bluuebunny/crossref_metadata_2025 huggingface dataset:
A pediatric case report and literature review of facioscapulohumeral muscular dystrophy type1
Authors: Xiao Ting , Yang Haiyan , Gan Siyi , Wu Liwen
Published: December 2021

Rationale:

Early-onset facioscapulohumeral muscular dystrophy (FSHD) is defined as facial weakness before the age of 5 and shoulder weakness before the age of 10. Early-onset facioscapulohumeral muscular dystrophy is relatively rare in the clinic. This onset is relatively early, the symptoms are serious, and it is likely to be accompanied by retinal vascular disease, sensorineural deafness, epilepsy and other extramuscular multisystem diseases. We report the clinical characteristics of 2 patients with early-onset facial and shoulder brachial muscular dystrophy to improve clinicians’ understanding of this particular condition.

Patient concerns:

We report 2 pediatric patients with FSHD type 1. Patient 1 is an 11-year-old boy with reduced facial expression for 9 years and proximal muscle weakness for 6 years. Patient 2 is a 4-year and 6-month-old girl with developmental delay for 3 years and facial weakness for 1 year.

Diagnosis:

According to the clinical manifestations and molecular genetic testing (such as Southern blot analysis), the patients were diagnosed with early-onset FSHD1.

Interventions:

The patients received cocktail therapy (vitamin B1 tablets, vitamin B2 tablets, vitamin B6 tablets, vitamin C tablets, vitamin E tablets, idebenone tablets, etc.) to improve their muscle metabolism.

Outcomes:

Both patients’ condition did not improve after being given cocktail treatment. According to a recent follow-up, the symptoms of facial weakness and proximal muscle weakness were aggravated.

Lessons:

Early-onset FSHD presents early and has frequent systemic features, and it is a severe subtype of FSHD. Early identification and genetic diagnosis should be performed to improve patient prognosis.
Breast osteosarcoma originating from a malignant phyllodes tumor
Authors: Jin Ying , Bi Lirong , Yang Ruming , Jiang Tinghan , Zhang Xiaoxiao , Li Sijie
Published: December 2021

Rationale:

Malignant phyllodes tumors with osteosarcomatous transformation are exceedingly rare. The clinical manifestations are similar to those associated with benign giant calcification, resulting in nonspecific and complex clinical symptoms.

Patient concerns:

A 59-year-old woman presented with a firm, painless, movable, 5.0 × 4.0 cm lump in the lower inner quadrant of the left breast that she had detected 1 month prior.

Diagnoses:

Breast osteosarcoma originating from a malignant phyllodes tumor was confirmed by histopathologic and immunohistochemical evaluation.

Interventions:

The patient underwent a wide local excision.

Outcomes:

The patient recovered uneventfully and was discharged after the operation. The 6-month postoperative follow-up assessment revealed no evidence of recurrence.

Lessons:

Diagnosing malignant phyllodes tumors with osteosarcomatous transformation requires a high level of suspicion and awareness by both surgeons and pathologists. They should be aware of the extent of such disease, which might be mistaken as benign giant calcification. Medical history and imaging findings are important for accurate diagnosis. Phyllodes tumor with an osteosarcomatous component is an aggressive neoplasm associated with distant metastasis. Delayed diagnosis and insufficient excision might negatively impact both treatment and survival.
Efficacy and safety of Chinese herbal for carotid atherosclerosis
Authors: Li Haitao , Zhi Hongwei , Xu Xiying , Wang Yahan , Zhang Shuai , Zhang Sishuo
Published: December 2021

Background:

Carotid atherosclerosis (CAS) can cause acute events such as myocardial infarction and stroke, seriously injuring human health. There are some shortcomings for statins and surgical in the treatment of CAS. Research has proved that Chinese herbal shows its unique advantages with the multichannel and multitarget treatment strategy. As a result, we propose this study to evaluate the efficacy and safety of Chinese herbal in the treatment of CAS.

Method:

We will retrieve the relevant databases to collect the studies of Chinese herbal treatment of CAS up to July 2021. The retrieval language is limited to Chinese and English. Researchers will be responsible for screening studies and extracting data, and use STATA16.0 and WinBUGS1.4.3 for data analysis. We will conduct a bias risk assessment based on the Cochrane Collaboration's bias risk assessment tool and use the grading of recommendations assessment development and evaluation tool to assess the confidence of cumulative evidence.

Results:

The study will evaluate the efficacy and safety of Chinese herbal in the treatment of carotid atherosclerosis.

Conclusion:

The study will offer more evidence for the treatment of CAS with Chinese herbal and expand the selection range of clinicians.

Protocol registration number:

INPLASY2021100112.
The diagnostic value of interleukin 6 as a biomarker for gastric cancer
Authors: Wang Xiaozi , Li Jie , Liu Wenjing , Zhang Xianghong , Xue Liying
Published: December 2021

Background:

Gastric cancer is one of the most common cancers and a main cause of global cancer death. The expression of interleukin 6 is associated with the risk of gastric cancer. But the diagnostic accuracy of interleukin 6 remains unclear. This study was designed to assess the diagnostic performance of interleukin 6 in gastric cancer diagnosis.

Methods:

The related data was obtained from Oncomine and studied using bioinformatics analysis. The PubMed, Embase, Cochrane Library, Web of science databases were searched for related studies published from inception to July 14, 2020. Measuring tools of diagnostic performance including sensitivity, specificity, and diagnostic odds ratio were pooled using bivariate mixed-effects meta-analysis model. The summery receiver operator characteristic curves were plotted.

Results:

The result from Oncomine showed that the expression of interleukin 6 in gastric cancer (GC) patients was higher than the normal groups (P < .05). Furthermore, a total of 4 eligible articles were enrolled, containing 390 cases and 404 controls. The diagnostic results were as follows: a sensitivity of 0.80 (95% confidence interval [CI] 0.57–0.92), a specificity of 0.86 (95% CI 0.74–0.93), a positive likelihood ratio of 5.76 (95% CI 3.49–9.49), a negative likelihood ratio of 0.23 (95% CI 0.11–0.51) and a diagnostic odds ratio of 24.58 (95% CI 14.14–42.73). The summary area under the receiver operating characteristic curves was 0.90 (95% CI 0.87–0.93).

Conclusion:

Higher interleukin 6 expression was detected in GC patients, and interleukin 6 could be a helpful indicator of diagnosis of gastric cancer. Further large-scale prospective studies are required for identifying the diagnostic value of interleukin 6 in gastric cancer.
Evaluation of efficacy and safety of traditional Chinese medicine in the treatment of hip synovitis in children
Authors: Chen Junming , He Peilin , Liu Qianhua , Liu Ning , Liu Youwen , Yue Chen
Published: December 2021

Background:

Hip synovitis is a common hip disorder in children and a frequent cause of hip or groin pain in children. Its onset is rapid and poses a threat to patient health. Conventional treatment methods have suboptimal efficacy and large side effects. Clinical study surface, the therapeutic effect of traditional Chinese medicine (TCM) on hip synovitis in children is obvious. Therefore, we aimed to systematically review the efficacy and safety of TCM on hip synovitis in children.

Methods:

We will search databases including PubMed, Web of Science, EMBASE database, Cochrane Library, MEDLINE, Wanfang Data, Chinese biomedical literature database, China National Knowledge Infrastructure, Chinese science and technology journals database, and World Health Organization International Clinical Trials Registry Platform (since the databases were established). We also searched secondary resources, including the reference lists of studies. Included articles were carefully screened and reviewed by 2 researchers. Statistical analysis was performed using Review Manager 5.3 software.

Results:

This study will comprehensively evaluate the efficacy and safety of TCM for the treatment of hip synovitis in children.

Conclusion:

This systematic review explores the efficacy and safety of TCM for the treatment of hip synovitis in children and provides an update on its clinical use.
The efficacy and safety of Tuina for diabetic gastroparesis
Authors: Yan Huixin , An Yun , Zhang Tao , Zhao Jiangna , Yan Juntao
Published: December 2021

Background:

Diabetic gastroparesis (DGP) is one of the most common complication of diabetes. At present, despite the increasing number of clinical researches of treatment with Tuina have been reported, there are no systematic reviews of Tuina therapy for DGP. Therefore, it is of great significance to evaluate its safety and efficacy as a complementary and alternative therapy.

Methods and analysis:

Randomized controlled trials (RCTs) of Tuina therapy in the treatment of DGP will be retrieved from PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang Database (Wan Fang), Chinese Biomedical Literature Database (CBM), VIP Database for Chinese Technical Periodicals (VIP), Medline, and Clinical Trial Register (CTR). We will consider articles published in English or Chinese between database initiation and October 2021. Research selection, data extraction, risk of bias assessment, and meta-analyses will be independently completed by 2 researchers. Our researchers will use Revman 5.3 software, provided by the Cochrane Collaborative Network for conducting systematic reviews and meta-analysis.

Results:

This systematic review provides a high-quality synthesis to assess the effectiveness and safety of Tuina therapy for treating DGP.

Conclusion:

The conclusions of our study will provide evidence to determine whether Tuina therapy is an effective and safe intervention for patients with DGP.

Systematic review registration

: INPLASY2021110019
Circulation collapse caused by intracardiac thrombosis associated with tranexamic acid administration
Authors: Xie Qing , Huang Chang-Jun , Gu Kai-Peng , Yao Yong-Xing
Published: December 2021

Rationale:

Perioperative administration of tranexamic acid has been suggested to reduce bleeding and blood transfusion requirements in patients undergoing orthopedic surgery. Despite being sporadic, the potential risk for thrombotic complications cannot be ignored. However, intracardiac thrombosis associated with tranexamic acid administration is rare. We described a case of circulatory collapse caused by intracardiac thrombosis associated with tranexamic acid administration for a scheduled knee arthroplasty.

Patient concerns:

A 62-year-old male patient was scheduled for a right knee arthroplasty. He had a history of hypertension and had undergone surgery for treatment of right femur fracture 30 years previously. Other than a high platelet count (498 × 109/L), results of laboratory investigations were within normal limits. The ultrasonic examination of both lower limbs showed no thrombosis. Upon sterilizing the surgical area, tranexamic acid (1.6 g) was intravenously administered after induction of anesthesia and intubation. Then the patient had a sudden circulatory collapse. Through cardiopulmonary resuscitation, the patient recovered spontaneous circulation. Transesophageal echocardiography revealed extensive thrombosis in the right atrium and ventricle.

Diagnosis:

Circulation collapse caused by intracardiac thrombosis

Interventions:

Thrombolytic therapy was recommended after urgent multidisciplinary consultation. Thus, urokinase was administered intravenously. Fifty minutes after thrombolysis, the mass in ventricle disappeared. A shrunken mass was observed in the right atrium. After another half an hour, no abnormal echoes were seen in the right heart chambers.

Outcomes:

The patient was discharged after 43 days without any organ dysfunction.

Lessons:

This case reminds clinicians that perioperative tranexamic acid administration may increase the risk of thrombosis, which needs focused attention from anesthesiologists. Prompt transesophageal echocardiography examination should be done to allow immediate diagnosis and effective thrombolysis therapy when unexplained cardiac arrest occurs during anesthesia.
A simple and quick PCR based method for detection of Omicron variant of SARS-CoV-2
Authors: Puvar Apurvasinh , Pandit Ramesh , Chaudhari Armi M , Travadi Tasnim , Shukla Nitin , Joshi Chaitanya , Joshi Madhvi
Published: December 2021

SARS-CoV-2 pandemic has changed the global landscape since last two years. Against many challenges posed by the COVID-19 pandemic to the humanity, the pace of solutions created by mankind is exemplary; diagnostics, vaccines, alternate therapies, to name a few. With a rapidly changing virus strain, its early identification in the community can be a quick solution to trace the individuals and thus control its spread. This paper describes PCR based quick method for differentiation of Omicron variant of SARS-CoV-2 from other variants. Timely identification of this new variant will enable better management of pandemic control in the population.

Graphical Abstract
High Rate of Asymptomatic Carriage Associated with Variant Strain Omicron
Authors: Garrett Nigel , Tapley Asa , Andriesen Jessica , Seocharan Ishen , Fisher Leigh H. , Bunts Lisa , Espy Nicole , Wallis Carole L. , Randhawa April Kaur , Ketter Nzeera , Yacovone Margaret , Goga Ameena , Bekker Linda-Gail , Gray Glenda E. , Corey Lawrence
Published: December 2021

The early widespread dissemination of Omicron indicates the urgent need to better understand the transmission dynamics of this variant, including asymptomatic spread among immunocompetent and immunosuppressed populations. In early December 2021, the Ubuntu clinical trial, designed to evaluate efficacy of the mRNA-1273 vaccine (Moderna) among persons living with HIV (PLWH), began enrolling participants. Nasal swabs are routinely obtained at the initial vaccination visit, which requires participants to be clinically well to receive their initial jab. Of the initial 230 participants enrolled between December 2 and December 17, 2021, 71 (31%) were PCR positive for SARS-CoV-2: all of whom were subsequently confirmed by S gene dropout to be Omicron; 48% of the tested samples had cycle threshold (CT) values <25 and 18% less than 20, indicative of high titers of asymptomatic shedding. Asymptomatic carriage rates were similar in SARS-CoV-2 seropositive and seronegative persons (27% respectively). These data are in stark contrast to COVID-19 vaccine studies conducted pre-Omicron, where the SARS-CoV-2 PCR positivity rate at the first vaccination visit ranged from <1%-2.4%, including a cohort of over 1,200 PLWH largely enrolled in South Africa during the Beta outbreak. We also evaluated asymptomatic carriage in a sub study of the Sisonke vaccine trial conducted in South African health care workers, which indicated 2.6% asymptomatic carriage during the Beta and Delta outbreaks and subsequently rose to 16% in both PLWH and PHLWH during the Omicron period.

These findings strongly suggest that Omicron has a much higher rate of asymptomatic carriage than other VOC and this high prevalence of asymptomatic infection is likely a major factor in the widespread, rapid dissemination of the variant globally, even among populations with high prior rates of SARS-COV-2 infection.
Development of reference equations for the six-minute walk distance of school-aged Nigerian children
Authors: Ubuane Peter Odion , Ajiboye Olufunke Adewumi , Adekunle Motunrayo Oluwabukola , Akinola Ayodeji Olushola , Akinyosoye Gbenga , Kayode-Awe Mogbafolu Olugbemiga , Ajayi Omotola Aderiyike , Ohagwu Chidimma Imma , Animasahun Barakat Adeola , Njokanma Fidelis Olisamedua
Published: December 2021

Background

The six-minute walk test (6MWT), a simple, reliable and valid test that uses the distance walked in six minutes (six-minute walk distance, 6MWD) to quantify functional capacity, is widely used in chronic cardiopulmonary and non-cardiopulmonary disorders. However, absence of reference standards for Nigerian school-age children limits its use in this age group.

Objectives

To develop normative values and equations for the 6MWT of school-aged Nigerian children.

Methods

In a cross-sectional study, healthy children aged 6-11 years in Lagos, Nigeria, completed 6MWT on 20-meter straight outdoor courses in their schools following standardized guidelines. Potential predictors: demographic (age, sex), anthropometric (height, weight, chest circumference, leg length) and physiologic data [pre-walk, immediate post-walk and 5th minute-post-walk heart rate (HR), oxygen saturation (SpO2), systolic pressure (SBP), diastolic blood pressure (DBP) and rating of perceived exertion (RPE)] and difference between pre-walk and post-walk HR (ΔHR), SpO2 ((ΔSpO2), SBP (ΔSBP), DBP (ΔDBP) and RPE (ΔRPE). Primary outcome: six-minute walk distance (6MWD) in metres.

Results

Overall, 627 pupils (52.1% girls) walked 504.6 ± 66.6 m (95% CI: 499.4, 509.8), ranging from 326.6 m to 673.0 m; 16 m longer in boys (p=0.002). Stepwise linear regression yielded: 6MWD (m) = 347.9 + 14 (Age) + 1.6 (ΔHR) + 17.6 (Sex) + 1.2 (ΔSBP); R2 =0.25. Previously published reference equations over-estimated Nigerian children’s 6MWD.

Conclusion

The reference values and prediction equations, after validation in other Nigerian populations, may be useful for functional evaluation of Nigerian children aged 6-11 years with chronic childhood disorders.
Development and validation of blood-based predictive biomarkers for response to PD-(L)-1 checkpoint inhibitors: evidence of a universal systemic core of 3D immunogenetic profiling across multiple oncological indications
Authors: Hunter Ewan , Dezfouli Mehrnoush , Koutsothanasi Christina , Wilson Adam , Santos Francisco C. , Salter Matthew , Westra Jurjen W. , Powell Ryan , Dring Ann , Egan Benedict , Parnall Matthew , Thacker Morgan , Green Jayne , Ramadass Aroul , Ng Serene , Lim Chun Ren , Keat Cheah Soon , Suan Ang Tick , Raman Rakesh , Fatt Ho Kean , Wei Luen Fabian Lee , Guiel Thomas , Heaton Robert , Levine Jedd , Akoulitchev Alexandre
Published: December 2021

Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICI) remain limited to a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetics and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint pathways reveals a highly prevalent patient molecular profiles predictive of response to PD-(L)1 immune checkpoint inhibitors. A clinical blood test based on the set of 8 3D genomic biomarkers has been developed and validated on several independent cancer patient cohorts to predict response to PD-(L)1 immune checkpoint inhibition. The predictive 8 biomarker set is derived from prospective observational clinical trials, representing 229 treatments with Pembrolizumab, Atezolizumab, Durvalumab, in diverse indications: melanoma, non-small cell lung, urethral, hepatocellular, bladder, prostate cancer, head and neck, vulvar, colon, breast, bone, brain, lymphoma, larynx cancer, and cervix cancers.

The 3D genomic 8 biomarker panel for response to immune checkpoint therapy achieved high accuracy up to 85%, sensitivity of 93% and specificity of 82%. This study demonstrates that a 3D genomic approach could be used to develop a predictive clinical assay for response to PD-(L)1 checkpoint inhibition in cancer patients.
Prognostic implications of structural heart disease and premature ventricular contractions in recovery of exercise
Authors: Lindow Thomas , Ekström Magnus , Brudin Lars , Hedman Kristofer , Ugander Martin
Published: December 2021

Background

Premature ventricular contractions (PVCs) during recovery of exercise stress testing are associated with increased cardiovascular mortality, but the cause remains unknown. We aimed to evaluate the association of PVCs during recovery with echocardiographic abnormalities, and their combined prognostic performance.

Methods

Echocardiographic abnormalities (reduced left ventricular (LV) ejection fraction, valvular heart disease, LV dilatation, LV hypertrophy, or increased filling pressures) and PVCs during recovery (≥1/min) were identified among patients having undergone echocardiography within median [interquartile range] 0 [0-2] days of an exercise stress test. The association between such changes and cardiovascular mortality was analyzed using Cox regression adjusted for age, sex, clinical and exercise variables.

Results

Among included patients (n=3,106), PVCs during recovery were found in 1,327 (43%) patients, among which the prevalence of echocardiographic abnormalities was increased (58% vs. 44%, p<0.001). Overall, PVCs during recovery were associated with increased cardiovascular mortality (219 total events, 7.9 [5.4–11.1] years follow-up; adjusted hazard ratio (HR [95% confidence interval]) 1.6 [1.2–2.1], p<0.001). When combined with echocardiographic abnormalities, PVCs during recovery were associated with increased risk when such were present (HR 3.3 [1.9–5.5], p<0.001) but not when absent (HR 1.5 [0.8–2.8], p=0.22), in reference to those with neither.

Conclusion

PVCs during recovery were associated with increased prevalence of echocardiographic abnormalities. Increased risk of cardiovascular mortality was observed only for subjects with PVCs if concomitant echocardiographic abnormalities were present. Our findings provide mechanistic insights to the increased CV risk reported in patients with PVCs during recovery.
The Relationship Between Soldier Height, Weight and Army Combat Fitness Scores
Authors: Palmer Ryan , DeBeliso Mark
Published: December 2021

The United States Army recently implemented the Army Combat Fitness Test (ACFT) which was designed to more accurately measure functional-combat fitness constructs. The ACFT replaced the former Army Physical Fitness Test (APFT). The three advent APFT consisted of: two-minute push-ups (PU), two-minute sit-ups (SU), and a timed two-mile run (RUN). The ACFT consists of six events; 3 Rep Max Deadlift (MDL), Standing Power Throw (SPT), Hand Release Push-up (HRP), Sprint-Drag-Carry (SDC), Hanging Leg Tuck (LTK), and a timed two-mile run (2MR). This study investigated the relationship between Soldier height (1.79±0.07 m) and weight (body mass 86.8±14.2 kg, BMI 27.1±3.9) on ACFT scores (442.3±54.4) of 655 male U.S. Army National Guard Soldiers in a Field Artillery Brigade. For the purpose of the investigation body mass index (BMI) was calculated as the metric representing the Soldier’s height and weight. The mean and standard deviation (sd) were calculated for the ACFT event and total scores. Pearson correlation coefficients (PCCs or r) were calculated between BMI and ACFT event and total scores. Likewise, PCCs were calculated between the ACFT event and total scores. The ACFT mean±sd scores were as follows: MDL=92.2±31.8 (3 maximum repetitions), SPT=9.5±2.2 (meters), HRP=24.6±13.1 (repetitions), SDC=119.8±21.7 (seconds), LTK=6.2±5.4 (repetitions), 2MR=1095.0±233.7 (seconds), ACFT total score=442.3±54.4 (points). Significant positive correlations were found between the ACFT total score: MDL (r=0.70), SPT (r=0.50), HRP (r=0.74), and LTK (r=0.76) events. Conversely, significant negative correlations were identified between ACFT total score: SDC (r=−0.68) and 2MR (r=−0.53) events. Within the parameters of this study, Soldier BMI demonstrated “no to weak” association with individual ACFT event or ACFT total scores. Further, the range of PCCs between the ACFT event scores were “no to moderately high”. Military leaders may consider the results provided as combat and fitness tests continue to evolve.
Strong off-target antibody reactivity to malarial antigens induced by RTS,S/AS01E vaccination is associated with increased protection
Authors: Macià Dídac , Campo Joseph J. , Moncunill Gemma , Jairoce Chenjerai , Nhabomba Augusto J. , Mpina Maximilian , Sorgho Hermann , Dosoo David , Traore Ousmane , Kusi Kwadwo Asamoah , Williams Nana Aba , Randall Arlo , Sanz Hèctor , Valim Clarissa , Asante Kwaku Poku , Owusu-Agyei Seth , Tinto Halidou , Agnandji Selidji Todagbe , Kariuki Simon , Gyan Ben , Daubenberger Claudia , Mordmüller Benjamin , Petrone Paula , Dobaño Carlota
Published: December 2021

The RTS,S/AS01E vaccine targets the circumsporozoite protein (CSP) of the Plasmodium falciparum parasite. Using protein microarrays, levels of IgG to 1,000 P. falciparum antigens were measured in 2,138 infants (age 6-12 weeks) and children (age 5-17 months) from 6 African sites of the phase 3 trial, sampled before and at four longitudinal visits after vaccination. One month post-vaccination, IgG responses to 17% of all probed antigens showed differences between RTS,S/AS01E and comparator vaccination groups, whereas no pre-vaccination differences were found. A small subset of antigens presented IgG levels reaching 4- to 8-fold increases in the RTS,S/AS01E group, comparable in magnitude to anti-CSP IgG levels (∼11-fold increase). They were strongly cross-correlated and correlated with anti-CSP levels, waning similarly over time and re-increasing with the booster dose. Such an intriguing phenomenon may be due to cross-reactivity of anti-CSP antibodies with these antigens. RTS,S/AS01E vaccinees with strong off-target IgG responses had an estimated lower clinical malaria incidence after adjusting for age group, site and post-vaccination anti-CSP levels. RTS,S/AS01E-induced IgG may bind strongly not only to CSP, but to unrelated malaria antigens, and this seems to either confer, or at least be a marker of, increased protection from clinical malaria.
Preserved Omicron Spike specific antibody binding and Fc-recognition across COVID-19 vaccine platforms
Authors: Bartsch Yannic , Tong Xin , Kang Jaweon , Avendaño María José , Serrano Eileen F. , García-Salum Tamara , Pardo-Roa Catalina , Riquelme Arnoldo , Medina Rafael A. , Alter Galit
Published: December 2021

Despite the dramatic spread of Omicron globally, even among highly vaccinated populations, death rates have not increased concomitantly. These data argue that alternative immune mechanisms, beyond neutralization, may continue to confer protection against severe disease. Beyond their ability to bind and block infection, antibodies contribute to control and clearance of multiple infections via their ability to direct antiviral immunity via Fc-effector mechanisms. Thus, here we probed the ability of vaccine induced antibodies, across three COVID-19 vaccines, to drive Fc-effector activity against Omicron. Despite the significant loss of IgM, IgA and IgG binding to the Omicron Receptor Binding Domain (RBD) across BNT162b2, mRNA-1273, and CoronaVac vaccines, stable isotype binding was observed across all of these vaccines to the Omicron Spike. Compromised RBD binding IgG was accompanied by a significant loss of cross RBD-specific antibody Fcγ-receptor binding by the CoronaVac vaccine, but preservation of RBD-specific FcγR2a and Fcγ3a binding across the mRNA vaccines. Conversely, Spike-specific antibodies exhibited persistent binding to Fcγ-receptors, across all three vaccines, albeit higher binding was observed with the mRNA vaccines, marked by a selective preservation of FcγR2a and Fcγ3a binding antibodies. Thus, despite the significant to near complete loss of Omicron neutralization across several vaccine platforms against Omicron, vaccine induced Spike-specific antibodies continue to recognize the virus and recruit Fc-receptors pointing to a persistent capacity for extra-neutralizing antibodies to contribute Omicron disease attenuation.
Homologous or Heterologous Booster of Inactivated Vaccine Reduces SARS-CoV-2 Omicron Variant Escape from Neutralizing Antibodies
Authors: Wang Xun , Zhao Xiaoyu , Song Jieyu , Wu Jing , Zhu Yuqi , Li Minghui , Cui Yuchen , Chen Yanjia , Yang Lulu , Liu Jun , Zhu Huanzhang , Jiang Shibo , Wang Pengfei
Published: December 2021

The massive and rapid transmission of SARS-CoV-2 has led to the emergence of several viral variants of concern (VOCs), with the most recent one, B.1.1.529 (Omicron), which accumulated a large number of spike mutations, raising the specter that this newly identified variant may escape from the currently available vaccines and therapeutic antibodies. Using VSV-based pseudovirus, we found that Omicron variant is markedly resistant to neutralization of sera form convalescents or individuals vaccinated by two doses of inactivated whole-virion vaccines (BBIBP-CorV). However, a homologous inactivated vaccine booster or a heterologous booster with protein subunit vaccine (ZF2001) significantly increased neutralization titers to both WT and Omicron variant. Moreover, at day 14 post the third dose, neutralizing antibody titer reduction for Omicron was less than that for convalescents or individuals who had only two doses of the vaccine, indicating that a homologous or heterologous booster can reduce the Omicron escape from neutralizing. In addition, we tested a panel of 17 SARS-CoV-2 monoclonal antibodies (mAbs). Omicron resists 7 of 8 authorized/approved mAbs, as well as most of the other mAbs targeting distinct epitopes on RBD and NTD. Taken together, our results suggest the urgency to push forward the booster vaccination to combat the emerging SARS-CoV-2 variants.
BNT162b2 boosted immune responses six months after heterologous or homologous ChAdOx1nCoV-19/BNT162b2 vaccination against COVID-19
Authors: Behrens Georg M. N. , Barros-Martins Joana , Cossmann Anne , Ramos Gema Morillas , Stankov Metodi V. , Odak Ivan , Dopfer-Jablonka Alexandra , Hetzel Laura , Köhler Miriam , Patzer Gwendolyn , Binz Christoph , Ritter Christiane , Friedrichsen Michaela , Schultze-Florey Christian , Ravens Inga , Willenzon Stefanie , Bubke Anja , Ristenpart Jasmin , Janssen Anika , Ssebyatika George , Bernhardt Günter , Hoffmann Markus , Pöhlmann Stefan , Krey Thomas , Bošnjak Berislav , Hammerschmidt Swantje I. , Förster Reinhold
Published: December 2021

Reports suggest that COVID-19 vaccine effectiveness is decreasing, either due to waning immune protection, emergence of new variants of concern, or both. Heterologous prime/boost vaccination with a vector-based approach (ChAdOx-1nCov-19, ChAd) followed by an mRNA vaccine (e.g. BNT162b2, BNT) appeared to be superior in inducing protective immunity, and large scale second booster vaccination is ongoing. However, data comparing declining immunity after homologous and heterologous vaccination as well as effects of a third vaccine application after heterologous ChAd/BNT vaccination are lacking. We longitudinally monitored immunity in ChAd/ChAd (n=41) and ChAd/BNT (n=88) vaccinated individuals and assessed the impact of a second booster with BNT in both groups. The second booster greatly augmented waning anti-spike IgG but only moderately increased spike-specific CD4+ and CD8+ T cells in both groups to cell frequencies already present after the boost. More importantly, the second booster efficiently restored neutralizing antibody responses against Alpha, Beta, Gamma, and Delta, but neutralizing activity against B.1.1.529 (Omicron) stayed severely impaired. Our data suggest that inferior SARS-CoV-2 specific immune responses after homologous ChAd/ChAd vaccination can be cured by a heterologous BNT vaccination. However, prior heterologous ChAd/BNT vaccination provides no additional benefit for spike-specific T cell immunity or neutralizing Omicron after the second boost.
Nuclear localization and transactivation of SYS-1/β-catenin is the result of serial gene duplications and subfunctionalizations
Authors: Wolf Arielle K. , Adams-Phillips Lori C. , Adams Amanda N. D. , Erives Albert J. , Phillips Bryan T.
Published: December 2021

β-catenin is a multifunctional protein capable of mediating cell adhesion via E-cadherin and transactivation of target genes of the canonical Wnt signaling pathway. The nematode, C. elegans contains four paralogs of β-catenin which are highly specific in their functions. Though similar in overall structure, the four beta-catenins are functionally distinct, each regulating different aspects of development. Of the four, SYS-1 is a key player in Wnt dependent asymmetric cell division (ACD). In ACD, a polarized mother will give rise to a daughter with high nuclear SYS-1 and another with low nuclear SYS-1. Despite sequence dissimilarity, SYS-1 shares a close structural resemblance with human β-catenin where it retains an unstructured amino-terminus (NTD) and 12 armadillo repeats. Using existing genome sequence data from several nematode species, we find that the four β-catenin paralogs result from 3 sequential gene duplications and neofunctionalizations during nematode evolution. SYS-1, however, lacks an unstructured carboxyl-terminus (CTD) that is essential for human β-catenin transactivation processes. This work supports the hypothesis that SYS-1 compensated for the lack of CTD by acquiring novel transactivation domains with cryptic nuclear localization signals in the NTD and the first four armadillo repeats, as shown by transactivation assays in worms and yeast. Furthermore, SYS-1 regulatory domains are not localized to the NTD as in canonical β-catenin and instead spans the entire length of the protein. Truncating SYS-1 abolishes the classical SYS-1 nuclear asymmetry, resulting in daughter cells with symmetrical SYS-1 truncation localization. A screen for SYS-1 physical interactors followed by in vivo cell fate and SYS-1 localization analyses suggest that proper SYS-1 nuclear export is facilitated by XPO-1, while an interaction with IMB-3, an importin β-like protein, suggests import mechanisms. Interestingly, XPO-1 is especially required for lowering SYS-1 in the Wnt-unsignaled nucleus, suggesting a distinct mechanism for regulating asymmetric nuclear SYS-1. In summary, we provide insights on the mechanism of β-catenin evolution within nematodes and inform SYS-1 transactivation and nuclear transport.
SARS-CoV-2 Omicron-B.1.1.529 Variant leads to less severe disease than Pango B and Delta variants strains in a mouse model of severe COVID-19
Authors: Bentley Eleanor G. , Kirby Adam , Sharma Parul , Kipar Anja , Mega Daniele F. , Bramwell Chloe , Penrice-Randal Rebekah , Prince Tessa , Brown Jonathan C. , Zhou Jie , Screaton Gavin R. , Barclay Wendy S. , Owen Andrew , Hiscox Julian A. , Stewart James P.
Published: December 2021

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The B.1.1.529 Omicron variant is rapidly emerging and has been designated a Variant of Concern (VOC). The variant is highly transmissible and partially or fully evades a spectrum of neutralising antibodies due to a high number of substitutions in the spike glycoprotein. A major question is the relative severity of disease caused by the Omicron variant compared with previous and currently circulating variants of SARS-CoV-2. To address this, a mouse model of infection that recapitulates severe disease in humans, K18-hACE2 mice, were infected with either a Pango B, Delta or Omicron variant of SARS-CoV-2 and their relative pathogenesis compared. In contrast to mice infected with Pango B and Delta variant viruses, those infected with the Omicron variant had less severe clinical signs (weight loss), showed recovery and had a lower virus load in both the lower and upper respiratory tract. This is also reflected by less extensive inflammatory processes in the lungs. Although T cell epitopes may be conserved, the antigenic diversity of Omicron from previous variants would suggest that a change in vaccine may be required to mitigate against the higher transmissibility and global disease burden. However, the lead time to develop such a response may be too late to mitigate the spread and effects of Omicron. These animal model data suggest the clinical consequences of infection with the Omicron variant may be less severe but the higher transmissibility could still place huge burden upon healthcare systems even if a lower proportion of infected patients are hospitalised.
Genomic evidence of speciation by fusion linked to trophic niche expansion in a recent radiation of grasshoppers
Authors: Noguerales Víctor , Ortego Joaquín
Published: December 2021

Post-divergence gene flow can trigger a number of creative evolutionary outcomes, ranging from the transfer of beneficial alleles across species boundaries (i.e., adaptive introgression) to the formation of new species (i.e., hybrid speciation). While neutral and adaptive introgression has been broadly documented in nature, hybrid speciation is assumed to be rare and the evolutionary and ecological context facilitating this phenomenon still remains controversial. Through combining genomic and phenotypic data, we evaluate the hypothesis that the dual feeding regime (scrub legumes and gramineous herbs) of the taxonomically controversial grasshopper Chorthippus saulcyi algoaldensis resulted from hybridization between two sister taxa that exhibit contrasting host-plant specializations: C. binotatus (scrub legumes) and C. saulcyi (gramineous herbs). Genetic clustering analyses and inferences from coalescent-based demographic simulations confirmed that C. s. algoaldensis represents a uniquely evolving lineage and supported the ancient hybrid origin of this taxon (ca. 1.4 Ma), which provides a mechanistic explanation for its broader trophic niche and sheds light on its uncertain phylogenetic position. We propose a Pleistocene hybrid speciation model where range shifts resulting from climatic oscillations can promote the formation of hybrid swarms and facilitate its long-term persistence through geographic isolation from parental forms in topographically complex landscapes.
Simultaneous Optimization of Excitation Wavelength and Emission Window for Semiconducting Polymer Nanoparticles to Improve Imaging Quality
Authors: Xue Dingwei , Zhou Hongli , Lu Zeyi , Zhang Yuhuang , Li Mengyuan , Xu Zhousu , Zebiluba Abudureheman , Feng Zhe , Li Lin , Liu Jie , Qian Jun , Li Gonghui
Published: December 2021

Optimized excitation wavelength and emission window are essential for fluorescence imaging with high quality. Semiconducting polymer nanoparticles (SPNs) as fluorescent contrast agents have been extensively studied, but their imaging abilities in the second near-infrared IIb window (NIR-IIb, 1500–1700 nm) with long excitation wavelength have not been reported yet. Herein, as a proof-of-concept, we demonstrate for the first time that an SPN named L1057 nanoparticles (NPs) exhibit intense NIR-IIb signal due to its ultra-high brightness and broad emission spectrum. After screening 915 nm as an optimal excitation wavelength, we applied L1057 NPs to visualize the whole-body vessels, cerebral vessels, gastrointestinal tract, and tumor progression in different stages, achieving superior spatial resolution and signal to background ratio in the NIR-IIb window with respect to NIR-II window (1000–1700 nm). This study reveals that simultaneous optimization of excitation wavelength and emission window is an efficient strategy to enhance imaging quality and that L1057 NPs can serve as a promising NIR-IIb contrast agent for high-resolution and deep-tissue imaging.
Histone neutralization in a rat model of acute lung injury induced by double-hit lipopolysaccharide
Authors: Ge Yangyang , Wang Chenchen , Zhen Yuduo , Luo Junjie , Chen Jiayi , Wang Yu , Wang Fuquan , Wang Li , Lin Yun , Shi Lin , Yao Shanglong
Published: December 2021

Background

Acute respiratory distress syndrome (ARDS) remains a challenge because of its high morbidity and mortality. Circulation histones levels in ARDS patients were correlated to disease severity and mortality. This study examined the impact of histone neutralization in a rat model of acute lung injury (ALI) induced by a lipopolysaccharide (LPS) double-hit.

Methods

Sixty-eight male Sprague-Dawley rats were randomized to sham (N=8, received saline only) or LPS (N=60). The LPS double-hit consisted of a 0.8 mg/kg intraperitoneal injection followed after 16 hours by 5 mg/kg intra-tracheal nebulized LPS. The LPS group was then randomized into five groups: LPS only (N=12); LPS + 5, 25, or 100 mg/kg intravenous STC3141 every 8 hours (LPS+L, LPS+M, LPS+H, respectively, each N=12); or LPS + intraperitoneal dexamethasone 2.5 mg/kg every 24 hours for 56 hours (LPS+D, N=12) The animals were observed for 72 hours.

Results

LPS animals developed ALI as suggested by lower oxygenation, lung edema formation, and histological changes compared to the sham animals. Compared to the LPS group, LPS+H and +D animals had significantly lower circulating histone levels; only the LPS+D group had significantly lower bronchoalveolar lavage fluid (BALF) histone concentrations. The LPS+L, +M, +H and +D groups had improved oxygenation compared to the LPS group and the LPS+H and +D groups had a lower lung wet-to-dry ratio. All animals survived.

Conclusion

Neutralization of histone using STC3141, especially at high dose, had similar therapeutic effects to dexamethasone in this LPS double-hit rat ALI model, with significantly decreased circulating histone concentration, improved oxygenation, and decreased lung edema formation.
Influence of sequencing depth on the fidelity and sensitivity of 1%-5% low-frequency mutation detection and recommendation for standardization of sequencing depth
Authors: Liu Zhe , Qiu Weijin , Fu Shujin , Zhao Xia , Xia Jun , Geng Chunyu , Yu Youqian , Li Ziling , Li Mingzhu , Jiang Hui , Chen Fang
Published: December 2021

Sequencing depth has always played an important role in the accurate detection of low-frequency mutations. The increase of sequencing depth and the reasonable setting of threshold can maximize the probability of true positive mutation, or sensitivity. Here, we found that when the threshold was set as a fixed number of positive mutated reads, the probability of both true and false-positive mutations increased with depth. However, When the number of positive mutated reads increased in an equal proportion with depth (the threshold was transformed from a fixed number to a fixed percentage of mutated reads), the true positive probability still increased while false positive probability decreased. Through binomial distribution simulation and experimental test, it is found that the “fidelity” of detected-VAFs is the cause of this phenomenon. Firstly, we used the binomial distribution to construct a model that can easily calculate the relationship between sequencing depth and probability of true positive (or false positive), which can standardize the minimum sequencing depth for different low-frequency mutation detection. Then, the effect of sequencing depth on the fidelity of NA12878 with 3% mutation frequency and circulating tumor DNA (ctDNA of 1%, 3% and 5%) showed that the increase of sequencing depth reduced the fluctuation range of detected-VAFs around the expected VAFs, that is, the fidelity was improved. Finally, based on our experiment result, the consistency of single-nucleotide variants (SNVs) between paired FF and FFPE samples of mice increased with increasing depth, suggesting that increasing depth can improve the precision and sensitivity of low-frequency mutations.

Highlights

The normalized relationship between sequencing depth and the probability of true positive mutation (sensitivity) is established based on binomial distribution.

The probability of true positive increases and the probability of false positive decreases when the number of positive mutated reads increases (threshold) in an equal proportion with depth.

Detected-VAFs fluctuates regularly around expected-VAFs. The amplitude of detected-VAFs fluctuation decreases with sequencing depth and the “fidelity” increases.

The increase of “fidelity” leads to a higher degree of differentiation between true and false positive mutations, which ultimately increases the true positive probability and decreases the false positive probability.
TOP-2 is differentially required for the proper maintenance of cohesin on meiotic chromosomes in C. elegans spermatogenesis and oogenesis
Authors: Rourke Christine , Jaramillo-Lambert Aimee
Published: December 2021

During meiotic prophase I, accurate segregation of homologous chromosomes requires the establishment of a chromosomes with a meiosis-specific architecture. Sister chromatid cohesins and the enzyme Topoisomerase II are important components of meiotic chromosome axes, but the relationship of these proteins in the context of meiotic chromosome segregation is poorly defined. Here, we analyzed the role of Topoisomerase II (TOP-2) in the timely release of sister chromatid cohesins during spermatogenesis and oogenesis of Caenorhabditis elegans. We show that there is a different requirement for TOP-2 in meiosis of spermatogenesis and oogenesis. The loss-of-function mutation top-2(it7) results in premature REC-8 removal in spermatogenesis, but not oogenesis. This is due to a failure to maintain the HORMA- domain proteins HTP-1 and HTP-2 (HTP-1/2) on chromosome axes at diakinesis and mislocalization of the downstream components that control sister chromatid cohesion release including Aurora B kinase. In oogenesis, top-2(it7) causes a delay in the localization of Aurora B to oocyte chromosomes but can be rescued through premature activation of the maturation promoting factor via knock-down of the inhibitor kinase WEE-1.3. The delay in Aurora B localization is associated with an increase in the length of diakinesis chromosomes and wee-1.3 RNAi mediated rescue of Auorora B localization in top-2(it7) is associated with a decrease in chromosome length. Our results imply that the sex-specific effects of Topoisomerase II on sister chromatid cohesion release are due to differences in the temporal regulation of meiosis and chromosome structure in late prophase I in spermatogenesis and oogenesis.
ABCnet : Self-Attention based Atom, Bond Message Passing Network for Predicting Drug-Target Interaction
Authors: Lee Segyu , Bang Junil , Hong Sungeun , Jang Woojung
Published: December 2021

Drug-target interaction (DTI) is a methodology for predicting the binding affinity between a compound and a target protein, and a key technology in the derivation of candidate substances in drug discovery. As DTI experiments have progressed for a long time, a substantial volume of chemical, biomedical, and pharmaceutical data have accumulated. This accumulation of data has occurred contemporaneously with the advent of the field of big data, and data-based machine learning methods could significantly reduce the time and cost of drug development. In particular, the deep learning method shows potential when applied to the fields of vision and speech recognition, and studies to apply deep learning to various other fields have emerged. Research applying deep learning is underway in drug development, and among various deep learning models, a graph-based model that can effectively learn molecular structures has received more attention as the SOTA in experimental results were achieved. Our study focused on molecular structure information among graph-based models in message passing neural networks. In this paper, we propose a self-attention-based bond and atom message passing neural network which predicts DTI by extracting molecular features through a graph model using an attention mechanism. Model validation experiments were performed after defining binding affinity as a regression and classification problem: binary classification to predict the presence or absence of binding to the drug-target, and regression to predict binding affinity to the drug-target. Classification was performed with BindingDB, and regression was performed with the DAVIS dataset. In the classification problem, ABCnet showed higher performance than MPNN, as it does in the existing study, and in regression, the potential of ABCnet was checked compared to that of SOTA. According to experiments, for Binary classification ABCnet have an average performance improvement of 1% for higher performance on DTI task than other MPNN and for regresssion ABCnet have CI with an average 0.01 to 0.02 performance degradation compared to SOTA. https://www.overleaf.com/project/618a05533676801d8f68ccf6