bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatiotemporal evolution of pyroptosis and canonical inflammasome pathway in hSOD1G93A ALS mouse model
Authors: Zhang Haoyun , Li Hao , Huang Bingkun , Wang Shaoye , Gao Ying , Meng Fandi , Chen Yanchun , Zhou Fenghua , Guan Yingjun , Wang Xin
Published: August 2022

Background

Evidences indicate that inflammasome compounds participate in amyotrophic lateral sclerosis (ALS), a fatal progressive motoneuron degenerative disease. Researchers have observed the expressions of nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) related inflammasome components in specific regions of the central nervous system in different ALS models, but the cellular spatiotemporal evolution of this canonical inflammasome pathway and pyroptosis during ALS progression are unclear.

Methods

The spinal cords of hSOD1G93A mice (ALS mice) and age-matched littermates (CON mice) were dissected at pre-symptomatic stage (60 d), early- symptomatic stage (95 d), symptomatic stage (108 d) and late-symptomatic stage (122 d) of the disease. By using Nissl staining, double immunofluorescence labelling, qRT-PCR or western blot, we detected morphology change and the expression, cellular location of GSDMD, NLRP3, caspase-1 and IL-1β in the ventral horn of lumbar spinal cords over the course of disease.

Results

Neural morphology changes and GSDMD+/NeuN+ double positive cells were observed in ventral horn from ALS mice even at 60 d of age, even though there were no changes of GSDMD mRNA and protein expressions at this stage compared with CON mice. With disease progression, compared with age-matched CON mice, increased expressions of GSDMD, NLRP3, activated caspase-1 and IL-1β were detected. Double immunofluorescence labeling revealed that NLRP3, caspase-1, IL-1β positive signals mainly localized in ventral horn neurons at pre- and early-symptomatic stages. From symptomatic stage to late-symptomatic stage, robust positive signals were co-expressed in reactive astrocytes and microglia.

Conclusions

Early activation of the canonical NLRP3 inflammasome induced pyroptosis in ventral horn neurons, which may participate in motor neuron degeneration and initiate neuroinflammatory processes during ALS progression.
The reliability, functional quality, understandability, and actionability of fall prevention content in YouTube: an observational study
Authors: Yang Xinyi , Xue Xiaoqiang , Shi Ziqiu , Nan Sha , Lian Chengying , Ji Zhigang , Xie Yi , Liu Xiaoxuan
Published: August 2022

Background

Falls are common but dangerous in the elderly. More and more seniors are searching for healthcare information online. YouTube has become the world’s most popular video streaming platform. Albeit thousands of fall prevention videos are available on YouTube, their reliability, functional quality, understandability, and actionability have not been verified.

Methods

The top 300 watched videos on YouTube related to fall prevention were retrieved. After exclusion, all qualified sample videos were evaluated by three validated assessment instruments (the PEMAT scale, the HONCode scale, and the DISCERN instrument) regarding their reliability, functional quality, understandability, and actionability. Each video’s length, number of views/likes/comments, forms of expression, and the uploader’s profile were collected as well. The Wilcoxon rank sum test was performed for further analysis from the perspective of expression forms and uploaders’ identities.

Results

One hundred thirty-seven videos (45.67%) were qualified as sample videos, and individuals/organizations with medical backgrounds posted 54.01% of them. Most of the excluded videos (n = 163) were irrelevant (n = 91, 55.83%), and commercial (n = 52, 31.90%). The median video length for sample videos was 470 seconds. The DISCERN instrument indicated that 115 videos (83.94%) were of moderate to high overall quality. Medical practitioners and organizations gained the highest scores in functional quality and reliability (P < 0.05), while they also tended to use technical terms more often (mean = 3.15). The HONCode scale suggested a lack of traceability was common. The most popular and actionable form of expression was workout (n = 58, median score = 86.90, P < 0.05), while monolog and keynote presentations scored the highest in understandability (no significant difference between them). The PEMAT scale suggested videos uploaded by medical teams were the easiest to be understood (P = 0.011 and P < 0.001, respectively), whereas they were less actionable than those made by fitness trainers (P = 0.039 and P < 0.001, respectively).

Conclusions

Cooperation between the medical team and fitness trainers is expected for better health promotion. Plain language is advised, and sources should be provided. As for expression form, monolog or keynote presentations, plus workout clips, might be the most effective.
Promoting independence in Lewy body dementia through exercise: the PRIDE study
Authors: Inskip Michael J. , Mavros Yorgi , Sachdev Perminder S. , Hausdorff Jeffrey M. , Hillel Inbar , Singh Maria A. Fiatarone
Published: August 2022

Background

Lewy body dementia (LBD) is an aggressive type of dementia of rapid, fluctuating disease trajectory, higher incidence of adverse events, and poorer functional independence than observed in Alzheimer’s disease dementia. Non-pharmacological treatments such as progressive, high-intensity exercise are effective in other neurological cohorts but have been scarcely evaluated in LBD.

Methods

The Promoting Independence in Lewy Body Dementia through Exercise (PRIDE) trial was a non-randomised, non-blinded, crossover pilot trial involving older adults with LBD consisting of a baseline assessment, an 8-week wait-list, and an 8-week exercise intervention. The aims of this study were to evaluate the determinants of the primary outcome functional independence, as measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale, and the feasibility and preliminary efficacy of an exercise intervention on this outcome. Additionally, important clinical characteristics were evaluated to explore associations and treatment targets. The exercise intervention was supervised, clinic-based, high-intensity progressive resistance training (PRT), challenging balance, and functional exercises, 3 days/week.

Results

Nine participants completed the baseline cross-sectional study, of which five had a diagnosis of Parkinson’s disease dementia (PDD), and four dementia with Lewy Bodies (DLB). Six completed the exercise intervention (three PDD, three DLB). The cohort was diverse, ranging from mild to severe dementia and living in various residential settings. Greater functional independence at baseline was significantly associated with better physical function, balance, cognition, quality of life, muscle mass ratio, walking endurance, faster walking speed and cadence, and lower dementia severity (p < 0.05). Participants declined by clinically meaningful amounts in functional independence, cognition, physical function, muscle mass, and weight over the wait-list period (p < 0.05). Following exercise, participants improved by clinically meaningful amounts in functional independence, cognition, physical function, and strength (p < 0.05). Progressive, high intensity exercise was well-tolerated (> 80% adherence), and only one minor exercise-related adverse event occurred.

Conclusions

PRIDE is the first exercise trial conducted specifically within individuals diagnosed with LBD, and provides important insight for the design of larger, randomized trials for further evaluation of progressive, high-intensity exercise as a valuable treatment in LBD.

Trial registration

The PRIDE trial protocol has previously been prospectively registered (08/04/2016, ANZCTR: ACTRN12616000466448).
Pyogenic liver abscess-caused Klebsiella pneumoniae in a tertiary hospital in China in 2017: implication of hypervirulent carbapenem-resistant strains
Authors: Chen Hongchao , Fang Lanfang , Chen Wenjie , Yang Qing , Li Dan , Hu Dakang , Zhang Jin
Published: August 2022

Background

To investigate the epidemiology of Klebsiella pneumoniae (K. pneumoniae) inducing pyogenic liver abscess (PLA) in east China and the role of hypervirulent carbapenem-resistant K. pneumoniae (Hv-CRKP).

Methods

Forty-three K. pneumoniae strains were collected from 43 patients with PLA at Hangzhou, China in 2017. Antimicrobial susceptibility tests, string test, multilocus sequence typing, pulsed-field gel electrophoresis, mobile genetic elements typing, regular PCR and sequencing, and Galleria mellonella (G. mellonella) lethality test were used to elucidate the epidemiology. Clinical data were collected.

Results

K. pneumoniae strains with serotypes K1 and K2 accounted for 69.8%, which shared 46.5% and 23.3% respectively. K. pneumoniae strains with clonal group 23 were predominant with a rate of 34.9%. Such antimicrobials showed susceptible rates over 80.0%: cefuroxime, cefotaxime, gentamycin, ticarcillin/clavulanate, ceftazidime, cefoperazone/tazobactam, cefepime, aztreonam, imipenem, meropenem, amikacin, tobramycin, ciprofloxacin, levofloxacin, doxycycline, minocycline, tigecycline, chloramphenicol, and trimethoprim-sulfamethoxazole. PFGE dendrogram showed 29 clusters for the 43 K. pneumoniae strains. Three Hv-CRKP strains were confirmed by G. mellonella lethality test, showing a constituent ratio of 7.0% (3/43). Totally three deaths were found, presenting a rate of 7.0% (3/43). The three died patients were all infected with Hv-CRKP.

Conclusions

K1 and K2 are the leading serotypes of K. pneumoniae causing PLA, which show highly divergent genetic backgrounds. Aminoglycosides, Generation 2nd to 4th cephalosporins, β-lactamase/β-lactamase inhibitors, carbapenems, fluoroquinolones are empirical choices. Hv-CRKP may confer an urgent challenge in the future.
Women’s holistic self-care behaviors during pregnancy and associations with psychological well-being: implications for maternal care facilities
Authors: Nguyen Lam Duc , Nguyen Long Hoang , Ninh Ly Thi , Nguyen Ha Thu Thi , Nguyen Anh Duy , Vu Linh Gia , Nguyen Hao Si Anh , Nguyen Son Hoang , Doan Linh Phuong , Vu Thuc Minh Thi , Tran Bach Xuan , Latkin Carl A. , Ho Cyrus S. H. , Ho Roger C. M.
Published: August 2022

Background

Self-care behaviors during pregnancy significantly impacts mother and children's health. This study aimed to explore the self-care behaviors and the associations of these behaviors with the psychological well-being of women during pregnancy, as well as the mediating effects of different social support with these associations.

Methods

A cross-sectional data of 562 pregnant women at Hanoi Obstetrics & Gynecology Hospital and Ca Mau Obstetrics & Pediatrics in Vietnam were analyzed. Questions about self-care behaviors, pregnancy characteristics, social support, and psychological well-being were asked. Multivariate regression models were performed. Structural Equation Modeling (SEM) was employed to test the mediating effects of different social support with the association between self-care behaviors and psychological well-being.

Findings

Only 13% of pregnant women often or always did physical exercise at least three times a week, and 40% consumed enough fiber and five servings of vegetables a day. Only 78.7% always avoided alcohol drinking, and 53.9% of pregnant women avoided being exposed to second-hand smoking and 71,7% avoided using traditional medicine without physicians’ prescriptions. Around 66% of pregnant women always or often had prenatal care checkups as scheduled. Information sources, social support and childbirth expectation were major drivers for self-care practices. SEM model showed that social support mediated the relationship between maternal health behaviors and mental well-being.

Conclusion

This study highlighted the remarkable gaps in self-care practices among our pregnant women, which were significantly associated with their mental well-being. Social support-oriented consultancy and interventions should be warranted for improving behaviors and the mental well-being of pregnant women in Vietnam.
Predictive value of proteomic markers for advanced rectal cancer with neoadjuvant chemoradiotherapy
Authors: Wang Hanyang , Ji Dengbo , Tian Huifang , Gao Zhaoya , Song Can , Jia Jinying , Cui Xinxin , Zhong Lijun , Shen Jing , Gu Jin
Published: August 2022

Background

Preoperative neoadjuvant chemoradiation (nCRT) has been the standard treatment for locally advanced rectal cancer. Serum biomarkers to stratify patients with respect to prognosis and response to nCRT are needed due to the diverse response to the therapy.

Methods

Thirteen paired pre- and post-nCRT sera from rectal cancer patients were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) method. Twenty-five proteins were selected for validation by parallel reaction monitoring (PRM) in ninety-one patients.

Results

Totally, 310 proteins were identified and quantified in sera samples. Reactome pathway analysis showed that the immune activation-related pathways were enriched in response to nCRT. Twenty-five proteins were selected for further validation. PRM result showed that the level of PZP was higher in pathological complete response (pCR) patients than non-pCR patients. The Random Forest algorithm identified a prediction model composed of 10 protein markers, which allowed discrimination between pCR patients and non-pCR patients (area under the curve (AUC) = 0.886 on testing set). Higher HEP2 and GELS or lower S10A8 in baseline sera were associated with better prognosis. Higher APOA1 in post nCRT sera was associated with better disease-free survival (DFS).

Conclusions

We identified and confirmed a 10-protein panel for nCRT response prediction and four potential biomarkers HEP2, GELS, S10A8 and APOA1 for prognosis of rectal cancer based on iTRAQ-based comparative proteomics screening and PRM-based targeted proteomic validation.
Correlation between national surveillance and search engine query data on respiratory syncytial virus infections in Japan
Authors: Uda Kazuhiro , Hagiya Hideharu , Yorifuji Takashi , Koyama Toshihiro , Tsuge Mitsuru , Yashiro Masato , Tsukahara Hirokazu
Published: August 2022

Background

The respiratory syncytial virus (RSV) disease burden is significant, especially in infants and children with an underlying disease. Prophylaxis with palivizumab is recommended for these high-risk groups. Early recognition of a RSV epidemic is important for timely administration of palivizumab. We herein aimed to assess the correlation between national surveillance and Google Trends data pertaining to RSV infections in Japan.

Methods

The present, retrospective survey was performed between January 1, 2018 and November 14, 2021 and evaluated the correlation between national surveillance data and Google Trends data. Joinpoint regression was used to identify the points at which changes in trends occurred.

Results

A strong correlation was observed every study year (2018 [r = 0.87, p < 0.01], 2019 [r = 0.83, p < 0.01], 2020 [r = 0.83, p < 0.01], and 2021 [r = 0.96, p < 0.01]). The change-points in the Google Trends data indicating the start of the RSV epidemic were observed earlier than by sentinel surveillance in 2018 and 2021 and simultaneously with sentinel surveillance in 2019. No epidemic surge was observed in either the Google Trends or the surveillance data from 2020.

Conclusions

Our data suggested that Google Trends has the potential to enable the early identification of RSV epidemics. In countries without a national surveillance system, Google Trends may serve as an alternative early warning system.
From motorised to active travel: using GPS data to explore potential physical activity gains among adolescents
Authors: Loh Venurs , Sahlqvist Shannon , Veitch Jenny , Thornton Lukar , Salmon Jo , Cerin Ester , Schipperijn Jasper , Timperio Anna
Published: August 2022

Background

A high proportion of adolescents worldwide are not doing enough physical activity for health benefits. Replacing short motorised trips with walking or cycling has the potential to increase physical activity at the population level. This study aimed to estimate the proportion of short distance motorised trips that could be replaced with walking or cycling, and the potential physical activity gains by sociodemographic and trip characteristics.

Methods

Data were from a subsample of the NEighbourhood Activity in Youth (NEArbY) study conducted among adolescents in Melbourne. A total of 217 adolescents with at least one motorised trip completed a survey and wore a Global Positioning Systems (GPS) device for eight consecutive days. Classification of travel modes were based on speed. GPS data points were geocoded in ArcGIS. Motorised trips within walkable (1.3 km) and cyclable (4.2 km) distances were identified (threshold based on 80th percentile of walking and cycling trip distances among Victorian adolescents), and the additional physical activity minutes that could be accrued by replacing walkable or cyclable motorised trip to active trips were quantified. Multilevel linear regression was used to assess differences in physical activity minutes gain by sociodemographic and trip characteristics.

Results

A total of 4,116 motorised trips were made. Of these, 17% were walkable and 61% were cyclable. Replacing motorised trips by walking and cycling resulted in estimated gains of six minutes and 15 min of physical activity per day, respectively.

Conclusion

The sizable proportion of replaceable trips and potential physical activity gains from this shift calls for attention to improve safe and connected infrastructure to support active travel.
Concurrence of IgG4-related disease and Kimura disease with pulmonary embolism and lung cancer: a case report
Authors: Lu Ye , Liu Junxiu , Yan Hengyi , Feng Wei , Zhao Li , Chen Yu
Published: August 2022

Background

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic disease that involves the infiltration of IgG4-positive plasma cells in multiple organs. Kimura disease (KD) presents as subcutaneous masses on the head and neck, frequently accompanied by eosinophilia and high immunoglobulin E (IgE) levels. Here, we report a rare case of concurrence of IgG4-RD and KD with manifestations of asthma, pulmonary embolism, and central diabetes insipidus accompanied by lung carcinoma.

Case presentation

A 65-year-old Chinese male with an eight-year history of KD was admitted to our hospital with complaints of dyspnea and expectoration for one month. Laboratory examination showed a considerable elevation in the serum eosinophil count and total IgE and IgG4 levels. Chest enhanced computed tomography showed filling defects in the right pulmonary artery and a nodule in the left inferior lobe. Pancreatic enhanced magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography showed a swollen pancreatic tail and local stricture of the pancreatic duct section of the common bile duct. Enhanced MRI of the pituitary gland showed thickening of the pituitary stalk. Additionally, immunohistochemistry of the specimens collected eight years prior revealed IgG4-positive cells. Following the diagnosis of IgG4-RD with KD, glucocorticoids with immunosuppressants were initiated; there was a prompt improvement in the patient’s condition. One-year post-discharge, the patient underwent wedge-shaped resection of the lung due to enlargement of the pulmonary nodule, and the pathology revealed lung squamous carcinoma.

Conclusions

This case presents a rare clinical condition in which the concurrence of IgG4-RD and KD causes various rare manifestations including asthma, pulmonary embolism, central diabetes insipidus, and complicated lung carcinoma. This highlights the importance of monitoring for malignancies in IgG4-RD patients during follow-up.
KMT2C mutation in a Chinese man with primary multidrug-resistant metastatic adenocarcinoma of rete testis: a case report
Authors: Zhang Yue , He Xiaoyan , Gao Hui
Published: August 2022

Background

Adenocarcinoma of the rete testis (AORT) is an extremely rare malignant tumor with poor prognosis and limited responsiveness to traditional chemotherapy. Few previous studies have focused on the molecular mechanisms underlying therapy resistance in AORT and further scrutiny is required to enable searches for targeted drugs to guide treatment selection.

Case presentation

The current case concerns a 55-year-old man with AORT who presented with isolated bone metastasis at initial diagnosis and experienced rapid disease progression after multi-line platinum-based combination chemotherapy. Next-generation sequencing revealed a novel somatic lysine methyltransferase 2C (KMT2C) c.5605 T > C mutation in exon 36 with an abundance of 49.27%. The patient received antiangiogenic drug treatment for 2 months but this was discontinued due to unacceptable anorexia and nausea. He survived for 12 months after diagnosis.

Conclusion

A potential correlation between AORT primary multi-drug resistance and KMT2C mutations is implied. Further studies are needed to determine the efficacy of PARP1/2 inhibitors for tumors with KMT2C mutations.
Transition to practice curriculum for general internal medicine physicians: scoping review and Canadian national survey
Authors: Thomson Benjamin , O’Halloran Heather , Wu Luke , Gauthier Stephen , Taylor David
Published: August 2022

Background

There remains a paucity of evidence for curricula for the transition to practice (TTP) stage of Competence by Design internal medicine (IM) training programs. Current entrustable professional activities are based on expert consensus rather than robust subspecialty-specific needs assessment.

Methods

A scoping review was completed to identify studies with TTP focus. A national survey was conducted to identify transition experiences for general internal medicine physicians. Results were assessed by grounded theory analysis to identify core topics for TTP curricula.

Results

Neither scoping review nor national survey identified TTP topics related to the CanMEDS Medical Expert role. Scoping Review: 41 relevant studies were identified. Most (97.6%) were from North America. The most common study types were observational (survey) or curriculum (13/41 31.7% for each). Only two studies were exclusively in IM, and the most common subspecialty studied was surgical (13/41, 31.7%). The most common TTP topics were mentorship, billing and coding, practice management, negotiating contract and job, and financial aspects of practice. National Survey: There were 44 respondents, with the majority (25/44, 56.8%) having completed an IM subspecialty fellowship. Most (38/44) completed medical school in Canada, and most were from academic practice settings (33/44, 75.0%). The most common TTP topics were billing and coding, personal financial planning, practice management, work-life balance and mentorship. Grounded Theory Analysis: There were six themes that encompassed all TTP topics from the scoping review and national survey, being (i) building a career, (ii) continuing professional development, (iii) expectations of the profession, (iv) practice management, (v) Life, health and well-being and (vi) clinical skills. Curriculum competencies and resources for curriculum development were provided.

Conclusions

This study identifies topics critical for curricula development for IM transition to practice. Further research is required to evaluate effectiveness of curricula including topics and themes developed from this scoping review and national survey.
The test characteristics of a biased or ignorant diagnostician
Authors: Sonnenberg Amnon
Published: August 2022

Background

A human diagnostician may harbour a special bias towards favourable positive or negative test results. The aim of the present analysis is to describe in quantitative terms how bias can affect the test characteristics of a human tester.

Methods

Whereas an unbiased tester would give absolute (100%) preference to true positive or true negative test results, and no (0%) preference to any false positive or false negative test results, a biased tester may harbour some preferences towards false positive or false negative tests. Such bias can be phrased in terms of a separate sensitivity–specificity matrix. The bias matrix multiplied with the original test matrix yields the biased test matrix. Similarly, the extent of ignorance by a human tester about the diagnosis is modelled as a separate sensitivity–specificity matrix, which captures the concordance between positive and negative diagnoses made by an ignorant and expert diagnostician.

Results

Increasing bias or ignorance result in decreasing test performance with decreasing positive predictive values until the test completely loses its discriminatory power. With more pronounced bias towards false test results, any positive test outcome may even become misinterpreted as predicting the non-existence of a given diagnosis.

Conclusions

The proposed model helps to understand in quantitative terms, how bias and ignorance can alter a diagnostician’s interpretation of test outcomes and result in diagnostic errors.
A true congenital pancreatic cyst in a dog
Authors: Healy D. M. , Cassidy J. P. , Martin S. A.
Published: August 2022

Background

True congenital pancreatic cysts are a rare pathological process reported within feline and human literature. To date there has been no documented case of a true congenital cyst affecting a canine patient. The objective of this case report is to document the clinical findings, diagnostic investigations, surgical treatment, histopathological diagnosis and long-term outcome of a dog with a true pancreatic cyst.

Case presentation

A 5-month-old crossbreed dog was presented with a six-week history of abdominal pain, apparent bilateral pelvic limb weakness, reluctance to walk and intermittent vomiting and diarrhoea. An abdominal ultrasound examination performed by the dog’s primary care veterinarian identified a large intra-abdominal structure of unclear origin. A computed tomographic examination identified a large ovoid structure measuring 156 mm in length, 95 mm in height and 89 mm in width and apparently originating from the left limb of the pancreas. An exploratory coeliotomy was performed and a partial pancreatectomy was performed to allow complete removal of the cystic structure. Histopathological analysis of sections of the wall of the large fluid-filled cyst identified a thick fibromuscular wall lined by a well regimented hyperplastic tall columnar epithelium with basally located round to ovoid nuclei featuring fine chromatin stippling and abundant apically located and surface mucin, concurrent with a true congenital pancreatic cyst. A long-term follow-up of twenty-nine months identified no clinical signs of recurrence.

Conclusion

A partial pancreatectomy and en bloc excision of a true pancreatic cyst provided an excellent long-term outcome in a dog.
Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with COVID-19: an open-label randomized controlled trial
Authors: De Leeuw Elisabeth , Van Damme Karel F. A. , Declercq Jozefien , Bosteels Cedric , Maes Bastiaan , Tavernier Simon J. , Detalle Laurent , Smart Trevor , Glatt Sophie , Debeuf Nincy , Deckers Julie , Lameire Sahine , Vandecasteele Stefaan J. , De Neve Nikolaas , Demedts Ingel K. , Govaerts Elke , Knoop Christiane , Vanhove Karolien , Moutschen Michel , Terryn Wim , Depuydt Pieter , Van Braeckel Eva , Haerynck Filomeen , Hendrickx Tine C. J. , Parrein Vanessa , Lalla Marianna , Brittain Claire , Lambrecht Bart N.
Published: August 2022

Background

The efficacy and safety of complement inhibition in COVID-19 patients is unclear.

Methods

A multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO2/FiO2 below 350 mmHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15.

Results

81 patients were randomly assigned to zilucoplan (n = 55) or the control group (n = 26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO2/FiO2 from baseline to day 6 was 56.4 mmHg in the zilucoplan group and 20.6 mmHg in the control group (mean difference + 35.8; 95% confidence interval (CI) − 9.4 to 80.9; p = 0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0.4; 95% CI 0.1 to 1.5). At long-term follow up, the distance walked in a 6-min test was 539.7 m in zilucoplan and 490.6 m in the control group (p = 0.18). Zilucoplan lowered serum C5b-9 (p < 0.001) and interleukin-8 (p = 0.03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified.

Conclusion

Administration of zilucoplan to COVID-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function (PaO2/FiO2) and clinical outcome (mortality and 6-min walk test) suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.
Metabolic engineering of the l-serine biosynthetic pathway improves glutathione production in Saccharomyces cerevisiae
Authors: Kobayashi Jyumpei , Sasaki Daisuke , Hara Kiyotaka Y. , Hasunuma Tomohisa , Kondo Akihiko
Published: August 2022

Background

Glutathione is a valuable tri-peptide that is industrially produced by fermentation using the yeast Saccharomyces cerevisiae, and is widely used in the pharmaceutical, food, and cosmetic industries. It has been reported that addition of l-serine (l-Ser) is effective at increasing the intracellular glutathione content because l-Ser is the common precursor of l-cysteine (l-Cys) and glycine (Gly) which are substrates for glutathione biosynthesis. Therefore, we tried to enhance the l-Ser biosynthetic pathway in S. cerevisiae for improved glutathione production.

Results

The volumetric glutathione production of recombinant strains individually overexpressing SER2, SER1, SER3, and SER33 involved in l-Ser biosynthesis at 48 h cultivation was increased 1.3, 1.4, 1.9, and 1.9-fold, respectively, compared with that of the host GCI strain, which overexpresses genes involved in glutathione biosynthesis. We further examined simultaneous overexpression of SHM2 and/or CYS4 genes involved in Gly and l-Cys biosynthesis, respectively, using recombinant GCI strain overexpressing SER3 and SER33 as hosts. As a result, GCI overexpressing SER3, SHM2, and CYS4 showed the highest volumetric glutathione production (64.0 ± 4.9 mg/L) at 48 h cultivation, and this value is about 2.5-fold higher than that of the control strain.

Conclusions

This study first revealed that engineering of l-Ser and Gly biosynthetic pathway are useful strategies for fermentative glutathione production by S. cerevisiase.
Exercise and colorectal cancer: prevention and molecular mechanisms
Authors: Amirsasan Ramin , Akbarzadeh Maryam , Akbarzadeh Shabnam
Published: August 2022

Exercise and physical activity have been shown to be strongly associated with a decreased incidence rate of various chronic diseases especially numerous human malignancies. A huge number of clinical trials and meta-analysis have demonstrated that exercise is significantly effective in lowering the risk of colorectal cancer. In addition, it is suggested as an effective therapeutic modality against this cancer type. Therefore, in this review, we will review comprehensibly the effects of exercise in preventing, treating, and alleviating the adverse effects of conventional therapeutic options in colorectal cancer. Moreover, the possible mechanisms underlying the positive effects of exercise and physical activity in colorectal cancer, including regulation of inflammation, apoptosis, growth factor axis, immunity, epigenetic, etc. will be also discussed.
Short-term and long-term outcomes of indocyanine green for sentinel lymph node biopsy in early-stage breast cancer
Authors: Hua Bin , Li Yao , Yang Xin , Ren Xiaotian , Lu Xu
Published: August 2022

Background

Indocyanine green (ICG) is becoming a frequently used sentinel lymph node (SLN) tracer of breast cancer in China. However, there is still a lack of data on its safety. We reported the clinical outcome of ICG as a tracer of SLN over a median 67-month follow-up period to evaluate its feasibility in clinically node-negative patients with breast cancer.

Methods

A total of 194 consecutive patients underwent sentinel lymph node biopsy (SLNB) with ICG, radioisotopes (RI) and methylene blue (MB), or with ICG and MB. The SLN mapping data by each tracer was recorded, and safety outcomes were analyzed through follow-up.

Results

With the triad mapping (N = 44), the identification rate of SLN by ICG was 95.5%, slightly higher than that of MB (86.4%) and comparable with RI (95.5%) and combined methods (95.5%, 100%) (p = 0.068). Analysis of all candidates (N = 194) demonstrated that the identification rate of SLN by ICG or by ICG and MB was 99%, significantly higher than that by MB (92.8%) (p < 0.0001). No tracer-related allergic reaction and permanent skin staining of ICG were observed. Local disease progression was reported in 2 of the 194 patients at the ipsilateral axilla. After remedial axillary lymph node dissection, no disease progression was detected at follow-up.

Conclusions

ICG as an SLN tracer is more accurate than MB and comparable to the combined methods and has good clinical safety. ICG can be considered a useful supplement or suitable alternative to traditional tracers.
Microglia-specific deletion of histone deacetylase 3 promotes inflammation resolution, white matter integrity, and functional recovery in a mouse model of traumatic brain injury
Authors: Zhao Yongfang , Mu Hongfeng , Huang Yichen , Li Sicheng , Wang Yangfan , Stetler R. Anne , Bennett Michael V. L. , Dixon C. Edward , Chen Jun , Shi Yejie
Published: August 2022

Background

Histone deacetylases (HDACs) are believed to exacerbate traumatic brain injury (TBI) based on studies using pan-HDAC inhibitors. However, the HDAC isoform responsible for the detrimental effects and the cell types involved remain unknown, which may hinder the development of specific targeting strategies that boost therapeutic efficacy while minimizing side effects. Microglia are important mediators of post-TBI neuroinflammation and critically impact TBI outcome. HDAC3 was reported to be essential to the inflammatory program of in vitro cultured macrophages, but its role in microglia and in the post-TBI brain has not been investigated in vivo.

Methods

We generated HDAC3LoxP mice and crossed them with CX3CR1CreER mice, enabling in vivo conditional deletion of HDAC3. Microglia-specific HDAC3 knockout (HDAC3 miKO) was induced in CX3CR1CreER:HDAC3LoxP mice with 5 days of tamoxifen treatment followed by a 30-day development interval. The effects of HDAC3 miKO on microglial phenotype and neuroinflammation were examined 3–5 days after TBI induced by controlled cortical impact. Neurological deficits and the integrity of white matter were assessed for 6 weeks after TBI by neurobehavioral tests, immunohistochemistry, electron microscopy, and electrophysiology.

Results

HDAC3 miKO mice harbored specific deletion of HDAC3 in microglia but not in peripheral monocytes. HDAC3 miKO reduced the number of microglia by 26%, but did not alter the inflammation level in the homeostatic brain. After TBI, proinflammatory microglial responses and brain inflammation were markedly alleviated by HDAC3 miKO, whereas the infiltration of blood immune cells was unchanged, suggesting a primary effect of HDAC3 miKO on modulating microglial phenotype. Importantly, HDAC3 miKO was sufficient to facilitate functional recovery for 6 weeks after TBI. TBI-induced injury to axons and myelin was ameliorated, and signal conduction by white matter fiber tracts was significantly enhanced in HDAC3 miKO mice.

Conclusion

Using a novel microglia-specific conditional knockout mouse model, we delineated for the first time the role of microglial HDAC3 after TBI in vivo. HDAC3 miKO not only reduced proinflammatory microglial responses, but also elicited long-lasting improvement of white matter integrity and functional recovery after TBI. Microglial HDAC3 is therefore a promising therapeutic target to improve long-term outcomes after TBI.
Effectiveness of the online Acceptance and Commitment Therapy intervention “Embrace Pain” for cancer survivors with chronic painful chemotherapy-induced peripheral neuropathy: study protocol for a randomized controlled trial
Authors: van de Graaf Daniëlle L. , Mols Floortje , Trompetter Hester R. , van der Lee Marije L. , Schreurs Karlein M. G. , Børøsund Elin , Nes Lise Solberg , Smeets Tom
Published: August 2022

Background

About 30% of cancer survivors suffer from chemotherapy-induced peripheral neuropathy (CIPN) ≥6 months after completion of chemotherapy. This condition, for which treatment options are scarce, comes with limitations in daily life functioning and decreased quality of life. The current study examines the effectiveness of an online self-help intervention based on Acceptance and Commitment Therapy (ACT) in comparison to a waiting list condition (WLC) to deal with CIPN. In addition, it examines which factors moderate effects and to what extent the effects differ between guided and unguided ACT intervention.

Methods

A two-parallel, non-blinded randomized controlled trial (RCT) will be carried out. Adult cancer survivors who experience painful CIPN for at least 3 months and completed chemotherapy at least 6 months ago will be recruited (n=146). In the intervention condition, participants will follow an 8-week self-management course containing 6 modules regarding psychoeducation and ACT processes, including therapeutic email guidance. By means of text and experiential exercises, supplemented with illustrations, metaphors, and audio files, people will learn to carry out value-oriented activities in their daily life with pain. Participants will learn new ways of coping with pain, including reducing pain avoidance and increasing pain acceptance. Participants in the WLC will be invited to follow the intervention without therapeutic guidance 5 months after start. Pain interference is the primary outcome, while psychological distress, quality of life, CIPN symptom severity, pain intensity, psychological flexibility, mindfulness skills, values-based living, and pain catastrophizing will serve as secondary outcomes. All outcome measures will be evaluated at inclusion and baseline, early-intervention, mid-intervention, post-treatment, and 3- and 6-month post-treatment. Qualitative interviews will be conducted post-treatment regarding experiences, usage, usability, content fit, and satisfaction with the intervention.

Discussion

This study will provide valuable information on the effectiveness of an online self-help intervention based on ACT versus WLC for chronic painful CIPN patients.

Trial registration

ClinicalTrials.govNCT05371158. Registered on May 12, 2022.

Protocol version: version 1, 24-05-2022
Changes of regional cerebral blood flow after deep brain stimulation in cervical dystonia
Authors: Park Sungjin , Jeong Hyeonseok , Chung Yong-An , Kang Ilhyang , Kim Seunghee , Song In-Uk , Huh Ryoong
Published: August 2022

Introduction

Cervical dystonia is considered as a network disorder affecting various brain regions in recent days. Presumably, deep brain stimulation (DBS) of the internal segment of globus pallidus (GPi) may exert therapeutic effects for cervical dystonia through modulation of the aberrant brain networks. In the present study, we investigated postoperative regional cerebral blood flow (rCBF) changes after GPi DBS using single-photon emission computed tomography (SPECT) to identify significant activity changes in several relevant brain areas of cervical dystonia patients.

Methods

A total of 9 patients with idiopathic cervical dystonia were recruited, and SPECT scans were conducted at baseline and 3 months after the bilateral GPi DBS. Voxel-wise changes of rCBF were analyzed using Statistical Parametric Mapping. Symptom severity of dystonia was measured using Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at the baseline, and 1 week, and 3 months after GPi DBS.

Results

At the 3-month follow-up after DBS, rCBF was increased in the left pons and right postcentral gyrus and decreased in the left middle frontal gyrus, left cerebellum, right putamen and pallidum, and left thalamus (p < 0.001). Severity of cervical dystonia assessed by TWSTRS was significantly decreased at 1-week and 3-month follow-up (p = 0.004).

Conclusions

Clinical improvement of cervical dystonia after GPi DBS may be accompanied by rCBF changes in several brain areas of the cortico-basal ganglia-cerebellar network which are important for sensorimotor integration.
Geomagnetic conjugacy of plasma bubbles extending to mid-latitudes during a geomagnetic storm on March 1, 2013
Authors: Sori Takuya , Otsuka Yuichi , Shinbori Atsuki , Nishioka Michi , Perwitasari Septi
Published: August 2022

This study, for the first time, reports the geomagnetically conjugate structure of a plasma bubble extending to the mid-latitudes and the asymmetrical structure of the decay of the plasma bubble during a geomagnetic storm. We investigated the temporal and spatial variations of plasma bubbles in the Asian sector during a geomagnetic storm on March 1, 2013, using Global Navigation Satellite System-total electron content data with high spatiotemporal resolutions. The first important point of our data analysis results is that the plasma bubble extended from the equator to the mid-latitudes with geomagnetic conjugacy along the magnetic field lines. The total electron content data showed that the plasma bubbles appeared in the equatorial regions near 150° E after sunset during the main phase of the geomagnetic storm. From ionosonde data over both Japan and Australia, they suggest that a large eastward electric field existed in the Asian sector. Finally, the plasma bubbles extended up to the mid-latitudes (~ 43° geomagnetic latitude) in both hemispheres, maintaining geomagnetic conjugacy. The second point is that the mid-latitude plasma bubble disappeared 1–2 h earlier in the northern hemisphere than in the southern hemisphere at close to midnight. In the northern hemisphere, the ionospheric virtual height decreased near midnight, followed by a rapid decrease in the total electron content and a rapid increase in the ionospheric virtual height. These results imply that the mid-latitude plasma bubble disappeared as the background plasma density decreased after midnight due to the recombination resulting from the descent of the F layer. Therefore, we can conclude that mid-latitude plasma bubbles can be asymmetric between the northern and southern hemispheres because of the rapid decay of plasma bubbles in one of the hemispheres.

Graphical Abstract
Space weathering signatures in sulfide and silicate minerals from asteroid Itokawa
Authors: Chaves Laura C. , Thompson Michelle S.
Published: August 2022

Transmission electron microscopy analyses of the polymineralic regolith particle RC-MD01-0025 show microstructural and microchemical characteristics indicative of space weathering on the surface of asteroid Itokawa. The depletion of sulfur and nickel was identified in space weathered rims on troilite and pentlandite minerals. This corresponds to the first report of nickel depletion in samples returned from asteroid Itokawa by the Hayabusa mission. Microstructurally, the sulfide minerals present crystalline rims and the olivine presents both crystalline and amorphous zones in the rim. These results suggest that sulfides might be more resistant to amorphization caused by solar wind irradiation. The space weathering features identified in the regolith particle analyzed here are likely formed via solar wind irradiation. Additionally, the differences in the space weathering features in olivine, pentlandite, and troilite suggest that silicates and sulfides respond differently to the same space weathering conditions in interplanetary space.

Graphical Abstract
Antibiogram profile prediction of selected bacterial strains by in silico determination of acquired antimicrobial resistance genes from their whole-genome sequence
Authors: Babatunde Olamide Joshua , Okiti Ayomide Faith , Bayode Michael Tosin , Babatunde Samson Oloruntola , Olaniran Ayo Mercy
Published: August 2022

Background

The continuous increase in the resistance of pathogenic bacteria to antimicrobial agents elicits a source of concern for public health. Developing a method that allows for swift evaluation of the antibiotic sensitivity profile of bacteria is a major leap in antimicrobial research and could be one of the deciding factors in providing a lasting solution to antimicrobial resistance. The gradual and continuous reduction in the cost and turnaround time of whole-genome sequencing (WGS) has enabled scientists to develop WGS-based antimicrobial susceptibility testing using computational methods. The genes present on the ResFinder database were blasted against the WGS of the bacterial isolates obtained from NCBI database, and the best-matching genes were automatically generated by the system.

Results

Antimicrobial resistance genes were detected from the strains tested though not innate, thereby suggesting that they must have been acquired through horizontal gene transfer. Additionally, it was revealed that specific genes confer resistance to specific group of antibiotics.

Conclusion

The in silico method of antimicrobial resistance research provides for easy interpretation and reproducibility of results thereby reducing the cost and time utilized.
Audio-vestibular manifestations in Kawasaki disease (KD): a rare atypical case presentation
Authors: Rao R. Mayuri , Rajils Raveendran E. R. , Nidha K. , Namitha K. , Prashanth Prabhu P. , Nisha K. V.
Published: August 2022

Background

Kawasaki disease (KD) is an acute febrile, usually self-limiting illness of infancy and childhood, that can show audiological manifestation of sensorineural hearing loss (SNHL, 36% of patients), usually bilateral in nature.

Case presentation

We report a 12-year-old female diagnosed with KD at 6 years, showing atypical manifestation of asymmetrical SNHL since 1.5 years after the episode of febrile illness. The patient was administered Immune Globulin intravenously and aspirin, which were tapered to a low dose. The patient later reported reduced hearing sensitivity, ear pain, blocking in both ears, and tinnitus (intermittent) in the left ear. The audio-vestibular manifestations in the case using test battery approach (Pure tone audiometry, speech audiometry, tympanometry, reflexometry, otoacoustic emissions, auditory brainstem response, and behavioral and objective vestibular tests) is discussed. The rehabilitative measures taken, and the need for sensitization of school teachers for early identification of hearing loss in children with KD is highlighted.

Conclusions

This case presentation concentrates on the rare asymmetrical SNHL and vestibular finding post-KD and emphasizes the need for health care professionals to refer patients with KD to an audiologist to trace the possible sequelae including hearing loss and vestibular disorders. The atypical manifestations of KD in hearing domain is suggestive of the need for early identification, adequate profiling of not just hearing but also balance-related manifestations, instigation of appropriate rehabilitative measures, effective counselling of parents and school teachers to facilitate better academic learning, and communication opportunities.