranft Alexander , Straeter Ronald
Published: February 2022

Background

Neonatal stroke remains a rare condition that has not yet been assessed in the field of endovascular treatment.

Case

We present the first case report of a successful mechanical thrombectomy in a newborn with a basilar occlusion the treatment was 14 hours after birth. Complete reperfusion of the basilar artery was achieved after the two thrombectomy maneuvers with stent retrievers. Imaging follow-up proved patency of the target vessel and at day 30, the patient showed no neurologic deficits.

Conclusions

Mechanical thrombectomy appears to be technically feasible and can be an individual option in selected cases to treat stroke in neonates with proven persistent proximal cerebral artery occlusion.
Free-Breathing, Non-Gated Heart-To-Brain CTA in Acute Ischemic Stroke: A Feasibility Study on Dual-Source CT
Authors: Liu Jiabin , Wang Chen , Li Qing , Duan Xianggong , Zhu Xiaolian , Wang Jiahong , Du Xiangying , Lu Jie , Li Kuncheng
Published: February 2022

Purpose

To validate the feasibility of free-breathing, non-gated, high-pitch heart-to-brain computed tomography arteriography (CTA) in acute ischemic stroke and the capability of non-gated heart-to-brain CTA in showing cardiac anatomy.

Materials and Methods

The study protocol was approved by the institutional medical ethics review board. Free-breathing, non-gated, high-pitch heart-to-brain CTA was performed on patients with acute ischemic stroke referred for multimodal CT using a third-generation dual-source CT. Patients scheduled for ECG-triggered heart-to-brain CTA served as controls. Quantitative and/or qualitative image quality of the four cardiac chambers, left atrial appendage, interventricular and interatrial septa, carotid arteries, and coronary arteries were evaluated and compared between the two groups.

Results

Free-breathing, non-gated, high-pitch heart-to-brain CTA was performed on 30 patients with acute ischemic stroke, whereas the control group included 31 cases. There is no significant difference in the image quality of CTAs between the two groups at cardiac chambers and carotid arteries. The image quality of coronary arteries also showed no significant difference between the two groups. The mean dose length products of CTA in the two groups were 129.1 ± 30.5 mGy cm and 121.6 ± 30.3 mGy cm, respectively. Cardiac abnormality can be shown in patients with acute ischemic stroke.

Conclusion

It is feasible to use free-breathing, non-gated, high-pitch heart-to-brain CTA with dual-source CT in acute ischemic stroke for cardiac etiology screening.
On Therapeutic Plasma Exchange Against Severe COVID-19-Associated Pneumonia: An Observational Clinical Study
Authors: Cegolon Luca , Einollahi Behzad , Panahi Yunes , Imanizadeh Sina , Rezapour Mohammad , Javanbakht Mohammad , Nikpouraghdam Mohammad , Abolghasemi Hassan , Mastrangelo Giuseppe
Published: February 2022

Background

There is a risk of novel mutations of SARS-CoV-2 that may render COVID-19 resistant to most of the therapies, including antiviral drugs and vaccines. The evidence around the application of therapeutic plasma exchange (TPE) for the management of critically ill patients with COVID-19 is still provisional, and further investigations are needed to confirm its eventual beneficial effects.

Aims

To assess the effect of TPE on the risk of mortality in patients with COVID-19-associated pneumonia, using three statistical procedures to rule out any threats to validity.

Methods

We therefore carried out a single-centered retrospective observational non-placebo-controlled trial enrolling 73 inpatients from Baqiyatallah Hospital in Tehran (Iran) with the diagnosis of COVID-19-associated pneumonia confirmed by real-time polymerase chain reaction (RT-qPCR) on nasopharyngeal swabs and high-resolution computerized tomography chest scan. These patients were broken down into two groups: Group 1 (30 patients) receiving standard care (corticosteroids, ceftriaxone, azithromycin, pantoprazole, hydroxychloroquine, lopinavir/ritonavir), and Group 2 (43 patients) receiving the above regimen plus TPE (replacing 2 l of patients' plasma by a solution, 50% of normal plasma, and 50% of albumin at 5%) administered according to various time schedules. The follow-up time was 30 days and all-cause mortality was the endpoint.

Results

Deaths were 6 (14%) in Group 2 and 14 (47%) in Group 1. However, different harmful risk factors prevailed among patients not receiving TPE rather than being equally split between the intervention and control group. We used an algorithm of structural equation modeling (of STATA) to summarize a large pool of potential confounders into a single score (called with the descriptive name “severity”). Disease severity was lower (Wilkinson rank-sum test p < 0.001) among patients with COVID-19 undergoing TPE (median: −2.82; range: −5.18; 7.96) as compared to those not receiving TPE (median: −1.35; range: −3.89; 8.84), confirming that treatment assignment involved a selection bias of patients according to the severity of COVID-19 at hospital admission. The adjustment for confounding was carried out using severity as the covariate in Cox regression models. The univariate hazard ratio (HR) of 0.68 (95%CI: 0.26; 1.80; p = 0.441) for TPE turned to 1.19 (95%CI: 0.43; 3.29; p = 0.741) after adjusting for severity.

Conclusions

In this study sample, the lower mortality observed among patients receiving TPE was due to a lower severity of COVID-19 rather than the TPE effects.
Endothelial Function and Postprandial Glucose Control in Response to Test-Meals Containing Herbs and Spices in Adults With Overweight/Obesity
Authors: Huang Yudai , Tsai Meng-Fu , Thorat Rajrajeshwari Sunil , Xiao Di , Zhang Xuhuiqun , Sandhu Amandeep K. , Edirisinghe Indika , Burton-Freeman Britt M.
Published: February 2022

Objectives

Herbs and Spices (H/S) contain bioactive compounds with purported health benefits. This study investigated the effect of H/S intake on indicators of vascular and metabolic health over 24 h using a test-meal challenge paradigm in adults with overweight or obesity.

Methods

In a randomized, single-blinded, 4-arm, 24 h, multi-sampling, crossover clinical trial, adults (n = 25) aged 36.6 ± 3.1 years with BMI 28.5 ± 0.6 kg/m2 (mean ± SEM) consumed a high-fat, high-carbohydrate challenge meal (~810 kcal) with salt/pepper only (control) or control with one of three different H/S combinations: Italian herb (rosemary, basil, thyme, oregano, and parsley), cinnamon, or pumpkin pie spice mix (cinnamon, ginger, nutmeg, and allspice) on four separate visits at least 3 days apart. Meals provided 35% of subjects' energy to maintain weight and ~1 g H/S per 135 kcal of the meal. Flow-mediated dilation (FMD) and blood samples were collected at 0, 1, 2, 4, 5.5, 7, and 24 h for endpoint analysis (additional blood draw at 0.5 h for insulin/glucose). Mixed-model analysis of repeated measures via PROC MIXED PC-SAS 9.4 was performed on the primary outcome (FMD) and secondary outcome variables. This study was registered at ClinicalTrials.gov (NCT03926442).

Results

Italian herb and pumpkin spice meals significantly increased %FMD at 24 h compared to the control meal (P = 0.048 and P = 0.027, respectively). The cinnamon meal reduced postprandial glycemia (Δ) compared to control (P = 0.01), and pumpkin pie spice mix and cinnamon meals reduced postprandial insulin at 0.5 h compared to the control meal (P = 0.01 and P = 0.04, respectively). IL-6 and triglycerides increased in response to all meals (Time, P < 0.0001) but were not significantly different between meals.

Conclusions

The test-meal challenge study design coupled with multiple sampling over 24 h provides insights into time-course bioactivity of H/S on vascular function and metabolic indices in overweight/obese adults.

Clinical Trial Registration

ClinicalTrials.gov, identifier: NCT03926442.
Effect of Probiotics on Respiratory Tract Allergic Disease and Gut Microbiota
Authors: Huang Jinli , Zhang Juan , Wang Xingzhi , Jin Zenghui , Zhang Panpan , Su Hui , Sun Xin
Published: February 2022

Allergy is a hypersensitivity reaction triggered by specific cell or antibody-mediated immune mechanisms. Allergies have increased in industrialized countries in recent decades. The rise in allergic respiratory diseases such as allergic rhinitis (AR) and allergic asthma (AA) is a potential threat to public health. Searches were conducted using PubMed, Google Scholar and Medline using the following key terms: allergic rhinitis OR asthma AND probiotics, allergic airway inflammation AND immune disorders, probiotics OR gut microbiota AND allergic disease, probiotics AND inflammatory. Studies from all years were included, specifically those published within the last 10 years. Some review articles and their reference lists were searched to identify related articles. The role of microbiota in respiratory allergic diseases has attracted more and more attention. Pieces of evidence suggested that the development of allergic diseases causes a possible imbalance in the composition of the gut microbiota. Compared to colonized mice, germ-free mice exhibit exaggerated allergic airway responses, suggesting that microbial host interactions play an important role in the development of allergic diseases. Probiotics modulate both the innate and adaptive inflammatory immune responses, often used as dietary supplements to provide health benefits in gastrointestinal disorders. Probiotics may serve as immunomodulators and activators of host defense pathways. Besides, oral probiotics can modulate the immune response in the respiratory system. Recently, studies in humans and animals have demonstrated the role of probiotic in RA and AA. To understand the characterization, microbiota, and the potential role of probiotics intervention of AA/AR, this review provides an overview of clinical features of AA and AR, probiotics for the prevention and treatment of AR, AA, changes in gut microbiota, and their mechanisms of action.
Study on Appropriate Rectal Volume for External Irradiation in Patients With Cervical Cancer
Authors: Wu Yanjiao , Liu Chunmei , Wang Wenyan , Tian Lei , Xiao Zhiqing , Wang Yanqiang , Guo Han , Xue Xiaoying
Published: February 2022

Objective

To investigate the appropriate rectal volume for external irradiation of cervical cancer.

Methods

A retrospective study of 143 patients with cervical cancer who underwent external radiotherapy from January 2017 to September 2020 was conducted. Average rectum volumes and the cumulative dose (V30, V40, V50, D2cc) to organs at risk (bladder, rectum, and small bowel) during radiotherapy were evaluated using the treatment planning system. Rates of radiation cystitis and radiation proctitis were assessed.

Results

The median follow-up was 48 months, and the included patients had a median age of 53 years. Patients were divided into 3 groups based on their average rectum volume: Group A: <40 ml; Group B: 40–70 ml; and Group C: ≥70 ml. V30 and V40 in the rectum bladder and small bowel were highest in Group A (mean ± SD standard deviation), but V50 and D2cc in the rectum and bladder were highest in Group C (mean ± SD). Patients in Group B had the lower incidence of both radiation cystitis and radiation proctitis. (p<0.05).

Conclusions

For external irradiation in patients with cervical cancer, a rectum volume of 40–70 ml seems most appropriate, whereas >70 ml increases the risk of severe radiation cystitis and radiation proctitis, and <40 ml increases the risk of mild radiation cystitis and mild radiation proctitis.
Faces of Pain in Dementia: Learnings From a Real-World Study Using a Technology-Enabled Pain Assessment Tool
Authors: Atee Mustafa , Hoti Kreshnik , Chivers Paola , Hughes Jeffery D.
Published: February 2022

Pain is common in people living with dementia (PLWD), including those with limited verbal skills. Facial expressions are key behavioral indicators of the pain experience in this group. However, there is a lack of real-world studies to report the prevalence and associations of pain-relevant facial micro-expressions in PLWD. In this observational retrospective study, pain-related facial features were studied in a sample of 3,144 PLWD [mean age 83.3 years (SD = 9.0); 59.0% female] using the Face domain of PainChek®, a point-of-care medical device application. Pain assessments were completed by 389 users from two national dementia-specific care programs and 34 Australian aged care homes. Our analysis focused on the frequency, distribution, and associations of facial action units [AU(s)] with respect to various pain intensity groups. A total of 22,194 pain assessments were completed. Of the AUs present, AU7 (eyelid tightening) was the most frequent facial expression (48.6%) detected, followed by AU43 (closing eyes; 42.9%) and AU6 (cheek raising; 42.1%) during severe pain. AU20 (horizontal mouth stretch) was the most predictive facial action of higher pain scores. Eye-related AUs (AU6, AU7, AU43) and brow-related AUs (AU4) were more common than mouth-related AUs (e.g., AU20, AU25) during higher pain intensities. No significant effect was found for age or gender. These findings offer further understanding of facial expressions during clinical pain in PLWD and confirm the usefulness of artificial intelligence (AI)-enabled real-time analysis of the face as part of the assessment of pain in aged care clinical practice.
Evaluation of Local Pediatric Out-of-Hospital Cardiac Arrest and Emergency Services Response
Authors: McKenzie Kate , Cameron Saoirse , Odoardi Natalya , Gray Katelyn , Miller Michael R. , Tijssen Janice A.
Published: February 2022

Background

Survival after pediatric out-of-hospital cardiac arrest is poor. Paramedic services provide critical interventions that impact survival outcomes. We aimed to describe local pediatric out-of-hospital cardiac arrest (POHCA) events and evaluate the impact of the paramedic service response to POHCA.

Methods

The Canadian Resuscitation Outcomes Consortium and corresponding ambulance call records were used to evaluate deviations from best practice by paramedics for patients aged 1 day to <18 years who had an atraumatic out-of-hospital cardiac arrest between 2012 and 2020 in Middlesex-London County. Deviations were any departure from protocol as defined by Middlesex-London Paramedic Services.

Results

Fifty-one patients were included in this study. All POHCA events had at least one deviation, with a total of 188 deviations for the study cohort. Return of spontaneous circulation (ROSC) was achieved in 35.3% of patients and 5.8% survived to hospital discharge. All survivors developed a new, severe neurological impairment. Medication deviations were most common (n = 40, 21.3%) followed by process timing (n = 38, 20.2%), vascular access (n = 27, 14.4%), and airway (n = 27, 14.4%). A delay in vascular access was the most common deviation (n = 25, 49.0%). The median (IQR) time to epinephrine administration was 8.6 (5.90–10.95) min from paramedic arrival. Cardiac arrests occurring in public settings had more deviations than private settings (p = 0.04). ROSC was higher in events with a deviation in any circulation category (p = 0.03).

Conclusion

Patient and arrest characteristics were similar to other POHCA studies. This cohort exhibited high rates of ROSC and bystander cardiopulmonary resuscitation but low survival to hospital discharge. The study was underpowered for its primary outcome of survival. The total deviations scored was low relative to the total number of tasks in a resuscitation. Epinephrine was frequently administered outside of the recommended timeframe, highlighting an important quality improvement opportunity.
560G>A (rs4986782) (R187Q) Single Nucleotide Polymorphism in Arylamine N-Acetyltransferase 1 Increases Affinity for the Aromatic Amine Carcinogens 4-Aminobiphenyl and N-Hydroxy-4-Aminobiphenyl: Implications for Cancer Risk Assessment
Authors: Doll Mark A. , Hein David W.
Published: February 2022

Human arylamine N-acetyltransferase 1 (NAT1) catalyzes the N-acetylation of arylamine carcinogens such as 4-aminobiphenyl (ABP), and following N-hydroxylation, the O-acetylation of N-hydroxy-arylamine carcinogens such as N-hydroxy-ABP (N-OH-ABP). Genetic polymorphisms in NAT1 are linked to cancer susceptibility following exposures. The effects of individual single nucleotide polymorphisms (SNPs) in the NAT1 coding exon on Michaelis-Menten kinetic constants was assessed for ABP N-acetyltransferase and N-OH-ABP O-acetyltransferase activity following transfection of human NAT1 into COS-1 cells (SV40-transformed African green monkey kidney cells). NAT1 coding region SNPs 97C > T (rs56318881) (R33stop), 190C > T (rs56379106) (R64W), 559C > T (rs5030839) (R187stop) and 752A > T (rs56172717) (D251V) reduced ABP N- acetyltransferase and N-OH-ABP O-acetyltransferase activity below detection. 21T > G (rs4986992) (synonymous), 402T > C (rs146727732) (synonymous), 445G > A (rs4987076) (V149I), 613A > G (rs72554609) (M205V) and 640T > G (rs4986783) (S241A) did not significantly affect Vmax for ABP N-acetyltransferase or N-OH-ABP O-acetyltransferase. 781G > A (rs72554610) (E261K), and 787A > G (rs72554611) (I263V) slightly reduced ABP N-acetyltransferase and N-OH-ABP O-acetyltransferase activities whereas 560G > A (rs4986782) (R187Q) substantially and significantly reduced them. 560G > A (rs4986782) (R187Q) significantly reduced the apparent Km for ABP and N-OH-ABP a finding that was not observed with any of the other NAT1 SNPs tested. These findings suggest that the role of the 560G > A (rs4986782) (R187Q) SNP cancer risk assessment may be modified by exposure level to aromatic amine carcinogens such as ABP.
Steroid Treatment in Macular Edema: A Bibliometric Study and Visualization Analysis
Authors: Lin Yu , Ren Xiang , Chen Danian
Published: February 2022

The use of steroids to treat macular edema (ME) is a research hotspot in ophthalmology. We utilized CiteSpace and VOSviewer software to evaluate the Web of Science Core Collection publications and to build visualizing maps to describe the research progress in this topic. There were 3,252 publications for three decades during 1988–2021. The number of studies was low during the first 14 years but has risen consistently in the following two decades. The average publications per year were only 4.8 during 1988–2002, which jumped to 113 per year during 2003–2012, and 227 per year during 2013–2021. These publications came from 83 countries/regions, with the United States, Germany, and Italy leading positions. Most studies were published in Investigative Ophthalmology Visual Science, and Ophthalmology was the most cited journal. We found 9,993 authors, with Bandello F having the most publications and Jonas JB being the most frequently co-cited. According to our research, the most popular keyword is triamcinolone acetonide (TA). Macular edema, diabetic macular edema (DME), retinal vein occlusion (RVO), dexamethasone (DEX), fluocinolone acetonide (FA), and some other keywords were commonly studied in this field. In conclusion, the bibliometric analysis provides a comprehensive overview of steroid hotspots and developmental tendencies in the macular edema study. While anti-VEGF therapy is the first-line treatment for DME and RVO-induced macular edema, steroids implant is a valid option for these DME patients not responding to anti-VEGF therapy and non-DME patients with macular edema. Combined therapy with anti-VEGF and steroid agents is vital for future research.
Autophagy-Inflammation Interplay During Infection: Balancing Pathogen Clearance and Host Inflammation
Authors: Pang Yuqian , Wu Lanxi , Tang Cheng , Wang Hongna , Wei Yongjie
Published: February 2022

Inflammation is an essential immune response of the host against infections but is often over-activated, leading to a variety of disorders. Autophagy, a conserved degradation pathway, also protects cells by capturing intracellular pathogens that enter the cell and transporting them to the lysosome for clearance. Dysfunctional autophagy is often associated with uncontrolled inflammatory responses during infection. In recent years, more and more research has focused on the crosstalk between autophagy and inflammation. In this paper, we review the latest research advances in this field, hoping to gain insight into the mechanisms by which the body balances autophagy and inflammation in infections and how this mechanism can be used to fight infections better.
House Dust Mite Aeroallergen Suppresses Leukocyte Phagocytosis and Netosis Initiated by Pneumococcal Lung Infection
Authors: Papanicolaou Angelica , Wang Hao , McQualter Jonathan , Aloe Christian , Selemidis Stavros , Satzke Catherine , Vlahos Ross , Bozinovski Steven
Published: February 2022

Asthmatics are highly susceptible to developing lower respiratory tract infections caused byStreptococcus pneumoniae(SPN, the pneumococcus). It has recently emerged that underlying allergic airway disease creates a lung microenvironment that is defective in controlling pneumococcal lung infections. In the present study, we examined how house dust mite (HDM) aeroallergen exposure altered immunity to acute pneumococcal lung infection. Alveolar macrophage (AM) isolated from HDM-exposed mice expressed alternatively activated macrophage (AAM) markers including YM1, FIZZ1, IL-10, and ARG-1.In vivo, prior HDM exposure resulted in accumulation of AAMs in the lungs and 2-log higher bacterial titres in the bronchoalveolar (BAL) fluid of SPN-infected mice (Day 2). Acute pneumococcal infection further increased the expression of IL-10 and ARG1 in the lungs of HDM-exposed mice. Moreover, prior HDM exposure attenuated neutrophil extracellular traps (NETs) formation in the lungs and dsDNA levels in the BAL fluid of SPN-infected mice. In addition, HDM-SPN infected animals had significantly increased BAL fluid cellularity driven by an influx of macrophages/monocytes, neutrophils, and eosinophils. Increased lung inflammation and mucus production was also evident in HDM-sensitised mice following acute pneumococcal infection, which was associated with exacerbated airway hyperresponsiveness. Of note, PCV13 vaccination modestly reduced pneumococcal titres in the BAL fluid of HDM-exposed animals and did not prevent BAL inflammation. Our findings provide new insights on the relationship between pneumococcal lung infections and allergic airways disease, where defective AM phagocytosis and NETosis are implicated in increased susceptibility to pneumococcal infection.
Long-Term Cardiac Damage Associated With Abdominal Irradiation in Mice
Authors: Wang Zhaojia , Jia Ziheng , Zhou Zandong , Zhao Xiaotong , Wang Feng , Zhang Xu , Tse Gary , Li Guangping , Liu Yang , Liu Tong
Published: February 2022

Aims: Irradiation is an effective treatment for tumors but has been associated with cardiac dysfunction. However, the precise mechanisms remain incompletely elucidated. This study investigated the long-term cardiac damage associated with abdominal irradiation and explored possible mechanisms.

Methods and Results: Wild-type C57BL6/J mice were divided into two groups: untreated controls (Con) and treatment group receiving 15 Gy of abdominal gamma irradiation (AIR). Both groups received normal feeding for 12 months. The AIR group showed reductions in left ventricular ejection fraction (LVEF), fractional shortening (FS), left ventricular end-diastolic internal diameter (LVID; d), left ventricular end-diastolic volume (LV Vol. diastolic volume (LV Vol; d) and mitral transtricuspid flow late diastolic filling velocity (MV A). It also showed increased fibrosis, reduced conduction velocity and increased conduction heterogeneity. Non-targeted metabolomics showed the differential metabolites were mainly from amino acid metabolism. Further KEGG pathway annotation and enrichment analysis revealed that abnormalities in arginine and proline metabolism, lysine degradation, d-arginine and d-ornithine metabolism, alanine, aspartate and glutamate metabolism, and arginine biosynthesis.

Conclusion: Abdominal irradiation causes long-term damage to the non-irradiated heart, as reflected by electrical and structural remodeling and mechanical dysfunction associated with abnormal amino acid biosynthesis and metabolism.
Advanced Biophotonics Techniques: The Role of Optical Tweezers for Cells and Molecules Manipulation Associated With Cancer
Authors: Spyratou Ellas
Published: February 2022

Rapid advances in Biophotonics are revolutionizing the illumination of several diseases and, among them, the monitoring of cancer pathogenesis and therapy. Today, several efforts aim to miniaturize the Biophotonics tools, leading to the namely Nanobiophotonics. This scientific field refer to the development of novel technologies, biosensors, and drug delivery systems for prevention, diagnosis, and treatment of diseases at the nanoscale, in sub-cellular and molecular level. Modern non-invasive laser-based techniques are applied in different domains, from practical, clinical applications to molecular and cellular biology fundamental research. Among the plethora of photon-based techniques, optical trapping is a very promising tool for improving the understanding of cancer at cellular level. Recently, optical tweezers are revived as a potential technique for cell characterization, tracking cells behavior and probing interactions forces between cells, cells-biomolecules, and cells-nanoparticles. In this review, we aim to exhibit the state-of the art advances of Biophotonics in the diagnostic and therapeutic field of cancer focusing on the role of optical tweezers.
N-(3-Oxododecanoyl) Homoserine Lactone Is a Generalizable Plasma Membrane Lipid-Ordered Domain Modifier
Authors: Ruan Hefei , Zou Chunlin , Xu Yanni , Fang Xiaohong , Xia Tie , Shi Yan
Published: February 2022

A mammalian plasma membrane is a structure on which several layers of complexity are built. The first order of complexity comes from the heterogeneity of lipid-ordered domains. Gangliosides in concert with cholesterol are preferentially packed on the outer leaflet and form lipid-ordered domains, commonly known as lipid rafts. The formation and dynamics of these domains impact nearly all membrane protein functions and are an intensely studied topic. However, tools suited for lipid domain alteration are extremely limited. Currently, methyl-β-cyclodextrin (MβCD) appears to be the most common way to disrupt lipid domains, which is believed to operate via cholesterol extraction. This significantly limits our ability in membrane biophysics research. Previously, we found that N-(3-oxo-dodecanoyl) homoserine lactone (3oc), a small signaling chemical produced by Pseudomonas aeruginosa, is highly efficient in altering lipid-ordered domains. In this study, 3oc was compared with MβCD in a series of biochemical, biophysical, and cell biological analyses. Per molarity, 3oc is more efficient than MβCD in domain alteration and appears to better retain membrane lipids after treatment. This finding will provide an essential reagent in membrane biophysics research.
Motor Unit Number Estimation of the Second Lumbrical Muscle in Human Hand
Authors: Zong Ya , Lu Zhiyuan , Chen Maoqi , Deng Lianfu , Xie Qin , Zhou Ping
Published: February 2022

The number of motor units of the lumbrical muscles in human hand has not been explored. The objective of this study was to fill this gap by estimating the number of motor units in the second lumbrical muscle. Compound muscle action potential scan of the second lumbrical muscle was performed in 12 healthy subjects, with 10 of them being tested on two separate occasions. Motor unit number estimation (MUNE) was derived from the MScanFit program. The average MUNE of the second lumbrical muscle was 41.6 ± 2.1 (mean ± standard error) from 12 subjects in the first test, and 42.0 ± 2.2 from 10 of the 12 subjects in the retest, demonstrating excellent measurement reliability. Findings of the study provide novel information about the motor unit number of the second lumbrical muscle in human hand. The relatively low motor unit number in the muscle can facilitate motor unit investigations, especially at high level muscle activation.
CRISPR/Cas9-Mediated Targeted Mutagenesis of GmUGT Enhanced Soybean Resistance Against Leaf-Chewing Insects Through Flavonoids Biosynthesis
Authors: Zhang Yongxing , Guo Wei , Chen Limiao , Shen Xinjie , Yang Hongli , Fang Yisheng , Ouyang Wenqi , Mai Sihua , Chen Haifeng , Chen Shuilian , Hao Qingnan , Yuan Songli , Zhang Chanjuan , Huang Yi , Shan Zhihui , Yang Zhonglu , Qiu Dezhen , Zhou Xinan , Cao Dong , Li Xia , Jiao Yongqing
Published: February 2022

Leaf-chewing insects are important pests that cause yield loss and reduce seed quality in soybeans (Glycine max). Breeding soybean varieties that are resistant to leaf-chewing insects can minimize the need for insecticide use and reduce yield loss. The marker gene for QTL-M, Glyma.07g110300 (LOC100775351) that encodes a UDP-glycosyltransferase (UGT) is the major determinant of resistance against leaf-chewing insects in soybean; it exhibits a loss of function in insect-resistant soybean germplasms. In this study, Agrobacterium-mediated transformation introduced the CRISPR/Cas9 expression vector into the soybean cultivar Tianlong No. 1 to generate Glyma.07g110300-gene mutants. We obtained two novel types of mutations, a 33-bp deletion and a single-bp insertion in the GmUGT coding region, which resulted in an enhanced resistance to Helicoverpa armigera and Spodoptera litura. Additionally, overexpressing GmUGT produced soybean varieties that were more sensitive to H. armigera and S. litura. Both mutant and overexpressing lines exhibited no obvious phenotypic changes. The difference in metabolites and gene expression suggested that GmUGT is involved in imparting resistance to leaf-chewing insects by altering the flavonoid content and expression patterns of genes related to flavonoid biosynthesis and defense. Furthermore, ectopic expression of the GmUGT gene in the ugt72b1 mutant of Arabidopsis substantially rescued the phenotype of H. armigera resistance in the atugt72b1 mutant. Our study presents a strategy for increasing resistance against leaf-chewing insects in soybean through CRISPR/Cas9-mediated targeted mutagenesis of the UGT genes.
Conditioning to Enhance the Effects of Repetitive Transcranial Magnetic Stimulation on Experimental Pain in Healthy Volunteers
Authors: Proulx-Bégin Léa , Herrero Babiloni Alberto , Bouferguene Sabrina , Roy Mathieu , Lavigne Gilles J. , Arbour Caroline , De Beaumont Louis
Published: February 2022

Objective

In this proof-of-concept study we sought to explore whether the combination of conditioning procedure based on a surreptitious reduction of a noxious stimulus (SRPS) could enhance rTMS hypoalgesic effects [i.e., increase heat pain threshold (HPT)] and augment intervention expectations in a healthy population.

Methods

Forty-two healthy volunteers (19–35 years old) were enrolled in a randomized crossover-controlled study and were assigned to one of two groups: (1) SRPS and (2) No SRPS. Each participant received two consecutive sessions of active or sham rTMS over the M1 area of the right hand on two visits (1) active, (2) sham rTMS separated by at least one-week interval. HPT and the temperature needed to elicit moderate heat pain were measured before and after each rTMS intervention on the right forearm. In the SRPS group, conditioning consisted of deliberately decreasing thermode temperature by 3°C following intervention before reassessing HPT, while thermode temperature was held constant in the No SRPS group. Intervention expectations were measured before each rTMS session.

Results

SRPS conditioning procedure did not enhance hypoalgesic effects of rTMS intervention, neither did it modify intervention expectations. Baseline increases in HPT were found on the subsequent intervention session, suggesting variability of this measure over time, habituation or a possible “novelty effect.”

Conclusion

Using a SRPS procedure in healthy volunteers did not enhance rTMS modulating effects on experimental pain sensation (i.e., HPT). Future studies are therefore needed to come up with a conditioning procedure which allows significant enhancement of rTMS pain modulating effects in healthy volunteers.
Incorporating Baseline Outcome Data in Individual Participant Data Meta-Analysis of Non-randomized Studies
Authors: Syrogiannouli Lamprini , Wildisen Lea , Meuwese Christiaan , Bauer Douglas C. , Cappola Anne R. , Gussekloo Jacobijn , den Elzen Wendy P. J. , Trompet Stella , Westendorp Rudi G. J. , Jukema J. Wouter , Ferrucci Luigi , Ceresini Graziano , Åsvold Bjørn O. , Chaker Layal , Peeters Robin P. , Imaizumi Misa , Ohishi Waka , Vaes Bert , Völzke Henry , Sgarbi Josè A. , Walsh John P. , Dullaart Robin P. F. , Bakker Stephan J. L. , Iacoviello Massimo , Rodondi Nicolas , Del Giovane Cinzia
Published: February 2022

Background

In non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC).

Methods

For the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA.

Results

Ten of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score.

Conclusion

ANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.