Gravity waves and the LHC: Towards high-scale inflation with low-energy SUSY

It has been argued that rather generic features of string-inspired inflationary theories with low-energy supersymmetry (SUSY) make it difficult to achieve inflation with a Hubble scale H > m_{3/2}, where m_{3/2} is the gravitino mass in the SUSY-breaking vacuum state. We present a class of string-inspired supergravity realizations of chaotic inflation where a simple, dynamical mechanism yields hierarchically small scales of post-inflationary supersymmetry breaking. Within these toy models we can easily achieve small ratios between m_{3/2} and the Hubble scale of inflation. This is possible because the expectation value of the superpotential relaxes from large to small values during the course of inflation. However, our toy models do not provide a reasonable fit to cosmological data if one sets the SUSY-breaking scale to m_{3/2} < TeV. Our work is a small step towards relieving the apparent tension between high-scale inflation and low-scale supersymmetry breaking in string compactifications.Comment: 21+1 pages, 5 figures, LaTeX, v2: added references, v3: very minor changes, version to appear in JHE

Spontaneous Creation of Inflationary Universes and the Cosmic Landscape

We study some gravitational instanton solutions that offer a natural realization of the spontaneous creation of inflationary universes in the brane world context in string theory. Decoherence due to couplings of higher (perturbative) modes of the metric as well as matter fields modifies the Hartle-Hawking wavefunction for de Sitter space. Generalizing this new wavefunction to be used in string theory, we propose a principle in string theory that hopefully will lead us to the particular vacuum we live in, thus avoiding the anthropic principle. As an illustration of this idea, we give a phenomenological analysis of the probability of quantum tunneling to various stringy vacua. We find that the preferred tunneling is to an inflationary universe (like our early universe), not to a universe with a very small cosmological constant (i.e., like today's universe) and not to a 10-dimensional uncompactified de Sitter universe. Such preferred solutions are interesting as they offer a cosmological mechanism for the stabilization of extra dimensions during the inflationary epoch.Comment: 52 pages, 7 figures, 1 table. Added discussion on supercritical string vacua, added reference

Spinflation with Angular Potentials

We investigate in detail the cosmological consequences of realistic angular dependent potentials in the brane inflation scenario. Embedding a warped throat into a compact Calabi-Yau space with all moduli stabilized breaks the no-scale structure and induces angular dependence in the potential of the probe D3-brane. We solve the equations of motion from the DBI action in the warped deformed conifold including linearized perturbations around the imaginary self-dual solution. Our numerical solutions show that angular dependence is a next to leading order correction to the dominant radial motion of the brane, however, just as angular motion typically increases the amount of inflation (spinflation), having additional angular dependence also increases the amount of inflation. We also derive an analytic approximation for the number of e-foldings along the DBI trajectory in terms of the compactification parameters.Comment: 20 pages, 10 figures. Revised to published version: minor errors corrected, references and discussion adde

Advances in Malaria Pharmacology and the online Guide to MALARIA PHARMACOLOGY: IUPHAR Review X

Antimalarial drug discovery has until recently been driven by high-throughput phenotypic cellular screening, allowing millions of compounds to be assayed and delivering clinical drug candidates. In this review, we will focus on target-based approaches, describing recent advances in our understanding of druggable targets in the malaria parasite. Targeting multiple stages of the Plasmodium lifecycle, rather than just the clinically symptomatic asexual blood stage, has become a requirement for new antimalarial medicines, and we link pharmacological data clearly to the parasite stages to which it applies. Finally, we highlight the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY, a web resource developed for the malaria research community that provides open and optimized access to published data on malaria pharmacology

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all &gt;0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

State of the climate in 2018

In 2018, the dominant greenhouse gases released into Earth’s atmosphere—carbon dioxide, methane, and nitrous oxide—continued their increase. The annual global average carbon dioxide concentration at Earth’s surface was 407.4 ± 0.1 ppm, the highest in the modern instrumental record and in ice core records dating back 800 000 years. Combined, greenhouse gases and several halogenated gases contribute just over 3 W m−2 to radiative forcing and represent a nearly 43% increase since 1990. Carbon dioxide is responsible for about 65% of this radiative forcing. With a weak La Niña in early 2018 transitioning to a weak El Niño by the year’s end, the global surface (land and ocean) temperature was the fourth highest on record, with only 2015 through 2017 being warmer. Several European countries reported record high annual temperatures. There were also more high, and fewer low, temperature extremes than in nearly all of the 68-year extremes record. Madagascar recorded a record daily temperature of 40.5°C in Morondava in March, while South Korea set its record high of 41.0°C in August in Hongcheon. Nawabshah, Pakistan, recorded its highest temperature of 50.2°C, which may be a new daily world record for April. Globally, the annual lower troposphere temperature was third to seventh highest, depending on the dataset analyzed. The lower stratospheric temperature was approximately fifth lowest. The 2018 Arctic land surface temperature was 1.2°C above the 1981–2010 average, tying for third highest in the 118-year record, following 2016 and 2017. June’s Arctic snow cover extent was almost half of what it was 35 years ago. Across Greenland, however, regional summer temperatures were generally below or near average. Additionally, a satellite survey of 47 glaciers in Greenland indicated a net increase in area for the first time since records began in 1999. Increasing permafrost temperatures were reported at most observation sites in the Arctic, with the overall increase of 0.1°–0.2°C between 2017 and 2018 being comparable to the highest rate of warming ever observed in the region. On 17 March, Arctic sea ice extent marked the second smallest annual maximum in the 38-year record, larger than only 2017. The minimum extent in 2018 was reached on 19 September and again on 23 September, tying 2008 and 2010 for the sixth lowest extent on record. The 23 September date tied 1997 as the latest sea ice minimum date on record. First-year ice now dominates the ice cover, comprising 77% of the March 2018 ice pack compared to 55% during the 1980s. Because thinner, younger ice is more vulnerable to melting out in summer, this shift in sea ice age has contributed to the decreasing trend in minimum ice extent. Regionally, Bering Sea ice extent was at record lows for almost the entire 2017/18 ice season. For the Antarctic continent as a whole, 2018 was warmer than average. On the highest points of the Antarctic Plateau, the automatic weather station Relay (74°S) broke or tied six monthly temperature records throughout the year, with August breaking its record by nearly 8°C. However, cool conditions in the western Bellingshausen Sea and Amundsen Sea sector contributed to a low melt season overall for 2017/18. High SSTs contributed to low summer sea ice extent in the Ross and Weddell Seas in 2018, underpinning the second lowest Antarctic summer minimum sea ice extent on record. Despite conducive conditions for its formation, the ozone hole at its maximum extent in September was near the 2000–18 mean, likely due to an ongoing slow decline in stratospheric chlorine monoxide concentration. Across the oceans, globally averaged SST decreased slightly since the record El Niño year of 2016 but was still far above the climatological mean. On average, SST is increasing at a rate of 0.10° ± 0.01°C decade−1 since 1950. The warming appeared largest in the tropical Indian Ocean and smallest in the North Pacific. The deeper ocean continues to warm year after year. For the seventh consecutive year, global annual mean sea level became the highest in the 26-year record, rising to 81 mm above the 1993 average. As anticipated in a warming climate, the hydrological cycle over the ocean is accelerating: dry regions are becoming drier and wet regions rainier. Closer to the equator, 95 named tropical storms were observed during 2018, well above the 1981–2010 average of 82. Eleven tropical cyclones reached Saffir–Simpson scale Category 5 intensity. North Atlantic Major Hurricane Michael’s landfall intensity of 140 kt was the fourth strongest for any continental U.S. hurricane landfall in the 168-year record. Michael caused more than 30 fatalities and $25 billion (U.S. dollars) in damages. In the western North Pacific, Super Typhoon Mangkhut led to 160 fatalities and$6 billion (U.S. dollars) in damages across the Philippines, Hong Kong, Macau, mainland China, Guam, and the Northern Mariana Islands. Tropical Storm Son-Tinh was responsible for 170 fatalities in Vietnam and Laos. Nearly all the islands of Micronesia experienced at least moderate impacts from various tropical cyclones. Across land, many areas around the globe received copious precipitation, notable at different time scales. Rodrigues and Réunion Island near southern Africa each reported their third wettest year on record. In Hawaii, 1262 mm precipitation at Waipā Gardens (Kauai) on 14–15 April set a new U.S. record for 24-h precipitation. In Brazil, the city of Belo Horizonte received nearly 75 mm of rain in just 20 minutes, nearly half its monthly average. Globally, fire activity during 2018 was the lowest since the start of the record in 1997, with a combined burned area of about 500 million hectares. This reinforced the long-term downward trend in fire emissions driven by changes in land use in frequently burning savannas. However, wildfires burned 3.5 million hectares across the United States, well above the 2000–10 average of 2.7 million hectares. Combined, U.S. wildfire damages for the 2017 and 2018 wildfire seasons exceeded $40 billion (U.S. dollars)

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Sedimentary response to a collision orogeny recorded in detrital zircon provenance of Greater Caucasus foreland basin sediments

The Greater Caucasus orogen on the southern margin of Eurasia is hypothesized to be a young collisional system and may present an opportunity to probe the structural, sedimentary and geodynamic effects of continental collision. We present detrital zircon U‐Pb age data from the Caucasus region that constrain changes in sediment routing and source exposure during the late Cenozoic convergence and collision between the Greater Caucasus orogen and the Lesser Caucasus, an arc terrane on the lower plate of the system. During Oligocene to Middle Miocene time, following the initiation of deformation within the Greater Caucasus, marine sandstones and shales were deposited between the Greater and Lesser Caucasus, and detrital zircon age data suggest no mixing of Greater Caucasus and Lesser Caucasus detritus. During Middle to Late Miocene time, Greater Caucasus detritus was deposited onto the Lesser Caucasus basin margin, and terrestrial, largely conglomeratic, sedimentation began between the Greater and Lesser Caucasus. Around 5.3 Ma, upper plate exhumation rates increased and shortening migrated to pro‐ and retro‐wedge fold‐thrust belts, coinciding with the initiation of foreland basin erosion. Sediment composition, provenance and structural data from the orogen together suggest the existence of a wide (230–280 km) marine basin that was progressively closed during Oligocene to Late Miocene time, probably by subduction/lithospheric underthrusting beneath the Greater Caucasus, followed by initiation of collision between the Lesser Caucasus arc terrane and the Greater Caucasus in Late Miocene to Pliocene time. The pace of the transition from hypothesized subduction to collision in the Caucasus is consistent with predictions from numerical modeling for a system with moderate convergence rates (<13 mm/yr) and hot lower plate continental lithosphere. Basement crystallization histories implied by our detrital zircon age data suggest the presence of two pre‐Jurassic sutures between stable Eurasia and the Lesser Caucasus, which likely guided later deformation.The Greater Caucasus may constitute a natural example of early continental collision. New detrital zircon U‐Pb geochronology data, together with published Cenozoic stratigraphy and structural data from the Greater Caucasus, suggests collision began in the Late Miocene to Pliocene, leading to diachronous changes in deformation and sedimentation in the orogen and associated basins.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167026/1/bre12499.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167026/2/bre12499-sup-0002-FigS2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167026/3/bre12499-sup-0001-FigS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167026/4/bre12499-sup-0003-FigS3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167026/5/bre12499_am.pd

Risk Factors Associated with 90-day Readmissions Following Odontoid Fractures- A Nationwide Readmissions Database Study.

STUDY DESIGN: Nationwide Readmissions Database Study. OBJECTIVE: To investigate readmission rates and factors related to readmission after surgical and non-surgical management of odontoid fractures. SUMMARY OF BACKGROUND DATA: Management of odontoid fractures, which are the most common isolated spine fracture in the elderly, continues to be debated. The choice between surgical or non-surgical treatment has been reported to impact mortality and might influence readmission rates. Hospital readmissions represent a large financial burden upon our healthcare system. Factors surrounding hospital readmissions, would benefit from a better understanding of their associated causes in order to lower health care costs. METHODS: A retrospective study was performed using the 2016 Healthcare Utilization Project (HCUP) Nationwide Readmission Database (NRD). Demographic information and factors associated with readmission were collected. Readmission rates, complications, length of hospital stay were collected. Patients treated operatively, non-operatively, and patients who were readmitted or not readmitted were compared. Statistical analysis was performed using open source software SciPy (Python v1.3.0) for all analyses. RESULTS: We identified 2,921 patients who presented with Type II dens fractures from January 1st 2016 to September 30th 2016, 555 of which underwent surgical intervention. The readmission rate in patients who underwent surgery was 16.4% (91/555) and 29.4% (696/2366) in the non-operative group. Hospital costs for readmitted and non-readmitted patients were $353,704 and$174,922, and $197,099 and$80,715 for non-operatively managed patients, respectively. Medicaid and Medicare patients had the highest readmission rate in both groups. Charlson and Elixhauser comorbidity indices were significantly higher in patients who were readmitted (p \u3c 0.0001). CONCLUSION: We report an overall 90-day readmission rate of 16.4% and 29.4%, in operative and non-operative management of type II odontoid fractures, respectively. In the face of a rising incidence of this fracture in the elderly population, an understanding of the comorbidities and age-related demographics associated with 90-day readmissions following both surgical and non-surgical treatment are critical.Level of Evidence: 3