bluuebunny/crossref_metadata_2025 huggingface dataset:
Auditory phenotype of Smith–Lemli–Opitz syndrome
Authors: Zalewski Christopher K. , Sydlowski Sarah A. , King Kelly A. , Bianconi Simona , Dang Do An , Porter Forbes D. , Brewer Carmen C.
Published: February 2021

Smith–Lemli–Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation and intellectual disability syndrome resulting from variants in DHCR7. Auditory characteristics of persons with SLOS have been described in limited case reports but have not been systematically evaluated. The objective of this study is to describe the auditory phenotype in SLOS. Age‐ and ability‐appropriate hearing evaluations were conducted on 32 patients with SLOS. A subset of 21 had auditory brainstem response testing, from which an auditory neural phenotype is described. Peripheral or retrocochlear auditory dysfunction was observed in at least one ear of 65.6% (21) of the patients in our SLOS cohort. The audiometric phenotype was heterogeneous and included conductive, mixed, and sensorineural hearing loss. The most common presentation was a slight to mild conductive hearing loss, although profound sensorineural hearing loss was also observed. Abnormal auditory brainstem responses indicative of retrocochlear dysfunction were identified in 21.9% of the patients. Many were difficult to test behaviorally and required objective assessment methods to estimate hearing sensitivity. Individuals with SLOS are likely to have hearing loss that may impact communication, including speech and language development. Routine audiologic surveillance should be conducted to ensure prompt management of hearing loss.
Julius Wagner von Jauregg, Otto Diem and research methods for assessing the contributions of hereditary burden to mental illness risk: 1902–1906
Authors: Kendler Kenneth S. , Klee Astrid
Published: February 2021

After decades of methodological stasis in 19th century psychiatric genetics, when uncontrolled studies reported high rates of hereditary burden in hospitalized patients, Koller completed the first controlled study in 1895. We pick up this narrative 7 years later when the well‐known Julius Wagner v. Jauregg published a biting critique of the then current psychiatric genetics' literature. In 1905, partially in response to Wagner v. Jauregg, Otto Diem attempted to replicate and extend Koller's study. Wagner v. Jauregg then wrote a follow‐up to his earlier critique in 1906, commenting on Diem's investigation. Themes discussed in this point‐counterpoint included the necessity of statistical methods to draw meaningful conclusions about the impact of hereditary burden on mental illness, the required sample size and proper selection of controls, the classes of relatives which should optimally be studied, the problems of obtaining accurate information on familial illnesses, the nature of the disorders in families which contribute to mental illness risk and the common unquestioned dogmatic belief that insanity is very often due to hereditary causes. Both Wagner v. Jauregg and Diem spoke out forcefully against the common assumption that hereditary burden operated in a deterministic fashion and emphasized the need to consider other causes of illness.
Negotiating While Female
Authors: Schneider Andrea Kupfer
Published: February 2021

Why are women paid less than men?
Structure–Function Dataset Reveals Environment Effects within a Fluorescent Protein Model System**
Authors: De Zitter Elke , Hugelier Siewert , Duwé Sam , Vandenberg Wim , Tebo Alison G. , Van Meervelt Luc , Dedecker Peter
Published: February 2021

Anisotropic environments can drastically alter the spectroscopy and photochemistry of molecules, leading to complex structure‐function relationships. We examined this using fluorescent proteins as easy‐to‐modify model systems. Starting from a single scaffold, we have developed a range of 27 photochromic fluorescent proteins that cover a broad range of spectroscopic properties, including the determination of 43 crystal structures. Correlation and principal component analysis confirmed the complex relationship between structure and spectroscopy, but also allowed us to identify consistent trends and to relate these to the spatial organization. We find that changes in spectroscopic properties can come about through multiple underlying mechanisms, of which polarity, hydrogen bonding and presence of water molecules are key modulators. We anticipate that our findings and rich structure/spectroscopy dataset can open opportunities for the development and evaluation of new and existing protein engineering methods.
Tautomeric Molecule Acts as a “Sunscreen” for Metal Halide Perovskite Solar Cells
Authors: Wang Yang , Zhang Zemin , Lan Yangjie , Song Qian , Li Mingzhu , Song Yanlin
Published: February 2021

UV light always does great harm to perovskite solar cells, relentlessly degrading perovskites and shortening the lifetime of perovskite devices. Meanwhile, surface defects in perovskite films further accelerate the degradation process and serve as nonradiative charge recombination centers to deteriorate device efficiency. Herein, we demonstrate that a “sunscreen” molecule, 2‐hydroxy‐4‐methoxybenzophenone, not only protects the perovskite solar cell from UV degradation but also enables molecular defect passivation through interaction between functional groups and defects by molecular tautomerism under UV light illumination. Therefore, the sunscreen strategy efficiently enhances the UV endurance of PSCs and improves defect formation energy to −1.35 eV. The perovskite solar cell with sunscreen (sunscreen PSC) exhibits outstanding efficiencies of up to 23.09 % (0.04 cm2) and 19.73 % (1.00 cm2) as well as long‐term UV (UVa: 365 nm and UVb: 285 nm) stability.
Direct CO2 Capture and Reduction to High‐End Chemicals with Tetraalkylammonium Borohydrides
Authors: Lombardo Loris , Ko Youngdon , Zhao Kun , Yang Heena , Züttel Andreas
Published: February 2021

We demonstrate the ability of tetraalkylammonium borohydrides to capture large amounts of CO2, even at low CO2 concentrations, and reduce it to formate under ambient conditions. These materials show CO2 absorption capacities up to 30 mmol
 g−1 at room temperature and 1 bar CO2. Every BH4− anion can react with three CO2 molecules to form triformatoborohydride ([HB(OCHO)3]−). The thermodynamics and kinetics of the reaction were monitored by a magnetic suspension balance (MSB). Direct CO2 capture and reduction from air was achieved with tetraethyl, ‐propyl, and ‐butylammonium borohydride. The alkyl chain length played an important role in the kinetics and thermodynamics of the reaction, especially in CO2 diffusivity (crystallinity and free‐volume), activation energy (charge‐transfer dependent on the alkyl chain), and hydrophobicity. Adding HCl gave formic acid and the corresponding chloride ammonium salt, which can be recycled. In addition, transfer of formate was achieved for the N‐formylation of an amine.
The Protein Corona Leads to Deformation of Spherical Micelles
Authors: Cao Cheng , Zhang Lin , Kent Ben , Wong Sandy , Garvey Christopher J. , Stenzel Martina H.
Published: February 2021

The formation of a non‐specific protein corona around nanoparticles (NPs) has been identified as one of the culprits for failed nanomedicine. The amount and type of adsorbed protein from the blood plasma are known to determine the fate of NPs and the accessibility of targeting ligands. Herein, we show that the adsorbed protein may not only enlarge the NPs and change their surface properties but also, in the case of soft NPs such as polymer micelles, lead to deformation. Poly(1‐O‐methacryloyl ‐β‐D‐fructopyranose)‐b‐poly(methylmethacrylate) (P(1‐O‐MAFru)‐b‐PMMA) block co‐polymers were self‐assembled into NPs with a spherical core–shell morphology as determined by small angle neutron scattering (SANS). Upon incubation with albumin, TEM, SANS, and small angle X‐ray scattering (SAXS) revealed the adsorption of albumin and deformation of the NPs with a spheroid geometry. Removal of the protein led to the reversal of the morphology back to the spherical core–shell structure. Structural studies and cell studies of uptake of the NPs imply that the observed deformation may influence blood circulation time and cell uptake.
Stimuli‐Responsive Manganese Single‐Atom Nanozyme for Tumor Therapy via Integrated Cascade Reactions
Authors: Zhu Yang , Wang Wenyu , Cheng Junjie , Qu Yunteng , Dai Yi , Liu Manman , Yu Jianing , Wang Chengming , Wang Huijuan , Wang Sicong , Zhao Chao , Wu Yuen , Liu Yangzhong
Published: February 2021

The single‐atom enzyme (SAE) is a novel type of nanozyme that exhibits extraordinary catalytic activity. Here, we constructed a PEGylated manganese‐based SAE (Mn/PSAE) by coordination of single‐atom manganese to nitrogen atoms in hollow zeolitic imidazolate frameworks. Mn/PSAE catalyzes the conversion of cellular H2O2to.OH through a Fenton‐like reaction; it also promotes the decomposition of H2O2to O2and continuously catalyzes the conversion of O2to cytotoxic.O2−via oxidase‐like activity. The catalytic activity of Mn/PSAE is more pronounced in the weak acidic tumor environment; therefore, these cascade reactions enable the sufficient generation of reactive oxygen species (ROS) and effectively kill tumor cells. The prominent photothermal conversion property of the amorphous carbon can be utilized for photothermal therapy. Hence, Mn/PSAE exhibits significant therapeutic efficacy through tumor microenvironment stimulated generation of multiple ROS and photothermal activity.
Engineering the Bandgap and Surface Structure of CsPbCl3 Nanocrystals to Achieve Efficient Ultraviolet Luminescence
Authors: Zhang Yunqin , Cheng Xiyue , Tu Datao , Gong Zhongliang , Li Renfu , Yang Yingjie , Zheng Wei , Xu Jin , Deng Shuiquan , Chen Xueyuan
Published: February 2021

Herein, we report the design of novel ultraviolet luminescent CsPbCl3 nanocrystals (NCs) with the emission peak at 381 nm through doping of cadmium ions. Subsequently, a surface passivation strategy with CdCl2 is adopted to improve their photoluminescence quantum yield (PLQY) with the maximum value of 60.5 %, which is 67 times higher than that of the pristine counterparts. The PLQY of the surface passivated NCs remains over 50 % after one week while the pristine NCs show negligible emission. By virtue of density functional theory calculations, we reveal that the higher PLQY and better stability after surface passivation may result from the significant elimination of surface chloride vacancy (VCl) defects. These findings provide fundamental insights into the optical manipulation of metal ion‐doped CsPbCl3 NCs.
Combined transverse thoracis plane and pectoral nerve blocks for breast surgery under sedation
Authors: Helmich E. J. , Van Den Broek R. J. , Bloemen J. G.
Published: February 2021

The pectoral nerves 2 (pecs 2) block is widely used as adjunct to general anaesthesia for breast surgery. There are a few case reports and a single case series that describe regional anaesthesia as a single technique or supplemented by light to moderate sedation. Here we describe the management of a 91‐year‐old ASA physical status 4 patient who presented with a T4 breast malignancy. She was considered unfit for general anaesthesia due to significant valvular heart disease. A wide local excision was successfully performed under a pecs 2 block and a transverse thoracis plane block, supplemented with light sedation. We consider this technique to be a good option for selected patients who are considered unfit for general anaesthesia.
Elucidating the Roles of Fenton Reactants in Drug‐Treated Cells by Using a Selective Rhodamine‐Thiophenol Fluorogenic Sensor
Authors: Wang Zhanlong , Yeo Jia Hao , New Elizabeth J.
Published: February 2021

While Fenton chemistry has long been known to play a role in inducing cellular stress, there has been recent renewed interest in understanding its roles in health and disease. Here we describe a fluorogenic rhodamine‐thiophenol probe, RTFt1, which applies both chelation and recognition strategies to sense the Fenton reactants, Fe(II) and H2O2. RTFt1 undergoes a 200‐fold increase in red fluorescence emission in the presence of both Fe(II) and H2O2. After confirming the suitability of this new probe in cellular models, we demonstrated its utility in sensing the Fenton chemistry that accompanies ferroptosis and cisplatin‐induced cytotoxicity. We found that levels of the Fenton reactants increased when cells were treated with cisplatin or co‐treated with cisplatin and tubastatin A. This points to a role for Fenton chemistry in the cytotoxic effects of these treatments. We expect that RTFt1 will be able to provide a deeper understanding of Fenton reactants more broadly in biological systems.
Proton exchange composite membranes comprisingSiO2, sulfonatedSiO2, and metal–organic frameworks loaded inSPEEKpolymer for fuel cell applications
Authors: Bisht Sanjay , Balaguru Sasikumar , Ramachandran Sathish Kumar , Gangasalam Arthanareeswaran , Kweon Jihyang
Published: February 2021

Proton exchange membrane fuel cell (PEMFC) is a promising technology that offers a clean and efficient renewable energy source. The hybrid SiO2, sulfonated SiO2(SSiO2), and metal–organic framework‐5 (MOF‐5) incorporated sulfonated poly (ether ether ketone) (SPEEK) ternary composite membranes are fabricated using dry phase inversion technique for PEMFC. The membrane performance is evaluated in terms of water uptake, ion exchange capacity, methanol permeability, and proton conductivity (PC) measurements. The morphological study of fabricated membranes was carried out using scanning electron microscopy and atomic force microscopy analysis. The mechanical stability is strengthened up to 30–40%, and the PC gets enhanced with the incorporation of MOF‐5, achieving simultaneous improvement in proton conduction and membrane stability. The PC of the ternary SPEEK/SSiO2/MOF‐5 membrane is 3.69 × 10−3S cm−1, 32% more than the neat membrane. A significant increase in selectivity of 23% is observed by incorporating SSiO2and MOF‐5 fillers when compared with the neat membrane. The synergistic effect of MOF‐5 and SSiO2in the ternary membrane has significantly improved water retention and proton conductivity. The functional SO3H groups of SiO2and MOF‐5 bonded via acid–base electrostatic interactions with the SPEEK; enhances proton conduction accompanied by suppressing the methanol penetration through membranes.
Amine/epoxy stoichiometric ratio dependence of crosslinked structure and ductility inamine‐curedepoxy thermosetting resins
Authors: Odagiri Nobuyuki , Shirasu Keiichi , Kawagoe Yoshiaki , Kikugawa Gota , Oya Yutaka , Kishimoto Naoki , Ohuchi Fumio S. , Okabe Tomonaga
Published: February 2021

Epoxy‐amine thermosetting resins undergo different reactions depending on the amine/epoxy stoichiometric ratio (r). Although many desirable properties can be achieved by varying the stoichiometric ratio, the effects of the variation on the crosslinked structure and mechanical properties and the contribution of these factors to the ductility of materials have not been fully elucidated. This study investigates the brittle‐ductile behavior of epoxies with various stoichiometric ratios and performs curing simulations using molecular dynamics (MD) to evaluate the crosslinked structures. The molecular structure is predominantly branched in low‐stoichiometric ratio samples, whereas the chain extension type structure dominates the high‐stoichiometric ratio samples. As a result, the higher‐stoichiometric ratio samples enhances the ductility of materials and the elongation at break increases form 1.4% (r= 0.6) to 11.4% (r= 1.4). Additionally, the tensile strength (105.4 MPa) and strain energy (7.96 J/cm3) are maximum atr= 0.8 and 1.2, respectively. On the other hand, the Young's modulus is negatively impacted and it decreased from 4.2 to 2.7 GPa with increasing stoichiometric ratio.
Influence of chain extenders on the melt strength and thermal stability of polyglycolic acid
Authors: Chen Lanlan , Sun Xiaojie , Ren Yueqing , Wang Rong , Liang Wenbin , Duan Xuelei
Published: February 2021

Biodegradable polyglycolic acid (PGA) has been attracting much attention recently. However, poor melt strength and thermal stability limit the processing of PGA by methods such as film blowing and injection molding. To improve melt strength and thermal stability, two reactive chain extenders, styrene–acrylonitrile‐glycidyl methacrylate terpolymer (poly(St‐AN‐GMA)) and 4, 4′‐methylenebis(phenyl isocyanate) (MDI), were incorporated respectively into PGA using twin‐screw extrusion. MDI was found to be more effective in chain extension and enhancing thermal stability than poly(St‐AN‐GMA). The T‐5% (the temperature where the remaining weight percentage is 95%) of PGA modified with 3 wt% MDI increased to 334.5°C from 310.8°C for pure PGA. Melt flow rate for the same materials decreased from 47.2 g/10 min to 13 g/10 min. The activation energy of thermal degradations for MDI‐modified PGA was twice that of the unmodified PGA as evaluated by the Flynn‐Wall‐Ozawa method.
Design, synthesis, molecular docking, and some metabolic enzyme inhibition properties of novel quinazolinone derivatives
Authors: Tokalı Feyzi S. , Taslimi Parham , Demircioğlu İbrahim H. , Karaman Muhammet , Gültekin Mehmet S. , Şendil Kıvılcım , Gülçin İlhami
Published: February 2021

3‐Amino‐2‐ethylquinazolin‐4(3H)‐one (3) was synthesized in two steps from the reaction of amide (2), which was obtained from the treatment of methyl anthranilate (1) with propionyl chloride, with hydrazine. From the reaction of 3‐amino‐2‐ethylquinazolin‐4(3H)‐one (3) with various aromatic aldehydes, novel benzylidenaminoquinazolin‐4(3H)‐one (3a–n) derivatives were synthesized. The structures of the novel molecules were characterized using infrared spectroscopy, nuclear magnetic resonance spectroscopy (1H‐NMR and 13C‐NMR), and high‐resolution mass spectroscopy. The novel compounds were tested against some metabolic enzymes, including α‐glucosidase (α‐Glu), acetylcholinesterase (AChE), and human carbonic anhydrases I and II (hCA I and II). The novel compounds showed Ki values in the range of 244–988 nM for hCA I, 194–900 nM for hCA II, 30–156 nM for AChE, and 215–625 nM for α‐Glu. The binding affinities of the most active compounds were calculated as −7.636, −6.972, −10.080, and −8.486 kcal/mol for hCA I, hCA II, AChE, and α‐Glu enzymes, respectively. The aromatic ring of the quinazoline moiety plays a critical role in the inhibition of the enzymes.
Tumor Necrosis Factor Inhibitors Reduce Spinal Radiographic Progression in Patients With Radiographic Axial Spondyloarthritis: A Longitudinal Analysis From the Alberta Prospective Cohort
Authors: Sepriano Alexandre , Ramiro Sofia , Wichuk Stephanie , Chiowchanwisawakit Praveena , Paschke Joel , van der Heijde Désirée , Landewé Robert , Maksymowych Walter P.
Published: February 2021

Objective

To investigate whether tumor necrosis factor inhibitors (TNFi) impact spinal radiographic progression in patients with axial spondyloarthritis (SpA) and whether this is coupled to their effect on inflammation.

Methods

Patients with axial SpA fulfilling the modified New York criteria were included in a prospective cohort (the ALBERTA Follow Up Research Cohort in Ankylosing Spondylitis Treatment). Spine radiographs, performed every 2 years for up to 10 years, were scored by 2 central readers, using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The indirect effect of TNFi on mSASSS was evaluated with generalized estimating equations by testing the interaction between TNFi and Ankylosing Spondylitis Disease Activity Score (ASDAS) at the start of each 2‐year interval (t). If significant, the association between ASDAS at t and mSASSS at the end of the interval (t+1) was assessed in 1) patients treated with TNFi at all visits, 2) patients treated with TNFi at some visits, and 3) patients who were never treated with TNFi. In addition, the association between TNFi at t and mSASSS at t+1 (adjusting for ASDAS at t) was also tested (direct effect).

Results

In total, 314 patients were included. A gradient was seen for the effect of ASDAS at t on mSASSS at t+1 (interaction P = 0.10), with a higher progression in patients never treated with TNFi (β = 0.41 [95% confidence interval (95% CI) 0.13, 0.68]) compared to those continuously treated (β = 0.16 [95% CI 0.00, 0.31]) (indirect effect). However, TNFi also directly slowed progression, as treated patients had on average an mSASSS 0.85 units lower at t+1 compared to untreated patients (β = −0.85 [95% CI −1.35, −0.35]).

Conclusion

Our findings indicate that TNFi reduce spinal radiographic progression in patients with radiographic axial SpA, which might be partially uncoupled from their effects on inflammation as measured by the ASDAS.
Tocilizumab Prevents Progression of Early Systemic Sclerosis–Associated Interstitial Lung Disease
Authors: Roofeh David , Lin Celia J. F. , Goldin Jonathan , Kim Grace Hyun , Furst Daniel E. , Denton Christopher P. , Huang Suiyuan , Khanna Dinesh ,   the focuSSced Investigators
Published: February 2021

Objective

Tocilizumab (TCZ) has demonstrated lung function preservation in 2 randomized controlled trials in early systemic sclerosis (SSc). This effect has yet to be characterized in terms of radiographically evident quantitative lung involvement. We undertook this study to assess the impact of TCZ on lung function preservation in a post hoc analysis, stratifying treatment arms according to the degree of lung involvement.

Methods

The focuSSced trial was a phase III randomized placebo‐controlled trial of TCZ in patients with SSc and progressive skin disease. Participants underwent baseline and serial spirometry along with high‐resolution chest computed tomography at baseline and at week 48. Quantitative interstitial lung disease (QILD) and fibrosis scores were assessed by computer software. We classified QILD into the following categories of lung involvement: mild (>5–10%), moderate (>10–20%), and severe (>20%).

Results

Of 210 participants recruited for the trial, 136 patients (65%) had ILD. The majority of these patients (77%) had moderate‐to‐severe involvement (defined as >10% lung involvement). The TCZ arm demonstrated preservation of forced vital capacity percent predicted (FVC%) over 48 weeks (least squares mean change in FVC% = −0.1) compared to placebo (−6.3%). For mild, moderate, and severe QILD, the mean ± SD change in FVC% in the TCZ arm at 48 weeks were −4.1 ± 2.5% (n = 11), 0.7 ± 1.9% (n =19), and 2.1 ± 1.6% (n = 26), respectively, and in the placebo group were −10.0 ± 2.6% (n = 11), −5.7 ± 1.6% (n = 26), and −6.7 ± 2.0% (n = 16), respectively. Similar treatment‐related preservation findings were seen independent of fibrosis severity.

Conclusion

TCZ in early SSc–associated ILD with progressive skin disease stabilized FVC% over 48 weeks, independent of the extent of radiographically evident QILD.
Long‐Term Outcomes in Patients With Connective Tissue Disease–Associated Pulmonary Arterial Hypertension in the Modern Treatment Era: Meta‐Analyses of Randomized, Controlled Trials and Observational Registries
Authors: Khanna Dinesh , Zhao Carol , Saggar Rajan , Mathai Stephen C. , Chung Lorinda , Coghlan J. Gerry , Shah Mehul , Hartney John , McLaughlin Vallerie
Published: February 2021

Objective

Data on the magnitude of benefit of modern therapies for pulmonary arterial hypertension (PAH) in connective tissue disease (CTD)–associated PAH are limited. In this study, we performed meta‐analyses of randomized, controlled trials (RCTs) and registries to quantify the benefit of these modern therapies in patients with CTD‐PAH.

Methods

The PubMed and Embase databases were searched for articles reporting data from RCTs or registries published between January 1, 2000 and November 25, 2019. Eligibility criteria included multicenter studies with ≥30 CTD‐PAH patients. For an RCT to be included, the trial had to evaluate an approved PAH therapy, and long‐term risks of clinical morbidity and mortality or 6‐minute walk distance had to be reported. For a registry to be included, survival rates had to be reported. Random‐effects models were used to pool the data.

Results

Eleven RCTs (total of 4,329 patients; 1,267 with CTD‐PAH) and 19 registries (total of 9,739 patients; 4,008 with CTD‐PAH) were included. Investigational therapy resulted in a 36% reduction in the risk of clinical morbidity/mortality events both in the overall PAH population (hazard ratio [HR] 0.64, 95% confidence interval [95% CI] 0.54, 0.75; P < 0.001) and in CTD‐PAH patients (HR 0.64, 95% CI 0.51, 0.81; P < 0.001) as compared to control subjects. The survival rate was lower in CTD‐PAH patients compared to all PAH patients (survival rate 62%, 95% CI 57, 67% versus 72%, 95% CI 69, 75% at 3 years). The survival rate in CTD‐PAH patients treated primarily after 2010 was higher than that in CTD‐PAH patients treated before 2010 (survival rate 73%, 95% CI 62, 81% versus 65%, 95% CI 59, 71% at 3 years).

Conclusion

Modern therapy provides a similar reduction in morbidity/mortality risk in patients with CTD‐PAH when compared to the PAH population overall. Risk of death is higher in CTD‐PAH patients than in those with PAH overall, but survival has improved in the last 10 years, which may be related to increased screening and/or new treatment approaches. Early detection of PAH in patients with CTD and up‐front intensive treatment are warranted.
Long‐Term Safety and Efficacy of Subcutaneous Tanezumab Versus Nonsteroidal Antiinflammatory Drugs for Hip or Knee Osteoarthritis: A Randomized Trial
Authors: Hochberg Marc C. , Carrino John A. , Schnitzer Thomas J. , Guermazi Ali , Walsh David A. , White Alexander , Nakajo Satoru , Fountaine Robert J. , Hickman Anne , Pixton Glenn , Viktrup Lars , Brown Mark T. , West Christine R. , Verburg Kenneth M.
Published: February 2021

Objective

To assess the long‐term safety and 16‐week efficacy of subcutaneous tanezumab in patients with hip or knee osteoarthritis (OA).

Methods

This was a phase III randomized, double‐blind, active treatment–controlled (using nonsteroidal antiinflammatory drugs [NSAIDs] as the active treatment control) safety trial of tanezumab (56‐week treatment/24‐week posttreatment follow‐up) in adults who were receiving stable‐dose NSAID therapy at the time of screening and who had Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores of ≥5; patient global assessment (PtGA) of OA of fair, poor, or very poor; history of inadequate pain relief with standard analgesics; and no history or radiographic evidence of prespecified bone/joint conditions beyond OA. Patients received oral naproxen, celecoxib, or diclofenac twice daily (NSAID group; n = 996) or tanezumab 2.5 mg (n = 1,002) or 5 mg (n = 998) subcutaneously every 8 weeks. Coprimary efficacy end points at week 16 were changes in WOMAC pain and physical function scores and changes in PtGA. The primary joint safety end point over 80 weeks comprised adjudicated rapidly progressive OA type 1 or 2, primary osteonecrosis, subchondral insufficiency fracture, or pathologic fracture. Mean values, least squares mean values, and least squares mean differences between groups (with 95% confidence intervals [95% CIs]) were calculated.

Results

Of 3,021 randomized patients, 2,996 received ≥1 treatment dose. Adverse events (AEs) were similar between patients treated with tanezumab 2.5 mg and those treated with NSAIDs, and were more prevalent in those treated with tanezumab 5 mg. Composite joint safety events were significantly more prevalent with tanezumab 2.5 mg and tanezumab 5 mg than with NSAIDs (observation time–adjusted rate/1,000 patient‐years 38.3 [95% CI 28.0, 52.5] and 71.5 [95% CI 56.7, 90.2], respectively, versus 14.8 [95% CI 8.9, 24.6]; P = 0.001 for tanezumab 2.5 mg versus NSAIDs; P < 0.001 for tanezumab 5 mg versus NSAIDs). Tanezumab 5 mg significantly improved pain and physical function but did not improve PtGA at week 16 when compared to NSAIDs; corresponding differences between the tanezumab 2.5 mg and NSAID groups were not statistically significant.

Conclusion

In patients previously receiving a stable dose of NSAIDs, tanezumab administered subcutaneously resulted in more joint safety events than continued NSAIDs, with differences being dose dependent. Pain and physical function improved with both doses of tanezumab compared to NSAIDs, reaching statistical significance with tanezumab 5 mg at 16 weeks.
A stability analysis of the static Einstein‐Klein‐Gordon Boson Stars
Authors: Suarez Fontanella Duvier , de Oca Alenjandro Cabo Montes
Published: February 2021

The stability of the recently proposed static solutions for boson stars is analyzed. These solutions of Einstein‐Klein‐Gordon (EKG) equations are obtained by considering the interaction of a real scalar field with matter. We assume that the inclusion of the scalar field in addition to matter allows one to justify that stability implies that the total mass of the solution should grow when the initial condition for the density of matter at the origin is also increased. Employing numerical values for the static boson star based on a linear relation between the source and the energy density and between this and the pressure, we found the relation that linked the scalar field at the origin with the matter energy density at the same point. We also determine the behavior of the total mass with the matter energy density in the origin by obtaining through this and the weak energy condition two possible ranges for stable solutions of static boson stars.
Hybrid star properties from an extended linear sigma model
Authors: Takátsy János , Kovács Péter , Wolf György
Published: February 2021

The equation of state provided by effective models of strongly interacting matter should comply with the restrictions imposed by current astrophysical observations on compact stars. Using the equation of state given by the (axial‐)vector meson extended linear sigma model, we determine the mass–radius relation and study whether these restrictions are satisfied under the assumption that most of the star is filled with quark matter. We study the dependence of the mass–radius relation on the parameters of the model.
A test of the fermionic dark matter nature of the supermassive compact object at the center of our galaxy
Authors: Becerra‐Vergara E. A. , Rueda J. A. , Ruffini R.
Published: February 2021

The extensive and continuous monitoring of the closest stars to the Galactic center has been producing over decades a large amount of high‐quality data of their positions and velocities. The explanation of these data, especially the S2 star motion, reveals the presence of a compact source, Sagittarius A* (Sgr A*), whose mass must be about 4 × 106 M⊙. This result has been protagonist of the awarded Nobel Prize in Physics 2020 to Reinhard Genzel and Andrea Ghez “for the discovery of a supermassive compact object at the centre of our galaxy.” Traditionally, the nature of Sgr A* has been attributed to a supermassive black hole (SMBH), even though a proof of its existence is absent. Further, recent data on the motion of the G2 cloud show that its post‐peripassage velocity is lower than the expected one from a Keplerian orbit around the hypothesized SMBH. An attempt to overcome this difficulty has used a friction force, produced (arguably) by an accretion flow whose presence is also observationally unconfirmed. We advance an alternative scenario that identifies the nature of the supermassive compact object in a highly concentrated core of dark matter (DM) made of fermions, that is, inos, which we here refer to as darkinos. This DM concentration is predicted by the core‐halo profile obtained from the Ruffini‐Argüelles‐Rueda fermionic DM model, which also fits the Galactic‐halo rotation curves. We show that the sole DM core, for 56 keV darkinos, explains the orbits of S2 and G2. No drag force or other external agents are needed, that is, their motion is purely geodesic. A core made of these darkinos becomes unstable against gravitational collapse into a BH for a mass of ∼108M⊙; hence, they can provide the BH seeds from which grow the observed central SMBHs in active galaxies, for example, M87.
Thyroglobulin determination on silane–antibody functionalized interdigitated dielectrode surface to diagnose thyroid tumor
Authors: Wang Yujie , Sun Xia , Gopinath Subash C.B. , Saheed Mohamed Shuaib Mohamed , Wang Xiaofei
Published: February 2021

Thyroid cancer appears in endocrine glands and specific to thyroid glands has been reported widely. This work was targeted to identify and quantify thyroglobulin by using antithyroglobulin antibody complexed silane surface on interdigitated electrode (IDE) sensing surface. (3‐Aminopropyl)triethoxysilane linker was used to make silane‐coupling with antibody and attached on the hydroxylated IDE. This electroanalytical IDE revealed the dose‐dependent responses with thyroglobulin concentrations. By getting increments with the thyroglobulin concentrations, the current responses were enhanced concomitantly and the thyroglobulin detection limit was noted as 1 pM on the linear curve [y = 0.1311x + 0.5386; R² = 0.9707] with the sensitivity at lower picomolar range. Moreover, the control experiments with thyroid peroxidase and nonimmune antibody cannot yield any response of current, confirming the specific detection of thyroglobulin. This research set‐up is useful to determine and quantify the thyroglobulin and diagnose thyroid cancer.
Wärmemarktstudie für das Großherzogtum Luxemburg
Authors: Bechtel Steffen , Scholzen Frank
Published: February 2021

In 2020 hat Luxemburg seinen Klimaplan für den Zeitraum 2021 bis 2030 beschlossen, welcher ehrgeizige Ziele für den Wärmesektor enthält. Die Datenlage im Wärmesektor, vor allem bei der Schlüsseltechnologie Wärmepumpe, ist jedoch unzureichend, zum Nachteil aller beteiligten Akteure. Die Universität Luxemburg hat deshalb eine Wärmemarktstudie erstellt, die Verkaufszahlen nationaler Hersteller und Händler im Zeitraum von 2014 bis 2018 auswertet und auf diese Weise wesentliche Trends im Hinblick auf die Klimaziele aufzeigt. Die Auswertung zeigt signifikante Unterschiede zur bisherigen Datenlage bei Wärmepumpen, die sich aufgrund der Nichtinanspruchnahme der staatlichen Förderung ergeben. Insgesamt werden deutlich mehr Anlagen installiert als bisher angenommen Der Absatz fossiler Heizkessel ist konstant, wobei eine Verschiebung des Energieträgers von Öl zu Erdgas zu verzeichnen ist. Der allgemeine Trend bewegt sich in Richtung der gesteckten Ziele. Dennoch besteht signifikanter Handlungsbedarf, da zum Erreichen der nationalen Klimaziele u. a. ein jährliches Wachstum des Luxemburger Wärmepumpenmarktes von 16 % bis 2030 angenommen wurde.
Recent advances in the integrated biorefinery concept for the valorization of algal biomass through sustainable routes
Authors: Katiyar Richa , Banerjee Shivali , Arora Amit
Published: February 2021

Microalgae have garnered significant interest among researchers and industries as a potential source of valuable products that can find applications in the food, feed, biofuels, cosmetics, pharmaceuticals, and nutraceuticals industries. Microalgae can remediate various waste streams. This review discusses the current trends in the valorization of algal biomass and proposes integrated biorefinery approaches to produce high‐value products by sustainable routes. In such processes, the waste streams can be used as a source of nutrients for the production of microalgal biomass, rich in high‐quality lipids, digestible proteins and bioactive compounds. The integrated approaches presented in this study offer cost‐effective and environment‐friendly processing techniques while expanding the bioproducts portfolio in the food and therapeutics sector. The simultaneous or sequential extraction of valuable compounds from microalgae makes the biorefinery proposition appealing for waste minimization, revenue diversification, and complete feedstock utilization. The systematic exploration of microalgae on a large scale is required to evaluate its future as a favorable resource for biorefinery products. This would also necessitate detailed techno‐economic, environmental, and lifecycle assessment for the biorefinery processes. © 2021 Society of Chemical Industry and John Wiley & Sons, Ltd
M1a prostate cancer: Results of a Dutch multidisciplinary consensus meeting
Authors: Aluwini Shafak , Oprea‐Lager Daniela E. , de Barros Hilda , Mehra Niven , Stoevelaar Herman , Yakar Derya , van der Poel Henk ,   Dutch M1a Prostate Cancer Working Group
Published: February 2021

Objectives

To determine the consensus of a Dutch multidisciplinary expert panel on the diagnostic evaluation and treatment of de novo and recurrent metastatic prostate cancer (PCa) limited to non‐regional lymph nodes (M1a) in daily clinical practice.

Materials and methods

The panel consisted of 37 Dutch specialists from disciplines involved in the management of M1a PCa (urology, medical and radiation oncology, radiology, and nuclear medicine). We used a modified Delphi method consisting of two voting rounds and a consensus meeting (video conference). Consensus (good agreement) was defined as the situation in which ≥ 75% of the panelists chose the same option.

Results

Consensus existed for 57% of the items. The panel agreed that prostate‐specific membrane antigen positron emission tomography/computed tomography (PSMA‐PET/CT) is the most appropriate standard imaging modality to identify de novo (100%) and recurrent (97%) M1a PCa. Androgen deprivation therapy (ADT) combined with radiotherapy to the prostate ± the M1a lesion(s) was most frequently considered an option for de novo M1a PCa. For M1a as recurrent disease, ADT alone, deferring treatment, or local radiotherapy to the M1a lesion(s) were judged to be the most important treatment options. However, no specific indications for treatment choice in relation to disease characteristics could be formulated.

Conclusions

The Dutch consensus panel preferred PSMA‐PET/CT as the standard diagnostic modality to detect M1a PCa. Although potential treatment options were identified, explicit recommendations could not be formulated. This might (partly) be explained by the absence of high‐level clinical evidence in this subset of patients. Further research is, therefore, strongly encouraged.
Exkursionen als Beitrag zur praxisorientierten akademischen Lehre – Wilhelm Kählers Besichtigungen der pommerschen Wirtschaft in der Weimarer Zeit
Authors: Grube Klemens
Published: February 2021

In the German Weimar Republic of the 1920s, the field of economic science found itself in a crisis environment beyond the limits of its understanding. Very few contributions from academia found their way into practice, and thus the limited interplay between the two was of little consequence. During this era, universities responded by introducing various new approaches to make the teaching of economics more relevant to practice. In many universities, this included the participation of practitioners as lecturers and examiners. In addition, Professor Wilhelm Kähler of the University of Greifswald organised field trips within the province of Pomerania so that students could see economics in practice and better grasp its real‐world peculiarities. In this paper, the historical records of these excursions, as recorded in a log, are analysed and insights gained from the numerous teaching visits to companies, welfare institutions, organisations and associations as well as to municipalities, housing developments and infrastructural establishments. The paper concludes with an examination of how practical relevance in university teaching subsequently shifted during the Nazi era.
Why do cancer cells break from host circadian rhythm? Insights from unicellular organisms
Authors: Alamoudi Aliaa A.
Published: February 2021

It is not clear why cancer cells choose to disrupt their circadian clock rhythms, and whether such disruption governs a selective fitness and a survival advantage. In this review, I focus on understanding the impacts of clock gene disruption on a simpler model, such as the unicellular cyanobacterium, in order to explain how cancer cells may alter the circadian rhythm to reprogram their metabolism based on their needs and status. It appears to be that the activation of the oxidative pentose phosphate pathway (OPPP) and production of NADPH, the preferred molecule for detoxification of reactive oxygen species, is a critical process for night survival in unicellular organisms. The circadian clock acts as a gatekeeper that controls how the organism will utilize its sugar, shifting sugar influx between glycolysis and OPPP. The circadian clock can thus act as a gatekeeper between an anabolic, proliferative mode and a homeostatic, survival mode.
Environmental sustainability engagement of firms: The roles of social capital, resources, and managerial entrepreneurial orientation of small and medium enterprises in Vietnam
Authors: Roxas Banjo
Published: February 2021

How firms in transition economies demonstrate their strategic engagement in sustainable environmental management given their limited resources and capabilities is less understood in the literature. This study explores how small and medium enterprises (SMEs) in Vietnam, an exemplar of a country in transition from a closed and socialist economy to an open and liberal market, draw on their external social capital to access critical resources that are leveraged by the entrepreneurial orientation or capabilities of the firms' top management towards engagement in business‐wide environmentally sustainable practices. Drawing on a database of more than 2000 firms from a large‐scale survey of firms in Vietnam, this study tests the relationships between two facets of social capital, environmental management resources and environmental sustainability engagement. This study further contends that managerial entrepreneurial orientation moderates by enhancing the strategic utilisation of resources to enable firms in Vietnam to engage in environmental sustainability. The results offer novel theoretical insights and timely managerial or practical implications as well as promising directions for future research on the resources, strategies and capabilities of firms in transition economies.
Risk–need–responsivity: Evaluating need‐to‐service matching with reach, effectiveness, adoption, implementation, maintenance
Authors: Drawbridge Dara C. , Truong Debbie , Nguyen Ngoc T. , Lorenti Vincent L. , Vincent Gina M.
Published: February 2021

With a sample of 125 adults under community supervision (71.20% male, 76.00% White, mean age = 33.17 years), this study evaluated need‐to‐service matching using an evaluation framework from implementation science. Need‐to‐service matching is a case management strategy intended to align service referrals in case plans with justice‐involved persons' criminogenic needs. The results indicated that need‐to‐service matching reached a high percentage of its target population at 81.70%. Within criminogenic need areas, good match frequencies ranged from 80.00% in family/marital problems to 98.29% in alcohol/drug problems. Clinical staff also met the adherence benchmark applied by the current study, which required a 75.00% match between individuals' criminogenic needs and the services they received. Justice‐involved persons had, on average, 90.46% of their criminogenic needs matched with at least one service referral. Over‐prescription of services (i.e., recommendation of services that were not needed) was high, with frequencies in need areas ranging from 60.98% in education/employment to 82.21% in antisocial patterns. Methods from implementation science are useful for structuring evaluations of need‐to‐service matching, understanding implementation success and failure, and generating recommendations for improving implementation practice. The field would benefit greatly from benchmarks for need‐to‐service matching evaluation elements.
Safety, tolerability, and pharmacokinetics of BAT8001 in patients with HER2‐positive breast cancer: An open‐label, dose‐escalation, phase I study
Authors: Hong Ruoxi , Xia Wen , Wang Liye , Lee Kaping , Lu Qianyi , Jiang Kuikui , Li Shengfeng , Yu Jinquan , Wei Jin , Tang Weijia , Zhou Danyang , An Xin , Huang Jiajia , Xue Cong , Bi Xiwen , Shi Yanxia , Yuan Zhongyu , Xu Fei , Wang Shusen
Published: February 2021

Background

The introductions of anti‐ human epidermal growth factor receptor‐2 (HER2) agents have significantly improved the treatment outcome of patients with HER2‐positive breast cancer. BAT8001 is a novel antibody‐drug conjugate targeting human epidermal growth factor receptor‐2 (HER2)‐expressing cells composed of a trastuzumab biosimilar linked to the drug‐linker Batansine. This dose‐escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti‐tumor activity of BAT8001 in patients with HER2‐positive locally advanced or metastatic breast cancer.

Methods

This trial was conducted in subjects with histologically confirmed HER2‐positive breast cancer (having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1) using a 3 + 3 design of escalating BAT8001 doses. Patients received BAT8001 intravenously in a 21‐day cycle, with dose escalation in 5 cohorts: 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg. The primary objective was to evaluate the safety and tolerability of BAT8001. Preliminary activity of BAT8001 was also assessed as a secondary objective.

Results

Between March 2017 to May 2018, 29 HER2‐positive breast cancer patients were enrolled. The observed dose‐limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase. The maximum tolerated dose was determined to be 3.6 mg/kg. Grade 3 or greater adverse events (AEs) occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, γ‐glutamyl transferase increased in 2 (6.9%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhea in 2 (6.9%) patients. Objective response was observed in 12 (41.4%; 95% confidence interval [CI] = 23.5%‐61.1%) and disease control (including patients achieving objective response and stable disease) was observed in 24 (82.8%; 95% CI = 64.2%‐94.2%) patients.

Conclusions

BAT8001 demonstrated favorable safety profiles, with promising anti‐tumor activity in patients with HER2‐positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2‐positive breast cancer.
Tuning the Transglycosylation Reaction of a GH11 Xylanase by a Delicate Enhancement of its Thumb Flexibility
Authors: Marneth Kim , van den Elst Hans , Cramer‐Blok Anneloes , Codee Jeroen , Overkleeft Hermen S. , Aerts Johannes M. F. G. , Ubbink Marcellus , Ben Bdira Fredj
Published: February 2021

Glycoside hydrolases (GHs) are attractive tools for multiple biotechnological applications. In conjunction with their hydrolytic function, GHs can perform transglycosylation under specific conditions. In nature, oligosaccharide synthesis is performed by glycosyltransferases (GTs); however, the industrial use of GTs is limited by their instability in solution. A key difference between GTs and GHs is the flexibility of their binding site architecture. We have used the xylanase from Bacillus circulans (BCX) to study the interplay between active‐site flexibility and transglycosylation. Residues of the BCX “thumb” were substituted to increase the flexibility of the enzyme binding site. Replacement of the highly conserved residue P116 with glycine shifted the balance of the BCX enzymatic reaction toward transglycosylation. The effects of this point mutation on the structure and dynamics of BCX were investigated by NMR spectroscopy. The P116G mutation induces subtle changes in the configuration of the thumb and enhances the millisecond dynamics of the active site. Based on our findings, we propose the remodelling of the GH enzymes glycon site flexibility as a strategy to improve the transglycosylation efficiency of these biotechnologically important catalysts.