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Abstract We present a measurement of the cosmic-ray spectrum above 100 PeV using the part of the surface detector of the Pierre Auger Observatory that has a spacing of 750 m. An inflection of the spectrum is observed, confirming the presence of the so-called second-knee feature. The spectrum is then combined with that of the 1500 m array to produce a single measurement of the flux, linking this spectral feature with the three additional breaks at the highest energies. The combined spectrum, with an energy scale set calorimetrically via fluorescence telescopes and using a single detector type, results in the most statistically and systematically precise measurement of spectral breaks yet obtained. These measurements are critical for furthering our understanding of the highest energy cosmic rays.

Abstract Neuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.

Abstract The hybrid design of the Pierre Auger Observatory allows for the measurement of the properties of extensive air showers initiated by ultra-high energy cosmic rays with unprecedented precision. By using an array of prototype underground muon detectors, we have performed the first direct measurement, by the Auger Collaboration, of the muon content of air showers between $$2\times 10^{17}$$ 2×1017 and $$2\times 10^{18}$$ 2×1018 eV. We have studied the energy evolution of the attenuation-corrected muon density, and compared it to predictions from air shower simulations. The observed densities are found to be larger than those predicted by models. We quantify this discrepancy by combining the measurements from the muon detector with those from the Auger fluorescence detector at $$10^{{17.5}}\, {\mathrm{eV}} $$ 1017.5eV and $$10^{{18}}\, {\mathrm{eV}} $$ 1018eV . We find that, for the models to explain the data, an increase in the muon density of $$38\%$$ 38% $$\pm 4\% (12\%)$$ ±4%(12%) $$\pm {}^{21\%}_{18\%}$$ ±18%21% for EPOS-LHC, and of $$50\% (53\%)$$ 50%(53%) $$\pm 4\% (13\%)$$ ±4%(13%) $$\pm {}^{23\%}_{20\%}$$ ±20%23% for QGSJetII-04, is respectively needed.

Abstract Elves are a class of transient luminous events, with a radial extent typically greater than 250 km, that occur in the lower ionosphere above strong electrical storms. We report the observation of 1,598 elves, from 2014 to 2016, recorded with unprecedented time resolution (100 ns) using the fluorescence detector (FD) of the Pierre Auger Cosmic‐Ray Observatory. The Auger Observatory is located in the Mendoza province of Argentina with a viewing footprint for elve observations of 3·106 km 2, reaching areas above the Pacific and Atlantic Oceans, as well as the Córdoba region, which is known for severe convective thunderstorms. Primarily designed for ultrahigh energy cosmic‐ray observations, the Auger FD turns out to be very sensitive to the ultraviolet emission in elves. The detector features modified Schmidt optics with large apertures resulting in a field of view that spans the horizon, and year‐round operation on dark nights with low moonlight background, when the local weather is favorable. The measured light profiles of 18% of the elve events have more than one peak, compatible with intracloud activity. Within the 3‐year sample, 72% of the elves correlate with the far‐field radiation measurements of the World Wide Lightning Location Network. The Auger Observatory plans to continue operations until at least 2025, including elve observations and analysis. To the best of our knowledge, this observatory is the only facility on Earth that measures elves with year‐round operation and full horizon coverage.

An overview of the multi-messenger capabilities of the Pierre Auger Observatory is presented. The techniques and performance of searching for Ultra-High Energy neutrinos, photons and neutrons are described. Some of the most relevant results are reviewed, such as stringent upper bounds that were placed to a flux of diffuse cosmogenic neutrinos and photons, bounds placed on neutrinos emitted from compact binary mergers that were detected by LIGO and Virgo during their first and second observing runs, as well as searches for high energy photons and neutrons from the Galactic center that constrain the properties of the putative Galactic PeVatron, observed by the H.E.S.S. collaboration. The observation of directional correlations between ultra-high energy cosmic rays and either high energy astrophysical neutrinos or specific source populations, weighted by their electromagnetic radiation, are also discussed. They constitute additional multi-messenger approaches aimed at identifying the sources of high energy cosmic rays.

Here we present the results of a multi-proxy investigation – integrating geomorphology, ground-penetrating radar, and luminescence dating – of a high-elevation lunette and beach berm in northern New South Wales, eastern Australia. The lunette occurs on the eastern shore of Little Llangothlin Lagoon and provides evidence for a lake high stand combined with persistent westerly winds at the Last Glacial Maximum (LGM – centring on 21.5 ka) and during the early Holocene (ca. 9 and 6 ka). The reconstructed atmospheric circulation is similar to the present-day conditions, and we infer no significant changes in circulation at those times, as compared to the present day. Our results suggest that the Southern Hemisphere westerlies were minimally displaced in this sector of Australasia during the latter part of the last ice age. Our observations also support evidence for a more positive water balance at the LGM and early Holocene in this part of the Australian sub-tropics.

Digital skills are beneficial for young people and society, but some individuals, particularly girls, are less likely to choose computing post-compulsory education. Coding is a crucial skill in the school computing curriculum. The authors collected survey data from 4983 secondary-school students (ages 11-16) as well as conducted exploratory factor analysis and created multivariable logistic regression models. Their findings revealed that high coding attitudes were associated with various factors, including student experience in computing lessons, teacher and parent support, perceptions of computer scientists, computing at home and gender. These findings have implications for classroom practice and curriculum design, highlighting the importance of addressing barriers and fostering positive coding attitudes among all students. The authors' findings highlight the need to reconsider the coding content within the computing curriculum in England, as certain groups of young people, including girls, will continue to be less well represented in this subject.

Through interpretations of remote-sensing data and/or theoretical propositions, the idea that forest and savanna represent "alternative stable states" is gaining increasing acceptance. Filling an observational gap, we present detailed stratified floristic and structural analyses for forest and savanna stands located mostly within zones of transition (where both vegetation types occur in close proximity) in Africa, South America and Australia. Woody plant leaf area index variation was related to tree canopy cover in a similar way for both savanna and forest with substantial overlap between the two vegetation types. As total woody plant canopy cover increased, so did the relative contribution of middle and lower strata of woody vegetation. Herbaceous layer cover declined as woody cover increased. This pattern of understorey grasses and herbs progressively replaced by shrubs as the canopy closes over was found for both savanna and forests and on all continents. Thus, once subordinate woody canopy layers are taken into account, a less marked transition in woody plant cover across the savanna–forest-species discontinuum is observed compared to that inferred when trees of a basal diameter > 0.1 m are considered in isolation. This is especially the case for shrub-dominated savannas and in taller savannas approaching canopy closure. An increased contribution of forest species to the total subordinate cover is also observed as savanna stand canopy closure occurs. Despite similarities in canopy-cover characteristics, woody vegetation in Africa and Australia attained greater heights and stored a greater amount of above-ground biomass than in South America. Up to three times as much above-ground biomass is stored in forests compared to savannas under equivalent climatic conditions. Savanna–forest transition zones were also found to typically occur at higher precipitation regimes for South America than for Africa. Nevertheless, consistent across all three continents coexistence was found to be confined to a well-defined edaphic–climate envelope with soil and climate the key determinants of the relative location of forest and savanna stands. Moreover, when considered in conjunction with the appropriate water availability metrics, it emerges that soil exchangeable cations exert considerable control on woody canopy-cover extent as measured in our pan-continental (forest + savanna) data set. Taken together these observations do not lend support to the notion of alternate stable states mediated through fire feedbacks as the prime force shaping the distribution of the two dominant vegetation types of the tropical lands.

Tropical tree height-diameter (H:D) relationships may vary by forest type and region making large-scale estimates of above-ground biomass subject to bias if they ignore these differences in stem allometry. We have therefore developed a new global tropical forest database consisting of 39 955 concurrent H and D measurements encompassing 283 sites in 22 tropical countries. Utilising this database, our objectives were: 1. to determine if H:D relationships differ by geographic region and forest type (wet to dry forests, including zones of tension where forest and savanna overlap). 2. to ascertain if the H:D relationship is modulated by climate and/or forest structural characteristics (e.g. stand-level basal area, A). 3. to develop H:D allometric equations and evaluate biases to reduce error in future local-to-global estimates of tropical forest biomass. Annual precipitation coefficient of variation (PV), dry season length (SD), and mean annual air temperature (TA) emerged as key drivers of variation in H:D relationships at the pantropical and region scales. Vegetation structure also played a role with trees in forests of a high A being, on average, taller at any given D. After the effects of environment and forest structure are taken into account, two main regional groups can be identified. Forests in Asia, Africa and the Guyana Shield all have, on average, similar H:D relationships, but with trees in the forests of much of the Amazon Basin and tropical Australia typically being shorter at any given D than their counterparts elsewhere. The region-environment-structure model with the lowest Akaike's information criterion and lowest deviation estimated stand-level H across all plots to within amedian −2.7 to 0.9% of the true value. Some of the plot-to-plot variability in H:D relationships not accounted for by this model could be attributed to variations in soil physical conditions. Other things being equal, trees tend to be more slender in the absence of soil physical constraints, especially at smaller D. Pantropical and continental-level models provided less robust estimates of H, especially when the roles of climate and stand structure in modulating H:D allometry were not simultaneously taken into account.

Abstract. Background:. Patients with schizophrenia (SCZ) and major depressive disorder (MDD) share significant clinical overlap, although it remains unknown to what extent this overlap reflects shared neural profiles. To identify the shared and specific abnormalities in SCZ and MDD, we performed a whole-brain voxel-based meta-analysis using magnetization transfer imaging, a technique that characterizes the macromolecular structural integrity of brain tissue in terms of the magnetization transfer ratio (MTR). Methods:. A systematic search based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in PubMed, EMBASE, International Scientific Index (ISI) Web of Science, and MEDLINE for relevant studies up to March 2022. Two researchers independently screened the articles. Rigorous scrutiny and data extraction were performed for the studies that met the inclusion criteria. Voxel-wise meta-analyses were conducted using anisotropic effect size-signed differential mapping with a unified template. Meta-regression was used to explore the potential effects of demographic and clinical characteristics. Results:. A total of 15 studies with 17 datasets describing 365 SCZ patients, 224 MDD patients, and 550 healthy controls (HCs) were identified. The conjunction analysis showed that both disorders shared higher MTR than HC in the left cerebellum (P=0.0006) and left fusiform gyrus (P=0.0004). Additionally, SCZ patients showed disorder-specific lower MTR in the anterior cingulate/paracingulate gyrus, right superior temporal gyrus, and right superior frontal gyrus, and higher MTR in the left thalamus, precuneus/cuneus, posterior cingulate gyrus, and paracentral lobule; and MDD patients showed higher MTR in the left middle occipital region. Meta-regression showed no statistical significance in either group. Conclusions:. The results revealed a structural neural basis shared between SCZ and MDD patients, emphasizing the importance of shared neural substrates across psychopathology. Meanwhile, distinct disease-specific characteristics could have implications for future differential diagnosis and targeted treatment.

Abstract Vicarious traumatization (VT), a negative reaction to witnessing others’ trauma, has been experienced by some people during the COVID-19 pandemic, and can lead to mental health problems. This study aimed to identify functional brain markers of COVID-specific VT and explore the psychological mechanism underlying the brain-VT link. One hundred healthy participants underwent resting-state functional magnetic resonance imaging before the pandemic (October 2019–January 2020) and completed VT measurement during the pandemic (February–April 2020). Whole-brain correlation analysis based on global functional connectivity density (FCD) mapping revealed that VT was negatively correlated with FCD in the right inferior temporal gyrus (ITG) (i.e., the lower FCD in ITG, the worse the VT), identified by mapping onto known large-scale networks as part of the default-mode network (DMN). Resting-state functional connectivity (RSFC) analysis using ITG as seed found that VT was predicted by lower functional connectivity between ITG and other DMN regions including left medial prefrontal cortex, left orbitofrontal cortex, right superior frontal gyrus, right inferior parietal lobule and bilateral precuneus (i.e., the lower the ITG-DMN connectivity, the worse the VT). Mediation analyses suggested that psychological resilience served as a mediator in these associations of ITG FCD and ITG-DMN RSFC with VT. Our results provide novel evidence on the brain basis of VT and emphasize psychological resilience as an important link from DMN functional connectivity to COVID-specific-VT. This may facilitate public health interventions by helping identify individuals at risk of stress- and trauma-related psychopathologies.

Abstract Background Health benefits have been linked with physical activity (PA), as well as some domains of PA among youth (e.g. organized PA and active transport). However, less is known about whether some PA domains are more beneficial than others. There is also a lack of evidence about whether health outcomes are related to the composition of PA (i.e. the share of PA spent in different domains). This study aimed to identify: (1) how the absolute durations of organized PA, non-organized PA, active transport and active chores/work at 10-11y are individually associated with physical, psychosocial and total health-related quality of life (HRQOL) at 10-11y and 12-13y; and (2) how the domain-specific composition of PA at 10-11y is associated with HRQOL at 10-11y and 12-13y. Methods Data from the Longitudinal Study of Australian Children were used in cross-sectional (n ≥ 2730) and longitudinal analyses (n ≥ 2376). Measurement included the Pediatric Quality of Life Inventory (PedsQL™) for HRQOL domains and one-day time-use diaries (TUDs) for PA domains. Robust linear regression models were used, controlling for age, sex, pubertal status, socioeconomic position, body mass index and TUD context (season and school attendance). Compositional models additionally adjusted for total PA duration and longitudinal models controlled for baseline PedsQL™ scores. Results Non-compositional models indicated that the duration of organized PA, and to a lesser extent non-organized PA, were positively but weakly associated with some HRQOL outcomes at 10-11y. These trends were not reflected in longitudinal models, although a 30-min increase in non-organized PA per day did predict marginally better psychosocial HRQOL at 12-13y (+ 0.17%; 95%CI = + 0.03%, + 0.32%). Compositional models revealed that a 30-min increase in organized PA relative to other domains was positively but weakly associated with physical (+ 0.32%; 95%CI = + 0.01%, + 0.63%), psychosocial (+ 0.41%; 95%CI = + 0.11%, + 0.72%) and total HRQOL (+ 0.39%; 95%CI = + 0.12%, + 0.66%) at 10-11y. However, the overall PA composition at 10-11y was not related to HRQOL at 12-13y. Conclusions Non-compositional and compositional models generally concurred on the direction of cross-sectional and longitudinal relationships (and lack thereof) between PA domains and HRQOL outcomes. The strongest associations were cross-sectional between organized PA and HRQOL at 10-11y. However, all associations between PA domains and HRQOL outcomes were weak and may not be clinically meaningful.

Abstract Low-grade serous ovarian cancer (LGSOC) typically responds poorly to standard platinum-based chemotherapy and new therapeutic approaches are needed. We describe a remarkable response to targeted therapy in a patient with platinum-resistant, advanced LGSOC who had failed standard-of-care chemotherapy and two surgeries. The patient was in rapid decline and entering hospice care on home intravenous (i.v.) opioid analgesics and a malignant bowel obstruction requiring a G-tube. Genomic analysis of the patient’s tumor did not indicate obvious therapeutic options. In contrast, a CLIA-certified drug sensitivity assay of an organoid culture derived from the patient’s tumor identified several therapeutic choices, including Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, as well as the EGFR inhibitors afatinib and erlotinib. Following off-label administration of daily ibrutinib as monotherapy, the patient had an exceptional clinical turnaround over the following 65 weeks with normalization of CA-125 levels, resolution of the malignant bowel obstruction, halting of pain medications, and improvement of performance status from ECOG 3 to ECOG 1. After 65 weeks of stable disease, the patient’s CA-125 levels began to rise, at which point the patient discontinued ibrutinib and began taking afatinib as monotherapy. The patient’s CA-125 levels remained stable for an additional 38 weeks but due to anemia and rising CA-125 levels, the patient switched to erlotinib and is currently being monitored. This case highlights the clinical utility of ex vivo drug testing of patient-derived tumor organoids as a new functional precision medicine approach to identify effective personalized therapies for patients who have failed standard-of-care treatments.

Novel measurements of clay hydroxyl isotopic composition show an enhanced hydrological cycle during a period of intense global warming at the Paleocene-Eocene boundary 55.9 million years ago.

Certain aspects of the immunogenicity and effectiveness of the messenger ribonucleic acid (mRNA) vaccines (mRNA-1273 and BNT162b2) developed in response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are still uncharacterized. Serum or plasma samples from healthy donor recipients of either vaccine (BNT162b2 n = 53, mRNA-1273 n = 49; age 23–67), and individuals naturally infected with SARS-CoV-2 (n = 106; age 18–82) were collected 0–2 months post-infection or 1- and 4 months after second dose of vaccination. Anti-Spike antibody levels and avidity were measured via an enzyme-linked immunosorbent assay (ELISA). Overall, vaccination induced higher circulating anti-Spike protein immunoglobulin G (IgG) antibody levels and avidity compared to infection at similar time intervals. Both vaccines produced similar anti-Spike IgG concentrations at 1 month, while mRNA-1273 demonstrated significantly higher circulating antibody concentrations after 4 months. mRNA-1273 induced significantly higher avidity at month 1 compared to BNT162b2 across all age groups. However, the 23–34 age group was the only group to maintain statistical significance by 4 months. Male BNT162b2 recipients were approaching statistically significant lower anti-Spike IgG avidity compared to females by month 4. These findings demonstrate enhanced anti-Spike IgG levels and avidity following vaccination compared to natural infection. In addition, the mRNA-1273 vaccine induced higher antibody levels by 4 months compared to BNT162b2.

The HPV Serology Laboratory is leading a global partnership initiative aiming for standardization and harmonization of current serology assay platforms being used to assess immune responses to HPV vaccines. Serology standardization is particularly important given the increasing number of immunobridging trials relying on serology data for approval of new vaccine dosing schedules or vaccine formulations. The initiative was established in 2017 to enable comparisons of data between different vaccines and relevant studies as well as expedite the implementation of new vaccines and vaccine indications. The HPV Serology Laboratory has held or attended several meetings with partnering laboratories, including international meetings in 2017, 2018, and 2021.

ABSTRACT The Coronavirus disease 2019 (COVID-19) pandemic presented the scientific community with an immediate need for accurate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology assays, resulting in an expansion of assay development, some without following a rigorous quality control and validation, and with a wide range of performance characteristics. Vast amounts of data have been gathered on SARS-CoV-2 antibody response; however, performance and ability to compare the results have been challenging. This study seeks to analyze the reliability, sensitivity, specificity, and reproducibility of a set of widely used commercial, in-house, and neutralization serology assays, as well as provide evidence for the feasibility of using the World Health Organization (WHO) International Standard (IS) as a harmonization tool. This study also seeks to demonstrate that binding immunoassays may serve as a practical alternative for the serological study of large sample sets in lieu of expensive, complex, and less reproducible neutralization assays. In this study, commercial assays demonstrated the highest specificity, while in-house assays excelled in antibody sensitivity. As expected, neutralization assays demonstrated high levels of variability but overall good correlations with binding immunoassays, suggesting that binding may be reasonably accurate as well as practical for the study of SARS-CoV-2 serology. All three assay types performed well after WHO IS standardization. The results of this study demonstrate there are high performing serology assays available to the scientific community to rigorously dissect antibody responses to infection and vaccination. IMPORTANCE Previous studies have shown significant variability in SARS-CoV-2 antibody serology assays, highlighting the need for evaluation and comparison of these assays using the same set of samples covering a wide range of antibody responses induced by infection or vaccination. This study demonstrated that there are high performing assays that can be used reliably to evaluate immune responses to SARS-CoV-2 in the context of infection and vaccination. This study also demonstrated the feasibility of harmonizing these assays against the International Standard and provided evidence that the binding immunoassays may have high enough correlation with the neutralization assays to serve as a practical proxy. These results represent an important step in standardizing and harmonizing the many different serological assays used to evaluate COVID-19 immune responses in the population.

Abstract Background Sarcopenia is an age‐related loss of skeletal muscle mass (SMM) and function, associated with falls, frailty, and functional decline. It is more prevalent and often accelerated in people with Type 2 diabetes (T2D), especially when co‐existing with obesity (sarcopenic obesity). Accurate whole‐body SMM measurement, feasible using dual‐energy X‐ray absorptiometry (DXA) or magnetic resonance imaging (MRI), has utility both in clinical practice and in epidemiological and mechanistic research, considering the dual mechanical and metabolic function of skeletal muscle. Compared with MRI, DXA may underestimate age‐related muscle mass by up to 30%, and so direct comparison of DXA/MRI‐derived SMM measurements may be invalid in patients with obesity and T2D, who have potentially even more pronounced sarcopenia/sarcopenic obesity. We aimed to validate single‐slice or multiple‐slice measures of SMM, using MRI, with whole‐body SMM measures derived from DXA scans of appendicular lean soft tissue, specifically in patients with obesity and T2D. Methods We undertook a cross‐sectional study in which we performed paired DXA and whole‐body 3.0‐T MRI on 36 people with T2D and obesity (body mass index [BMI] > 30 kg/m2). Single‐slice and seven‐slice estimates of muscle mass, taken from mid‐thigh/thigh MRI images, respectively, were determined, and compared with whole‐body SMM derived from DXA scans of appendicular lean soft tissue, in men and women separately. Results Seventeen men (age 48.4 ± 8.2 years, BMI 37.5 ± 5.1 kg/m2, body fat 39.1 ± 6.0%) and 19 women (age 51.8 years ± 9.7, BMI 37.8 ± 5.8 kg/m2, body fat 47.6 ± 5.1%) were recruited. Whole‐body SMM estimated by seven‐slice thigh MRI correlated strongly with DXA‐derived SMM in both men (r = 0.94, P

Abstract Background Physical activity (PA) participation among youth tends to be insufficient and is prone to decline with age. In Australia, this decline has been shown to particularly occur in the domain of non-organized PA (e.g. active play and informal sport) between childhood and adolescence. However, information about changes in more specific groupings of activities within non-organized PA (i.e. subdomains) is needed, as this could support more targeted intervention strategies. This study aimed to investigate changes in the duration of specific subdomains of non-organized PA between late childhood (10–11 years) and early adolescence (12–13 years) in Australia, as well as whether these changes are moderated by sex. Methods Data were sourced from Waves 6 and 7 of the Longitudinal Study of Australian Children (n = 3614). Youth time-use diaries (24-h) were used to measure the duration of eight subdomains of non-organized PA at both waves (athletics/gymnastics, ball sports, cycling/motor/roller sports, fitness/gym/exercise, martial arts/dancing, water/ice/snow sports, active play and other outdoor/nature PA). Multilevel mixed modelling was used to explore longitudinal changes between waves and the potential moderation effect of sex. Results Active play declined the most of all subdomains (β = –20.5 min/day; 95% CI = –23.4, –17.6, p

BackgroundThe global epidemic of type 2 diabetes (T2D) and obesity has been translated into pregnancy, with approximately 18% of women being diagnosed worldwide with Gestational Diabetes Mellitus (GDM). Whilst preventive strategies have proven effective in the non-pregnant context, attrition rates are high and there is an urgent need to develop a customized, pragmatic lifestyle intervention for women both during and after pregnancy. Diet and exercise modification, behavioral support, and Commercial Weight Management Organizations have been strongly recommended to aid postpartum weight reduction for mothers with previous GDM, subsequently reducing their risk of developing obesity and T2D. This study, informed by a previous pilot study, aims to determine the effectiveness of a pragmatic pregnancy and postpartum lifestyle modification program for overweight women with previous GDM (PAIGE2) to reduce body weight at 12 months postpartum.Methods/designThis paper summarizes the protocol for the PAIGE2 study, which has been developed based on results from a pilot study (PAIGE). A six center, two parallel arm, 12-month, randomized controlled trial will be conducted across Northern Ireland and the Republic of Ireland (3 centers each), involving 340 women with GDM and body mass index ≥25 kg/m2 recruited during pregnancy. The lifestyle intervention involves a one-hour virtual educational program (to take place at 32-36 weeks gestation). Postpartum, the intervention will include monthly phone calls, weekly motivational text messages, weekly step counts, and referral for three months to a Commercial Weight Management Organization (Slimming World). The control arm will receive usual care as offered by the local maternity hospital. The primary outcome is weight loss at 12 months postpartum. Study visits for anthropometric and clinical measurements, fasting blood samples, questionnaires pertaining to health, wellbeing and physical activity will take place at 6 weeks, 6- and 12-months postpartum. Focus groups will be conducted with intervention mothers’ post-intervention to determine the acceptability of the study design including utility of a Commercial Weight Management Organization, feasibility of remote patient contact, family involvement and patient satisfaction.DiscussionThe PAIGE2 study will address the gaps in previously conducted research and, if positive, has the potential to have major public health implications for the prevention of future GDM and subsequent T2D.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04579016?term=NCT04579016&draw=2&rank=1, identifier NCT04579016.

Abstract β2-adrenoreceptor (β2AR) agonists have been associated with a decreased risk of developing Parkinson’s disease (PD) and are hypothesized to decrease expression of both alpha-synuclein mRNA (Snca) and protein (α-syn). Effects of β2AR agonist clenbuterol on the levels of Snca mRNA and α-syn protein were evaluated in vivo (rats and mice) and in rat primary cortical neurons by two independent laboratories. A modest decrease in Snca mRNA in the substantia nigra was observed after a single acute dose of clenbuterol in rats, however, this decrease was not maintained after multiple doses. In contrast, α-syn protein levels remained unchanged in both single and multiple dosing paradigms. Furthermore, clenbuterol did not decrease Snca in cultured rat primary cortical neurons, or decrease Snca or α-syn in mice. Additionally, compared to the single-dose paradigm, repeat dosing resulted in substantially lower levels of clenbuterol in plasma and brain tissue in rodents. Based on our observations of a transient decrease in Snca and no effect on α-syn protein in this preclinical study, these data support the conclusion that clenbuterol is not likely a viable disease-modifying strategy for PD.

Prostate‐specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68Ga‐PSMA‐11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68Ga‐PSMA‐11 PET was prospectively performed in patients with treatment‐naïve HCC on a digital PET scanner using cyclotron‐produced 68Ga. Uptake was graded qualitatively and semi‐quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P

Synthetic lethal interactions (SLIs), genetic interactions in which the simultaneous inactivation of two genes leads to a lethal phenotype, are promising targets for therapeutic intervention in cancer, as exemplified by the recent success of PARP inhibitors in treating BRCA1/2-deficient tumors. We present SL-Cloud, a new component of the Institute for Systems Biology Cancer Gateway in the Cloud (ISB-CGC), that provides an integrated framework of cloud-hosted data resources and curated workflows to enable facile prediction of SLIs. This resource addresses two main challenges related to SLI inference: the need to wrangle and preprocess large multi-omic datasets and the availability of multiple comparable prediction approaches. SL-Cloud enables customizable computational inference of SLIs and testing of prediction approaches across multiple datasets. We anticipate that cancer researchers will find utility in this tool for discovery of SLIs to support further investigation into potential drug targets for anticancer therapies.