Additive manufacturing (AM) has gained significant attention due to its ability to drive technological development as a sustainable, flexible, and customizable manufacturing scheme. Among the various ...AM techniques, direct ink writing (DIW) has emerged as the most versatile 3D printing technique for the broadest range of materials. DIW allows printing of practically any material, as long as the precursor ink can be engineered to demonstrate appropriate rheological behavior. This technique acts as a unique pathway to introduce design freedom, multifunctionality, and stability simultaneously into its printed structures. Here, a comprehensive review of DIW of complex 3D structures from various materials, including polymers, ceramics, glass, cement, graphene, metals, and their combinations through multimaterial printing is presented. The review begins with an overview of the fundamentals of ink rheology, followed by an in‐depth discussion of the various methods to tailor the ink for DIW of different classes of materials. Then, the diverse applications of DIW ranging from electronics to food to biomedical industries are discussed. Finally, the current challenges and limitations of this technique are highlighted, followed by its prospects as a guideline toward possible futuristic innovations.
The comprehensive review comprises recent development in direct‐ink‐writing (DIW) 3D printing technology for the development of 3D structures from various materials such as polymers, ceramics, glass, cement, graphene, metals, and multimaterials. The work describes the fundamentals and engineering of ink rheology required for DIW. In addition, a multitude of applications, current challenges, and future prospects of the technology are discussed.
We derive an estimate for the chemical composition of the depleted MORB mantle (DMM), the source reservoir to mid-ocean ridge basalts (MORBs), which represents at least 30% the mass of the whole ...silicate Earth. A database for the chemical and physical properties of abyssal peridotites has become robust and complete enough to truly access a reference DMM. Using trace element depletion trends from the abyssal peridotites, it is possible to construct a large part of DMM's trace element pattern. Splicing this information with isotopic constraints (Sr–Nd–Pb–Hf) and canonical ratios (Ce/Pb, Nb/Ta, Nb/U, Ba/Rb, H
2O/Ce, CO
2/Nb and Cl/K), we can extend abundance estimates to all the incompatible elements including volatile content. The resulting trace element pattern for average DMM constrains parental MORB to be generated by 6% aggregated fractional melting, consistent with recent models for hydrous melting of the mantle P.D. Asimow, J.E. Dixon, C.H. Langmuir, A hydrous melting and fractionation model for mid-ocean ridge basalts: application to the Mid-Atlantic Ridge near the Azores, Geochem. Geophys. Geosyst. 5 (2004) 10.1029/2003GC000568. We show that DMM is roughly balanced by the continental crust and better balanced upon inclusion of ocean island basalt source and oceanic crust components. Compared to the primitive mantle, DMM has been depleted by 2–3% melt extraction and has only 15% the radiogenic heat production.
Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively ...preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity.
This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1–3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy.
A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS 6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107).
Trilaciclib demonstrated an improvement in the patient’s tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib’s myelopreservation benefits.
NCT02499770.
To develop latent classes of exposure to traumatic experiences before the age of 13 years in an urban community sample and to use these latent classes to predict the development of negative ...behavioral outcomes in adolescence and young adulthood.
A total of 1815 participants in an epidemiologically based, randomized field trial as children completed comprehensive psychiatric assessments as young adults. Reported experiences of nine traumatic experiences before age 13 years were used in a latent class analysis to create latent profiles of traumatic experiences. Latent classes were used to predict psychiatric outcomes at age ⩾13 years, criminal convictions, physical health problems and traumatic experiences reported in young adulthood.
Three latent classes of childhood traumatic experiences were supported by the data. One class (8% of sample), primarily female, was characterized by experiences of sexual assault and reported significantly higher rates of a range of psychiatric outcomes by young adulthood. Another class (8%), primarily male, was characterized by experiences of violence exposure and reported higher levels of antisocial personality disorder and post-traumatic stress. The final class (84%) reported low levels of childhood traumatic experiences. Parental psychopathology was related to membership in the sexual assault group.
Classes of childhood traumatic experiences predict specific psychiatric and behavioral outcomes in adolescence and young adulthood. The long-term adverse effects of childhood traumas are primarily concentrated in victims of sexual and non-sexual violence. Gender emerged as a key covariate in the classes of trauma exposure and outcomes.
Hotspot lavas erupted at ocean islands exhibit tremendous isotopic variability, indicating that there are numerous mantle components hosted in upwelling mantle plumes that generate volcanism at ...hotspots like Hawaii and Samoa. However, it is not known how the surface expression of the various geochemical components observed in hotspot volcanoes relates to their spatial distribution within the plume. Here we present a relationship between He and Pb isotopes in Samoan lavas that places severe constraints on the distribution of geochemical species within the plume. The Pb-isotopic compositions of the Samoan lavas reveal several distinct geochemical groups, each corresponding to a different geographic lineament of volcanoes. Each group has a signature associated with one of four mantle endmembers with low (3)He/(4)He: EMII (enriched mantle 2), EMI (enriched mantle 1), HIMU (high µ = (238)U/(204)Pb) and DM (depleted mantle). Critically, these four geochemical groups trend towards a common region of Pb-isotopic space with high (3)He/(4)He. This observation is consistent with several low-(3)He/(4)He components in the plume mixing with a common high-(3)He/(4)He component, but not mixing much with each other. The mixing relationships inferred from the new He and Pb isotopic data provide the clearest picture yet of the geochemical geometry of a mantle plume, and are best explained by a high-(3)He/(4)He plume matrix that hosts, and mixes with, several distinct low-(3)He/(4)He components.
Summary
Background
The management of perianal Crohn's fistulas represents a significant challenge. A combination of medical and surgical therapy, guided by radiology, is often required.
Aim
To review ...systematically the literature to assess fistula healing rates with medical treatment (anti‐TNF‐α therapies ± immunomodulators) or surgical treatment alone, compared with combined medical and surgical treatment in fistulising perianal Crohn's disease (CD).
Methods
The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines were used. Two independent reviewers searched the literature.
Results
Twenty‐four articles were included. The total population was 1139 patients; 460 (40%) received single treatment with either medical or surgical therapy, and 679 (60%) received combined medical and surgical therapy. Eight studies compared single and combination therapy, with a total population of 797 patients (single therapy: n = 448, combination therapy: n = 349). In the single therapy group, 191/448 were in complete remission (43%). This was lower than the healing rate of the combination therapy group 180/349 (52%). No response to therapy was noted in 34% (153/448) of the single therapy group compared with 23% (80/349) of the combination group.
Conclusions
Combined surgical and medical (anti‐TNF‐α ± immunomodulators) therapy may have additional beneficial effects on perianal fistula healing in patients with Crohn's disease, compared with surgery or medical therapy alone. A well‐designed Crohn's perianal fistula clinical trial is required in a multidisciplinary medical and surgical setting, with clearly defined end points of clinical (and likely patient reported outcomes) and radiological healing.
Imaging modalities such as endoanal ultrasound or MRI can be useful preoperative adjuncts before the appropriate surgical intervention for perianal fistulas.
We present a systematic review of ...published literature comparing endoanal ultrasound with MRI for the assessment of idiopathic and Crohn's perianal fistulas.
A meta-analysis was performed to obtain pooled values for specificity and sensitivity.
Electronic databases were searched from January 1970 to October 2010 for published studies.
Four studies were used in our analysis. There were 241 fistulas in the ultrasound group and 240 in the magnetic resonance group.
The combined sensitivity and specificity of magnetic resonance for fistula detection were 0.87 (95% CI: 0.63-0.96) and 0.69 (95% CI: 0.51-0.82). There was a high degree of heterogeneity between studies reporting on MRI sensitivity (df = 3, I = 93%). This compares to a sensitivity and specificity for endoanal ultrasound of 0.87 (95% CI: 0.70-0.95) and 0.43 (95% CI: 0.21-0.69). There was a high degree of heterogeneity between studies reporting on endoanal ultrasound sensitivity (df = 3, I = 92%).
From the available literature, the summarized performance characteristics for MRI and endoanal ultrasound demonstrate comparable sensitivities at detecting perianal fistulas, although the specificity for MRI was higher than that for endoanal ultrasound. Both specificity values are considered to be diagnostically poor, however. The high degree of data heterogeneity and the shortage of applicable studies precludes any firm conclusions being made for clinical practice. Future trials with improved study design (including prospective data collection and consideration of verification bias) may help to further clarify the role of MRI in the assessment and treatment response monitoring of perianal fistulas (particularly in patients with Crohn's disease).
The relationship between stress and behavior can help us to understand how physiological adaptations shape primate societies. Most studies have focused on glucocorticoids (GC) as stress biomarkers, ...but other extrinsic and intrinsic factors can influence GC levels and confound the results. To overcome this issue, including analyses of dehydroepiandrosterone-sulfate (DHEAS), a GC antagonist, can be useful in evaluating overall adrenal function in response to biological, social, and environmental factors. Our goal was to evaluate the effect of reproductive state, social behavior, ambient temperature, and season (mating and non-mating) on DHEAS levels and the ratio between GC metabolites and DHEAS (GCM:DHEAS) in 11 free-ranging, female, Japanese macaques (
Macaca fuscata
) (7 pregnant/lactating, 4 nonpregnant/nonlactating) from Jigokudani Monkey Park (Japan). We validated and measured fecal DHEAS levels in 354 samples by enzyme immunoassay and calculated GCM:DHEAS by using previously reported data for GC metabolites. We tested the effects of reproductive state, dominance rank, social behavior, season, and ambient temperature on adrenal steroids using Generalized Linear Mixed-Effect Models. We found that pregnant and lactating females had higher DHEAS levels than nonpregnant/nonlactating females and that DHEAS levels were higher during the mating season. Temperature was positively correlated with GCM:DHEAS. Dominant females had higher DHEAS levels and lower GCM:DHEAS than subordinate females. We suggest that the high DHEAS to GC ratio in high-ranking females explains why they have better body condition than low-ranking females despite high GCM levels. This study confirms that including DHEAS provides valuable information for evaluating the stress response in primates.
Is the metabolic health of men conceived using ICSI different to that of IVF and spontaneously conceived (SC) men?
ICSI-conceived men aged 18-24 years, compared with SC controls, showed differences ...in some metabolic parameters including higher resting diastolic blood pressure (BP) and homeostasis model assessment for insulin resistance (HOMA-IR) scores, although the metabolic parameters of ICSI- and IVF-conceived singleton men were more comparable.
Some studies suggest that IVF-conceived offspring may have poorer cardiovascular and metabolic profiles than SC children. Few studies have examined the metabolic health of ICSI-conceived offspring.
This cohort study compared the metabolic health of ICSI-conceived men to IVF-conceived and SC controls who were derived from prior cohorts. Participants included 121 ICSI-conceived men (including 100 singletons), 74 IVF-conceived controls (all singletons) and 688 SC controls (including 662 singletons).
Resting systolic and diastolic BP (measured using an automated sphygmomanometer), height, weight, BMI, body surface area and fasting serum metabolic markers including fasting insulin, glucose, total cholesterol, high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol, triglycerides, highly sensitive C-reactive protein (hsCRP) and HOMA-IR were compared between groups. Data were analysed using multivariable linear regression adjusted for various covariates including age and education level.
After adjusting for covariates, compared to 688 SC controls, 121 ICSI-conceived men had higher diastolic BP (β 4.9, 95% CI 1.1-8.7), lower fasting glucose (β -0.7, 95% CI -0.9 to -0.5), higher fasting insulin (ratio 2.2, 95% CI 1.6-3.0), higher HOMA-IR (ratio 1.9, 95% CI 1.4-2.6), higher HDLC (β 0.2, 95% CI 0.07-0.3) and lower hsCRP (ratio 0.4, 95% CI 0.2-0.7) levels. Compared to 74 IVF-conceived singletons, only glucose differed in the ICSI-conceived singleton men (β -0.4, 95% CI -0.7 to -0.1). No differences were seen in the paternal infertility subgroups.
The recruitment rate of ICSI-conceived men in this study was low and potential for recruitment bias exists. The ICSI-conceived men, the IVF-conceived men and SC controls were from different cohorts with different birth years and different geographical locations. Assessment of study groups and controls was not contemporaneous, and the measurements differed for some outcomes (BP, insulin, glucose, lipids and hsCRP).
These observations require confirmation in a larger study with a focus on potential mechanisms. Further efforts to identify whether health differences are due to parental characteristics and/or factors related to the ICSI procedure are also necessary.
This study was funded by an Australian National Health and Medical Research Council Partnership Grant (NHMRC APP1140706) and was partially funded by the Monash IVF Research and Education Foundation. S.R.C. was supported through an Australian Government Research Training Program Scholarship. R.J.H. is supported by an NHMRC project grant (634457), and J.H. and R.I.M. have been supported by the NHMRC as Senior and Principal Research Fellows respectively (J.H. fellowship number: 1021252; R.I.M. fellowship number: 1022327). L.R. is a minority shareholder and the Group Medical Director for Monash IVF Group, and reports personal fees from Monash IVF Group and Ferring Australia, honoraria from Ferring Australia and travel fees from Merck Serono and MSD and Guerbet; R.J.H. is the Medical Director of Fertility Specialists of Western Australia and has equity in Western IVF; R.I.M. is a consultant for and shareholder of Monash IVF Group and S.R.C. reports personal fees from Besins Healthcare and nonfinancial support from Merck outside of the submitted work. The remaining authors have no conflicts of interest to declare.
N/A.
Intermittent (or bolus) feeding regimens in critically ill patients have been of increasing interest to clinicians and scientists. Changes in amino acid, fat and carbohydrate metabolites over time ...might yet deliver other benefits (e.g. modulation of the circadian rhythm and sleep, and impacts on ghrelin secretion, insulin resistance and autophagy). We set out to characterise these changes in metabolite concentration. The Intermittent versus Continuous Feeding in Critically Ill paitents study (NCT02358512) was an eight-centre single-blinded randomised controlled trial. Patients were randomised to received a continuous (control arm) or intermittent (6x/day, intervention arm) enteral feeding regimen. Blood samples were taken on trial days 1, 7 and 10 immediately before and 30 min after intermittent feeds, and at equivalent timepoints in the control arm. A pre-planned targeted metabolomic analysis was performend using Nuclear Resonance Spectroscopy. Five hundred and ninety four samples were analysed from 75 patients. A total of 24 amino acid-, 19 lipid based-, and 44 small molecule metabolite features. Across the main two axes of variation (40-60% and 6-8% of variance), no broad patterns distinguished between intermittent or continuous feeding arms, across intra-day sampling times or over the 10 days from initial ICU admission. Logfold decreases in abundance were seen in metabolites related to amino acids (Glutamine - 0.682; Alanine - 0.594), ketone body metabolism (Acetone - 0.64; 3-Hydroxybutyric Acid - 0.632; Acetonacetic Acid - 0.586), fatty acid (carnitine - 0.509) and carbohydrate metabolism ( Maltose - 0.510; Citric Acid - 0.485). 2-3 Butanediol, a by-product of sugar-fermenting microbial metabolism also decreased (- 0.489). No correlation was seen with change in quadriceps muscle mass for any of the 20 metabolites varying with time (all p > 0.05). Increasing severity of organ failure was related to increasing ketone body metabolism (3 Hydroxybutyric Acid-1 and - 3; p = 0.056 and p = 0.014), carnitine deficiency (p = 0.002) and alanine abundancy (p - 0.005). A 6-times a day intermittent feeding regimen did not alter metabolite patterns across time compared to continuous feeding in critically ill patients, either within a 24 h period or across 10 days of intervention. Future research on intermittent feeding regimens should focus on clinical process benefits, or extended gut rest and fasting.
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