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Stagnant lid planets are characterized by a globe-encircling, conducting lid that is thick and strong, which leads to reduced global surface heat flows. Consequently, the mantles of such planets can have warmer interiors than Earth, and interestingly, a pyrolitic mantle composition under warmer conditions is predicted to have a distinctly different mantle transition zone compared to the present-day Earth (Hirose, 2002; Stixrude and Lithgow-Bertelloni, 2011; Ichikawa et al., 2014; Dannberg et al, 2022). Instead of olivine primarily transforming into its higher-pressure polymorphs such as wadsleyite and then ringwoodite, at pressures corresponding to 410 km and 520 km depth in Earth, respectively, it instead transforms into a mineral assemblage of wadsleyite, majorite, and ferropericlase (WMF), and then to majorite + ferropericlase (MF), before finally transforming into bridgmanite at pressures corresponding to 660 km depth in Earth (Stixrude and Lithgow-Bertelloni, 2011; Ichikawa et al., 2014). Convective motions in stagnant lid planets are dominated by small-scale instabilities (cold drips) forming within the mobile rheological sublayer under the rigid lid. Using ASPECT and a thermodynamic model of a pyrolitic mantle composition generated by HeFESTo, we show that under certain conditions, the small drips can pond atop the WMF-MF mineral phase transition. The barrier to convective flow arises from the WMF mineral phase assemblage having an effective negative thermal expansivity (Stixrude and Lithgow-Bertelloni, 2022). Although large-scale downwellings that typically occur within mobile lid planets are able to pass through the WMF zone without difficulty (Dannberg et al., 2022; Li RP et al., 2024), the smaller and less negatively buoyant nature of downwelling drips in stagnant lid planets are more susceptible to these effects, which leads to an ephemeral layering of the mantle. Our numerical models show that in stagnant lid planets with mantle potential temperatures that exceed 1900 K, the smaller, cold drips from the lid continue to pile up until enough of them have coalesced that they collectively avalanche as a larger instability into the deeper interior.

Abstract Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)+ metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD+ metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD+ precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD+ precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy.

Abstract The formation of Lau Basin records an extreme event of plate tectonics, with the associated Tonga trench exhibiting the fastest retreat in the world (16 cm/yr). Yet paleogeographic reconstructions suggest that seafloor spreading in the Lau Basin only initiated around 6 Ma. This kinematics is difficult to reconcile with our present understanding of how subduction drives plate motions. Using numerical models, we propose that eastward migration of the Lau Ridge concurrent with trench retreat explains both the narrow width and thickened crust of the Lau Basin. To match the slab geometry and basin width along the Tonga‐Kermadec trench, our models suggest that fast trench retreat rate of 16 cm/yr might start ~15 Ma. Tonga slab rollback induced vigorous mantle flow underneath the South Fiji Basin which is driving the extension and thinning of the basin and contributing to its observed deeper bathymetry compared to neighboring basins.

ABSTRACTThe ecological impacts of long-term (press) disturbance on mechanisms regulating the relative abundance (i.e., commonness or rarity) and temporal dynamics of species within a community remain largely unknown. This is particularly true for the functionally important arbuscular mycorrhizal (AM) fungi; obligate plant-root endosymbionts that colonize more than two-thirds of terrestrial plant species. Here, we use high-resolution amplicon sequencing to examine how AM fungal communities in a specific extreme ecosystem—mofettes or natural CO2 springs caused by geological CO2 exhalations—are affected by long-term stress. We found that in mofettes, specific and temporally stable communities form as a subset of the local metacommunity. These communities are less diverse and dominated by adapted, “stress tolerant” taxa. Those taxa are rare in control locations and more benign environments worldwide, but show a stable temporal pattern in the extreme sites, consistently dominating the communities in grassland mofettes. This pattern of lower diversity and high dominance of specific taxa has been confirmed as relatively stable over several sampling years and is independently observed across multiple geographic locations (mofettes in different countries). This study implies that the response of soil microbial community composition to long-term stress is relatively predictable, which can also reflect the community response to other anthropogenic stressors (e.g., heavy metal pollution or land use change). Moreover, as AM fungi are functionally differentiated, with different taxa providing different benefits to host plants, changes in community structure in response to long-term environmental change have the potential to impact terrestrial plant communities and their productivity.IMPORTANCEArbuscular mycorrhizal (AM) fungi form symbiotic relationships with more than two-thirds of plant species. In return for using plant carbon as their sole energy source, AM fungi improve plant mineral supply, water balance, and protection against pathogens. This work demonstrates the importance of long-term experiments to understand the effects of long-term environmental change and long-term disturbance on terrestrial ecosystems. We demonstrated a consistent response of the AM fungal community to a long-term stress, with lower diversity and a less variable AM fungal community over time under stress conditions compared to the surrounding controls. We have also identified, for the first time, a suite of AM fungal taxa that are consistently observed across broad geographic scales in stressed and anthropogenically heavily influenced ecosystems. This is critical because global environmental change in terrestrial ecosystems requires an integrative approach that considers both above- and below-ground changes and examines patterns over a longer geographic and temporal scale, rather than just single sampling events.

Background: After the arterial switch operation (ASO) for transposition of the great arteries (TGA), neo-aortic dilatation and coronary arterial anomalies, especially an interarterial course and acute coronary artery take-off angle, are commonly found. Long-term follow-up data after ASO is scarce. Aim of this study was to determine the prevalence of neo-aortic dilatation and coronary abnormalities, with special emphasis on acute coronary take-off angle, in adult TGA-ASO patients. Methods: In this retrospective cohort study, all adult TGA-ASO patients with ≥1 CT-angiography (CTA) at the age of ≥16 years were included. Results: Eighty-one patients, 69 % male and median age 21.0 [18.5–22.8] years, were included. At baseline, maximum neo-aortic diameter was 39.2 ± 5.3 mm; 35 (43 %) patients had neo-aortic dilatation (neo-aortic diameter of >40 mm), 22 (27 %) patients had an acute coronary take-off angle (40 mm or a coronary take-off angle of

Abstract Background We have previously shown that iatrogenic dehydration is associated with a shift to organic osmolyte production in the general ICU population. The aim of the present investigation was to determine the validity of the physiological response to dehydration known as aestivation and its relevance for long-term disease outcome in COVID-19. Methods The study includes 374 COVID-19 patients from the Pronmed cohort admitted to the ICU at Uppsala University Hospital. Dehydration data was available for 165 of these patients and used for the primary analysis. Validation was performed in Biobanque Québécoise de la COVID-19 (BQC19) using 1052 patients with dehydration data. Dehydration was assessed through estimated osmolality (eOSM = 2Na + 2 K + glucose + urea), and correlated to important endpoints including death, invasive mechanical ventilation, acute kidney injury, and long COVID-19 symptom score grouped by physical or mental. Results Increasing eOSM was correlated with increasing role of organic osmolytes for eOSM, while the proportion of sodium and potassium of eOSM were inversely correlated to eOSM. Acute outcomes were associated with pronounced dehydration, and physical long-COVID was more strongly associated with dehydration than mental long-COVID after adjustment for age, sex, and disease severity. Metabolomic analysis showed enrichment of amino acids among metabolites that showed an aestivating pattern. Conclusions Dehydration during acute COVID-19 infection causes an aestivation response that is associated with protein degradation and physical long-COVID. Trial registration: The study was registered à priori (clinicaltrials.gov: NCT04316884 registered on 2020-03-13 and NCT04474249 registered on 2020-06-29). Graphical abstract

Background and Aims: Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to prevent chemotherapy induced infertility are urgently needed. Here we investigate whether pharmacological elevation of nicotinamide adenine dinucleotide (NAD+) ameliorates chemotherapy induced female infertility in mice. Method: 8-week-old C57BL6 female mice were treated +/- chemotherapy (doxorubicin, Dox; 10 mg/kg) and +/- nicotinamide mononucleotide (NMN; 200 mg/kg i.p. once and 2 g/L in drinking water on-going), an orally bioavailable metabolic precursor to NAD+. Effects on fertility were measured by impact on ovarian reserve and folliculogenesis, ovulation rates and breeding performance. Effects on the ovarian NAD+ metabolome were assessed by mass spectrometry. A potential adverse effect of NMN on the efficiency of chemotherapy was assessed using a xenograft model of mammary cancer. Results: NMN treatment did not prevent a decline in the ovarian reserve caused by chemotherapy but did maintain the health of the remaining primordial follicle and total follicle populations, leading to a restoration in oocyte yield in chemo-treated mice (Dox vs Dox+NMN; P

In-barn heat processing of mass swine mortalities to inactivate pathogens could facilitate more carcass disposal options and reduce the risk of pathogen spread in the event of a foreign animal disease (FAD) outbreak. A 12.2 × 12.2 × 2.4 m (W × L × H) heat processing room was created using a temporary wall inside a de-commissioned commercial gestation barn in northwest Iowa. Eighteen swine carcasses (six per group) divided into three weight groups (mean ± SD initial carcass weights: 31.8 ± 3.3, 102.7 ± 8.1, and 226.3 ± 27.6 kg) were randomly assigned a location inside the room. Three carcasses per weight group were placed directly on concrete slats and on a raised platform. One carcass per weight group and placement (n=6) was instrumented with five temperature sensors, inserted into the brain, pleura, peritoneal, ham, and bone marrow of the femur, and a sensor was attached directly to the skin surface. Environmental conditions (ambient and room) and carcass temperatures were collected at 15-min intervals. Carcasses were subjected to an average room temperature of 57.3 ± 1.2°C for 14 days. The average (±SD) reduction from initial weight for the carcasses on slats was 45.0 ± 4.70% (feeder), 33.0 ± 8.30% (market), and 34.0 ± 15.80% (sow), and for the carcasses on a raised platform, it was 39.0 ± 6.80% (feeder), 49.0 ± 11.30% (market), and 45.0 ± 6.70% (sow). There was a significant interaction between carcass placement (slats and raised) and carcass weight loss for the market weight group. When average carcass surface temperature was at 40.6, 43.3, and 46.1°C (data grouped for analysis), the average internal carcass temperature for most measurement locations was significantly different across carcass weight groups and between the carcasses on a raised platform and those on slats. This preliminary analysis of carcass weight loss, leachate production, and temperature variation in carcasses of different sizes can be used for planning and evaluating mass swine mortality management strategies.

Abstract Background Kawasaki disease (KD) is a pediatric vasculitis. Mainly the coronary arteries become affected due to acute inflammation and formation of coronary artery aneurysms (CAAs) can occur. The larger the CAA, the higher the risk for clinical complications and major adverse cardiac events, as the blood flow changes to vortex or turbulent flow facilitating thrombosis. Such patients may develop life threatening thrombotic coronary artery occlusion and myocardial ischemiaunless anti-platelet and anti-coagulation therapy is timely initiated. Case presentation We present a unique case of a 5-year-old girl with KD associated giant CAAs suffering from myocardial ischemia due to acute progressive thrombus growth despite intensive anticoagulation treatment (acetylsalicylic acid, acenocoumarol and clopidogrel) after 21 months of onset of disease. Thrombus growth continued even after percutaneous coronary intervention (PCI) with thrombolytic treatment and subsequent systemic thrombolysis, finally causing lasting myocardial damage. Acute coronary artery bypass grafting (CABG) was performed, although technically challenging at this very young age. Whereas myocardial infarction was not prevented, follow-up fortunately showed favorable recovery of heart failure. Conclusions Anticoagulation and thrombolysis may be insufficient for treatment of acute coronary syndrome in case of impending thrombotic occlusion of giant coronary aneurysms in KD. Our case demonstrates that a thrombus can still continue to grow despite triple anticoagulation therapy and well-tailored cardiovascular follow-up, which can be most likely attributed to the state of low blood flow inside the aneurysm.

Abstract Background Hemolysis occurs in many injury settings and can trigger disease processes. In the kidney, extracellular hemoglobin can induce damage via several mechanisms. These include oxidative stress, mitochondrial dysfunction, and inflammation, which promote fibrosis and chronic kidney disease. Understanding the pathophysiology of these injury pathways offers opportunities to develop new therapeutic strategies. Methods To model hemolysis-induced kidney injury, human kidney organoids were treated with hemin, an iron-containing porphyrin, that generates reactive oxygen species. In addition, we developed an induced pluripotent stem cell line expressing the biosensor, CytochromeC-GFP (CytoC-GFP), which provides a real-time readout of mitochondrial morphology, health, and early apoptotic events. Results We found that hemin-treated kidney organoids show oxidative damage, increased expression of injury markers, impaired functionality of organic anion and cation transport and undergo fibrosis. Injury could be detected in live CytoC-GFP organoids by cytoplasmic localization of fluorescence. Finally, we show that 4-(phenylthio)butanoic acid, an HDAC inhibitor with anti-fibrotic effects in vivo, reduces hemin-induced human kidney organoid fibrosis. Conclusion This work establishes a hemin-induced model of kidney organoid injury. This platform provides a new tool to study the injury and repair response pathways in human kidney tissue and will assist in the development of new therapeutics.

ObjectivePatients with Marfan syndrome (MFS) and patients with a bicuspid aortic valve (BAV) have a significantly increased risk to develop thoracic aortopathy. Both conditions share many pathophysiological mechanisms leading to aortic complications. Bicuspidy is known to have a low risk for acquired coronary artery sclerosis. The aim of this study is to determine the risk of coronary sclerosis in MFS patients.MethodsMarfan syndrome patients with an aortic root dilatation, which were surgically treated between 1999 and 2017, were included and matched with BAV and tricuspid aortic valves (TAV) patients based on sex and age. Cardiovascular risk profiles were determined in all three groups. Coronary sclerosis was graded in all patients on coronary imaging (coronary angiography or computed tomography) using a coronary artery scoring method, which divides the coronaries in 28 segments and scores non-obstructive (20–49% sclerosis) and obstructive coronary sclerosis (>49% sclerosis) in each segment.ResultsA total of 90 matched patients (30 within each group) were included. MFS patients showed less cardiovascular risk factors compared to BAV and TAV patients. TAV patients had higher amounts of obstructive coronary sclerosis as compared to BAV patients (p = 0.039) and MFS patients (p = 0.032). No difference in non- and obstructive coronary artery disease (CAD) was found between the MFS and BAV population.ConclusionMarfan syndrome and bicuspid aortic valve patients have a significantly lower risk for, and prevalence of CAD as compared to TAV individuals.

Introduction Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality.Methods Prospective cohort study in 109 institutions in 41 countries. Inclusion criteria: children

BackgroundPatients with transposition of the great arteries (TGA) after an atrial switch or congenitally corrected TGA (ccTGA) are prone to systemic right ventricular (sRV) failure. Tricuspid valve (TV) regurgitation aggravates sRV dysfunction. Timely TV surgery stabilizes sRV function, yet the development of atrioventricular (AV)-conduction disturbances in the course of sRV failure can contribute to sRV dysfunction through pacing-induced dyssynchrony. This study aims to explore the incidence, timing, and functional consequences of AV-block requiring ventricular pacing after TV surgery in patients with sRV.MethodsConsecutive adolescent and adult patients with an sRV who underwent TV surgery between 1989 and 2020 and followed-up at our center were included in this observational cohort study.ResultsThe data of 28 patients (53% female, 57% ccTGA, and a mean age at surgery 38 ± 13 years) were analyzed. The mean follow-up was 9.7 ± 6.8 years. Of the remaining 22 patients at the risk of developing high degree AV-block after TV surgery, 9 (41%) developed an indication for chronic ventricular pacing during follow-up, of which 5 (56%) within 24 months postoperatively (3 prior to hospital discharge). The QRS duration, a surrogate marker for dyssynchrony, was significantly higher in patients with chronic left ventricular pacing than in patients with native AV-conduction (217 ± 24 vs. 116 ± 23 ms, p = 0.000), as was the heart failure biomarker NT-pro-BNP [2,746 (1,242–6,879) vs. 495 (355–690) ng/L, p = 0.004] and the percentage of patients with ≥1 echocardiographic class of deterioration of systolic sRV function (27 vs. 83%, p = 0.001). Of the patients receiving chronic subpulmonary ventricular pacing (n = 12), 9 (75%) reached the composite endpoint of progressive heart failure [death, ventricular assist device implantation, or upgrade to cardiac resynchronization therapy (CRT)]. Only 4 (31%) patients with native AV-conduction (n = 13) reached this composite endpoint (p = 0.027).ConclusionPatients with a failing sRV who undergo TV surgery are prone to develop AV-conduction abnormalities, with 41% developing an indication for chronic ventricular pacing during 10 years of follow-up. Patients with chronic subpulmonary ventricular pacing have a significantly longer QRS complex duration, have higher levels of the heart failure biomarker NT-pro-BNP, and are at a higher risk of deterioration of systolic sRV function and progressive heart failure.

Tinnitus is the perception of sound without an external source. The flocculus (FL) and paraflocculus (PFL), which are small lobules of the cerebellum, have recently been implicated in its pathophysiology. In a previous study, the volume of the (P)FL-complex correlated with tinnitus severity in patients that had undergone cerebellopontine angle (CPA) tumor removal. In this study, the relation between tinnitus and gray matter volume (GMV) of the (P)FL-complex, GMV of the other cerebellar lobules and GMV of the cerebellar nuclei is investigated in otherwise healthy participants. Data was processed using the SUIT toolbox, which is dedicated to analysis of imaging data of the human cerebellum. GMV of all cerebellar lobules and nuclei were similar between tinnitus and non-tinnitus participants. Moreover, no relation was present between tinnitus severity, as measured by the Tinnitus Handicap Inventory, and (P)FL-complex GMV, tonsil GMV, or total cerebellar cortical GMV. These results suggest that in otherwise healthy participants, in contrast to participants after CPA tumor removal, no relation between the GMV of neither the (P)FL-complex nor other cerebellar lobules and tinnitus presence and severity exists. These findings indicate that a relation only exists when the (P)FL-complex is damaged, for instance by a CPA tumor. Alternatively, it is possible that differences in (P)FL-complex GMVs are too small to detect with a voxel-based morphometry study. Therefore, the role of the (P)FL-complex in tinnitus remains to be further studied.

Objectives Paediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs.Design A multicentre, international, collaborative cohort study.Setting 91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020.Participants Patients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkin’s lymphoma, Hodgkin lymphoma, Wilms’ tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer.Main outcome measure All-cause mortality at 30 days and 90 days.Results 1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n=182/219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (p

Abstract: The Tonga‐Kermadec subduction zone exhibits the fastest observed trench retreat and convergence near its northern end. However, a paradox exists: despite the rapid trench retreat, the Tonga slab maintains a relatively steep dip angle above 400 km depth. The slab turns flat around 400 km, then steepening again until encountering a stagnant segment near 670 km. Despite its significance for understanding slab dynamics, no existing numerical model has successfully demonstrated how such a distinct slab morphology can be generated under the fast convergence. Here we run subduction models that successfully reproduce the slab geometries while incorporating the observed subduction rate. We use a hybrid velocity boundary condition, imposing velocities on the arc and subducting plate while allowing the overriding plate to respond freely. This approach is crucial for achieving a good match between the modeled and observed Tonga slab. The results explain how the detailed slab structure is highly sensitive to physical parameters including the seafloor age and the mantle viscosity. Notably, a nonlinear rheology, where dislocation creep reduces upper mantle viscosity under strong mantle flow, is essential. The weakened upper mantle allows for a faster slab sinking rate, which explains the large dip angle. Our findings highlight the utilizing rheological parameters that lead to extreme viscosity variations within numerical models to achieve an accurate representation of complex subduction systems like the Tonga‐Kermadec zone. Our study opens new avenues for further study of ocean‐ocean subduction systems, advancing our understanding of their role in shaping regional and global tectonics.

Abstract Cerebral adrenoleukodystrophy is an inflammatory demyelinating condition that is the result of a mutation in the X‐linked ABCD1 gene, a peroxisomal very long chain fatty acid transporter. Although mutations in this gene result in adrenal insufficiency in the majority of affected individuals, 40% of those affected develop the demyelinating cerebral form, cerebral adrenoleukodystrophy (CALD). CALD is characterized by imaging findings of demyelination and contrast enhancement on magnetic resonance imaging (MRI). Although allogeneic hematopoietic cell transplantation can arrest progression of CALD early in its course, there is no accepted therapy for patients with advanced CALD. Mesenchymal stem cells (MSCs) have been used in a variety of clinical trials to capitalize on their anti‐inflammatory properties as well as promote tissue repair. We delivered MSCs via intrathecal (IT) route to two boys with rapidly advancing CALD. The first boy received three doses 1 week apart, whereas the second boy received a single dose of IT MSCs. We note delivery of IT MSCs was feasible and without complication. Follow‐up MRI scans after IT MSC delivery showed progressive demyelination in the first patient and no change in demyelination or contrast enhancement in the second patient. Although the infusion of IT MSCs was safe, it did not halt CALD progression in this setting, and future studies should focus on patient selection and dose optimization.

Abstract Background The capacity of reef-building corals to tolerate (or adapt to) heat stress is a key factor determining their resilience to future climate change. Changes in coral microbiome composition (particularly for microalgal endosymbionts and bacteria) is a potential mechanism that may assist corals to thrive in warm waters. The northern Red Sea experiences extreme temperatures anomalies, yet corals in this area rarely bleach suggesting possible refugia to climate change. However, the coral microbiome composition, and how it relates to the capacity to thrive in warm waters in this region, is entirely unknown. Results We investigated microbiomes for six coral species (Porites nodifera, Favia favus, Pocillopora damicornis, Seriatopora hystrix, Xenia umbellata, and Sarcophyton trocheliophorum) from five sites in the northern Red Sea spanning 4° of latitude and summer mean temperature ranges from 26.6 °C to 29.3 °C. A total of 19 distinct dinoflagellate endosymbionts were identified as belonging to three genera in the family Symbiodiniaceae (Symbiodinium, Cladocopium, and Durusdinium). Of these, 86% belonged to the genus Cladocopium, with notably five novel types (19%). The endosymbiont community showed a high degree of host-specificity despite the latitudinal gradient. In contrast, the diversity and composition of bacterial communities of the surface mucus layer (SML)—a compartment particularly sensitive to environmental change—varied significantly between sites, however for any given coral was species-specific. Conclusion The conserved endosymbiotic community suggests high physiological plasticity to support holobiont productivity across the different latitudinal regimes. Further, the presence of five novel algal endosymbionts suggests selection of certain genotypes (or genetic adaptation) within the semi-isolated Red Sea. In contrast, the dynamic composition of bacteria associated with the SML across sites may contribute to holobiont function and broaden the ecological niche. In doing so, SML bacterial communities may aid holobiont local acclimatization (or adaptation) by readily responding to changes in the host environment. Our study provides novel insight about the selective and endemic nature of coral microbiomes along the northern Red Sea refugia.

Purpose: To generate an evidence-based opioid-prescribing guideline by assessing the pattern of total opioid consumption and the factors that may predict opioid consumption following arthroscopic release of elbow contracture and to investigate whether the use of continuous passive motion (CPM), as compared to physical therapy (PT), was associated with a decrease in pain and opioid consumption after arthroscopic release of elbow contracture. Methods: Data collected from a randomized controlled trial that compared continuous passive motion (CPM) (n = 24) to physical therapy (PT) (n = 27) following arthroscopic release of elbow contracture was analyzed for opioid use. Fifty-one participants recorded their daily opioid consumption in a postoperative diary for 90 days. Multivariate analysis was performed to identify factors associated with opioid use. Recommended quantities for postoperative prescription were generated using the 50th percentile for patients without and the 75th percentile for patients with factors associated with higher opioid use. Results: The median total opioid prescription was 437.5-mg morphine milligram equivalents (MMEs) (58 pills of 5 mg oxycodone) and the median total opioid consumption was 75 MMEs (10 pills of 5-mg oxycodone). Twenty-two percent of patients took no opioid medication, 53% took ≤10 pills, 69% took ≤20 pills and 75% took ≤30 pills. Predictors of higher opioid use were preoperative opioid use, age

Non-communicable diseases account for most deaths globally and they are the main reason for patient consultations. Conventional medicine focuses on pharmaceutical and surgical interventions to manage these diseases. Most management protocols recognise the foundational role of lifestyle changes, but practical lifestyle medicine interventions need to become part of the medical curriculum and part of each consultation to make an impact. This article presents the rationale for the launch of the South African Lifestyle Medicine Association as an important facilitator of that process.

Phase 1 and phase 2 gene therapy trials using intramuscular (IM) administration of a recombinant adeno-associated virus serotype 1 (rAAV1) for replacement of serum alpha-1 antitrypsin (AAT) deficiency have shown long-term (5-year) stable transgene expression at approximately 2% to 3% of therapeutic levels, arguing for the long-term viability of this approach to gene replacement of secreted serum protein deficiencies. However, achieving these levels required 100 IM injections to deliver 135 mL of vector, and further dose escalation is limited by the scalability of direct IM injection. To further advance the dose escalation, we sought to bridge the rAAV-AAT clinical development program to regional limb perfusion, comparing two methods previously established for gene therapy, peripheral venous limb perfusion (VLP) and an intra-arterial push and dwell (IAPD) using rAAV1 and rAAV8 in a non-human primate (rhesus macaque) study. The rhesus AAT transgene was used with a c-myc tag to enable quantification of transgene expression. 5 cohorts of animals were treated with rAAV1-IM, rAAV1-VLP, rAAV1-IAPD, rAAV8-VLP, and rAAV8-IAPD (n = 2–3), with a dose of 6 × 1012 vg/kg. All methods were well tolerated clinically. Potency, as determined by serum levels of AAT, of rAAV1 by the VLP method was twice that observed with direct IM injection; 90 μg/mL with VLP versus 38 μg/mL with direct IM injection. There was an approximately 25-fold advantage in estimated vector genomes retained within the muscle tissue with VLP and a 5-fold improvement in the ratio of total vector genomes retained within muscle as compared with liver. The other methods were intermediate in the potency and retention of vector genomes. Examination of muscle enzyme (CK) levels indicated rAAV1-VLP to be equally safe as compared with IM injection, while the IAPD method showed significant CK elevation. Overall, rAAV1-VLP demonstrates higher potency per vector genome injected and a greater total vector retention within the muscle, as compared to IM injection, while enabling a much greater total dose to be delivered, with equivalent safety. These data provide the basis for continuation of the dose escalation of the rAAV1-AAT program in patients and bode well for rAAV-VLP as a platform for replacement of secreted proteins.

Abstract: The formation of Lau Basin records an extreme event of plate tectonics, with the associated Tonga trench exhibiting the fastest retreat in the world (16 cm/yr). Yet paleogeographic reconstructions suggest that seafloor spreading in the Lau Basin only initiated around 6 Ma. This kinematics is difficult to reconcile with our present understanding of how subduction drives plate motions. Using numerical models, we propose that eastward migration of the Lau Ridge concurrent with trench retreat explains both the narrow width and thickened crust of the Lau Basin. To match the slab geometry and basin width along the Tonga‐Kermadec trench, our models suggest that fast trench retreat rate of 16 cm/yr might start ~15 Ma. Tonga slab rollback induced vigorous mantle flow underneath the South Fiji Basin which is driving the extension and thinning of the basin and contributing to its observed deeper bathymetry compared to neighboring basins.

Over the last few years, there is an apparent growing concern amongst O&G trainees of the inadequacy in exposure to minimally invasive gynaecology surgical training, which has been inadvertently compounded by the more stringent working hour regulations and disproportionately increasing number of trainees relative to surgical volume. Therefore, it is vitally important for trainees to maximise opportunities in the operating theatre and develop autonomy in carrying out more complex surgical procedures. This case report outlines the step-by-step approach of laparoscopic excision of a cornual ectopic pregnancy performed by a trainee under the supervision of a surgical mentor. This manuscript highlights key characteristic traits of a trainee that serve to foster surgical trust and simple but effective steps to foster surgical preparedness.

In September 2017 the Agia Zoni II sank in the Saronic Gulf, Greece, releasing approximately 500 tonnes of heavy fuel oil, contaminating the Salamina and Athens coastlines. Effects of the spill, and remediation efforts, on sediment microbial communities were quantified over the following 7 months. Five days post-spill, the concentration of measured hydrocarbons within surface sediments of contaminated beaches was 1,093–3,773 μg g–1 dry sediment (91% alkanes and 9% polycyclic aromatic hydrocarbons), but measured hydrocarbons decreased rapidly after extensive clean-up operations. Bacterial genera known to contain oil-degrading species increased in abundance, including Alcanivorax, Cycloclasticus, Oleibacter, Oleiphilus, and Thalassolituus, and the species Marinobacter hydrocarbonoclasticus from approximately 0.02 to >32% (collectively) of the total bacterial community. Abundance of genera with known hydrocarbon-degraders then decreased 1 month after clean-up. However, a legacy effect was observed within the bacterial community, whereby Alcanivorax and Cycloclasticus persisted for several months after the oil spill in formerly contaminated sites. This study is the first to evaluate the effect of the Agia Zoni II oil-spill on microbial communities in an oligotrophic sea, where in situ oil-spill studies are rare. The results aid the advancement of post-spill monitoring models, which can predict the capability of environments to naturally attenuate oil.

Summary: Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD+). Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD+-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD+ levels represents an opportunity to rescue female reproductive function in mammals. : Declining oocyte quality is considered an irreversible feature of aging and is rate limiting for human fertility. Bertoldo et al. show that reversing an age-dependent decline in NAD(P)H restores oocyte quality, embryo development, and functional fertility in aged mice. These findings may be relevant to reproductive medicine. Keywords: oocyte, nicotinamide adenine dinucleotide (NAD+), nicotinamide mononucleotide (NMN), SIRT2, female fertility, infertility, reproductive aging, aging, embryo development, in vitro fertilization

According to the U.S. Special Operations Command (SOCOM), new clinical trials of an anti-aging oral treatment using nicotinamide adenine nucleotide are planned for 2022. All over the globe, the discovery of the fountain of youth is still a great goal to reach, not only among aging researchers, since people desire to stay longer healthy and feel young when reaching old age. Since the 1960s, women delaying pregnancy to pursue higher educational levels and a career path has contributed to drastically diminished overall female fertility rates (e.g., number of born offspring/woman). Consequently, a growing number of advanced-aged women depend on assisted reproductive technologies (ART) to become pregnant. In 2019, the Society for Assisted Reproductive Technology reported 293,672 cycles for oocyte retrieval. This change of demographics influenced women’s age of having their first child, which has increased significantly. However, their reproductive tract shows hallmarks of aging very early in life without an effective preventive treatment. Therefore, we will present whether NAD+ could help to prevent oocyte aging.

This study evaluated the effects of three commercial dispersants (Finasol OSR 52, Slickgone NS, Superdispersant 25) and three biosurfactants (rhamnolipid, trehalolipid, sophorolipid) in crude-oil seawater microcosms. We analysed the crucial early bacterial response (1 and 3 days). In contrast, most analyses miss this key period and instead focus on later time points after oil and dispersant addition. By focusing on the early stage, we show that dispersants and biosurfactants, which reduce the interfacial surface tension of oil and water, significantly increase the abundance of hydrocarbon-degrading bacteria, and the rate of hydrocarbon biodegradation, within 24 h. A succession of obligate hydrocarbonoclastic bacteria (OHCB), driven by metabolite niche partitioning, is demonstrated. Importantly, this succession has revealed how the OHCB Oleispira, hitherto considered to be a psychrophile, can dominate in the early stages of oil-spill response (1 and 3 days), outcompeting all other OHCB, at the relatively high temperature of 16 °C. Additionally, we demonstrate how some dispersants or biosurfactants can select for specific bacterial genera, especially the biosurfactant rhamnolipid, which appears to provide an advantageous compatibility with Pseudomonas, a genus in which some species synthesize rhamnolipid in the presence of hydrocarbons.

Following publication of the original article [1], the authors reported an error on the legend of of P.damicornis in Fig. 1.

Background Substantial proximal humeral bone loss may compromise reverse shoulder arthroplasty secondary to limited implant support, insufficient soft tissue tension due to shortening, lack of attachment sites for the posterosuperior cuff when present, and lack of lateral offset of the deltoid. In these circumstances, use of a proximal humeral replacement may be considered. Patients/Methods Between 2012 and 2014, 34 consecutive reverse shoulder arthroplasties were performed using a proximal humeral replacement system. The indications were failed shoulder arthroplasty (15), oncology reconstruction (9), humeral malunion/nonunion (7), prior resection arthroplasty (2), and intraoperative fracture (1). All patients were included in the survival analysis. Twenty-two patients with minimum 2-year follow-up were included in analysis of clinical results. Results Among the cohort of 34 patients, there were 8 additional reoperations: humeral loosening (3), periprosthetic fracture (2), irrigation and debridement (2), and glenoid loosening (1). Humeral component loosening occurred exclusively in patients undergoing revision shoulder arthroplasty. The 4 patients had an average 3.75 prior procedures before the proximal humeral replacement. Two of the revisions were from cemented to uncemented stems. Among the 23 patients with minimum 2-year follow-up, there was significant improvement in pain scores (4.1 vs 0.6), forward elevation (31 vs 109) degrees, and 81% were satisfied. Conclusion Use of a proximal humeral replacement when performing a reverse shoulder arthroplasty in the complex setting of substantial proximal humerus bone loss provides good clinical results and a particularly low dislocation rate. However, the rate of loosening of the humeral component in the revision setting suggests that proximal humeral replacement components should be cemented when revising a previously cemented stem. IRB 16-006966.

Understanding the genetic architecture of adaptation is of great importance in evolutionary biology. U.S. weedy rice is well adapted to the local conditions in U.S. rice fields. Rice blast disease is one of the most destructive diseases of cultivated rice worldwide. However, information about resistance to blast in weedy rice is limited. Here, we evaluated the disease reactions of 60 U.S. weedy rice accessions with 14 blast races, and investigated the quantitative trait loci (QTL) associated with blast resistance in two major ecotypes of U.S. weedy rice. Our results revealed that U.S. weedy rice exhibited a broad resistance spectrum. Using genotyping by sequencing, we identified 28 resistance QTL in two U.S. weedy rice ecotypes. The resistance QTL with relatively large and small effects suggest that U.S. weedy rice groups have adapted to blast disease using two methods, both major resistance (R) genes and QTL. Three genomic loci shared by some of the resistance QTL indicated that these loci may contribute to no-race-specific resistance in weedy rice. Comparing with known blast disease R genes, we found that the R genes at these resistance QTL are novel, suggesting that U.S. weedy rice is a potential source of novel blast R genes for resistant breeding.

Abstract: Venus' tectonic evolution is not well understood. Thousands of kilometers of possible subduction sites on Venus have been identified along networks of rift zone trenches called chasmata. Rift zones are strong candidates for tectonic recycling due to pre‐existing weaknesses in the lithosphere. Recently, peel‐back delamination (PBD) was proposed as a mechanism of regional‐scale lithospheric recycling initiated at Venusian rift zones (Adams et al., 2022, https://doi.org/10.1029/2022je007460). PBD occurs when the lithospheric mantle becomes sufficiently thick and negatively buoyant to decouple and peel away from the overlying crust remaining at the surface. Both positively and negatively buoyant lithosphere were shown to undergo buoyancy‐driven PBD, though delamination is inhibited by increasing positive plate buoyancy. In this study, we use 2D numerical models to verify that delamination can be initiated in thinner, more positively buoyant lithosphere than in models with no plume‐rift interactions. Our results show that plume‐induced PBD in positively buoyant plates is facilitated by the excess negative buoyancy in the lithospheric mantle and increasing plume buoyancy force, and it is inhibited by increasing crustal buoyancy and decreasing rift width. We propose an age‐progressive framework for delamination at rift zones, where young, thin plates require a larger plume buoyancy force to be destabilized than thicker, yet still positively buoyant plates. We use lithospheric thickness constraints to predict PBD may be most likely to initiate near the Dali‐Diana Chasmata system.

Accurate carbon and water flux simulations for croplands are greatly dependent on high quality representation of management practices and meteorological conditions, which are key drivers of the surface-atmosphere exchange processes. Fourteen site-years of carbon and water fluxes were simulated using the CropSyst model over four agricultural sites in the inland Pacific Northwest (iPNW) US from October 1, 2011 to September 30, 2015. Model performance for field-scale net ecosystem exchange of CO2 (NEE) and evapotranspiration (ET) was evaluated by comparing simulations with long-term eddy covariance measurements. The model captured the temporal variations of NEE and ET reasonably well with an overall r of 0.78 and 0.80, and a low RMSE of 1.82 g C m−2 d−1 and 0.84 mm d−1 for NEE and ET, respectively. The model slightly underestimated NEE and ET by 0.51 g C m−2 d−1 and 0.09 mm d−1, respectively. ET simulations showed better agreement with eddy covariance measurements than NEE. The model performed much better for the sites with detailed initial conditions (e.g., SOC content) and management practice information (e.g., tillage type). The CropSyst results showed that the winter wheat fields could be annual net carbon sinks or close to neutral with the net ecosystem carbon balance (NECB) ranging from 92 to −17 g C m−2, while the spring crop fields were net carbon sources or neutral with an annual NECB of −327 to −3 g C m−2. Simulations for the paired tillage sites showed that the no-till site resulted in lower CO2 emissions for the crop rotations of winter wheat-spring garbanzo, but had higher carbon loss into the atmosphere for spring canola compared to the conventional tillage site. Water budgets did not differ significantly between the two tillage systems. Winter wheat in the high-rainfall area had higher crop yields and water use efficiency but emitted larger amounts of CO2 into the atmosphere than in the low-rainfall area. Based on model evaluations in this study, CropSyst appears promising as a tool to simulate field-scale carbon and water budgets and assess the effects of different management practices and local meteorological conditions for the wheat-based cropping systems in this region.

We describe the efforts of the Taiwan-America Occultation Survey (TAOS) project to develop a data acquisition and analysis scheme for fast CCD imaging photometry. The TAOS project aims to conduct a census of the Kuiper-belt objects (KBOs) by detecting chance stellar occultation events by these small bodies in the outer reach of the solar system. An array of telescopes, each with fast optics (f/2) of 0.5 m aperture and equipped with a 2K CCD camera (3 square degrees FOV), have been set up in central Taiwan to monitor a couple thousand stars simultaneously. By reading out the CCD chip sequentially a few rows of pixels at a time (pause-and-shift), it is possible to achieve stellar photometry with a sampling rate up to several hertz. Here we report how such a setup has been used to observe the SX Phoenicis type variable CY Aqr to illustrate the potential usefulness of the TAOS database in stellar variability studies.

Tinnitus is a percept of sound that is not related to an acoustic source outside the body. For many forms of tinnitus, mechanisms in the central nervous system are believed to play a role in the pathology. In this work we specifically assessed possible neural correlates of unilateral tinnitus. Functional magnetic resonance imaging (fMRI) was used to investigate differences in sound-evoked neural activity between controls, subjects with left-sided tinnitus, and subjects with right-sided tinnitus. We assessed connectivity patterns between auditory nuclei and the lateralization of the sound-evoked responses. Interestingly, these response characteristics did not relate to the laterality of tinnitus. The lateralization for left- or right ear stimuli, as expressed in a lateralization index, was considerably smaller in subjects with tinnitus compared to that in controls, reaching significance in the right primary auditory cortex (PAC) and the right inferior colliculus (IC). Reduced functional connectivity between the brainstem and the cortex was observed in subjects with tinnitus. These differences are consistent with two existing models that relate tinnitus to i) changes in the corticothalamic feedback loops or ii) reduced inhibitory effectiveness between the limbic system and the thalamus. The vermis of the cerebellum also responded to monaural sound in subjects with unilateral tinnitus. In contrast, no cerebellar response was observed in control subjects. This suggests the involvement of the vermis of the cerebellum in unilateral tinnitus.

The aphidophagous midge Aphidoletes aphidimyza (Diptera: Cecidomyiidae) is used in biological control programs against aphids in many crops. Short-term trials with this natural enemy demonstrated that that females prefer to oviposit among aphids colonizing the new growth of plants, leading to differential attack rates for aphid species that differ in their within-plant distributions. Thus, we hypothesized that biological control efficacy could be compromised when more than one aphid species is present. We further hypothesized that control outcomes may be different at different crop stages if aphid species shift their preferred feeding locations. Here, we used greenhouse trials to determine biological control outcomes using A. aphidimyza under multi-prey conditions and at different crop stages. At all plant stages, aphid species had a significant effect on the number of predator eggs laid. More eggs were found on M. persicae versus A. solani-infested plants, since M. persicae consistently colonized plant meristems across plant growth stages. This translated to higher numbers of predatory larvae on M. periscae-infested plants in two out of our three experiments, and more consistent control of this pest (78%–95% control across all stages of plant growth). In contrast, control of A. solani was inconsistent in the presence of M. persicae, with 36%–80% control achieved. An additional experiment demonstrated control of A. solani by A. aphidimyza was significantly greater in the absence of M. persicae than in its presence. Our study illustrates that suitability of a natural enemy for pest control may change over a crop cycle as the position of prey on the plant changes, and that prey preference based on within-plant prey location can negatively influence biological control programs in systems with pest complexes. Careful monitoring of the less-preferred pest and its relative position on the plant is suggested.