bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic Age Acceleration Was Delayed in Schizophrenia
Authors: Wu Xiaohui , Ye Junping; , Wang Zhongju , Zhao Cunyou
Published: October 2020

Schizophrenia is a serious neuropsychiatric disorder with abnormal age-related neurodevelopmental (or neurodegenerative) trajectories. Although an accelerated aging hypothesis of schizophrenia has been proposed, the quantitative study of the disruption of the physiological trajectory caused by schizophrenia is inconclusive. In this study, we employed 3 “epigenetic clock” methods to quantify the epigenetic age of a large sample size of whole blood (1069 samples from patients with schizophrenia vs 1264 samples from unaffected controls) and brain tissues (500 samples from patients with schizophrenia vs 711 samples from unaffected controls). We observed significant positive correlations between epigenetic age and chronological age in both blood and brain tissues from unaffected controls and patients with schizophrenia, as estimated by 3 methods. Furthermore, we observed that epigenetic age acceleration was significantly delayed in schizophrenia from the whole blood samples (aged 20–90 years) and brain frontal cortex tissues (aged 20–39 years). Intriguingly, the genes regulated by the epigenetic clock also contained schizophrenia-associated genes, displaying differential expression and methylation in patients with schizophrenia and involving in the regulation of cell activation and development. These findings were further supported by the dysregulated leukocyte composition in patients with schizophrenia. Our study presents quantitative evidence for a neurodevelopmental model of schizophrenia from the perspective of a skewed “epigenetic clock.” Moreover, landmark changes in an easily accessible biological sample, blood, reveal the value of these epigenetic clock genes as peripheral biomarkers for schizophrenia.
HbCOI1 perceives jasmonate to trigger signal transduction in Hevea brasiliensis
Authors: Chen Juan , Yang Haitao , Ma Sui , Yao Ruifeng , Huang Xi , Yan Jianbin , Xie Daoxin
Published: October 2020

Natural rubber, a strategically essential raw material used in manufacturing throughout the world, is produced from coagulated and refined latex of rubber tree (Hevea brasiliensis). It is known that phytohormone jasmonate (JA) plays an essential role in regulating latex biosynthesis. However, it is unclear how the JA signal is sensed in a rubber tree. Here, we showed that H. brasiliensis CORONATINE-INSENSITIVE 1 (HbCOI1) acts as a receptor that perceives JA to recruit H. brasiliensis JASMONATE ZIM DOMAIN1 (HbJAZ1) for signal transduction. We found that HbCOI1 restores male sterility and JA responses of the coi1-1 mutant in Arabidopsis. The identification of a JA receptor in the rubber tree is essential for elucidating the molecular mechanisms underlying JA-regulated latex biosynthesis. Our results elucidate the mechanism of JA perception in H. brasiliensis and also provide an efficient strategy to identify JA receptors in woody plants.
The OHADA Company Law and de facto companies
Authors: Ndangoh Medret Lekunga
Published: October 2020

The propagation of de facto companies in the Organization for the Harmonization of Corporate Law in Africa’s (OHADA) Uniform Act on Company Law is so evident that it cannot be neglected. Some are permitted by the legislator (joint ventures) and others impose themselves (sociétés de fait and sociétés créées de faits). Contrary to other fields of law that reject factual situations, the OHADA Uniform Act on Company Law receives de facto companies and submits them to rules naturally meant for legal companies or legal entities. The purpose of this article is to determine the position of the OHADA Company Law with regard to the invasion of company law by de facto companies. A study of the Uniform Act on Company Law has revealed that de facto companies are recognized and treated as legal entities. We believe that the essence of this recognition is linked to the OHADA legislator’s desire to attain his or her objectives—namely, to secure business relations that can only be possible through the protection of the business, the interest of its partners, and even the interest of third parties.
Occurrence of Viruses and Clavibacter michiganensis in Winter Wheat in Illinois, 2009 to 2011 and 2019 to 2020
Authors: Kleczewski Nathan , Chapara Venkataramana , Bradley Carl A.
Published: October 2020

Field surveys in 2009, 2010, 2011, 2019, and 2020 determined the incidence and diversity of viruses present in fields of soft red winter wheat (Triticum aestivum) in Illinois. In addition, the putative presence of the bacterial mosaic pathogen, Clavibacter michiganensis subsp. tessellarius (Cmt), was evaluated. A total of 341 fields were sampled across years, and plants were tested for barley yellow dwarf virus (BYDV-PAV; BYDV-MAV), barley stripe mosaic virus (BSMV), brome mosaic virus (BMV), cereal yellow dwarf virus (CYDV-RPV), High Plains virus (HPV), Potyvirus group (POTY), soil-borne wheat mosaic virus (SBWMV), tobacco mosaic virus (TMV), wheat spindle streak mosaic virus (WSSMV), wheat streak mosaic virus (WSMV), and Cmt using ELISA. Average field incidence across years varied by virus with BYDV-PAV (22%), WSSMV (16%), CYDV-RPV (7%), WSMV (3%), and HPV (0.5%) detected in samples. The bacterial mosaic pathogen (Cmt), or potentially a related species of Clavibacter, was detected the most frequently in each year, with an average incidence of 77%. The consistent detection of Cmt warrants further study to determine the nature of the organisms associated with positive Cmt tests and their role in Illinois wheat production systems.
Powering Bias and Clinically Important Treatment Effects in Randomized Trials of Critical Illness*
Authors: Abrams Darryl , Montesi Sydney B. , Moore Sarah K. L. , Manson Daniel K. , Klipper Kaitlin M. , Case Meredith A. , Brodie Daniel , Beitler Jeremy R.
Published: October 2020

Objectives:

Recurring issues in clinical trial design may bias results toward the null, yielding findings inconclusive for treatment effects. This study evaluated for powering bias among high-impact critical care trials and the associated risk of masking clinically important treatment effects.

Design, Setting, and Patients:

Secondary analysis of multicenter randomized trials of critically ill adults in which mortality was the main endpoint. Trials were eligible for inclusion if published between 2008 and 2018 in leading journals. Analyses evaluated for accuracy of estimated control group mortality, adaptive sample size strategy, plausibility of predicted treatment effect, and results relative to the minimal clinically important difference. The main outcome was the mortality risk difference at the study-specific follow-up interval.

Interventions:

None.

Measurements and Main Results:

Of 101 included trials, 12 met statistical significance for their main endpoint, five for increased intervention-associated mortality. Most trials (77.3%) overestimated control group mortality in power calculations (observed minus predicted difference, –6.7% ± 9.8%; p < 0.01). Due to this misestimation of control group mortality, in 14 trials, the intervention would have had to prevent at least half of all deaths to achieve the hypothesized treatment effect. Seven trials prespecified adaptive sample size strategies that might have mitigated this issue. The observed risk difference for mortality fell within 5% of predicted in 20 trials, of which 16 did not reach statistical significance. Half of trials (47.0%) were powered for an absolute risk reduction greater than or equal to 10%, but this effect size was observed in only three trials with a statistically significant treatment benefit. Most trials (67.3%) could not exclude clinically important treatment benefit or harm.

Conclusions:

The design of most high-impact critical care trials biased results toward the null by overestimating control group mortality and powering for unrealistic treatment effects. Clinically important treatment effects often cannot be excluded.
Adjuvant Trastuzumab Emtansine (T-DM1) and Concurrent Radiotherapy for Residual Invasive HER2-positive Breast Cancer
Authors: Zolcsák Zita , Loirat Delphine , Fourquet Alain , Kirova Youlia M.
Published: October 2020

Objectives:

The treatment of nonmetastatic HER2-positive breast cancer with residual invasive disease using concurrent Trastuzumab emtansine (T-DM1) and radiotherapy appears to be an effective option. Our aim was to evaluate the acute side effects of this treatment regime.

Methods:

Fourteen patients were treated between March 2019 and April 2020 concurrent T-DM1 and radiotherapy. Left ventricular ejection fraction was assessed at baseline, before and after radiotherapy. All toxicities were evaluated using Common Terminology Criteria of Adverse Events (CTCAE) version 3.0.

Results:

The median age was 55 years (range 36 to 72). All patients received total dose of 50 Gy for the breast/ chest wall, 10 patients got lymph node irradiation, 4 patients received an additional tumor bed boost. The most common side effect was grade 1 radiodermatitis. A reversible grade 2 left ventricular ejection fraction decrease occurred in 2 patients. During our examination 3 patients showed alanine aminotransferases increase after the cycle 4 of T-DM1, 1 patient had grade 1, 1 patient grade 2, and 1 patient grade 3 alanine aminotransferase increases.

Conclusions:

The acute toxicity rate especially focusing on skin and cardiac toxicity were assumed acceptable in our cohort. To safely administer this concomitant treatment, further examination and prospective data are needed.
Review of the Protective Effects of Statins on Cognition
Authors: Chadha Bhawneet , Frishman William H.
Published: October 2020

Elevated cholesterol is a major risk factor in the development of cardiovascular disease. Statins have proven to be effective in lowering low-density lipoprotein cholesterol as well as the incidence of cardiovascular events. As a result, statins are widely prescribed in the United States, with an estimated 35 million patients on statins. Many of these patients are older than age 65 and suffer from various comorbidities, including mild to severe cognitive impairment. Early studies looking at the effects of statins on cognition have shown that statin use may lead to mild reversible cognitive decline, although long-term studies have shown inconclusive findings. In recent years, studies have shown that the use of statins in certain groups of patients may lead to a reduction in the rate of cognitive decline. One hypothesis for this finding is that statin use can reduce the risk of cerebrovascular disease which may, in turn, reduce the risk of mild cognitive decline and dementia. With numerous patients currently prescribed statins and the likelihood that more patients will be prescribed the medication in the coming years, it is important to review the current literature to determine the association between statin use and cognitive decline, as well as determine how statins may be beneficial in preventing cognitive decline.
Changing dietary approaches to prevent cardiovascular disease
Authors: Nestel Paul J. , Beilin Lawrence J. , Mori Trevor A.
Published: October 2020

Purpose of review

We have focused on recent research relevant to effects of dietary patterns and major food groups on cardiovascular outcomes, taking into account guidelines and position statements from expert authorities, with an emphasis on important changes in recommendations, some of which remain controversial.

Recent findings

Major findings include: refocusing on qualitative patterns of food consumption replacing quantitative prescriptive advice on nutrients; increasing intake of plant foods; substituting saturated fats with polyunsaturated and monounsaturated oils; reducing salt intake; regular consumption of fish with a focus on omega-3 enrichment; not restricting dairy foods, other than butter and cream, with encouragement of some fermented products; reducing cholesterol intake for those at increased cardiovascular risk and diabetes, allowing 7-eggs weekly; restricting processed meats and allowing moderate lean meat consumption; preference for fiber-rich complex carbohydrates and reduced sugar intake; maintaining healthy bodyweight; and although water is the preferred beverage, allowing moderate alcohol consumption to national guidelines and avoiding alcohol in specific cardiovascular disorders.

The new approach that focuses on healthier patterns of food intake is more readily understood by health practitioners and translatable to consumers and patients.
Radiation exposure in modified barium swallow studies
Authors: Bonilha Heather Shaw , Martin-Harris Bonnie , O’Rourke Ashli K. , Tipnis Sameer V.
Published: October 2020

Purpose of review

The modified barium swallow study (MBSS) is an X-ray examination of swallowing used to detect the presence and type impairment, aspiration risk, and to develop intervention plans. In this review, we will cover the use of ionizing radiation in MBSSs and review recent literature concerning radiation exposure and cancer risks to patients undergoing MBSSs. Lastly, we will discuss the clinical implications of these findings.

Recent findings

Recent literature confirms that the MBSS is a low-dose examination and that reducing pulse rate negatively impacts diagnostic accuracy. Importantly, cancer risks to adults undergoing MBSSs were also reported to be low.

An adult undergoing MBSS using a standardized, valid protocol, like the Modified Barium Swallow Impairment Profile (MBSImP), has low-radiation exposure and very low associated cancer risks. MBSSs should be used whenever relevant to adult patient care without undue concern regarding radiation exposure. Children also have low radiation exposure from MBSSs; however, cancer risks from that exposure remain unknown. Best practices in radiation safety must always be followed. Reducing pulse rates in the adult or pediatric population to reduce radiation exposure is not a valid strategy because of the resulting reduction in diagnostic accuracy.
Pediatric tracheostomy care updates
Authors: Smith Matthew M. , Benscoter Dan , Hart Catherine K.
Published: October 2020

Purpose of review

The aim of this review is to provide an update on the management of pediatric tracheostomies.

Recent findings

Recent literature has focused on optimization of care for children with tracheostomies including prevention and management of skin breakdown, timing of tracheostomy tube changes, the role of multidisciplinary and team-based approaches to education and management of tracheostomy patients, ideal timing of surveillance endoscopy, and the emerging role of telemedicine in the care of tracheostomy patients.

A focus on quality improvement and a systematic, team-based approach to care has the potential to improve the quality of care for pediatric tracheostomy patients.
Can we prevent allergic disease? Understanding the links between the early life microbiome and allergic diseases of childhood
Authors: Petersen Charisse , Turvey Stuart E.
Published: October 2020

Purpose of review

The microbiome and immune system are intrinsically linked, and during infancy these crucial biological systems undergo a concurrent and expansive maturation process. As these maturation processes progress, some children develop a sequence of IgE-mediated immune disorders termed the ‘Allergic March’, and unfortunately the prevalence of these lifelong and burdensome allergic conditions has increased over the past half century. Our current treatment strategies are unable to prevent or cure components of the Allergic March. However, recent discoveries have enhanced our mechanistic understanding of early-life microbiota–immune interactions with exciting implications for preventing these allergic disorders.

Recent findings

The current review will detail recent literature regarding perinatal factors (e.g. birth mode, antibiotic exposure, breastmilk seeding of the microbiota, built environment) that shape the infant gut microbiota composition. Furthermore, we will discuss new findings that have highlighted immune cells which are particularly sensitive to microbial influences in utero and during the early-life window of development.

As our understanding of the dynamic relationship between the developing infant microbiota and immune system grows, a priority toward preserving critical early-life interactions may provide life-long protection to these diseases in the future.
Long-Term Outcome of PICU Patients Discharged With New, Functional Status Morbidity
Authors: Pollack Murray M. , Banks Russell , Holubkov Richard , Meert Kathleen L.
Published: October 2020

Objectives:

To determine the long-term (> 6 mo) functional status of PICU patients with significant new functional morbidities at hospital discharge.

Design:

Longitudinal cohort followed-up using structured chart reviews of electronic health records.

Setting:

Electronic health records of former PICU patients at seven sites.

Patients:

Randomly selected patients from the Trichotomous Outcome Prediction in Critical Care study discharged from the hospital with new functional status morbidity who had sufficient electronic health record data to determine functional status.

Interventions:

None.

Measurements and Main Results:

Long-term functional status was measured with the Functional Status Scale and categorized by comparison to hospital discharge Functional Status Scale. Improvement or new morbidity was based on a change in Functional Status Scale of greater than or equal to 2 in a single domain. Overall, 56% (n = 71) improved, 15% (n = 19) did not change, 9% (n = 11) developed a new morbidity, and 21% (n = 26) died. The shortest median follow-up time from PICU discharge was 1.4 years for those who died and the longest was 4.0 years for those improved. Functional status at baseline (pre-acute illness) was different among the outcome groups with those that improved having the highest frequency of baseline normal status or only mild dysfunction. Of the long-term survivors with improvement, 82% (n = 58) improved to normal status or mild dysfunction, 11% (n = 8) improved to moderate dysfunction, and 7% (n = 5) improved to severe dysfunction. Trauma patients improved and cancer patients died more frequently than other diagnoses. The long-term outcome groups were not associated with hospital discharge functional status.

Conclusions:

A majority of PICU survivors discharged with significant new functional morbidity with follow-up after 6 or more months improved, many to normal status or only mild dysfunction, while 29% died or developed new morbidity. Of the long-term survivors, 70% had significant improvement after a median follow-up time of 4.0 years.
Integrase Inhibitors Use and Cytomegalovirus Infection Predict Immune Recovery in People Living With HIV Starting First-Line Therapy
Authors: Fabbiani Massimiliano , Borghetti Alberto , Squillace Nicola , Colafigli Manuela , Taramasso Lucia , Lombardi Andrea , Rossetti Barbara , Ciccullo Arturo , Colella Elisa , Picarelli Chiara , Berruti Marco , Latini Alessandra , Montagnani Francesca , Sambo Margherita , Di Biagio Antonio , Gori Andrea , Di Giambenedetto Simona , Bandera Alessandra
Published: October 2020

Background:

We explored predictors of CD4/CD8 ratio improvement and optimal immunological recovery (OIR) after initiation of antiretroviral therapy (ART) in naive people living with HIV (PLWH).

Methods:

Retrospective multicenter study including naive PLWH starting ART with 2 nucleos(t)ide reverse transcriptase inhibitors + 1 integrase strand transfer inhibitor (InSTI) or non-NRTI or protease inhibitor (PI). PLWH were followed from the time of ART initiation (baseline) to the discontinuation of first-line regimen, virological failure, death, or loss to follow-up. Estimated incidence and predictors of time to CD4/CD8 ratio normalization (defined as ≥1) and OIR (defined as CD4/CD8 ratio ≥ 1 plus CD4 ≥ 500 cells/µL plus CD4% ≥ 30%) were explored by Kaplan–Meier curves and Cox regression analysis.

Results:

Overall, 1428 PLWH (77.8% males, median age 39 years, 55.1% with positive cytomegalovirus (CMV) antibodies, median HIV-RNA 4.80 log copies/mL, median CD4 323 cells/µL, median CD4/CD8 ratio 0.32) were included, of which 21.5% (n = 307), 44.5% (n = 636), and 34% (n = 485) treated with InSTI-, PI-, and NNRTI-based regimens, respectively. The estimated proportion of CD4/CD8 normalization and OIR at 36 months was 38.6% and 32.9%, respectively. Multivariate analysis showed that InSTI-based regimens had a higher probability of CD4/CD8 ratio normalization and OIR both in the total population (P < 0.001 versus PI) and in advanced naive PLWH (P ≤ 0.001 versus PI and NNRTI). Moreover, subjects with positive CMV serology showed a lower probability of CD4/CD8 ratio normalization and OIR (P < 0.001).

Conclusions:

InSTI-based regimens showed a better immune recovery, suggesting that the type of first-line ART can influence immune reconstitution. PLWH with positive CMV serology showed an increased risk of suboptimal immune recovery.
Cerebrospinal Fluid Leak After Septoplasty in Crouzon Syndrome
Authors: Demir Berat , Abuzaid Ghazi , Binnetoglu Adem
Published: October 2020

Crouzon syndrome presents with craniofacial deformities due to early fusion of cranial sutures. Deviation of the nasal septum could be seen clinically in Crouzon syndrome. Cerebrospinal fluid leaks (CSF) after septoplasty are extremely rare and typically present with simple rhinorrhea, meningitis, and pneumocephalus. Herein, we report an adult patient with Crouzon syndrome who experienced CSF complication after septoplasty surgery.

Supplemental Video: CSF leak repair operation, http://links.lww.com/SCS/B930
Radiological Findings of Nontraumatic Thrombosed Temporal Artery Aneurysm Mimicking Parotid Gland Mass
Authors: Polat Gökhan , Sade Recep , Pirimoglu Berhan , Yalcin Ahmet
Published: October 2020

A 54-year-old male patient had preauricular swelling mimicking parotid gland mass. Computed tomography and magnetic resonance imaging findings were showed a connection with the temporal artery. There wasn’t a trauma history. The aneurysm wall showed contrast enhancement. The patient was diagnosed with true temporal artery aneurysm. The aneurysm was excised.
Is chemotherapy alone an option as initial treatment for low-grade oligodendrogliomas?
Authors: Rudà Roberta , Touat Mehdi , Soffietti Riccardo
Published: October 2020

Purpose of review

The management of low-grade (grade II) oligodendrogliomas is still controversial, due to their rarity and long-term survival. According to recent WHO 2016 Classification of central nervous system tumors oligodendrogliomas are defined by the coexistence of molecular alterations, such as isocitrate dehydrogenase (IDH)1/2 mutations and 1p/19q codeletion. These tumors have better outcome and higher response to chemotherapy compared with diffuse astrocytomas.

Recent findings

The association of radiotherapy and procarbazine, lomustine (CCNU), vincristine chemotherapy in low-grade oligodendrogliomas is definitely superior over radiotherapy alone, and yields median progression-free survival and overall survival values exceeding by far 10 years. Chemotherapy alone yields results that are inferior compared with radiotherapy + procarbazine, CCNU, vincristine but may better preserve cognitive functions from radiotherapy-induced damage. Chemosensitivity of oligodendrogliomas is related to a high percentage of O6-methylguanine-DNA methyltransferase methylation and low expression of DNA repair genes. Recurrent defects in mismatch repair pathways may induce hypermutation and secondary resistance to temozolomide, but not to nitrosoureas.

Reoperation at progression following initial chemotherapy is increasingly adopted, thus allowing a further delay of radiotherapy. In the future targeting IDH1/2 mutations following incomplete surgery may represent a new innovative option.
Heavy metal contamination and ecological risk assessment of the agricultural soil in Shanxi Province, China
Authors: Qi Hongxue , Zhao Bingqing , Li Lihong , Chen Xiuling , An Jing , Liu Xiuping
Published: October 2020

To assess contamination levels and ecological risks of heavy metals in agricultural soil from Shanxi Province of China, a total of 33 samples in the surface soil were collected from 11 cities in Shanxi. The soil samples were digested by a mixed acid of nitric acid and hydrofluoric acid on a microwave digestion system, then the levels of eight heavy metals were analysed using an inductively coupled plasma mass spectrometer. The pollution levels of soil heavy metals were evaluated using a geo-accumulation index and their ecological risks were assessed using risk index calculated by Hakanson's method. As a result, the average concentrations of the heavy metals As, Cd, Cr, Cu, Hg, Ni, Pb and Zn were 12.9 ± 4.8, 0.35 ± 0.23, 43 ± 14, 27 ± 19, 0.25 ± 0.14, 21.7 ± 5.7, 17 ± 13 and 89 ± 53 mg kg
−1
, respectively. By comparison to the
Chinese soil environmental quality
(GB15618-2018), only 9% of Cd samples and 3% of Cu samples exceeded their corresponding screening criteria. Subsequently, the results of geo-accumulation indices suggested that Shanxi's soil suffered from moderate to heavy contamination posed by Cd and Hg, and risk indices exhibited a similar trend that Cd and Hg were the main contributors for considerable to very high ecological risk. Finally, the analysis of variance indicated that the mean levels of Cd significantly occurred at Yuncheng areas among the 11 cities (
n
= 3,
p
< 0.05), but Hg concentrations did not have significantly statistical differences. This study demonstrated that metals Cd and Hg had higher levels and ecological risks for agricultural soil in Shanxi, especially, Yuncheng City suffered from heavy Cd contamination. The findings of the present study will provide basic information on management and control of the agricultural soil contamination in Shanxi Province, China.
Maths attitudes, school affect and teacher characteristics as predictors of maths attainment trajectories in primary and secondary education
Authors: Evans Danielle , Field Andy P.
Published: October 2020

Maths attainment is essential for a wide range of outcomes relating to further education, careers, health and the wider economy. Research suggests a significant proportion of adults and adolescents are underachieving in maths within the UK, making this a key area for research. This study investigates the role of children's perceptions of the school climate (children's affect towards school and student–teacher relationships), their attitudes towards maths and teacher characteristics as predictors of maths attainment trajectories, taking the transition from primary to secondary education into consideration. Two growth models were fit using secondary data analysis of the Avon Longitudinal Study of Parents and Children (ALSPAC). The first model, which looked at predictors of maths attainment in primary education, found significant associations only between positive maths attitudes and increased maths attainment. The second model, which looked at predictors of maths attainment in secondary education, found significant associations between increased maths attainment and positive maths attitudes, decreased school belonging, positive student–teacher relationships and increased teacher fairness. The findings suggest that the secondary education school environment is particularly important for maths attainment.
A green extraction design for enhancing flavonoid compounds from
Ixora javanica
flowers using a deep eutectic solvent
Authors: Oktaviyanti Nina Dewi , Kartini Kartini , Hadiyat Mochammad Arbi , Rachmawati Ellen , Wijaya Andre Chandra , Hayun Hayun , Mun'im Abdul
Published: October 2020

In this study, an environmentally friendly extraction method for flavonoid compound from
Ixora javanica
, as a new raw material candidate for herbal medicine and cosmetics, was developed. The objectives of the present work were to provide recommendations for the optimal extraction conditions and to investigate the effects of any extraction parameters on flavonoid yields from the
I. javanica
flower. The extraction process was performed using deep eutectic solvent (DES) (choline chloride and propylene glycol at molar ratio of 1 : 1) and the ultrasound-assisted extraction method. Both single-factor and response surface analyses using three-level and three-factor Box Behnken designs were conducted to obtain the optimum flavonoid concentrations. The results showed that the optimum extraction conditions for total flavonoids featured an extraction time of 40 min, 25% water content in DES and a solid-to-liquid ratio of 1 : 25 g ml
−1
. An extract obtained under optimum extraction conditions showed higher total flavonoid yields than an ethanolic extract which was used for comparison. Scanning electron microscope images demonstrated that both of the solvents also showed different effects on the outer surface of the
I. javanica
flower during the extraction process. In summary, our work succeeded in determining the optimum conditions for total flavonoids in the
I. javanica
flower using a green extraction method.
Variola virus genome sequenced from an eighteenth-century museum specimen supports the recent origin of smallpox
Authors: Ferrari Giada , Neukamm Judith , Baalsrud Helle T. , Breidenstein Abagail M. , Ravinet Mark , Phillips Carina , Rühli Frank , Bouwman Abigail , Schuenemann Verena J.
Published: October 2020

Smallpox, caused by the variola virus (VARV), was a highly virulent disease with high mortality rates causing a major threat for global human health until its successful eradication in 1980. Despite previously published historic and modern VARV genomes, its past dissemination and diversity remain debated. To understand the evolutionary history of VARV with respect to historic and modern VARV genetic variation in Europe, we sequenced a VARV genome from a well-described eighteenth-century case from England (specimen P328). In our phylogenetic analysis, the new genome falls between the modern strains and another historic strain from Lithuania, supporting previous claims of larger diversity in early modern Europe compared to the twentieth century. Our analyses also resolve a previous controversy regarding the common ancestor between modern and historic strains by confirming a later date around the seventeenth century. Overall, our results point to the benefit of historic genomes for better resolution of past VARV diversity and highlight the value of such historic genomes from around the world to further understand the evolutionary history of smallpox as well as related diseases.

This article is part of the theme issue ‘Insights into health and disease from ancient biomolecules’.
Investigating the demographic history of Japan using ancient oral microbiota
Authors: Eisenhofer Raphael , Kanzawa-Kiriyama Hideaki , Shinoda Ken-ichi , Weyrich Laura S.
Published: October 2020

While microbial communities in the human body (microbiota) are now commonly associated with health and disease in industrialised populations, we know very little about how these communities co-evolved and changed with humans throughout history and deep prehistory. We can now examine these communities by sequencing ancient DNA preserved within calcified dental plaque (calculus), providing insights into the origins of disease and their links to human history. Here, we examine ancient DNA preserved within dental calculus samples and their associations with two major cultural periods in Japan: the Jomon period hunter–gatherers approximately 3000 years before present (BP) and the Edo period agriculturalists 400–150 BP. We investigate how human oral microbiomes have changed in Japan through time and explore the presence of microorganisms associated with oral diseases (e.g. periodontal disease, dental caries) in ancient Japanese populations. Finally, we explore oral microbial strain diversity and its potential links to ancient demography in ancient Japan by performing phylogenomic analysis of a widely conserved oral species—
Anaerolineaceae
oral taxon 439. This research represents, to our knowledge, the first study of ancient oral microbiomes from Japan and demonstrates that the analysis of ancient dental calculus can provide key information about the origin of non-infectious disease and its deep roots with human demography.

This article is part of the theme issue ‘Insights into health and disease from ancient biomolecules’.
Evolutionary history ofMycobacterium lepraein the Pacific Islands
Authors: Blevins Kelly E. , Crane Adele E. , Lum Christopher , Furuta Kanako , Fox Keolu , Stone Anne C.
Published: October 2020

As one of the oldest known human diseases, leprosy or Hansen's disease remains a public health concern around the world with over 200 000 new cases in 2018. Most human leprosy cases are caused byMycobacterium leprae, but a small number of cases are now known to be caused byMycobacterium lepromatosis, a sister taxon ofM. leprae. The global pattern of genomic variation inM. lepraeis not well defined. Particularly, in the Pacific Islands, the origins of leprosy are disputed. Historically, it has been argued that leprosy arrived on the islands during nineteenth century colonialism, but some oral traditions and palaeopathological evidence suggest an older introduction. To address this, as well as investigate patterns of pathogen exchange across the Pacific Islands, we extracted DNA from 39 formalin-fixed paraffin-embedded biopsy blocks dating to 1992–2016. Using whole-genome enrichment and next-generation sequencing, we produced nineM. lepraegenomes dating to 1998–2015 and ranging from 4-63× depth of coverage. Phylogenetic analyses indicate that these strains belong to basal lineages within theM. lepraephylogeny, specifically falling in branches 0 and 5. The phylogeographical patterning and evolutionary dating analysis of these strains support a pre-modern introduction ofM. lepraeinto the Pacific Islands.

This article is part of the theme issue ‘Insights into health and disease from ancient biomolecules’.
‘TB or not TB’: the conundrum of pre-European contact tuberculosis in the Pacific
Authors: McDonald S. K. , Matisoo-Smith E. A. , Buckley H. R. , Walter R. K. , Aung H. L. , Collins C. J. , Cook G. M. , Kardailsky O. , Krause J. , Knapp M.
Published: October 2020

Tuberculosis (TB) is a major global health threat, infecting one-third of the world's population. Despite this prominence, the age, origin and spread of the disease have been topics of contentious debate. Molecular studies suggest that
Mycobacterium tuberculosis ‘sensu stricto’
, the most common strain of TB infecting humans today, originated in Africa and from there spread into Europe and Asia. The
M. tuberculosis
strains most commonly found across the Pacific and the Americas today are most closely related to European strains, supporting a hypothesis that the disease only reached these regions relatively recently via European sailors or settlers. However, this hypothesis is inconsistent with palaeopathological evidence of TB-like lesions in human remains from across the Pacific that predate European contact. Similarly, genetic evidence from pre-European South American mummies challenges the notion of a European introduction of the disease into the Pacific. Here, we review the complex evidence for the age and origin of TB in the Pacific, and discuss key gaps in our knowledge and how these may be addressed.

This article is part of the theme issue ‘Insights into health and disease from ancient biomolecules’.
Multi-omic detection ofMycobacterium lepraein archaeological human dental calculus
Authors: Fotakis Anna K. , Denham Sean D. , Mackie Meaghan , Orbegozo Miren Iraeta , Mylopotamitaki Dorothea , Gopalakrishnan Shyam , Sicheritz-Pontén Thomas , Olsen Jesper V. , Cappellini Enrico , Zhang Guojie , Christophersen Axel , Gilbert M. Thomas P. , Vågene Åshild J.
Published: October 2020

Mineralized dental plaque (calculus) has proven to be an excellent source of ancient biomolecules. Here we present aMycobacterium lepraegenome (6.6-fold), the causative agent of leprosy, recovered via shotgun sequencing of sixteenth-century human dental calculus from an individual from Trondheim, Norway. When phylogenetically placed, this genome falls in branch 3I among the diversity of other contemporary ancient strains from Northern Europe. Moreover, ancient mycobacterial peptides were retrieved via mass spectrometry-based proteomics, further validating the presence of the pathogen.Mycobacterium lepraecan readily be detected in the oral cavity and associated mucosal membranes, which likely contributed to it being incorporated into this individual's dental calculus. This individual showed some possible, but not definitive, evidence of skeletal lesions associated with early-stage leprosy. This study is the first known example of successful multi-omics retrieval ofM. lepraefrom archaeological dental calculus. Furthermore, we offer new insights into dental calculus as an alternative sample source to bones or teeth for detecting and molecularly characterizingM. lepraein individuals from the archaeological record.

This article is part of the theme issue ‘Insights into health and disease from ancient biomolecules’.
“Corticosteroid pulses for hospitalized patients with COVID-19: Effects on mortality”
Authors: Cusacovich Ivan , Aparisi Álvaro , Marcos Miguel , Ybarra-Falcón Cristina , Iglesias-Echevarria Carolina , Lopez-Veloso Maria , Barraza-Vengoechea Julio , Dueñas Carlos , Juarros Martínez Santiago Antonio , Rodríguez-Alonso Beatriz , Martín-Oterino José-Ángel , Montero-Baladia Miguel , Moralejo Leticia , Andaluz-Ojeda David , Gonzalez-Fuentes Roberto
Published: October 2020

Background: COVID-19 has high mortality in hospitalized patients, and we need effective treatments. Our objective was to assess corticosteroid pulses’ influence on 60-days mortality in hospitalized patients with severe COVID-19, intensive care admission, and hospital stay. Methods: We designed a multicenter retrospective cohort study in three teaching hospitals of Castilla y León, Spain (865.096 people). We selected patients with confirmed COVID-19 and lung involvement with a pO2/FiO2 < 300, excluding those exposed to immunosuppressors before or during hospitalization, patients terminally ill at admission, or died the first 24 hours. We performed a propensity score matching (PSM) adjusting covariates that modify the probability of being treated. Then we used a Cox regression model in the PSM group to consider factors affecting mortality. Findings: From 2933 patients, 257 fulfilled the inclusion and exclusion criteria. One hundred and twenty-four patients were on corticosteroid pulses, and 133 were not. 30·3% (37/122) of patients died in the corticosteroid pulses group and 42·9% (57/133) in the non-exposed cohort. These differences (12·6% CI95% [8·54-16·65]) were statically significant (log-rank 4·72, p=0·03). We performed PSM using the exact method. Mortality differences remained in the PSM group (log-rank 5·31, p=0·021) and were still significant after a Cox regression model (HR for corticosteroid pulses 0·561, p= 0·039). There were no significant differences in intensive care admission rate (p=0·173). The hospital stay was longer in the corticosteroid group (p<0,001). Interpretation: This study provides evidence about treatment with corticosteroid pulses in severe COVID-19 that might significantly reduce mortality. Strict inclusion and exclusion criteria with that selection process set a reliable frame to compare mortality in both exposed and non-exposed groups. Funding: There was no funding provided.
HLA allele-specific expression loss in tumors can shorten survival and hinder immunotherapy
Authors: Filip Ioan , Orenbuch Rose , Zhao Junfei , Manji Gulam , de Maturana Evangelina López , Malats Núria , Olive Kenneth P. , Rabadan Raul
Published: October 2020

Efficient presentation of aberrant peptide fragments by the human leukocyte antigen class I (HLA-I) genes is necessary for immune detection and killing of cancer cells. Patient HLA-I genotypes are known to impact the efficacy of cancer immunotherapy, and the somatic loss of HLA-I heterozygosity has been established as a factor in immune evasion. While global deregulated expression of HLA-I has been reported in different tumor types, the role of HLA-I allele-specific expression loss – that is, the preferential RNA expression loss of specific HLA-I alleles – has not been fully characterized in cancer. In the present study, we quantified HLA-I allele-specific expression (ASE) across eleven TCGA tumor types using a novel method from input RNA and whole-exome sequencing data. Allele-specific loss in at least one of the three HLA-I genes (ASE loss) was pervasive and associated to worse overall survival across tumor types, including pancreatic adenocarcinomas, prostate carcinomas and glioblastomas, among others. In particular, our analysis shows that detection of neoantigens with binding affinity to the specific HLA-I genes subject to ASE loss was a top prognostic indicator of overall survival. Additionally, we found that ASE loss hindered immunotherapy in retrospective analyses. Together, these results highlight the prevalence of HLA-I ASE loss – a previously uncharacterized phenomenon in cancer – and provide initial evidence of its clinical significance in cancer prognosis and immunotherapy treatment.
Long Covid: quantitative and qualitative analyses of online Long Haulers’ experiences, emotions and practices in the UK
Authors: Martin Sam , Miyake Esperanza
Published: October 2020

WITHDRAWAL/DISCLAIMER STATEMENT

The authors have withdrawn this manuscript because of issues that have been raised regarding the process of data collection. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
COVID-19 Classification of X-ray Images Using Deep Neural Networks
Authors: Goldstein Elisha , Keidar Daphna , Yaron Daniel , Shachar Yair , Blass Ayelet , Charbinsky Leonid , Aharony Israel , Lifshitz Liza , Lumelsky Dimitri , Neeman Ziv , Mizrachi Matti , Hajouj Majd , Eizenbach Nethanel , Sela Eyal , Weiss Chedva , Levin Philip , Benjaminov Ofer , Bachar Gil N , Tamir Shlomit , Rapson Yael , Suhami Dror , dror amiel a , Bogot Naama , Grubstein Ahuva , Shabsin Nogah , Elyada Yishai M , Eldar Yonina
Published: October 2020

Objectives

In the midst of the coronavirus disease 2019 (COVID-19) outbreak, chest X-ray (CXR) imaging is playing an important role in diagnosis and monitoring of patients with COVID-19. Machine learning solutions have been shown to be useful for X-ray analysis and classification in a range of medical contexts. In this study, we propose a machine learning model for detection of patients tested positive for COVID-19 from CXRs that were collected from inpatients hospitalized in four different hospitals. We additionally present a tool for retrieving similar patients according to the model’s results on their CXRs.

Methods

In this retrospective study, 1384 frontal CXRs, of COVID-19 confirmed patients imaged between March-August 2020, and 1024 matching CXRs of non-COVID patients imaged before the pandemic, were collected and used to build a deep learning classifier for detecting patients positive for COVID-19. The classifier consists of an ensemble of pre-trained deep neural networks (DNNS), specifically, ReNet34, ReNet50, ReNet152, vgg16, and is enhanced by data augmentation and lung segmentation. We further implemented a nearest-neighbors algorithm that uses DNN-based image embeddings to retrieve the images most similar to a given image.

Results

Our model achieved accuracy of 90.3%, (95%CI: 86.3%-93.7%) specificity of 90% (95%CI: 84.3%-94%), and sensitivity of 90.5% (95%CI: 85%-94%) on a test dataset comprising 15% (350/2326) of the original images. The AUC of the ROC curve is 0.96 (95%CI: 0.93-0.97).

Conclusion

We provide deep learning models, trained and evaluated on CXRs that can assist medical efforts and reduce medical staff workload in handling COVID-19.

Key Points

A machine learning model was able to detect chest X-ray (CXR) images of patients tested positive for COVID-19 with accuracy and detection rate above 90%.

A tool was created for finding existing CXR images with imaging characteristics most similar to a given CXR, according to the model’s image embeddings.
Network controllability in transmodal cortex predicts psychosis spectrum symptoms
Authors: Parkes Linden , Moore Tyler M. , Calkins Monica E. , Cieslak Matthew , Roalf David R. , Wolf Daniel H. , Gur Ruben C. , Gur Raquel E. , Satterthwaite Theodore D. , Bassett Danielle S.
Published: October 2020

Background

The psychosis spectrum is associated with structural dysconnectivity concentrated in transmodal association cortex. However, understanding of this pathophysiology has been limited by an exclusive focus on the direct connections to a region. Using Network Control Theory, we measured variation in both direct and indirect structural connections to a region to gain new insights into the pathophysiology of the psychosis spectrum.

Methods

We used psychosis symptom data and structural connectivity in 1,068 youths aged 8 to 22 years from the Philadelphia Neurodevelopmental Cohort. Applying a Network Control Theory metric called average controllability, we estimated each brain region’s capacity to leverage its direct and indirect structural connections to control linear brain dynamics. Next, using non-linear regression, we determined the accuracy with which average controllability could predict negative and positive psychosis spectrum symptoms in out-of-sample testing. We also compared prediction performance for average controllability versus strength, which indexes only direct connections to a region. Finally, we assessed how the prediction performance for psychosis spectrum symptoms varied over the functional hierarchy spanning unimodal to transmodal cortex.

Results

Average controllability outperformed strength at predicting positive psychosis spectrum symptoms, demonstrating that indexing indirect structural connections to a region improved prediction performance. Critically, improved prediction was concentrated in association cortex for average controllability, whereas prediction performance for strength was uniform across the cortex, suggesting that indexing indirect connections is crucial in association cortex.

Conclusions

Examining inter-individual variation in direct and indirect structural connections to association cortex is crucial for accurate prediction of positive psychosis spectrum symptoms.
Use of seat belts among public transport drivers in Tacna, Peru: Prevalence and risk factors
Authors: Miñan-Tapia Armando , Torres-Riveros Gloria S. , Choque-Vargas José , Aycachi-Incacoña Madeleyni , Flores-Valdez Neil , Vargas-Anahua Orlando , Mejia Christian R.
Published: October 2020

Introduction

There are individuals who still refuse to wear seat belts, despite its effectiveness in reducing morbidity and mortality in road traffic accidents. We aimed to determine the prevalence and risk factors according to the use of seat belts among public transport drivers in Tacna, Peru.

Methodology

This analytical transversal study was carried out among public transport drivers (buses and taxis) in a Peruvian city. Questionnaires were used to evaluate the general and occupational characteristics and the use of seat belts (observed). Descriptive statistics and risk factors were obtained, these latter through generalized linear models.

Results

Of the 460 drivers, 77% used their seat belts, with a difference in use depending on the type of public transport (p<0.001). In the multivariate model, the risk of not using the belt was associated with the following: older age (p<0.001), having complete studies (p<0.001), a higher level/category of driving license (3 categories had p<0.001), having a higher number of previous road traffic accidents (p=0.011), and received medical attention in that accident (p<0.001), those who reported using a cell phone while driving (p=0.005), if the co-driver’s belt had 3 anchorage points (p<0.001), and working for > 5 hours that day (p=0.002). However, male drivers and those who had their belt with 3 anchorage points had greater use (both p<0.001).

Conclusions

One in five drivers did not use a seat belt, and important characteristics of those who did not comply with this traffic law were evaluated to generate control and intervention measures.