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To provide some causal evidence concerning the effects of metformin on osteoarthritis (OA) using two metformin targets, namely AMP-activated protein kinase (AMPK) and growth differentiation factor 15 (GDF-15) as metformin proxies.This is a 2-sample Mendelian randomization design. We constructed 44 AMPK-related variants genetically predicted in HbA1c (%) as instruments for AMPK and five variants strongly predicted GDF-15 as instruments for GDF-15. Summary-level data for three OA phenotypes, including OA at any site, knee OA, and hip OA were obtained from the largest genome-wide meta-analysis across the UK Biobank and arcOGEN with 455,211 Europeans. Main analyses were conducted using the inverse-variance weighted method. Weighted median and MR-Egger were conducted as sensitivity analyses to assess the robustness of our results.Genetically predicted AMPK were negatively associated with OA at any site (OR: 0.60; 95% CI: 0.43-0.83) and hip OA (OR: 0.42; 95% CI: 0.22-0.80), but with not knee OA (OR: 0.85; 95% CI: 0.49-1.50). Higher levels of genetically predicted GDF-15 reduced the risk of hip OA (OR: 0.95; 95% CI: 0.90-0.99), but not OA at any site (OR: 1.00; 95% CI: 0.98-1.02) and knee OA (OR: 1.02; 95% CI: 0.98-1.07).This study indicates that AMPK and GDF-15 can be potential therapeutic targets for OA, especially for hip OA, and metformin would be repurposed for OA therapy which needs to be verified in randomized controlled trials.

After studying this article, the participant should be able to: 1. Describe the bilateral cleft lip and nasal deformity and associated anatomical variations. 2. Understand the history and evolution of the bilateral cleft lip repair. 3. Understand the key principles of the surgical repair.This article describes characteristics of the bilateral cleft lip and nasal deformity and its management, including presurgical orthopedics, operative techniques, and postsurgical care.

Purpose Plenty of studies have examined the long term effect of weight loss on bone mineral density. This study aimed to explore the effects of 10% weight loss on early changes in bone metabolism as well as the possible influencing factors. Methods Overweight and obese outpatients (BMI > 24.0 kg/m2) were recruited from the nutrition clinic and followed a calorie-restricted, high-protein, low-carbohydrate diet program. Dietary intake, body composition, serum procollagen type I N-propeptide (PINP), β-Crosslaps, PTH, 25(OH) VitD, a series of inflammatory cytokines and adipokines were measured for the participants before starting to lose weight and after 10% weight loss (NCT 04207879). Results A total of 75 participants were enrolled and 37 participants achieved a weight loss of at least 10%. It was found that PINP decreased (p = 0.000) and the β-Crosslaps increased (p = 0.035) in female participants. Decreases in PTH (p = 0.001), serum IL-2 (p = 0.013), leptin (p = 0.001) and increases in 25(OH) VitD (p = 0.001), serum ghrelin (p = 0.033) were found in 37 participants after 10% of their weight had been lost. Change in PINP was detected to be significantly associated with change in lean body mass (r = 0.418, p = 0.012) and change in serum ghrelin(r = − 0.374, p = 0.023). Conclusions Bone formation was suppressed and bone absorption was increased in female subjects after a 10% weight loss. Bone turnover was found to be associated with lean body mass and affected by the circulating ghrelin level.

The New Robotic Telescope (NRT) is an international collaboration to build and operate a 4m diameter fully robotic telescope. The telescope will take advantage of the superb atmospheric conditions at the Observatory of the Roque de los Muchachos (ORM). In conjunction with a large aperture, entirely robotic operation, quick response, and a set of versatile instrumentation in the optical and near-infrared this guarantees a high scientific impact focused mainly in the area of time domain astronomy. This paper presents the scientific motivation and the status of the project, discussing possible technical solutions under evaluation for the optics, mechanics and control system.

Dual innervation in free muscle flap facial reanimation has been used to create a functional synergy between the powerful commissure excursion that can be achieved with the masseter nerve and the spontaneity that can be derived from a cross-face nerve graft. The gracilis has been the most frequently used muscle flap, and multiple combinations of neurorrhaphies have been described, including the masseter to the obturator (end-to-end) combined with a cross-face nerve graft to the obturator (end-to-side) and vice versa. Single and staged approaches have been reported. Minimally, dual innervation is as effective as using the motor nerve to masseter alone.

After studying this article, the participant should be able to: 1. Describe the unilateral cleft lip and nasal deformity and associated anatomical variations. 2. Understand the history and evolution of the unilateral cleft lip repair. 3. List different presurgical treatment options. 4. Differentiate between surgical techniques.This article describes characteristics of the unilateral cleft lip and nasal deformity and its management, including presurgical orthopedics, operative techniques, and postsurgical care. The rotation-advancement and straight-line repairs are discussed in detail, as are the current concepts in primary cleft nose repair.

In analogy with GRB 190114C, we here analyze the ultrarelativistic prompt emission (UPE) of GRB 180720B observed in the rest-frame time interval $t_{\rm rf}=4.84$--$10.89$~s by Fermi-GBM. We reveal the UPE hierarchical structure from the time-resolved spectral analysis performed in time sub-intervals: the spectrum in each shorter time interval is always fitted by a composite blackbody plus cutoff power-law model. We explain this structure with the \textit{inner engine} of binary-driven hypernova (BdHN) model operating in a quantum electrodynamics (QED) regime. In this regime, the electric field induced by the gravitomagnetic interaction of the newborn Kerr BH with the surrounding magnetic field is overcritical, i.e., $|{\bf E}|\geq E_c$, where $E_c=m_e^2 c^3/(e\hbar)$. The overcritical field polarizes the vacuum leading to an $e^+~e^-$ pair plasma that loads baryons from the surroundings during its expansion. We calculate the dynamics of the self-acceleration of the pair-electromagnetic-baryon (PEMB) pulses to their point of transparency. We characterize the quantum vacuum polarization process in the sequences of decreasing time bins of the UPE by determining the radiation timescale, Lorentz factors, and transparency radius of the PEMB pulses. We also estimate the strength of the surrounding magnetic field $\sim 10^{14}$ G, and obtain a lower limit to the BH mass, $M=2.4~M_\odot$, and correspondingly an upper limit to the spin, $\alpha = 0.6$, from the conditions that the UPE is powered by the Kerr BH extractable energy and its mass is bound from below by the NS critical mass., Comment: Accepted for publication in EPJC

Background Ordered transposon-insertion collections, in which specific transposon-insertion mutants are stored as monocultures in a genome-scale collection, represent a promising tool for genetic dissection of human gut microbiota members. However, publicly available collections are scarce and the construction methodology remains in early stages of development. Results Here, we describe the assembly of a genome-scale ordered collection of transposon-insertion mutants in the model gut anaerobe Bacteroides thetaiotaomicron VPI-5482 that we created as a resource for the research community. We used flow cytometry to sort single cells from a pooled library, located mutants within this initial progenitor collection by applying a pooling strategy with barcode sequencing, and re-arrayed specific mutants to create a condensed collection with single-insertion strains covering >2500 genes. To demonstrate the potential of the condensed collection for phenotypic screening, we analyzed growth dynamics and cell morphology. We identified both growth defects and altered cell shape in mutants disrupting sphingolipid synthesis and thiamine scavenging. Finally, we analyzed the process of assembling the B. theta condensed collection to identify inefficiencies that limited coverage. We demonstrate as part of this analysis that the process of assembling an ordered collection can be accurately modeled using barcode sequencing data. Conclusion We expect that utilization of this ordered collection will accelerate research into B. theta physiology and that lessons learned while assembling the collection will inform future efforts to assemble ordered mutant collections for an increasing number of gut microbiota members.

Background Naturally occurring aflatoxins may contribute to poor growth and nutritional statuses in children. Objectives We analyzed the relationship between contemporary and lagged aflatoxin exposure and 1) length-for-age z-score (LAZ); and 2) length, knee-heel length, stunting, weight-for-age z-score (WAZ), and weight-for-length z-score (WLZ). Methods We conducted a longitudinal birth cohort study involving 1675 mother-infant dyads in rural Nepal. Participants were repeatedly visited from pregnancy to 2 years of age (2015–2019). One blood sample was collected during pregnancy and 4 samples were collected from the children at 3, 6, 12, and 18–22 months of age to measure concentrations of aflatoxin B1 (AFB1)-lysine adduct. Multivariate linear fixed-effects and logistic models with generalized estimating equations were used to identify associations between child growth and aflatoxin exposure. Results AFB1-lysine adducts were detected in the majority of children (at 3 months, 80.5%; at 6 months, 75.3%; at 12 months, 81.1%; and at 18–22 months, 85.1%) and in 94.3% of pregnant women. Changes in contemporary ln child AFB1‐lysine adduct concentrations were significantly associated with changes in LAZ (β, −0.05; 95% CI, −0.09 to −0.02; P = 0.003), length (β, −0.19; 95% CI, −0.29 to −0.10; P

Background: Coronavirus disease 2019 (COVID-19) has greatly impacted pediatric healthcare facilities throughout the United States due to widespread case rescheduling and the implementation of supplementary COVID-19 perioperative protocols. To our knowledge, no studies have investigated the impact of COVID-19 on case volume, surgical timing, or operational aspects of cleft surgical procedures. The aim of this study is to investigate the impact that COVID-19 has had on cleft surgical care at our institution. Methods: A retrospective study comparing cleft surgical care in 2019 (the pre-pandemic cohort) and 2020 (the COVID-19 cohort) was designed. All patients who underwent a cleft surgical procedure from April 1st to August 31st in 2019 and 2020 were included for analysis. Procedures were stratified into 4 groups: primary cleft lip repairs, primary cleft palate repairs, alveolar bone grafting procedures, and revisional/secondary repair procedures. Variables investigated in this study included: surgical volume, number of patients receiving timely surgery, causes for untimely surgery, number of combined cases, number of delayed cases, delay time, time under anesthesia, and procedure length. Results: A total of 191 cleft surgeries, 102 in 2019 and 89 in 2020, were identified during the study period. We observed no statistically significant differences in cleft surgical volume and other investigated variables across all surgical subgroups from 2019 to 2020. Conclusion: Cleft surgical care was largely unaffected by COVID-19 despite high rates of case rescheduling and the addition of supplementary perioperative safety protocols. More studies are needed to assess the impact of COVID-19 on cleft surgical care at other cleft centers and to investigate the long-term outcomes of these patients.

Study question Does transfer of low grade blastocysts results in acceptable live birth rates the birth of healthy babies? Summary answer While BC/CB/CC blastocysts have a reduced chance of live birth compared with AA/AB/BA/BB blastocysts, the absolute chances are still reasonable. What is known already Transfer of poorer quality embryos and blastocysts result in lower live birth rates, though to what extent is unclear, nor if there is an absolute threshold below which live births are very rare or even do not occur. Further, the developmental competence of the inner cell mass (ICM) or trophectoderm (TE) could at least theoretically impact the pregnancy and/or the health of the baby. Many clinics do not transfer or freeze poor quality embryos and blastocysts, and prefer to submit the patient to a further stimulation cycle. Study design, size, duration We performed a retrospective analysis of 10,978 couples undergoing singleton blastocyst transfers between 2009 and March 2020. We included all single blastocyst transfers for which there was complete data on blastocyst quality, singleton or twin births, birthweight and gestation at delivery, irrespective of blastocyst grading, female age, cause of infertility, ovarian response or endometrial thickness. We recorded live birth rates, birth weight and gestational age. Participants/materials, setting, methods Data from 14 clinics in 3 countries, 8 from China, 5 from New Zealand, and 1 from Australia were included in the final dataset. We compared the impact of blastocyst grading using multiple logistic regression. Blastocyst grading was based on the Gardner classification, in which the first letter denotes the grade of the inner cell mass (A is best), and the second letter the grade of the trophectoderm. Main results and the role of chance Overall, 10,978 single blastocyst cycles resulted in 4,261 live births (38.8%) (4195 singletons and 132 twins). Live birth rates were 47% after transfer of AA blastocysts (n = 2306); 42% after AB/BA (n = 2088); 33% after BC (n = 1973); 25% after CB (n = 715) and 14% after CC (n = 117). There were too few AC (n = 27) or CA (n = 12) blastocysts to include in the analysis. The odds of live birth for BC/CB/CC blastocysts compared with AA/AB/BA blastocysts, vary between 0.8 and 0.9. The live birth rate appears to be more dependent on ICM quality (C grade, n = 844, 23.2%) rather than TE quality (C grade, n = 2117, 32.1%), with the odds of live birth 0.43 and 0.57 respectively compared to A grade ICM or TE. The average birth weight (singleton only) was 3336.9+/-570.3 g (range 3323 to 3386 g), and the average gestation at delivery (singleton only) was 38+6+/-2.0 weeks (range 38+2 to 39+1). There was no significant difference for birth weight or gestational age at delivery between blastocysts of different grades. Limitations, reasons for caution This was a retrospective study. Grading was based on inner cell mass and trophectoderm and not on degree of expansion, or on day of transfer. It is likely that higher quality blastocysts were transferred first, in a fresh cycle, and poorer quality blastocysts frozen for later transfer. Wider implications of the findings The most important finding is that reasonable live birth rates are obtained in CC-blastocysts. We therefore advocate that CC-blastocysts should be replaced or frozen for later transfer. It is reassuring that there was no impact of blastocyst quality on birth weights or gestational age at the time of delivery. Trial registration number Not applicable