bluuebunny/crossref_metadata_2025 huggingface dataset:
EHF is essential for epidermal and colonic epithelial homeostasis, and suppresses Apc-initiated colonic tumorigenesis
Authors: Reehorst Camilla M. , Nightingale Rebecca , Luk Ian Y. , Jenkins Laura , Koentgen Frank , Williams David S. , Darido Charbel , Tan Fiona , Anderton Holly , Chopin Michael , Schoffer Kael , Eissmann Moritz F. , Buchert Michael , Mouradov Dmitri , Sieber Oliver M. , Ernst Matthias , Dhillon Amardeep S. , Mariadason John M.
Published: July 2021

Ets homologous factor (EHF) is a member of the epithelial-specific Ets (ESE) family of transcription factors. To investigate its role in development and epithelial homeostasis, we generated a series of novel mouse strains in which the Ets DNA-binding domain of Ehf was deleted in all tissues (Ehf−/−) or specifically in the gut epithelium. Ehf−/− mice were born at the expected Mendelian ratio, but showed reduced body weight gain, and developed a series of pathologies requiring most Ehf−/− mice to reach an ethical endpoint before reaching 1 year of age. These included papillomas in the facial skin, abscesses in the preputial glands (males) or vulvae (females), and corneal ulcers. Ehf−/−mice also displayed increased susceptibility to experimentally induced colitis, which was confirmed in intestinal-specific Ehf knockout mice. Gut-specific Ehf deletion also impaired goblet cell differentiation, induced extensive transcriptional reprogramming in the colonic epithelium and enhanced Apc-initiated adenoma development. The Ets DNA-binding domain of EHF is therefore essential for postnatal homeostasis of the epidermis and colonic epithelium, and its loss promotes colonic tumour development.
Current market rates for scholarly publishing services
Authors: Grossmann Alexander , Brembs Björn
Published: July 2021

For decades, the supra-inflation increase of subscription prices for scholarly journals has concerned scholarly institutions. After years of fruitless efforts to solve this “serials crisis”, open access has been proposed as the latest potential solution. However, also the prices for open access publishing are high and are rising well beyond inflation. What has been missing from the public discussion so far is a quantitative approach to determine the actual costs of efficiently publishing a scholarly article using state-of-the-art technologies, such that informed decisions can be made as to appropriate price levels. Here we provide a granular, step-by-step calculation of the costs associated with publishing primary research articles, from submission, through peer-review, to publication, indexing and archiving. We find that these costs range from less than US$200 per article in modern, large scale publishing platforms using post-publication peer-review, to about US$1,000 per article in prestigious journals with rejection rates exceeding 90%. The publication costs for a representative scholarly article today come to lie at around US$400. These results appear uncontroversial as they not only match previous data using different methodologies, but also conform to the costs that many publishers have openly or privately shared. We discuss the numerous additional non-publication items that make up the difference between these publication costs and final price at the more expensive, legacy publishers.
Case Report: Pseudomonas can take a toll on a patient
Authors: Buchbinder David K. , Singh Jasjit , Dao Tuan , Sassoon Aaron , Arrieta Antonio
Published: July 2021

Pseudomonas aeruginosa (P. aeruginosa) is an aerobic Gram-negative bacterium that is implicated in the development of severe systemic infections among pediatric patients.  It is identified in hospitalized chronically ill pediatric patients in association with genitourinary, respiratory tract, and skin or soft tissue infections as well as severe and life-threating infection including sepsis.  A variety of immunologic mechanisms play a vital role in the host defense mechanisms against invasive infections with P. aeruginosa. Rarely, specific inborn errors of immune function are implicated in deficiencies that predispose to invasive infections with P. aeruginosa.  Innate immune function including germ-line encoded pattern recognition receptors such as toll-like receptors (TLRs) and their downstream signaling is vital in the host defense against P. aeruginosa through the generation of antimicrobial peptides, cytokines/chemokines, and shaping of adaptive immune responses. Herein, we describe a previously healthy two-year-old female with an invasive skin, soft tissue, and central nervous system infection secondary to P. aeruginosa.  The invasive nature of this infection prompted a careful evaluation for an inborn error of immunity. Decreased cytokine response to agonists of TLRs was documented. Targeted sequencing of interleukin-1 receptor-associated kinase (IRAK)-4 documented a homozygous deletion of exons 8-13 consistent with IRAK-4 deficiency.  This report provides a vital educative message in the existing scientific literature by underscoring the importance of considering inborn errors of immunity in all patients with severe P. aeruginosa infections.  Functional assessments of immune function often in combination with sequencing can accurately assign a diagnosis in a timely fashion allowing for definitive treatment and the use of necessary supportive care.
DIE ATTRIBUTE DER REVALER KAUFLEUTE – EIN BLICK AUF DAS RETABEL DES MARIENALTARES DER BRUDERSCHAFT DER SCHWARZENHÄUPTER
Authors: Palginõmm Kerttu
Published: July 2021

The article focuses on the Tallinn (Reval) altarpiece of St. Mary's altar ofthe Brotherhood of the Blackheads, attributed to the Bruges Master ofthe Legend of St. Lucy, which arrived in the late medieval city in 1493.The altarpiece is noteworthy for its very dense network of luxuriousdetails like silk, velvet and gold cloth from Italy, ceramics from Spain,tapestries from Netherlands and an oriental carpet from Anatolia. Early

Netherlandish painting is notable for the very detailed, texture andlight-sensitive rendering of everyday and luxury objects, from whichthe works of Jan van Eyck are the best examples.
CARL JULIUS SENFF (1804–1832) ALS ARCHITEKT UND GRAFIKER. ERGÄNZUNGEN ZUR BAUGESCHICHTE DER UNIVERSITÄT ZU TARTU (DORPAT)
Authors: Ormisson-Lahe Anu , Tiideberg Kristiina
Published: July 2021

Carl Julius Senff (1804–1832) as an Architect and Graphic Arti st. Additionsto the Building Hi story of the University of Tartu Ensemble.
THE BALTIC PORTRAIT AND STILL LIFE PAINTER ALEXANDRA VON BERCKHOLTZ (1821–1899)
Authors: Gutgesell Natalie
Published: July 2021

The Baltic artist Alexandra von Berckholtz was among the mostimportant portrait painters of her time. However, her works haddisappeared from art-historical memory because, after her death, theywere sold and spread all over the world. An international researchproject started in 2014 was able to rediscover her works and her lifestory.Von Berckholtz was given her first art lessons in 1841 by the courtpainter Louis Wagner in Karlsruhe, Germany. From 1847 until 1854she studied in Paris at the studio of the history painter Joseph-NicolasRobert-Fleury, who had considerable influence on her pictorialstyle which combined realism and idealism. Another significantinfluence was Richard Lauchert, a former student and close friendof Franz Xaver Winterhalter. Von Berckholtz’s numerous travels,e.g. to Switzerland, France, and the Czech Republic, were also arich source of inspiration. She changed the conventions of nobilityportrait and concentrated on still lifes in her later work, in whichshe reflected the Dutch style of the Baroque period. Alexandra vonBerckholtz associated with important personalities from the fieldsof art, music, politics, and technology, and was socially active.
Cost of Cash: Evidence from Cashiers
Authors: Png I. P. L. , Tan Charmaine H. Y.
Published: July 2021

An important but overlooked cost of payments in retailing is the cost on checkout cashiers. This paper examines the compensating wage differential that cashiers require to handle payments in cash. First, a multicountry panel data study shows that cashier wages increase with retail cash usage, which is consistent with cashiers requiring compensation to handle cash. Second, in a discrete choice experiment where supermarket cashiers chose between collecting card and cash payments, eight of 10 cashiers preferred card to cash. Among those who preferred card, the median cashier required a wage premium of S$37.50 (US$27) a month to handle cash. The premium was lower among cashiers who are local, less risk averse, and younger. Third, in a laboratory study, subjects traded off earnings against stress. With higher frequency of cash payments, high earners experienced greater physiological stress than low earners. Earnings also increased with abilities in arithmetic and coping with stress. Collectively, these studies show that cashiers require higher wages to handle cash payments, in part due to higher stress. We offer policy, managerial, and research implications for job design, payment systems, and workplace stress.
A Novel, Eco-Friendly and Economical Process for Desalination of Water Using Waste Food Materials
Authors: Tandon Runjhun , Lzaod Stanzin , Singh Mandeep , Tandon Nitin , Majumdar Agnibha Das , Santra Soumava , Pramanik Tanay
Published: July 2021

Scarcity of water in this world can be solved by removal of salinity from sea-water but this salinity removal is usually a costly and tedious task. In this work an efficient process has been developed for desalination of water using food waste materials which is completely eco-friendly and economic. A large number of starch rich food materials have been employed for the purpose of desalination of water and it was observed that all of them are effective to remove the salt contained from water, however it was observed that all of those food materials were not equally effective to remove salt contained. Cornflour was seen to be most effective which can remove salinity from sea water up 75-80%. This technology has a great prospect to evolve as a novel and green method for the purpose of desalination of water in near future.
DE Fluoridation of Domestic Waste Water by using Activated Diatomaceous Earth in fixed Mattress Column Adsorption System
Authors: Kumar Pawan. , Gupta Pankaj.
Published: July 2021

Study aims to eliminate fluoride from treated waste water or ground water through adsorption technique by using Activated Diatomaceous Earth as a sorbent. Study found that there is no change in pH and TDS, but the concentration of Fluoride ions reduced. The most elimination potential of 71.97 mg/kg turned into achieved for activated diatomaceous earth with particle sizes of 0.075-0.425 mm. The absorbance capability of diatomaceous earth (DE) is 20.73% when used as a filtration media. In this analysis, activated diatomaceous earth was used as an adsorbent in a fixed-mattress column adsorption system for DE fluoridation of water. The XRD, BET surface area, FTIR, XRF, Scanning Electron Microscopy (SEM), and pH Point of Zero Charges (pHPZC) evaluation had been executed for adsorbent to explain the mechanisms of absorption and fluoride elimination. The Bradley equation was used to calculate the isothermal data and adsorbent dose. The statistical analyses were performed using Langmuir and Freundlich equations.
Transitional vertebrae and numerical variants of the spine
Authors: Sugiura Kosuke , Morimoto Masatoshi , Higashino Kosaku , Takeuchi Makoto , Manabe Akihiro , Takao Shoichiro , Maeda Toru , Sairyo Koichi
Published: July 2021

Aims

Although lumbosacral transitional vertebrae (LSTV) are well-documented, few large-scale studies have investigated thoracolumbar transitional vertebrae (TLTV) and spinal numerical variants. This study sought to establish the prevalence of numerical variants and to evaluate their relationship with clinical problems.

Methods

A total of 1,179 patients who had undergone thoracic, abdominal, and pelvic CT scanning were divided into groups according to the number of thoracic and lumbar vertebrae, and the presence or absence of TLTV or LSTV. The prevalence of spinal anomalies was noted. The relationship of spinal anomalies to clinical symptoms (low back pain, Japanese Orthopaedic Association score, Roland-Morris Disability Questionnaire) and degenerative spondylolisthesis (DS) was also investigated.

Results

Normal vertebral morphology (12 thoracic and five lumbar vertebrae without TLTV and LSTV) was present in 531 male (76.7%) and 369 female patients (75.8%). Thoracolumbar transitional vertebrae were present in 15.8% of males and 16.0% of females. LSTV were present in 7.1% of males and 9.0% of females. The prevalence of the anomaly of 16 presacral mobile vertebrae (total number of thoracolumbar vertebrae and TLTV) without LSTV was 1.0% in males and 4.1% in females, and that of the anomaly of 18 vertebrae without LSTV was 5.3% in males and 1.2% in females. The prevalence of DS was significantly higher in females with a total of 16 vertebrae than in those with normal morphology. There was no significant correlation between a spinal anomaly and clinical symptoms.

Conclusion

Overall, 24% of subjects had anomalies in the thoracolumbar region: the type of anomaly differed between males and females, which could have significant implications for spinal surgery. A decreased number of vertebrae was associated with DS: numerical variants may potentially be a clinical problem. Cite this article: Bone Joint J 2021;103-B(7):1301–1308.
Is there a problem with modular dual mobility acetabular components in revision total hip arthroplasty at mid-term follow-up?
Authors: Hernandez Nicholas M. , Hinton Zoe W. , Wu Christine J. , Lachiewicz Paul F. , Ryan Sean P. , Wellman Samuel S.
Published: July 2021

Aims

Modular dual mobility (MDM) acetabular components are often used with the aim of reducing the risk of dislocation in revision total hip arthroplasty (THA). There is, however, little information in the literature about its use in this context. The aim of this study, therefore, was to evaluate the outcomes in a cohort of patients in whom MDM components were used at revision THA, with a mean follow-up of more than five years.

Methods

Using the database of a single academic centre, 126 revision THAs in 117 patients using a single design of an MDM acetabular component were retrospectively reviewed. A total of 94 revision THAs in 88 patients with a mean follow-up of 5.5 years were included in the study. Survivorship was analyzed with the endpoints of dislocation, reoperation for dislocation, acetabular revision for aseptic loosening, and acetabular revision for any reason. The secondary endpoints were surgical complications and the radiological outcome.

Results

The overall rate of dislocation was 11%, with a six-year survival of 91%. Reoperation for dislocation was performed in seven patients (7%), with a six-year survival of 94%. The dislocations were early (at a mean of 33 days) in six patients, and late (at a mean of 4.3 years) in four patients. There were three intraprosthetic dissociations. An outer head diameter of ≥ 48 mm was associated with a lower risk of dislocation (p = 0.013). Lumbrosacral fusion was associated with increased dislocation (p = 0.004). Four revision THAs (4%) were further revised for aseptic acetabular loosening, and severe bone loss (Paprosky III) at the time of the initial revision was significantly associated with further revision for aseptic acetabular loosening (p = 0.008). Fourteen acetabular components (15%) were re-revised for infection, and a pre-revision diagnosis of reimplantation after periprosthetic joint infection (PJI) was associated with subsequent PJI (p < 0.001). Two THAs had visible metallic changes on the backside of the cobalt chromium liner.

Conclusion

When using this MDM component in revision THA, at a mean follow-up of 5.5 years, there was a higher rate of dislocation (11%) than previously reported. The size of the outer bearing was related to the risk of dislocation. There was a low rate of aseptic acetabular loosening. Longer follow-up of this MDM component and evaluation of other designs are warranted. Cite this article: Bone Joint J 2021;103-B(7 Supple B):66–72.
Early experience and patient-reported outcomes of 503 INFINITY total ankle arthroplasties
Authors: Townshend David N. , Bing Andrew J. F. , Clough Timothy M. , Sharpe Ian T. , Goldberg Andy ,   On behalf of the UK INFINITY study group
Published: July 2021

Aims

This is a multicentre, non-inventor, prospective observational study of 503 INFINITY fixed bearing total ankle arthroplasties (TAAs). We report our early experience, complications, and radiological and functional outcomes.

Methods

Patients were recruited from 11 specialist centres between June 2016 and November 2019. Demographic, radiological, and functional outcome data (Ankle Osteoarthritis Scale, Manchester Oxford Questionnaire, and EuroQol five-dimension five-level score) were collected preoperatively, at six months, one year, and two years. The Canadian Orthopaedic Foot and Ankle Society (COFAS) grading system was used to stratify deformity. Early and late complications and reoperations were recorded as adverse events. Radiographs were assessed for lucencies, cysts, and/or subsidence.

Results

In all, 500 patients reached six-month follow-up, 420 reached one-year follow-up, and 188 reached two-year follow-up. The mean age was 67.8 years (23.9 to 88.5). A total of 38 patients (7.5%) presented with inflammatory arthritis. A total of 101 (20.0%) of implantations used patient-specific instrumentation; 167 patients (33.1%) underwent an additional procedure at the time of surgery. A total of seven patients died of unrelated causes, two withdrew, and one was lost to follow-up. The mean follow-up was 16.2 months (6 to 36). There was a significant improvement from baseline across all functional outcome scores at six months, one, and two years. There was no significant difference in outcomes with the use of patient-specific instrumentation, type of arthritis, or COFAS type. Five (1.0%) implants were revised. The overall complication rate was 8.8%. The non-revision reoperation rate was 1.4%. The 30-day readmission rate was 1.2% and the one-year mortality 0.74%.

Conclusion

The early experience and complications reported in this study support the current use of the INFINITY TAA as a safe and effective implant in the treatment of end-stage ankle arthritis. Cite this article: Bone Joint J 2021;103-B(7):1270–1276.
2021 John Charnley Award: A protocol-based strategy when using hemiarthroplasty or total hip arthroplasty for femoral neck fractures decreases mortality, length of stay, and complications
Authors: Roberts Heather J. , Barry Jeffrey , Nguyen Kevin , Vail Thomas , Kandemir Utku , Rogers Stephanie , Ward Derek
Published: July 2021

Aims

While interdisciplinary protocols and expedited surgical treatment improve the management of hip fractures in the elderly, the impact of such interventions on patients specifically undergoing arthroplasty for a femoral neck fracture is not clear. We sought to evaluate the efficacy of an interdisciplinary protocol for the management of patients with a femoral neck fracture who are treated with an arthroplasty.

Methods

In 2017, our institution introduced a standardized interdisciplinary hip fracture protocol. We retrospectively reviewed adult patients who underwent hemiarthroplasty (HA) or total hip arthroplasty (THA) for femoral neck fracture between July 2012 and March 2020, and compared patient characteristics and outcomes between those treated before and after the introduction of the protocol.

Results

A total of 157 patients were treated before the introduction of the protocol (35 (22.3%) with a THA), and 114 patients were treated after its introduction (37 (32.5%) with a THA). The demographic details and medical comorbidities were similar in the two groups. Patients treated after the introduction of the protocol had a significantly reduced median time between admission and surgery (22.8 hours (interquartile range (IQR) 18.8 to 27.7) compared with 24.8 hours (IQR 18.4 to 43.3) (p = 0.042), and a trend towards a reduced mean time to surgery (24.1 hours (SD 10.7) compared with 46.5 hours (SD 165.0); p = 0.150), indicating reduction in outliers. Patients treated after the introduction of the protocol had a significantly decreased rate of major complications (4.4% vs 17.2%; p = 0.005), decreased median hospital length of stay in hospital (4.0 days vs 4.8 days; p = 0.008), increased rate of discharge home (26.3% vs 14.7%; p = 0.030), and decreased one-year mortality (14.7% vs 26.3%; p = 0.049). The 90-day readmission rate (18.2% vs 21.7%; p = 0.528) and 30-day mortality (3.7% vs 5.1%; p = 0.767) did not significantly differ. Patients who underwent HA were significantly older than those who underwent THA (82.1 years (SD 10.4) vs 71.1 years (SD 9.5); p < 0.001), more medically complex (mean Charlson Comorbidity Index 6.4 (SD 2.6) vs 4.1 (SD 2.2); p < 0.001), and more likely to develop delirium (8.5% vs 0%; p = 0.024).

Conclusion

The introduction of an interdisciplinary protocol for the management of elderly patients with a femoral neck fracture was associated with reduced time to surgery, length of stay, complications, and one-year mortality. Such interventions are critical in improving outcomes and reducing costs for an ageing population. Cite this article: Bone Joint J 2021;103-B(7 Supple B):3–8.
Assessment of referral complexity and case acceptance for NHS hospital orthodontic treatment
Authors: Sedgwick Matthew , Nirmal Heena , Bhamrah Gurprit
Published: July 2021

Introduction

NHS orthodontic service provision is restricted to those who present with the highest level of need. By auditing the complexity of referrals received and assessing those accepted by a hospital orthodontic department for treatment, we can quality assure the processes in place and demonstrate compliance with commissioning guidelines.

Methods

This was a prospective audit carried out over a 12-month period to assess referrals received between March 2019 and February 2020. The participants were all patients referred to the hospital orthodontic department. The index of orthodontic treatment need (IOTN) and index of orthognathic functional treatment need (IOFTN) were recorded, and an evaluation of treatment complexity was made according to current commissioning guidance. The standard set was that ≥80% of patients accepted for treatment should be complexity level 3b.

Results

A total of 610 patients were seen, with 597 referrals included in the dataset. Thirteen referrals (2%) were excluded owing to missing information. Just under two-thirds (60%) of referrals came from specialist orthodontists in practice, 34% from general dental practitioners, 3% from community dental services and 3% from other hospitals. Over half (56%) were IOTN grade 5, 32% were grade 4, 9% were grade 3 and 3% were grade 2. The majority (79%) of cases met complexity level 3b, 18% were level 3a and 4% were level 2. Overall, 33% were accepted for secondary care and 96% of these met complexity level 3b with 4% at level 3a.

Conclusions

The gold standard for case acceptance in secondary care was met. This audit demonstrates that cases of appropriate complexity are being accepted for treatment in our department, including training cases for specialty trainees.
Gender Equality and Sustainable Development in Nigeria: Issues and Challenges
Authors: Abolade Dupe Adesubomi
Published: July 2021

Purpose of the article: The objective of this study was to examine issues and challenges of gender equality in Nigeria in relation to the achievement of the desired sustainable development in the nation.Methodology: The study adopted survey research design. One hundred and sixty females were randomly selected from the State Secretariat, Ibadan as a sample population for the study. A set of self-structured questionnaire which had four sections were used as instrument for data collection. One hundred and forty properly filled questionnaire were analysed. Three hypotheses were generated and tested.Scientific aim: The study examined these three factors: socio-cultural factors, workplace discrimination and women participation in political activities in Nigeria to find out if there is equality between male and female genders in Nigeria that could translate to sustainable development in the nation.Findings: The study establishes that there is no equality between the genders; that women are discriminated against and they still play the second fiddle and that the inequality hinders the coveted sustainable development in the nation.Conclusion: It therefore recommends that the government and its agencies and employers of the workforce have the political will to include the female gender in the scheme of things and put them on the same level as their male counterparts for the achievement of development in the nation that will indeed be sustainable.
Delivery routes in pregnancy with COVID-19 and the risk of intrapartum vertical transmission: a meta-analysis
Authors: Sarastry Razmaeda , Layarta Crismanto , Aladini Ussisti , Pramono Besari Adi
Published: July 2021

BACKGROUND Mode of delivery has become an important highlight in managing pregnancy with coronavirus disease 2019 (COVID-19) due to the possible risk of viral transmission from mother to baby, especially during the peripartum period. This study aimed to review the mode of delivery and the possible risk of vertical transmission related to delivery routes in pregnant women with COVID-19.

METHODS Literature research was conducted using PubMed, Scopus, Embase, and EBSCO database with the following keywords: SARS-CoV-2, COVID-19, pregnancy, vertical transmission, and delivery. The extracted data were as follows: author, country, study design number of cases, maternal age, mode of delivery, and the SARS-CoV-2 status in neonates.

RESULTS Of 11 studies found, vaginal birth was reported in 218 cases (34.53%) and cesarean delivery was reported in 385 women (65.47%). The indication for cesarean delivery was majority due to COVID-19 related condition (53.61%). In total, 8 neonates who confirmed positive for COVID-19 by real-time polymerase chain reaction assay were reported. The pooled odds ratio (95% confidence interval) for SARS-CoV-2-positive neonates in cesarean delivery compared with vaginal birth was 0.622 (0.237–1.633) with p = 0.335.

CONCLUSIONS Cesarean delivery is more common than vaginal delivery in patient with SARS-CoV-2 infection. Any delivery route is not related to possible risk of intrapartum vertical transmission, and cesarean delivery should be carried out based on the obstetric indication.
Almanac: Diffraction & Reading Diffractively
Authors: Geerts Evelien , Van der Tuin Iris
Published: July 2021

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Single-cavity bi-color laser enabled by optical anti-parity-time symmetry
Authors: Duan Yao , Zhang Xingwang , Ding Yimin , Ni Xingjie
Published: July 2021

The exploration of quantum inspired symmetries in optical systems has spawned promising physics and provided fertile ground for developing devices exhibiting exotic functionalities. Founded on the anti-parity–time (APT) symmetry that is enabled by both spatial and temporal interplay between gain and loss, we demonstrate theoretically and numerically bi-color lasing in a single micro-ring resonator with spatiotemporal modulation along its azimuthal direction. In contrast to conventional multi-mode lasers that have mixed-frequency output, our laser exhibits stable, demultiplexed, tunable bi-color emission at different output ports. Our APT-symmetry-based laser may point out a new route for realizing compact on-chip coherent multi-color light sources.
Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity
Authors: Besterman Aaron D. , Althoff Thorsten , Elfferich Peter , Gutierrez-Mejia Irma , Sadik Joshua , Bernstein Jonathan A. , van Ierland Yvette , Kattentidt-Mouravieva Anja A. , Nellist Mark , Abramson Jeff , Martinez-Agosto Julian A.
Published: July 2021

Smith-Kingsmore syndrome (SKS) is a rare neurodevelopmental disorder characterized by macrocephaly/megalencephaly, developmental delay, intellectual disability, hypotonia, and seizures. It is caused by dominant missense mutations in MTOR. The pathogenicity of novel variants in MTOR in patients with neurodevelopmental disorders can be difficult to determine and the mechanism by which variants cause disease remains poorly understood. We report 7 patients with SKS with 4 novel MTOR variants and describe their phenotypes. We perform in vitro functional analyses to confirm MTOR activation and interrogate disease mechanisms. We complete structural analyses to understand the 3D properties of pathogenic variants. We examine the accuracy of relative accessible surface area, a quantitative measure of amino acid side-chain accessibility, as a predictor of MTOR variant pathogenicity.

We describe novel clinical features of patients with SKS. We confirm MTOR Complex 1 activation and identify MTOR Complex 2 activation as a new potential mechanism of disease in SKS. We find that pathogenic MTOR variants disproportionately cluster in hotspots in the core of the protein, where they disrupt alpha helix packing due to the insertion of bulky amino acid side chains. We find that relative accessible surface area is significantly lower for SKS-associated variants compared to benign variants. We expand the phenotype of SKS and demonstrate that additional pathways of activation may contribute to disease. Incorporating 3D properties of MTOR variants may help in pathogenicity classification. We hope these findings may contribute to improving the precision of care and therapeutic development for individuals with SKS.
Sales of antibiotics and hydroxychloroquine in India during the COVID-19 epidemic: An interrupted time series analysis
Authors: Sulis Giorgia , Batomen Brice , Kotwani Anita , Pai Madhukar , Gandra Sumanth
Published: July 2021

Background

We assessed the impact of the coronavirus disease 2019 (COVID-19) epidemic in India on the consumption of antibiotics and hydroxychloroquine (HCQ) in the private sector in 2020 compared to the expected level of use had the epidemic not occurred.

Methods and findings

We performed interrupted time series (ITS) analyses of sales volumes reported in standard units (i.e., doses), collected at regular monthly intervals from January 2018 to December 2020 and obtained from IQVIA, India. As children are less prone to develop symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a predominant increase in non-child-appropriate formulation (non-CAF) sales. COVID-19-attributable changes in the level and trend of monthly sales of total antibiotics, azithromycin, and HCQ were estimated, accounting for seasonality and lockdown period where appropriate. A total of 16,290 million doses of antibiotics were sold in India in 2020, which is slightly less than the amount in 2018 and 2019. However, the proportion of non-CAF antibiotics increased from 72.5% (95% CI: 71.8% to 73.1%) in 2019 to 76.8% (95% CI: 76.2% to 77.5%) in 2020. Our ITS analyses estimated that COVID-19 likely contributed to 216.4 million (95% CI: 68.0 to 364.8 million; P = 0.008) excess doses of non-CAF antibiotics and 38.0 million (95% CI: 26.4 to 49.2 million; P < 0.001) excess doses of non-CAF azithromycin (equivalent to a minimum of 6.2 million azithromycin treatment courses) between June and September 2020, i.e., until the peak of the first epidemic wave, after which a negative change in trend was identified. In March 2020, we estimated a COVID-19-attributable change in level of +11.1 million doses (95% CI: 9.2 to 13.0 million; P < 0.001) for HCQ sales, whereas a weak negative change in monthly trend was found for this drug. Study limitations include the lack of coverage of the public healthcare sector, the inability to distinguish antibiotic and HCQ sales in inpatient versus outpatient care, and the suboptimal number of pre- and post-epidemic data points, which could have prevented an accurate adjustment for seasonal trends despite the robustness of our statistical approaches.

Conclusions

A significant increase in non-CAF antibiotic sales, and particularly azithromycin, occurred during the peak phase of the first COVID-19 epidemic wave in India, indicating the need for urgent antibiotic stewardship measures.
Optimizing the microscopic agglutination test (MAT) panel for the diagnosis of Leptospirosis in a low resource, hyper-endemic setting with varied microgeographic variation in reactivity
Authors: Jayasundara Dinesha , Gamage Chandika , Senavirathna Indika , Warnasekara Janith , Matthias Michael A. , Vinetz Joseph M. , Agampodi Suneth
Published: July 2021

The microscopic agglutination test (MAT) is the standard serological reference test for the diagnosis of leptospirosis, despite being a technically demanding and laborious procedure. The use of a locally optimised MAT panel is considered essential for proper performance and interpretation of results. This paper describes the procedure of selecting such an optimised panel for Sri Lanka, a country hyper-endemic for leptospirosis. MAT was performed using 24 strains on 1132 serum samples collected from patients presenting with acute undifferentiated fever. Of 24 strains, 15 were selected as the optimised panel, while only 11% of serum samples showed positivity. A geographical variation in predominantly reactive serovars was observed, whereas reactivity was low with the saprophytic strain Patoc. Testing with paired sera yielded a higher sensitivity but provided only a retrospective diagnosis. Serological tests based on ELISA with complementary molecular diagnosis using PCR are a feasible and robust alternative approach to diagnose leptospirosis in countries having a higher burden of the disease.
Trypanosoma cruzi-infected Rhodnius prolixus endure increased predation facilitating parasite transmission to mammal hosts
Authors: Marliére Newmar Pinto , Lorenzo Marcelo Gustavo , Guarneri Alessandra Aparecida
Published: July 2021

Triatomine bugs aggregate with conspecifics inside shelters during daylight hours. At dusk, they leave their refuges searching for hosts on which to blood feed. After finding a host, triatomines face the threat of being killed, because hosts often prey on them. As it is known that many parasites induce the predation of intermediate hosts to promote transmission, and that ingestion of Trypanosoma cruzi-infected bugs represents a very effective means for mammal infection, we hypothesized that trypanosomes induce infected bugs to take increased risk, and, as a consequence, be predated when approaching a host. Therefore, we evaluated whether the predation risk and predation rates endured by Rhodnius prolixus increase when infected with T. cruzi. Assays were performed in square glass arenas offering one central refuge to infected and uninfected 5th instar nymphs. A caged mouse was introduced in each arena after a three-day acclimation interval to activate sheltered insects and induce them to approach it. As hypothesized, a significantly higher proportion of infected insects was predated when compared with uninfected ones (36% and 19%, respectively). Indeed, T. cruzi-infected bugs took higher risk (Approximation Index = 0.642) when compared with healthy ones (Approximation Index = 0.302) and remained outside the shelters when the host was removed from the arena. Our results show that infection by T. cruzi induces bugs to assume higher risk and endure higher predation rates. We reveal a hitherto unknown trypanosome-vector interaction process that increases infected bug predation, promoting increased rates of robust oral transmission. The significant consequences of the mechanism revealed here make it a fundamental component for the resilient maintenance of sylvatic, peridomestic and domestic cycles.
Profiling DNA break sites and transcriptional changes in response to contextual fear learning
Authors: Stott Ryan T. , Kritsky Oleg , Tsai Li-Huei
Published: July 2021

Neuronal activity generates DNA double-strand breaks (DSBs) at specific loci in vitro and this facilitates the rapid transcriptional induction of early response genes (ERGs). Physiological neuronal activity, including exposure of mice to learning behaviors, also cause the formation of DSBs, yet the distribution of these breaks and their relation to brain function remains unclear. Here, following contextual fear conditioning (CFC) in mice, we profiled the locations of DSBs genome-wide in the medial prefrontal cortex and hippocampus using γH2AX ChIP-Seq. Remarkably, we found that DSB formation is widespread in the brain compared to cultured primary neurons and they are predominately involved in synaptic processes. We observed increased DNA breaks at genes induced by CFC in neuronal and non-neuronal nuclei. Activity-regulated and proteostasis-related transcription factors appear to govern some of these gene expression changes across cell types. Finally, we find that glia but not neurons have a robust transcriptional response to glucocorticoids, and many of these genes are sites of DSBs. Our results indicate that learning behaviors cause widespread DSB formation in the brain that are associated with experience-driven transcriptional changes across both neuronal and glial cells.
Isolation and characterization of a novel bacteriophage WO from Allonemobius socius crickets in Missouri
Authors: Kupritz Jonah , Martin John , Fischer Kerstin , Curtis Kurt C. , Fauver Joseph R. , Huang Yuefang , Choi Young-Jun , Beatty Wandy L. , Mitreva Makedonka , Fischer Peter U.
Published: July 2021

Wolbachia are endosymbionts of numerous arthropod and some nematode species, are important for their development and if present can cause distinct phenotypes of their hosts. Prophage DNA has been frequently detected in Wolbachia, but particles of Wolbachia bacteriophages (phage WO) have been only occasionally isolated. Here, we report the characterization and isolation of a phage WO of the southern ground cricket, Allonemobius socius, and provided the first whole-genome sequence of phage WO from this arthropod family outside of Asia. We screened A. socius abdomen DNA extracts from a cricket population in eastern Missouri by quantitative PCR for Wolbachia surface protein and phage WO capsid protein and found a prevalence of 55% and 50%, respectively, with many crickets positive for both. Immunohistochemistry using antibodies against Wolbachia surface protein showed many Wolbachia clusters in the reproductive system of female crickets. Whole-genome sequencing using Oxford Nanopore MinION and Illumina technology allowed for the assembly of a high-quality, 55 kb phage genome containing 63 open reading frames (ORF) encoding for phage WO structural proteins and host lysis and transcriptional manipulation. Taxonomically important regions of the assembled phage genome were validated by Sanger sequencing of PCR amplicons. Analysis of the nucleotides sequences of the ORFs encoding the large terminase subunit (ORF2) and minor capsid (ORF7) frequently used for phage WO phylogenetics showed highest homology to phage WOAu of Drosophila simulans (94.46% identity) and WOCin2USA1 of the cherry fruit fly, Rhagoletis cingulata (99.33% identity), respectively. Transmission electron microscopy examination of cricket ovaries showed a high density of phage particles within Wolbachia cells. Isolation of phage WO revealed particles characterized by 40–62 nm diameter heads and up to 190 nm long tails. This study provides the first detailed description and genomic characterization of phage WO from North America that is easily accessible in a widely distributed cricket species.
Numerical modeling on hybrid nanofluid (Fe3O4+MWCNT/H2O) migration considering MHD effect over a porous cylinder
Authors: Shah Zahir , Saeed Anwar , Khan Imran , M. Selim Mahmoud , Ikramullah  , Kumam Poom
Published: July 2021

The free convective hybrid nanofluid (Fe3O4+MWCNT/H2O) magnetized non-Darcy flow over a porous cylinder is examined by considering the effects constant heat source and uniform ambient magnetic field. The developed coupled PDEs (partial differential equations) are numerically solved using the innovative computational technique of control volume finite element method (CVFEM). The impact of increasing strength of medium porousness and Lorentz forces on the hybrid nanofluid flow are presented through contour plots. The variation of the average Nusselt number (Nuave) with the growing medium porosity, buoyancy forces, radiation parameter, and the magnetic field strength is presented through 3-D plots. It is concluded that the enhancing medium porosity, buoyancy forces and radiation parameter augmented the free convective thermal energy flow. The rising magnetic field rises the temperature of the inner wall more drastically at a smaller Darcy number. An analytical expression for Nusselt number (Nuave) is obtained which shows its functional dependence on the pertinent physical parameters. The augmenting Lorentz forces due to the higher estimations of Hartmann retard the hybrid nanoliquid flow and hence enhance the conduction.
Utilization of target lesion heterogeneity for treatment efficacy assessment in late stage lung cancer
Authors: Chen Dung-Tsa , Chan Wenyaw , Thompson Zachary J. , Thapa Ram , Beg Amer A. , Saltos Andreas N. , Chiappori Alberto A. , Gray Jhanelle E. , Haura Eric B. , Rose Trevor A. , Creelan Ben
Published: July 2021

Rationale

Recent studies have discovered several unique tumor response subgroups outside of response classification by Response Evaluation Criteria for Solid Tumors (RECIST), such as mixed response and oligometastasis. These subtypes have a distinctive property, lesion heterogeneity defined as diversity of tumor growth profiles in RECIST target lesions. Furthermore, many cancer clinical trials have been activated to evaluate various treatment options for heterogeneity-related subgroups (e.g., 29 trials so far listed in clinicaltrials.gov for cancer patients with oligometastasis). Some of the trials have shown survival benefit by tailored treatment strategies. This evidence presents the unmet need to incorporate lesion heterogeneity to improve RECIST response classification.

Method

An approach for Lesion Heterogeneity Classification (LeHeC) was developed using a contemporary statistical approach to assess target lesion variation, characterize patient treatment response, and translate informative evidence to improving treatment strategy. A mixed effect linear model was used to determine lesion heterogeneity. Further analysis was conducted to classify various types of lesion variation and incorporate with RECIST to enhance response classification. A study cohort of 110 target lesions from 36 lung cancer patients was used for evaluation.

Results

Due to small sample size issue, the result was exploratory in nature. By analyzing RECIST target lesion data, the LeHeC approach detected a high prevalence (n = 21; 58%) of lesion heterogeneity. Subgroup classification revealed several informative distinct subsets in a descending order of lesion heterogeneity: mix of progression and regression (n = 7), mix of progression and stability (n = 9), mix of regression and stability (n = 5), and non-heterogeneity (n = 15). Evaluation for association of lesion heterogeneity and RECIST best response classification showed lesion heterogeneity commonly occurred in each response group (stable disease: 16/27; 59%; partial response: 3/5; 60%; progression disease: 2/4; 50%). Survival analysis showed a differential trend of overall survival between heterogeneity and non-heterogeneity in RECIST response groups.

Conclusion

This is the first study to evaluate lesion heterogeneity, an underappreciated metric, for RECIST application in oncology clinical trials. Results indicated lesion heterogeneity is not an uncommon event. The LeHeC approach could enhance RECIST response classification by utilizing granular lesion level discovery of heterogeneity.
Gender and intersectional analysis of livestock vaccine value chains in Kaffrine, Senegal
Authors: McKune Sarah , Serra Renata , Touré Alioune
Published: July 2021

Among livestock species, poultry and small ruminants are of particular importance to rural women in low- and middle-income countries, as means to generate income, provide nutritious food for the family, accumulate wealth, and confer social status. Newcastle disease (ND) and Peste des Petits Ruminants (PPR) are widespread livestock diseases of poultry and small ruminants, respectively. While both diseases are vaccine preventable, numerous constraints limit the availability of and access to livestock vaccines, especially among the most vulnerable populations in developing countries. The literature on equity and effectiveness of livestock vaccine distribution systems has emphasized many of these constraints, however a gendered analysis and deeper understanding of the vaccine system remain insufficient. This paper applies a gendered and intersectional transformational approach, or GITA, to highlight how gender and other social factors affect the provision and utilization of vaccines for ND and PPR diseases in the region of Kaffrine, Senegal. We first articulate and describe the vaccine value chains (VVCs) for these diseases in Kaffrine, and then analyze the gendered and intersectional dynamics at different nodes of the VVCs, including actors at the national level, through the regional and district levels, down to providers of animal health at community level and the livestock keepers themselves. Our findings indicate that actors’ various experiences are shaped and defined mainly by rigid gender norms, location and remoteness, and to a lesser degree by other social stratifications of age, ethnicity, and livelihood. Given the significant role that gender norms play in the livestock vaccine value chains, differences according to the livestock species, regulation of vaccine administration, and vaccine distribution systems emerge as highly relevant for understanding barriers that women specifically face within the livestock vaccination system.
A humanized monoclonal antibody against the endothelial chemokine CCL21 for the diagnosis and treatment of inflammatory bowel disease
Authors: Capitano Maegan L. , Jaiswal Aruna , Broxmeyer Hal E. , Pride Yilianys , Glover Sarah , Amlashi Fatemah G. , Kirby Austin , Srinivasan Gayathri , Williamson Elizabeth A. , Mais Daniel , Hromas Robert
Published: July 2021

Chemokines are small proteins that promote leukocyte migration during development, infection, and inflammation. We and others isolated the unique chemokine CCL21, a potent chemo-attractant for naïve T-cells, naïve B-cells, and immature dendritic cells. CCL21 has a 37 amino acid carboxy terminal extension that is distinct from the rest of the chemokine family, which is thought to anchor it to venule endothelium where the amino terminus can interact with its cognate receptor, CCR7. We and others have reported that venule endothelium expressing CCL21 plays a crucial role in attracting naïve immune cells to sites of antigen presentation. In this study we generated a series of monoclonal antibodies to the amino terminus of CCL21 in an attempt to generate an antibody that blocked the interaction of CCL21 with its receptor CCR7. We found one humanized clone that blocked naïve T-cell migration towards CCL21, while memory effector T-cells were less affected. Using this monoclonal antibody, we also demonstrated that CCL21 is expressed in the mucosal venule endothelium of the large majority of inflammatory bowel diseases (IBD), including Crohn’s disease, ulcerative colitis, and also in celiac disease. This expression correlated with active IBD in 5 of 6 cases, whereas none of 6 normal bowel biopsies had CCL21 expression. This study raises the possibility that this monoclonal antibody could be used to diagnose initial or recurrent of IBD. Significantly, this antibody could also be used for therapeutic intervention in IBD by selectively interfering with recruitment of naïve immune effector cells to sites of antigen presentation, without harming overall memory immunity.