Intervention strategies for microbial therapeutics in cancer immunotherapy.

Immunotherapies have drastically improved clinical outcomes in a wide range of malignancies. Nevertheless, patient responses remain highly variable, and reliable biomarkers that predict responses accurately are not yet fully understood. Compelling evidence from preclinical studies and observational data from clinical cohorts have shown that commensal microorganisms that reside in the human gastrointestinal tract, collectively termed the 'microbiome', can actively modify responses to chemotherapeutic agents and immunotherapies by influencing host immunosurveillance. Notably, microbial correlates are largely context specific, and response signatures may vary by patient population, geographic location and type of anticancer treatment. Therefore, the incongruence of beneficial microbiome signatures across studies, along with an emerging understanding of the mechanisms underlying the interactions between the microbiome, metabolome and host immune system, highlight a critical need for additional comprehensive and standardized multi-omics studies. Future research should consider key host factors, such as diet and use of medication, in both preclinical animal models and large-scale, multicenter clinical trials. In addition, there is a strong rationale to evaluate the microbiome as a tumor-extrinsic biomarker of clinical outcomes and to test the therapeutic potential of derived microbial products (e.g. defined microbial consortia), with the eventual goal of improving the efficacy of existing anticancer treatments. This review discusses the importance of the microbiome from the perspective of cancer immunotherapies, and outlines future steps that may contribute to wide-ranging clinical and translational benefits that may improve the health and quality of life of patients with cancer.

Organizational Readiness to Implement System Changes in an Alaskan Tribal Dental Care Organization.

INTRODUCTION: Tribal health care systems are striving to implement internal changes to improve dental care access and delivery and reduce health inequities for American Indian and Alaska Native children. Within similar systems, organizational readiness to implement change has been associated with adoption of system-level changes and affected by organizational factors, including culture, resources, and structure. OBJECTIVES: The objectives of this study were to assess organizational readiness to implement changes related to delivery of evidence-based dental care within a tribal health care organization and determine workforce- and perceived work environment-related factors associated with readiness. METHODS: A 92-item questionnaire was completed online by 78 employees, including dental providers, dental assistants, and support staff (88% response rate). The questionnaire queried readiness for implementation (Organizational Readiness for Implementing Change), organizational context and resources, workforce issues, organizational functioning, and demographics. RESULTS: Average scores for the change commitment and change efficacy domains (readiness for implementation) were 3.93 (SD = .75) and 3.85 (SD = .80), respectively, where the maximum best score was 5. Perceived quality of management, a facet of organizational functioning, was the only significant predictor of readiness to implement change (B = .727, SE = .181, P < .0002) when all other variables were accounted for. CONCLUSION: Results suggest that when staff members (including dentists, dental therapists, hygienists, assistants, and support staff) from a tribal health care organization perceive management to be high quality, they are more supportive of organizational changes that promote evidence-based practices. Readiness-for-change scores indicate an organization capable of institutional adoption of new policies and procedures. In this case, use of more effective management strategies may be one of the changes most critical for enhancing institutional behaviors to improve population health and reduce health inequities. KNOWLEDGE TRANSFER STATEMENT: The results of this study can be used by clinicians and other leaders implementing changes within dental care organizations. To promote organizational readiness for change and, ultimately, more expedient and efficient adoption of system-level changes by stakeholders, consideration should be given to organizational functioning generally and quality of management practices specifically.

Biomimetic hydroxyapatite/collagen composite drives bone niche recapitulation in a rabbit orthotopic model.

Synthetic osteoinductive materials that mimic the human osteogenic niche have emerged as ideal candidates to address this area of unmet clinical need. In this study, we evaluated the osteoinductive potential in a rabbit orthotopic model of a magnesium-doped hydroxyapatite/type I collagen â€‹(MHA/Coll) composite. The composite was fabricated to exhibit a highly fibrous structure of carbonated MHA with 70% (±2.1) porosity and a Ca/P ratio of 1.5 (±0.03) as well as a diverse range of elasticity separated to two distinct stiffness peaks of low (2.35 â€‹± â€‹1.16 â€‹MPa) and higher (9.52 â€‹± â€‹2.10 â€‹MPa) Young's Modulus. Data suggested that these specific compositional and nanomechanical material properties induced the deposition of de novo mineral phase, while modulating the expression of early and late osteogenic marker genes, in a 3D in vitro model using human bone marrow-derived mesenchymal stem cells (hBM-MSCs). When tested in the rabbit orthotopic model, MHA/Col1 scaffold induction of new trabecular bone mass was observed by DynaCT scan, only 2 weeks after implantation. Bone histomorphometry at 6 weeks revealed a significant amount of de novo bone matrix formation. qPCR demonstrated MHA/Coll scaffold full cellularization in vivo and the expression of both osteogenesis-associated genes (Spp1, Sparc, Col1a1, Runx2, Dlx5) as well as hematopoietic (Vcam1, Cd38, Sele, Kdr) and bone marrow stromal cell marker genes (Vim, Itgb1, Alcam). Altogether, these data provide â€‹evidence of the solid osteoinductive potential of MHA/Coll and its suitability for multiple approaches of bone regeneration.

Innovative approach to the design and evaluation of treatment adherence interventions for drug-resistant TB.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) treatment is expensive, lengthy, and can cause severe side effects. Patients face socio-economic, psychosocial, and systemic barriers to adherence; poor adherence results in poor treatment outcomes. OBJECTIVE: To estimate the effects of the components of the information-motivation-behavioral skills model on DR-TB treatment adherence. DESIGN: We recruited 326 adults receiving DR-TB treatment and 86 of their health care service providers from 40 health centers in Lima, Peru. The main outcome was adherence (i.e., the proportion of prescribed doses taken by a patient). Exposure measures were adherence information, motivation, and behavioral skills; loss to follow-up during previous TB treatment(s); providers' work engagement; and patient-perceived support from his/her social network. RESULTS: Structural equation modeling revealed that adherence information and motivation had positive effects on adherence, but only if mediated through behavioral skills (ß = 0.02, P < 0.01 and ß = 0.07, P < 0.001, respectively). Behavioral skills had a direct positive effect on adherence (ß = 0.27, P < 0.001). Loss to follow-up during previous treatment had a direct negative effect, providers' work engagement had a direct positive effect, and perceived support had indirect positive effects on adherence. The model's overall R2 was 0.76. CONCLUSION: The components of the information-motivation-behavioral skills model were associated with adherence and could be used to design, monitor, and evaluate interventions targeting adherence to DR-TB treatment.

Characterization of biochars and dissolved organic matter phases obtained upon hydrothermal carbonization of Elodea nuttallii.

The invasive aquatic plant Elodea nuttallii was subjected to hydrothermal carbonization at 200 °C and 240 °C to produce biochar. About 58% w/w of the organic carbon of the pristine plant was translocated into the solid biochar irrespectively of the operating temperature. The process water rich in dissolved organic matter proved a good substrate for biogas production. The E. nuttallii plants showed a high capability of incorporating metals into the biomass. This large inorganic fraction which was mainly transferred into the biochar (except sodium and potassium) may hamper the prospective application of biochar as soil amendment. The high ash content in biochar (∼ 40% w/w) along with its relatively low content of organic carbon (∼ 36% w/w) is associated with low higher heating values. Fatty acids were completely hydrolyzed from lipids due to hydrothermal treatment. Low molecular-weight carboxylic acids (acetic and lactic acid), phenols and phenolic acids turned out major organic breakdown products.

Organic breakdown products resulting from hydrothermal carbonization of brewer's spent grain.

Hydrothermal carbonization of brewer's spent grain resulted in a solid hydrochar and an aqueous phase rich in macromolecular dissolved organic matter. Both phases were analyzed with regard to low molecular weight organic compounds (MW<500 Da) in lyophilized form by exhaustive solvent extraction followed by pre-chromatographic derivatization and GC/MS-analysis. Low molecular weight acids, O-functionalized phenols, cyclopentenone derivatives, and benzenediols accounted for the majority of organic analytes in both hydrothermal carbonization product streams while being absent in solvent extracts of the pristine biomass. The pattern of short chain functionalized acids in the pristine biomass and in the hydrothermally produced matrices turned out very different. Acylglycerines as the most abundant lipids in pristine brewer's spent grain were quantitatively hydrolyzed under hydrothermal conditions. The recovery of total fatty acids present in the pristine biomass amounted to 19%. The major fraction of hydrophobic breakdown products including fatty acids, fatty alcohols, and sterols was sorbed onto the hydrochar.

Hydrothermal carbonization of poly(vinyl chloride).

Poly(vinyl chloride) (PVC) was subjected to hydrothermal carbonization in subcritical water at 180-260 °C. Dehydrochlorination increased with increasing reaction temperature. The release of chlorine was almost quantitative above ∼235 °C. The fraction of organic carbon (OC) recovered in the hydrochar decreased with increasing operating temperature from 93% at 180 °C to 75% at 250 °C. A wide array of polycyclic aromatic hydrocarbons (PAHs) could be detected in the aqueous phase, but their combined concentration amounted to only ∼140 µg g(-1) PVC-substrate at 240 °C. A pathway for the formation of cyclic hydrocarbons and O-functionalized organics was proposed. Chlorinated hydrocarbons including chlorophenols could only be identified at trace levels (low ppb). Polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs) could not be detected. The sorption potential of the hydrochar turned out to be very low, in particular for polar organic pollutants. Our results provide strong evidence that hydrothermal carbonization of household organic wastes which can be tied to co-discarded PVC-plastic residues is environmentally sound regarding the formation of toxic organic products. Following these findings, hydrothermal treatment of PVC-waste beyond operating temperatures of ∼235 °C to allow complete release of organic chlorine should be further pursued.

Characterization of biocoals and dissolved organic matter phases obtained upon hydrothermal carbonization of brewer's spent grain.

The wet biomass brewer's spent grain was subjected to hydrothermal carbonization to produce biocoal. Mass balance considerations indicate for about two thirds of the organic carbon of the input biomass to be transferred into the biocoal. The van Krevelen plot refers to a high degree of defunctionalization with decarboxylation prevailing over dehydration. Calorific data revealed a significant energy densification of biocoals as compared to the input substrate. Sorption coefficients of organic analytes covering a wide range of hydrophobicities and polarities on biocoal were similar to those for dissolved humic acids. Data from GC/MS analysis indicated that phenols and benzenediols along with fatty acids released from bound lipids during the hydrothermal process constituted abundant products. Our findings demonstrate that the brewer's spent grain by-product is a good feedstock for hydrothermal carbonization to produce biocoal, the latter offering good prospects for energetic and soil-improving application fields.

A galaxy rapidly forming stars 700 million years after the Big Bang at redshift 7.51.

Of several dozen galaxies observed spectroscopically that are candidates for having a redshift (z) in excess of seven, only five have had their redshifts confirmed via Lyman α emission, at z = 7.008, 7.045, 7.109, 7.213 and 7.215 (refs 1-4). The small fraction of confirmed galaxies may indicate that the neutral fraction in the intergalactic medium rises quickly at z > 6.5, given that Lyman α is resonantly scattered by neutral gas. The small samples and limited depth of previous observations, however, makes these conclusions tentative. Here we report a deep near-infrared spectroscopic survey of 43 photometrically-selected galaxies with z > 6.5. We detect a near-infrared emission line from only a single galaxy, confirming that some process is making Lyman α difficult to detect. The detected emission line at a wavelength of 1.0343 micrometres is likely to be Lyman α emission, placing this galaxy at a redshift z = 7.51, an epoch 700 million years after the Big Bang. This galaxy's colours are consistent with significant metal content, implying that galaxies become enriched rapidly. We calculate a surprisingly high star-formation rate of about 330 solar masses per year, which is more than a factor of 100 greater than that seen in the Milky Way. Such a galaxy is unexpected in a survey of our size, suggesting that the early Universe may harbour a larger number of intense sites of star formation than expected.

Organic compounds in olive mill wastewater and in solutions resulting from hydrothermal carbonization of the wastewater.

Organic components in olive mill wastewater (OMW) were analyzed by exhaustive solvent extraction of the lyophilisate followed by pre-chromatographic derivatization techniques and GC/MS-analysis of the extracts. Simple biophenols including tyrosol (Tyr), hydroxytyrosol (OH-Tyr) and homovanillic alcohol as well as complex biophenols including decarbomethoxy ligostride aglycon and decarbomethoxy oleuropein aglycon proved most abundant analytes. Hydroxylated benzoic and cinnamic acids are less abundant, which may indicate a humification process to have occurred. The pattern of organic components obtained from native OMW was compared with that obtained from hydrothermal carbonization (HTC) of the waste product. Former results provided strong evidence that HTC of OMW at 220°C for 14h results in an almost complete hydrolysis of complex aglycons. However, simple biophenols were not decomposed on hydrothermal treatment any further. Phenol and benzenediols as well as low molecular weight organic acids proved most abundant analytes which were generated due to HTC. Similarly to aglycons, lipids including most abundant acylglycerines and less abundant wax esters were subjected almost quantitatively to hydrolysis under hydrothermal conditions. Fatty acids (FAs) released from lipids were further decomposed. The pathways of volatile analytes in both native OMW and aqueous HTC solutions were studied by solventless headspace-Solid Phase Micro Extraction. Basically, a wide array low molecular alcohols and ketones occurring in native OMW survived the HTC process.

Hydrothermal carbonization of olive mill wastewater.

Hydrothermal carbonization (HTC) is an emerging technology to treat wet biomasses aimed at producing a biochar material. Herein, olive mill wastewater (OMW) was subjected to HTC. Mass balance considerations provide evidence that the yield of biochar is low (~30%, w/w), which is associated with a low fraction of carbohydrates in OMW. The combination of different preparation schemes, pre-chromatographic derivatization reactions and GC/MS analysis for the analysis of organic compounds in aqueous HTC-solutions allowed to identify and quantify a wide array of analytes which belong either to intrinsic constituents of OMW or to characteristic HTC-breakdown products. Biophenols, such as hydroxyl-tyrosol (OH-Tyr), tyrosol (Tyr) account for the most abundant members of the first group. Most abundant breakdown products include phenol and benzenediols as well as short-chain organic acids. Secoiridoids, such as decarbomethoxy ligostride aglycon and decarbomethoxy oleuropein aglycon, all of them being typical components of OMW, are less abundant in HTC-solutions.

High molecular gas fractions in normal massive star-forming galaxies in the young Universe.

Stars form from cold molecular interstellar gas. As this is relatively rare in the local Universe, galaxies like the Milky Way form only a few new stars per year. Typical massive galaxies in the distant Universe formed stars an order of magnitude more rapidly. Unless star formation was significantly more efficient, this difference suggests that young galaxies were much more molecular-gas rich. Molecular gas observations in the distant Universe have so far largely been restricted to very luminous, rare objects, including mergers and quasars, and accordingly we do not yet have a clear idea about the gas content of more normal (albeit massive) galaxies. Here we report the results of a survey of molecular gas in samples of typical massive-star-forming galaxies at mean redshifts of about 1.2 and 2.3, when the Universe was respectively 40% and 24% of its current age. Our measurements reveal that distant star forming galaxies were indeed gas rich, and that the star formation efficiency is not strongly dependent on cosmic epoch. The average fraction of cold gas relative to total galaxy baryonic mass at z = 2.3 and z = 1.2 is respectively about 44% and 34%, three to ten times higher than in today's massive spiral galaxies. The slow decrease between z approximately 2 and z approximately 1 probably requires a mechanism of semi-continuous replenishment of fresh gas to the young galaxies.

Patient race/ethnicity, age, gender and education are not related to preference for or response to disclosure.

OBJECTIVE: The purpose of this study was to (a) characterise patients' preferences for disclosure of medical errors and reporting, (b) assess patients' responses to disclosure of error and (c) determine how these preferences differ by patient race/ethnicity, gender, age and level of education. METHODS: A survey was conducted of consecutive patients presenting at any hour to a tertiary care academic emergency department. Inclusion criteria were: >21 years, competent to conduct the interview (ie, conscious, not demented, delirious, intoxicated or undergoing a psychiatric evaluation), initial Glasgow Coma Scale >12, and patient not transferred from another institution and not in state custody. A four-scenario survey was used to assess patients' preferences for: disclosure, reporting and responses to disclosure. The responses to the scenarios were analysed using Somers D. Independent effects of study variables were assessed with a generalised estimating equation. RESULTS: Of 512 eligible patients, 394 (77% response rate) participated, and 238/394 (61%) met the criteria for analysis. Overall, in 902 (98%) responses to the scenarios, participants wanted disclosure, in 404 (45%), they wanted the error reported and in 311 (35%) they were less likely to seek legal action if informed of the error. In all three categories there was no relation with race/ethnicity, gender, age and education, with the exception of an increased desire for reporting in younger patients and those with less education. CONCLUSIONS: Interventions that aim to assist doctors with disclosure of medical error must emphasise the uniformity of patient preferences for disclosure and the diminished likelihood of legal action following disclosure.

Nanosphere dispersed liquid crystals for tunable negative-zero-positive index of refraction in the optical and terahertz regimes.

An analysis of aligned nematic liquid crystal cells containing core-shell nanospheres shows that it is possible to devise a new type of metamaterial whose index of refraction is tunable from negative, through zero, to positive values. The design parameters for the constituents can be scaled for application in the optical as well as very long wavelength (e.g., terahertz and microwave) regions.

The shaping of individual meanings assigned to assistive technology: a review of personal factors.

PURPOSE: This review article examines the development of individualized meanings assigned to assistive technology and how these personal meanings influence the integration of assistive technology into daily activities. METHODS: A review of the published literature regarding assistive technology use and abandonment was conducted by performing two independent searches using 26 search terms and three databases. Publications were reviewed for whether they addressed device use, device abandonment, coping, adjustment, adaptation, values, outcomes and/or cultural issues; 81 publications met these criteria. RESULTS: The evidence suggests that psychosocial and cultural issues influence the shaping of individualized meanings assigned to assistive technology. Theoretical arguments suggest that the process of adapting to disability is another influential factor. CONCLUSIONS: The synthesis of evidence and theories suggests that successful integration of assistive technology into daily lives requires potential device users to explore: (1) the meanings they assign to devices; (2) their expectations of assistive technology; (3) the anticipated social costs; and (4) ways to understand that disability is one, but not the defining, feature of one's identity.

Automated molecular weight assignment of electrospray ionization mass spectra.

Process improvements in the synthesis of therapeutic agents and their intermediates are often facilitated by identification of reaction by-products. Analysis by liquid chromatography/mass spectrometry (LC/MS) with electrospray ionization is a powerful approach for obtaining molecular weight information for these compounds. Such analyses are well suited for 'open-access' mass spectrometry using generic chromatographic conditions, provided spectral interpretation for unknown compounds is facile. We have developed a software application (MassAssign) that facilitates automated data processing and molecular weight assignment for chromatographic peaks detected by any standard ultraviolet-visible wavelength detector. The program assigns [M + H](+) ions (and thus molecular weight) in the mass spectra using predetermined criteria. This evaluation process differentiates [M + H](+) ions from other signals in a complex mass spectrum such as those resulting from chromatographic coelution or the presence of multiple species (i.e., fragment ions, singly charged ions, doubly charged ions, adduct ions, proton-bound dimers, etc.). Once the program has evaluated all ions in a mass spectrum that exceed a preset abundance threshold, MassAssign reports either a numeric value-indicating the chromatographic peak consists of a single component having the displayed molecular weight, 'MC'-indicating the peak consisted of multiple components, or 'ND'-that a molecular weight could not be determined unequivocally. The performance of the program was evaluated by comparing mass assignments made by MassAssign against manual interpretation for 55 samples analyzed by positive electrospray ionization using a generic HPLC method. Correct molecular weight assignments were obtained in 90% of the cases.

Survival following coronary angioplasty versus coronary artery bypass surgery in anatomic subsets in which coronary artery bypass surgery improves survival compared with medical therapy. Results from the Bypass Angioplasty Revascularization Investigation (BARI).

OBJECTIVES: We sought to compare survival after coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA) in high-risk anatomic subsets. BACKGROUND: Compared with medical therapy, CABG decreases mortality in patients with three-vessel disease and two-vessel disease involving the proximal left anterior descending artery (LAD), particularly if left ventricular (LV) dysfunction is present. How survival after PTCA and CABG compares in these high-risk anatomic subsets is unknown. METHODS: In the Bypass Angioplasty Revascularization Investigation (BARI), 1,829 patients with multivessel disease were randomized to an initial strategy of PTCA or CABG between 1988 and 1991. Stents and IIb/IIIa inhibitors were not utilized. Since patients in BARI with diabetes mellitus had greater survival with CABG, separate analyses of patients without diabetes were performed. RESULTS: Seven-year survival among patients with three-vessel disease undergoing PTCA and CABG (n = 754) was 79% versus 84% (p = 0.06), respectively, and 85% versus 87% (p = 0.36) when only non-diabetics (n = 592) were analyzed. In patients with three-vessel disease and reduced LV function (ejection fraction <50%), seven-year survival was 70% versus 74% (p = 0.6) in all PTCA and CABG patients (n = 176), and 82% versus 73% (p = 0.29) among non-diabetic patients (n = 124). Seven-year survival was 87% versus 84% (p = 0.9) in all PTCA and CABG patients (including diabetics) with two-vessel disease involving the proximal LAD (n = 352), and 78% versus 71% (p = 0.7) in patients with two-vessel disease involving the proximal LAD with reduced LV function (n = 72). CONCLUSION: In high-risk anatomic subsets in which survival is prolonged by CABG versus medical therapy, revascularization by PTCA and CABG yielded equivalent survival over seven years.

Do facet joint capsular ligaments contain estrogen receptors? Application to pathogenesis of degenerative spondylolisthesis.

Studies showing that degenerative spondylolisthesis is 4 to 5 times more common in females than in males have suggested that hormonal influences account for this gender difference. Estrogen has been shown to play a role in other instabilities, such as those of the anterior cruciate ligament and the shoulder capsular ligaments, and estrogen receptors have been identified in these tissues. We wanted to assess facet joint capsular ligaments for the presence of such receptors. Accordingly, we collected facet joint capsular ligaments from 14 consecutive patients undergoing lumbar spinal fusion. Tissue sample analysis was performed by immunohistology using prediluted estrogen monoclonal antibody (Vantana) and automated immunostaining on a Vantana instrument. None of the specimens analyzed contained estrogen receptors. We conclude that, though degenerative spondylolisthesis may have hormonal influences, estrogen seems not to play a direct role in its development.

Changes in the structure, composition, and activity of hospital governing boards, 1989-1997: evidence from two national surveys.

Hospital governance arrangements affect institutional policymaking and strategic decisions and can vary by such organizational attributes as ownership type/control, size, and system membership. A comparison of two national surveys shows how hospital governing boards changed in response to organizational and environmental pressures between 1989 and 1997. The magnitude and direction of changes in (1) board structure, composition, and selection; (2) CEO-board relations; and (3) board activity, evaluation, and compensation are examined for the population of hospitals and for different categories of hospitals. The findings suggest that hospital boards are engaging in selective rather than wholesale change to meet the simultaneous demands of a competitive market and traditional institutional orientations to community, the disenfranchised, and philanthropic service. Results also suggest parallel increases in collaboration between boards and CEOs and in board scrutiny of CEOs.