Determinants of antibody persistence across doses and continents after single-dose rVSV-ZEBOV vaccination for Ebola virus disease: an observational cohort study.

BACKGROUND: The recombinant vesicular stomatitis virus (rVSV) vaccine expressing the Zaire Ebola virus (ZEBOV) glycoprotein is efficacious in the weeks following single-dose injection, but duration of immunity is unknown. We aimed to assess antibody persistence at 1 and 2 years in volunteers who received single-dose rVSV-ZEBOV in three previous trials. METHODS: In this observational cohort study, we prospectively followed-up participants from the African and European phase 1 rVSV-ZEBOV trials, who were vaccinated once in 2014-15 with 300 000 (low dose) or 10-50 million (high dose) plaque-forming units (pfu) of rVSV-ZEBOV vaccine to assess ZEBOV glycoprotein (IgG) antibody persistence. The primary outcome was ZEBOV glycoprotein-specific IgG geometric mean concentrations (GMCs) measured yearly by ELISA compared with 1 month (ie, 28 days) after immunisation. We report GMCs up to 2 years (Geneva, Switzerland, including neutralising antibodies up to 6 months) and 1 year (Lambaréné, Gabon; Kilifi, Kenya) after vaccination and factors associated with higher antibody persistence beyond 6 months, according to multivariable analyses. Trials and the observational study were registered at ClinicalTrials.gov (Geneva: NCT02287480 and NCT02933931; Kilifi: NCT02296983) and the Pan-African Clinical Trials Registry (Lambaréné PACTR201411000919191). FINDINGS: Of 217 vaccinees from the original studies (102 from the Geneva study, 75 from the Lambaréné study, and 40 from the Kilifi study), 197 returned and provided samples at 1 year (95 from the Geneva study, 63 from the Lambaréné, and 39 from the Kilifi study) and 90 at 2 years (all from the Geneva study). In the Geneva group, 44 (100%) of 44 participants who had been given a high dose (ie, 10-50 million pfu) of vaccine and who were seropositive at day 28 remained seropositive at 2 years, whereas 33 (89%) of 37 who had been given the low dose (ie, 300 000 pfu) remained seropositive for 2 years (p=0·042). In participants who had received a high dose, ZEBOV glycoprotein IgG GMCs decreased significantly between their peak (at 1-3 months) and month 6 after vaccination in Geneva (p0·05). Neutralising antibodies seem to be less durable, with seropositivity dropping from 64-71% at 28 days to 27-31% at 6 months in participants from the Geneva study. INTERPRETATION: Antibody responses to single-dose rVSV-ZEBOV vaccination are sustained across dose ranges and settings, a key criterion in countries where booster vaccinations would be impractical. FUNDING: The Wellcome Trust and Innovative Medicines Initiative 2 Joint Undertaking

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P < 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100 years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

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

Minnesota Farm Business Notes No. 423

Credit Problems in Farm Supply Cooperative

Structural Diversity of Lanthanum–Organic Frameworks Based on 1,4-Phenylenebis(methylene)diphosphonic Acid

The preparation of five different compounds, [La₂(H₂pmd)₃(H₂O)₁₂] (<b>1</b>: 1D), [La₂(H₂pmd)­(pmd)­(H₂O)₂] (<b>2</b>: 3D), [La­(H₃pmd)­(H₂pmd)­(H₂O)] (<b>3</b>: 3D), [La₂(H₂pmd)₃(H₂O)₂] (<b>4</b>: 3D), and [La₂(H₂pmd)­(pmd)­(H₂O)₄] (<b>5</b>: 3D), as crystalline materials from the reaction of 1,4-phenylenebis­(methylene)­diphosphonic acid (H₄pmd) with lanthanum chloride is reported. Two different, fast, and economically viable synthetic approaches were employed with their various parameters being probed and, when possible, optimized to increase yields and purity: microwave-assisted synthesis (MWAS, in ca. 1 min) and a <i>bench</i> procedure using standard ambient conditions (one-pot, ca. 10 min). Compounds <b>1</b> and <b>2</b> were isolated as phase-pure crystalline materials. Compounds <b>3</b> and <b>4</b> were characterized by single-crystal X-ray diffraction from mixtures, and compound <b>5</b> was identified by powder X-ray diffraction studies (also from a physical mixture with <b>2</b>). Structural details for all compounds were investigated by using in tandem X-ray diffraction (single-crystal and powder), electron microscopy (SEM and EDS), and FT-IR spectroscopy. Topological studies were also performed for all 3D networks. The conversion of compound <b>1</b> (1D) into 3D networks was investigated using hydrothermal, microwave, and one-pot methods: <b>1</b> was totally converted into phase-pure <b>2</b> via the hydrothermal method and one-pot method

Structural Diversity of Lanthanum–Organic Frameworks Based on 1,4-Phenylenebis(methylene)diphosphonic Acid

The preparation of five different compounds, [La₂(H₂pmd)₃(H₂O)₁₂] (<b>1</b>: 1D), [La₂(H₂pmd)­(pmd)­(H₂O)₂] (<b>2</b>: 3D), [La­(H₃pmd)­(H₂pmd)­(H₂O)] (<b>3</b>: 3D), [La₂(H₂pmd)₃(H₂O)₂] (<b>4</b>: 3D), and [La₂(H₂pmd)­(pmd)­(H₂O)₄] (<b>5</b>: 3D), as crystalline materials from the reaction of 1,4-phenylenebis­(methylene)­diphosphonic acid (H₄pmd) with lanthanum chloride is reported. Two different, fast, and economically viable synthetic approaches were employed with their various parameters being probed and, when possible, optimized to increase yields and purity: microwave-assisted synthesis (MWAS, in ca. 1 min) and a <i>bench</i> procedure using standard ambient conditions (one-pot, ca. 10 min). Compounds <b>1</b> and <b>2</b> were isolated as phase-pure crystalline materials. Compounds <b>3</b> and <b>4</b> were characterized by single-crystal X-ray diffraction from mixtures, and compound <b>5</b> was identified by powder X-ray diffraction studies (also from a physical mixture with <b>2</b>). Structural details for all compounds were investigated by using in tandem X-ray diffraction (single-crystal and powder), electron microscopy (SEM and EDS), and FT-IR spectroscopy. Topological studies were also performed for all 3D networks. The conversion of compound <b>1</b> (1D) into 3D networks was investigated using hydrothermal, microwave, and one-pot methods: <b>1</b> was totally converted into phase-pure <b>2</b> via the hydrothermal method and one-pot method

Structural Diversity of Lanthanum–Organic Frameworks Based on 1,4-Phenylenebis(methylene)diphosphonic Acid

The preparation of five different compounds, [La₂(H₂pmd)₃(H₂O)₁₂] (<b>1</b>: 1D), [La₂(H₂pmd)­(pmd)­(H₂O)₂] (<b>2</b>: 3D), [La­(H₃pmd)­(H₂pmd)­(H₂O)] (<b>3</b>: 3D), [La₂(H₂pmd)₃(H₂O)₂] (<b>4</b>: 3D), and [La₂(H₂pmd)­(pmd)­(H₂O)₄] (<b>5</b>: 3D), as crystalline materials from the reaction of 1,4-phenylenebis­(methylene)­diphosphonic acid (H₄pmd) with lanthanum chloride is reported. Two different, fast, and economically viable synthetic approaches were employed with their various parameters being probed and, when possible, optimized to increase yields and purity: microwave-assisted synthesis (MWAS, in ca. 1 min) and a <i>bench</i> procedure using standard ambient conditions (one-pot, ca. 10 min). Compounds <b>1</b> and <b>2</b> were isolated as phase-pure crystalline materials. Compounds <b>3</b> and <b>4</b> were characterized by single-crystal X-ray diffraction from mixtures, and compound <b>5</b> was identified by powder X-ray diffraction studies (also from a physical mixture with <b>2</b>). Structural details for all compounds were investigated by using in tandem X-ray diffraction (single-crystal and powder), electron microscopy (SEM and EDS), and FT-IR spectroscopy. Topological studies were also performed for all 3D networks. The conversion of compound <b>1</b> (1D) into 3D networks was investigated using hydrothermal, microwave, and one-pot methods: <b>1</b> was totally converted into phase-pure <b>2</b> via the hydrothermal method and one-pot method

The Sulfur Shift: An Activation Mechanism for Periplasmic Nitrate Reductase and Formate Dehydrogenase

A structural rearrangement known as sulfur shift occurs in some Mo-containing enzymes of the DMSO reductase family. This mechanism is characterized by the displacement of a coordinating cysteine thiol (or SeCys in Fdh) from the first to the second shell of the Mo-coordination sphere metal. The hexa-coordinated Mo ion found in the as-isolated state cannot bind directly any exogenous ligand (substrate or inhibitors), while the penta-coordinated ion, attained upon sulfur shift, has a free binding site for direct coordination of the substrate. This rearrangement provides an efficient mechanism to keep a constant coordination number throughout an entire catalytic pathway. This mechanism is very similar to the carboxylate shift observed in Zn-dependent enzymes, and it has been recently detected by experimental means. In the present paper, we calculated the geometries and energies involved in the sulfur-shift mechanism using QM-methods (M06/(6-311++G­(3df,2pd),SDD)//B3LYP/(6-31G­(d),SDD)). The results indicated that the sulfur-shift mechanism provides an efficient way to enable the metal ion for substrate coordination