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From crystalline tetrahydrofuran clathrate hydrate, THF-CH (THF·17H2O, cubic structure II), three distinct polyamorphs can be derived. First, THF-CH undergoes pressure-induced amorphization when pressurized to 1.3 GPa in the temperature range 77-140 K to a form which, in analogy to pure ice, may be called high-density amorphous (HDA). Second, HDA can be converted to a densified form, VHDA, upon heat-cycling at 1.8 GPa to 180 K. Decompression of VHDA to atmospheric pressure below 130 K produces the third form, recovered amorphous (RA). Results from neutron scattering experiments and molecular dynamics simulations provide a generalized picture of the structure of amorphous THF hydrates with respect to crystalline THF-CH and liquid THF·17H2O solution (∼2.5 M). Although fully amorphous, HDA is heterogeneous with two length scales for water-water correlations (less dense local water structure) and guest-water correlations (denser THF hydration structure). The hydration structure of THF is influenced by guest-host hydrogen bonding. THF molecules maintain a quasiregular array, reminiscent of the crystalline state, and their hydration structure (out to 5 Å) constitutes ∼23H2O. The local water structure in HDA is reminiscent of pure HDA-ice featuring 5-coordinated H2O. In VHDA, the hydration structure of HDA is maintained but the local water structure is densified and resembles pure VHDA-ice with 6-coordinated H2O. The hydration structure of THF in RA constitutes ∼18 H2O molecules and the water structure corresponds to a strictly 4-coordinated network, as in the liquid. Both VHDA and RA can be considered as homogeneous.

Although multiple consensus statements have called for large-scale efforts to improve clinicians' communication skills regarding a variety of difficult conversations in medicine, this goal will be difficult to attain because there are no readily scalable, validated communication skills training programs for clinicians. However, novel applications of existing technologies and approaches grounded in learning science can overcome the scalability barriers. Moreover, future advances in virtual reality and artificial intelligence are likely to greatly enhance the possibilities for communication skills training programs. The purpose of this paper is to propose a scalable, theoretically grounded method to train clinicians in advanced communication skills in medicine. First, we summarize four key principles of adult learning relevant to communication skills training in medicine. Second, we discuss recommended practices to design effective technology-enhanced educational interventions, with an emphasis on achieving high amounts of user engagement. Third, we synthesize these principles into a framework for a web- and videoconference-based platform for teaching advanced communication skills in medicine. Once developed, this low-cost, scalable training platform has the potential to allow thousands of clinicians to acquire the advanced communication skills needed for difficult conversations in medicine.

Type II clathrate hydrates (CHs) with tetrahydrofuran (THF), cyclobutanone (CB) or 1,3-dioxolane (DXL) guest molecules collapse to an amorphous state near 1 GPa on pressurization below 140 K. On subsequent heating in the 0.2-0.7 GPa range, thermal conductivity and heat capacity results of the homogeneous amorphous solid show two glass transitions, first a thermally weak glass transition, GT1, near 130 K; thereafter a thermally strong glass transition, GT2, which implies a transformation to an ultraviscous liquid on heating. Here we compare the GTs of normal and deuterated samples and samples with different guest molecules. The results show that GT1 and GT2 are unaffected by deuteration of the THF guest and exchange of THF with CB or DXL, whereas the glass transition temperatures (Tgs) shift to higher temperatures on deuteration of water; Tg of GT2 increases by 2.5 K. These results imply that both GTs are associated with the water network. This is corroborated by the fact that GT2 is detected only in the state which is the amorphized CH's counterpart of expanded high density amorphous ice. The results suggest a rare transition sequence of an orientational glass transition followed by a glass to liquid transition, i.e., kinetic unfreezing of H2O reorientational and translational mobility in two distinct processes.

The lack of reproducibility of animal experimental results between laboratories, particularly in studies investigating the microbiota, has raised concern among the scientific community. Factors such as environment, stress and sex have been identified as contributors, whereas dietary composition has received less attention. This study firstly evaluated the use of commercially available rodent diets across research institutions, with 28 different diets reported by 45 survey respondents. Secondly, highly variable ingredient, FODMAP (Fermentable Oligo-, Di-, Mono-saccharides And Polyols) and gluten content was found between different commercially available rodent diets. Finally, 40 mice were randomized to four groups, each receiving a different commercially available rodent diet, and the dietary impact on cecal microbiota, short- and branched-chain fatty acid profiles was evaluated. The gut microbiota composition differed significantly between diets and sexes, with significantly different clusters in β-diversity. Total BCFA were highest (p = 0.01) and SCFA were lowest (p = 0.03) in mice fed a diet lower in FODMAPs and gluten. These results suggest that nutritional composition of commercially available rodent diets impact gut microbiota profiles and fermentation patterns, with major implications for the reproducibility of results across laboratories. However, further studies are required to elucidate the specific dietary factors driving these changes.

The high pressure structural behavior of H2 and Ne clathrate hydrates with approximate composition H2/Ne·~4H2O and featuring cubic structure II (CS-II) was investigated by neutron powder diffraction using the deuterated analogues at ~95 K. CS-II hydrogen hydrate transforms gradually to isocompositional C1 phase (filled ice II) at around 1.1 GPa but may be metastably retained up to 2.2 GPa. Above 3 GPa a gradual decomposition into C2 phase (H2·H2O, filled ice Ic) and ice VIII’ takes place. Upon heating to 200 K the CS-II to C1 transition completes instantly whereas C1 decomposition appears sluggish also at 200 K. C1 was observed metastably up to 8 GPa. At 95 K C1 and C2 hydrogen hydrate can be retained below 1 GPa and yield ice II and ice Ic, respectively, upon complete release of pressure. In contrast, CS-II neon hydrate undergoes pressure-induced amorphization at 1.9 GPa, thus following the general trend for noble gas clathrate hydrates. Upon heating to 200 K amorphous Ne hydrate crystallizes as a mixture of previously unreported C2 hydrate and ice VIII’.

Background Clinical and biologic phenotypes of sepsis are proposed in human studies, yet it is unknown whether prognostic or drug response phenotypes are present in animal models of sepsis. Using a biotelemetry-enhanced, murine cecal ligation and puncture (CLP) model, we determined phenotypes of polymicrobial sepsis prior to physiologic deterioration, and the association between phenotypes and outcome in a randomized trial of prompt or delayed antibiotics and fluids. Methods We performed a secondary analysis of male C57BL/6J mice in two observational cohorts and two randomized, laboratory animal experimental trials. In cohort 1, mice (n = 118) underwent biotelemetry-enhanced CLP, and we applied latent class mixed models to determine optimal number of phenotypes using clinical data collected between injury and physiologic deterioration. In cohort 2 (N = 73 mice), inflammatory cytokines measured at 24 h after deterioration were explored by phenotype. In a subset of 46 mice enrolled in two trials from cohort 1, we tested the association of phenotypes with the response to immediate (0 h) vs. delayed (2 to 4 h) antibiotics or fluids initiated after physiologic deterioration. Results Latent class mixture modeling derived a two-class model in cohort 1. Class 2 (N = 97) demonstrated a shorter time to deterioration (mean SD 7.3 (0.9) vs. 9.7 (3.2) h, p p p = 0.75). In cohort 2 used for biomarker measurement, class 2 mice had greater plasma concentrations of IL6 and IL10 at 24 h after CLP (p = 0.05). In pilot randomized trials, the effects of sepsis treatment (immediate vs. delayed antibiotics) differed by phenotype (p = 0.03), with immediate treatment associated with greater survival in class 2 mice only. Similar differential treatment effect by class was observed in the trial of immediate vs. delayed fluids (p = 0.02). Conclusions We identified two sepsis phenotypes in a murine cecal ligation and puncture model, one of which is characterized by faster deterioration and more severe inflammation. Response to treatment in a randomized trial of immediate versus delayed antibiotics and fluids differed on the basis of phenotype.

The high pressure structural behavior of H2 and Ne clathrate hydrates with approximate composition H2/Ne·~4H2O and featuring cubic structure II (CS-II) was investigated by neutron powder diffraction using the deuterated analogues at ~95 K. CS-II hydrogen hydrate transforms gradually to isocompositional C1 phase (filled ice II) at around 1.1 GPa but may be metastably retained up to 2.2 GPa. Above 3 GPa a gradual decomposition into C2 phase (H2·H2O, filled ice Ic) and ice VIII’ takes place. Upon heating to 200 K the CS-II to C1 transition completes instantly whereas C1 decomposition appears sluggish also at 200 K. C1 was observed metastably up to 8 GPa. At 95 K C1 and C2 hydrogen hydrate can be retained below 1 GPa and yield ice II and ice Ic, respectively, upon complete release of pressure. In contrast, CS-II neon hydrate undergoes pressure-induced amorphization at 1.9 GPa, thus following the general trend for noble gas clathrate hydrates. Upon heating to 200 K amorphous Ne hydrate crystallizes as a mixture of previously unreported C2 hydrate and ice VIII’.

The development of a shared data infrastructure across health systems could improve research, clinical care, and health policy across a spectrum of diseases, including sepsis. Awareness of the potential value of such infrastructure has been heightened by COVID-19, as the lack of a real-time, interoperable data network impaired disease identification, mitigation, and eradication. The Sepsis on FHIR collaboration establishes a dynamic, federated, and interoperable system of sepsis data from 55 hospitals using 2 distinct inpatient electronic health record systems. Here we report on phase 1, a systematic review to identify clinical variables required to define sepsis and its subtypes to produce a concept mapping of elements onto Fast Healthcare Interoperability Resources (FHIR). Relevant papers described consensus sepsis definitions, provided criteria for sepsis, severe sepsis, septic shock, or detailed sepsis subtypes. Studies not written in English, published prior to 1970, or "grey" literature were prospectively excluded. We analyzed 55 manuscripts yielding 151 unique clinical variables. We then mapped variables to their corresponding US Core FHIR resources and specific code values. This work establishes the framework to develop a flexible infrastructure for sharing sepsis data, highlighting how FHIR could enable the extension of this approach to other important conditions relevant to public health.

Background: There is wide heterogeneity in sepsis in causative pathogens, host response, organ dysfunction, and outcomes. Clinical and biologic phenotypes of sepsis are proposed, but the role of pathogen data on sepsis classification is unknown.Methods: We conducted a secondary analysis of the Recombinant Human Activated Protein C (rhAPC) Worldwide Evaluation in Severe Sepsis (PROWESS) Study. We used latent class analysis (LCA) to identify sepsis phenotypes using, (i) only clinical variables (“host model”) and, (ii) combining clinical with microbiology variables (e.g., site of infection, culture-derived pathogen type, and anti-microbial resistance characteristics, “host-pathogen model”). We describe clinical characteristics, serum biomarkers, and outcomes of host and host-pathogen models. We tested the treatment effects of rhAPC by phenotype using Kaplan-Meier curves.Results: Among 1,690 subjects with severe sepsis, latent class modeling derived a 4-class host model and a 4-class host-pathogen model. In the host model, alpha type (N = 327, 19%) was younger and had less shock; beta type (N=518, 31%) was older with more comorbidities; gamma type (N = 532, 32%) had more pulmonary dysfunction; delta type (N = 313, 19%) had more liver, renal and hematologic dysfunction and shock. After the addition of microbiologic variables, 772 (46%) patients changed phenotype membership, and the median probability of phenotype membership increased from 0.95 to 0.97 (P < 0.01). When microbiology data were added, the contribution of individual variables to phenotypes showed greater change for beta and gamma types. In beta type, the proportion of abdominal infections (from 20 to 40%) increased, while gamma type patients had an increased rate of lung infections (from 50 to 78%) with worsening pulmonary function. Markers of coagulation such as d-dimer and plasminogen activator inhibitor (PAI)-1 were greater in the beta type and lower in the gamma type. The 28 day mortality was significantly different for individual phenotypes in host and host-pathogen models (both P < 0.01). The treatment effect of rhAPC obviously changed in gamma type when microbiology data were added (P-values of log rank test changed from 0.047 to 0.780).Conclusions: Sepsis host phenotype assignment was significantly modified when microbiology data were added to clinical variables, increasing cluster cohesiveness and homogeneity.

Three amorphous forms of Ar hydrate were produced using the crystalline clathrate hydrate Ar·6.5H

The high-pressure structural behavior of the noble gas (Ng) clathrate hydrates $\mathrm{Ar}\ifmmode\cdot\else\textperiodcentered\fi{}6.5\phantom{\rule{0.16em}{0ex}}{\mathrm{H}}_{2}\mathrm{O}$ and $\mathrm{Xe}\ifmmode\cdot\else\textperiodcentered\fi{}7.2\phantom{\rule{0.16em}{0ex}}{\mathrm{H}}_{2}\mathrm{O}$ featuring cubic structures II and I, respectively, was investigated by neutron powder diffraction (using the deuterated analogues) at 95 K. Both hydrates undergo pressure-induced amorphization (PIA), indicated by the disappearance of Bragg diffraction peaks, but at rather different pressures, at 1.4 and above 4.0 GPa, respectively. Amorphous Ar hydrate can be recovered to ambient pressure when annealed at $g1.5\phantom{\rule{0.16em}{0ex}}\mathrm{GPa}$ and 170 K and is thermally stable up to 120 K. In contrast, it was impossible to retain amorphous Xe hydrate at pressures below 3 GPa. Molecular dynamics (MD) simulations were used to obtain general insight into PIA of Ng hydrates, from Ne to Xe. Without a guest species, both cubic clathrate structures amorphize at 1.2 GPa, which is very similar to hexagonal ice. Filling of large-sized H cages does not provide stability toward amorphization for structure II, whereas filled small-sized dodecahedral D cages shift PIA successively to higher pressures with increasing size of the Ng guest. For structure I, filling of both kinds of cages, large-sized T and small-sized D, acts to stabilize in a cooperative fashion. Xe hydrate represents a special case. In MD, disordering of the guest hydration structure is already seen at around 2.5 GPa. However, the different coordination numbers of the two types of guests in the crystalline cage structure are preserved, and the state is shown to produce a Bragg diffraction pattern. The experimentally observed diffraction up to 4 GPa is attributed to this semicrystalline state.

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care.

Layered zinc hydroxides (LZHs) with the general formula (Zn2+)(x)(OH-)(2x-my ),(A(m-))(y)center dot nH(2)O (A(m-) = Cl- , NO3- , ac(-) , SO42-, etc) are considered as useful precursors for the fabrication of functional ZnO nanostructures. Here, we report the synthesis and structure characterization of the hitherto unknown "binary" representative of the LZH compound family, Zn-5(OH)(10)center dot 2H(2)O, with A(m-) = OH- , x = 5, y = 2, and n = 2. Zn-5(OH)(10)center dot 2H(2)O was afforded quantitatively by pressurizing mixtures of epsilon-Zn(OH)(2) (wulfingite) and water to 1-2 GPa and applying slightly elevated temperatures, 100-200 degrees C. The monoclinic crystal structure was characterized from powder X-ray diffraction data (space group C2/c, a = 15.342(7) angstrom, b = 6.244(6) angstrom, c = 10.989(7) angstrom, beta = 100.86(1)degrees). It features neutral zinc hydroxide layers, composed of octahedrally and tetrahedrally coordinated Zn ions with a 3:2 ratio, in which H2O is intercalated. The interlayer d(200) distance is 7.53 angstrom. The H-bond structure of Zn-5(OH)(10)center dot 2H(2)O was analyzed by a combination of infrared/Raman spectroscopy, computational modeling, and neutron powder diffraction. Interlayer H2O molecules are strongly H-bonded to five surrounding OH groups and appear orientationally disordered. The decomposition of Zn-5(OH)(10)center dot 2H(2)O, which occurs thermally between 70 and 100 degrees C, was followed in an in situ transmission electron microscopy study and ex situ annealing experiments. It yields initially 5-15 nm sized hexagonal w-ZnO crystals, which, depending on the conditions, may intergrow to several hundred nm-large two-dimensional, flakelike crystals within the boundary of original Zn-5(OH)(10)center dot 2H(2)O particles. Funding Agencies|Swedish Research Council (VR)Swedish Research Council [2016-04413, 2019-05551]; Stiftelsen Olle Engkvist Byggmastare (SOEB); Swedish Foundation for Strategic Research (SSF) within the Swedish National Graduate School in neutron scattering (SwedNess); Swedish Government Strategic Research Area Grant in Materials Science on Functional Materials at Linkoping University (Faculty Grant SFO-Mat-LiU) [2009 00971]

Purpose/Objective(s) Tumor Treating Fields (TTFields) therapy is a clinically applied loco-regional, non-invasive, anti-mitotic treatment modality delivering to the tumor low intensity (1-3 V/cm) alternating electric fields (100-300 kHz). While TTFields therapy has demonstrated proven efficacy in management of glioblastoma and malignant pleural mesothelioma, tumor recurrence still occurs in some patients. In order to anticipate potential molecular mechanisms of resistance to TTFields, we developed TTFields-resistant cancer cell lines, and analyzed the changes in their signaling pathways. We also examined the in vitro efficacy of TTFields when combined with agents targeting the molecular candidates that possibly confer resistance to TTFields. Materials/Methods To evaluate the mechanisms of cellular resistance to TTFields, we developed resistant ovarian (A2780), glioma (U-87-MG), and non-small cell lung carcinoma (H1299) cancer cell lines through continued long-term application of TTFields (one or two weeks, depending on the cell line), without treatment breaks. We then assessed the concomitant changes in cellular signaling pathways using an immunoassay followed by Western blot analysis. Finally, we characterized the mechanism of resistance by examining the in vitro efficacy of continued long-term application of TTFields in combination with pharmacological inhibitors including a PI3K/mTOR dual inhibitor (BGT226), and Pan- and isoform-specific inhibitors of PI3K (alpelisib, pictilisib, and BKM120), using cell count, apoptosis, and colony formation assays. Results Continued long-term application of TTFields resulted in reduced sensitivity to TTFields in all tested cell lines. Immunoassay and Western blot analysis showed significant activation of the PI3K/AKT/mTOR signaling pathway in response to TTFields treatment. The combination therapy of TTFields with either alpelisib, pictilisib, BKM120 or BGT226, inhibited AKT S473 phosphorylation and sensitized cancer cells to “long-term” TTFields application. Conclusion Our study demonstrates that the PI3K/ AKT/ mTOR signaling pathway confers resistance to TTFields. This provides a rationale for the combined targeting of PI3K in patients treated with TTFields.

Background: Patients with acute illness who receive intravenous (IV) fluids prior to hospital arrival may have a lower in-hospital mortality. To better understand whether this is a direct treatment effect or epiphenomenon of downstream care, we tested the association between a prehospital fluid bolus and the change in inflammatory cytokines measured at prehospital and emergency department timepoints in a sample of non-trauma, non-cardiac arrest patients at risk for critical illness. Methods: In a prospective cohort study, we screened 4,013 non-trauma, non-cardiac arrest encounters transported by City of Pittsburgh Emergency Medical Services (EMS) to 2 hospitals from August 2013 to February 2014. In 345 patients, we measured prehospital biomarkers (IL-6, IL-10, and TNF) at 2 time points: the time of prehospital IV access placement by EMS and at ED arrival. We determined the relative change for marker X as: ([XED – XEMS]/XEMS). We determined the risk-adjusted association between prehospital IV fluid bolus and relative change for each marker using multivariable linear regression. Results: Among 345 patients, 88 (26%) received a prehospital IV fluid bolus and 257 (74%) did not. Compared to patients who did not receive prehospital fluids, median prehospital IL-6 was greater initially in subjects receiving a prehospital IV fluid bolus (22.3 [IQR 6.4–113] vs. 11.5 [IQR 5.5–47.6]). Prehospital IL-10 and TNF were similar in both groups (IL-10: 3.5 [IQR 2.2–25.6] vs. 3.0 [IQR 1.9–9.0]; TNF: 7.5 [IQR 6.4–10.4] vs. 6.9 [IQR 6.0–8.3]). After adjustment for demographics, illness severity, and prehospital transport time, we observed a relative decrease in IL-6 at hospital arrival in those receiving a prehospital fluid bolus (adjusted β = −10.0, 95% CI: −19.4, −0.6, p = 0.04), but we did not detect a significant change in IL-10 (p = 0.34) or TNF (p = 0.53). Conclusions: Among non-trauma, non-cardiac arrest patients at risk for critical illness, a prehospital IV fluid bolus was associated with a relative decrease in IL-6, but not IL-10 or TNF.

The type II clathrate hydrate (CH) THF·17 H