bluuebunny/crossref_metadata_2025 huggingface dataset:
Osseointegration of retrieved 3D-printed, off-the-shelf acetabular implants
Authors: Dall’Ava Lorenzo , Hothi Harry , Henckel Johann , Di Laura Anna , Tirabosco Roberto , Eskelinen Antti , Skinner John , Hart Alister
Published: July 2021

Aims

The main advantage of 3D-printed, off-the-shelf acetabular implants is the potential to promote enhanced bony fixation due to their controllable porous structure. In this study we investigated the extent of osseointegration in retrieved 3D-printed acetabular implants.

Methods

We compared two groups, one made via 3D-printing (n = 7) and the other using conventional techniques (n = 7). We collected implant details, type of surgery and removal technique, patient demographics, and clinical history. Bone integration was assessed by macroscopic visual analysis, followed by sectioning to allow undecalcified histology on eight sections (~200 µm) for each implant. The outcome measures considered were area of bone attachment (%), extent of bone ingrowth (%), bone-implant contact (%), and depth of ingrowth (%), and these were quantified using a line-intercept method.

Results

The two groups were matched for patient sex, age (61 and 63 years), time to revision (30 and 41 months), implant size (54 mm and 52 mm), and porosity (72% and 60%) (p > 0.152). There was no difference in visual bony attachment (p = 0.209). Histological analysis showed greater bone ingrowth in 3D-printed implants (p < 0.001), with mean bone attachment of 63% (SD 28%) and 37% (SD 20%), respectively. This was observed for all the outcome measures.

Conclusion

This was the first study to investigate osseointegration in retrieved 3D-printed acetabular implants. Greater bone ingrowth was found in 3D-printed implants, suggesting that better osseointegration can be achieved. However, the influence of specific surgeon, implant, and patient factors needs to be considered. Cite this article: Bone Joint Res 2021;10(7):388–400.
Mid- to long-term outcomes of contemporary total knee arthroplasty in Charcot neuroarthropathy: a systematic review and meta-analysis
Authors: Rattanaprichavej Piti , Towiwat Patapong , Laoruengthana Artit , Dilokthornsakul Piyameth , Chaiyakunapruk Nathorn
Published: July 2021

Total knee arthroplasty (TKA) is an effective procedure to treat many patients with end-stage knee arthropathy. However, the extension of TKA for patients with Charcot neuroarthropathy (CNA) is controversial, with relatively limited evidence defining optimal reconstruction techniques. This systematic review of relevant studies that were published from January 2000 to June 2020 aimed to define survivorship, complications, reoperation, and component revision rates of contemporary TKA performed for CNA. We identified 127 TKA performed for CNA in five studies that comprised ≥ 7 knees with ≥ 5 years of follow-up. Overall implant survivorship was 85.4%. The overall complication rate was 26.4%, with the most common complications including instability (24.0%), periprosthetic fracture (17.4%), infection (13.0%), ligament injury (10.9%) and aseptic loosening (10.9%). The aetiology of CNA and prosthesis type had no influence on clinical outcomes, whereas the effect of staging of disease and ataxia status was still inconclusive. Understanding the potential determinants, survivorship and risk of complications related to TKA performed in CNA may help surgeons to deal with patient expectations.

Cite this article: EFORT Open Rev 2021;6:556-564. DOI: 10.1302/2058-5241.6.200103
Resonance fluorescence of laser-driven barium plasma
Authors: Kosarev N. I.
Published: July 2021

The kinetics of barium photoplasma upon absorption of laser radiation by atoms in the resonant transition at

λ
=
553.5

n
m

is studied by numerical simulation. At resonance transition saturation, seed electrons are generated. They gain energy through the superelastic processes and cause avalanche ionization of the gas. The brightening of the medium begins. After the metastable levels of barium are quenched by electrons, the brightening changes to darkening. The numerical results explain the experiment from [J. Appl. Phys. 57, 4968 (1985)JAPIAU0021-897910.1063/1.335271], where the darkening effect of barium vapor was first obtained. The second probe laser affected the barium resonance ion line at

λ
=
493.41

n
m

and induced fluorescence. The limits of applicability of the optically thin medium model for diagnosing photoplasma are discussed.
Nonimaging optics: erratum
Authors: Winston Roland , Jiang Lun , Ricketts Melissa
Published: July 2021

We present an erratum to correct the
x, z labels in Figs. 6 and 7 from
Adv. Opt.
Photon. 10, 484
(2018)10.1364/AOP.10.000484.
In vivo measurement of the attenuation coefficient of the sclera and ciliary muscle
Authors: Monterano Mesquita Gabrielle , Patel Disha , Chang Yu-Cherng , Cabot Florence , Ruggeri Marco , Yoo Sonia H. , Ho Arthur , Parel Jean-Marie A. , Manns Fabrice
Published: July 2021

We acquired 1325 nm OCT images of the sclera and ciliary muscle of human subjects. The attenuation coefficients of the sclera and ciliary muscle were determined from a curve fit of the average intensity profile of about 100 A-lines in a region of interest after correction for the effect of beam geometry, using a single scattering model. The average scleral attenuation coefficient was 4.13 ± 1.42 mm-1 with an age-related decrease that was near the threshold for statistical significance (p = 0.053). The average ciliary muscle attenuation coefficient was 1.72 ± 0.88 mm-1, but this value may be an underestimation due to contributions from multiple scattering. Overall, the results suggest that inter-individual variations in scleral attenuation contribute to variability in the quality of transscleral OCT images of the ciliary muscle and the outcome of transscleral laser therapies.
Nano shell impact on Huygens’ metasurface dipolar resonances and optical response
Authors: Kocer Hasan , Isik Halil , Durna Yilmaz , Khalichi Bahram , Kurt Hamza , Ozbay Ekmel
Published: July 2021

Due to several advantages over conventional devices for the control of electromagnetic (EM) radiation, the demand for metasurface utilization based on artificially engineered micro and nanostructures is boosted, especially in new generation devices. Among the metasurfaces family, there has been a growing interest in Huygens’ metasurfaces that are easy to fabricate due to their lower aspect ratio compared to their counterparts and also provide alternative electromagnetic radiation control by tuning the dipolar electric and magnetic resonances. In this study, an all-dielectric Huygens’ metasurface consisting of the high-refractive-index nano shells embedded in the low-refractive-index environment is designed and extensively investigated numerically and analytically in the near-infrared spectrum. By simply tuning the nano shell inner radius, the effects on the dipolar resonances are unveiled specific to the proposed design. To assess the EM wave interactions in the designed Huygens’ metasurface, an analytical model based on the coupled discrete dipole approach is applied for selected distinct cases of the designed metasurface. It is shown that the spectral position of the dipolar resonances can be detuned or tuned simultaneously depending on the structural parameter of the meta-atoms arranged in a periodic array. This study sheds light on the physics and abilities of the nano shell structure as a Huygens’ metasurface for the potential applications of metasurface-based light–matter interaction including imaging and sensing.
Utilization of slow light enhancement of four-wave mixing within a silicon photonic crystal for microwave frequency measurement purposes
Authors: Ebnali-Heidari Majid , Ebnali-Heidari Aliakbar , Emami Hossein
Published: July 2021

We report the demonstration of an instantaneous frequency measurement system based on the four-wave mixing (FWM) effect in short dispersion engineered slow-light silicon photonic crystal waveguides for RF frequency measurement purposes within a range of 10 MHz to 80 GHz. Three nonlinear media were investigated including 3 mm ridge waveguide, 80 µm nanowire, and 80 µm photonic crystal (PhC). The system size could thus be decreased, and as a result system integration would become possible. We have shown that the optical power required to excite FWM is low enough to remove any need for optical amplification, and hence the system noise floor will be kept low. Issues due to the amplifier saturation will also be resolved this way. As a result, no noise reduction system, like lock-in amplification, would be required. A better system latency will also be achieved accordingly. The system dynamic range would also be improved in two ways. First, due to the low noise floor, and second, because of removing any optical amplifier that possibly could become saturated at higher power levels. All three media behaviors were simulated by the split step Fourier method, and the results showed that the best medium to be used is PhC.
Active alignment of space astronomical telescopes by matching arbitrary multi-field stellar image features
Authors: Bai Xiaoquan , Ju Guohao , Xu Boqian , Gao Yan , Zhang Chunyue , Wang Shuaihui , Ma Hongcai , Xu Shuyan
Published: July 2021

Space-based optical astronomical telescopes are susceptible to mirror misalignments due to space disturbance in mechanics and temperature. Therefore, it is of great importance to actively align the telescope in orbit to continuously maintain imaging quality. Traditional active alignment methods usually need additional delicate wavefront sensors and complicated operations (such as instrument calibration and pointing adjustment). This paper proposes a novel active alignment approach by matching the geometrical features of several stellar images at arbitrary multiple field positions. Based on nodal aberration theory and Fourier optics, the relationship between stellar image intensity distribution and misalignments of the system can be modeled for an arbitrary field position. On this basis, an objective function is established by matching the geometrical features of the collected multi-field stellar images and modeled multi-field stellar images, and misalignments can then be solved through nonlinear optimization. Detailed simulations and a real experiment are performed to demonstrate the effectiveness and practicality of the proposed approach. This approach eliminates the need for delicate wavefront sensors and pointing adjustment, which greatly facilitates the maintainance of imaging quality.
Modeling, experimental validation, and model order reduction of mirror thermal dynamics
Authors: Haber Aleksandar , Draganov John E. , Heesh Kevin , Cadena Jorge , Krainak Michael
Published: July 2021

A large variety of optical systems and devices are highly sensitive to temperature variations and gradients induced by the absorption of thermal energy. Temperature gradients developed across optical elements, mounts, and supporting structures can lead to thermally induced wavefront aberrations and, consequently, to the reduction of optical performance. Consequently, modeling, estimation, and control of thermal dynamics are important problems that need to be carefully addressed by optical system designers. However, the development of accurate and experimentally validated models of thermal dynamics that are suitable for prediction, estimation, and control is a challenging problem. The main modeling challenges originate from model uncertainties, nonlinearities, and the fact that the thermal dynamics is inherently large-dimensional. In this manuscript, we present a synergistic modeling framework that combines first-principle heat transfer modeling, experimental validation, finite element techniques, and model order reduction techniques. We experimentally validate our approach on a recently developed 8-inch mirror prototype equipped with heaters and temperature sensors. We are able to accurately predict the temperature transients lasting for several hours. Furthermore, we apply our modeling approach to a parabolic mirror with an optimized honeycomb back structure. We investigate how the choice of mirror materials, such as aluminum, beryllium, Zerodur, and ULE, influence the ability to derive reduced-order models. Our results show that mirror thermal dynamics can be approximated by low-order state-space models. The modeling approach used in this manuscript is relevant for the prediction, estimation, and control of thermal dynamics and thermally induced aberrations in optical systems. MATLAB, COMSOL Multiphysics, and LiveLink codes used in this manuscript are available online.
Laser refrigeration of optically levitated sodium yttrium fluoride nanocrystals
Authors: Luntz-Martin Danika R. , Felsted R. Greg , Dadras Siamak , Pauzauskie Peter J. , Vamivakas A. Nick
Published: July 2021

Solid state laser refrigeration can cool optically levitated nanocrystals in an optical dipole trap, allowing for internal temperature control by mitigating photothermal heating. This work demonstrates cooling of ytterbium-doped cubic sodium yttrium fluoride nanocrystals to 252 K on average with the most effective crystal cooling to 241 K. The amount of cooling increases linearly with the intensity of the cooling laser and is dependent on the pressure of the gas surrounding the nanocrystal. Cooling optically levitated nanocrystals allows for crystals prone to heating to be studied at lower pressures than currently achievable and for temperature control and stabilization of trapped nanocrystals.
Simultaneous imaging of two-phase velocities in particle-laden flows by two-color optical phase discrimination
Authors: Bi Xiaopeng , Sun Zhiwei , Lau Timothy , Alwahabi Zeyad , Nathan Graham
Published: July 2021

In this Letter, we present a particle image/tracking velocimetry (PIV/PTV) technique for simultaneous velocity measurement of both fluid and particle phases, adopting newly developed optical phase discrimination methods and novel optical particles. Spherical acrylic (PMMA) particles of diameter

∼

O

(

100

µ

m

)

were used as the particle phase, while fine

B
A
M

:

E
u

2
+

phosphors of diameter

∼

O

(

1

µ

m

)

were used as the fluid tracer. Under Nd:YAG 355 nm laser excitation, both the laser-induced fluorescence (LIF) from PMMA and laser-induced phosphorescence (LIP) from

B
A
M

:

E
u

2
+

provided sufficiently strong signals for PIV imaging with two non-intensified cameras and were clearly separable for phase discrimination using spectral filters and temporal profiles. The advantages of the PIV/PTV method include the relatively low cost of

B
A
M

:

E
u

2
+

phosphors, high sphericity and narrow size distribution of PMMA particles with LIF emission, and direct optical discrimination eliminating artifacts, while requiring much less computational capacity for PIV/PTV processing of complex particle-laden flows.
Enhancing SERS detection on a biocompatible metallic substrate for diabetes diagnosing
Authors: Cui Zhiquan , Lu Libin , Guan Yingchun , Ramakrishna Seeram , Hong Minghui
Published: July 2021

A method to realize surface-enhanced Raman spectroscopy (SERS) at a titanium alloy substrate for glucose detection has been experimentally demonstrated. A silver-coated laser-induced periodic surface structure (LIPSS) was prepared via femtosecond laser micro-processing. The low detection limit of glucose is

10

−
7

m
o
l

/

L

and, a good linear relationship between the glucose concentration and Raman intensity is found in the range between

1

×

10

−
7

and

1

×

10

−
3

m
o
l

/

L

. Moreover, we investigate SERS detection for glucose sensing in human urine samples, while the results are in good agreement with clinical results. The Letter provides a facile method for producing a structure-controlled SERS substrate to realize glucose detection, which is promising for long-term in vivo diagnostics.
Topological photonic crystal fibers based on second-order corner modes
Authors: Gong Ruirong , Zhang Ming , Li Haibin , Lan Zhihao
Published: July 2021

Photonic crystal fibers represent one of the most active research fields in modern fiber optics. The recent advancements in topological photonics have inspired new fiber concepts and designs. Here, we demonstrate a new, to the best of our knowledge, type of topological photonic crystal fiber based on second-order photonic corner modes from the Su–Schrieffer–Heeger model. Different from previous works where the in-plane properties at

k
z

=
0

have been mainly studied, we find that in the fiber configuration of

k
z

>
0

, a topological bandgap exists only when the propagation constant

k
z

along the fiber axis is larger than a certain threshold and the emergent topological bandgap at large

k
z

hosts two sets of corner fiber modes. We further investigate the propagation diagrams, propose a convenient way to tune the frequencies of the corner fiber modes within the topological bandgap, and envisage multi-frequency and multi-channel transmission capabilities of this new type of fiber. Our work will not only have practical importance, but could also open a new area for fiber exploration where many existing higher-order topological photonic modes could bring exciting new opportunities for fiber designs and applications.
GeSn-on-insulator dual-waveband resonant-cavity-enhanced photodetectors at the 2  µm and 1.55  µm optical communication bands
Authors: Chen Qimiao , Wu Shaoteng , Zhang Lin , Burt Daniel , Zhou Hao , Nam Donguk , Fan Weijun , Tan Chuan Seng
Published: July 2021

Germanium-tin-on-insulator (GSOI) has emerged as a new platform for three-dimensional (3D) photonic-integrated circuits (PICs). We report, to our knowledge, the first demonstration of GeSn dual-waveband resonant-cavity-enhanced photodetectors (RCE PDs) on GSOI platforms with resonance-enhanced responsivity at both 2 µm and 1.55 µm bands. 10% Sn is introduced to the GeSn absorbing layer to extend the detection wavelength to the 2 µm band. A vertical Fabry–Perot cavity is designed to enhance the responsivity. The measured responsivity spectra show resonance peaks that cover a wide wavelength range near both the 2 µm and conventional telecommunication bands. This work demonstrates that GeSn dual-waveband RCE PDs on a GSOI platform are promising for CMOS-compatible 3D PICs for optoelectronic applications in 2 µm and telecommunication bands.
Characteristics of thin InAlAs digital alloy avalanche photodiodes
Authors: Wang Wenyang , Yao Jinshan , Wang Jingyi , Deng Zhuo , Xie Zhiyang , Huang Jian , Lu Hong , Chen Baile
Published: July 2021

InP-based avalanche photodiodes (APDs) are widely used in short-wave infrared (SWIR) communications. In this work, a thin (200 nm nominal) InAlAs digital alloy layer consisting of two monolayer (ML) InAs and two ML AlAs was grown on InP substrate and investigated in detail. APDs with p-i-n and n-i-p structures were fabricated and characterized. The current-voltage, capacitance-voltage characteristics, and excess noise were measured at room temperature with different laser wavelengths, and the measured effective

k

value (ratio of impact ionization coefficients) is about 0.15 with the multiplication gain up to 12. The randomly-generated path length (RPL) model was carried out to analyze the dead space effect. Our thin digital alloy successfully reduced excess noise compared with conventional

I
n

0.52

A
l

0.48

A
s

random alloy without introducing new elements and shows the potential for high-speed, low noise APD applications.
Single-layer substrate wideband reflectarray with dual-polarization for multiple OAM beams
Authors: Huang Hui-Fen , Xie Shu-Hui
Published: July 2021

In this paper, a single-layer wideband dual-linearly polarized reflective element is developed operating from 13GHz to 15.5GHz. The developed reflective metasurface can produce orbital angular momentum (OAM) vortex waves with required modes, beam numbers, direction, x-, y- or both x- and -y polarizations. To demonstrate this versatility, three reflectarrays with multiple modes, multiple beams, and both x- and -y polarizations are designed, and one is fabricated and measured to validate the design. The measured peak gain, aperture efficiency, divergence angle is 19dBi, 11.54%, 6°, respectively. The designed reflectarray has potential applications for high communication rate.
Choice of method of place cell classification determines the population of cells identified
Authors: Grijseels Dori M. , Shaw Kira , Barry Caswell , Hall Catherine N.
Published: July 2021

Place cells, spatially responsive hippocampal cells, provide the neural substrate supporting navigation and spatial memory. Historically most studies of these neurons have used electrophysiological recordings from implanted electrodes but optical methods, measuring intracellular calcium, are becoming increasingly common. Several methods have been proposed as a means to identify place cells based on their calcium activity but there is no common standard and it is unclear how reliable different approaches are. Here we tested four methods that have previously been applied to two-photon hippocampal imaging or electrophysiological data, using both model datasets and real imaging data. These methods use different parameters to identify place cells, including the peak activity in the place field, compared to other locations (the Peak method); the stability of cells’ activity over repeated traversals of an environment (Stability method); a combination of these parameters with the size of the place field (Combination method); and the spatial information held by the cells (Information method). The methods performed differently from each other on both model and real data. In real datasets, vastly different numbers of place cells were identified using the four methods, with little overlap between the populations identified as place cells. Therefore, choice of place cell detection method dramatically affects the number and properties of identified cells. Ultimately, we recommend the Peak method be used in future studies to identify place cell populations, as this method is robust to moderate variations in place field within a session, and makes no inherent assumptions about the spatial information in place fields, unless there is an explicit theoretical reason for detecting cells with more narrowly defined properties.
Why are viral genomes so fragile? The bottleneck hypothesis
Authors: Merleau Nono S. C. , Pénisson Sophie , Gerrish Philip J. , Elena Santiago F. , Smerlak Matteo
Published: July 2021

If they undergo new mutations at each replication cycle, why are RNA viral genomes so fragile, with most mutations being either strongly deleterious or lethal? Here we provide theoretical and numerical evidence for the hypothesis that genetic fragility is partly an evolutionary response to the multiple population bottlenecks experienced by viral populations at various stages of their life cycles. Modelling within-host viral populations as multi-type branching processes, we show that mutational fragility lowers the rate at which Muller’s ratchet clicks and increases the survival probability through multiple bottlenecks. In the context of a susceptible-exposed-infectious-recovered epidemiological model, we find that the attack rate of fragile viral strains can exceed that of more robust strains, particularly at low infectivities and high mutation rates. Our findings highlight the importance of demographic events such as transmission bottlenecks in shaping the genetic architecture of viral pathogens.
The interplay of SARS-CoV-2 evolution and constraints imposed by the structure and functionality of its proteins
Authors: Jaroszewski Lukasz , Iyer Mallika , Alisoltani Arghavan , Sedova Mayya , Godzik Adam
Published: July 2021

The unprecedented pace of the sequencing of the SARS-CoV-2 virus genomes provides us with unique information about the genetic changes in a single pathogen during ongoing pandemic. By the analysis of close to 200,000 genomes we show that the patterns of the SARS-CoV-2 virus mutations along its genome are closely correlated with the structural and functional features of the encoded proteins. Requirements of foldability of proteins’ 3D structures and the conservation of their key functional regions, such as protein-protein interaction interfaces, are the dominant factors driving evolutionary selection in protein-coding genes. At the same time, avoidance of the host immunity leads to the abundance of mutations in other regions, resulting in high variability of the missense mutation rate along the genome. “Unexplained” peaks and valleys in the mutation rate provide hints on function for yet uncharacterized genomic regions and specific protein structural and functional features they code for. Some of these observations have immediate practical implications for the selection of target regions for PCR-based COVID-19 tests and for evaluating the risk of mutations in epitopes targeted by specific antibodies and vaccine design strategies.
COVID-19 modeling and non-pharmaceutical interventions in an outpatient dialysis unit
Authors: Jang Hankyu , Polgreen Philip M. , Segre Alberto M. , Pemmaraju Sriram V.
Published: July 2021

This paper describes a data-driven simulation study that explores the relative impact of several low-cost and practical non-pharmaceutical interventions on the spread of COVID-19 in an outpatient hospital dialysis unit. The interventions considered include: (i) voluntary self-isolation of healthcare personnel (HCPs) with symptoms; (ii) a program of active syndromic surveillance and compulsory isolation of HCPs; (iii) the use of masks or respirators by patients and HCPs; (iv) improved social distancing among HCPs; (v) increased physical separation of dialysis stations; and (vi) patient isolation combined with preemptive isolation of exposed HCPs. Our simulations show that under conditions that existed prior to the COVID-19 outbreak, extremely high rates of COVID-19 infection can result in a dialysis unit. In simulations under worst-case modeling assumptions, a combination of relatively inexpensive interventions such as requiring surgical masks for everyone, encouraging social distancing between healthcare professionals (HCPs), slightly increasing the physical distance between dialysis stations, and—once the first symptomatic patient is detected—isolating that patient, replacing the HCP having had the most exposure to that patient, and relatively short-term use of N95 respirators by other HCPs can lead to a substantial reduction in both the attack rate and the likelihood of any spread beyond patient zero. For example, in a scenario with R0 = 3.0, 60% presymptomatic viral shedding, and a dialysis patient being the infection source, the attack rate falls from 87.8% at baseline to 34.6% with this intervention bundle. Furthermore, the likelihood of having no additional infections increases from 6.2% at baseline to 32.4% with this intervention bundle.
Transcriptomic and epigenomic profiling of young and aged spermatogonial stem cells reveals molecular targets regulating differentiation
Authors: Liao Jinyue , Suen Hoi Ching , Luk Alfred Chun Shui , Yang Lele , Lee Annie Wing Tung , Qi Huayu , Lee Tin-Lap
Published: July 2021

Spermatogonial stem cells (SSC), the foundation of spermatogenesis and male fertility, possess lifelong self-renewal activity. Aging leads to the decline in stem cell function and increased risk of paternal age-related genetic diseases. In the present study, we performed a comparative genomic analysis of mouse SSC-enriched undifferentiated spermatogonia (Oct4-GFP+/KIT-) and differentiating progenitors (Oct4-GFP+/KIT+) isolated from young and aged testes. Our transcriptome data revealed enormous complexity of expressed coding and non-coding RNAs and alternative splicing regulation during SSC differentiation. Further comparison between young and aged undifferentiated spermatogonia suggested these differentiation programs were affected by aging. We identified aberrant expression of genes associated with meiosis and TGF-β signaling, alteration in alternative splicing regulation and differential expression of specific lncRNAs such as Fendrr. Epigenetic profiling revealed reduced H3K27me3 deposition at numerous pro-differentiation genes during SSC differentiation as well as aberrant H3K27me3 distribution at genes in Wnt and TGF-β signaling upon aging. Finally, aged undifferentiated spermatogonia exhibited gene body hypomethylation, which is accompanied by an elevated 5hmC level. We believe this in-depth molecular analysis will serve as a reference for future analysis of SSC aging.
Light affects behavioral despair involving the clock gene Period 1
Authors: Olejniczak Iwona , Ripperger Jürgen A. , Sandrelli Federica , Schnell Anna , Mansencal-Strittmatter Laureen , Wendrich Katrin , Hui Ka Yi , Brenna Andrea , Ben Fredj Naila , Albrecht Urs
Published: July 2021

Light at night has strong effects on physiology and behavior of mammals. It affects mood in humans, which is exploited as light therapy, and has been shown to reset the circadian clock in the suprachiasmatic nuclei (SCN). This resetting is paramount to align physiological and biochemical timing to the environmental light-dark cycle. Here we provide evidence that light at zeitgeber time (ZT) 22 affects mood-related behaviors also in mice by activating the clock gene Period1 (Per1) in the lateral habenula (LHb), a brain region known to modulate mood-related behaviors. We show that complete deletion of Per1 in mice led to depressive-like behavior and loss of the beneficial effects of light on this behavior. In contrast, specific deletion of Per1 in the region of the LHb did not affect mood-related behavior, but suppressed the beneficial effects of light. RNA sequence analysis in the mesolimbic dopaminergic system revealed profound changes of gene expression after a light pulse at ZT22. In the nucleus accumbens (NAc), sensory perception of smell and G-protein coupled receptor signaling were affected the most. Interestingly, most of these genes were not affected in Per1 knock-out animals, indicating that induction of Per1 by light serves as a filter for light-mediated gene expression in the brain. Taken together we show that light affects mood-related behavior in mice at least in part via induction of Per1 in the LHb with consequences on mood-related behavior and signaling mechanisms in the mesolimbic dopaminergic system.
Prediction of risk of prolonged post-concussion symptoms: Derivation and validation of the TRICORDRR (Toronto Rehabilitation Institute Concussion Outcome Determination and Rehab Recommendations) score
Authors: Langer Laura Kathleen , Alavinia Seyed Mohammad , Lawrence David Wyndham , Munce Sarah Elizabeth Patricia , Kam Alice , Tam Alan , Ruttan Lesley , Comper Paul , Bayley Mark Theodore
Published: July 2021

Background

Approximately 10% to 20% of people with concussion experience prolonged post-concussion symptoms (PPCS). There is limited information identifying risk factors for PPCS in adult populations. This study aimed to derive a risk score for PPCS by determining which demographic factors, premorbid health conditions, and healthcare utilization patterns are associated with need for prolonged concussion care among a large cohort of adults with concussion.

Methods and findings

Data from a cohort study (Ontario Concussion Cohort study, 2008 to 2016; n = 1,330,336) including all adults with a concussion diagnosis by either primary care physician (ICD-9 code 850) or in emergency department (ICD-10 code S06) and 2 years of healthcare tracking postinjury (2008 to 2014, n = 587,057) were used in a retrospective analysis. Approximately 42.4% of the cohort was female, and adults between 18 and 30 years was the largest age group (31.0%). PPCS was defined as 2 or more specialist visits for concussion-related symptoms more than 6 months after injury index date. Approximately 13% (73,122) of the cohort had PPCS. Total cohort was divided into Derivation (2009 to 2013, n = 417,335) and Validation cohorts (2009 and 2014, n = 169,722) based upon injury index year. Variables selected a priori such as psychiatric disorders, migraines, sleep disorders, demographic factors, and pre-injury healthcare patterns were entered into multivariable logistic regression and CART modeling in the Derivation Cohort to calculate PPCS estimates and forward selection logistic regression model in the Validation Cohort. Variables with the highest probability of PPCS derived in the Derivation Cohort were: Age >61 years (p^ = 0.54), bipolar disorder (p^ = 0.52), high pre-injury primary care visits per year (p^ = 0.46), personality disorders (p^ = 0.45), and anxiety and depression (p^ = 0.33). The area under the curve (AUC) was 0.79 for the derivation model, 0.79 for bootstrap internal validation of the Derivation Cohort, and 0.64 for the Validation model. A limitation of this study was ability to track healthcare usage only to healthcare providers that submit to Ontario Health Insurance Plan (OHIP); thus, some patients seeking treatment for prolonged symptoms may not be captured in this analysis.

Conclusions

In this study, we observed that premorbid psychiatric conditions, pre-injury health system usage, and older age were associated with increased risk of a prolonged recovery from concussion. This risk score allows clinicians to calculate an individual’s risk of requiring treatment more than 6 months post-concussion.
Stopping azithromycin mass drug administration for trachoma: A systematic review
Authors: Mahmud Hamidah , Landskroner Emma , Amza Abdou , Aragie Solomon , Godwin William W. , de Hostos Barth Anna , O’Brien Kieran S. , Lietman Thomas M. , Oldenburg Catherine E.
Published: July 2021

The World Health Organization (WHO) recommends continuing azithromycin mass drug administration (MDA) for trachoma until endemic regions drop below 5% prevalence of active trachoma in children aged 1–9 years. Azithromycin targets the ocular strains of Chlamydia trachomatis that cause trachoma. Regions with low prevalence of active trachoma may have little if any ocular chlamydia, and, thus, may not benefit from azithromycin treatment. Understanding what happens to active trachoma and ocular chlamydia prevalence after stopping azithromycin MDA may improve future treatment decisions. We systematically reviewed published evidence for community prevalence of both active trachoma and ocular chlamydia after cessation of azithromycin distribution. We searched electronic databases for all peer-reviewed studies published before May 2020 that included at least 2 post-MDA surveillance surveys of ocular chlamydia and/or the active trachoma marker, trachomatous inflammation–follicular (TF) prevalence. We assessed trends in the prevalence of both indicators over time after stopping azithromycin MDA. Of 140 identified studies, 21 met inclusion criteria and were used for qualitative synthesis. Post-MDA, we found a gradual increase in ocular chlamydia infection prevalence over time, while TF prevalence generally gradually declined. Ocular chlamydia infection may be a better measurement tool compared to TF for detecting trachoma recrudescence in communities after stopping azithromycin MDA. These findings may guide future trachoma treatment and surveillance efforts.
Time to reconsider the role of ribavirin in Lassa fever
Authors: Salam Alex Paddy , Cheng Vincent , Edwards Tansy , Olliaro Piero , Sterne Jonathan , Horby Peter
Published: July 2021

Ribavirin is the only available Lassa fever treatment. The rationale for using ribavirin is based on one clinical study conducted in the early 1980s. However, reanalysis of previous unpublished data reveals that ribavirin may actually be harmful in some Lassa fever patients. An urgent reevaluation of ribavirin is therefore needed.
Zoonotic enteric parasites in Mongolian people, animals, and the environment: Using One Health to address shared pathogens
Authors: Barnes Amber N. , Davaasuren Anu , Baasandavga Uyanga , Lantos Paul M. , Gonchigoo Battsetseg , Gray Gregory C.
Published: July 2021

Background

Cryptosporidium spp. andGiardia duodenalisare important zoonotic enteric pathogens of One Health concern for humans, animals, and the environment. For this study, we investigated parasite prevalence and risk factors among rural, peri-urban, and urban households and environments of Mongolia.

Methods

This cross-sectional study implemented a household risk factor survey at 250 home sites along with sample collection from humans, animals, flies, and drinking water. Multiplex real-time PCR analysis was conducted to look forCryptosporidium spp. and/orGiardia duodenaliswithin household samples.

Results

Lab analysis found one or both zoonotic parasites at 20% of the participating households (51/250). Human samples had a parasite prevalence of 6.4% (27/419), domestic animals at 3.3% (19/570), pooled filth flies at 14.8% (17/115), and drinking water samples at 2% (5/250). Parasite presence at the household was significantly associated with a household’s use of an improved drinking water source (OR 0.27; CI 0.12–0.61; p = < 0.01), having an indoor handwashing site (OR 0.41; CI 0.19–0.92; p = 0.03), domestic animal ownership (OR 2.40; CI 1.02–5.65; p = 0.05), and rural location (OR 0.50; CI 0.25–0.98; p = 0.04). Household use of an improved drinking water source remained significant in the multivariate model (OR 0.16; CI 0.04–0.68; p = 0.01).

Conclusion

In Mongolia, public and veterinary health are intertwined, particularly for rural herding households. Increased access to safe water, sanitation and hygiene infrastructure could help prevent further transmission of zoonotic enteric parasites. Public health interventions, policy and messaging should utilize a One Health framework employing joint leadership from local human and animal health sectors.
Relationships between climate and phylogenetic community structure of fossil pollen assemblages are not constant during the last deglaciation
Authors: Pradhan Kavya , Nieto-Lugilde Diego , Fitzpatrick Matthew C.
Published: July 2021

Disentangling the influence of environmental drivers on community assembly is important to understand how multiple processes influence biodiversity patterns and can inform understanding of ecological responses to climate change. Phylogenetic Community Structure (PCS) is increasingly used in community assembly studies to incorporate evolutionary perspectives and as a proxy for trait (dis)similarity within communities. Studies often assume a stationary relationship between PCS and climate, though few studies have tested this assumption over long time periods with concurrent community data. We estimated two PCS metrics—Nearest Taxon Index (NTI) and Net Relatedness index (NRI)—of fossil pollen assemblages of Angiosperms in eastern North America over the last 21 ka BP at 1 ka intervals. We analyzed spatiotemporal relationships between PCS and seven climate variables, evaluated the potential impact of deglaciation on PCS, and tested for the stability of climate-PCS relationships through time. The broad scale geographic patterns of PCS remained largely stable across time, with overdispersion tending to be most prominent in the central and southern portion of the study area and clustering dominating at the longitudinal extremes. Most importantly, we found that significant relationships between climate variables and PCS (slope) were not constant as climate changed during the last deglaciation and new ice-free regions were colonized. We also found weak, but significant relationships between both PCS metrics (i.e., NTI and NRI) and climate and time-since-deglaciation that also varied through time. Overall, our results suggest that (1) PCS of fossil Angiosperm assemblages during the last 21ka BP have had largely constant spatial patterns, but (2) temporal variability in the relationships between PCS and climate brings into question their usefulness in predictive modeling of community assembly.
Prognostic role and biologic features of Musashi-2 expression in colon polyps and during colorectal cancer progression
Authors: Kharin Leonid , Bychkov Igor , Karnaukhov Nikolay , Voloshin Mark , Fazliyeva Rushaniya , Deneka Alexander , Frantsiyants Elena , Kit Oleg , Golemis Erica , Boumber Yanis
Published: July 2021

Background

The RNA-binding protein Musashi-2 (MSI2) controls the translation of proteins that support stem cell identity and lineage determination and is associated with progression in some cancers. We assessed MSI2 as potential clinical biomarker in colorectal cancer (CRC) and tubulovillous adenoma (TA) of colon mucosa.

Methods

We assessed 125 patients, of whom 20 had polyps of the colon (TAs), and 105 had CRC. Among 105 patients with CRC, 45 had stages I-III; among metastatic CRC (mCRC) patients, 31 had synchronous and 29 metachronous liver metastases. We used immunohistochemistry to measure MSI2 expression in matching specimens of normal tissue versus TAs, primary CRC tumors, and metastases, correlating expression to clinical outcomes. We analyzed the biological effects of depleting MSI2 expression in human CRC cells.

Results

MSI2 expression was significantly elevated in polyps versus primary tissue, and further significantly elevated in primary tumors and metastases. MSI2 expression correlated with decreased progression free survival (PFS) and overall survival (OS), higher tumor grade, and right-side localization (p = 0.004) of tumors. In metastases, high MSI2 expression correlated with E-cadherin expression. Knockdown of MSI2 in CRC cells suppressed proliferation, survival and clonogenic capacity, and decreased expression of TGFβ1, E-cadherin, and ZO1.

Conclusion

Elevated expression of MSI2 is associated with pre-cancerous TAs in the colonic mucosa, suggesting it is an early event in transformation. MSI2 expression is further elevated during CRC progression, and associated with poor prognosis. Depletion of MSI2 reduces CRC cell growth. These data imply a causative role of MSI2 overexpression at multiple stages of CRC formation and progression.
The drug development pipeline for glioblastoma—A cross sectional assessment of the FDA Orphan Drug Product designation database
Authors: Johann Pascal , Lenz Dominic , Ries Markus
Published: July 2021

Background

Glioblastoma (GBM) is the most common malignant brain tumour among adult patients and represents an almost universally fatal disease. Novel therapies for GBM are being developed under the orphan drug legislation and the knowledge on the molecular makeup of this disease has been increasing rapidly. However, the clinical outcomes in GBM patients with currently available therapies are still dismal. An insight into the current drug development pipeline for GBM is therefore of particular interest.

Objectives

To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat GBM.

Methods

Quantitative cross-sectional analysis of the U.S. Food and Drug Administration Orphan Drug Product database between 1983 and 2020. STROBE criteria were respected.

Results

Four orphan drugs out of 161 (2,4%) orphan drug designations were approved for the treatment for GBM by the FDA between 1983 and 2020. Fourteen orphan drug designations were subsequently withdrawn for unknown reasons. The number of orphan drug designations per year shows a growing trend. In the last decade, the therapeutic mechanism of action of designated compounds intended to treat glioblastoma shifted from cytotoxic drugs (median year of designation 2008) to immunotherapeutic approaches and small molecules (median year of designation 2014 and 2015 respectively) suggesting an increased focus on precision in the therapeutic mechanism of action for compounds the development pipeline.

Conclusion

Despite the fact that current pharmacological treatment options in GBM are sparse, the drug development pipeline is steadily growing. In particular, the surge of designated immunotherapies detected in the last years raises the hope that elaborate combination possibilities between classical therapeutic backbones (radiotherapy and chemotherapy) and novel, currently experimental therapeutics may help to provide better therapies for this deadly disease in the future.
Angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers on insulin sensitivity in hypertensive patients: A meta-analysis of randomized controlled trials
Authors: Yao Jia , Fan Simin , Shi Xiaoyan , Gong Xiayu , Zhao Jia , Fan Guanjie
Published: July 2021

Introduction

This meta-analysis aimed to summarize the available evidence to compare angiotensin-converting enzyme (ACE) inhibitors with angiotensin II receptor blockers (ARBs) on improving insulin sensitivity in hypertensive patients.

Methods

Randomized controlled trials (RCTs) comparing ACE inhibitors versus ARBs published with outcomes on homeostasis model assessment of IR (HOMA-IR), glucose infusion rate (GIR), the quantitative insulin sensitivity check index (QUICKI), insulin sensitivity index (ISI) composite, fasting plasma glucose (FPG), fasting plasma insulin (FPI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were searched through 5 databases. Data were searched from their inception to July 5, 2020. Stata 14.0 was used to perform the meta-analysis.

Results

Eleven RCTs (n = 1015) were included in this meta-analysis. Pooled analysis of studies showed no significant difference in HOMA-IR between ARBs and ACE inhibitors (WMD = -0.09, 95% CI: -0.69 to 0.50, P = 0.755); however, subgroup analysis of therapeutic duration showed a significant difference in HOMA-IR between ARBs and ACE inhibitors among the long-term intervention subgroup (>12 weeks) (WMD = 0.41, 95% CI: 0.06 to 0.76, P = 0.022) and hypertensive patients with diabetes mellitus subgroup (WMD = 0.55, 95% CI: 0.49 to 0.61, P < 0.001); results showed no significant difference between ARBs and ACE inhibitors on QUICKI score (WMD = -0.00, 95% CI: -0.03 to 0.03, P = 0.953) in hypertensive patients; however, the efficacy of ACE inhibitors on improving GIR and ISI composite was significantly better than that of ARBs (WMD = -1.09, 95% CI: -1.34 to -0.85, P < 0.001; WMD = -0.80, 95% CI: -1.24 to -0.36, P < 0.001, respectively). Furthermore, no significant differences were noted on FPG (WMD = 0.72, 95% CI: -1.39 to 2.83, P = 0.505), FPI (WMD = -0.48, 95% CI: -1.60 to 0.64, P = 0.398), SBP (WMD = -0.65, 95% CI: -1.76 to 0.46, P = 0.254), and DBP (WMD = -0.30, 95% CI: -1.70 to 1.10, P = 0.675) between ARBs and ACE inhibitors.

Conclusion

Results from this meta-analysis showed that ACE inhibitors resulted in more effective improvement of HOMA-IR compared with ARBs among the long-term intervention and hypertensive patients with DM subgroup; furthermore, the efficacy of ACE inhibitors on improving GIR and ISI composite was significantly better than that of ARBs in hypertensive patients. However, ARBs had no significant difference in QUICKI score, FPG, FPI, SBP, and DBP compared with ACE inhibitors. Larger and better-designed studies are needed to further verify this conclusion.