Restriction of Intravenous Fluid in ICU Patients with Septic Shock.

BACKGROUND: Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU). METHODS: In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization. RESULTS: We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], -4.7 to 4.9; P = 0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, -1.7 percentage points; 99% CI, -7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups. CONCLUSIONS: Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, NCT03668236.).

How computational chemistry develops: a tribute to Peter Goodford.

This editorial discusses the foundation of aspects of computational chemistry and is a tribute to Peter Goodford, one of those founders, who recently passed away. Several colleagues describe Professor Goodford's work and the person himself.

How medicinal chemists learned about log P.

Although log P is now recognized to be a key factor that determines the bioactivity of a molecule, the focus of medicinal chemists on hydrophobicity and log P started with the quantitative structure-activity relationships (QSAR) publications of Hansch and Fujita. Their original publication represents a dramatic change of focus to incorporate consideration of log P after a decade of work unsuccessfully attempting to use the Hammett equation to explain the structure-activity relationships of plant growth regulators. QSAR allows one to explore the quantitative relationship between log P and biological activity even when other factors also influence potency. In particular, Hansch's publications of thousands of QSAR equations demonstrate that a relationship of biological activity with log P is indeed a general phenomenon. Hansch's group also provided data and tools that enable others to explore the relationship between log P and the biological activity of compounds of interest.

Leaving us with fond memories, smiles, SMILES and, alas, tears: a tribute to David Weininger, 1952-2016.

David Weininger's career, accomplishments, genius, and friendship are warmly remembered by several of his colleagues, friends, and admirers.

Experimental and pKa prediction aspects of tautomerism of drug-like molecules.

Molecules that can tautomerize are a challenge to scientists because one must consider the possible tautomers in most tasks involving chemical structures: for example, searching databases, interpreting experimental property measurements, calculating properties, virtual screening, and analyzing structure-bioactivity relationships. The challenge in interpreting property measurements such as pKa values feeds into the general lack of extensive information not only of the relative tautomer stability in water but also the properties of the individual tautomers. This lack of information results in the lack of reliability of computational predictions of tautomer stability or properties. In spite of these problems, pKa calculations are reliable enough that they can be used to filter out high-energy tautomers from databases used for virtual screening. Continuous improvements in both pKa prediction software and theoretical calculations promise further improvements in solving the challenges of tautomers. The expected availability of high-resolution structures of many more tautomer-protein complexes will help guide the selection of the bioactive tautomer when the structure of the complex is not known.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock.

PURPOSE: To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock included in the European Conservative versus Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care (CLASSIC) trial. METHODS: We conducted the pre-planned analyses of mortality, health-related quality of life (HRQoL) using EuroQol (EQ)-5D-5L index values and EQ visual analogue scale (VAS), and cognitive function using Mini Montreal Cognitive Assessment (Mini MoCA) test at 1 year. Deceased patients were assigned numerical zero for HRQoL as a state equal to death and zero for cognitive function outcomes as worst possible score, and we used multiple imputation for missing data on HRQoL and cognitive function. RESULTS: Among 1554 randomized patients, we obtained 1-year data on mortality in 97.9% of patients, HRQoL in 91.3%, and cognitive function in 86.3%. One-year mortality was 385/746 (51.3%) in the restrictive-fluid group versus 383/767 (49.9%) in the standard-fluid group, absolute risk difference 1.5%-points [99% confidence interval (CI) - 4.8 to 7.8]. Mean differences were 0.00 (99% CI - 0.06 to 0.05) for EQ-5D-5L index values, - 0.65 for EQ VAS (- 5.40 to 4.08), and - 0.14 for Mini MoCA (- 1.59 to 1.14) for the restrictive-fluid group versus the standard-fluid group. The results for survivors only were similar in both groups. CONCLUSIONS: Among adult ICU patients with septic shock, restrictive versus standard IV fluid therapy resulted in similar survival, HRQoL, and cognitive function at 1 year, but clinically important differences could not be ruled out.

Frozen out: molecular modeling in the age of cryocrystallography.

As molecular modellers we need to remember that the flexibility of a protein is necessary for it to function. Unfortunately, this flexibility is not readily apparent from the seductive molecular graphics rendering of cryocrystallographic results.

The maternal health-related issues that matter most to women in Ireland as they transition to motherhood - A qualitative study.

BACKGROUND: Many studies on women's maternity care experiences reveal recurring issues that are poor or less than optimal. Women's opinions on the maternal health-related issues that matter most to them are essential if care and services are to be improved. AIMS: To identify the maternal health-related issues that matter most to women in Ireland, based on their own experiences of maternity care, services and motherhood. METHODS: A qualitative exploratory study with 24 women. Following university ethical approval, audio-recorded one-to-one telephone interviews were conducted and thematically analysed. FINDINGS: We identified two themes, each with four subthemes, connected to a central concept of the invisible woman. Pendulum of care, and subthemes Inconsistent services, All about the baby, Induced anxiety and Information seesaw, illustrated the extremes of care and services that women experienced. Magnitude of motherhood, and subthemes Weight of responsibility, Real-time reassurance, Change of identity and Growth into advocacy, depicted the intensity of their new role while transitioning to motherhood. DISCUSSION: Findings articulate the issues that mattered most to women in Ireland as they transitioned to motherhood. Some women identified specific research topics/areas, but all of the issues identified can be translated into researchable topics that seek to improve local care and service provision. CONCLUSION: Given the recurring nature of women's less than satisfactory experiences of aspects of maternity care in many countries, it is likely that conducting research on issues that matters most to women will have the greatest impact on their health, wellbeing and lives as they transition to motherhood.

A crowdsourcing evaluation of the NIH chemical probes.

Between 2004 and 2008, the US National Institutes of Health Molecular Libraries and Imaging initiative pilot phase funded 10 high-throughput screening centers, resulting in the deposition of 691 assays into PubChem and the nomination of 64 chemical probes. We crowdsourced the Molecular Libraries and Imaging initiative output to 11 experts, who expressed medium or high levels of confidence in 48 of these 64 probes.

Overview of the perspectives devoted to tautomerism in molecular design.

This communication summarizes the important points made in each contribution. They show that there remain issues in the cheminformatic handling of tautomers and predicting the relative energies of various tautomers.

Tautomerism, Hammett sigma, and QSAR.

A consideration of equilibrium model-based equations suggests that tautomeric equilibria do not markedly affect observed potency if the tautomer bound represents at least 50% of the compound in solution. Tautomeric equilibria can enhance or attenuate the correlation of potency with Hammett sigma. Additionally, tautomeric equilibria can lead to a correlation of potency with sigma even in the absence of a correlation of binding with sigma.

Optimization of leaf morphology in relation to leaf water status: A theory.

The leaf economic traits such as leaf area, maximum carbon assimilation rate, and venation are all correlated and related to water availability. Furthermore, leaves are often broad and large in humid areas and narrower in arid/semiarid and hot and cold areas. We use optimization theory to explain these patterns. We have created a constrained optimization leaf model linking leaf shape to vein structure that is integrated into coupled transpiration and carbon assimilation processes. The model maximizes net leaf carbon gain (NPPleaf) over the loss of xylem water potential. Modeled relations between leaf traits are consistent with empirically observed patterns. As the results of the leaf shape-venation relation, our model further predicts that a broadleaf has overall higher NPPleaf compared to a narrowleaf. In addition, a broadleaf has a lower stomatal resistance compared to a narrowleaf under the same level of constraint. With the same leaf area, a broadleaf will have, on average, larger conduits and lower total leaf xylem resistance and thus be more efficient in water transportation but less resistant to cavitation. By linking venation structure to leaf shape and using water potential as the constraint, our model provides a physical explanation for the general pattern of the covariance of leaf traits through the safety-efficiency trade-off of leaf hydraulic design.

Let's not forget tautomers.

A compound exhibits tautomerism if it can be represented by two structures that are related by an intramolecular movement of hydrogen from one atom to another. The different tautomers of a molecule usually have different molecular fingerprints, hydrophobicities and pKa's as well as different 3D shape and electrostatic properties; additionally, proteins frequently preferentially bind a tautomer that is present in low abundance in water. As a result, the proper treatment of molecules that can tautomerize, approximately 25% of a database, is a challenge for every aspect of computer-aided molecular design. Library design that focuses on molecular similarity or diversity might inadvertently include similar molecules that happen to be encoded as different tautomers. Physical property measurements might not establish the properties of individual tautomers with the result that algorithms based on these measurements may be less accurate for molecules that can tautomerize-this problem influences the accuracy of filtering for library design and also traditional QSAR. Any 2D or 3D QSAR analysis must involve the decision of if or how to adjust the observed Ki or IC50 for the tautomerization equilibria. QSARs and recursive partitioning methods also involve the decision as to which tautomer(s) to use to calculate the molecular descriptors. Docking virtual screening must involve the decision as to which tautomers to include in the docking and how to account for tautomerization in the scoring. All of these decisions are more difficult because there is no extensive database of measured tautomeric ratios in both water and non-aqueous solvents and there is no consensus as to the best computational method to calculate tautomeric ratios in different environments.

A bioavailability score.

Responding to a demonstrated need for scientists to forecast the permeability and bioavailability (F) properties of compounds before their purchase, synthesis, or advanced testing, we have developed a score that assigns the probability that a compound will have F > 10% in the rat. Neither the rule-of-five, log P, log D, nor the combination of the number of rotatable bonds and polar surface area successfully categorized compounds. Instead, different properties govern the bioavailability of compounds depending on their predominant charge at biological pH. The fraction of anions with >10% F falls from 85% if the polar surface area (PSA) is < or = 75 A(2), to 56% if 75 < PSA < 150 A(2), to 11% if PSA is > or = 150 A(2). On the other hand, whereas 55% of the neutral, zwitterionic, or cationic compounds that pass the rule-of-five have >10% F, only 17% of those that fail have > 10% F. This same categorization distinguishes compounds that are poorly permeable from those that are permeable in Caco-2 cells. Further validation is provided with human bioavailability values from the literature.