bluuebunny/crossref_metadata_2025 huggingface dataset:
Two-Layer Palatal Reconstruction Reduces Postoperative Intraoral Complications in Head and Neck Surgery
Authors: Nemoto Hitoshi , Cheong David Chon-Fok , Hung Shao-Yu , Tsao Chung-Kan
Published: January 2022

Background:

Although microvascular free flaps are commonly performed and have high success rates, postoperative oronasal fistulas or infections do occur. The authors hypothesized that a two-layer closure is effective for prevention of intraoral complications.

Methods:

Patients who underwent palatal reconstruction with a microvascular free flap were evaluated retrospectively. The cases were divided into two groups (palatal reconstruction with or without a two-layer closure). A two-layer closure involves unilateral reconstruction with a free flap, then reconstruction of the nasal lining with a local flap or folding free flap. The postoperative complication rates between these two groups were compared.

Results:

One hundred fifty-five cases were evaluated. A two-layer closure was performed in 65 cases (41.9 percent). The incidence of infections, dehiscence of the recipient site, and oronasal fistula were significantly higher in the single-layer closure group than in the two-layer closure group [10.0 percent versus 0 percent (p = 0.011); 15.6 percent versus 4.6 percent (p = 0.036); and 17.8 percent versus 4.6 percent (p = 0.013), respectively].

Conclusions:

A two-layer closure in palatal reconstruction was shown to reduce the rate of infection, intraoral wound dehiscence, and oronasal fistula in the current study. A two-layer closure provides greater support and stability and reduces the risk of failure in reconstruction of the palate with a microvascular free flap.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Long-Term Resorption Rate of Autogenous Onlay Graft in East Asian Rhinoplasty: A Retrospective Study
Authors: Lee Tae-Yul , Lee Kyu-Il , Dhong Eun-Sang , Jeong Seong-Ho , Kim Deok-Woo , Han Seung-Kyu
Published: January 2022

Background:

Autologous material remains the preferred graft material for use in rhinoplasty. However, resorption rates of autografts remain controversial. In addition, long-term follow-up studies on autografts are rare. Thus, the objective of the present study was to access long-term resorption rates of various autologous grafts on the upper nasal third.

Methods:

Medical records of patients who had undergone septorhinoplasty with dorsal augmentation using autologous tissues between 2009 and 2018 were retrospectively reviewed. Autogenous grafts applied on the nasal dorsum were categorized into three groups: rolled superficial mastoid fascia, diced cartilage wrapped with superficial mastoid fascia, and rolled sacral dermis. Preoperative and postoperative photographs were used to evaluate resorption rates and projection.

Results:

The rolled sacral dermis group showed a steep increase in postoperative projection but a sharp decrease in long-term follow-up projection compared to the other two groups. Among these three groups, there were statistically significant trend differences in rhinion (p < 0.001) and ½ nasion-rhinion point (p < 0.001), but not in nasion. Of these three groups, the rolled sacral dermis group showed the most projection, followed by the diced cartilage wrapped with superficial mastoid fascia group. The resorption rate was the highest in the rolled superficial mastoid fascia group (p < 0.001). Regarding resorption rates in the other two groups, the rolled sacral dermis group had a higher rate than the diced cartilage wrapped with superficial mastoid fascia group.

Conclusions:

At least 50 percent of resorption was observed in almost all groups in the long term. The choice of graft material and proper decision-making could determine success or failure.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Perforator and Perforator Flap Spinoffs: A Historical Journey
Authors: Hallock Geoffrey G.
Published: January 2022

The concept of the perforator has now become a fundamental topic well known in every training program. However, that has not always been so. The mere definition of the word has historically been argued relentlessly; nevertheless, its major derivative, the perforator flap, has become accepted as a basic consideration whenever flaps need be selected. However, this has not been the only spinoff derived from the author’s investigations of the perforator, a point that should be stressed in addition to some reiterations of pertinent and perhaps confusing nomenclature that deserve to be reemphasized. Truly, it has been amazing to see how our ideas and innovations arise simultaneously and independently throughout the world of reconstructive surgery. A final plea is made to sustain the future—each of us must continue to contribute our passion and our knowledge to all others by means of that technology now globally so instantaneously available.
Application of the Buccal Fat Pad in Oral Reconstruction: Covered With Collagen Membrane or Not?
Authors: Huang Wei , Ye Hui-Sheng , Tan Jie-Wen , Huang Shan
Published: January 2022

Objective:

To evaluate the clinical effectiveness of collagen membrane as biological dressing in protecting the covered buccal fat pad (BFP) from physical damage during postoperative healing phase in the reconstruction of oral soft tissue defect.

Methods:

A retrospective cohort study was performed in patients undergoing oral defects reconstruction using BFP. The predictor variable was the application of collagen membrane or not. The primary outcome variable was the wound healing. Other variables considered included age, gender, pain score, time taken for epithe-lialization, defect size and site. Postoperative follow-up was done at 1 week, 3 weeks, 6 months, and 1 year.

Results:

Thirty patients in Zhuhai People’s Hospital were selected and randomly divided in 2 groups. Group i patients were reconstructed using BFP alone, whereas collagen membrane was used as a covering over BFP in group II patients. In group I, 4 patients developed dehiscence 1-week postoperative, and underwent infection with food lodgment along with another 1 patient at 3-week follow-up, whereas none of the group II patients developed dehiscence or infection. Pain score was lesser in group II patients as compared to group I. Time taken for epithelialization was about 3 weeks in both groups.

Conclusions:

Combined application of collagen membrane protects the covered BFP from masticatory physical damage and food lodgment, which reduces infection and graft loss. It is worthy of consideration as an effective method for the reconstruction of selected moderate-sized oral defects, especially in larger size or at distant location.
Celiac Axis Stenosis is an Underestimated Risk Factor for Increased Morbidity After Pancreatoduodenectomy
Authors: Al-Saeedi Mohammed , Sauer Hendrik B. , Ramouz Ali , Koch Julian M. , Frank-Moldzio Leonie , Bruckner Tom , Loos Martin , Mayer Philipp , Klauss Miriam , Kulu Yakup , Berchtold Christoph , Hoffmann Katrin , Mehrabi Arianeb , Schneider Martin , Müller-Stich Beat , Hackert Thilo , Büchler Markus W. , Strobel Oliver
Published: January 2022

Objective:

To assesses the prevalence and severity of CAS in patients undergoing PD/total pancreatectomy and its association with major postoperative complications after PD.

Summary of background data:

CAS may increase the risk of ischemic complications after PD. However, the prevalence of CAS and its relevance to major morbidity remain unknown.

Methods:

All patients with a preoperative computed tomography with arterial phase undergoing partial PD or TP between 2014 and 2017 were identified from a prospective database. CAS was assessed based on computed tomography and graded according to its severity: no stenosis (<30%), grade A (30%–<50%), grade B (50%–≤80%), and grade C (>80%). Postoperative complications were assessed and uni- and multivariable risk analyses were performed.

Results:

Of 989 patients, 273 (27.5%) had CAS: 177 (17.9%) with grade A, 83 (8.4%) with grade B, and 13 (1.3%) with grade C. Postoperative morbidity and 90-day mortality occurred in 278 (28.1%) patients and 41 (4.1%) patients, respectively. CAS was associated with clinically relevant pancreatic fistula (P=0.019), liver perfusion failure (P=0.003), gastric ischemia (P=0.001), clinically relevant biliary leakage (P=0.006), and intensive care unit (P=0.016) and hospital stay (P=0.001). Multivariable analyses confirmed grade B and C CAS as independent risk factors for liver perfusion failure; in addition, grade C CAS was an independent risk factor for clinically relevant pancreatic fistula and gastric complications.

Conclusions:

CAS is common in patients undergoing PD. Higher grade of CAS is associated with an increased risk for clinically relevant complications, including liver perfusion failure and postoperative pancreatic fistula. Precise radiological assessment may help to identify CAS. Future studies should investigate measures to mitigate CAS-associated risks.
Advances in understanding of the innate immune response to human norovirus infection using organoid models
Authors: Mboko Wadzanai P. , Chhabra Preeti , Valcarce Marta Diez , Costantini Veronica , Vinjé Jan
Published: January 2022

Norovirus is the leading cause of epidemic and endemic acute gastroenteritis worldwide and the most frequent cause of foodborne illness in the United States. There is no specific treatment for norovirus infections and therapeutic interventions are based on alleviating symptoms and limiting viral transmission. The immune response to norovirus is not completely understood and mechanistic studies have been hindered by lack of a robust cell culture system. In recent years, the human intestinal enteroid/human intestinal organoid system (HIE/HIO) has enabled successful human norovirus replication. Cells derived from HIE have also successfully been subjected to genetic manipulation using viral vectors as well as CRISPR/Cas9 technology, thereby allowing studies to identify antiviral signaling pathways important in controlling norovirus infection. RNA sequencing using HIE cells has been used to investigate the transcriptional landscape during norovirus infection and to identify antiviral genes important in infection. Other cell culture platforms such as the microfluidics-based gut-on-chip technology in combination with the HIE/HIO system also have the potential to address fundamental questions on innate immunity to human norovirus. In this review, we highlight the recent advances in understanding the innate immune response to human norovirus infections in the HIE system, including the application of advanced molecular technologies that have become available in recent years such as the CRISPR/Cas9 and RNA sequencing, as well as the potential application of single cell transcriptomics, viral proteomics, and gut-on-a-chip technology to further elucidate innate immunity to norovirus.
Poly (acetyl, arginyl) glucosamine disrupts Pseudomonas aeruginosa biofilms and enhances bacterial clearance in a rat lung infection model
Authors: Garcia Bryan A. , McDaniel Melissa S. , Loughran Allister J. , Johns J. Dixon , Narayanaswamy Vidya , Fernandez Petty Courtney , Birket Susan E. , Baker Shenda M. , Barnaby Roxanna , Stanton Bruce A. , Foote Jeremy B. , Rowe Steven M. , Swords W. Edward
Published: January 2022

Pseudomonas aeruginosa

is a common opportunistic pathogen that can cause chronic infections in multiple disease states, including respiratory infections in patients with cystic fibrosis (CF) and non-CF bronchiectasis. Like many opportunists,

P. aeruginosa

forms multicellular biofilm communities that are widely thought to be an important determinant of bacterial persistence and resistance to antimicrobials and host immune effectors during chronic/recurrent infections. Poly (acetyl, arginyl) glucosamine (PAAG) is a glycopolymer that has antimicrobial activity against a broad range of bacterial species, and also has mucolytic activity, which can normalize the rheological properties of cystic fibrosis mucus. In this study, we sought to evaluate the effect of PAAG on

P. aeruginosa

bacteria within biofilms in vitro, and in the context of experimental pulmonary infection in a rodent infection model. PAAG treatment caused significant bactericidal activity against

P. aeruginosa

biofilms, and a reduction in the total biomass of preformed

P. aeruginosa

biofilms on abiotic surfaces, as well as on the surface of immortalized cystic fibrosis human bronchial epithelial cells. Studies of membrane integrity indicated that PAAG causes changes to

P. aeruginosa

cell morphology and dysregulates membrane polarity. PAAG treatment reduced infection and consequent tissue inflammation in experimental

P. aeruginosa

rat infections. Based on these findings we conclude that PAAG represents a novel means to combat

P. aeruginosa

infection, and may warrant further evaluation as a therapeutic.
A qualitative process analysis of DCT as an alternative to self-isolation following close contact with a confirmed case of COVID-19
Authors: Denford Sarah , Martin Alex F , Towler Lauren , Mowbray Fiona , Essery Rosie , Bloomer Rachael , Ready Derren , Love Nicola , Amlôt Richard , Oliver Isabel , Rubin G James , Yardley Lucy
Published: January 2022

Background

In July 2021, a randomised controlled trial was conducted to compare the effect on SARS-CoV-2 transmission of seven days of daily contact testing (DCT) using lateral flow devise (LFT) and 2 PCR tests as an alternative to 10 days of standard self-isolation with 1 PCR, following close contact with a confirmed case of COVID-19. DCT appeared equivalent to self-isolation in terms of transmission in the trial, however it was not clear how tests were viewed and used in practice. In this qualitative study, we used a nested process to aid interpretation of the trial and provide insight into factors influencing use of tests, understanding of test results, and how tests were used to inform behavioural decisions.

Methods

Interviews were conducted with 60 participants (42 randomised to DCT and 18 randomised to self-isolation) who had been in close contact with a confirmed positive case of COVID-19 and had consented to take part in the trial.

Results

Sub-themes emerging from the data were organised into three overarching themes: (1) assessing the risks and benefits of DCT; (2) use of testing during the study period and (3) future use of testing. Attitudes toward DCT as an alternative to self-isolation, and behaviour during the testing period appeared to be informed by an assessment of the associated risks and benefits. Participants reported how important it was for them to avoid isolation, how necessary self-isolation was considered to be, and the ability of LFTs to detect infection. Behaviour during the testing period was modified to reduce risks and harms as much as possible. Testing was considered a potential compromise, reducing both risk of transmission and the negative impact of self-isolation and was highly regarded as a way to ‘return to new normal’.

Conclusion

Participants in this study viewed DCT as a sensible, feasible and welcome means of avoiding unnecessary self-isolation. Although negative LFTs provided reassurance, most people still restricted their activity as recommended. DCT was also highly valued by those in vulnerable households as a means of providing reassurance of the absence of infection, and as an important means of detecting infection and prompting self-isolation when necessary.
Hierarchical true prevalence, risk factors and clinical symptoms of tuberculosis among suspects in Bangladesh
Authors: Khan Mohammad Kamruzzaman , Islam Md. Nazimul , Hassan Jayedul , Paul Shaymal Kumar , Islam M. Ariful , Pateras Konstantinos , Kostoulas Polychronis , Ward Michael P. , Anisur Rahman A. K. M. , Alam Md. Mahbub
Published: January 2022

Background

The study was aimed to estimate the true prevalence of human tuberculosis (TB); identify risk factors and clinical symptoms of TB; and detect rifampicin (RIF) sensitivity in Bangladesh.

Methods

The cross-sectional study was conducted in three Bangladesh districts during 2018. Potential risk factors, clinical symptoms, and comorbidities were collected from 684 TB suspects. Sputum specimens were examined by LED microscopy. TB hierarchical true prevalence, risk factors and clinical symptoms were estimated and identified using a Bayesian analysis framework. Rifampicin sensitivity of M. tuberculosis (MTB) was detected by GeneXpert MTB/RIF assay.

Results

The median TB true prevalence was 14.2% (3.8; 34.5). Although overall clustering of prevalence was not found, several DOTS centers were identified with high prevalence (22.3% to 43.7%). Risk factors for TB identified (odds ratio) were age (> 25 to 45 years 2.67 (1.09; 6.99), > 45 to 60 years 3.43 (1.38; 9.19) and individuals in families/neighborhoods where a TB patient(s) has (ve) already been present (12.31 (6.79; 22.60)). Fatigue, night sweat, fever and hemoptysis were identified as important clinical symptoms. Seven of the GeneXpert MTB/RIF positive sputum specimens (65) were resistant to rifampicin.

Conclusions

About one in every seven TB suspects was affected with TB. Around 11% of the TB patients carry multi drug resistant MTB. Hierarchical true prevalence estimation allowed identifying DOTS centers with high TB burden. Insights from this study will enable more efficient use DOTS centers-based TB surveillance to end the TB epidemic in Bangladesh by 2035.
The Effect of Ethanolic Extract of Acacia Seyal Bark on Induced Diabetic rats
Authors: Elamin Elhasan LM , Elhkotam Basmat , Abdelgadir Tomader Salah , Allah Ibraheim Smaher Greeb , Eldin Othman Omar Musa Izz
Published: January 2022

Background

Diabetes mellitus Type 2 is a chronic metabolic disorder characterized by insulin insensitivity that leads to a decrease in glucose transport into the other cells. Many drugs are being developed, while no cure is available regarding to this disease although, there are limitations due to high cost and certain side effects. The Traditional Medicines are preferred due to lesser side effects and low cost. Acacia species have wide traditional medicinal using as anti-diabetic, antimicrobial, and anti-inflammatory activities.

Objective

The study aimed to examine the effect of ethanolic extract of Acacia Seyal bark in induced diabetic rats.

Materials and methods

Acacia Seyal bark was extracted in ethanol 80%. The Ethanolic extract was analyzed for phytochemicals screening tests using standard methods. To investigate the effect of the extract thirty induced diabetic albino rats introduced by injection of glucose 2g\kg were divided to 5 groups equally; Group 1 was treated with 10mg\kg of glibenclamide, group 2 left as control treated with distilled water 10mg\kg, Group 3 was treated with 200mg of plant extract, Group 4 was treated with 400mg of plant extract, and Group 5 was treated with 800mg of plant extract. The Glucose Tolerant Test were done after 1 hour, 2 hour and 4 hour to determine blood glucose level of rats. Estimation of in vitro glucose uptake by rat diaphragm experiment was done to evaluate the glucose utilization capacity of extract.

Results

The effect of different concentration of ethanolic extract of Acacia Seyal bark on the blood glucose level of diabetic induced rats is significantly different (0.05 p 0.01 <p). The phytochemical screening of extract indicated the presence of Saponin, Tannins Steroids, Triterpens, and Anthraquinone, While the absence of flavonoids. In vitro glucose consumption by diaphragm study the level of utilized glucose from the media is 69.4% in the presence of extract compared to control group.

Conclusion

Study concluded that the ethanolic bark extract of A. seyal showed significant anti-diabetic activity. This results might have a great potential for translation to humans and the obtained data might set the stage for clinical trials investigating the effects of anti-diabetic effect in patients with diabetes mellitus type2. In the best of our knowledge, this is the first study that has conducted to study the anti-diabetics effect of ethanolic extract of Acacia Seyal bark in diabetic rats.
Augmenting Transcranial Magnetic Stimulation Coil with Magnetic Material: An Optimization Approach
Authors: Lu Charles , Deng Zhi-De , Choa Fow-Sen
Published: January 2022

Transcranial magnetic stimulation (TMS) is a neuromodulation technique that has been approved by the U.S. Food and Drug Administration for several neuropsychiatric disorders, including major depression and obsessive-compulsive disorder. However, the therapeutic efficacy of TMS treatment has been modest, despite decades of research. While there are many potential reasons as to why, one of the most obvious is the limitations of current technologies. One prominent example is the penetration depth–focality tradeoff of existing TMS coils. The most widely used figure-of-8 coils stimulate brain regions just superficially under the coil, missing deep brain regions known to be critically involved in psychiatric disorders; while ring-type coils can stimulate deep into the brain, but stimulate a large brain volume (lack of focality). A new coil design strategy is proposed: magnetic materials encompassing the human head are optimized to shape the electromagnetic field generated by the primary coil. Specifically, a mathematical model was developed to describe the physical problem; the magnetic materials were discretized into unit blocks; Newton’s gradient descent method was applied to iteratively optimize the spatial distribution of the unit blocks to achieve a desired electric field distribution inside a head model. Results reveal that the proposed design achieves a coil penetration depth equal to or better than state-of-the art commercial coils, while improving the depth–focality tradeoff by a factor of 2.2 to 2.7. As a proof-of-concept, a prototype coil and a spherical head model were constructed; the spatial distribution of the induced electric field inside the head model was mapped. Results validated the proposed coil design. TMS coils based on this novel design strategy could potentially lead to better therapeutic outcome.
The Epidemiology of Hundreds of Individuals Infected with Omicron BA.1 in Middle-Eastern Jordan
Authors: Hajjo Rima , AbuAlSamen Mahmoud M. , Alzoubi Hamed M. , Alqutob Raeda
Published: January 2022

In less than two months of its detection in Jordan, lineage B.1.1.529 recognized as Omicron, is constituting 55% of all confirmed coronavirus disease of 2019 (COVID-19) infections causing a rise in the daily cases in the country. Herein, we report on 500 cases, among the first identified Omicron infections in Jordan. We also report on the genomic diversity of 25 Omicron viruses identified in nasopharyngeal swabs from Jordan. Our results indicated that 96% of study participants were vaccinated who had asymptomatic, mild or moderate disease. One unvaccinated individual developed severe disease. The median age of Omicron cases was 30 years, and most frequent disease symptoms were: fever, coughing, sore throat, runny nose, general fatigue and muscle/joint pain. Viral genomic analysis results revealed that the BA.1 is the dominant Omicron sublineage in Jordan, with 45 to 58 total mutations. We identified a few amino acid modifications that could impact the accuracy of some polymerase chain reaction (PCR) tests. In summary, infections caused by BA.1 seem milder than earlier infections. However, it is unknown whether this change is due to alterations in the immunity landscape of the infected population or is the result of viral genetic mutations that reduced viral virulence. Hence, comparing similar studies from different countries is likely to give us a get a better understanding of this variant, its behavior and the impact on disease characteristics.
Association of Sleep Behaviors with Risk of Esophageal Cancer
Authors: Wang Xiaoyan , Tian Ruiyi , Zong Xiaoyu , Jeon Myung Sik , Luo Jingqin , Colditz Graham A. , Wang Jean , Tsilidis Konstantinos K. , Ju Yo-El S , Govindan Ramaswamy , Puri Varun , Cao Yin
Published: January 2022

IMPORTANCE

Esophageal cancer is among the most lethal type of cancers worldwide. However, risk factors contributing to more than tenfold increase in esophageal cancer in the last 50 years remain underexplored.

OBJECTIVE

This study aimed to examine the associations between sleep behaviors and esophageal cancer overall, by histology, and according to genetic predispositions.

DESIGN

A prospective cohort study.

SETTING

A population-based study.

PARTICIPANTS

A total of 410,428 participants aged 37-73 years at enrollment between 2006 and 2010 in the UK Biobank were followed up until March 31st, 2016 for England and Wales and October 31st, 2015 for Scotland.

MAIN OUTCOME AND MEASURE

The risk of incident esophageal cancer.

RESULTS

During 2,799,342 person-years of follow-up, 410 incident esophageal cancer cases (294 adenocarcinomas) were diagnosed. Evening chronotype, sleep <6 or >9 h/day, daytime napping, and daytime sleepiness were significantly associated with increased risk of esophageal cancer in age-adjusted models and had aPlikelihood ratio test≤0.20 after multivariable adjustment. Compared with the group without these high-risk behaviors, participants with one high-risk behavior had a 41% (HR=1.41, 95%CI: 1.13, 1.77) increased risk of esophageal cancer, and those with two or more behaviors showed a 79% higher risk (HR=1.79, 95%CI: 1.32, 2.42) (Ptrend<0.001). These associations were largely driven by esophageal adenocarcinoma (Ptrend<0.001) but not squamous cell carcinoma (Ptrend=0.340). The elevated risks for esophageal adenocarcinoma were similar within strata of PRS quintiles (Pinteraction=0.791).

CONCLUSION AND RELEVANCE

Unhealthy sleep behaviors were associated with an increased risk of esophageal cancer, primarily adenocarcinoma, independent of genetic risk. Sleep behaviors may serve as modifiable factors for the prevention of esophageal cancer, particularly esophageal adenocarcinomas.

Key Points

Question

Are sleep behaviors associated with the risk of esophageal cancer?

Findings

In this prospective cohort study that included 410,428 participants in the UK Biobank, evening chronotype, sleep <6 or >9 h/day, daytime napping, and sleepiness were associated with increased risk of esophageal cancer. A greater number of these unhealthy sleep behaviors was associated with a higher risk of esophageal cancer. The elevated risks were primarily observed for esophageal adenocarcinoma and were independent of genetic risk.

Meaning

Sleep behaviors may serve as modifiable factors for the esophageal cancer prevention, particularly esophageal adenocarcinoma, independent of genetic risk.
Multiplexed strain phenotyping defines consequences of genetic diversity in Mycobacterium tuberculosis for infection and vaccination outcomes
Authors: Carey Allison F. , Wang Xin , Cicchetti Nico , Spaulding Caitlin N. , Liu Qingyun , Hopkins Forrest , Brown Jessica , Sixsmith Jaimie , Ioerger Thomas R. , Fortune Sarah M.
Published: January 2022

There is growing evidence that genetic diversity in Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, contributes to the outcomes of infection and public health interventions, such as vaccination. Epidemiological studies suggest that among the phylogeographic lineages of Mtb, strains belonging to Lineage 2 (L2) are associated with concerning clinical features including hypervirulence, treatment failure, and vaccine escape. The global expansion and increasing prevalence of L2 has been attributed to the selective advantage conferred by these characteristics, yet confounding host and environmental factors make it difficult to identify the bacterial determinants driving these associations in human studies. Here, we developed a molecular barcoding strategy to facilitate high-throughput, experimental phenotyping of Mtb clinical isolates. This approach allowed us to characterize growth dynamics for a panel of genetically diverse Mtb strains during infection and after vaccination in the mouse model. We found that L2 strains exhibit distinct growth dynamics in vivo and are resistant to the immune protection conferred by Bacillus Calmette-Guerin (BCG) vaccination. The latter finding corroborates epidemiological observations and demonstrates that mycobacterial features contribute to vaccine efficacy. To investigate the genetic and biological basis of L2 strains’ distinctive phenotypes, we performed variant analysis, transcriptional studies, and genome-wide transposon sequencing. We identified functional genetic changes across multiple stress- and host-response pathways in a representative L2 strain that are associated with variants in regulatory genes. These adaptive changes may underlie the distinct clinical characteristics and epidemiological success of this lineage.
Probabilistic Learning of Treatment Trees in Cancer
Authors: Yao Tsung-Hung , Wu Zhenke , Bharath Karthik , Li Jinju , Baladandayuthapan Veerabhadran
Published: January 2022

Abstract

Accurate identification of synergistic treatment combinations and their underlying biological mechnisms is critical across many disease domains, especially cancer. In translational oncology research, preclinical systems such as patient-derived xenografts (PDX) have emerged as a unique study design evaluating multiple treatments administered to samples from the same human tumor implanted into genetically identical mice. In this paper, we propose a novel Bayesian probabilistic tree-based framework for PDX data to investigate the hierarchical relationships between treatments by inferring treatment cluster trees, referred to as treatment trees (Rx-tree). The framework motivates a new metric of mechanistic similarity between two or more treatments accounting for inherent uncertainty in tree estimation; treatments with a high estimated similarity have potentially high mechanistic synergy. Building upon Dirichlet Diffusion Trees, we derive a closed-form marginal likelihood encoding the tree structure, which facilitates computationally efficient posterior inference via a new two-stage algorithm. Simulation studies demonstrate superior performance of the proposed method in recovering the tree structure and treatment similarities. Our analyses of a recently collated PDX dataset produce treatment similarity estimates that show a high degree of concordance with known biological mechanisms across treatments in five different cancers. More importantly, we uncover new and potentially effective combination therapies that confer synergistic regulation of specific downstream biological pathways for future clinical investigations. Our accompanying code, data, and shiny application for visualization of results are available at: https://github.com/bayesrx/RxTree.
RNA-Targeting CRISPR/Cas13d System Eliminates Disease-Related Phenotypes in Pre-clinical Models of Huntington’s Disease
Authors: Morelli Kathryn H. , Wu Qian , Gosztyla Maya L. , Liu Hongshuai , Zhang Chuangchuang , Chen Jiaxu , Marina Ryan , Lee Kari , Jones Krysten L. , Duan Wenzhen , Yeo Gene W.
Published: January 2022

Huntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Although the pathogenesis of HD remains complex, the CAG-expanded (CAGEX) HTT mRNA and protein ultimately causes disease through a toxic gain-of-function mechanism. As the reduction of pathogenic mutant HTT mRNA is beneficial as a treatment, we developed a CAGEX RNA-eliminating CRISPR-Cas13d system (Cas13d/CAGEX) that binds and eliminates toxic CAGEX RNA in HD patient iPSC-derived striatal neurons. We show that intrastriatal delivery of Cas13d/CAGEX via a single adeno-associated viral vector, serotype 9 (AAV9) mediates significant and selective reduction of mutant HTT mRNA and protein levels within the striatum of heterozygous zQ175 mice, an established mouse model of HD. Moreover, the reduction of mutant HTT mRNA renders a sustained reversal of HD phenotypes, including improved motor coordination, attenuated striatal atrophy, and reduction of mutant HTT protein aggregates. Importantly, phenotypic improvements were durable for at least 8 months without gross or behavioral adverse effects, and with minimal off-target interactions of Cas13d/CAGEX in the mouse transcriptome. Taken together, we demonstrate a proof-of-principle of an RNA-targeting CRISPR/Cas13d system as a therapeutic approach for HD, a strategy with broad implications for the treatment of other dominantly inherited neurodegenerative disorders.
COVID-19 vaccines effectiveness against symptomatic SARS-CoV-2 during Delta variant surge: a population-based case-control study in St. Petersburg, Russia
Authors: Barchuk Anton , Bulina Anna , Cherkashin Mikhail , Berezina Natalia , Rakova Tatyana , Kuplevatskaya Darya , Stanevich Oksana , Skougarevskiy Dmitriy , Okhotin Artemiy
Published: January 2022

Background

Studies of mRNA and vector-based vaccines used in different countries report acceptable levels of effectiveness against SARS-CoV-2 infection caused by the Delta variants of SARS-CoV-2. No studies estimated vaccine effectiveness (VE) of Gam-COVID-Vac and other vaccines used in Russia against symptomatic infection with Delta variant. In this population-based case-control study, we aimed to estimate the effectiveness of the Russian COVID-19 vaccines against symptomatic SARS-CoV-2 during the recent outbreak caused by the Delta VOC in October 2021 in St. Petersburg, Russia.

Methods

In a population-based case-control study with density sampling of controls, we acquired information on cases and controls from two independent studies conducted in St. Petersburg. Cases were symptomatic patients with confirmed SARS-CoV-2 (using polymerase chain reaction (PCR) test) referred to low-dose computed tomography (LDCT) triage in two outpatient centres between October 6 and 14, 2021 during the Delta variant outbreak. We recruited the controls during the representative survey of the seroprevalence study conducted during the same period in St. Petersburg using random digit dialling. In the primary analysis, we used logistic regression models to estimate the adjusted (age, gender, and history of confirmed COVID-19) VE against symptomatic SARS-CoV-2 resulted in a referral to triage centre for three vaccines used in Russia: Gam-COVID-Vac, EpiVacCorona, and CoviVac.

Findings

We included 1,254 cases and 2,747 controls recruited between the 6th and 14th of October in the final analysis. VE was 56% (95% CI: 48 to 63) for Gam-COVID-Vac (Sputnik V), 49% (95% CI: 29 to 63) for 1-dose Gam-COVID-Vac (Sputnik V) or Sputnik Light, -58% (95% CI: -225 to 23) for EpiVacCorona and 40% (95% CI: 3 to 63) for CoviVac. Without adjustment for the history of confirmed COVID-19 VE for all vaccines was lower, except for one-dose Gam-COVID-Vac (Sputnik Light). The adjusted VE was slightly lower in women — 51% (95% CI: 39 to 60) than men — 65% (95% CI: 5 to 73). It was also higher in younger age. However, in the analysis restricted to participants without a history of confirmed COVID-19, the differences in VE by age group were smaller.

Interpretation

In contrast to other Russian vaccines, Gam-COVID-Vac is effective against symptomatic SARS-CoV-2 infection caused by Delta VOC. Effectiveness is likely higher than the estimated 56% due to bias arising from high prevalence of the past COVID-19 in St. Petersburg.

Funding

Population-based survey in St. Petersburg was funded by Polymetal International, plc.
Assembly and comparative analysis of the complete mitochondrial genome of three Macadamia species (M. integrifolia, M. ternifolia and M. tetraphylla)
Authors: Niu Yingfeng , Lu Yongjie , Song Weicai , He Xiyong , Liu Ziyan , Zheng Cheng , Wang Shuo , Shi Chao , Liu Jin
Published: January 2022

Background

Macadamia is a true dicotyledonous plant that thrives in a mild, humid, low wind environment. It is cultivated and traded internationally due to its high-quality nuts thus, has significant development prospects and scientific research value. However, information on the genetic resources of Macadamia spp. remains scanty.

Results

The mitochondria (mt) genomes of three economically important Macadamia species, Macadamia integrifolia, M. ternifolia and M. tetraphylla, were assembled through the Illumina sequencing platform. The results showed that each species has 71 genes, including 42 protein-coding genes, 26 tRNAs, and 3 rRNAs. Repeated sequence analysis, RNA editing site prediction, and analysis of genes migrating from chloroplast (cp) to mt were performed in the mt genomes of the three Macadamia species. Phylogenetic analysis based on the mt genome of the three Macadamia species and 35 other species was conducted to reveal the evolution and taxonomic status of Macadamia. Furthermore, the characteristics of the plant mt genome, including genome size and GC content, were studied through comparison with 36 other plant species. The final non-synonymous (Ka) and synonymous (Ks) substitution analysis showed that most of the protein-coding genes in the mt genome underwent negative selections, indicating their importance in the mt genome.

Conclusion

The findings of this study provide a better understanding of the Macadamia genome and will inform future research on the genus.
Inversion of a topological domain leads to restricted changes in its gene expression and affects inter-domain communication
Authors: Galupa Rafael , Picard Christel , Servant Nicolas , Nora Elphège Pierre , Zhan Yinxiu , Bemmel Joke van , Marjou Fatima El , Johanneau Colin , Borensztein Maud , Ancelin Katia , Giorgetti Luca , Heard Edith
Published: January 2022

The interplay between the topological organization of the genome and the regulation of gene expression remains unclear. Depletion of molecular factors underlying genome topology, such as CTCF and cohesin, leads to modest alterations in gene expression, while genomic rearrangements involving boundaries of topologically associating domains (TADs) disrupt normal gene expression and can lead to pathological phenotypes. Here we inverted an almost entire TAD (245kb out of 300kb) within the X-inactivation centre (Xic), leaving its boundaries intact. This led to a significant rearrangement of topological contacts within the TAD, mostly in accordance to the orientation of underlying CTCF binding sites but suggesting heterogeneity in the “contact” potential of different CTCF sites. The inversion also led to increased contact insulation with the neighbouring TAD. Expression of most genes within the inverted TAD remained unaffected in mouse embryonic stem cells and during differentiation. Interestingly, expression in the neighbouring TAD of the noncoding transcript Xist, which controls X-chromosome inactivation, was ectopically upregulated. The same inversion in mouse embryos led to a bias in Xist expression, but X-inactivation choice ratios did not significantly deviate from wild type. Smaller deletions and inversions of specific clusters of CTCF sites within the TAD led to similar results: rearrangement of contacts, limited changes in local gene expression but significant changes in Xist expression. Our study suggests that the wiring of regulatory interactions within a TAD can influence the expression of genes in neighbouring TADs, highlighting the existence of mechanisms for inter-TAD communication.
Hippocampal fear engrams modulate ethanol-induced maladaptive contextual generalization in mice
Authors: Cincotta C. , Ruesch E. , Senne R. , Ramirez S.
Published: January 2022

The compounding symptomatology of comorbid alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) gives rise to an interaction of maladaptive neurobiological processes, the etiology of which remains elusive. Here, we devised an optogenetic strategy aimed at rescuing maladaptive responses to fearful stimuli in male c57BL/6 mice following chronic ethanol administration and forced abstinence. In the first experiment, we confirmed that fear acquisition and maladaptive contextual generalization was potentiated in ethanol-exposed mice during fear conditioning and exposure to a novel environment, respectively. In the second experiment, using an activity-dependent tet-tag system, we labeled and artificially inhibited the neural ensemble selectively activated by contextual fear conditioning in the dorsal hippocampus to attenuate behavioral dysfunctions resulting from ethanol exposure. We found that acute optogenetic inhibition during exposure to a novel environment suppressed maladaptive generalization in ethanol-exposed mice. These results provide further evidence for a crucial link between ethanol exposure and impaired fear memory processing by providing cellular and behavioral insights into the neural circuitry underlying AUD and PTSD comorbidity.
Weak intermolecular interactions in a series of biologically active 4′-methylthio-trans-stilbenes
Authors: Grześkiewicz Anita M. , Stefański Tomasz , Dutkiewicz Zbigniew , Kubicki Maciej
Published: January 2022

The crystal structures of nine methoxy-substituted 4′-methylthiostilbenes, which are potential inhibitors of human recombinant cytochrome P450 enzymes, were determined. These compounds included two mono-methoxy-substituted derivatives: 2-methoxy-4′-methylthio-trans-stilbene {systematic name: 1-[(E)-2-(2-methoxyphenyl)ethenyl]-4-(methylsulfanyl)benzene} (1) and 3-methoxy-4′-methylthio-trans-stilbene (2), both C16H16OS; four dimethoxy derivatives: 2,3-dimethoxy-4′-methylthio-trans-stilbene (3), 2,5-dimethoxy-4′-methylthio-trans-stilbene (4), 3,5-dimethoxy-4′-methylthio-trans-stilbene (5) and 2,4-dimethoxy-4′-methylthio-trans-stilbene (6), all C17H18O2S; and three trimethoxy compounds: 2,4,5-trimethoxy-4′-methylthio-trans-stilbene (7), 3,4,5-trimethoxy-4′-methylthio-trans-stilbene (8) and 2,4,6-trimethoxy-4′-methylthio-trans-stilbene (9), all C18H20O3S. The geometries of the compounds in the crystal structures were compared with those found during docking studies at the active site of the receptor, and some relevant differences were identified. Intermolecular interactions were analyzed using three different methods. First, the (3,−1) critical points of the gradient field of the electron density were identified, and then the appropriate contacts were analyzed using their geometrical characteristics and interaction energy calculations. The results confirmed the importance of weak delocalized interactions in the construction of the crystal structures, and the results of different methods (PIXEL and DFT) were comparable in the absence of strong well-defined intermolecular interactions.
Crystal structure and Hirshfeld surface analysis of 2-{[7-acetyl-4-cyano-6-hydroxy-8-(4-methoxyphenyl)-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3-yl]sulfanyl}acetic acid ethyl ester
Authors: Al-Taifi Elham A. , Marae Islam S. , El-Ossaily Yasser A. , Mohamed Shaaban K. , Mague Joel T. , Akkurt Mehmet , Bakhite Etify A.
Published: January 2022

In the title molecule, C25H28N2O5S, (alternative name ethyl 2-{[7-acetyl-4-cyano-6-hydroxy-8-(4-methoxyphenyl)-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3-yl]sulfanyl}acetate) the 4-methoxyphenyl group is disposed on one side of the bicyclic core and the oxygen atoms of the hydroxyl and acetyl groups are disposed on the other side. In the crystal, a layered structure parallel to the ac plane is generated by O—H...O and C—H...O hydrogen bonds plus C—H...π(ring) interactions.
The icon as a collaborative performance: non-standard solutions, invisible work and networks of trust in the construction of the Elbe Philharmonic Hall, Hamburg
Authors: Dimitrova Venetsiya , Grubbauer Monika
Published: January 2022

Purpose

The main goal of this paper is to shift the focus from the symbolic and aesthetic features of iconic projects to the complex process of their actual materialisation. Hereby, the authors conceptualise iconic projects as the “collaborative performance” of a wide range of built environment professionals. The authors seek to unravel the complexity of organisational action, professional practices, knowledge and expertise, and the inter-firm networks required for the creation of iconic architecture.

Design/methodology/approach

The analysis is based on an in-depth case study of the Elbe Philharmonic Hall, Hamburg's new icon. This included 26 semi-structured interviews with a broad range of interview partners, which were conducted by an interdisciplinary team.

Findings

Besides by spectacular architectural design, iconic buildings are characterised by the meticulous execution of even the smallest details as well as of more hidden building elements unlikely to be seen by the public. Execution is usually contingent on the specific building processes and construction practices and requires the continuous engagement of project architects, as well as trusting collaborations with their partners in the construction industry. Yet the making of iconic projects is challenging and (financially) risky, and the interfaces between project partners cannot be easily translated into contractual agreements, which potentially compromises the collaboration between architects and construction firms.

Originality/value

This paper advances a cross-sectoral view on professional practices by providing in-depth insight into the work of less prominent project architects and their partners in the construction industry. This paper hereby bridges design and construction practices and provides a more holistic understanding of how iconic projects are constructed on the ground.
How large is the farm income loss due to climate change? Evidence from India
Authors: Kalli Rajesh , Jena Pradyot Ranjan
Published: January 2022

Purpose

Climate change is the most concerned issue in the global economy; increase in climate variability and uncertain climate events have caused distress in agriculture sector. The study estimates economic effect of climate change on agriculture income for the Indian state of Karnataka. The study reports the difference of result from past studies, where estimates from present study indicate higher negative impact of rise in temperature.

Design/methodology/approach

Fixed effect panel regression method was used to examine change in agriculture revenue to climate response. Climate variables were classified based on the crop calendar to capture the damage caused by climate change. The authors use fine scale climate data set constructed at regional context for 20 districts and time period of 21 years (1992–2012).

Findings

The result showed that with 1-degree rise in average maximum temperature, the revenue declined by 17–21%. The prediction behavior of the different models was evaluated using out-of-sample forecast approach by training and testing historical data set.

Originality/value

The study adopts recent data sets on agriculture and the updated climate variables to estimate the climate change impact on agriculture. The study yields the better results when compared to previous traditional models applied in literature in Indian context. The study further evaluates the prediction behavior and robustness of the estimated models using out-of-sample forecast method.