bluuebunny/crossref_metadata_2025 huggingface dataset:
Foster Carers’ Receptiveness to New Innovations and Programmes: An Example from the Introduction of Social Pedagogy to UK Foster Care
Authors: McDermid Samantha , Trivedi Helen , Holmes Lisa , Boddy Janet
Published: June 2021

Foster carers characterise a highly diverse workforce that shares the choice to provide a home and family for children who can no longer reside with their family. This diversity makes supporting and providing for carers’ training needs a complex task for fostering services. Understanding what might influence their engagement in training would be useful. This article outlines themes related to foster carers’ engagement with social pedagogy, using data from the Head, Heart, Hands (HHH) programme evaluation. Analysis of interviews with seventy-six foster carers over a period of three years is presented. The emerging themes were used to devise an illustrative typology of receptiveness to training. The themes relate to the perceived impact of HHH on their practice and compatibility with the existing children’s social care (CSC) system. The article explores the factors that may influence foster carers’ positioning within the typology. The contributions that such a typology might make to the wider evidence base across CSC, in terms of the implementation and potential impacts of intervention, are discussed.
Contemporary approach to soft-tissue reconstruction of the lower extremity after trauma
Authors: Zeiderman Matthew R , Pu Lee L Q
Published: June 2021

The complex lower extremity wound is frequently encountered by orthopedic and plastic surgeons. Innovations in wound care, soft tissue coverage and surgical fixation techniques allow for improved functional outcomes in this patient population with highly morbid injuries. In this review, the principles of reconstruction of complex lower extremity traumatic wounds are outlined. These principles include appropriate initial evaluation of the patient and mangled extremity, as well as appropriate patient selection for limb salvage. The authors emphasize proper planning for reconstruction, timing of reconstruction and the importance of an understanding of the most appropriate reconstructive option. The role of different reconstructive and wound care modalities is discussed, notably negative pressure wound therapy and dermal substitutes. The role of pedicled flaps and microvascular free-tissue transfer are discussed, as are innovations in understanding of perforator anatomy and perforator flap surgery that have broadened the reconstruction surgeon’s armamentarium. Finally, the importance of a multidisciplinary team is highlighted via the principle of the orthoplastic approach to management of complex lower extremity wounds. Upon completion of this review, the reader should have a thorough understanding of the principles of contemporary lower extremity reconstruction.
Brain and Behavioral Evidence for Reweighting of Vestibular Inputs with Long-Duration Spaceflight
Authors: Hupfeld K E , McGregor H R , Koppelmans V , Beltran N E , Kofman I S , De Dios Y E , Riascos R F , Reuter-Lorenz P A , Wood S J , Bloomberg J J , Mulavara A P , Seidler R D
Published: June 2021

Microgravity alters vestibular signaling. In-flight adaptation to altered vestibular afferents is reflected in post-spaceflight aftereffects, evidenced by declines in vestibularly mediated behaviors (e.g., walking/standing balance), until readaptation to Earth’s 1G environment occurs. Here we examine how spaceflight affects neural processing of applied vestibular stimulation. We used fMRI to measure brain activity in response to vestibular stimulation in 15 astronauts pre- and post-spaceflight. We also measured vestibularly-mediated behaviors, including balance, mobility, and rod-and-frame test performance. Data were collected twice preflight and four times postflight. As expected, vestibular stimulation at the preflight sessions elicited activation of the parietal opercular area (“vestibular cortex”) and deactivation of somatosensory and visual cortices. Pre- to postflight, we found widespread reductions in this somatosensory and visual cortical deactivation, supporting sensory compensation and reweighting with spaceflight. These pre- to postflight changes in brain activity correlated with changes in eyes closed standing balance, and greater pre- to postflight reductions in deactivation of the visual cortices associated with less postflight balance decline. The observed brain changes recovered to baseline values by 3 months postflight. Together, these findings provide evidence for sensory reweighting and adaptive cortical neuroplasticity with spaceflight. These results have implications for better understanding compensation and adaptation to vestibular functional disruption.
Monitoring anti-PLA2R antibody titres to predict the likelihood of spontaneous remission of membranous nephropathy
Authors: Jatem-Escalante Elias , Martín-Conde María Luisa , Gràcia-Lavedan Esther , Benítez Ivan D , Gonzalez Jorge , Colás Laura , Garcia-Carrasco Alicia , Martínez Cristina , Segarra-Medrano Alfons
Published: June 2021

Background

In anti-phospholipase A2 receptor (PLA2R) membranous nephropathy (MN) there is controversy whether spontaneous remission (SR) can be predicted using a single titre or by assessing the dynamic changes in anti-PLA2R antibody (ab) titres. The study objective was to identify the optimal dynamics of anti-PLA2Rab titres to predict SR in MN.

Methods

A total of 127 nephrotic patients with anti-PLA2R-MN were prospectively followed up for 6 months under conservative treatment. Anti-PLA2Rabs and proteinuria were assessed at diagnosis and monthly thereafter. The primary endpoint (PEP) was a reduction of proteinuria ≥50% at 6 months. Logistic models with baseline and evolutive anti-PLA2Rab titres were developed to predict the PEP.

Results

A total of 28 patients (22%) reached the PEP. These patients were more frequently female and had significantly lower baseline proteinuria and anti-PLA2Rab titres. An anti-PLA2R titre ≤97.5 RU/mL at diagnosis had a sensitivity of 71% and a specificity of 81% to predict the PEP. The model including baseline anti-PLA2Rabs and a reduction ≥15% at 3 months predicted the PEP with a sensitivity of 93% and a specificity of 80%, with an area under the curve that was significantly greater than that obtained with relative changes of proteinuria in the same period of time {odds ratio [OR] 0.95 [95% confidence interval (CI) 0.91–0.98 versus OR 0.79 [95% CI 0.70–0.88], respectively; P = 0.0013}.

Conclusions

Combining the baseline anti-PLA2Rab titres with their relative changes at 3 months after diagnosis gives the earliest prediction for achieving a reduction of urinary protein excretion ≥50% at 6 months in MN, thereby shortening the observation period currently recommended to make individualized decisions to start immunosuppressive therapy.
Analytical Quality Controls for ddPCR Detection of Minimal Residual Disease in Acute Lymphoblastic Leukemia
Authors: Chen Dan , Sutton Rosemary , Giles Jodie , Venn Nicola C , Huang Libby , Law Tamara , Subhash Vinod Vijay , Trahair Toby N , Henderson Michelle J
Published: June 2021

Background

Droplet digital PCR (ddPCR) is a promising technique for absolute quantification of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL), but there is no comprehensive quality assurance program to enable its application in clinical laboratories. Current guidelines for real-time quantitative PCR (qPCR) assays targeting immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements needed adaptation for ddPCR to cover droplet generation, intraassay variation, and interassay variation in the absence of standard curves.

Methods

Six qPCR MRD assays for Ig/TCR gene rearrangements and a standard albumin control gene assay were migrated to a ddPCR platform and used to test 82 remission samples from 6 patients with ALL. Three analytical quality controls (QC) were developed and evaluated for ddPCR MRD detection.

Results

Analytical QC for droplet number generation (DN-QC), for albumin ddPCR assay performance (Alb-QC) and for patient-specific marker assay performance (PS-QC) were established with pass/fail limits and corresponding QC rules. Compared to established qPCRs, the ddPCR assays had comparable sensitivity and quantitative range. Overall, there was close agreement (91%) of MRD results between qPCR and ddPCR (κ = 0.86, P < 0.0001) and stronger concordance in 32 quantifiable samples (R2 = 0.97, P < 0.0001).

Conclusions

The use of this newly developed quality control system for ddPCR MRD testing avoids the need to repeat standard curves and provides reliable results comparable to standardized qPCR methods for MRD detection in ALL.
Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy
Authors: Michel Lars , Helfrich Iris , Hendgen-Cotta Ulrike Barbara , Mincu Raluca-Ileana , Korste Sebastian , Mrotzek Simone Maria , Spomer Armin , Odersky Andrea , Rischpler Christoph , Herrmann Ken , Umutlu Lale , Coman Cristina , Ahrends Robert , Sickmann Albert , Löffek Stefanie , Livingstone Elisabeth , Ugurel Selma , Zimmer Lisa , Gunzer Matthias , Schadendorf Dirk , Totzeck Matthias , Rassaf Tienush
Published: June 2021

Aims

Cardiac immune-related adverse events (irAEs) from immune checkpoint inhibition (ICI) targeting programmed death 1 (PD1) are of growing concern. Once cardiac irAEs become clinically manifest, fatality rates are high. Cardio-oncology aims to prevent detrimental effects before manifestation of severe complications by targeting early pathological changes. We therefore aimed to investigate early consequences of PD1 inhibition for cardiac integrity to prevent the development of overt cardiac disease.

Methods and results

We investigated cardiac-specific consequences from anti-PD1 therapy in a combined biochemical and in vivo phenotyping approach. Mouse hearts showed broad expression of the ligand PDL1 on cardiac endothelial cells as a main mediator of immune-crosstalk. Using a novel melanoma mouse model, we assessed that anti-PD1 therapy promoted myocardial infiltration with CD4+ and CD8+ T cells, the latter being markedly activated. Left ventricular (LV) function was impaired during pharmacological stress, as shown by pressure–volume catheterization. This was associated with a dysregulated myocardial metabolism, including the proteome and the lipidome. Analogous to the experimental approach, in patients with metastatic melanoma (n = 7) receiving anti-PD1 therapy, LV function in response to stress was impaired under therapy. Finally, we identified that blockade of tumour necrosis factor alpha (TNFα) preserved LV function without attenuating the anti-cancer efficacy of anti-PD1 therapy.

Conclusions

Anti-PD1 therapy induces a disruption of cardiac immune homeostasis leading to early impairment of myocardial functional integrity, with potential prognostic effects on the growing number of treated patients. Blockade of TNFα may serve as an approach to prevent the manifestation of ICI-related cardiotoxicity.
Assessment of the physical performance in children with asymptomatic pre-excitation
Authors: Książczyk Tomasz M , Jaroń Anna , Pietrzak Radosław , Werner Bożena
Published: June 2021

Aims

Pre-excitation syndrome can lead to recurrent supraventricular tachycardias (SVTs) and carries a risk of sudden cardiac death (SCD). However, an underestimated consequence of antegrade conduction through an accessory pathway is fusion of intrinsic and accessory conduction that causes asynchronous activation and myocardial contraction that could be a cause for cardiac dysfunction and dilation. It is not known to what extent pre-excitation affects myocardial and physical performance in those patients. The aim of the study was to assess to what degree ventricular pre-excitation affects physical performance in children, using cardio-pulmonary exercise testing (CPET).

Methods and results

The study group consisted of 30 asymptomatic children, aged 8–17 years, with pre-excitation and no history or documentation of SVT compared to 31 healthy controls matched according to sex and age. All patients underwent routine cardiology assessment and then CPET. Echocardiography showed there were no differences in the left ventricular size and function between the study and control group. During the CPET both, patients and controls achieved maximal effort. Patients in the study group showed significantly lower values of VO2max and anaerobic threshold when compared to controls. The most affected subgroup was patients with persistent pre-excitation throughout the exercise.

Conclusions

Physical performance is affected in children with pre-excitation. This effect is stronger in patients with persistent delta wave observed throughout the exercise.
Male–Female Differences in the Effects of Age on Performance Measures Recorded for 23 Hours in Mice
Authors: Tran Trang , Mach John , Gemikonakli Gizem , Wu Harry , Allore Heather , Howlett Susan E , Little Christopher B , Hilmer Sarah N
Published: June 2021

Functional independence is an important aspect of successful aging and differs with age and by sex in humans. Physical performance often declines earlier than other age-associated functional impairments. Rodent models are used to study pharmacological/toxicological effects of human therapies. However, physical outcomes in mice are usually assessed for short periods, with limited information on the influence of age and sex. Here, we investigated how age and sex affected murine physical performance over 23 hours of continuous observation. Young (3 months) and old (22 months) C57BL/6JArc male and female mice were assessed using the Laboratory Animal Behavior Observation, Registration, and Analysis System. Mice were individually housed for recording of distance travelled, mean gait speed, and durations of different physical activities. Compared to young mice of the same sex, old mice travelled significantly shorter distances with slower gait speeds and shorter durations of locomotion, rearing, climbing, and immobility. Older mice groomed significantly more than young mice. Old females reared more during the light cycle than old males. Young females climbed substantially more than young males. Significant Age * Sex interactions were detected for rearing and climbing, whereby an age-related decline was greater in males than in females. Our results suggest that old age reduces exploratory activities and increases grooming in mice. Age-related declines vary between sexes and tend to be greater in males. This noninvasive assessment can be applied to investigate how different interventions affect rodents of different ages and sexes, through the day–night cycle.
Squirt flow in partially saturated cracks: a simple analytical model
Authors: Solazzi Santiago G , Lissa Simón , Rubino J Germán , Holliger Klaus
Published: June 2021

Obtaining the seismic response of rocks containing cracks whose scales are much smaller than the prevailing wavelengths is a classic and important problem in rock physics. Seminal analytical models yield the seismic signatures of cracked rocks saturated with a single fluid phase. However, in a wide variety of practically relevant scenarios, cracks may be partially saturated with multiple immiscible fluids of contrasting compressibilities, such as gas and water. When a passing seismic wave deforms the medium, fluid pressure gradients arise within such partially saturated cracks, which, in turn, tend to relax through a process commonly known as squirt flow. The corresponding viscous dissipation may greatly affect the seismic amplitudes and velocities, as well as the anisotropic behaviour of the medium. To date, extensions of classical analytical models to include squirt flow occurring within isolated partially saturated cracks remain limited either in the saturation or in the frequency range. In this work, we present a simple analytical model to compute the seismic response of rocks containing partially saturated aligned cracks accounting for squirt flow effects. First, we solve the linearized Navier–Stokes equations within a partially saturated penny-shaped crack subjected to an oscillatory strain. Then, we obtain a closed analytical expression for a complex-valued frequency-dependent effective fluid bulk modulus which accounts for the stiffness variations of each crack due to squirt flow. Using classic effective medium models, together with such an effective saturating fluid, we retrieve the effective compliance matrix of the probed partially saturated cracked rock. The proposed analytical solution is validated by comparison with corresponding 3-D numerical simulations and existing analytical models.
A unique case of a typical carcinoid of the middle mediastinum: en bloc surgical resection on cardiopulmonary bypass
Authors: Rizzardi Giovanna , Brascia Debora , Marulli Giuseppe , Bortolotti Luigi
Published: June 2021

We report a unique case of a 67-year-old man with a typical carcinoid of the middle mediastinum that adhered tightly to the pericardium, the posterior part of the ascending aorta and the pulmonary trunk, that was radically resected with the patient on cardiopulmonary bypass by clamping, sectioning and suturing the ascending aorta.
Seasonal variation in mortality and the role of temperature: a multi-country multi-city study
Authors: Madaniyazi Lina , Armstrong Ben , Chung Yeonseung , Ng Chris Fook Sheng , Seposo Xerxes , Kim Yoonhee , Tobias Aurelio , Guo Yuming , Sera Francesco , Honda Yasushi , Gasparrini Antonio , Hashizume Masahiro ,   the Multi-Country Multi-City (MCC) Collaborative Research Network, Abrutzky Rosana , Acquaotta Fiorella , Ameling Caroline , Analitis Antonis , Åström Christofer , Pan Shih-Chun , Coelho Micheline de Sousa Zanotti Stagliorio , Correa Patricia Matus , Dang Tran Ngoc , de'Donato Francesca , Diaz Magali Hurtado , Van Dung Do , Entezari Alireza , Forsberg Bertil , Fratianni Simona , Goodman Patrick , Guo Yue Leon , Holobâca Iulian Horia , Houthuijs Danny , Huber Veronika , Indermitte Ene , Íñiguez Carmen , Jaakkola Jouni , Kan Haidong , Katsouyanni Klea , Kim Ho , Kyselý Jan , Lavigne Eric , Lee Whanhee , Li Shanshan , Mayvaneh Fatemeh , Michelozzi Paola , Nunes Baltazar , Orru Hans , Ortega Nicolás Valdés , Osorio Samuel , Overcenco Ala , Pascal Mathilde , Ragettli Martina S , Rao Shilpa , Ryti Niilo , Saldiva Paulo Hilario Nascimento , Schneider Alexandra , Schwartz Joel , Scovronick Noah , Teixeira João Paulo , Tong Shilu , Urban Aleš , Valencia César De la Cruz , Vicedo-Cabrera Ana Maria , Zanobetti Antonella , Zeka Ariana
Published: June 2021

Background

Although seasonal variations in mortality have been recognized for millennia, the role of temperature remains unclear. We aimed to assess seasonal variation in mortality and to examine the contribution of temperature.

Methods

We compiled daily data on all-cause, cardiovascular and respiratory mortality, temperature and indicators on location-specific characteristics from 719 locations in tropical, dry, temperate and continental climate zones. We fitted time-series regression models to estimate the amplitude of seasonal variation in mortality on a daily basis, defined as the peak-to-trough ratio (PTR) of maximum mortality estimates to minimum mortality estimates at day of year. Meta-analysis was used to summarize location-specific estimates for each climate zone. We estimated the PTR with and without temperature adjustment, with the differences representing the seasonal effect attributable to temperature. We also evaluated the effect of location-specific characteristics on the PTR across locations by using meta-regression models.

Results

Seasonality estimates and responses to temperature adjustment varied across locations. The unadjusted PTR for all-cause mortality was 1.05 [95% confidence interval (CI): 1.00–1.11] in the tropical zone and 1.23 (95% CI: 1.20–1.25) in the temperate zone; adjusting for temperature reduced the estimates to 1.02 (95% CI: 0.95–1.09) and 1.10 (95% CI: 1.07–1.12), respectively. Furthermore, the unadjusted PTR was positively associated with average mean temperature.

Conclusions

This study suggests that seasonality of mortality is importantly driven by temperature, most evidently in temperate/continental climate zones, and that warmer locations show stronger seasonal variations in mortality, which is related to a stronger effect of temperature.
Placental Expression of ACE2 and TMPRSS2 in Maternal Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Are Placental Defenses Mediated by Fetal Sex?
Authors: Shook Lydia L , Bordt Evan A , Meinsohn Marie-Charlotte , Pepin David , De Guzman Rose M , Brigida Sara , Yockey Laura J , James Kaitlyn E , Sullivan Mackenzie W , Bebell Lisa M , Roberts Drucilla J , Kaimal Anjali J , Li Jonathan Z , Schust Danny , Gray Kathryn J , Edlow Andrea G
Published: June 2021

Background

Expression of angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), host molecules required for viral entry, may underlie sex differences in vulnerability to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated whether placental ACE2 and TMPRSS2 expression vary by fetal sex in the presence of maternal SARS-CoV-2 infection.

Methods

Placental ACE2 and TMPRSS2 expression was quantified by quantitative reverse transcription polymerase chain reaction (RT-PCR) and by Western blot in 68 pregnant women (38 SARS-CoV-2 positive, 30 SARS-CoV-2 negative) delivering at Mass General Brigham from April to June 2020. The impact of fetal sex and maternal SARS-CoV-2 exposure on ACE2 and TMPRSS2 was analyzed by 2-way analysis of variance (ANOVA).

Results

Maternal SARS-CoV-2 infection impacted placental TMPRSS2 expression in a sexually dimorphic fashion (2-way ANOVA interaction, P = .002). We observed no impact of fetal sex or maternal SARS-CoV-2 status on ACE2. TMPRSS2 expression was significantly correlated with ACE2 expression in males (Spearman ρ = 0.54, P = .02) but not females (ρ = 0.23, P = .34) exposed to maternal SARS-CoV-2.

Conclusions

Sex differences in placental TMPRSS2 but not ACE2 were observed in the setting of maternal SARS-CoV-2 infection, which may have implications for offspring vulnerability to placental infection.
Combination treatment of liposomal amphotericin B and isavuconazole is synergistic in treating experimental mucormycosis
Authors: Gebremariam Teclegiorgis , Gu Yiyou , Singh Shakti , Kitt Therese M , Ibrahim Ashraf S
Published: June 2021

Objectives

Liposomal amphotericin B (L-AMB) and isavuconazonium sulphate are commonly used antifungal drugs to treat mucormycosis. However, the efficacy of combination therapy of L-AMB/isavuconazonium sulphate versus monotherapy is unknown. We used an immunosuppressed mouse model of pulmonary mucormycosis to compare the efficacy of L-AMB/isavuconazonium sulphate versus either drug alone.

Methods

Neutropenic mice were intratracheally infected with either Rhizopus delemar or Mucor circinelloides. Treatment with L-AMB, isavuconazonium sulphate, or a combination of both started 8 h post-infection and continued through to Day +4. Placebo mice received vehicle control. Survival to Day +21 and tissue fungal burden (by conidial equivalent using quantitative PCR) on Day +4, served as primary and secondary endpoints, respectively.

Results

For mice infected with R. delemar, L-AMB and isavuconazonium sulphate equally prolonged median survival time and enhanced survival versus placebo (an overall survival of 50% for either drug alone, versus 5% for placebo). Importantly, combination treatment resulted in an overall survival of 80%. Both antifungal drugs reduced tissue fungal burden of lungs and brain by ∼1.0–2.0 log versus placebo-treated mice. Treatment with combination therapy resulted in 2.0–3.5 log reduction in fungal burden of either organ versus placebo and 1.0 log reduction versus either drug alone. Similar treatment outcomes were obtained using mice infected with M. circinelloides.

Conclusions

The L-AMB/isavuconazonium sulphate combination demonstrated greater activity versus monotherapy in immunosuppressed mice infected with either of the two most common causes of mucormycosis. These studies warrant further investigation of L-AMB/isavuconazonium sulphate combination therapy as an optimal therapy of human mucormycosis.
Generative design and fabrication of a locust-inspired gliding wing prototype for micro aerial robots
Authors: Isakhani Hamid , Bellotto Nicola , Fu Qinbing , Yue Shigang
Published: June 2021

Gliding is generally one of the most efficient modes of flight in natural fliers that can be further emphasized in the aircraft industry to reduce emissions and facilitate endured flights. Natural wings being fundamentally responsible for this phenomenon are developed over millions of years of evolution. Artificial wings, on the other hand, are limited to the human-proposed conceptual design phase often leading to sub-optimal results. However, the novel Generative Design (GD) method claims to produce mechanically improved solutions based on robust and rigorous models of design conditions and performance criteria. This study investigates the potential applications of this Computer-Associated Design (CAsD) technology to generate novel micro aerial vehicle wing concepts that are structurally more stable and efficient. Multiple performance-driven solutions (wings) with high-level goals are generated by an infinite scale cloud computing solution executing a machine learning-based GD algorithm. Ultimately, the highest performing CAsD concepts are numerically analysed, fabricated, and mechanically tested according to our previous study, and the results are compared to the literature for qualitative as well as quantitative analysis and validations. It was concluded that the GD-based tandem wings’ (forewing and hindwing) ability to withstand fracture failure without compromising structural rigidity was optimized by 78% compared to its peer models. However, the weight was slightly increased by 11% with 14% drop in stiffness when compared to our models from previous study.
Whole-cell display of Pyrococcus horikoshii glutamate decarboxylase in Escherichia coli for high-titer extracellular gamma-aminobutyric acid production
Authors: Somasundaram Sivachandiran , Jeong Jaehoon , Kumaravel Ashokkumar , Hong Soon Ho
Published: June 2021

We investigated the effect of cell-surface display of glutamate decarboxylase (GadB) on gamma-aminobutyric acid (GABA) production in recombinant Escherichia coli. We integrated GadB from the hyperthermophilic, anaerobic archaeon Pyrococcus horikoshii to the C-terminus of the E. coli outer membrane protein C (OmpC). After 12 hr of culturing GadB-displaying cells, the GABA concentration in the extracellular medium increased to 3.2 g/l, which is eight times that obtained with cells expressing GadB in the cytosol. To further enhance GABA production, we increased the temperatures of the culture. At 60°C, the obtained GABA concentration was 4.62 g/l after 12 hr of culture, and 5.35 g/l after 24 hr, which corresponds to a yield of 87.7%.
ABA signalling promotes cell totipotency in the shoot apex of germinating embryos
Authors: Chen Baojian , Fiers Martijn , Dekkers Bas J W , Maas Lena , van Esse G Wilma , Angenent Gerco C , Zhao Yang , Boutilier Kim
Published: June 2021

Somatic embryogenesis (SE) is a type of induced cell totipotency where embryos develop from vegetative tissues of the plant instead of from gamete fusion after fertilization. SE can be induced in vitro by exposing explants to growth regulators, such as the auxinic herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). The plant hormone abscisic acid (ABA) has been proposed to be a downstream signalling component at the intersection between 2,4-D- and stress-induced SE, but it is not known how these pathways interact to induce cell totipotency. Here we show that 2,4-D-induced SE from the shoot apex of germinating Arabidopsis thaliana seeds is characterized by transcriptional maintenance of an ABA-dependent seed maturation pathway. Molecular–genetic analysis of Arabidopsis mutants revealed a role for ABA in promoting SE at three different levels: ABA biosynthesis, ABA receptor complex signalling, and ABA-mediated transcription, with essential roles for the ABSCISIC ACID INSENSITIVE 3 (ABI3) and ABI4 transcription factors. Our data suggest that the ability of mature Arabidopsis embryos to maintain the ABA seed maturation environment is an important first step in establishing competence for auxin-induced cell totipotency. This finding provides further support for the role of ABA in directing processes other than abiotic stress response.
Constraining alternatives to the Kerr black hole
Authors: Shaikh Rajibul , Pal Kunal , Pal Kuntal , Sarkar Tapobrata
Published: June 2021

The recent observation of the shadow of the supermassive compact object M87* by the Event Horizon Telescope (EHT) collaboration has opened up a new window to probe the strong gravity regime. In this paper, we study shadows cast by two viable alternatives to the Kerr black hole, and compare them with the shadow of M87*. The first alternative is a horizonless compact object (HCO) having radius r0 and exterior Kerr geometry. The second one is a rotating generalization of the recently obtained one parameter (r0) static metric by Simpson and Visser. This latter metric, constructed using the Newman–Janis algorithm, is a special case of a parametrized rotating non-Kerr geometry obtained by Johannsen. Here, we constrain the parameter r0 of these alternatives using the results from M87* observation. We find that, for the mass, inclination angle and the angular diameter of the shadow of M87* reported by the EHT collaboration, the maximum value of the parameter r0 must be in the range 2.54r+ ≤ r0, max ≤ 3.51r+ for the dimensionless spin range 0.5 ≤ a* ≤ 0.94, with r+ being the outer horizon radius of the Kerr black hole at the corresponding spin value. We conclude that these black hole alternatives having r0 below this maximum range (i.e. r0 ≤ r0, max) is consistent with the size and deviation from circularity of the observed shadow of M87*.
The Global Magneto-Ionic Medium Survey (GMIMS): the brightest polarized region in the southern sky at 75 cm and its implications for Radio Loop II
Authors: Thomson Alec J M , Landecker T L , McClure-Griffiths N M , Dickey John M , Campbell J L , Carretti Ettore , Clark S E , Federrath Christoph , Gaensler B M , Han J L , Haverkorn Marijke , Hill Alex S , Mao S A , Ordog Anna , Pratley Luke , Reich Wolfgang , Van Eck Cameron L , West J L , Wolleben M
Published: June 2021

Using the Global Magneto-Ionic Medium Survey (GMIMS) Low-Band South (LBS) southern sky polarization survey, covering 300–480 MHz at 81  arcmin resolution, we reveal the brightest region in the southern polarized sky at these frequencies. The region, G150−50, covers nearly 20 $\deg ^2$, near (l, b) ≈ (150○, −50○). Using GMIMS-LBS and complementary data at higher frequencies (∼0.6–30 GHz), we apply Faraday tomography and Stokes QU-fitting techniques. We find that the magnetic field associated with G150−50 is both coherent and primarily in the plane of the sky, and indicates that the region is associated with Radio Loop II. The Faraday depth spectra across G150−50 are broad and contain a large-scale spatial gradient. We model the magnetic field in the region as an expanding shell, and we can reproduce both the observed Faraday rotation and the synchrotron emission in the GMIMS-LBS band. Using QU fitting, we find that the Faraday spectra are produced by several Faraday dispersive sources along the line of sight. Alternatively, polarization horizon effects that we cannot model are adding complexity to the high-frequency polarized spectra. The magnetic field structure of Loop II dominates a large fraction of the sky, and studies of the large-scale polarized sky will need to account for this object. Studies of G150−50 with high angular resolution could mitigate polarization horizon effects, and clarify the nature of G150−50.
Uptake, transport, and metabolism of selenium and its protective effects against toxic metals in plants: a review
Authors: Jiang Haiyan , Lin Weiqiang , Jiao Hongpeng , Liu Jinggong , Chan Leung , Liu Xiaoying , Wang Rui , Chen Tianfeng
Published: June 2021

Selenium (Se) is an essential trace element of fundamental importance to humans, animals, and plants. However, the uptake, transport, and metabolic processes of Se and its underlying mechanisms in plants have not been well characterized. Here, we review our current understanding of the adsorption and assimilation of Se in plants. First, we discussed the conversion of Se from inorganic Se into organic forms, the mechanisms underlying the formation of seleno-amino acids, and the detoxification of Se. We then discussed the ways in which Se protects plants against toxic metal ions in the environment, such as by alleviating oxidative stress, regulating the activity of antioxidant enzymes, sequestering metal ions, and preventing metal ion uptake and accumulation. Generally, this review will aid future research examining the molecular mechanisms underlying the antagonistic relationships between Se and toxic metals in plants.
Rank-in: enabling integrative analysis across microarray and RNA-seq for cancer
Authors: Tang Kailin , Ji Xuejie , Zhou Mengdi , Deng Zeliang , Huang Yuwei , Zheng Genhui , Cao Zhiwei
Published: June 2021

Though transcriptomics technologies evolve rapidly in the past decades, integrative analysis of mixed data between microarray and RNA-seq remains challenging due to the inherent variability difference between them. Here, Rank-In was proposed to correct the nonbiological effects across the two technologies, enabling freely blended data for consolidated analysis. Rank-In was rigorously validated via the public cell and tissue samples tested by both technologies. On the two reference samples of the SEQC project, Rank-In not only perfectly classified the 44 profiles but also achieved the best accuracy of 0.9 on predicting TaqMan-validated DEGs. More importantly, on 327 Glioblastoma (GBM) profiles and 248, 523 heterogeneous colon cancer profiles respectively, only Rank-In can successfully discriminate every single cancer profile from normal controls, while the others cannot. Further on different sizes of mixed seq-array GBM profiles, Rank-In can robustly reproduce a median range of DEG overlapping from 0.74 to 0.83 among top genes, whereas the others never exceed 0.72. Being the first effective method enabling mixed data of cross-technology analysis, Rank-In welcomes hybrid of array and seq profiles for integrative study on large/small, paired/unpaired and balanced/imbalanced samples, opening possibility to reduce sampling space of clinical cancer patients. Rank-In can be accessed at http://www.badd-cao.net/rank-in/index.html.
Temporal changes and risk factors for death from early withdrawal within 12 months of dialysis initiation—a cohort study
Authors: Chen Jenny H C , Brown Mark A , Jose Matthew , Brennan Frank , Johnson David W , Roberts Matthew A , Wong Germaine , Cheikh Hassan Hicham , Kennard Alice , Walker Rachael , Davies Christopher E , Boudville Neil , Borlace Monique , Hawley Carmel , Lim Wai H
Published: June 2021

Background

Mortality risk is high soon after dialysis initiation in patients with kidney failure, and dialysis withdrawal is a major cause of early mortality, attributed to psychosocial or medical reasons. The temporal trends and risk factors associated with cause-specific early dialysis withdrawal within 12 months of dialysis initiation remain uncertain.

Methods

Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the temporal trends and risk factors associated with mortality attributed to early psychosocial and medical withdrawals in incident adult dialysis patients in Australia between 2005 and 2018 using adjusted competing risk analyses.

Results

Of 32 274 incident dialysis patients, 3390 (11%) experienced death within 12 months post-dialysis initiation. Of these, 1225 (36%) were attributed to dialysis withdrawal, with 484 (14%) psychosocial withdrawals and 741 (22%) medical withdrawals. These patterns remained unchanged over the past two decades. Factors associated with increased risk of death from early psychosocial and medical withdrawals were older age, dialysis via central venous catheter, late referral and the presence of cerebrovascular disease; obesity and Asian ethnicity were associated with decreased risk. Risk factors associated with early psychosocial withdrawals were underweight and higher socioeconomic status. Presence of peripheral vascular disease, chronic lung disease and cancers were associated with early medical withdrawals.

Conclusions

Death from dialysis withdrawal accounted for >30% of early deaths in kidney failure patients initiated on dialysis and remained unchanged over the past two decades. Several shared risk factors were observed between mortality attributed to early psychosocial and medical withdrawals.
Association Between Statewide Opioid Prescribing Interventions and Opioid Prescribing Patterns in North Carolina, 2006–2018
Authors: Maierhofer Courtney N , Ranapurwala Shabbar I , DiPrete Bethany L , Fulcher Naoko , Ringwalt Christopher L , Chelminski Paul R , Ives Timothy J , Dasgupta Nabarun , Go Vivian F , Pence Brian W
Published: June 2021

Objective

To examine the impact of three sequential statewide policy and legislative interventions on opioid prescribing practices among privately insured individuals in North Carolina.

Methods

An interrupted time series approach was used to examine level and trajectory changes of new and prevalent opioid prescription rates, days’ supply, and daily morphine milligram equivalents before and after implementation of a 1) prescription drug monitoring program, 2) state medical board initiative, and 3) legislative action. Analyses were conducted using individual-level claims data from a large private health insurance provider serving North Carolina residents, ages 18–64 years, from January 2006 to August 2018.

Results

Rates of new and prevalent prescription opioid patients were relatively unaffected by the prescription monitoring program but sharply declined in the months immediately following both medical board (−3.7 new and −19.3 prevalent patients per 10,000 person months) and legislative (−14.1 new and −26.7 prevalent patients) actions. Among all opioid prescriptions, days’ supply steadily increased on average over the study period but declined after legislative action (−1.5 days’ supply per year).

Conclusions

The voluntary prescription drug monitoring program launched in 2010 only marginally affected opioid prescribing patterns on its own, but its redeployment as an investigative and clinical tool in multifaceted public policy approaches by the state medical board and legislature later in the decade plausibly contributed to notable declines in prescription rates and days’ supply. This study lends new emphasis to the importance of enforcement mechanisms for state and national policies seeking to reverse this critical public health crisis.
Global health governance and disaster recovery for rebel returnees during COVID-19
Authors: Kahambing Jan Gresil
Published: June 2021

This article highlights the need for governing some gradual ruptures from the past to achieve a sense of new normalcy in public health. The rebel returnees during the pandemic form a case of a vulnerable group who triply experience disasters: from the pandemic and natural disasters to terrorism. Global health governance carries on the management of past problems attaining their maturation and faces new ones for disaster recovery.
Treat-to-target in axial spondyloarthritis: an observational study in daily practice
Authors: Beckers Esther , Boonen Annelies , Webers Casper , ten Klooster Peter , Vonkeman Harald , Efdé Monique , van Tubergen Astrid
Published: June 2021

Objectives

To evaluate the extent to which internationally agreed treat-to-target recommendations were applied in clinical practice in patients with axial spondyloarthritis.

Methods

Data were used from a web-based patient registry for monitoring SpA in daily practice in the Netherlands. The extent to which treat-to-target was applied was evaluated through four indicators: the proportion of patients (i) with ≥1 Ankylosing Spondylitis Disease Activity Score (ASDAS) assessed during a 1-year period, (ii) having inactive disease/low disease activity (i.e. ASDAS < 2.1), (iii) in whom re-evaluation of ASDAS within recommended intervals occurred, and (iv) with high disease activity (HDA, i.e. ASDAS ≥ 2.1) in whom treatment was adapted ≤6 weeks after obtaining ASDAS ≥ 2.1. Patients with HDA with treatment adaptations were compared with patients with HDA without treatment adaptations.

Results

In 185 out of 219 patients (84%), disease activity was monitored with ≥1 ASDAS during a 1-year period, of whom 71 (38%) patients had a score below the target (ASDAS < 2.1) at first measurement. Re-evaluation of ASDAS ≤3 months occurred in 11% and 23% of the patients with inactive disease/low disease activity and HDA, respectively. Treatment adaptation occurred in 19 out of 114 patients (17%) with HDA. Patients in whom treatment was adapted had significantly higher ASDAS (P < 0.01), CRP levels (P < 0.05) and physician global assessment (P < 0.05) compared with patients without treatment adaptations.

Conclusions

Treat-to-target was applied to a limited extent in clinical practice in patients with axial spondyloarthritis. Available disease activity scores seemed not to be used for determining the frequency of re-evaluation nor treatment adaptation.
Early prediction of clinical response to anti-TNF treatment using multi-omics and machine learning in rheumatoid arthritis
Authors: Yoosuf Niyaz , Maciejewski Mateusz , Ziemek Daniel , Jelinsky Scott A , Folkersen Lasse , Müller Malin , Sahlström Peter , Vivar Nancy , Catrina Anca , Berg Louise , Klareskog Lars , Padyukov Leonid , Brynedal Boel
Published: June 2021

Objectives

Advances in immunotherapy by blocking TNF have remarkably improved treatment outcomes for Rheumatoid arthritis (RA) patients. Although treatment specifically targets TNF, the downstream mechanisms of immune suppression are not completely understood. The aim of this study was to detect biomarkers and expression signatures of treatment response to TNF inhibition.

Methods

Peripheral blood mononuclear cells (PBMCs) from 39 female patients were collected before anti-TNF treatment initiation (day 0) and after 3 months. The study cohort included patients previously treated with MTX who failed to respond adequately. Response to treatment was defined based on the EULAR criteria and classified 23 patients as responders and 16 as non-responders. We investigated differences in gene expression in PBMCs, the proportion of cell types and cell phenotypes in peripheral blood using flow cytometry and the level of proteins in plasma. Finally, we used machine learning models to predict non-response to anti-TNF treatment.

Results

The gene expression analysis in baseline samples revealed notably higher expression of the gene EPPK1 in future responders. We detected the suppression of genes and proteins following treatment, including suppressed expression of the T cell inhibitor gene CHI3L1 and its protein YKL-40. The gene expression results were replicated in an independent cohort. Finally, machine learning models mainly based on transcriptomic data showed high predictive utility in classifying non-response to anti-TNF treatment in RA.

Conclusions

Our integrative multi-omics analyses identified new biomarkers for the prediction of response, found pathways influenced by treatment and suggested new predictive models of anti-TNF treatment in RA patients.
Self-oriented neural circuitry predicts other-oriented adaptive risks in adolescence: a longitudinal study
Authors: Kwon Seh-Joo , Turpyn Caitlin C , Prinstein Mitchell J , Lindquist Kristen A , Telzer Eva H
Published: June 2021

Adolescence is marked by changes in decision-making and perspective-taking abilities. Although adolescents make more adaptive decisions with age, little is understood about how adolescents take adaptive risks that impact others and how this behavior changes developmentally. Functional coupling between reward [e.g., ventral striatum (VS)] and ‘social brain’ [e.g. temporal parietal junction (TPJ)/ posterior superior temporal sulcus (pSTS), medial prefrontal cortex (mPFC)] systems may be differentially shape adaptive risks for the self and other. A total of 173 participants completed between one and three sessions across three waves [a total of 433 behavioral and 403 functional magnetic resonance imaging (fMRI) data points]. During an fMRI scan, adolescents completed a risky decision-making task where they made risky decisions to win money for themselves and their parent. The risky decisions varied in their expected value (EV) of potential reward. Results show that from the 6th through 9th grades, adolescents took increasingly more adaptive risks for themselves than for their parent. Additionally, greater VS–TPJ/pSTS and VS–mPFC connectivity that tracks EV when making risky decisions for themselves in 6th grade, but a lower VS–mPFC connectivity in 9th grade, predicted greater adaptive risk-taking for their parent. This study contributes to our understanding of the self as a neural proxy for promoting adaptive social behaviors in youth.
When death is literally the deadline: the “cut-off” point for assessing detriment in proprietary estoppel
Authors: Leung Samuel Yee Ching , Au-Yeung Bennett
Published: June 2021

Throughout the brief history of proprietary estoppel, it has been rare to find a case where it was argued that the promisor passed away before the promisee suffers sufficient detriment. Rarer still, to find this promise made jointly by co-owners as tenants-in-common of a property. In Cheung Lai Mui v Cheung Wai Shing [2021], the Hong Kong Court of Final Appeal found the “cut-off” point for assessing detriment in such a case to be the death of the last surviving co-owner—but why should it be? This article explores the theoretical interactions between proprietary estoppel, unconscionability and co-ownership in seeking to answer this question.
Prevalence and genotype distribution of human papillomavirus among 29 263 women from the Longgang community of Shenzhen
Authors: Chen Tingting , Cai Songtao , Lin Jinbo , Yang Xue , He Xuesen , Tu Changqing , Yang Chunxia
Published: June 2021

Background

Human papillomavirus (HPV) vaccination and screening have been demonstrated to be effective methods for controlling cervical cancer. To provide evidence for effective targeted interventions, we investigated the HPV prevalence and genotypic distribution in women of different age groups in the Longgang community of Shenzhen, China.

Methods

A total of 29 263 women were enrolled in the Longgang District Central Hospital from January 2018 to October 2020. Cervical specimens were collected at enrolment. We used a polymerase chain reaction diagnostic kit to detect the genotypes of HPV.

Results

The prevalence of overall, high-risk, probable high-risk (PHR) and low-risk HPV infection was 8.2% (95% confidence interval [CI] 7.9 to 8.5), 6.9% (95% CI 6.6 to 7.2), 0.9% (95% CI 0.8 to 1.1) and 1.6% (95% CI 1.5 to 1.8), respectively. High-risk HPV genotype infections accounted for 84.4% (95% CI 82.8 to 85.8) of the overall HPV infections. The five most predominant genotypes were HPV-52, HPV-16, HPV-58, HPV-53 and HPV-51.

Conclusion

Our study found that the prevalence of HPV infection increased with age and women 55–59 y of age presented the highest HPV prevalence. As a PHR subtype, HPV-53 has a higher infection rate in women. HPV-52, HPV-16 and HPV-58 are common infection genotypes.