bluuebunny/crossref_metadata_2025 huggingface dataset:
P-632 Evaluation of low AMH levels in young women
Authors: Martin B
Published: June 2022

Study question

The primary objective was to evaluate impact of a low AMH level on the live birth rate in a population of young women IVF/ICSI .

Summary answer

Low AMH level in young women in FIV/ICSI is not expected to have an impact on the live birth.

What is known already

AMH is an important criterion for defining ovarian reserve. The majority of studies have shown that the AMH level in the general population is not correlated with the chances of spontaneous pregnancy.

The management remains a challenge and must be individualized taking into account the new quantitative and qualitative criteria to be defined (POSEIDON classification). Finally, we know that the pregnancy rate is correlated to the rate of euploid embryos, and that the rate is higher before 35 years of age.

Study design, size, duration

In this single-center retrospective study from January 2015 to December 2020, 1824 IVF/ICSI attempts were analyzed.

We analyzed the live birth rate according to 2 categories of young women matched by AMH level.

Participants/materials, setting, methods

We analyzed the live birth rate according to 2 categories of young women managed in IVF/ICSI protocol.

A first group was ≤30 years old and a second group was between 31 and 35 years old.

Then, we matched each of these groups to an AMH level, AMH<1ng/mL and AMH ≥1ng/mL.

We analyzed the live birth rate of 4 groups of young women.

Main results and the role of chance

1824 IVF/ICSI attempts were analyzed in this study. We have 539 women under 30 years of age and 1285 women between 31 and 35 years of age.

For women aged ≤30 years, the group with AMH<1ng/mL had a non-statistically significant live birth rate compared to those with AMH≥1ng/mL (31% vs 32.7% p = 1).

For women aged 31-35 years, the group with AMH<1ng/mL, has a statistically significant lower live birth rate compared to those with AMH≥1ng/mL (14.5% vs 29.3% p = 0.001).

Limitations, reasons for caution

The main limitation of our study is the few number of patients.

Wider implications of the findings

This study tries to demonstrate that low AMH levels in young women do not predict a poor IVF/ICSI success rate. Conclusions should not be drawn too quickly for low AMH in this population. However, the threshold AMH level is still debated in the studies and should be further adjusted.

Trial registration number

not applicable
P-684 The impact of oral sphingosine-1-phosphate analogue on ovarian aging in women with multiple sclerosis
Authors: Kender Ertürk N , Erturk A , Karakoc Sokmensuer L , Yarali H , Bozdag G , Mumusoglu S
Published: June 2022

Study question

Is there a protective effect of oral sphingosine-1-phosphate analogue (S1P) on ovarian reserve?

Summary answer

The use of oral long acting S1P analogue may reduce spontaneous primordial follicle loss and preserve ovarian reserve in women of reproductive age.

What is known already

The number of primordial follicles decrease by apoptosis with advancing age in women. Seramid pathway is one of the apoptosis regulatory pathways in human ovaries. An increase in the balance between ceramide and S1P in S1P direction, known as cell membrane sphingomyelins, inhibits follicular apoptosis. Fingolimod (Novartis, Germany), a long-acting oral analogue of S1P, is a drug used in the treatment of multiple sclerosis (MS). We have previously found that use of fingolimod might reduce the spontaneous follicular apoptosis and increase the number of residual primordial follicles in a rat model.

Study design, size, duration

A prospective cohort study. Twenty-one consecutive women in reproductive age to whom fingolimod therapy were commenced for MS at Hacettepe University, Department of Neurology in between 2018 – 2021were included.

Participants/materials, setting, methods

Regularly menstruating women under <38 years old was included. Serum Anti-Mullerian Hormone (AMH) levels were measured at the beginning of Fingolimod, 6th and 12th months of the treatment. The decrease in serum AMH levels were calculated and compared with standard AMH decrease in healthy women.

Main results and the role of chance

The mean±standard deviation (SD) age of the 21 patients was 26.95±6.07. The mean±SD of AMH level at the beginning was 2,62±1,64 ng/ml. The respective figure for the 6th month and 12th month were 3,10±2,02 and 1,70±1,70 ng/ml. Overall, there was an increase of 0.6 ng/ml in mean AMH during this period. AMH level decreased in 2 patients, remained unchanged in 2 patients, and increased in 5 patients.

Limitations, reasons for caution

High (∼50%) loss to follow-up rate is a main limitation.

Wider implications of the findings

Oral long-acting MS drug fingolimod may have a protective effect on ovarian reserve in human by reducing spontaneous follicle loss rate, studies with larger sample size and longer follow-up period is warranted to demonstrate this effect.

Trial registration number

not applicable
P-728 Prevalence of Infertility among women with Multiple Sclerosis compared to the general population of women matched for age
Authors: Skvirsky S , Miller A , Yones G , Wiener-Magnezi Z , Ishai D , Lahav-Baratz S , Oron G
Published: June 2022

Study question

Is the prevalence of infertility among multiple sclerosis female patients higher compared to the general population?

Summary answer

The prevalence of infertility among women with multiple sclerosis is similar to the matched general population

What is known already

Multiple sclerosis (MS) is an autoimmune disease predominant in women (1:3 ratio) during childbearing years. Studies addressing the question of infertility among multiple sclerosis patients are inconclusive and whether fertility is impaired in this population is debatable.

Study design, size, duration

Data regarding multiple sclerosis diagnosis and treatment and data about infertility and ART treatments was collected for patients during childbearing years (18-45) between the years 2005 to 2020 from the health service computerized database.

Participants/materials, setting, methods

The prevalence of infertility among women with MS was analyzed and compared to healthy controls (1:5) matched for age. Association between multiple sclerosis and the different ART treatments: in vitro fertilization (IVF) versus controlled ovarian hyperstimulation (COH) were analyzed.

Main results and the role of chance

1,570 women with multiple sclerosis were compared to 7,851 healthy women matched for age. Mean age of both groups was 32 years old. The prevalence of infertility was 34.1% (534) in the MS population compared to 33.3% (2,601) in the matched general population (p = 0.4). 299 of the 536 MS patients were diagnosed with infertility after they were diagnosed with multiple sclerosis. The prevalence of the different ART treatments was similar between MS patients and healthy women matched for age: (IVF: 7.1% vs 7% p = 0.813 and COH: 5.7% vs 6% p = 0.6; respectively).

Limitations, reasons for caution

The major limitation of our study is its retrospective nature. Furthermore, we were not able to evaluate for confounding factors possibly contributing to postponed family planning.

Wider implications of the findings

To date this is the largest study evaluating the prevalence of infertility and ART treatment among MS patients during childbearing years. Our findings may reassure patients with MS that their risk for infertility and need for ART treatments is comparable to the health general population.

Trial registration number

not applicable
P-742 Cost reduction study in egg donation in a spanish third-level public hospital
Authors: Arias Fernández J.L , Guisado Fernández J , Lozano Arana M.D , Sánchez Andújar B , Antiñolo Gil G , García Lozano J.C
Published: June 2022

Study question

Is it possible to reduce the number of oocytes per recipient, thus reducing treatment costs and without compromising pregnancy rates?

Summary answer

Costs derived from egg donation techniques can be reduced without compromising pregnancy rates

What is known already

In the literature there is no limitation or optimal number of oocytes for performing techniques based on egg donation. Despite this, we see that the norm is to use between 6 and 8 oocytes per recipient woman.

Study design, size, duration

This is a cost-effectiveness study and a retrospective descriptive study of 75 patients undergoing IVF with egg donation (102 cycles) between the years 2014 and 2019 in the Assisted Human Reproduction Unit of the Virgen del Rocío University Hospital. Seville.

Participants/materials, setting, methods

We have proceeded to create a database, with the collection of different data: number of reserved oocytes, number of fresh embryos, number of vitrified embryos, number of clinical pregnancies achieved and budget.

Main results and the role of chance

Between 2014-2019, 102 cycles were performed, achieving a total of 52 clinical pregnancies, 45 with fresh embryos (44.1% of the total cycles) and 7 with vitrified embryos (6.9%). This reports a global percentage of clinical pregnancy of 51%. Analyzing the data per patient, a success rate of 69.3% in achieving clinical pregnancy has been demonstrated.

Between 2014-2017, 5 or more donated oocytes have been used for each patient, with a total figure of 285 oocytes. On average, 5.7 oocytes per patient have been requested. 50 IVF cycles have been performed. 22 of these cycles with fresh embryos have achieved clinical pregnancy (44%) and only one cycle with vitrified embryos has achieved pregnancy, giving an overall success rate of 46%. This costs €142,500, €6,195 for each clinical pregnancy achieved.

Between 2018-2019, donated oocytes per patient has been reduced to 3-4, with a total number of 188. On average, 3.6 oocytes per patient have been requested. 52 IVF cycles have been performed. 23 of these cycles with fresh embryos have achieved clinical gestation (44.2%), adding 5 more cycles when counting the cycles with vitrified embryos. All this has achieved a 53.8% clinical gestation. This costs €94,000, €3,357 for each clinical pregnancy achieved.

Limitations, reasons for caution

Over the years, IVF techniques have been perfected. This can be reflected in the percentage of clinical gestations achieved.

Wider implications of the findings

With an average reduction of 2.1 oocytes, a reduction in the cost per cycle of €1050 (36%) is achieved and for each clinical pregnancy achieved of €2,838. These savings could make it possible to expand inclusion criteria for cycles with oocyte donation, for example, including patients with poor ovarian reserve.

Trial registration number

Not applicable
Specificity and Breadth of the Neutralizing Antibody Response to a Live-Attenuated Tetravalent Dengue Vaccine
Authors: DeMaso Christina R , Karwal Lovkesh , Zahralban-Steele Melissa , Dominguez David , Springer Zhang-Li , Kaiser Maima , Palani Sunil , Rindfleisch Tim , Bohning Kelly , Hather Greg , Das Subash , Sharma Mayuri , Dean Hansi J
Published: June 2022

Background

An effective dengue vaccine should ideally induce broadly neutralizing antibody (nAb) responses against all 4 dengue virus (DENV) serotypes.

Methods

We characterized the specificity and breadth of the nAb response to TAK-003, a live-attenuated tetravalent dengue vaccine, in serum samples from phase 2 and 3 clinical trials.

Results

Microneutralization tests using postvaccination serum showed comparable neutralization against diverse DENV-1−4 genotypes. Reporter virus particle neutralization assays after depletion of anti-DENV-2 nAbs demonstrated that the nAb response to DENV-1, -3, and -4 comprises both type-specific (TS) and cross-reactive (CR) nAbs.

Conclusions

Therefore, TAK-003 induces broad tetravalent TS and CR nAb responses.
Radiotherapy-Related Dose and Irradiated Volume Effects on Breast Cancer Risk Among Hodgkin Lymphoma Survivors
Authors: Roberti Sander , van Leeuwen Flora E , Ronckers Cécile M , Krul Inge M , de Vathaire Florent , Veres Cristina , Diallo Ibrahima , Janus Cécile P M , Aleman Berthe M P , Russell Nicola S , Hauptmann Michael
Published: June 2022

Background

Breast cancer (BC) risk is increased among Hodgkin lymphoma (HL) survivors treated with chest radiotherapy. Case-control studies showed a linear radiation dose-response relationship for estimated dose to the breast tumor location. However, these relative risks cannot be used for absolute risk prediction of BC anywhere in the breasts. Furthermore, the independent and joint effects of radiation dose and irradiated volumes are unclear. Therefore, we examined the effects of mean breast dose and various dose-volume parameters on BC risk in HL patients.

Methods

We conducted a nested case-control study of BC among 5-year HL survivors (173 case patients, 464 matched control patients). Dose-volume histograms were obtained from reconstructed voxel-based 3-dimensional dose distributions. Summary parameters of dose-volume histograms were studied next to mean and median breast dose, Gini index, and the new dose metric mean absolute difference of dose, using categorical and linear excess odds ratio (EOR) models. Interactions between dose-volume parameters and mean dose were also examined.

Results

Statistically significant linear dose-response relationships were observed for mean breast dose (EOR per Gy = 0.19, 95% confidence interval [CI] = 0.05 to 1.06) and median dose (EOR/Gy = 0.06, 95% CI = 0.02 to 0.19), with no statistically significant curvature. All metrics except Gini and mean absolute difference were positively correlated with each other. These metrics all showed similar patterns of dose-response that were no longer statistically significant when adjusting for mean dose. No statistically significant modification of the effect of mean dose was observed.

Conclusion

Mean breast dose predicts subsequent BC risk in long-term HL survivors.
Projective classes as images of accessible functors
Authors: Wehrung Friedrich
Published: June 2022

We are dealing with projective classes (in short $\textrm {PC}$) over first-order vocabularies with no restrictions on the (possibly infinite) arities of relation or operation symbols. We verify that $\textrm {PC}(\mathbin {\mathscr {L}}_{\infty \lambda })=\textrm {RPC}(\mathbin {\mathscr {L}}_{\infty \lambda })$ for any infinite cardinal $\lambda $, and that if $\lambda $ is singular, then $\textrm {PC}(\mathbin {\mathscr {L}}_{\infty \lambda })=\textrm {PC}(\mathbin {\mathscr {L}}_{\infty \lambda ^+})$. If $\lambda $ is regular, then a class of structures over a $\lambda $-ary vocabulary is $\textrm {PC}(\mathbin {\mathscr {L}}_{\infty \lambda })$-definable iff it is the image of a $\lambda $-continuous functor on a $\lambda $-accessible category; we also provide separating counterexamples for the non $\lambda $-ary case. We prove that many $\textrm {PC}$ classes of structures, previously known not to be closed under elementary equivalence over any $\mathbin {\mathscr {L}}_{\infty \lambda }$, are not even $\textrm {co}\textrm {-}\textrm {PC}$ over $\mathbin {\mathscr {L}}_{\infty \infty }$. Those classes arise from diverse contexts including convex $\ell $-subgroup lattices of lattice-ordered groups, ideal lattices of rings, nonstable K$_0$-theory of rings, coordinatization of sectionally complemented modular lattices and real spectra of commutative unital rings. For example, the class of posets of finitely generated two-sided ideals of all unital rings is $\textrm {PC}$ but not $\textrm {co}\textrm {-}\textrm {PC}$ over $\mathbin {\mathscr {L}}_{\infty \infty }$. We also provide a negative solution to a problem, raised in 2011 by Gillibert and the author, asking whether essential surjectivity of a ‘well-behaved’ functor on objects entails its essential surjectivity on diagrams indexed by arbitrary finite posets.
Malassezia species: the need to establish epidemiological cutoff values
Authors: Rojas Florencia Dinorah , Sosa María de los Ángeles , Latorre Wenceslao , Mussin Javier , Alegre Liliana , Giusiano Gustavo
Published: June 2022

Malassezia are common yeasts in human skin microbiome. Under certain conditions these yeasts may cause disease from skin disorders to systemic infections. In the absence of clinical breakpoints, epidemiological cutoff values (ECVs) are useful to differentiate isolates with acquired or mutational resistance. The aim of this work was to propose tentative ECVs of Malassezia furfur, M. sympodialis, M. globosa for fluconazole (FCZ), itraconazole (ITZ), voriconazole (VCZ), ketoconazole (KTZ) and amphotericin B (AMB). A total of 160 isolates (80 M. furfur, 50 M. sympodialis, and 30 M. globosa) were tested. Minimal inhibitory concentrations (MICs) were determined by modified broth microdilution method (CLSI). ECVs were estimated by ECOFFinder software and twofold dilutions beyond the mode. ITZ, KTZ, and VCZ showed the lowest MICs. The highest MIC and widest ranges were for FCZ and AMB. For ITZ, KTZ, and VCZ both ECVs were similar. For FCZ, AMB especially M. furfur, modal ECVs were lower than values obtained by statistical method. When MIC distribution is the only data available, ECV could provide information to help guide therapy decisions. In that drug/species combination in which different peaks in the MIC distribution were observed, difference between both ECV was greater. This is the first study that provides ECV data of 160 Malassezia yeasts. Although ECVs cannot be used as predictors of clinical response, identification of non wild-type isolates suggests that it may be less likely to respond to a given antifungal agent.

Lay Summary

Malassezia species causes skin disorders to systemic infections. Epidemiological cutoff value (ECV) allows for differentiation of wild-type and non wild-type isolates. Based on MIC data of 160 isolates we propose tentative ECVs for three Malassezia species. ECVs are useful in surveillance and guide therapy decisions.
On the long-term stability of the Solar system in the presence of weak perturbations from stellar flybys
Authors: Brown Garett , Rein Hanno
Published: June 2022

The architecture and evolution of planetary systems are shaped in part by stellar flybys. Within this context, we look at stellar encounters that are too weak to immediately destabilize a planetary system but are nevertheless strong enough to measurably perturb the system’s dynamical state. We estimate the strength of such perturbations on secularly evolving systems using a simple analytic model and confirm those estimates with direct N-body simulations. We then run long-term integrations and show that even small perturbations from stellar flybys can influence the stability of planetary systems over their lifetime. We find that small perturbations to the outer planets’ orbits are transferred between planets, increasing the likelihood that the inner planetary system will destabilize. Specifically, our results for the Solar system show that relative perturbations to Neptune’s semimajor axis of order 0.1 per cent are strong enough to increase the probability of destabilizing the Solar system within 5 Gyr by one order of magnitude.
FAUST VI. VLA1623−2417 B: a new laboratory for astrochemistry around protostars on 50 au scale
Authors: Codella C , López-Sepulcre A , Ohashi S , Chandler C J , De Simone M , Podio L , Ceccarelli C , Sakai N , Alves F , Durán A , Fedele D , Loinard L , Mercimek S , Murillo N , Zhang Y , Bianchi E , Bouvier M , Busquet G , Caselli P , Dulieu F , Feng S , Hanawa T , Johnstone D , Lefloch B , Maud L T , Moellenbrock G , Oya Y , Svoboda B , Yamamoto S
Published: June 2022

The ALMA (Atacama Large Millimeter Array) interferometer, with its unprecedented combination of high sensitivity and high angular resolution, allows for (sub-)mm wavelength mapping of protostellar systems at Solar system scales. Astrochemistry has benefitted from imaging interstellar complex organic molecules in these jet–disc systems. Here, we report the first detection of methanol (CH3OH) and methyl formate (HCOOCH3) emission towards the triple protostellar system VLA1623−2417 A1+A2+B, obtained in the context of the ALMA Large Programme FAUST (Fifty AU STudy of the chemistry in the disc/envelope system of solar-like protostars). Compact methanol emission is detected in lines from Eu = 45 K up to 61 K and 537 K towards components A1 and B, respectively. Large velocity gradient analysis of the CH3OH lines towards VLA1623−2417 B indicates a size of 0.11–0.34 arcsec (14–45 au), a column density $N_{\rm CH_3OH}$ = 1016–1017 cm−2, kinetic temperature ≥ 170 K, and volume density ≥ 108 cm−3. A local thermodynamic equilibrium approach is used for VLA1623−2417 A1, given the limited Eu range, and yields Trot ≤ 135 K. The methanol emission around both VLA1623−2417 A1 and B shows velocity gradients along the main axis of each disc. Although the axial geometry of the two discs is similar, the observed velocity gradients are reversed. The CH3OH spectra from B show two broad (4–5 km s−1) peaks, which are red- and blueshifted by ∼ 6–7 km s−1 from the systemic velocity. Assuming a chemically enriched ring within the accretion disc, close to the centrifugal barrier, its radius is calculated to be 33 au. The methanol spectra towards A1 are somewhat narrower (∼ 4 km s−1), implying a radius of 12–24 au.
Extreme pebble accretion in ringed protoplanetary discs
Authors: Cummins Daniel P , Owen James E , Booth Richard A
Published: June 2022

Axisymmetric dust rings containing tens to hundreds of Earth masses of solids have been observed in protoplanetary discs with (sub-)millimetre imaging. Here, we investigate the growth of a planetary embryo in a massive (150 M⊕) axisymmetric dust trap through dust and gas hydrodynamics simulations. When accounting for the accretion luminosity of the planetary embryo from pebble accretion, the thermal feedback on the surrounding gas leads to the formation of an anticyclonic vortex. Since the vortex forms at the location of the planet, this has significant consequences for the planet’s growth: as dust drifts towards the pressure maximum at the centre of the vortex, which is initially co-located with the planet, a rapid accretion rate is achieved, in a distinct phase of ‘vortex-assisted’ pebble accretion. Once the vortex separates from the planet due to interactions with the disc, it accumulates dust, shutting off accretion on to the planet. We find that this rapid accretion, mediated by the vortex, results in a planet containing ≈100 M⊕ of solids. We follow the evolution of the vortex, as well as the efficiency with which dust grains accumulate at its pressure maximum as a function of their size, and investigate the consequences this has for the growth of the planet as well as the morphology of the protoplanetary disc. We speculate that this extreme formation scenario may be the origin of giant planets that are identified to be significantly enhanced in heavy elements.
Robust features of off-axis gamma-ray burst afterglow light curves
Authors: Beniamini Paz , Gill Ramandeep , Granot Jonathan
Published: June 2022

The ultra-relativistic outflows powering gamma-ray bursts (GRBs) acquire angular structure through their interaction with external material. They are often characterized by a compact, nearly uniform narrow core (with half-opening angle θc,{ϵ, Γ}) surrounded by material with energy per unit solid angle ($\epsilon =\epsilon _{\rm c}\Theta _{\epsilon }^{-a}$, where $\Theta _{\lbrace \epsilon ,\Gamma \rbrace }=[1+\theta ^2/\theta _{{\rm c},\lbrace \epsilon ,\Gamma \rbrace }^2]^{1/2}$) and initial specific kinetic energy ($\Gamma _0-1=[\Gamma _{\rm c}-1]\Theta _\Gamma ^{-b}$) declining as power laws. Multiwavelength afterglow light curves of off-axis jets (with viewing angle θobs > θc) offer robust ways to constrain a, b, and the external density radial profile (ρ ∝ R−k), even while other burst parameters may remain highly degenerate. We extend our previous work on such afterglows to include more realistic angular structure profiles derived from three-dimensional hydrodynamic simulations of both long and short GRBs (addressing also jets with shallow angular energy profiles, whose emission exhibits unique evolution). We present afterglow light curves based on our parametrized power-law jet angular profiles for different viewing angles θobs and k = {0, 1, 2}. We identify a unique evolutionary power-law phase of the characteristic synchrotron frequencies (νm and νc) that manifests when the light curve is dominated by emission sensitive to the angular structure of the outflow. We calculate the criterion for obtaining single or double peaked light curves in the general case when θc,Γ ≠ θc,ϵ. We emphasize how the shape of the light curve and the temporal evolution of νm and νc can be used to constrain the outflow structure and potentially distinguish between magnetic and hydrodynamic jets.
Clues from Garnet-Spinel-Bearing Peridotite and Pyroxenite Xenoliths about the Formation of the Subcratonic Lithospheric Mantle—a Case Study from the Orapa Kimberlite Cluster
Authors: Kaekane Jarious B , Proyer Alexander
Published: June 2022

A series of 18 ultramafic mantle xenoliths from the Orapa and Letlhakane mines containing both garnet and spinel were investigated petrographically and by means of classical and multi-equilibrium geothermobarometry in order to understand their P–T evolution and infer tectonic processes consistent with that evolution, assuming that samples from the shallow subcontinental lithospheric mantle (SCLM), may have remained cool enough to preserve memory of its formation. Samples broadly classify into peridotites, mainly harzburgites, and pyroxenites, mainly (olivine-) websterites with less than 15 vol% olivine. The websterites all show thin garnet coronas around xenomorphic spinel clusters and often coarse garnet and very fine spinel exsolving from pyroxenes. Classical geothermobarometry results vary consistently between the 40 mW/m2 geotherm at high pressures and the 50 mW/m2 geotherm at lower pressures but partly fail the reliability test indicating some degree of disequilibrium, particularly, as may be expected, toward lower P and T. Eleven samples were analyzed in detail for mineral modes, and pseudosections were calculated for the four compositionally most extreme samples. All four samples show systematic divergence of the mode and composition isopleths indicating overall chemical disequilibrium, but partial isopleth convergence in two distinct P–T regions that were interpreted as the main equilibration stage and a stage of late ‘freeze-in’ of a few composition isopleths at lower temperature and higher pressure. Specifically, the P–T changes between stage 1 and stage 2 were from 900°C and 13 kbar to 750°C and 23 kbar for a websterite and from 850°C and 24 kbar to 730°C and 33 kbar for a harzburgite. For an olivine-orthopyroxenite and -clinopyroxenite the change was from 910°C, 17 kbar and 770°C, 17 kbar for stage 1, respectively, to less well-constrained conditions for stage 2 of 650°C, 36 kbar and 630°C, 20 kbar, respectively. This interpretation of a protracted or stepwise freeze-in along a P–T path holds even after considering thermodynamic, analytical and, as far as possible, geological uncertainties. The result is consistent with a ‘subcretion’ or ‘buoyant subduction’ model for the formation of the SCLM, specifically with the down-drag of an already subcreted lithospheric platelet by a subsequently arriving platelet. In the framework of the crust–mantle evolution in the Orapa region this most likely occurred in the Neoarchean, between 2.8 and 2.5 Ga.
How was apical growth regulated in the ancestral land plant? Insights from the development of non-seed plants
Authors: Fouracre Jim P , Harrison C Jill
Published: June 2022

Land plant life cycles are separated into distinct haploid gametophyte and diploid sporophyte stages. Indeterminate apical growth evolved independently in bryophyte (moss, liverwort, and hornwort) and fern gametophytes, and tracheophyte (vascular plant) sporophytes. The extent to which apical growth in tracheophytes co-opted conserved gametophytic gene networks, or exploited ancestral sporophytic networks, is a long-standing question in plant evolution. The recent phylogenetic confirmation of bryophytes and tracheophytes as sister groups has led to a reassessment of the nature of the ancestral land plant. Here, we review developmental genetic studies of apical regulators and speculate on their likely evolutionary history.
Risk factors of clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy: A systematic review and meta-analysis
Authors: Zhang Biao , Yuan Qihang , Li Shuang , Xu Zhaohui , Chen Xu , Li Lunxu , Shang Dong
Published: June 2022

Background:

Clinically relevant postoperative pancreatic fistula (CR-POPF) is a common and troublesome complication after pancreatoduodenectomy (PD). We conducted a systematic review and meta-analysis to identify the risk factors of CR-POPF after PD.

Methods:

We searched PubMed, EMBASE, and Cochrane Library databases for studies related to risk factors of CR-POPF after PD. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were extracted from the included studies, then a meta-analysis was conducted. If necessary, sensitivity analysis would be performed by changing the effect model or excluding 1 study at a time. Publication bias was assessed by funnel plot and Begg test and Egger test.

Results:

A total of 27 studies with 24,740 patients were included, and CR-POPF occurred in 3843 patients (incidence = 17%, 95% CI: 16%–19%). Male (OR = 1.56, 95% CI: 1.42–1.70), body mass index >25 kg/m2 (OR = 1.98, 95% CI: 1.23–3.18), pancreatic duct diameter <3 mm (OR = 1.87, 95% CI: 1.66–2.12), soft pancreatic texture (OR = 3.49, 95% CI: 2.61–4.67), and blood transfusion (OR = 3.10, 95% CI: 2.01–4.77) can significantly increase the risk of CR-POPF. Pancreatic adenocarcinoma (OR = 0.54, 95% CI: 0.47–0.61), vascular resection (OR = 0.57, 95% CI: 0.39–0.83), and preoperative chemoradiotherapy (OR = 0.68, 95% CI: 0.57–0.81) can significantly decrease the factor of CR-POPF. Diabetes mellitus was not statistically associated with CR-POPF (OR = 0.66, 95% CI: 0.40–1.08). However, the analysis of body mass index, pancreatic texture, and diabetes mellitus had a high heterogeneity, then sensitivity analysis was performed, and the result after sensitivity analysis showed diabetes mellitus can significantly decrease the risk of CR-POPF. There was no significant publication bias in this meta-analysis.

Conclusions:

The current review assessed the effects of different factors on CR-POPF. This can provide a basis for the prevention and management of CR-POPF. Effective interventions targeting the above risk factors should be investigated in future studies for decreasing the occurrence of CR-POPF.
A systematic literature review of real-world treatment outcomes of small cell lung cancer
Authors: Stokes Michael , Berfeld Noami , Gayle Alicia , Descoteaux Andrew , Rohrmoser Oscar , Franks April
Published: June 2022

Background:

Robust evidence from real-world studies is needed to aid decision-makers and other stakeholders in choosing the best treatment options for patients. The objective of this work was to assess real-world outcomes of treatment strategies for limited- and extensive-stage small cell lung cancer (SCLC) prior to the global introduction of immunotherapies for this disease.

Methods:

Searches were conducted in MEDLINE and Embase to identify articles published in English from October 1, 2015, through May 20, 2020. Searches were designed using a combination of Medical Subject Heading (Medline), Emtree (Embase subject headings), and free-text terms such as SCLC. Observational studies reporting data on outcomes of initial treatment strategies in patients with limited- and extensive-stage SCLC were included. Studies with limited sample sizes (<100 patients), enrolled all patients prior to 2010, or did not report outcomes for limited- and extensive-stage SCLC separately were excluded. Data were extracted into a predesigned template by a single researcher. All extractions were validated by a second researcher, with disagreements resolved via consensus.

Results:

Forty articles were included in this review. Most enrolled patients from the United States (n = 18 articles) or China (n = 12 articles). Most examined limited-stage (n = 27 articles) SCLC. All studies examined overall survival as the primary outcome. Articles investigating limited-stage SCLC reported outcomes for surgery, chemotherapy and/or radiotherapy, and adjuvant prophylactic cranial irradiation. In studies examining multiple treatment strategies, chemoradiotherapy was the most commonly utilized therapy (56%–82%), with chemotherapy used in 18% to 44% of patients. Across studies, median overall survival was generally higher for chemoradiotherapy (15–45 months) compared with chemotherapy alone (6.0–15.6 months). Studies of extensive-stage SCLC primarily reported on chemotherapy alone, consolidative thoracic radiotherapy, and radiotherapy for patients presenting with brain metastases. Overall survival was generally lower for patients receiving chemotherapy alone (median: 6.4–16.5 months; 3 years, 5%–14.9%) compared with chemotherapy in combination with consolidative thoracic radiotherapy (median: 12.1–18.0 months; 3 years, 15.0%–18.1%). Studies examining whole-brain radiotherapy for brain metastases reported lower median overall survival (5.6–8.7 months) compared with stereotactic radiosurgery (10.0–14.5 months).

Conclusions:

Under current standard of care, which has remained relatively unchanged over the past few decades, prognosis remains poor for patients with SCLC.
MenDEL: automated search of BAC sets covering long DNA regions of interest
Authors: German Sergei , Pinglay Sudarshan , Camellato Brendan , Fenyö David , Boeke Jef D.
Published: June 2022

Motivation

Synthetic genomics as a field seeks to synthesize large regions of genomes from the ground up. Such large-scale projects, especially in complex genomes can rely on pre-existing BAC (Bacterial Artificial Chromosome) libraries as starting material to reduce cost. However, choosing BACs that cover long DNA regions, especially those that require many BACs, is a manual, idiosyncratic, time consuming, and error prone process. Automating this work would make the assembly of large DNA constructs more efficient.

Results

We have developed MenDEL – a web-based DNA design application, that provides efficient tools for finding BACs that cover long regions of interest and allow for sorting results based on multiple user defined criteria - total length, number of BACs, longest BAC. etc. In addition, it enables the user to find a combination of BACs from pre-existing libraries that cover a region of interest not found in any single BAC.

Availability and Implementation

MenDEL application is available to registered users at https://mendel-isg.nyumc.org, Java code used in the application to find BAC sets is available at https://github.com/MendelProject/BACFinder
The double-layered structure of amyloid-β assemblage on GM1-containing membranes catalytically promotes fibrillization
Authors: Yagi-Utsumi Maho , Itoh Satoru G. , Okumura Hisashi , Yanagisawa Katsuhiko , Kato Koichi , Nishimura Katsuyuki
Published: June 2022

Alzheimer’s disease (AD) is associated with progressive accumulation of amyloid-β (Aβ) cross-β fibrils in the brain. Aβ species tightly associated with GM1 ganglioside, a glycosphingolipid abundant in neuronal membranes, promote amyloid fibril formation; therefore, they could be attractive clinical targets. However, the active conformational state of Aβ in GM1-containing lipid membranes is still unknown. The present solid-state nuclear magnetic resonance study revealed a nonfibrillar Aβ assemblage characterized by a double-layered antiparallel β-structure specifically formed on GM1 ganglioside clusters. Our data show that this unique assemblage was not transformed into fibrils on GM1-containing membranes, but could promote conversion of monomeric Aβ into fibrils, suggesting that a solvent-exposed hydrophobic layer provides a catalytic surface evoking Aβ fibril formation. Our findings will offer structural clues for designing drugs targeting catalytically active Aβ conformational species for the development of anti-AD therapeutics.
A Novel Selective ERK1/2 Inhibitor, Laxiflorin B, Targets EGFR Mutation Subtypes in Non-small-cell Lung Cancer
Authors: Chiang Chengyao , Zhang Min , Huang Junrong , Zeng Juan , Chen Chunlan , Pan Dongmei , Yang Heng , Yang Min , Han Qiangqiang , Zou Wang , Xiao Tian , Zou Yongdong , Yin Feng , Li Zigang , Zhu Lizhi , Zheng Duo
Published: June 2022

Extracellular regulated protein kinases 1/2 (ERK1/2) are key members of multiple signaling pathways including the ErbB axis. ERK1/2 ectopic activation is responsible for various types of cancer, especially drug resistance to inhibitors of RTK, RAF and MEK, but specific ERK1/2 inhibitors are scarce. In this study, we identified a potential novel ERK covalent inhibitor, Laxiflorin B, a herbal compound with anticancer activity. However, Laxiflorin B is present at low levels in herbs; therefore, we adopted a semi-synthetic process for the efficient production of Laxiflorin B to improve the yield. Laxiflorin B induced mitochondria-mediated apoptosis via BAD activation in non-small-cell lung cancer (NSCLC) cells, especially in EGFR mutant subtypes. Transcriptomic analysis suggested that Laxiflorin B inhibits amphiregulin (AREG) and epiregulin (EREG) expression through ERK inhibition, and suppressed the activation of their receptors, ErbBs, via a positive feedback loop. More importantly, mass spectrometry combined with computer simulation analysis revealed that Laxiflorin B binds covalently to Cys-183 in the ATP-binding pocket of ERK1 through D-ring, and Cys-178 of ERK1 though non-inhibitory binding of A-ring, respectively. Laxiflorin B also exhibited strong tumor suppressive effects with low toxicity in a NSCLC tumor xenograft model in nude mice, and AREG and EREG were identified as biomarkers of Laxiflorin B efficacy. Finally, Laxiflorin B-4, a C-6 modification of Laxiflorin B, exhibited higher affinity for ERK1/2 and stronger tumor suppression. These findings provide a new approach to tumor inhibition using natural anticancer compounds.
Modelling vasopressin synthesis and storage dynamics during prolonged osmotic challenge and recovery based on activity dependent upregulation of mRNA transcription
Authors: MacGregor Duncan J.
Published: June 2022

Hypothalamic vasopressin neurons are neuroendocrine cells which form part of the homeostatic systems that maintain osmotic pressure. In response to synaptic inputs encoding osmotic pressure and changes in plasma volume, they generate spike triggered secretion of peptide hormone vasopressin from axonal terminals in the posterior pituitary. The thousands of neurons’ secretory signals generate a summed plasma vasopressin signal acting at the kidneys to regulate water loss. Vasopressin is synthesised in cell bodies, packaged into vesicles, and transported to large stores in the pituitary terminals. Supported by activity-dependent upregulation of synthesis and transport, these stores can maintain a secretion response for several days of elevated osmotic pressure, tested by dehydration or salt loading. However, despite upregulated synthesis, stores gradually decline during sustained challenge, followed by a slow recovery. With no evidence of a store encoding feedback signal, previous modelling explained these synthesis dynamics based on activity-dependent upregulation of transcription and mRNA content. Here this model is adapted and integrated into our existing spiking and secretion model to generate a neuronal population model, able to simulate the secretion, store depletion, and replenishment, response to sustained osmotic challenge, matching the dynamics observed experimentally and making functional predictions for the cell body mechanisms.
FLOW: maximum flow framework for the identification of factors mediating the signaling convergence of multiple receptors
Authors: Sheinin Ron , Dulberg Shai , Kaminitz Ayelet , Sharan Roded , Madi Asaf
Published: June 2022

Motivation

Cell-cell crosstalk involves simultaneous interactions of multiple receptors and ligands, followed by downstream signaling cascades working through receptors converging at dominant transcription factors which then integrate and propagate multiple signals into a cellular response. Single cell RNAseq of multiple cell subsets isolated from a defined microenvironment provides us with a unique opportunity to learn about such interactions reflected in their gene expression levels.

Results

We developed the FLOW framework to map the potential ligand-receptor interactions between different cell subsets based on a maximum flow computation in a network of protein-protein interactions (PPIs). The maximum flow approach further allows characterization of the intracellular downstream signal transduction from differentially expressed receptors towards dominant transcription factors, therefore, enabling the association between a set of receptors and their downstream activated pathways. Importantly, we were able to identify key transcription factors toward which the convergence of multiple receptor signaling occurs. These identified factors have a unique role in the integration and propagation of signaling following specific cell-cell interactions.
Masks Do No More Than Prevent Transmission: Theory and Data Undermine the Variolation Hypothesis
Authors: Koelle Katia , Lin Jack , Zhu Huisheng , Antia Rustom , Lowen Anice C. , Weissman Daniel
Published: June 2022

Background

Masking serves an important role in reducing the transmission of respiratory viruses, including SARS-CoV-2. During the COVID-19 pandemic, several perspective and review articles have also argued that masking reduces the risk of developing severe disease by reducing the inoculum dose received by the contact. This hypothesis – known as the ‘variolation hypothesis’ – has gained considerable traction since its development.

Methods

To assess the plausibility of this hypothesis, we develop a quantitative framework for understanding the relationship between (i) inoculum dose and the risk of infection and (ii) inoculum dose and the risk of developing severe disease. We parameterize the mathematical models underlying this framework with parameters relevant for SARS-CoV-2 to quantify these relationships empirically and to gauge the range of inoculum doses in natural infections. We then identify and analyze relevant experimental studies of SARS-CoV-2 to ascertain the extent of empirical support for the proposed framework.

Results

Mathematical models, when simulated under parameter values appropriate for SARS-CoV-2, indicate that the risk of infection and the risk of developing severe disease both increase with an increase in inoculum dose. However, the risk of infection increases from low to almost certain infection at low inoculum doses (with <1000 initially infected cells). In contrast, the risk of developing severe disease is only sensitive to dose at very high inoculum levels, above 106 initially infected cells. By drawing on studies that have estimated transmission bottleneck sizes of SARS-CoV-2, we find that inoculum doses are low in natural SARS-CoV-2 infections. As such, reductions in inoculum dose through masking or greater social distancing are expected to reduce the risk of infection but not the risk of developing severe disease conditional on infection. Our review of existing experimental studies support this finding.

Conclusions

We find that masking and other measures such as distancing that act to reduce inoculum doses in natural infections are highly unlikely to impact the contact’s risk of developing severe disease conditional on infection. However, in support of existing empirical studies, we find that masking and other mitigation measures that reduce inoculum dose are expected to reduce the risk of infection with SARS-CoV-2. Our findings therefore undermine the plausibility of the variolation hypothesis, underscoring the need to focus on other factors such as comorbidities and host age for understanding the heterogeneity in disease outcomes for SARS-CoV-2.
Assessing transmission risks and control strategy for monkeypox as an emerging zoonosis in a metropolitan area
Authors: Yuan Pei , Tan Yi , Yang Liu , Aruffo Elena , Ogden Nicholas H. , Bélair Jacques , Heffernan Jane , Arino Julien , Watmough James , Carabin Hélène , Zhu Huaiping
Published: June 2022

Objective

To model the spread of Monkeypox (MPX) in a metropolitan area for assessing the risk of possible outbreaks, and identifying essential public health measures to contain the virus spread.

Methods

The animal reservoir is the key element in the modelling of a zoonotic disease. Using a one health approach, we model the spread of the MPX virus in humans considering animal hosts like rodents (e.g., rats, mice, squirrels, chipmunks, etc.) and emphasize their role and transmission of the virus in a high-risk group, including gay and bisexual men-who-have-sex-with-men (gbMSM). From model and sensitivity analysis, we identify key public health factors and present scenarios under different transmission assumptions.

Findings

We find that the MPX virus may spill over from gbMSM high-risk groups to broader populations if efficiency of transmission increases in the higher-risk group. However, the risk of outbreak can be greatly reduced if at least 65% of symptomatic cases can be isolated and their contacts traced and quarantined. In addition, infections in an animal reservoir will exacerbate MPX transmission risk in the human population.

Conclusion

Regions or communities with a higher proportion of gbMSM individuals need greater public health attention. Tracing and quarantine (or “effective quarantine” by post-exposure vaccination) of contacts with MPX cases in high-risk groups would have a significant effect on controlling the spreading. Also, surveillance for animal infections would be prudent.
Genome-wide gene by environment study of time spent in daylight and chronotype identifies emerging genetic architecture underlying light sensitivity
Authors: Burns Angus C. , Phillips Andrew J. K. , Rutter Martin K. , Saxena Richa , Cain Sean W. , Lane Jacqueline M.
Published: June 2022

Light is the primary stimulus for synchronizing the circadian clock in humans. There are very large interindividual differences in the sensitivity of the circadian clock to light. Little is currently known about the genetic basis for these interindividual differences. We performed a genome-wide gene-by-environment interaction study (GWIS) in 280,897 individuals from the UK Biobank cohort to identify genetic variants that moderate the effect of daytime light exposure on chronotype (individual time of day preference), acting as ‘light sensitivity’ variants for the impact of daylight on the circadian system. We identified a genome-wide significant SNP mapped to the ARL14EP gene (rs3847634; p < 5×10−8), where additional minor alleles were found to enhance the morningness effect of daytime light exposure (βGxE = -.03, SE = 0.005) and were associated with increased gene ARL14EP expression in brain and retinal tissues. Gene-property analysis showed light sensitivity loci were enriched for genes in the G protein-coupled glutamate receptor signaling pathway and in Per2+ hypothalamic neurons. Linkage disequilibrium score regression identified significant genetic correlations of the light sensitivity GWIS with chronotype and sleep duration, such that greater light sensitivity was associated with later chronotype, greater insomnia symptoms and shorter sleep duration. Greater light sensitivity was also genetically correlated with greater risk for PTSD. This study is the first to assess light as an important exposure in the genomics of chronotype and is a critical first step in uncovering the genetic architecture of human circadian light sensitivity and its links to sleep and mental health.