bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural properties and anticoagulant/cytotoxic activities of heterochiral enantiomeric thrombin binding aptamer (TBA) derivatives
Authors: Virgilio Antonella , Esposito Veronica , Pecoraro Annalisa , Russo Annapina , Vellecco Valentina , Pepe Antonietta , Bucci Mariarosaria , Russo Giulia , Galeone Aldo
Published: November 2020

The thrombin binding aptamer (TBA) possesses promising antiproliferative properties. However, its development as an anticancer agent is drastically impaired by its concomitant anticoagulant activity. Therefore, suitable chemical modifications in the TBA sequence would be required in order to preserve its antiproliferative over anticoagulant activity. In this paper, we report structural investigations, based on circular dichroism (CD) and nuclear magnetic resonance spectroscopy (NMR), and biological evaluation of four pairs of enantiomeric heterochiral TBA analogues. The four TBA derivatives of the d-series are composed by d-residues except for one l-thymidine in the small TT loops, while their four enantiomers are composed by l-residues except for one d-thymidine in the same TT loop region. Apart from the left-handedness for the l-series TBA derivatives, CD and NMR measurements have shown that all TBA analogues are able to adopt the antiparallel, monomolecular, ‘chair-like’ G-quadruplex structure characteristic of the natural D-TBA. However, although all eight TBA derivatives are endowed with remarkable cytotoxic activities against colon and lung cancer cell lines, only TBA derivatives of the l-series show no anticoagulant activity and are considerably resistant in biological environments.
Optogenetic control of Neisseria meningitidis Cas9 genome editing using an engineered, light-switchable anti-CRISPR protein
Authors: Hoffmann Mareike D , Mathony Jan , Upmeier zu Belzen Julius , Harteveld Zander , Aschenbrenner Sabine , Stengl Christina , Grimm Dirk , Correia Bruno E , Eils Roland , Niopek Dominik
Published: November 2020

Optogenetic control of CRISPR–Cas9 systems has significantly improved our ability to perform genome perturbations in living cells with high precision in time and space. As new Cas orthologues with advantageous properties are rapidly being discovered and engineered, the need for straightforward strategies to control their activity via exogenous stimuli persists. The Cas9 from Neisseria meningitidis (Nme) is a particularly small and target-specific Cas9 orthologue, and thus of high interest for in vivo genome editing applications. Here, we report the first optogenetic tool to control NmeCas9 activity in mammalian cells via an engineered, light-dependent anti-CRISPR (Acr) protein. Building on our previous Acr engineering work, we created hybrids between the NmeCas9 inhibitor AcrIIC3 and the LOV2 blue light sensory domain from Avena sativa. Two AcrIIC3-LOV2 hybrids from our collection potently blocked NmeCas9 activity in the dark, while permitting robust genome editing at various endogenous loci upon blue light irradiation. Structural analysis revealed that, within these hybrids, the LOV2 domain is located in striking proximity to the Cas9 binding surface. Together, our work demonstrates optogenetic regulation of a type II-C CRISPR effector and might suggest a new route for the design of optogenetic Acrs.
Protein carbamylation and chronic kidney disease progression in the Chronic Renal Insufficiency Cohort Study
Authors: Kalim Sahir , Berg Anders H , Karumanchi Subbian Ananth , Thadhani Ravi , Allegretti Andrew S , Nigwekar Sagar , Zhao Sophia , Srivastava Anand , Raj Dominic , Deo Rajat , Frydrych Anne , Chen Jing , Sondheimer James , Shafi Tariq , Weir Matthew , Lash James P ,   the CRIC Study Investigators, Appel Lawrence J , Feldman Harold I , Go Alan S , He Jiang , Nelson Robert G , Rahman Mahboob , Rao Panduranga S , Shah Vallabh O , Townsend Raymond R , Unruh Mark L
Published: November 2020

Background

Protein carbamylation is a post-translational protein modification caused, in part, by exposure to urea’s dissociation product cyanate. Carbamylation is linked to cardiovascular outcomes and mortality in dialysis-dependent end-stage kidney disease (ESKD), but its effects in earlier pre-dialysis stages of chronic kidney disease (CKD) are not established.

Methods

We conducted two nested case–control studies within the Chronic Renal Insufficiency Cohort Study. First, we matched 75 cases demonstrating CKD progression [50% estimated glomerular filtration rate (eGFR) reduction or reaching ESKD] to 75 controls (matched on baseline eGFR, 24-h proteinuria, age, sex and race). In the second study, we similarly matched 75 subjects who died during follow-up (cases) to 75 surviving controls. Baseline carbamylated albumin levels (C-Alb, a validated carbamylation assay) were compared between cases and controls in each study.

Results

At baseline, in the CKD progression study, other than blood urea nitrogen (BUN) and smoking status, there were no significant differences in any matched or other parameter. In the mortality group, the only baseline difference was smoking status. Adjusting for baseline differences, the top tertile of C-Alb was associated with an increased risk of CKD progression [odds ratio (OR) = 7.9; 95% confidence interval (CI) 1.9–32.8; P = 0.004] and mortality (OR = 3.4; 95% CI 1.0–11.4; P = 0.05) when compared with the bottom tertile. C-Alb correlated with eGFR but was more strongly correlated with BUN.

Conclusions

Our data suggest that protein carbamylation is a predictor of CKD progression, beyond traditional risks including eGFR and proteinuria. Carbamylation’s association with mortality was smaller in this limited sample size.
Overexpression and Inhibition of 3-Hydroxy-3-Methylglutaryl-CoA Synthase Affect Central Metabolic Pathways in Tobacco
Authors: Liao Pan , Lung Shiu-Cheung , Chan Wai Lung , Hu Menglong , Kong Geoffrey Kwai-Wai , Bach Thomas J , Hao Quan , Lo Clive , Chye Mee-Len
Published: November 2020

Little has been established on the relationship between the mevalonate (MVA) pathway and other metabolic pathways except for the sterol and glucosinolate biosynthesis pathways. In the MVA pathway, 3-hydroxy-3-methylglutaryl-CoA synthase (HMGS) catalyzes the condensation of acetoacetyl-CoA and acetyl-CoA to form 3-hydroxy-3-methylglutaryl-coenzyme A. Our previous studies had shown that, while the recombinant Brassica juncea HMGS1 (BjHMGS1) mutant S359A displayed 10-fold higher enzyme activity than wild-type (wt) BjHMGS1, transgenic tobacco overexpressing S359A (OE-S359A) exhibited higher sterol content, growth rate and seed yield than OE-wtBjHMGS1. Herein, untargeted proteomics and targeted metabolomics were employed to understand the phenotypic effects of HMGS overexpression in tobacco by examining which other metabolic pathways were affected. Sequential window acquisition of all theoretical mass spectra quantitative proteomics analysis on OE-wtBjHMGS1 and OE-S359A identified the misregulation of proteins in primary metabolism and cell wall modification, while some proteins related to photosynthesis and the tricarboxylic acid cycle were upregulated in OE-S359A. Metabolomic analysis indicated corresponding changes in carbohydrate, amino acid and fatty acid contents in HMGS-OEs, and F-244, a specific inhibitor of HMGS, was applied successfully on tobacco to confirm these observations. Finally, the crystal structure of acetyl-CoA-liganded S359A revealed that improved activity of S359A likely resulted from a loss in hydrogen bonding between Ser359 and acyl-CoA, which is evident in wtBjHMGS1. This work suggests that regulation of plant growth by HMGS can influence the central metabolic pathways. Furthermore, this study demonstrates that the application of the HMGS-specific inhibitor (F-244) in tobacco represents an effective approach for studying the HMGS/MVA pathway.
Real-time simulation of (2+1)-dimensional lattice gauge theory on qubits
Authors: Yamamoto Arata
Published: November 2020

We study the quantum simulation of $Z_2$ lattice gauge theory in 2+1 dimensions. The dual variable formulation, the so-called Wegner duality, is utilized for reducing redundant gauge degrees of freedom. The problem of artificial charge unconservation is resolved for any charge distribution. As a demonstration, we simulate the real-time evolution of the system with two static electric charges, i.e. with two temporal Wilson lines. Some results obtained by a simulator (with no hardware noise) and a real quantum computing device (with sizable hardware noise) are shown.
Quantitative Evaluation of Embolic Load in Femoral and Tibial Shaft Fractures Treated With Reamed Intramedullary Fixation
Authors: Lee Christopher , O'Hara Nathan N. , Conti Bianca , Hyder Mary , Sepehri Aresh , Rudnicki Joshua , Hannan Zachary , Connelly Daniel , Baker Mitchell , Pollak Andrew N. , O'Toole Robert V.
Published: November 2020

Objectives:

To compare the volume of embolic load during intramedullary fixation of femoral and tibial shaft fractures. Our hypothesis was that tibial intramedullary nails (IMNs) would be associated with less volume of intravasation of marrow than IM nailing of femur fractures.

Design:

Prospective observational study.

Setting:

Urban Level I trauma center.

Patients/Participants:

Twenty-three patients consented for the study: 14 with femoral shaft fractures and 9 with tibial shaft fractures.

Intervention:

All patients underwent continuous transesophageal echocardiography, and volume of embolic load was evaluated during 5 distinct stages: postinduction, initial guide wire, reaming (REAM), nail insertion, and postoperative.

Main Outcome Measurements:

Volume of embolic load was measured based on previously described luminosity scores. The embolic load based on fracture location and procedure stage was evaluated using a mixed effects model.

Results:

The IMN procedure increased the embolic load by 215% (−12% to 442%, P = 0.07) in femur patients relative to tibia patients after adjusting for baseline levels. Of the 5 steps measured, REAM was associated with the greatest increase in embolic load relative to the guide wire placement and controlling for fracture location (421%, 95% confidence interval: 169%–673%, P < 0.01).

Conclusions:

Femoral shaft IMN fixation was associated with a 215% increase in embolic load in comparison with tibial shaft IMN fixation, with the greatest quantitative load during the REAM stage; however, both procedures produce embolic load.

Level of Evidence:

Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.
Validation of Relative Motion Measurement Method of Lateral Compression Pelvic Fractures During Examination Under Anesthesia
Authors: Jacobs Robert , Kleweno Conor , Wallace Stephen , Elliott Iain , Patterson Joseph , Agel Julie , Firoozabadi Reza
Published: November 2020

Objectives:

To determine if the relative distance between the acetabular teardrops on unstressed and lateral compressive stress examination under anesthesia (EUA) pelvic fluoroscopic images is reproducible between independent reviewers.

Design:

Retrospective database review.

Setting:

Level 1 trauma center.

Patients/Intervention:

Fifty-eight patients with a lateral compression type 1 pelvic ring injury who underwent EUA.

Main Outcome Measure:

Validation of EUA objective measurements between blinded, independent reviewers using interclass and intraclass correlation coefficients.

Results:

There was excellent interobserver and intraobserver reliability between all reviewers. Values for each intraclass correlation coefficients (including 95% confidence intervals) were between 0.96 (0.95–0.098) and 0.99 (0.99–0.99) for all measurements. P values were <0.0001 for all measured parameters.

Conclusions:

The relative change in distance between the acetabular tear drops during lateral compressive EUA of lateral compression type 1 pelvic injuries is reliable between independent reviewers. This allows for accurate, objective measurement of pelvic motion independent of patient size or body habitus.

Level of Evidence:

Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Prospective Randomized Trial on Smoking Cessation in Orthopaedic Trauma Patients: Results From the Let’s STOP (Smoking in Trauma Orthopaedic Patients) Now Trial
Authors: Matuszewski Paul E. , Joseph Katherine , O'Hara Nathan N. , DiClemente Carlo , O'Toole Robert V.
Published: November 2020

Objectives:

Determine if extended inpatient counseling increases smoking cessation.

Design:

Prospective randomized trial.

Setting:

Level I trauma center.

Patients/Participants:

Current smokers with an operative fracture.

Intervention:

Randomly assigned to control (no counseling), brief counseling (inpatient counseling), or extended counseling (brief counseling plus follow-up counseling) groups in a 1:3:3 ratio.

Main Outcome Measurements:

Smoking cessation confirmed by exhaled carbon monoxide at 3 and 6 months. Secondary outcomes are proportion accepting services from a nationally based quitline.

Results:

Overall, 266 patients participated, with 40, 111, and 115 patients in the control and 2 treatment groups, respectively. At 3 months, 17% of control patients versus 11% in the brief counseling and 10% in the extended counseling groups quit smoking, respectively (P = 0.45, 0.37). At 6 months, 15% of control, and 10% and 5% of the respective counseling groups quit (P = 0.45, 0.10). Extended counseling patients were 3 times more likely to accept referral to a quitline [odds ratio (OR), 3.1; 95% confidence interval (CI), 1.4-6.9], and brief counseling patients were more than 2 times as likely to accept referral (OR, 2.3; 95% CI, 1.0-5.1) than the control group. Extended counseling (OR, 8.2; 95% CI, 1.0-68.5) and brief counseling (OR, 5.3; 95% CI, 0.6-44.9) patients were more likely to use quitline services than the control group.

Conclusion:

Increasing levels of inpatient counseling can improve successful referral to a smoking quitline, but it does not seem to influence quit rates among orthopaedic trauma patients. Extended counseling does not appear to provide substantial benefit over brief counseling.

Level of Evidence:

Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
Acellular Porcine Corneal Stroma May Not Be Optimal for Peripheral Keratoplasty: Reports of 2 Cases
Authors: Li Saiqun , Xiao Peng , Deng Yuqing , Li Meng , Wang Qian , Yuan Jin
Published: November 2020

Purpose:

Although acellular porcine corneal stroma (APCS) is a promising alternative to the human donor cornea for lamellar keratoplasty, here, we report 2 patients who exhibited persistent epithelial defects and sterile keratolysis after APCS transplantation to treat peripheral corneal diseases.

Methods:

Two patients with different peripheral corneal diseases underwent lamellar keratoplasty by using D-shaped lamellar APCS as graft materials. Standard keratoplasty postoperative treatments, including topical antibiotic-corticosteroid, tacrolimus, and artificial tears, were applied.

Results:

Patient 1 was a 7-year-old boy with limbal dermoid, and patient 2 was a 50-year-old man suffered from simultaneous Mooren ulcer with pterygium. Both patients developed persistent graft epithelial defects postoperatively, which were refractory to conventional nonsurgical therapies. The APCS grafts were noted to start sterile keratolysis at approximately 1 month after implantation and were completely dissolved within 3 months, leaving vascularized scars in the previously grafted area.

Conclusions:

These 2 cases demonstrated that given the high risk of postoperative persistent epithelial defect and sterile keratolysis, the application of APCS in peripheral keratoplasty may need further evaluation.
Solitary Conjunctivocorneal Plasmacytoma Arising After Cataract Surgery
Authors: Davidson Max , Shah Vallari , Shah Chirag , Shahnazaryan David , Jones Sophie
Published: November 2020

Purpose:

To report a case of solitary plasmacytoma of the conjunctiva with corneal encroachment and to review the literature of all published cases.

Methods:

A 70-year-old man presented with 1-month history of pain and watering in the right eye, 7 months after undergoing cataract surgery in the same eye.

Results:

The mass was surgically excised. Pathology and immunohistochemistry were consistent with plasmacytoma. Staging studies found no evidence of systemic disease.

Conclusions:

To our knowledge, this is the first case of plasmacytoma in the literature to involve the cornea. This case was not associated with systemic disease. Surgical excision and brachytherapy remain options for cases without corneal involvement.
Indications for Wear, Visual Outcomes, and Complications of Custom Imprint 3D Scanned Scleral Contact Lens Use
Authors: Silverman Joanna I. M. , Huffman James M. , Zimmerman M. Bridget , Ling Jennifer J. , Greiner Mark A.
Published: November 2020

Purpose:

To report indications for wear, visual outcomes, and complications of EyePrintPRO (EPP) scleral contact lens (SCL) use.

Methods:

A retrospective review identified all patients fitted with this device between December 2013 and March 2018. Baseline demographics, wear indication, and contact lens history were determined. Habitual-corrected visual acuity was measured at baseline and follow-up. Adverse wear symptoms and signs, reprinting, and device cessation were tracked.

Results:

Ninety-five eyes from 69 patients were followed for a median of 12.1 months (interquartile range 4.4–19.6). Indications for wear included vision improvement and/or ocular surface stabilization in the setting of irregular corneal shape (n = 68 eyes, 72%), ocular surface disease (n = 17, 18%), exposure keratopathy (n = 7, 7%), neurotrophic keratitis (n = 5, 5%), and extracorneal topographical abnormalities preventing noncustom lens fitting such as glaucoma drainage devices (n = 8, 8%). Median habitual-corrected visual acuity improved from 0.67 to 0.08 (P = 0.0003). One-third of eyes (33.1%) developed adverse wear symptoms. Fifteen of 95 eyes (16%) developed adverse wear signs. Device cessation occurred in 10 eyes (10.5%) and reprinting occurred in 14 eyes (14.7%) unrelated to prior lens wear or indication (P = 0.67 and 0.15, respectively). In eyes that previously failed SCLs (n = 56), 12 eyes required reprinting and 49 eyes continued use.

Conclusions:

Indications for EPP wear include irregular corneal shape, ocular surface disease, and extracorneal topographic abnormalities. Visual acuity improves with the use of EPP. Clinicians and patients should be aware of potential adverse wear symptoms/signs and device cessation that may occur with EPP use. EPP is a viable salvage therapy in eyes that previously failed SCLs.
Workers’ Compensation Elements in Different Jurisdictions in the United States
Authors: Taylor Tanisha K. , Mueller Kathryn L. , Blink Robert C. , McKinney David W. , Silverman Warren , Das Rupali
Published: November 2020

Over the decades, the workers’ compensation system has provided many injured workers with a significant guarantee of both medical and financial support when they have been injured on the job. To be effective, workers’ compensation systems at a minimum should include principles that require the addressing of medical causation, determination of an individual's functional ability both pre- and post-injury to include activity restrictions, return-to-work capability and disability, meeting jurisdiction-specific reporting requirements of the workers’ compensation reporting requirements, and having knowledge of other perspectives of the various authorities and jurisdictions present in the United States. ACOEM lays out a description of various aspects of workers’ compensations systems in the United States, with recommendations for minimal standards and best practices. This paper limits itself to the discussion of jurisdictions within the United States and ACOEM strongly recommends that providers consult directly with the states in which they are working as there are state variations in workers’ compensation.
Cross-cultural Validation of the Spiritual Interests Related to Illness Tool-Korean Version
Authors: Kang Kyung-Ah , Mamier Iris , Chun Jiyoung , Taylor Elizabeth Johnston
Published: November 2020

Living with a terminal illness, whether as a patient or as the family member of a patient, often involves spiritual challenges. The ability to ascertain and meet the spiritual needs of terminally ill patients and their loved ones is an essential part of providing compassionate and competent whole person care. This study aimed to adapt the original Spiritual Interests Related to Illness Tool (SpIRIT) for use in Korea (SpIRIT-K) and to assess its reliability and validity as a tool to determine the spiritual needs of terminally ill Korean patients and their caregivers. After translation–back-translation and content validity indexing, SpIRIT-K was administered to 106 terminally ill patients and 105 family caregivers in 20 sites across South Korea. SPSS and AMOS were used for evaluating validity and reliability. The 37-item SpIRIT-K consisted of 8 factors (subscales), with each subscale consisting of between 3 and 8 items. Evidence for structural and convergent validity was observed. Internal reliability of the overall scale was 0.95. The findings showed patients and family caregivers reported no significant difference in 7 of the 8 subscales, demonstrating known-groups validity. The rigorous process of establishing cross-cultural validity for this scale provided evidence supporting its validity and reliability. The findings suggest that SpIRIT-K is suitable for research and for clinical purposes in palliative care settings in South Korea. This development also allows for comparisons between Korean and North American cultures in terms of spiritual needs among terminally ill patients and their caregivers.
Technical Report: The Mechanism of Contour Interaction Differs in the Fovea and Periphery
Authors: Pluháček František , Bedell Harold E. , Siderov John , Kratkoczká Daniela
Published: November 2020

SIGNIFICANCE

Both foveal and peripheral contour interactions are based on, as yet, unexplained neural mechanisms. Our results show that, unlike foveal contour interaction, peripheral contour interaction cannot be explained on the basis of the antagonistic structure of neural receptive fields.

PURPOSE

Foveal contour interaction is markedly reduced for mesopic compared with photopic targets. This finding is consistent with an explanation based on the antagonistic structure of neural receptive fields. However, no reduction was found for low-luminance targets in the periphery, possibly because the luminances used previously remained substantially above peripheral scotopic detection thresholds. In this study, we compared foveal and peripheral contour interactions for long-wavelength photopic and mesopic targets, which would be expected to significantly elevate the peripheral retinal detection threshold.

METHODS

Five normal observers viewed a randomly selected Sloan letter surrounded by four flanking bars at several edge-to-edge separations (min arc). Photopic and mesopic stimuli were viewed foveally and at 6° peripherally through a selective red filter that ensured that mesopic targets were within 1 log unit of detection threshold at both retinal locations.

RESULTS

Whereas the magnitude of foveal contour interaction was substantially less at mesopic compared with photopic luminance (20 vs. 46% reduction of percent correct, on average), no significant difference was observed in peripheral contour interaction, which had average mesopic and photopic magnitudes of 38 and 40%. Moreover, confusion matrices representing photopic and mesopic contour interaction differed in the fovea but not in the periphery. The extent of contour interaction did not change with luminance at either retinal location.

CONCLUSIONS

Our results indicate that, although the characteristics of foveal contour interaction can be accounted for by the antagonistic structure of neural receptive fields, the same mechanism is not compatible with the characteristics of peripheral contour interaction.
Effectiveness of Botulinum Toxin A Injection in Managing Mobility-Related Outcomes in Adult Patients With Cerebral Palsy
Authors: Andraweera Nalinda D. , Andraweera Prabha H. , Lassi Zohra S. , Kochiyil Venugopal
Published: November 2020

Purpose

Intramuscular botulinum toxin A (BTX-A) is used in the management of focal spasticity in cerebral palsy (CP). The aim was to conduct a systematic review to assess current literature on the use of BTX-A in the management of mobility-related outcomes among adult persons with spastic CP.

Methods

All studies reporting on the use of BTX-A in the management of spastic CP among adult persons were identified by searching the following electronic databases: PubMed, CINAHL, the Cochrane Library, and EMBASE.

Results

Six studies were included in the review. Most studies were conducted in mixed patient groups comprising patients with movement disorders, traumatic brain injury, CP, and other disorders requiring therapy for spasticity. BTX-A was shown to be effective in improving spasticity-related outcomes among persons with CP, but mixed results were shown for functional outcomes.

Conclusions

More studies are required on exclusive CP cohorts using recommended and currently used scales, incorporating quality of life and patient satisfaction scales. Results from long-term follow-up studies will be valuable for better evaluation of the effectiveness of BTX-A in the management of spasticity-related outcomes among adult persons with CP.
Differences in Plastic Surgery Training Programs in China and the United States: Similarities, Pitfalls, and Opportunities
Authors: An Yang , Liu Jinju , Zhao Jianfang , Li Dong
Published: November 2020

As fueled by the booming of China's plastic surgery industry, the demand for prominent plastic surgeons has been growing. Accordingly, a better and more standard training system of plastic surgery specialists should be urgently implemented in China. To delve into and optimize the training system of this study, Peking University Health Science Center and Harvard Medical School are selected as the representatives of China and the United States, and the plastic surgery specialist training system between these 2 countries are compared based on literature research. As revealed from the results, the United States has gained sufficient experience in training of plastic surgery specialists. Moreover, the management agency of such training is more professional, as characterized by its longer development history, higher access requirement, more standard training program, higher training demands, as well as more quantitative training assessment. Thus, there is rich experience of the United States that can be referenced by China.
Why are population growth rate estimates of past and present hunter–gatherers so different?
Authors: Tallavaara Miikka , Jørgensen Erlend Kirkeng
Published: November 2020

Hunter–gatherer population growth rate estimates extracted from archaeological proxies and ethnographic data show remarkable differences, as archaeological estimates are orders of magnitude smaller than ethnographic and historical estimates. This could imply that prehistoric hunter–gatherers were demographically different from recent hunter–gatherers. However, we show that the resolution of archaeological human population proxies is not sufficiently high to detect actual population dynamics and growth rates that can be observed in the historical and ethnographic data. We argue that archaeological and ethnographic population growth rates measure different things; therefore, they are not directly comparable. While ethnographic growth rate estimates of hunter–gatherer populations are directly linked to underlying demographic parameters, archaeological estimates track changes in the long-term mean population size, which reflects changes in the environmental productivity that provide the ultimate constraint for forager population growth. We further argue that because of this constraining effect, hunter–gatherer populations cannot exhibit long-term growth independently of increasing environmental productivity.

This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography’.
The past, present and future of skeletal analysis in palaeodemography
Authors: McFadden Clare
Published: November 2020

The study of past population dynamics is imperative to our understanding of demographic processes in the context of biology, evolution, environment and sociocultural factors. Retrospective consideration of a population's capacity to resist and adapt to change aims to contribute insights into our past, a point of comparison to the present and predictions for the future. If these aims are to be achieved, the accuracy and precision of palaeodemographic methods are of paramount importance. This article considers the emergence of skeletally based palaeodemographic methods, specifically life tables and demographic proxies, and early controversies and issues. It details the process of methodological development and refinement, and success in addressing many of the historical limitations. The contribution and potential of skeletally based methods are discussed and comparisons and contrasts made with alternative palaeodemographic approaches, and avenues for future research are proposed. Ultimately, it is concluded that skeletal analysis provides unique opportunities to investigate population dynamics with spatial specificity, examine individuals and groups within a population, and integrate demographic and pathological information to evaluate population health in the past.

This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography'.
Archaeology, demography and life history theory together can help us explain past and present population patterns
Authors: Shennan Stephen , Sear Rebecca
Published: November 2020

Population matters. Demographic patterns are both a cause and a consequence of human behaviour in other important domains, such as subsistence, cooperation, politics and culture. Demographers interested in contemporary and recent historical populations have rich data at their fingertips; the importance of demography means many interested parties have gathered demographic data, much of which is now readily available for all to explore. Those interested in the demography of the distant past are not so fortunate, given the lack of written records. Nevertheless, the emergence in recent years of a new interest in the demography of ancient populations has seen the development of a range of new methods for piecing together archaeological, skeletal and DNA evidence to reconstruct past population patterns. These efforts have found evidence in support of the view that the relatively low long-term population growth rates of prehistoric human populations, albeit ultimately conditioned by carrying capacities, may have been owing to ‘boom–bust’ cycles at the regional level; rapid population growth, followed by population decline. In fact, this archaeological research may have come to the same conclusion as some contemporary demographers: that demography can be remarkably hard to predict, at least in the short term. It also fits with evidence from biology that primates, and particularly humans, may be adapted to environmental variability, leading to associated demographic stochasticity. This evidence of the fluctuating nature of human demographic patterns may be of considerable significance in understanding our species' evolution, and of understanding what our species future demographic trajectories might be.

This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography’.
The Neolithic Demographic Transition in the Central Balkans: population dynamics reconstruction based on new radiocarbon evidence
Authors: Porčić Marko , Blagojević Tamara , Pendić Jugoslav , Stefanović Sofija
Published: November 2020

In this paper, we test the hypothesis of the Neolithic Demographic Transition in the Central Balkan Early Neolithic (6250–5300 BC) by applying the method of summed calibrated probability distributions to the set of more than 200 new radiocarbon dates from Serbia. The results suggest that there was an increase in population size after the first farmers arrived to the study area around 6250 BC. This increase lasted for approximately 250 years and was followed by a decrease in the population size proxy after 6000 BC, reaching its minimum around 5800 BC. This was followed by another episode of growth until 5600 BC when population size proxy rapidly declined, reaching the minimum again around 5500 BC. The reconstructed intrinsic growth rate value indicates that the first episode of growth might have been fuelled both by high fertility and migrations, potentially related to the effects of the 8.2 ky event. The second episode of population growth after 5800 BC was probably owing to the high fertility alone. It remains unclear what caused the episodes of population decrease.

This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography'.
Approaching prehistoric demography: proxies, scales and scope of the Cologne Protocol in European contexts
Authors: Schmidt Isabell , Hilpert Johanna , Kretschmer Inga , Peters Robin , Broich Manuel , Schiesberg Sara , Vogels Oliver , Wendt Karl Peter , Zimmermann Andreas , Maier Andreas
Published: November 2020

In many theories on the social and cultural evolution of human societies, the number and density of people living together in a given time and region is a crucial factor. Because direct data on past demographic developments are lacking, and reliability and validity of demographic proxies require careful evaluation, the topic has been approached from several different directions. This paper provides an introduction to a geostatistical approach for estimating prehistoric population size and density, the so-called Cologne Protocol and discusses underlying theoretical assumptions and upscaling transfer-functions between different spatial scale levels. We describe and compare the specifics for farming and for foraging societies and, using examples, discuss a diachronic series of estimates, covering the population dynamics of roughly 40 kyr of European prehistory. Ethnohistoric accounts, results from other approaches—including absolute (ethno-environmental models) and relative estimates (site-numbers, dates as data, etc.) allow a first positioning of the estimates within this field of research. Future enhancements, applications and testing of the Cologne Protocol are outlined and positioned within the general theoretical and methodological avenues of palaeodemographic research. In addition, we provide manuals for modelling Core Areas in MapInfo, ArcGIS, QGIS/Sagaand R.

This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography’.
Carrying capacity, population density and the later Pleistocene expression of backed artefact manufacturing traditions in Africa
Authors: Archer W.
Published: November 2020

As is the case today, both climate variability and population density influenced human behavioural change in the past. The mechanisms underpinning later Pleistocene human behavioural evolution, however, remain contested. Many complex behaviours evolved in Africa, but early evidence for these behaviours varies both spatially and temporally. Scientists have not been able to explain this flickering pattern, which is present even in sites and regions clearly occupied byHomo sapiens. To explore this pattern, here the presence and frequency of evidence for backed stone artefact production are modelled against climate-driven, time-series population density estimates (Timmermann and Friedrich. 2016Nature538, 92. (doi:10.1038/nature19365)), in all known African Late Pleistocene archaeological sites (n= 116 sites,n= 409 assemblages,n= 893 dates). In addition, a moving-window, site density population estimate is included at the scale of southern Africa. Backed stone artefacts are argued in many archaeological contexts to have functioned in elaborate technologies like composite weapons and, in the African Pleistocene, are accepted proxies for cultural complexity. They show a broad but sporadic distribution in Africa, prior to their association withHomo sapiensdispersing into Europe 45–40 ka. Two independent population estimates explain this pattern and potentially implicate the interaction of climate change and demography in the expression of cultural complexity in African PleistoceneHomo sapiens.

This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography’.
Late Glacial and Early Holocene human demographic responses to climatic and environmental change in Atlantic Iberia
Authors: McLaughlin T. Rowan , Gómez-Puche Magdalena , Cascalheira João , Bicho Nuno , Fernández-López de Pablo Javier
Published: November 2020

Successive generations of hunter–gatherers of the Late Glacial and Early Holocene in Iberia had to contend with rapidly changing environments and climatic conditions. This constrained their economic resources and capacity for demographic growth. The Atlantic façade of Iberia was occupied throughout these times and witnessed very significant environmental transformations. Archaeology offers a perspective on how past human population ecologies changed in response to this scenario. Archaeological radiocarbon data are used here to reconstruct demographics of the region over the long term. We introduce various quantitative methods that allow us to develop palaeodemographic and spatio-temporal models of population growth and density, and compare our results to independent records of palaeoenvironmental and palaeodietary change, and growth rates derived from skeletal data. Our results demonstrate that late glacial population growth was stifled by the Younger Dryas stadial, but populations grew in size and density during the Early to Middle Holocene transition. This growth was fuelled in part by an increased dependence on marine and estuarine food sources, demonstrating how the environment was linked to demographic change via the resource base, and ultimately the carrying capacity of the environment.

This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography’.
Effect of host-mimicking medium and biofilm growth on the ability of colistin to kill Pseudomonas aeruginosa
Authors: Sweeney Esther , Sabnis Akshay , Edwards Andrew M. , Harrison Freya
Published: November 2020

In vivo biofilms cause recalcitrant infections with extensive and unpredictable antibiotic tolerance. Here, we demonstrate increased tolerance of colistin by

Pseudomonas aeruginosa

when grown in medium that mimics cystic fibrosis (CF) sputum versus standard medium in in vitro biofilm assays, and drastically increased tolerance when grown in an ex vivo CF model versus the in vitro assay. We used colistin conjugated to the fluorescent dye BODIPY to assess the penetration of the antibiotic into ex vivo biofilms and showed that poor penetration partly explains the high doses of drug necessary to kill bacteria in these biofilms. The ability of antibiotics to penetrate the biofilm matrix is key to their clinical success, but hard to measure. Our results demonstrate both the importance of reduced entry into the matrix in in vivo-like biofilm, and the tractability of using a fluorescent tag and benchtop fluorimeter to assess antibiotic entry into biofilms. This method could be a relatively quick, cheap and useful addition to diagnostic and drug development pipelines, allowing the assessment of drug entry into biofilms, in in vivo-like conditions, prior to more detailed tests of biofilm killing.
Altered anterior default mode network dynamics in progressive multiple sclerosis
Authors: Bommarito Giulia , Tarun Anjali , Farouj Younes , Preti Maria Giulia , Petracca Maria , Droby Amgad , El Mendili Mohamed Mounir , Inglese Matilde , Van De Ville Dimitri
Published: November 2020

Background

Modifications in brain function remain relatively unexplored in progressive multiple sclerosis (PMS), despite their potential to provide new insights into the pathophysiology of this disease stage.

Objectives

To characterize the dynamics of functional networks at rest in patients with PMS, and the relation with clinical disability.

Methods

Thirty-two patients with PMS underwent clinical and cognitive assessment. The dynamic properties of functional networks, retrieved from transient brain activity, were obtained from patients and 25 healthy controls (HC). Sixteen HC and 19 patients underwent a one-year follow-up clinical and imaging assessment. Differences in the dynamic metrics between groups, their longitudinal changes, and the correlation with clinical disability were explored.

Results

PMS patients, compared to HC, showed a reduced dynamic functional activation of the anterior default mode network (aDMN) and its opposite-signed coactivation with the executive-control network, at baseline and follow-up. Processing speed and visuo-spatial memory negatively correlated to aDMN dynamic activity. The anti-coupling between aDMN and auditory/sensory-motor network, temporal-pole/amygdala or salience networks were differently associated to separate cognitive domains.

Conclusion

Patients with PMS presented an altered aDMN functional recruitment and anti-correlation with ECN. The aDMN dynamic functional activity and interaction with other networks explained cognitive disability.
Modelling the impact of health-related variables, age, migration, and socio-economic factors in the geographical distribution of early tested case-fatality risks associated with COVID-19 in Mexico
Authors: Ramírez-Aldana Ricardo , Gomez-Verjan Juan Carlos , Bello-Chavolla Omar Yaxmehen , García-Peña Carmen
Published: November 2020

COVID-19 is a respiratory disease caused by SARS-CoV-2, which has significantly impacted economic and public healthcare systems world-wide. SARS-CoV-2 is highly lethal in older adults (>65 years old) and in cases with underlying medical conditions including chronic respiratory diseases, immunosuppression, and cardio-metabolic diseases including severe obesity, diabetes, and hypertension. The course of the COVID-19 pandemic in Mexico has led to many fatal cases in younger patients attributable to cardio-metabolic conditions. Here, we aimed to perform an early spatial epidemiological analysis for the COVID-19 outbreak in Mexico to evaluate how tested case-fatality risks (t-CFRs) are geographically distributed and to explore spatial predictors of early t-CFRs considering the variation of their impact on COVID-19 fatality across different states in Mexico, controlling for the severity of the disease. As results, considering health related variables; diabetes and obesity were highly associated with COVID-19 fatality. We identified that both external and internal migration had an important impact over early COVID-19 risks in Mexico, with external migration having the second highest impact when analyzing Mexico as a whole. Physicians-to-population ratio, as a representation of urbanity, population density, and overcrowding households, has the highest impact on t-CFRs, whereas the age group of 10 to 39 years was associated with lower risks. Geographically, the states of Quintana Roo, Baja California, Chihuahua, and Tabasco had higher t-CFRs and relative risks comparing with a national standard, suggesting that risks in these states were above of what was nationally expected; additionally, the strength of the association between some spatial predictors and the COVID-19 fatality risks variates by zone depending on the predictor.
A randomized trial on the regular use of potent mouthwash in COVID-19 treatment
Authors: Mukhtar Khalid , Qassim Suelen , Al Qahtani Shaikha Ali , Danjuma Mohamed Ibn-Masud , Mohamedali Mohamed , Farhan Housamaddeen Al , Khudair Mohammed F. , El Tayeh Abdel Rehim , Al-Dosari Mohammed , Babiker Mohamed Elhassan , Hassib Ahmed , Elmustafa Rumaisa Mohamed , Elhadary Wesal , Abdulkarim Morwan , Singh Rajvir , Al.Maslamani Muna
Published: November 2020

1.

In this work we tried to study the effect of the regular use of potent mouthwash in COVID19 cases, on the premise that it may speedup the recovery, through the repeated reduction of microbial load, of both, the 2019-nCOV and oral microbiota; thus slowing the disease progression and lowering the incidence of superinfections.

Through a randomized controlled trial, a mixed solution of Hydrogen peroxide 2% and chlorhexidine gluconate, to be used for oral rinsing and gargling three times daily, was tested in cases admitted to COVID treatment facility, versus the standard (only) COVID19-treatment protocol, starting with 46 cases in each group, matched in terms of disease severity, of symptoms, and average cycle threshold value (CT-value) for the COVID PCR test on diagnosis.

Our findings showed statistically significant improvement in terms of a higher conversion rate to “COVID19-negative PCR” by five days of treatment (6/46 Vs 0/46), improvement in “symptoms severity” after two days of treatment, and less intubation and mortality (0/46 Vs 3/46) with all P-value < 0.05. There was also a trend of improvement in other outcome variables, though with no statistically significant difference; namely “shorter hospital stays,” “less progression in Oxygen requirements”, “less rate of plasma transfusion”, and better “gross extent of improvement”.

Our findings support a beneficial role in treating active cases (Disease) and anticipates better outcome should implemented earlier in course of the disease; thus, suggest a role in limiting the spread (Pandemic), as an additional preventive method. Additionally, we think the repeated reduction in the microbial load might have been sufficient to induce a strain in a possible viral-microbial interaction, resulting in slowing down of the disease progress.
Delay-robust Estimation of the Reproduction Number and Comparative Evaluation on Generated Synthetic Data
Authors: Heidrich Benedikt , Mühlpfordt Tillmann , Hagenmeyer Veit , Mikut Ralf
Published: November 2020

Abstract

The reproduction number is an indicator of the evolution of an epidemic. Consequently, accurate estimators for this number are essential for decision making in politics. Many estimators use filtered data as input to compensate for fluctuations of reported cases. However, for daily-based estimations, this filtering leads to delays. Some approaches use small window sizes for filtering to overcome this issue. This, in turn, leads to an increased periodic behavior of estimators. To overcome these issues, in the present paper, we introduce an estimator for the reproduction number that uses an acausally filtered number of cases as input, hence avoiding both the periodic behavior and the delay. For the filter size, we suggest using a multiple of one week since reported cases often exhibit a weekly pattern. We show that this approach is more robust against periodicities, and that it does not exhibit any delays in the estimation compared to estimators with smaller filter sizes.

Moreover, often it is hard to examine estimators in detail because a ground truth is missing. For analyzing different properties of the estimators, we propose a method to generate synthetic datasets that can be taken as ground truths. Importantly, the synthetic data contains all relevant real-world behavior.

Finally, we apply the proposed estimator to the publicly available coronavirus disease 2019 (COVID-19) data for Germany. We compare the proposed estimator to two estimators used by the federal German Robert Koch Institut (RKI). We observe that our estimator is more stable than the benchmarks especially if the reproduction number is close to 1. Based on the observation that the proposed estimator appears more robust, it may be a useful asset when considering governmental interventions.

The accompanying source code is published under the Apache-2.0 license (https://github.com/timueh/C0VID-19).