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We use a high-precision radial velocity survey of FGKM stars to study the conditional occurrence of two classes of planets: close-in small planets (0.023–1 au, 2–30 M ⊕) and distant giant planets (0.23–10 au, 30–6000 M ⊕). We find that 41−13+15% of systems with a close-in, small planet also host an outer giant, compared to 17.6−1.9+2.4% for stars irrespective of small planet presence. This implies that small planet hosts may be enhanced in outer giant occurrences compared to all stars with 1.7σ significance. Conversely, we estimate that 42−13+17% of cold giant hosts also host an inner small planet, compared to 27.6−4.8+5.8% of stars irrespective of cold giant presence. We also find that more massive and close-in giant planets are not associated with small inner planets. Specifically, our sample indicates that small planets are less likely to have outer giant companions more massive than approximately 120 M ⊕ and within 0.3–3 au, than to have less massive or more distant giant companions, with ∼2.2σ confidence. This implies that massive gas giants within 0.3–3 au may suppress inner small planet formation. Additionally, we compare the host-star metallicity distributions for systems with only small planets and those with both small planets and cold giants. In agreement with previous studies, we find that stars in our survey that only host small planets have a metallicity distribution that is consistent with the broader solar-metallicity-median sample, while stars that host both small planets and gas giants are distinctly metal rich with ∼2.3σ confidence.

Abstract Rationale Limited data exist about the international burden of severe sepsis in critically ill children. Objectives To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials. Methods A point prevalence study was conducted on 5 days throughout 2013–2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality. Measurements and Main Results Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6–8.9%). The patients’ median age was 3.0 (interquartile range [IQR], 0.7–11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0–25), and vasoactive-free days were 23 (IQR, 12–28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5–10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,437 patients per group. Conclusions Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted.

Cellular metabolites, such as acyl-CoA, can modify proteins, leading to protein posttranslational modifications (PTMs). One such PTM is lysine succinylation, which is regulated by sirtuin 5 (SIRT5). Although numerous proteins are modified by lysine succinylation, the physiological significance of lysine succinylation and SIRT5 remains elusive. Here, by profiling acyl-CoA molecules in various mouse tissues, we have discovered that different tissues have different acyl-CoA profiles and that succinyl-CoA is the most abundant acyl-CoA molecule in the heart. This interesting observation has prompted us to examine protein lysine succinylation in different mouse tissues in the presence and absence of SIRT5. Protein lysine succinylation predominantly accumulates in the heart when Sirt5 is deleted. Using proteomic studies, we have identified many cardiac proteins regulated by SIRT5. Our data suggest that ECHA, a protein involved in fatty acid oxidation, is a major enzyme that is regulated by SIRT5 and affects heart function. Sirt5 knockout (KO) mice have lower ECHA activity, increased long-chain acyl-CoAs, and decreased ATP in the heart under fasting conditions. Sirt5 KO mice develop hypertrophic cardiomyopathy, as evident from the increased heart weight relative to body weight, as well as reduced shortening and ejection fractions. These findings establish that regulating heart metabolism and function is amajor physiological function of lysine succinylation and SIRT5.

As the number of potential supplementary cementitious materials (SCMs) increase, there is a need to determine their reactivity. Most recent methods to assess pozzolanic reactivity are based on measuring certain outputs such as heat release (Q), calcium hydroxide (CH) consumption, and nonevaporable water. This paper uses thermodynamic modeling to aid in the interpretation of these tests and the quantifcation of reactivity. It is shown that pozzolanic reactivity should be interpreted based on the SCM type. The presence of sulfates and carbonates during reactivity quantification alter the reaction of the [Al.sub.2][O.sub.3] phases, making the interpretation of the reactivity test results challenging. The reactivity of commercial SCMs should be interpreted specific to the type of SCM as described by ASTM International/AASHTO. A proposed interpretation for commercial SCMs is provided in this paper. Keywords: pozzolanic reactivity test (PRT); reactivity; supplementary cementitious materials (SCMs); thermodynamic modeling.

Background: Chronic kidney disease of non-traditional origin (CKDnt) is common among Mesoamerican sugarcane workers. Recurrent heat stress and dehydration is a leading hypothesis. Evidence indicate a key role of inflammation. Methods: Starting in sports and heat pathophysiology literature, we develop a theoretical framework of how strenuous work in heat could induce kidney inflammation. We describe the release of pro-inflammatory substances from a leaky gut and/or injured muscle, alone or in combination with tubular fructose and uric acid, aggravation by reduced renal blood flow and increased tubular metabolic demands. Then, we analyze longitudinal data from >800 sugarcane cutters followed across harvest and review the CKDnt literature to assess empirical support of the theoretical framework. Results: Inflammation (CRP elevation and fever) and hyperuricemia was tightly linked to kidney injury. Rehydrating with sugary liquids and NSAID intake increased the risk of kidney injury, whereas electrolyte solution consumption was protective. Hypokalemia and hypomagnesemia were associated with kidney injury. Discussion: Heat stress, muscle injury, reduced renal blood flow and fructose metabolism may induce kidney inflammation, the successful resolution of which may be impaired by daily repeating pro-inflammatory triggers. We outline further descriptive, experimental and intervention studies addressing the factors identified in this study.

Antibody cocktails represent a promising approach to prevent SARS-CoV-2 escape. The determinants for selecting antibody combinations and the mechanism that antibody cocktails prevent viral escape remain unclear. We compared the critical residues in the receptor-binding domain (RBD) used by multiple neutralizing antibodies and cocktails and identified a combination of two antibodies CoV2-06 and CoV2-14 for preventing viral escape. The two antibodies simultaneously bind to non-overlapping epitopes and independently compete for receptor binding. SARS-CoV-2 rapidly escapes from individual antibodies by generating resistant mutations in vitro, but it doesn’t escape from the cocktail due to stronger mutational constraints on RBD-ACE2 interaction and RBD protein folding requirements. We also identified a conserved neutralizing epitope shared between SARS-CoV-2 and SARS-CoV for antibody CoV2-12. Treatments with CoV2-06 and CoV2-14 individually and in combination confer protection in mice. These findings provide insights for rational selection and mechanistic understanding of antibody cocktails as candidates for treating COVID-19. Antibody cocktails represent a promising approach to prevent SARS-CoV-2 escape. Here, Ku et al., identify SARS-CoV-2 neutralizing antibodies from a phage library and identify an antibody combination that prevents viral escape and protects mice from viral challenge.