bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and Evaluation of Compliant Constant-Force Mechanisms
Authors: Millar Alisa J. , Howell Larry L. , Leonard James N.
Published: February 2021

Compliant constant-force mechanisms combine the effects of mechanical advantage and stored strain energy of flexible members to obtain constant output forces for a large range of input displacements. This paper extends and compliments previous work by accomplishing the following: i) dimensional synthesis is performed for a number of compliant constant-force mechanism configurations, ii) a simplified method of determining the magnitude of the constant output force is presented, and iii) experimental validation of the theory is addressed by reporting the results of testing three constant-force configurations. The results of i) and ii) are presented in a manner to be easily used by engineers designing such mechanisms. The results of iii) show that the mechanisms do follow a nearly constant force for a large input displacement, as predicted.
Dual Polynomials and Complex Dual Numbers for Analysis of Spatial Mechanisms
Authors: Cheng Harry H. , Thompson Sean
Published: February 2021

Complex dual numbers w̌1=x1+iy1+εu1+iεv1 which form a commutative ring are for the first time introduced in this paper. Arithmetic operations and functions of complex dual numbers are defined. Complex dual numbers are used to solve dual polynomial equations. It is shown that the singularities of a dual input-output displacement polynomial equation of a mechanism correspond to its singularity positions. This new method of identifying singularities provides clear physical insight into the geometry of the singular configurations of a mechanism, which is illustrated through analysis of special configurations of the RCCC spatial mechanism. Numerical solutions for dual polynomial equations and complex dual numbers are conveniently implemented in the CH language environment for analysis of the RCCC spatial mechanism. Like the dual number, the complex dual number is a useful mathematical tool for analytical and numerical treatment of spatial mechanisms.
Globally-Optimal Synthesis of Mechanisms for Path Generation Using Simulated Annealing and Powell’s Method
Authors: Ullah Irfan , Kota Sridhar
Published: February 2021

Success in synthesis of mechanisms for path generation usually depends on providing a good starting point to the optimizer. This paper presents a completely automatic method that performs a global search from a random starting point. A two-step synthesis process involves searching for a coupler curve of optimal shape followed by optimization of size, orientation, and position of the solution mechanism. For the first step, an objective function evaluating shape difference between two curves, irrespective of the differences in their sizes, orientation, and position, is defined based on Fourier descriptors of the curves. This function is minimized using a stochastic global search method derived from simulated annealing, followed by Powell’s method for fast convergence. In the second stage, using properties of Fourier descriptors, a set of points is located on the solution curve that is analogous to points specified on the desired curve. The size, orientation, and position of the solution mechanism is then determined by minimizing the distance between analogous points.
An Alternative Formulation of the Linkage-Type Long Dwell Mechanism Synthesis Problem
Authors: Ogot Madara M. , Aly Sherif
Published: February 2021

Dwell mechanisms are utilized extensively in machine tools, packaging and textile machinery, and machines used for the closing and labeling of cans. For numerous applications, exact dwells are not required facilitating the use of linkage-type dwell mechanisms which produce approximate dwells. The advantages which these mechanisms provide over cams include lower maintenance and manufacturing costs, superior performance at high speeds and higher reliability. Despite these advantages, dwell linkages, especially those with long dwells, are more difficult to design. For this study dwell is defined as long if it occurs for more than 30% of the linkage cycle. Current numeric optimization-based formulations which make use of precision points, often converge to high lying local minima or fail to converge to a solution at all, since the structural error-based objective functions are typically highly nonlinear and multi-modal functions in a multi-dimensional design space. The purpose of this paper, therefore, is the presentation of an optimization-based method which addresses this problem. The redefinition of the structural error-based objective function about precision lines instead of precision points, results in a more efficient search of the design space for optimal solutions. Use of precision lines maps symmetrical points in the design space to one point, thereby effectively shrinking the design space without any loss of information. As a result, superior solutions can be attained without requiring more computational effort than current optimization-based methods. The approach is tailored to the synthesis of linkage-type mechanisms with slider outputs and relatively long dwells. Two examples, a six-bar with a single dwell and a six-bar with a double dwell, are presented to illustrate the efficacy of the proposed formulation.
Computing Near Optimal Paths in C-Space Using Simulated Annealing
Authors: Martínez-Alfaro Horacio , Ulloa-Pérez Antonio
Published: February 2021

This article describes a minimum-distance collision-free path planning technique of an object among fixed obstacles. The workspace is represented in C-space which reduces the original problem to one of path planning for a point in an expanded-obstacle workspace. We use B-spline curves for path representation and they are synthesized with the Simulated Annealing algorithm. We also give representative 2D and 3D examples to validate our results.
An Algebraic-Geometrical Method for the Identification and Elimination of Circuit Defect
Authors: Beloiu Alexandru S. , Gupta Krishna C.
Published: February 2021

In this paper, an algebraic-geometrical method is proposed which unifies the resolution of the circuit defect, and full or partial input link rotatability in mechanism synthesis. The circuit defect is a gross motion defect. Starting from the follower link, the method develops algebraic curves of 20th order (H20 = 0), in a body reference system, which define the boundaries of the regions where the choice of the floating pin of the driving (input) link either would yield a mechanism free of branch and circuit defects, or most likely would yield potential-circuit-defective-mechanisms (PCDM). The point (B) representing the floating pin of the follower (BA) is a quadruple point of this curve. Therefore, polar rays passing through this point (B) yield from H20, effectively, a nontrivial polynomial in one variable of 16th order, thus simplifying the root finding problem. This analytical method also enables the unification of the PCDM regions with the branch defect regions (due to Filemon) and those for the design of mechanisms with transmission angle within prescribed limits (due to Gupta). The main conclusion is that to avoid branch and circuit defects, avoid the Filemon-defective regions as well as the portions of the PCDM-regions which lie in the Filemon-feasible regions. Interestingly, large portions of the PCDM-region are within the Filemon-defective region and are therefore easily excluded. It has been our experience that the circuit defect, which is a gross motion defect, does not occur frequently; in many examples, the entire PCDM-region was contained in the Filemon-defective region. However, the Filemon-feasible region may contain portions of the PCDM-region and this sub-region must be examined for potentially circuit defective mechanisms. The method is developed and illustrated with examples for the planar four-bar mechanisms, some of the numerical aspects of the solution are also discussed here.
Sticking coefficients of selenium and tellurium
Authors: Liu Derrick S. H. , Hilse Maria , Engel-Herbert Roman
Published: February 2021

The sticking coefficients of selenium and tellurium were measured as a function of temperature. Molecular beams of the chalcogen elements supplied from thermal effusion cells were directed onto a heated quartz crystal microbalance, and the mass gain rate was detected as a function of temperature. Both sticking coefficients were found to sharply drop within a narrow temperature range of 20 and 30 °C from above 0.8 down to about 0.2 at film surface temperatures around 35 and 115 °C for selenium and tellurium, respectively. While the sticking coefficient of tellurium reached zero at temperatures above 150 °C, the sticking coefficient of selenium remained about 0.2 up to a film surface temperature of 60 °C, suggesting that selenium was supplied in different chemical forms. The direct and quantitative determination of the sticking coefficients provides important insights into the kinetics of chalcogenide-based film growth and points toward the need of a precise sample temperature control.
Intelligibility prediction for speech mixed with white Gaussian noise at low signal-to-noise ratios
Authors: Graetzer Simone , Hopkins Carl
Published: February 2021

The effect of additive white Gaussian noise and high-pass filtering on speech intelligibility at signal-to-noise ratios (SNRs) from −26 to 0 dB was evaluated using British English talkers and normal hearing listeners. SNRs below −10 dB were considered as they are relevant to speech security applications. Eight objective metrics were assessed: short-time objective intelligibility (STOI), a proposed variant termed STOI+, extended short-time objective intelligibility (ESTOI), normalised covariance metric (NCM), normalised subband envelope correlation metric (NSEC), two metrics derived from the coherence speech intelligibility index (CSII), and an envelope-based regression method speech transmission index (STI). For speech and noise mixtures associated with intelligibility scores ranging from 0% to 98%, STOI+ performed at least as well as other metrics and, under some conditions, better than STOI, ESTOI, STI, NSEC, CSIIMid, and CSIIHigh. Both STOI+ and NCM were associated with relatively low prediction error and bias for intelligibility prediction at SNRs from −26 to 0 dB. STI performed least well in terms of correlation with intelligibility scores, prediction error, bias, and reliability. Logistic regression modeling demonstrated that high-pass filtering, which increases the proportion of high to low frequency energy, was detrimental to intelligibility for SNRs between −5 and −17 dB inclusive.
The Effect of Creatine Supplementation on Markers of Exercise-Induced Muscle Damage: A Systematic Review and Meta-Analysis of Human Intervention Trials
Authors: Northeast Bethany , Clifford Tom
Published: February 2021

This systematic review and meta-analysis examined the effects of creatine supplementation on recovery from exercise-induced muscle damage, and is reported according to the PRISMA guidelines. MEDLINE and SPORTDiscus were searched for articles from inception until April 2020. Inclusion criteria were adult participants (≥18 years); creatine provided before and/or after exercise versus a noncreatine comparator; measurement of muscle function recovery, muscle soreness, inflammation, myocellular protein efflux, oxidative stress; range of motion; randomized controlled trials in humans. Thirteen studies (totaling 278 participants; 235 males and 43 females; age range 20–60 years) were deemed eligible for analysis. Data extraction was performed independently by both authors. The Cochrane Collaboration Risk of Bias Tool was used to critically appraise the studies; forest plots were generated with random-effects model and standardized mean differences. Creatine supplementation did not alter muscle strength, muscle soreness, range of motion, or inflammation at each of the five follow-up times after exercise (<30 min, 24, 48, 72, and 96 hr; p > .05). Creatine attenuated creatine kinase activity at 48-hr postexercise (standardized mean difference: −1.06; 95% confidence interval [−1.97, −0.14]; p = .02) but at no other time points. High (I2; >75%) and significant (Chi2; p < .01) heterogeneity was identified for all outcome measures at various follow-up times. In conclusion, creatine supplementation does not accelerate recovery following exercise-induced muscle damage; however, well-controlled studies with higher sample sizes are warranted to verify these conclusions. Systematic review registration (PROSPERO CRD42020178735).
Relationships Between Different Internal and External Training Load Variables and Elite International Women’s Basketball Performance
Authors: Coyne Joseph O.C. , Coutts Aaron J. , Newton Robert U. , Gregory Haff G.
Published: February 2021

Purpose: To investigate the relationships between internal and external training load (TL) metrics with elite international women’s basketball performance. Methods: Sessional ratings of perceived exertion, PlayerLoad™/minute, and training duration were collected from 13 elite international-level female basketball athletes (age 29.0 [3.7] y, stature 186.0 [9.8] cm, body mass 77.9 [11.6] kg) during the 18 weeks prior to the International Basketball Federation Olympic qualifying event for the 2016 Rio Olympic Games. Training stress balance, differential load, and the training efficiency index were calculated with 3 different smoothing methods. These TL metrics and their change in the last 21 days prior to competition were examined for their relationship to competition performance as coach ratings of performance. Results: For a number of TL variables, there were consistent significant small to moderate correlations with performance and significant small to large differences between successful and unsuccessful performances. However, these differences were only evident for external TL when using exponentially weighted moving averages to calculate TL. The variable that seemed most sensitive to performance was the change in training efficiency index in the last 21 days prior to competition (performance r = .47–.56, P < .001 and difference between successful and unsuccessful performance P < .001, f2 = 0.305–0.431). Conclusions: Internal and external TL variables were correlated with performance and distinguished between successful and unsuccessful performances among the same players during international women’s basketball games. Manipulating TL in the last 3 weeks prior to competition may be worthwhile for basketball players’ performance, especially in internal TL.
Implications and Opportunities for Sport Management Education in the COVID-19 Era
Authors: Rayner Mike , Webb Tom
Published: February 2021

In December 2019, a novel coronavirus (COVID-19) was detected in three patients from the city of Wuhan, China. By January 2020, COVID-19 was declared a widespread pandemic creating a global health crisis, resulting in millions of people contracting the virus and thousands losing their lives. Alongside the wide-reaching health crisis, the impact of COVID-19 had significant economic and societal effects leaving a historical legacy, which will affect countries throughout the world for a considerable period of time. As COVID-19 spread around the globe, the way people socialize, work, and study essentially changed forever. Therefore, this essay provides an insight into the rapid process that universities across the globe undertook to transition their teaching operations online. Projects and pedagogic reviews that traditionally would have taken months or years to devise were compressed into days, as the pandemic necessitated that traditional concerns about online teaching were cast aside. Consequently, this essay discusses these new educational platforms in sport management education and their future role in developing professionals who will be at the forefront of an unprecedented industry growth in the years and decades after COVID-19.
Hungry teen dinosaurs crowded out competitors
Authors: Vogel Gretchen
Published: February 2021

Study explains why ancient carnivores were tiny or huge, not medium-size.
Rare cosmic neutrino traced to star-shredding black hole
Authors: Clery Daniel
Published: February 2021

Particle points to black hole jets as high-energy accelerators.
Shirley Malcom leads a sea change for STEM equity
Authors: Korte Andrea
Published: February 2021

AAAS initiative draws upon a wealth of experience in improving diversity in science
In situ genome sequencing resolves DNA sequence and structure in intact biological samples
Authors: Payne Andrew C. , Chiang Zachary D. , Reginato Paul L. , Mangiameli Sarah M. , Murray Evan M. , Yao Chun-Chen , Markoulaki Styliani , Earl Andrew S. , Labade Ajay S. , Jaenisch Rudolf , Church George M. , Boyden Edward S. , Buenrostro Jason D. , Chen Fei
Published: February 2021

Visualizing the 3D genome in situ

The conformation of the genome within the cell changes depending on cell state, such that being able to visualize genome structure can identify cis and trans interactions among regulatory genetic elements. Payne
et al.
have developed an unbiased genome-sequencing technique in single cells in situ that can infer the chromatin structure by imaging. They were able to identify sequences at subnuclei locations to analyze the proximity relationships among genetic elements within and across chromosomes in single cells. Using this technique, they could detect chromosome territories and distinctions between different types of repetitive sequences and chromosomal features. This method can map and image genomic coordinates with submicrometer resolution in intact single cells.

Science
, this issue p.
eaay3446
Liver homeostasis is maintained by midlobular zone 2 hepatocytes
Authors: Wei Yonglong , Wang Yunguan G. , Jia Yuemeng , Li Lin , Yoon Jung , Zhang Shuyuan , Wang Zixi , Zhang Yu , Zhu Min , Sharma Tripti , Lin Yu-Hsuan , Hsieh Meng-Hsiung , Albrecht Jeffrey H. , Le Phuong T. , Rosen Clifford J. , Wang Tao , Zhu Hao
Published: February 2021

Zoning in on liver growth

For organ homeostasis or regrowth after injury or disease, one or more stem cell populations is needed to rebuild lost tissue. There is considerable debate about the source of new cells in the liver. Two groups now identify the source of new hepatocytes (see the Perspective by Andersson). Although the liver may seem to lack major variation across its structure, its lobule is organized into concentric zones where hepatocytes express different metabolic enzymes. Wei
et al.
sought to systematically define the source of new liver cells by comparing 14 fate-mapping mice that label different liver cell types. They found that different regions of the liver lobule exhibit differences in hepatocyte turnover, with zone 2 representing a primary source of new hepatocytes during homeostasis and regeneration. Similarly, He
et al.
designed a genetic approach to record cell proliferation in vivo with high spatial and temporal resolution to enable continuous recording of proliferative events of any specific cell type at the whole-cell population level. Using this method, they identified zone 2 as having the highest proliferative activity and contributing the most to liver regrowth. These findings have implications for the cellular basis of chronic disease pathogenesis, cancer development, and regenerative medicine strategies.

Science
, this issue p.
eabb1625
, p.
eabc4346
; see also p.
887
Photoinduced receptor confinement drives ligand-independent GPCR signaling
Authors: Sánchez M. Florencia , Els-Heindl Sylvia , Beck-Sickinger Annette G. , Wieneke Ralph , Tampé Robert
Published: February 2021

Laser-controlled receptor clustering

A strategy that allows light-controlled local confinement of a heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor may help to elucidate signal transduction mechanisms. Sánchez
et al.
developed just such an approach using a poly-L-lysine-graft-polyethylene glycol copolymer with a photoactivatable head. Laser light could locally activate a chelator that rapidly (within seconds) captured polyhistidine-tagged neuropeptide Y receptors. Such receptor confinement enhanced calcium signaling and increased spreading and cell motility in cultured human cells. The ability to control the location, size, and density of receptor clusters may help to elucidate receptor signaling mechanisms.

Science
, this issue p.
eabb7657
Comment on “Resolving spatial and energetic distributions of trap states in metal halide perovskite solar cells”
Authors: Ravishankar Sandheep , Unold Thomas , Kirchartz Thomas
Published: February 2021

Ni
et al
. (Research Articles, 20 March 2020, p. 1352) report bulk trap densities of 10
11
cm
–3
and an increase in interfacial trap densities by one to four orders of magnitude from drive-level capacitance profiling of lead halide perovskites. From electrostatic arguments, we show that the results are not trap densities but are a consequence of the geometrical capacitance and charge injection into the perovskite layer.
Response to Comment on “Resolving spatial and energetic distributions of trap states in metal halide perovskite solar cells”
Authors: Ni Zhenyi , Xu Shuang , Huang Jinsong
Published: February 2021

Ravishankar
et al
. claimed that drive-level capacitance profiling (DLCP) cannot resolve trap density in perovskites of given thickness. We point out that the trap densities derived by DLCP are from the differential capacitance at different frequencies; thus, the background charges caused by diffusion and geometry capacitance have been subtracted. Even for the nondifferential doping analysis, the contribution from diffusion capacitance is negligible and that from geometry capacitance is excluded.
Optical polarization–based seismic and water wave sensing on transoceanic cables
Authors: Zhan Zhongwen , Cantono Mattia , Kamalov Valey , Mecozzi Antonio , Müller Rafael , Yin Shuang , Castellanos Jorge C.
Published: February 2021

Waiting for earthquakes to call

Instrumenting the vast ocean floor is difficult and expensive but important for monitoring earthquakes and tsunamis. Zhan
et al.
used the polarization of regular telecommunication traffic to detect earthquakes and water swells in a 10,000-kilometer-long fiber-optic submarine cable (see the Perspective by Wilcock). The deep-water Curie cable is not as noisy as terrestrial counterparts, allowing the authors to detect strain from the cable. Results from the 9-month observation period showed how current submarine fiber-optic cables can also be used as a geophysical tool.

Science
, this issue p.
931
; see also p.
882
Evolution on other worlds
The Zoologist's Guide to the Galaxy
Arik Kershenbaum
Penguin Press, 2021. 368 pp.
Authors: Woolfson Adrian
Published: February 2021

Bound by finite natural laws, alien life may be more familiar than we imagine
Reconstructing drainage pathways in the North Atlantic during the Triassic utilizing heavy minerals, mineral chemistry, and detrital zircon geochronology
Authors: Andrews Steven D. , Morton Andrew , Decou Audrey , Frei Dirk
Published: February 2021

In this study, single-grain mineral geochemistry, detrital zircon geochronology, and conventional heavy-mineral analysis are used to elucidate sediment transport pathways that existed in the North Atlantic region during the Triassic. The presence of lateral and axial drainage systems is identified and their source regions are constrained.

Axial systems are suggested to have likely delivered sediment sourced in East Greenland (Milne Land–Renland) as far south as the south Viking Graben (>800 km). Furthermore, the data highlight the existence of lateral systems issuing from Western Norway and the Shetland Platform as well as a major east-west–aligned drainage divide positioned adjacent to the Milne Land–Renland region. This divide separated the catchments that flowed north to the Boreal Ocean from those that flowed south into a series of endoreic basins and, ultimately, the Tethys Sea. A further potential drainage divide is identified to the west of Shetland.

The data presented and the conclusions reached have major implications for reservoir prediction, as well as correlation, throughout the region. Furthermore, understanding the drainage networks that existed during the Triassic can help constrain paleogeographic reconstructions and provides an important framework for the construction of facies models in the region.
Detrital sanidine 40Ar/39Ar dating confirms <2 Ma age of Crooked Ridge paleoriver and subsequent deep denudation of the southwestern Colorado Plateau
Authors: Heizler Matthew T. , Karlstrom Karl E. , Albonico Micael , Hereford Richard , Beard L. Sue , Cather Steven M. , Crossey Laurie J. , Sundell Kurt E.
Published: February 2021

Crooked Ridge and White Mesa in northeastern Arizona (southwestern United States) preserve, as inverted topography, a 57-km-long abandoned alluvial system near the present drainage divide between the Colorado, San Juan, and Little Colorado Rivers. The pathway of this paleoriver, flowing southwest toward eastern Grand Canyon, has led to provocative alternative models for its potential importance in carving Grand Canyon. The ∼50-m-thick White Mesa alluvium is the only datable record of this paleoriver system. We present new 40Ar/39Ar sanidine dating that confirms a ca. 2 Ma maximum depositional age for White Mesa alluvium, supported by a large mode (n = 42) of dates from 2.06 to 1.76 Ma. Older grain modes show abundant 37–23 Ma grains mostly derived ultimately from the San Juan Mountains, as is also documented by rare volcanic and basement pebbles in the White Mesa alluvium. A tuff with an age of 1.07 ± 0.05 Ma is inset below, and hence provides a younger age bracket for the White Mesa alluvium. Newly dated remnant deposits on Black Mesa contain similar 37–23 Ma grains and exotic pebbles, plus a large mode (n = 71) of 9.052 ± 0.003 Ma sanidine. These deposits could be part of the White Mesa alluvium without any Pleistocene grains, but new detrital sanidine data from the upper Bidahochi Formation near Ganado, Arizona, have similar maximum depositional ages of 11.0–6.1 Ma and show similar 40–20 Ma San Juan Mountains–derived sanidine. Thus, we tentatively interpret the <9 Ma Black Mesa deposit to be a remnant of an 11–6 Ma Bidahochi alluvial system derived from the now-eroded southwestern fringe of the San Juan Mountains. This alluvial fringe is the probable source for reworking of 40–20 Ma detrital sanidine and exotic clasts into Oligocene Chuska Sandstone, Miocene Bidahochi Formation, and ultimately into the <2 Ma White Mesa alluvium. The <2 Ma age of the White Mesa alluvium does not support models that the Crooked Ridge paleoriver originated as a late Oligocene to Miocene San Juan River that ultimately carved across the Kaibab uplift. Instead, we interpret the Crooked Ridge paleoriver as a 1.9–1.1 Ma tributary to the Little Colorado River, analogous to modern-day Moenkopi Wash. We reject the “young sediment in old paleovalley” hypothesis based on mapping, stratigraphic, and geomorphic constraints. Deep exhumation and beheading by tributaries of the San Juan and Colorado Rivers caused the Crooked Ridge paleotributary to be abandoned between 1.9 and 1.1 Ma. Thermochronologic data also provide no evidence for, and pose substantial difficulties with, the hypothesis for an earlier (Oligocene–Miocene) Colorado–San Juan paleoriver system that flowed along the Crooked Ridge pathway and carved across the Kaibab uplift.
Adjuvant corticosteroids for prevention of kidney scarring in children with acute pyelonephritis: a systematic review and meta-analysis
Authors: Meena Jitendra , Kumar Jogender
Published: February 2021

Background

Acute pyelonephritis in children may result in permanent kidney scarring that is primarily caused by inflammation during acute infection. Antibiotic therapy alone is not enough to significantly reduce kidney scarring, and adjuvant corticosteroid therapy has shown a significant reduction in inflammatory cytokines in urine prompting its evaluation in randomised controlled trials. A few clinical trials showed a trend towards a reduction in renal scarring but did not have an adequate sample size to show a significant effect. Therefore, we planned to synthesise the available evidence on the role of corticosteroids as adjuvant therapy in reducing kidney scarring.

Objective

To assess the efficacy and safety of adjuvant corticosteroid therapy for the prevention of kidney scarring in children with acute pyelonephritis.

Design

Systematic review and meta-analysis.

Setting

Community-acquired febrile urinary tract infections.

Patients

Children (less than 18 years) with acute pyelonephritis.

Intervention

Adjuvant corticosteroid therapy (along with antibiotic treatment).

Main outcome measures

Primary: efficacy in preventing kidney scarring; secondary: serious adverse events associated with corticosteroid therapy.

Results

Three randomised trials (529 children) were included. Corticosteroids are effective in lowering the risk of kidney scarring as compared with placebo (risk ratio (RR): 0.57; 95% CI 0.36 to 0.90). No significant increase risk of bacteraemia (RR: 1.38; 95% CI 0.23 to 8.23) and hospitalisation (RR: 0.87; 95% CI 0.3 to 2.55) was observed in corticosteroid group.

Conclusion

Moderate quality evidence suggests that short duration ‘adjuvant corticosteroid therapy’ along with routine antibiotic therapy in acute febrile urinary tract infection significantly reduces the risk of kidney scarring without any significant adverse effects.
Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis
Authors: Ackley Sarah F , Zimmerman Scott C , Brenowitz Willa D , Tchetgen Tchetgen Eric J , Gold Audra L , Manly Jennifer J , Mayeda Elizabeth Rose , Filshtein Teresa J , Power Melinda C , Elahi Fanny M , Brickman Adam M , Glymour M Maria
Published: February 2021

Objective

To evaluate trials of drugs that target amyloid to determine whether reductions in amyloid levels are likely to improve cognition.

Design

Instrumental variable meta-analysis.

Setting

14 randomized controlled trials of drugs for the prevention or treatment of Alzheimer’s disease that targeted an amyloid mechanism, identified from ClinicalTrials.gov.

Population

Adults enrolled in randomized controlled trials of amyloid targeting drugs. Inclusion criteria for trials vary, but typically include adults aged 50 years or older with a diagnosis of mild cognitive impairment or Alzheimer’s disease, and amyloid positivity at baseline.

Main outcome measures

Analyses included trials for which information could be obtained on both change in brain amyloid levels measured with amyloid positron emission tomography and change in at least one cognitive test score reported for each randomization arm.

Results

Pooled results from the 14 randomized controlled trials were more precise than estimates from any single trial. The pooled estimate for the effect of reducing amyloid levels by 0.1 standardized uptake value ratio units was an improvement in the mini-mental state examination score of 0.03 (95% confidence interval −0.06 to 0.1) points. This study provides a web application that allows for the re-estimation of the results when new data become available and illustrates the magnitude of the new evidence that would be necessary to achieve a pooled estimate supporting the benefit of reducing amyloid levels.

Conclusions

Pooled evidence from available trials reporting both reduction in amyloid levels and change in cognition suggests that amyloid reduction strategies do not substantially improve cognition.
Geographical and temporal variation in reduction of malaria infection among children under 5 years of age throughout Nigeria
Authors: Oyibo Wellington , Ntadom Godwin , Uhomoibhi Perpetua , Oresanya Olusola , Ogbulafor Nnenna , Ajumobi Olufemi , Okoh Festus , Maxwell Kolawole , Ezeiru Sonachi , Nwokolo Ernest , Amajoh Chioma , Ezeigwe Nnenna , Audu Mohammed , Conway David
Published: February 2021

Introduction

Global progress in reducing malaria has stalled since 2015. Analysis of the situation is particularly needed in Nigeria, the country with by far the largest share of the burden, where approximately a quarter of all cases in the world are estimated to occur.

Methods

We analysed data from three nationwide surveys (Malaria Indicator Surveys in 2010 and 2015 and a National Demographic and Health Survey in 2018), with malaria parasite prevalence in children under 5 years of age determined by sampling from all 36 states of Nigeria, and blood slide microscopy performed in the same accredited laboratory for all samples. Changes over time were evaluated by calculating prevalence ratio (PR) values with 95% CIs for each state, together with Mantel-Haenszel-adjusted PRs (PRadj) for each of the six major geopolitical zones of the country.

Results

Between 2010 and 2018, there were significant reductions in parasite prevalence in 25 states, but not in the remaining 11 states. Prevalence decreased most in southern zones of the country (South West PRadj=0.53; South East PRadj=0.59; South South PRadj=0.51) and the North Central zone (PRadj=0.36). Changes in the north were less marked, but were significant and indicated overall reductions by more than 20% (North-West PRadj=0.74; North East PRadj=0.70). Changes in the south occurred mostly between 2010 and 2015, whereas those in the north were more gradual and most continued after 2015. Recent changes were not correlated with survey-reported variation in use of preventive measures.

Conclusion

Reductions in malaria infection in children under 5 have occurred in most individual states in Nigeria since 2010, but substantial geographical variation in the timing and extent indicate challenges to be overcome to enable global malaria reduction.
From the origin of NASH to the future of metabolic fatty liver disease
Authors: Geier Andreas , Tiniakos Dina , Denk Helmut , Trauner Michael
Published: February 2021

Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Understanding the pathological and molecular hallmarks from its first description to definitions of disease entities, classifications and molecular phenotypes is crucial for both appropriate clinical management and research in this complex disease. We provide an overview through almost two hundred years of clinical research from the beginnings as a nebulous disease entity of unknown origin in the 19th century to the most frequent and vigorously investigated liver disease today. The clinical discrimination between alcohol-related liver disease and NAFLD was uncommon until the 1950s and likely contributed to the late acceptance of NAFLD as a metabolic disease entity for long time. Although the term ‘fatty liver hepatitis’ first appeared in 1962, it was in 1980 that the term ‘non-alcoholic steatohepatitis’ (NASH) was coined and the histopathological hallmarks that are still valid today were defined. The 2005 NASH Clinical Research Network scoring was the first globally accepted grading and staging system for the full spectrum of NAFLD and is still used to semiquantify main histological features. In 2021, liver biopsy remains the only diagnostic procedure that can reliably assess the presence of NASH and early fibrosis but increasing efforts are made towards non-invasive testing and molecular classification of NAFLD subtypes.
Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency
Authors: Fromme Malin , Schneider Carolin V , Pereira Vitor , Hamesch Karim , Pons Monica , Reichert Matthias C , Benini Federica , Ellis Paul , H Thorhauge Katrine , Mandorfer Mattias , Burbaum Barbara , Woditsch Vivien , Chorostowska-Wynimko Joanna , Verbeek Jef , Nevens Frederik , Genesca Joan , Miravitlles Marc , Nuñez Alexa , Schaefer Benedikt , Zoller Heinz , Janciauskiene Sabina , Abreu Nélia , Jasmins Luís , Gaspar Rui , Liberal Rodrigo , Macedo Guilherme , Mahadeva Ravi , Gomes Catarina , Schneider Kai Markus , Trauner Michael , Krag Aleksander , Gooptu Bibek , Thorburn Douglas , Marshall Aileen , Hurst John R , Lomas David A , Lammert Frank , Gaisa Nadine T , Clark Virginia , Griffiths William , Trautwein Christian , Turner Alice M , McElvaney Noel G , Strnad Pavel
Published: February 2021

Objective

Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the ‘Pi*Z’ variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous ‘Pi*Z’ carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common ‘Pi*S’ variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD.

Design

Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption.

Results

Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8–53.7)) and primary liver cancer (aOR=44.5 (10.8–183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2–2.2)) and cholelithiasis (aOR=1.3 (1.2–1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1–8.2)) and primary liver cancer (aOR=6.6 (1.6–26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.

Conclusion

Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.
Increased risk of infective endocarditis after traumatic skin wound
Authors: Ohbe Hiroyuki , Iwagami Masao , Sasabuchi Yusuke , Yasunaga Hideo
Published: February 2021

Objective

Current data suggest that a history of traumatic open skin wounds may be a risk factor for infectious endocarditis, with limited evidence. We tested the hypothesis that traumatic skin wound is a risk factor for infectious endocarditis.

Methods

Using the Japan Medical Data Center (JMDC) database (4 650 927 people aged 20–64 years, 2012–2018) and the Kumamoto database (493 414 people aged ≥65 years, 2012–2017), we conducted nested case–control and self-controlled case series (SCCS) analyses.

Results

In the JMDC database, 544 cases hospitalised for infective endocarditis (IE) were matched with 2091 controls; 2.8% of cases and 0.5% of controls were exposed to traumatic skin wounds in the previous 1–4 weeks, with an adjusted OR of 4.31 (95% CI 1.74 to 10.7). In the Kumamoto database, 4.0% (27/670) of cases and 1.1% (29/2581) of controls were exposed to traumatic skin wounds in the previous 1–4 weeks, with an adjusted OR of 4.15 (95% CI 2.04 to 8.46). In the SCCS, the incidence rate ratios for IE were 2.61 (95% CI 1.67 to 4.09), 1.73 (95% CI 1.01 to 2.94), 1.19 (95% CI 0.63 to 2.27) and 1.52 (95% CI 0.82 to 2.74) for the Kumamoto database and 3.78 (95% CI 2.07 to 6.92), 1.58 (95% CI 0.64 to 3.89), 1.60 (95% CI 0.65 to 3.94) and 1.29 (95% CI 0.47 to 3.53) for the JMDC database at 1–4, 5–8, 9–12 and 13–16 weeks after traumatic skin wound, respectively, compared with the baseline period.

Conclusions

This study suggests that traumatic skin wound is a risk factor for IE 1–4 weeks after the wound.
Integrative transcriptome analysis of malignant pleural mesothelioma reveals a clinically relevant immune-based classification
Authors: Alay Ania , Cordero David , Hijazo-Pechero Sara , Aliagas Elisabet , Lopez-Doriga Adriana , Marín Raúl , Palmero Ramón , Llatjós Roger , Escobar Ignacio , Ramos Ricard , Padrones Susana , Moreno Víctor , Nadal Ernest , Solé Xavier
Published: February 2021

Background

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lung mesothelium. Immune checkpoint inhibitors (ICI) in MPM have not been extremely successful, likely due to poor identification of suitable candidate patients for the therapy. We aimed to identify cellular immune fractions associated with clinical outcome and classify patients with MPM based on their immune contexture. For each defined group, we sought for molecular specificities that could help further define our MPM classification at the genomic and transcriptomic level, as well as identify differential therapeutic strategies based on transcriptional signatures predictive of drug response.

Methods

The abundance of 20 immune cell fractions in 516 MPM samples from 7 gene expression datasets was inferred using gene set variation analysis. Identification of clinically relevant fractions was performed with Cox proportional-hazards models adjusted for age, stage, sex, and tumor histology. Immune-based groups were defined based on the identified fractions.

Results

T-helper 2 (TH2) and cytotoxic T (TC) cells were found to be consistently associated with overall survival. Three immune clusters (IG) were subsequently defined based on TH2 and TC immune infiltration levels: IG1 (54.5%) was characterized by high TH2 and low TC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high TC levels. IG1 and IG3 groups were associated with worse and better overall survival, respectively. While no differential genomic alterations were identified among immune groups, at the transcriptional level, IG1 samples showed upregulation of proliferation signatures, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, the integration of gene expression with functional signatures of drug response showed that IG3 patients might be more likely to respond to ICI.

Conclusions

This study identifies a novel immune-based signature with potential clinical relevance based on TH2 and TC levels, unveiling a fraction of patients with MPM with better prognosis and who might benefit from immune-based therapies. Molecular specificities of the different groups might be used to tailor specific potential therapies in the future.
6Ps…reflections on leadership in the NHS
Authors: Fillingham David James
Published: February 2021

In this article the author reflects on leadership lessons from a 30 year NHS career in local, regional and national roles. He explains how he has used a 6P model to diagnose and respond to the challenges he has encountered, encompassing purpose, patients, people, processes, partners and politics. Readers are encouraged to use the framework and learning from it to inform their own leadership journeys.
Public health decisions in the COVID-19 pandemic require more than ‘follow the science’
Authors: de Campos-Rudinsky Thana Cristina , Undurraga Eduardo
Published: February 2021

Although empirical evidence may provide a much desired sense of certainty amidst a pandemic characterised by uncertainty, the vast gamut of available COVID-19 data, including misinformation, has instead increased confusion and distrust in authorities’ decisions. One key lesson we have been gradually learning from the COVID-19 pandemic is that the availability of empirical data and scientific evidence alone do not automatically lead to good decisions. Good decision-making in public health policy, this paper argues, does depend on the availability of reliable data and rigorous analyses, but depends above all on sound ethical reasoning that ascribes value and normative judgement to empirical facts.
Rapid exponential increase in neurosurgery departmental scholarly output following an intensive research initiative
Authors: Karimov Zafar , Kazim Syed Faraz , Schmidt Meic , Gandhi Chirag , Vanderhooft Jordan , Cole Chad , Stein Alan , Al-Mufti Fawaz , Bowers Christian
Published: February 2021

There has been extensive research into methods of increasing academic departmental scholarly activity (DSA) through targeted interventions. Residency programmes are responsible for ensuring sufficient scholarly opportunities for residents. We sought to discover the outcomes of an intensive research initiative (IRI) on DSA in our department in a short-time interval. IRI was implemented, consisting of multiple interventions, to rapidly produce an increase in DSA through resident/medical student faculty engagement. We compare pre-IRI (8 years) and post-IRI (2 years) research products (RP), defined as the sum of oral presentations and publications, to evaluate the IRI. The study was performed in 2020. The IRI resulted in an exponential increase in DSA with an annual RP increase of 350% from 2017 (3 RP) to 2018 (14 RP), with another 92% from 2018 (14 RP) to 2019 (27 RP). RP/year exponentially increased from 2.1/year to 10.5/year for residents and 0.5/year to 10/year for medical students, resulting in a 400% and 1900% increase in RP/year, respectively. The common methods in literature to increase DSA included instituting protected research time (23.8%) and research curriculum (21.5%). We share our department's increase in DSA over a short 2-year period after implementing our IRI. Our goal in reporting our experience is to provide an example for departments that need to rapidly increase their DSA. By reporting the shortest time interval to achieve exponential DSA growth, we hope this example can support programmes in petitioning hospitals and medical colleges for academic support resources.
Maternal asthma is associated with reduced lung function in male infants in a combined analysis of the BLT and BILD cohorts
Authors: de Gouveia Belinelo Patricia , Collison Adam M , Murphy Vanessa E , Robinson Paul D , Jesson Kathryn , Hardaker Kate , de Queiroz Andrade Ediane , Oldmeadow Christopher , Martins Costa Gomes Gabriela , Sly Peter D , Usemann Jakob , Appenzeller Rhea , Gorlanova Olga , Fuchs Oliver , Latzin Philipp , Gibson Peter G , Frey Urs , Mattes Joerg
Published: February 2021

Rationale

Asthma in pregnancy is associated with respiratory diseases in the offspring.

Objective

To investigate if maternal asthma is associated with lung function in early life.

Methods

Data on lung function measured at 5–6 weeks of age were combined from two large birth cohorts: the Bern Infant Lung Development (BILD) and the Australian Breathing for Life Trial (BLT) birth cohorts conducted at three study sites (Bern, Switzerland; Newcastle and Sydney, Australia). The main outcome variable was time to reach peak tidal expiratory flow as a percentage of total expiratory time(tPTEF:tE%). Bayesian linear hierarchical regression analyses controlling for study site as random effect were performed to estimate the effect of maternal asthma on the main outcome, adjusting for sex, birth order, breast feeding, weight gain and gestational age. In separate adjusted Bayesian models an interaction between maternal asthma and sex was investigated by including an interaction term.

Measurements and main results

All 406 BLT infants were born to mothers with asthma in pregnancy, while 193 of the 213 (91%) BILD infants were born to mothers without asthma. A significant interaction between maternal asthma and male sex was negatively associated with tPTEF:tE% (intercept 37.5; estimate: –3.5; 95% credible interval –6.8 to –0.1). Comparing the model posterior probabilities provided decisive evidence in favour of an interaction between maternal asthma and male sex (Bayes factor 33.5).

Conclusions

Maternal asthma is associated with lower lung function in male babies, which may have lifelong implications on their lung function trajectories and future risk of wheezing and asthma.