bluuebunny/crossref_metadata_2025 huggingface dataset:
Rethinking Farkas: Updating Cephalic Index Norms in a Large, Diverse Population
Authors: Phelan Alannah L. , Gu Garrick , McCarthy Melissa , Barton Bruce A. , McIntyre Joyce K. , Lalikos Janice F.
Published: May 2021

Background:

Cephalic index, the ratio of head width to length, is one normative indicator used by insurers to derive criteria for plagiocephaly helmet authorization. Current norms were established by a small sample of white children in the 1987 Farkas and Munro data set. This study establishes updated cephalic index values for infants and children in a large, diverse patient population.

Methods:

Children aged 0 to 3 months, 3 to 6 months, 9 to 12 months, 2 to 3 years, and 12 to 14 years were recruited at their well-child appointment. Cephalic index was calculated for each age group and compared to previously established norms.

Results:

Eight hundred seventy patients met inclusion criteria. The means for boys and girls between 0 and 6 months were 83.5 (n = 155, SD 6.01) and 83.5 (n = 191, SD 5.80), respectively. Established means for boys and girls between 0 and 6 months were 74.4 (n = 38, SD 5.2) and 74.3 (n = 49, SD 6.1), respectively. The difference between norms is highly statistically significant (p < 0.0001). For this age range, insurance criteria for a helmet is >83.7 for boys and >82.7 for girls. Using previous norms, 74 boys (44.6 percent) and 104 girls (54.5 percent) would meet criteria for a helmet under current guidelines.

Conclusions:

The mean cephalic index of children has changed. The reasons could include diversifying populations in the United States and the introduction of the Back to Sleep campaign. Over 50 percent of children may inappropriately meet criteria for a helmet based on prior norms. Updating norms could change the definition of plagiocephaly for a helmet orthosis.
Breast Augmentation with Microtextured Anatomical Implants in 653 Women: Indications and Risk of Rotation
Authors: Weltz Tim K. , Larsen Andreas , Hemmingsen Mathilde N. , Ørholt Mathias , Rasmussen Louise E. , Andersen Peter S. , Sarmady Faye , Elberg Jens J. , Vester-Glowinski Peter V. , Herly Mikkel
Published: May 2021

Background:

Anatomical implants provide a wide range of options in terms of implant dimensions for breast augmentation. Nevertheless, many surgeons choose not to use anatomical implants due to the risk of rotation malposition and because their advantages over round implants are not clearly defined.

Methods:

A retrospective review of medical records was performed on all women who underwent breast augmentation or implant exchange with microtextured anatomical implants from 2012 to 2019 in a single private clinic. The authors focused on the outcomes of a subgroup of women with glandular ptosis and nipple placement below the inframammary fold who underwent breast augmentation with anatomical implants. Furthermore, the incidence and risk factors for implant rotation were analyzed.

Results:

In total, 653 women underwent primary breast augmentation (n = 529) or implant exchange (n = 124) with anatomical implants. The median follow-up period was 2.7 years (interquartile range, 1.6 to 3.9 years). The incidence of implant rotation was 14 (2.6 percent) in the primary augmentation group and four (3.2 percent) in the implant exchange group. Implant rotation was not associated with type of surgery (p = 0.76), implant projection (p = 0.23), or implant height (p = 0.48). The authors successfully used anatomical implants to elevate the nipple in 92.9 percent of the women with glandular ptosis without using a mastopexy.

Conclusions:

The study results indicate that the rotation risk with microtextured implants is similar to that with macrotextured implants. Furthermore, the authors found that high-projection anatomical implants can be used as an alternative to augmentation-mastopexy in women with glandular ptosis.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Using an electronic health record alert to prompt blood-borne virus testing in primary care
Authors: Chadwick David , Forbes Gareth , Lawrence Chris , Lorrimer Susan , van Schaik Paul
Published: May 2021

Background:

Late diagnosis of HIV, hepatitis B (HBV) and hepatitis C (HCV) remains relatively common in the UK and many people who present late have missed opportunities for testing in primary care. The objective was to assess the effectiveness and acceptance of a prototype application (BBV_TP1), embedded in a primary care electronic health record (EHR), to increase real-time blood-borne virus (BBV) testing.

Methods:

This prospective cohort study assessed BBV_TP1 in 14 general practices in North East England, in comparison with 54 similar practices in 2019. Rates of HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) testing in practices were measured before and after the application was activated. Patient and clinician acceptance of the technology was assessed by surveys.

Results:

In the 6 months following the intervention, HIV testing rates increased 555% and combined HBV/HCV testing rates increased 362%. No significant differences were observed for any BBV testing rates in the nonintervention practices over the same period. Monthly testing rates declined towards baseline after initial increases. Clinician's perceptions of the prompt system were positive, with average additional time required for BBV test discussion in consultations estimated at 2 min. The patient survey also showed high acceptance of the technology.

Conclusion:

This pilot study demonstrated that BBV_TP1 increased BBV testing rates in primary care via targeted screening, although testing rates subsequently fell whilst the application remained active. Such systems can potentially reduce late diagnoses, while having high acceptance by clinicians and patients. Larger studies with longer follow-up are needed to demonstrate efficacy and cost-effectiveness.
Comparison Between Veteran and Non-Veteran Populations With Clinical Stage I Non-small Cell Lung Cancer Undergoing Surgery
Authors: Heiden Brendan T. , Eaton Daniel B. , Chang Su-Hsin , Yan Yan , Schoen Martin W. , Patel Mayank R. , Kreisel Daniel , Nava Ruben G. , Meyers Bryan F. , Kozower Benjamin D. , Puri Varun
Published: May 2021

Objective:

The aim of this study was to compare quality of care and outcomes between Veteran and non-Veteran patients undergoing surgery for clinical stage I non-small cell lung cancer (NSCLC).

Background:

Prior studies and the lay media have questioned the quality of care that Veterans with lung cancer receive through the VHA. We hypothesized Veterans undergoing surgery for early-stage NSCLC receive high quality care and have similar outcomes compared to the general population.

Methods:

We performed a retrospective cohort study of patients with clinical stage I NSCLC undergoing resection from 2006 to 2016 using a VHA dataset. Propensity score matching for baseline patient- and tumor-related variables was used to compare operative characteristics and outcomes between the VHA and the National Cancer Database (NCDB).

Results:

The unmatched cohorts included 9981 VHA and 176,304 NCDB patients. The VHA had more male, non-White patients with lower education levels, higher incomes, and higher Charlson/Deyo scores. VHA patients had inferior unadjusted 30-day mortality (VHA 2.1% vs NCDB 1.7%, P = 0.011) and median overall survival (69.0 vs 88.7 months, P < 0.001). In the propensity matched cohort of 6792 pairs, VHA patients were more likely to have minimally invasive operations (60.0% vs 39.6%, P < 0.001) and only slightly less likely to receive lobectomies (70.1% vs 70.7%, P = 0.023). VHA patients had longer lengths of stay (8.1 vs 7.1 days, P < 0.001) but similar readmission rates (7.7% vs 7.0%, P = 0.132). VHA patients had significantly better 30-day mortality (1.9% vs 2.8%, P < 0.001) and median overall survival (71.4 vs 65.2 months, P < 0.001).

Conclusions:

Despite having more comorbidities, Veterans receive exceptional care through the VHA with favorable outcomes, including significantly longer overall survival, compared to the general population.
Chemoradiotherapy Followed by Active Surveillance Versus Standard Esophagectomy for Esophageal Cancer
Authors: van der Wilk Berend J. , Eyck Ben M. , Hofstetter Wayne L. , Ajani Jaffer A. , Piessen Guillaume , Castoro Carlo , Alfieri Rita , Kim Jong H. , Kim Sung-Bae , Furlong Heidi , Walsh Thomas N. , Nieboer Daan , Wijnhoven Bas P. L. , Lagarde Sjoerd M. , Lanschot J. Jan B. van
Published: May 2021

Objective:

To compare overall survival of patients with a cCR undergoing active surveillance versus standard esophagectomy.

Summary of Background Data:

One-third of patients with esophageal cancer have a pathologically complete response in the resection specimen after neoadjuvant chemoradiotherapy. Active surveillance may be of benefit in patients with cCR, determined with diagnostics during response evaluations after chemoradiotherapy.

Methods:

A systematic review and meta-analysis was performed comparing overall survival between patients with cCR after chemoradiotherapy undergoing active surveillance versus standard esophagectomy. Authors were contacted to supply individual patient data. Overall and progression-free survival were compared using random effects meta-analysis of randomized or propensity score matched data. Locoregional recurrence rate was assessed. The study-protocol was registered (PROSPERO: CRD42020167070).

Results:

Seven studies were identified comprising 788 patients, of which after randomization or propensity score matching yielded 196 active surveillance and 257 standard esophagectomy patients. All authors provided individual patient data. The risk of all-cause mortality for active surveillance was 1.08 [95% confidence interval (CI): 0.62–1.87, P = 0.75] after intention-to-treat analysis and 0.93 (95% CI: 0.56–1.54, P = 0.75) after per-protocol analysis. The risk of progression or all-cause mortality for active surveillance was 1.14 (95% CI: 0.83–1.58, P = 0.36). Five-year locoregional recurrence rate during active surveillance was 40% (95% CI: 26%–59%). 95% of active surveillance patients undergoing postponed esophagectomy for locoregional recurrence had radical resection.

Conclusions:

Overall survival was comparable in patients with cCR after chemoradiotherapy undergoing active surveillance or standard esophagectomy. Diagnostic follow-up is mandatory in active surveillance and postponed esophagectomy should be offered to operable patients in case of locoregional recurrence.
Single dose of BNT162b2 mRNA vaccine against SARS-CoV-2 induces high frequency of neutralising antibody and polyfunctional T-cell responses in patients with myeloproliferative neoplasms
Authors: Harrington Patrick , de Lavallade Hugues , Doores Katie J. , O’Reilly Amy , Seow Jeffrey , Graham Carl , Lechmere Thomas , Radia Deepti , Dillon Richard , Shanmugharaj Yogita , Espehana Andreas , Woodley Claire , Saunders Jamie , Curto-Garcia Natalia , O’Sullivan Jennifer , Raj Kavita , Kordasti Shahram , Malim Michael H. , Harrison Claire , McLornan Donal
Published: May 2021

Encouraging results have been observed from initial studies evaluating vaccines targeting the novel beta coronavirus which causes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, concerns have been raised around the efficacy of these vaccines in immunosuppressed populations, including patients with haematological malignancy. Myeloproliferative neoplasms (MPN), in particular myelofibrosis (MF), are associated with heterogenous immune defects which are influenced by patient age, disease subtype and the use of cytoreductive therapies. Patients with a WHO defined diagnosis of an MPN presenting to our clinic were recruited following first injection of 30μg BNT162b2. A positive anti-S IgG ELISA was seen in 76.1% (16) of patients following vaccination with positive neutralising antibodies detected in 85.7% (18) of patients. A memory T cell response was observed in 80% (16) of patients, with a CD4+ T cell response in 75% (15) and a CD8+ T cell response in 35% (7). These results, for the first time, provide some reassurance regarding the initial immune response to the BNT162b2 vaccine amongst patients with MPN, with response rates similar to that observed in the general population.
Physical activity promotion is lacking in local treatment protocols for patients hospitalized with myocardial infarction: A cross-sectional study
Authors: van Oorsouw R. , Koenders N. , Seeger J.P. , Hoogeboom T.J.
Published: May 2021

Objectives

To describe the content and methodological quality of local physiotherapy and nursing treatment protocols specifically regarding physical activity promotion in patients hospitalised with myocardial infarction.

Design

Cross-sectional study comprising the analysis of 18 physiotherapy and 14 nursing protocols.

Setting

Protocols from twenty Dutch hospitals were used.

Main outcome measures

Data were extracted from protocols for patients hospitalised with myocardial infarction according to a standardized data-extraction procedure. Descriptive statistics were used to describe the content of protocols, in specific, treatment goals, interventions, clinimetrics and discharge criteria. Methodological quality of the protocols was examined using the AGREE-II tool.

Results

Therapeutic goals concerning physical activity were described in 83% of the physiotherapy protocols and in 7% of the nursing protocols. Therapeutic interventions concerning physical activity were described in 100% of the physiotherapy protocols and in 57% of the nursing protocols. Two (14%) of the fourteen interventions described in the physiotherapy protocols and none in the nursing protocols, were interpreted as physical activity promotion. All protocols were rated as having low methodological quality, mainly due to a lack of supporting scientific evidence. The overall quality was rated with an average score of 3 out of 7 (range: 1-5).

Conclusions

Physiotherapy and nursing protocols for hospitalized patients with myocardial infarction are primarily aimed at physical activity under supervision, rather than physical activity promotion. Our work provides physiotherapists and nurses insights in how to further improve the content and methodological quality of their local treatment protocols for patients hospitalised with myocardial infarction.
Risk of COVID-19 infection and work place exposure of front-line mass media professionals
Authors: Tahura Sarabon , Banu Bilkis , Akter Nasrin , Hossain Sarder Mahmud , Mahumud Rashidul Alam , Ahmed Md Rishad
Published: May 2021

Introduction

Mass media plays a crucial role in creating awareness and knowledge sharing in this Corona virus disease 2019 (COVID-19) pandemic. However, the risk of exposure and extent of COVID-19 infection among media professional are less elucidated yet. Therefore, this study was intended to investigate the workplace-related risk of COVID-19 exposure and the association between exposure to COVID-19 and participant’s characteristics, including various forms of respiratory protection for mass-media professionals.

Methods

This closed web-based cross-sectional survey was conducted among 199 mass-media professionals in Bangladesh by snowball sampling approach. A multivariate logistic regression model was used for the analytical exploration. Adjusted and Unadjusted Odds Ratio (OR) with 95% confidence intervals (95% CI) were calculated for the specified exposures. Chi-square test was used to observe the association. Ethical issues were maintained according to the guidance of the declaration of the Helsinki.

Results

Of all, 39.2% of mass-media professionals were tested positive for COVID-19, whereas 6% of symptomatic or suspected participants did not do the test. Mass media professionals who worked in electronic media reported more COVID-19 infection (adjusted odds ratio, AOR= 6.25; 95% Confidence interval: Lower limit 1.43, upper limit 27.43; P =0.02). However, no significant relationship was found between the type of job role and COVID-19 infection. Furthermore, infected colleagues (OR/P=1.92/0.04) were identified as significant contact of acquiring infection. However, the study result showed that reused/new medical mask, homemade/cloth-made mask (vs. use of respirator mask) was not significantly (p=0.82) associated with mass media professional’s infection.

Conclusions

Professionals working in electronic media were at higher risk of being infected by COVID-19 and mostly acquired from infected colleagues. Using a respirator mask was not associated with a lower risk of test positive infection in mass media professionals. This study will aid the policy maker and public health authorities during the COVID-19 pandemic to make proper implementation strategies.
No difference in cognitive task-related oscillations between human internal globus pallidus and subthalamic nucleus
Authors: Navid Muhammad Samran , Kammermeier Stefan , Niazi Imran K. , Sharma Vibhash D. , Vuong Shawn M. , Greenlee Jeremy D. W. , Singh Arun
Published: May 2021

Recently it has been acknowledged that the basal ganglia nuclei play a major role in cognitive control; however, the contribution by their network remains unclear. Previous studies have demonstrated the role of the subthalamic nucleus (STN) in cognitive processing and suggested that its connections to cortical and other associated regions regulate response inhibition during conflict conditions. By contrast, the role of the internal globus pallidus (GPi) as the output nucleus before the thalamic relay has not yet been investigated during cognitive processing. We recorded local field potentials (LFPs) from externalized deep brain stimulation (DBS) electrodes implanted bilaterally in the GPi (n=9 participants with dystonia) and STN (n=8 participants with Parkinson’s disease (PD)) during a primed flanker task. Both dystonia (GPi group) and PD participants (STN group) responded faster to the congruent trials than the incongruent trials. Overall, the dystonic GPi group was significantly faster than the PD STN group. LFPs showed elevated cue-triggered theta (3-7 Hz) power in GPi and STN groups in a similar way. Response-triggered LFP beta power (13-25 Hz) was significantly increased in the GPi group compared to the STN group. Results demonstrate that GPi activity appears to be critical in the cognitive processing of action selection and response during the presence of conflict tasks similar to the STN group. As both GPi and STN nuclei are involved in cognitive processing; therefore, these nuclei may be targeted for neuromodulation to improve cognitive control via DBS.
ADVANCED AUTOLOGOUS LOWER DERMAL SLING TECHNIQUE FOR IMMEDIATE BREAST RECONSTRUCTION SURGERY IN SMALL AND NON-PTOTIC BREASTS
Authors: Koppiker Chaitanyanand B. , Noor Aijaz Ul , Dixit Santosh , Busheri Laleh , Sharan Gautam , Dhar Upendra , Allampati Hari Kiran , Nare Smeeta , Gangurde Nutan
Published: May 2021

Background

Breast reconstruction with an autologous lower dermal sling (ALDS) is an established one-stage procedure in patients with moderate to large ptotic breasts. However, this technique is difficult to perform in small and non/minimally ptotic breasts. We describe our experiences from a single institution about a novel Advanced Autologous Lower Dermal Sling (A-ALDS) technique for reconstruction in small breasts.

Methods

We performed one stage nipple/skin sparing mastectomies in 61 patients with immediate reconstruction either by conventional immediate breast reconstruction surgery or A-ALDS technique.

Results

Mean age of study patients was 46.9 years. We observed significantly better cosmetic score and lower immediate complication rate vis-a-vis skin necrosis, implant loss with the A-ALDS technique (i.e., nil versus 3 in Conventional Immediate Breast Reconstruction Surgery - IBRS). 40 patients completed 12 months follow-up. The PROMs-Patient Reported Outcomes Measures (Breast-Q) revealed good to excellent scores for satisfaction with breast, cosmetic outcome and psychosocial well-being in patients operated with both these techniques. However, sexual well-being was significantly better in the A-ALDS group.

Conclusion

The A-ALDS is a novel, cost-effective and safe technique for immediate one stage implant-based reconstruction for small breasts. It provides a dermal barrier flap and hence, ensures less complications, excellent cosmetic results and patient satisfaction.
Dual G9A and EZH2 inhibition stimulates an anti-tumour immune response in ovarian high-grade serous carcinoma
Authors: Spiliopoulou Pavlina , Spear Sarah , Mirza Hasan , Garner Ian , McGarry Lynn , Grundland-Freile Fabio , Cheng Zhao , Ennis Darren P. , McNamara Sophie , Natoli Marina , Mason Susan , Blyth Karen , Adams Peter D. , Roxburgh Patricia , Fuchter Matthew J. , Brown Bob , McNeish Iain A.
Published: May 2021

Ovarian high-grade serous carcinoma (HGSC) prognosis correlates directly with presence of intratumoral lymphocytes. However, cancer immunotherapy has yet to achieve meaningful survival benefit in patients with HGSC. Epigenetic silencing of immunostimulatory genes is implicated in immune evasion in HGSC and re-expression of these genes could promote tumour immune clearance. We discovered that simultaneous inhibition of the histone methyltransferases G9A and EZH2 activates the CXCL10-CXCR3 axis and increases homing of intratumoral effector lymphocytes and natural killer cells whilst suppressing tumour-promoting FoxP3+ CD4 T cells. The dual G9A/EZH2 inhibitor HKMTI-1-005 induced chromatin changes that resulted in the transcriptional activation of immunostimulatory gene networks, including the re-expression of elements of the ERV-K endogenous retroviral family. Importantly, treatment with HKMTI-1-005 improved the survival of mice bearing Trp53-/-null ID8 ovarian tumours and resulted in tumour burden reduction.

These results indicate that inhibiting G9A and EZH2 in ovarian cancer alters the immune microenvironment and reduces tumour growth and therefore positions dual inhibition of G9A/EZH2 as a strategy for clinical development.

Abstract Figure
Infection and vaccine-induced neutralizing antibody responses to the SARS-CoV-2 B.1.617.1 variant
Authors: Edara Venkata-Viswanadh , Lai Lilin , Sahoo Malaya K. , Floyd Katharine , Sibai Mamdouh , Solis Daniel , Flowers Maria W. , Hussaini Laila , Ciric Caroline Rose , Bechnack Sarah , Stephens Kathy , Mokhtari Elham Bayat , Mudvari Prakriti , Creanga Adrian , Pegu Amarendra , Derrien-Colemyn Alexandrine , Henry Amy R. , Gagne Matthew , Graham Barney S. , Wrammert Jens , Douek Daniel C. , Boritz Eli , Pinsky Benjamin A. , Suthar Mehul S.
Published: May 2021

SARS-CoV-2 has caused a devastating global pandemic. The recent emergence of SARS-CoV-2 variants that are less sensitive to neutralization by convalescent sera or vaccine-induced neutralizing antibody responses has raised concerns. A second wave of SARS-CoV-2 infections in India is leading to the expansion of SARS-CoV-2 variants. The B.1.617.1 variant has rapidly spread throughout India and to several countries throughout the world. In this study, using a live virus assay, we describe the neutralizing antibody response to the B.1.617.1 variant in serum from infected and vaccinated individuals. We found that the B.1.617.1 variant is 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and Moderna and Pfizer vaccinated individuals. Despite this, a majority of the sera from convalescent individuals and all sera from vaccinated individuals were still able to neutralize the B.1.617.1 variant. This suggests that protective immunity by the mRNA vaccines tested here are likely retained against the B.1.617.1 variant. As the B.1.617.1 variant continues to evolve, it will be important to monitor how additional mutations within the spike impact antibody resistance, viral transmission and vaccine efficacy.
High Dose Convalescent Plasma in COVID-19: Results from the Randomized Trial CAPSID
Authors: Körper Sixten , Weiss Manfred , Zickler Daniel , Wiesmann Thomas , Zacharowski Kai , M.Corman Victor , Grüner Beate , Ernst Lucas , Spieth Peter , Lepper Philipp M. , Bentz Martin , Zinn Sebastian , Paul Gregor , Kalbhenn Johannes , Dollinger Matthias , Rosenberger Peter , Kirschning Thomas , Thiele Thomas , Appl Thomas , Mayer Benjamin , Schmidt Michael , Drosten Christian , Wulf Hinnerk , Kruse Jan Matthias , Jungwirth Bettina , Seifried Erhard , Schrezenmeier Hubert ,   for the CAPSID Clinical Trial Group
Published: May 2021

Rationale

COVID-19 convalescent plasma (CCP) has been considered a treatment option in COVID-19.

Objectives

To assess the efficacy of neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment.

Methods

Patients (n=105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. Primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21. The trial is registered: clinicaltrials.gov #NCT04433910.

Measurements and main results

The primary outcome occurred in 43.4% of patients in the CCP and 32.7% in the control group (p=0.32). The median time to clinical improvement was 26 days (IQR 15-not reached (n.r.)) in the CCP group and 66 days (IQR 13-n.r.) in the control group (p=0.27). Median time to discharge from hospital was 31 days (IQR 16-n.r.) in the CCP and 51 days (IQR 20–n.r.) in the control group (p=0.24). In the subgroup that received a higher cumulative amount of neutralizing antibodies the primary outcome occurred in 56.0% (versus 32.1%), with a shorter interval to clinical improvement, shorter time to hospital discharge and better survival compared to the control group.

Conclusion

CCP added to standard treatment did not result in a significant difference in the primary and secondary outcomes. A pre-defined subgroup analysis showed a significant benefit for CCP among those who received a larger amount of neutralizing antibodies.
Sex-Specific Function and Morphology of the Anterior Cruciate Ligament During Skeletal Growth in a Porcine Model
Authors: Howe Danielle , Cone Stephanie G. , Piedrahita Jorge A. , Collins Bruce , Fordham Lynn A. , Griffith Emily H. , Spang Jeffrey T. , Fisher Matthew B.
Published: May 2021

Pediatric anterior cruciate ligament (ACL) injuries are on the rise, and females experience higher ACL injury risk than males during adolescence. Studies in skeletally immature patients indicate differences in ACL size and joint laxity between males and females after the onset of adolescence. However, functional data regarding the ACL and its anteromedial and posterolateral bundles in the pediatric population remain rare. Therefore, this study uses a porcine model to investigate the sex-specific morphology and function of the ACL and its bundles throughout skeletal growth. Hind limbs from male and female Yorkshire pigs aged early youth to late adolescence were imaged using magnetic resonance imaging to measure the size and orientation of the ACL and its bundles, then biomechanically tested under anterior-posterior drawer using a robotic testing system. Joint laxity decreased (p<0.001) while joint stiffness increased (p<0.001) throughout skeletal growth in both sexes. The ACL was the primary stabilizer against anterior tibial loading in all specimens, while the functional role of the anteromedial bundle increased with age (p<0.001), with an earlier shift in males. ACL and posterolateral bundle cross-sectional area and ACL and anteromedial bundle length were larger in males than females during adolescence (p<0.01 for all), while ACL and bundle sagittal angle remained similar between sexes. Additionally, in situ ACL stiffness correlated with cross-sectional area across skeletal growth (r2=0.75, p<0.001 in males and r2=0.64, p<0.001 in females), but not within age groups. This study has implications for age and sex-specific surgical intervention strategies and suggests the need for human studies.
O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation
Authors: Ciraku Lorela , Bacigalupa Zachary A. , Ju Jing , Moeller Rebecca A. , Lee Rusia H. , Smith Michael D. , Ferrer Christina M. , Trefely Sophie , Doan Mary T. , Gocal Wiktoria A. , D’Agostino Luca , Shi Wenyin , Jackson Joshua G. , Katsetos Christos D. , Snyder Nathaniel W. , Reginato Mauricio J.
Published: May 2021

Glioblastomas (GBMs) preferentially generate acetyl-CoA from acetate as a fuel source to promote tumor growth. O-GlcNAcylation has been shown to be elevated by increasing O-GlcNAc transferase (OGT) in many cancers and reduced O-GlcNAcylation can block cancer growth. Here, we identify a novel mechanism whereby OGT regulates acetate-dependent acetyl-CoA production by regulating phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5). OGT is required and sufficient for GBM cell growth and regulates acetate conversion to acetyl-CoA. Elevating O-GlcNAcylation in GBM cells increases phosphorylation of ACSS2 on Ser-267 in a CDK5-dependent manner. Importantly, we show that ACSS2 Ser-267 phosphorylation regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Importantly, we show that pharmacologically targeting OGT and CDK5 reduces GBM growth ex vivo. Thus, the OGT/CDK5/ACSS2 pathway may be a way to target altered metabolic dependencies in brain tumors.
A common SEC23B missense mutation in congenital dyserythropoietic anemia type II leads to growth restriction and symptoms of chronic pancreatitis in mice
Authors: Wei Wei , Liu Zhigang , Zhang Chao , Khoriaty Rami , Zhu Min , Zhang Bin
Published: May 2021

Human loss-of-function mutations in SEC23B result in congenital dyserythropoietic anemia type II (CDAII). Complete deficiency of SEC23B in mice leads to perinatal death caused by massive degeneration of professional secretory tissues. Functions of SEC23B in postnatal mice are unclear. In this study, we generated knockout (KO) mice with deletion of exons 5 and 6 of Sec23b and knockin (KI) mice with the E109K mutation, the most common CDAII missense mutation. Despite decreased SEC23B protein level, Sec23bki/ki mice showed no obvious abnormalities. Hemizygous (Sec23bki/ko) mice exhibit a partial lethal phenotype, with only half of expected mice survive past weaning. Sec23bki/ko pancreas had exocrine insufficiency and chronic pancreatitis histology, as well as increased ER stress and apoptosis. Moreover, Sec23bki/ko mice exhibited severe growth restriction accompanied by growth hormone (GH) insensitivity, reminiscent of the Laron syndrome. Growth restriction is not associated with hepatocyte-specific Sec23b deletion, suggesting non-liver origin of the phenotype. Inflammation associated with chronic pancreatic deficiency may explain GH insensitivity in Sec23bki/ko mice. Our results indicate that phenotype severities are linked to the residual functions of SEC23B, demonstrating the importance of SEC23B in pancreatic acinar function in adult mice. The Sec23bki/ko mice provide a novel model of chronic pancreatitis and growth retardation.
Convergent and divergent structural and functional brain abnormalities associated with developmental dyslexia: a cross-linguistic meta-analysis of neuroimaging studies
Authors: Yan Xiaohui , Jiang Ke , Li Hui , Wang Ziyi , Perkins Kyle , Cao Fan
Published: May 2021

Brain abnormalities in the reading network have been repeatedly reported in individuals with developmental dyslexia (DD); however, it is still not totally understood where and why the structural and functional abnormalities are consistent/inconsistent across languages. In the current multimodal meta-analysis, we found convergent structural and functional alterations in the left superior temporal gyrus across languages, suggesting a neural signature of DD. We found greater reduction in grey matter volume and brain activation in the left inferior frontal gyrus in morpho-syllabic languages (e.g. Chinese) than in alphabetic languages, and greater reduction in brain activation in the left middle temporal gyrus and fusiform gyrus in alphabetic languages than in morpho-syllabic languages. These language differences are explained as consequences of being DD while learning a specific language. In addition, we also found brain regions that showed increased grey matter volume and brain activation, presumably suggesting compensations and brain regions that showed inconsistent alterations in brain structure and function. Our study provides important insights about the etiology of DD from a cross-linguistic perspective with considerations of consistency/inconsistency between structural and functional alterations.
Comparative transcriptome analysis of human and murine choroidal neovascularization identifies fibroblast growth factor inducible-14 as phylogenetically conserved mediator of neovascular age-related macular degeneration
Authors: Wolf Julian , Schlecht Anja , Rosmus Dennis-Dominik , Boneva Stefaniya , Agostini Hansjürgen , Schlunck Günther , Wieghofer Peter , Lange Clemens
Published: May 2021

Background

Visual outcome of patients with neovascular age-related macular degeneration has significantly improved during the last years following the introduction of anti-vascular endothelial growth factor (VEGF) therapy. However, about one third of patients show persistent exudation and decreasing visual acuity despite recurrent anti-VEGF treatment, which implies a role of other, still unknown proangiogenic mediators.

Methods

The present study applied transcriptional profiling of human and mouse (C57BL/6J wildtype) choroidal neovascularization (CNV) membranes each with reference to healthy control tissue to identify yet unrecognized mediators of CNV formation. Key factors were further investigated by immunohistochemistry as well as by intravitreal inhibition experiments and multiplex protein assays in the laser-induced CNV mouse model.

Results

Transcriptional profiles of CNV membranes were characterized by enhanced activation of blood vessel development, cytoskeletal organization, and cytokine production, with angiogenesis and wound healing processes predominating in humans and activation of immune processes in mice. Besides several species-specific factors, 95 phylogenetically conserved CNV-associated genes were detected, among which fibroblast growth factor inducible-14 (FN14), a member of the tumor necrosis factor (TNF) receptor family, was identified as a key player of CNV formation. Blocking the pathway by intravitreal injection of a FN14 decoy receptor modulated the cytokine profile - most notably IL-6 - and led to a significant reduction of CNV size in vivo.

Conclusions

This study characterizes the transcriptome of human and mouse CNV membranes in an unprejudiced manner and identifies FN14 as a phylogenetically conserved mediator of CNV formation and a promising new therapeutic target for neovascular AMD.

Funding

This study was funded by the Helmut-Ecker-Stiftung and the Volker-Homann-Stiftung.
Neural codes in early sensory areas maximize fitness
Authors: Schaffner Jonathan , Tobler Philippe N. , Hare Todd A. , Polania Rafael
Published: May 2021

It has generally been presumed that sensory information encoded by a nervous system should be as accurate as its biological limitations allow. However, perhaps counter intuitively, accurate representations of sensory signals do not necessarily maximize the organism’s chances of survival. To test this hypothesis, we developed a unified normative framework for fitness-maximizing encoding by combining theoretical insights from neuroscience, computer science, and economics. Initially, we applied predictions of this model to neural responses from large monopolar cells (LMCs) in the blowfly retina. We found that neural codes that maximize reward expectation—and not accurate sensory representations—account for retinal LMC activity. We also conducted experiments in humans and find that early sensory areas flexibly adopt neural codes that promote fitness maximization in a retinotopically-specific manner, which impacted decision behavior. Thus, our results provide evidence that fitness-maximizing rules imposed by the environment are applied at the earliest stages of sensory processing.
ALKBH5 regulates somatic cell reprogramming in a phase specific manner
Authors: Khodeer Sherif , Klungland Arne , Dahl John Arne
Published: May 2021

Establishment of the pluripotency regulatory network in somatic cells by introducing four transcriptional factors, (Octamer binding transcription factor 4 (OCT4), SRY (sex determining region Y)-box 2 (SOX2), Kruppel - like factor 4 (KLF4), and cellular-Myelocytomatosis (c-MYC) provides a promising tool for cell-based therapies in regenerative medicine. Still, the mechanisms at play when generating induced pluripotent stem cells from somatic cells is only partly understood. Here we show that the RNA specific N6-methyladenosine (m6A) demethylase ALKBH5 regulates somatic cell reprogramming in a stage specific manner. Knockdown or knockout of Alkbh5 in the early reprogramming phase impairs the reprogramming efficiency by reducing the proliferation rate through arresting the cells at G2/M phase and decreasing the mesenchymal-to-epithelial transition (MET) rate. However, there is no significant change in reprogramming efficiency when Alkbh5 is depleted at the late phase of reprogramming. On the other hand, ALKBH5 overexpression at the earlyreprogramming phase has no significant impact on reprogramming efficiency, while overexpression at the late phase enhances the reprogramming by stabilizing Nanog transcripts resulting in upregulated Nanog expression. Our study provides mechanistic insight into the crucial dynamic role of ALKBH5 in regulating somatic cell reprogramming at the posttranscriptional level.
Quantitative monitoring of nucleotide sequence data from genetic resources in context of their citation in the scientific literature
Authors: Lange Matthias , Alako Blaise T.F. , Cochrane Guy , Ghaffar Mehmood , Mascher Martin , Habekost Pia-Katharina , Hillebrand Upneet , Scholz Uwe , Zunder Florian , Freitag Jens , Scholz Amber Hartman
Published: May 2021

Background

Linking nucleotide sequence data (NSD) to scientific publication citations can enhance understanding of NSDs provenance, scientific use, and re-use in the community. By connecting publications with NSD records, NSD geographical provenance information, and author geographical information, it becomes possible to assess the contribution of NSD to infer trends in scientific knowledge gain at the global level.

Findings

For this data note, we extracted and linked records from the European Nucleotide Archive to citations in open-access publications aggregated at Europe PubMed Central. A total of 8,464,292 ENA accessions with geographical provenance information were associated with publications. We conducted a data quality review to uncover potential issues in publication citation information extraction and author affiliation tagging and developed and implemented best-practice recommendations for citation extraction. Flat data tables and an data warehouse with an interactive web application were constructed to enable ad hoc exploration of NSD use and summary statistics.

Conclusions

The extraction and linking of NSD with associated publication citations enables transparency. The quality review contributes to enhanced text mining methods for identifier extraction and use. Furthermore, the global provision and use of NSD enables scientists around the world to join literature and sequence databases in a multidimensional fashion. As a concrete use case, statistics of country clusters were visualized with respect to NSD access in the context of discussions around digital sequence information under the United Nations Convention on Biological Diversity.
Post-glacial expansion dynamics, not refugial isolation, shaped the genetic structure of a migratory bird, the yellow warbler
Authors: Miller Eleanor F. , Leonardi Michela , Xue Zhe , Beyer Robert , Krapp Mario , Somveille Marius , Somma Gian Luigi , Delser Pierpaolo Maisano , Manica Andrea
Published: May 2021

During the glacial periods of the Pleistocene, swathes of the Northern Hemisphere were covered by ice sheets, tundra, and permafrost, leaving large areas uninhabitable for temperate and boreal species. The glacial refugia paradigm proposes that, during glaciations, species living in the Northern Hemisphere were forced southwards, forming isolated populations that persisted in disjunct regions known as refugia. According to this hypothesis, as ice sheets retreated, species recolonised the continent from these glacial refugia, and the mixing of these lineages is responsible for modern patterns of genetic diversity. An alternative hypothesis is that complex genetic patterns could also arise simply from heterogenous post-glacial expansion dynamics, without separate refugia. Both mitochondrial and genomic data from the North American yellow warbler (Setophaga petechia)shows the presence of an eastern and western clade, a pattern often ascribed to the presence of two refugia. However, species distribution modelling (SDM) of the past range of this species fails to identify obvious refugia during the Last Glacial Maximum. Using a climate-informed spatial genetic modelling (CISGeM) framework, which allows us to integrate knowledge of past geographic ranges based on SDM, we reconstructed past population sizes, range expansions, and likely recolonisation dynamics of this species, generating spatially and temporally explicit demographic reconstructions. The model captures the empirical genetic structure despite including only a single, large glacial refugium. The observed contemporary population structure was generated during the expansion dynamics after the glaciation and is due to unbalanced rates of northward advance to the east and west linked to the melting of the icesheets. Thus, modern population structure in this species is consistent with expansion dynamics, and refugial isolation is not required to explain it, highlighting the importance of explicitly testing drivers of geographic structure.

Significance statement

Patterns of population differentiation in many species have often been attributed to the mixing of isolates from distinct refugia that formed during periods of glaciation, when range fragmentation was likely. By formally bringing together multiple lines of evidence, we demonstrate that the patterns of genetic diversity seen across the range of the yellow warbler (Setophaga petechia) were not the result of multiple isolated refugia. Instead, asymmetric expansion from a single cohesive range generated the observed patterns; the expansion’s asymmetry was due to the uneven melting of the icesheets over time. Thus, we demonstrate the importance of reconstructing species’ range dynamics when trying to explain patterns of genetic differentiation.
Biohybrid Microswimmers Against Bacterial Infections
Authors: Shchelik I. S. , Molino J. V. D. , Gademann K.
Published: May 2021

Biohybrid microswimmers exploit the natural abilities of motile microorganisms e.g. in releasing cargo on-demand with high spatial and temporal control. However, using such engineered swarms to deliver antibiotics addressing bacterial infections has not yet been realized. In the present study, a design strategy for biohybrid microswimmers is reported, which features the covalent attachment of antibiotics to the motile green algae Chlamydomonas reinhardtii via a photo-cleavable linker. The surface engineering of the algae does not rely on genetic manipulations, proceeds with high efficiency, does not impair the viability or phototactic ability of microalgae, and allows for caging of the antibiotic on the surface for subsequent release via external stimuli. Two different antibiotic classes have been separately utilized, which result in activity against both gram-positive and gram-negative strains. Guiding the biohybrid microswimmers by an external beacon, and on-demand delivery of the drugs by light with high spatial and temporal control, allowed for strong inhibition of bacterial growth in vivo. This efficient strategy could potentially allow for the selective treatment of bacterial infections by engineered algal microrobots with high precision in space and time. Overall, this work presents an operationally simple production of biohybrid microswimmers loaded with antibiotic cargo to combat bacterial infections precisely delivered in three-dimensional space.
E3 ubiquitin ligase RNF213 employs a non-canonical zinc finger active site and is allosterically regulated by ATP
Authors: Ahel Juraj , Fletcher Adam , Grabarczyk Daniel B. , Roitinger Elisabeth , Deszcz Luiza , Lehner Anita , Virdee Satpal , Clausen Tim
Published: May 2021

RNF213 is a giant E3 ubiquitin ligase and a major susceptibility factor of Moyamoya disease, a cerebrovascular disorder that can result in stroke or death. In the cell, RNF213 is involved in lipid droplet formation, lipotoxicity, hypoxia, and NF-κB signaling, but its exact function in these processes is unclear. Structural characterization has revealed the presence of a dynein- like ATPase module and an unprecedented but poorly understood E3 module. Here, we demonstrate that RNF213 E3 activity is dependent on ATP binding, rather than ATP hydrolysis, and is particularly responsive to the ATP/ADP/AMP ratio. Biochemical and activity-based probe analyses identify a non-canonical zinc finger domain as the E3 active site, which utilizes the strictly conserved Cys4462, not involved in zinc coordination, as the reactive nucleophile. The cryo-EM structure of the trapped RNF213:E2∼Ub intermediate reveals RNF213 C-terminal domain as the E2 docking site, which positions the ubiquitin-loaded E2 proximal to the catalytic zinc finger, facilitating nucleophilic attack of Cys4462 on the E2∼Ub thioester. Our findings show that RNF213 represents an undescribed type of a transthiolation E3 enzyme and is regulated by adenine nucleotide concentration via its ATPase core, possibly allowing it to react to changing metabolic conditions in the cell.
Transient exposure of a buried phosphorylation site in an autoinhibited protein
Authors: Orioli Simone , Henning Hansen Carl G. , Lindorff-Larsen Kresten
Published: May 2021

Autoinhibition is a mechanism used to regulate protein function, often by making functional sites inaccessible through the interaction with a cis-acting inhibitory domain. Such autoinhibitory domains often display a substantial degree of structural disorder when unbound, and only become structured in the inhibited state. This conformational dynamics makes it difficult to study the structural origin of regulation, including effects of regulatory post-translational modifications. Here, we study the autoinhibition of the Dbl Homology domain in the protein Vav1 by the so-called acidic inhibitory domain. We use molecular simulations to study the process by which a mostly unstructured inhibitory domain folds upon binding and how transient exposure of a key buried tyrosine residue makes it accessible for phosphorylation. We show that the inhibitory domain, which forms a helix in the bound and inhibited stated, samples helical structures already before binding and that binding occurs via a molten-globule-like intermediate state. Together, our results shed light on key interactions that enable the inhibitory domain to sample a finely-tuned equilibrium between an inhibited and a kinase-accessible state.