The antitachycardia pacing ICD: impact on patient selection and outcome.
Implantable cardioverter defibrillators (ICD) currently undergoing clinical investigation incorporate antitachycardia pacing capabilities, but little is known about their effect on patient selection and outcome. The Bilitch registry database was reviewed to compare the 1,553 patients who initially received standard devices with the 242 patients initially implanted with antitachycardia pacing ICDs (ANT). Baseline characteristics including mean age, ejection fraction, sex, type of cardiac disease, and percent presenting with sudden cardiac death were reviewed. Cumulative first shock occurrence and survival from arrhythmic and all cause mortality were calculated for the two groups. Patient characteristics were similar in the two groups except that the ANT population had a greater male predominance and initially presented with a lower sudden cardiac death incidence (P < 0.05). Cumulative occurrence of first shock was significantly lower in the ANT group up to 24 months of follow-up (28% vs 36%, P < 0.05). ANT group survival from arrhythmic death (99% vs 96%) and all cause mortality (89% vs 94%) was significantly higher at 24 months of follow-up (P < 0.05). The addition of antitachycardia pacing to ICD therapy appears to significantly limit the occurrence of first ICD shock without adversely affecting mortality in a patient population similar to those implanted with standard ICDs.


Nitric oxide inhibits the positive chronotropic and inotropic responses to sympathetic nerve stimulation in the isolated guinea-pig atria.
This study was designed to determine whether nitric oxide (NO) modulates the positive chronotropic and inotropic (in paced atria) responses to cardiac sympathetic nerve stimulation (SNS) in the isolated guinea-pig double atrial/right stellate ganglion preparation. The ganglion was stimulated at 1, 2, 3 and 5 Hz at constant voltage and the changes in heart rate or force of contraction were measured. The selective neuronal NO synthase (nNOS) inhibitors TRIM (1-(2-trifluoromethylphenyl) imidazole; 100 microM) and 7-NiNa (Na+ salt of 7-nitroindazole; 100 microM) significantly enhanced the positive chronotropic and inotropic responses to SNS. Similar results for heart rate were seen with the non-isoform-selective NOS inhibitor N(omega)nitro-L-arginine (L-NA; 100 microM). All effects were reversed with L-arginine (1 mM). The NO donor sodium nitroprusside (SNP; 100 microM) increased baseline heart rate and force of contraction, and attenuated the positive chronotropic and inotropic responses to SNS. SNP also decreased the positive chronotropic response to bath-applied noradrenaline (NA; 1 microM). In contrast, 7-NiNa did not alter the increase in heart rate with bath-applied NA (0.1 or 1 microM). The guanylyl cyclase inhibitor ODQ (10 microM) enhanced (mimicking nNOS inhibition) and the cyclic GMP (guanosine 3':5'-cyclic monophosphate) analogue 8-Br-cGMP (8-bromoguanosine 3':5'-cyclic monophosphate; 1 mM) attenuated (mimicking exogenous NO) the positive inotropic response to SNS. Taken together, these results are consistent with endogenous NO, synthesized from nNOS, inhibiting the positive chronotropic and inotropic responses evoked by cardiac SNS via a cyclic GMP-dependent pathway.


Soy, isoflavones, and breast cancer risk in Japan.
Although isoflavones, such as those found in soy, have been shown to inhibit breast cancer in laboratory studies, associations between consumption of isoflavone-containing foods and breast cancer risk have been inconsistent in epidemiologic studies. We evaluated the relationship between isoflavone consumption and breast cancer risk among women in the Japan Public Health Center-Based Prospective Study on Cancer and Cardiovascular Diseases (JPHC Study). In January 1990, 21 852 Japanese female residents (aged 40-59 years) from four public health center areas completed a self-administered questionnaire, which included items about the frequency of soy consumption. Through December 1999 and 209 354 person-years of follow-up, 179 women were diagnosed with breast cancer. Cox proportional hazards regression was used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for breast cancer in relation to consumption of miso soup, soyfoods, and estimated isoflavones. All statistical tests were two-sided. Consumption of miso soup and isoflavones, but not of soyfoods, was inversely associated with the risk of breast cancer. The associations did not change substantially after adjustment for potential confounders, including reproductive history, family history, smoking, and other dietary factors. Compared with those in the lowest quartile of isoflavone intake, the adjusted RRs for breast cancer for women in the second, third, and highest quartiles were 0.76 (95% CI = 0.47 to 1.2), 0.90 (95% CI = 0.56 to 1.5), and 0.46 (95% CI = 0.25 to 0.84), respectively (P(trend) =.043). The inverse association was stronger in postmenopausal women (P(trend) =.006). In a population-based, prospective cohort study in Japan, frequent miso soup and isoflavone consumption was associated with a reduced risk of breast cancer.


Genomic data integration by WON-PARAFAC identifies interpretable factors for predicting drug-sensitivity in vivo.
Integrative analyses that summarize and link molecular data to treatment sensitivity are crucial to capture the biological complexity which is essential to further precision medicine. We introduce Weighted Orthogonal Nonnegative parallel factor analysis (WON-PARAFAC), a data integration method that identifies sparse and interpretable factors. WON-PARAFAC summarizes the GDSC1000 cell line compendium in 130 factors. We interpret the factors based on their association with recurrent molecular alterations, pathway enrichment, cancer type, and drug-response. Crucially, the cell line derived factors capture the majority of the relevant biological variation in Patient-Derived Xenograft (PDX) models, strongly suggesting our factors capture invariant and generalizable aspects of cancer biology. Furthermore, drug response in cell lines is better and more consistently translated to PDXs using factor-based predictors as compared to raw feature-based predictors. WON-PARAFAC efficiently summarizes and integrates multiway high-dimensional genomic data and enhances translatability of drug response prediction from cell lines to patient-derived xenografts.


Health care costs associated with treatment modification in type 2 diabetes mellitus patients taking oral anti-diabetic drugs.
To compare health care costs among patients with type 2 diabetes mellitus (T2DM) who added a new oral anti-diabetes drug (OAD) to an initial regimen with those who up-titrated their initial OAD. Insurance claims data were obtained from 94 health plans for patients aged ≥18 years with ICD-9-CM diagnosis of T2DM during the period Jan. 1, 2001-June 30, 2007, and a newly prescribed metformin or sulfonylurea monotherapy. Patients were followed after initiating monotherapy to identify occurrence of first-treatment modification (addition or up-titration). Health care costs were analyzed during 360 days after first treatment modification. Subgroup analyses included comparison of addition cohort with two titration subgroups: 1) titration up to or below intermediate doses and 2) titration to beyond intermediate doses. During the post-treatment modification period, all-cause medication costs were 9% higher (p < 0.0001), while inpatient costs were 14% lower for the addition cohort (p < 0.008) as compared to the up-titration cohort. The total risk-adjusted health care costs were slightly lower but statistically insignificant for the addition cohort compared to the up-titration cohort (ratio of cost = 0.99; p = 0.052). These costs patterns remained similar for both the up-titration subgroups. While addition of another OAD to the initial OAD regimen may result in higher medication costs, the lower inpatient costs and overall offset in the subsequent total costs may indicate clinical benefits with the add-on treatment. When appropriate and clinically beneficial, physicians may want to consider adding an OAD rather than up-titrating the current OAD, particularly beyond intermediate dose levels.


Ardipithecus ramidus and the evolution of the human cranial base.
The early Pliocene African hominoid Ardipithecus ramidus was diagnosed as a having a unique phylogenetic relationship with the Australopithecus + Homo clade based on nonhoning canine teeth, a foreshortened cranial base, and postcranial characters related to facultative bipedality. However, pedal and pelvic traits indicating substantial arboreality have raised arguments that this taxon may instead be an example of parallel evolution of human-like traits among apes around the time of the chimpanzee-human split. Here we investigated the basicranial morphology of Ar. ramidus for additional clues to its phylogenetic position with reference to African apes, humans, and Australopithecus. Besides a relatively anterior foramen magnum, humans differ from apes in the lateral shift of the carotid foramina, mediolateral abbreviation of the lateral tympanic, and a shortened, trapezoidal basioccipital element. These traits reflect a relative broadening of the central basicranium, a derived condition associated with changes in tympanic shape and the extent of its contact with the petrous. Ar. ramidus shares with Australopithecus each of these human-like modifications. We used the preserved morphology of ARA-VP 1/500 to estimate the missing basicranial length, drawing on consistent proportional relationships in apes and humans. Ar. ramidus is confirmed to have a relatively short basicranium, as in Australopithecus and Homo. Reorganization of the central cranial base is among the earliest morphological markers of the Ardipithecus + Australopithecus + Homo clade.


Heat Shock Protein member A2 forms a stable complex with angiotensin converting enzyme and protein disulfide isomerase A6 in human spermatozoa.
Given the importance of the chaperone Heat Shock Protein A2 (HSPA2) in the regulation of male fertility, this study aimed to identify and characterize additional proteins that may rely on the activity of this chaperone in human spermatozoa. In view of the findings in this study we propose that angiotensin converting enzyme (ACE) and protein disulfide isomerase A6 (PDIA6) are novel interacting proteins of HSPA2 and that this multimeric complex may participate in key elements of the fertilization cascade. The molecular chaperone HSPA2 plays a pivotal role in the remodelling of the sperm surface during capacitation. Indeed, human spermatozoa that are deficient in HSPA2 protein expression lack the ability to recognize human oocytes, resulting in repeated IVF failure in a clinical setting. Moreover, our recent work has shown that defective HSPA2 function induced by oxidative stress leads to the aberrant surface expression of one of its interacting proteins, arylsulfatase A, and thus contributes to a loss of sperm-zona pellucida adhesion. Human spermatozoa were collected from fertile donors, capacitated and prepared for Blue Native Polyacrylamide Gel Electrophoresis (BN-PAGE) analysis. Protein complexes resolved via BN-PAGE were excised and their constituents were identified using mass spectrometry. The interactions between ACE, PDIA6 and HSPA2 were then confirmed using immunoprecipitation and proximity ligation assays and the localization of these proteins was assessed in isolated spermatozoa and commercially available human testis tissue sections. Finally, pharmacological inhibition of ACE was performed to assess the role of ACE in human sperm capacitation. Herein we have identified ACE and PDIA6 as potential HSPA2-interacting proteins and shown that this assemblage resides in membrane raft microdomains located in the peri-acrosomal region of the sperm head. Additionally, the surface expression of PDIA6, but not ACE, was shown to be dynamically regulated during sperm capacitation and, like that of previously characterized HSPA2-interacting proteins, this surface expression proved vulnerable to oxidative stress. In terms of the functional significance of this protein complex, pharmacological inhibition of ACE significantly reduced the ability of human spermatozoa to undergo an agonist induced acrosome reaction (P < 0.01). While these results provide a descriptive analysis of the PDIA6/ACE/HSPA2 complex, this study provides the impetus for further investigation into the role of PDIA6 and ACE in human sperm function. As our research group, and others, have shown that HSPA2 is compromised in the spermatozoa of men with oocyte recognition defects, the characterization of these HSPA2-interacting proteins provides important insight into the complexity of the cellular pathways that may be affected in the spermatozoa of infertile individuals. Large scale proteomics data can be accessed through the Proteomics Identifications Database (PRIDE). This work was supported by the National Health and Medical Research Council. Grant # APP1046346. The authors have no competing interests to declare.


New recommendations for testing indirect effects in mediational models: The need to report and test component paths.
In light of current concerns with replicability and reporting false-positive effects in psychology, we examine Type I errors and power associated with 2 distinct approaches for the assessment of mediation, namely the component approach (testing individual parameter estimates in the model) and the index approach (testing a single mediational index). We conduct simulations that examine both approaches and show that the most commonly used tests under the index approach risk inflated Type I errors compared with the joint-significance test inspired by the component approach. We argue that the tendency to report only a single mediational index is worrisome for this reason and also because it is often accompanied by a failure to critically examine the individual causal paths underlying the mediational model. We recommend testing individual components of the indirect effect to argue for the presence of an indirect effect and then using other recommended procedures to calculate the size of that effect. Beyond simple mediation, we show that our conclusions also apply in cases of within-participant mediation and moderated mediation. We also provide a new R-package that allows for an easy implementation of our recommendations. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Combined inpatient rehabilitation and spa therapy for breast cancer patients: effects on quality of life and CA 15-3.
The present study investigated the changes of quality of life, mood, and the tumor marker CA 15-3 associated with a 3-week inpatient breast cancer rehabilitation program incorporating spa therapy. One hundred forty-nine women, 32 to 82 years, participated in the study 3 to 72 months after breast cancer surgery. Quality of life (QoL, EORTC QLQ-C30), anxiety, and depression (HADS) were measured 2 weeks before, at the end, and 6 months after rehabilitation; CA 15-3 at the beginning, end, and at 6 months follow-up. Patients received an individualized rehabilitation program incorporating manual lymph drainage, exercise therapy, massages, psychological counseling, relaxation training, carbon dioxide baths, and mud packs. Quality of life and mood improved significantly, the greatest short-term improvements found for mood-related aspects of quality of life, the most lasting improvements found for physical complaints (eg, fatigue). Also, the tumor marker CA 15-3 declined significantly to follow-up. Patient characteristics, as well as the time since surgery, moderated rehabilitation outcome to a limited extent. Older patients, nonobese patients, patients with a greater lymphedema, and patients with an active coping style showed slightly greater improvements. Hot mud packs inducing hyperthermia did not affect CA 15-3. In conclusion, the combination of inpatient rehabilitation with spa therapy provides a promising approach for breast cancer rehabilitation.


The Effect of Dietary Supplementation of Crocetin for Myopia Control in Children: A Randomized Clinical Trial.
The prevalence of myopia has been increasing in recent years. The natural carotenoid crocetin has been reported to suppress experimental myopia in mice. We evaluated the effects of crocetin on myopia suppression in children. A multicenter randomized double-blind placebo-controlled clinical trial was performed with 69 participants aged 6 to 12 years, whose cycloplegic spherical equivalent refractions (SER) were between -1.5 and -4.5 diopter (D). The participants were randomized to receive either a placebo or crocetin and followed up for 24 weeks. Axial length (AL) elongation and changes in SER were evaluated for 24 weeks. Both written informed assent from the participants and written informed consent from legal guardians were obtained in this study because the selection criteria of this trial included children aged between 6 and 12 years old. This trial was approved by the institutional review boards. A mixed-effects model was used for analysis, using both eyes. Two participants dropped out and 67 children completed this trial. The change in SER in the placebo group, -0.41 ± 0.05 D (mean ± standard deviation), was significantly more myopic compared to that in the crocetin group, -0.33 ± 0.05 D (p = 0.049). The AL elongation in the placebo group, 0.21 ± 0.02 mm, was significantly bigger than that in the crocetin group, 0.18 ± 0.02 mm (p = 0.046). In conclusion, dietary crocetin may have a suppressive effect on myopia progression in children, but large-scale studies are required in order to confirm this effect.


Visits to Registered Nurses: An Opportunity to Increase Contraceptive Access in California.
In 2013, California passed Assembly Bill (A.B.) 2348, approving registered nurses (RNs) to dispense patient self-administered hormonal contraceptives and administer injections of hormonal contraceptives. The Family Planning, Access, Care and Treatment (Family PACT) program, which came into effect in 1997 to expand low-income, uninsured California resident access to contraceptives at no cost, is one program in which qualified RNs can dispense and administer contraceptives. The aims of this study were to (a) describe utilization of RN visits within California's Family PACT program and (b) evaluate the impact of RN visits on client birth control acquisition during the first 18 months after implementation of A.B. 2348 (January 1, 2013 to June 30, 2014). A descriptive observational design using administrative databases was used. Family PACT claims were retrieved for RN visits and contraception. Paid claims for contraceptive dispensing and/or administration visits by physicians, nurse practitioners, certified nurse midwives, and physician assistants were compared before and after the implementation of A.B. 2348 at practice sites where RN visits were and were not utilized. Contraceptive methods and administration procedures were identified using Healthcare Common Procedure Coding System codes, National Drug Codes, and Common Procedural Terminology codes. Claims data for healthcare facilities were abstracted by site location based on a unique combination of National Provider Identifier (NPI), NPI Owner, and NPI location number. RN visits were found mainly in Northern California and the Central Valley (73%). Sixty-eight percent of RN visits resulted in same-day dispensing and/or administration of hormonal (and/or barrier) methods. Since benefit implementation, RN visits resulted in a 10% increase in access to birth control dispensing and/or administration visits. RN visits were also associated with future birth control acquisition and other healthcare utilization within the subsequent 30 days. RN visits, though underutilized across the state, have resulted in increased access to contraception in some communities, an effect that may continue to grow with time and can serve as a model for other states.


AN EXPERIMENTAL STUDY OF CIRCUMSCRIBED DILATION OF AN ARTERY IMMEDIATELY DISTAL TO A PARTIALLY OCCLUDING BAND, AND ITS BEARING ON THE DILATION OF THE SUBCLAVIAN ARTERY OBSERVED IN CERTAIN CASES OF CERVICAL RIB.
1. A partially occluded artery may dilate distal to the site of constriction. 2. The dilation is circumscribed. 3. When the constriction has been either slight in amount or complete, dilation has not been observed. 4. The dilation was greatest when the lumen of the artery (the aorta) was reduced to one-third or perhaps one-fourth of its original size (Figs. 8 and 11). 5. Dilation or aneurysm of the subclavian artery has been observed twenty-seven or more times in cases of cervical rib. 6. The dilation of the subclavian is circumscribed, is distal to the point of constriction, and strikingly resembles the dilation which we have produced experimentally. 7. The genesis of the experimental dilation and of the subclavian dilation occurring with cervical rib is probably the same. 8. When the lumen of the aorta is considerably constricted the systolic pressure may be permanently so lowered and the diastolic pressure so increased that the pulse pressure is greatly diminished. 9. The experimentally produced dilations and the aneurysms of the subclavian artery in cases of cervical rib are probably not due to vasomotor paralysis, trauma, or sudden variations in blood pressure. 10. The abnormal, whirlpool-like play of the blood in the relatively dead pocket just below the site of the constriction, and the lowered pulse pressure may be the chief factors concerned in the production of the dilations. 11. Intimal surfaces brought, however gently, in contact by bands or ligatures do not, in our experience, unite by first intention, for the force necessary to occlude the artery is sufficient to cause necrosis of the arterial wall. 12. Bands, rolled ever so tightly, do not rupture the intima. 13. The death of the arterial wall having been brought about by the pressure of the band, a gradual substitution of the necrotic tissue takes place, the new vessels penetrating it from both ends. It is, I believe, in this manner that an artery becomes occluded, and it is thus that a fibrous cord forms within the constricting band.


Preparation of Chitosan-Coated Nanostructured Lipid Carriers (CH-NLCs) to Control Iron Delivery and Their Potential Application to Food Beverage System.
Nanostructured lipid carriers (NLCs) and chitosan-coated NLCs (CH-NLCs) were prepared by a combined double emulsion and melt dispersion method. The physicochemical properties of them were investigated to determine the optimum conditions. At 3% emulsifier concentration, the NLCs showed about 191.0 ± 4.1 nm mean particle size and low polydispersity index value compared to those observed under other conditions. The encapsulation efficiency of CH-NLCs was 83.9% which was about 10% higher than that of NLCs. In vitro release test showed that low release amount of iron from the NLCs (11%) and CH-NLCs (5%) in simulated gastric condition within 3 h, whereas the iron release amounts of the NLCs and CH-NLCs were high (over 77%) in simulated intestinal condition because both NLCs and CH-NLCs were totally destructed in the intestinal condition after 3 h. In the thiobarbituric acid test, the absorbance of milk-fortified NLC and CH-NLCs was lower than that of original milk. Based on these results, CH-NLCs showed great potential for iron fortification in milk.


Theoretical Insights into a CO Dimerization Mechanism in CO2 Electroreduction.
In this work, we present DFT simulations that demonstrate the ability of Cu to catalyze CO dimerization in CO2 and CO electroreduction. We describe a previously unreported CO dimer configuration that is uniquely stabilized by a charged water layer on both Cu(111) and Cu(100). Without this charged water layer at the metal surface, the formation of the CO dimer is prohibitively endergonic. Our calculations also demonstrate that dimerization should have a lower activation barrier on Cu(100) than Cu(111), which, along with a more exergonic adsorption energy and a corresponding higher coverage of *CO, is consistent with experimental observations that Cu(100) has a high activity for C-C coupling at low overpotentials. We also demonstrate that this effect is present with cations other than H(+), a finding that is consistent with the experimentally observed pH independence of C2 formation on Cu.


Identification of critical control points for antibiotic resistance discharge in sewers.
Disrupting the spread of clinically relevant antibiotic resistance genes (ARGs) is one of the key components for the success of the One Health strategy. While waste water treatment plants (WWTPs) represent a final control point for daily discharges of antibiotic resistance genes (ARGs) to the aquatic environment, a decentralized upstream monitoring of wastewater feeds of selected urban drainage areas for blaCTX-M32, blaCTX-M15, blaOXA48, blaCMY-2, mecA, blaNDM-1, blaKPC3, vanA, and mcr-1 representing clinically relevant ARGs has been performed. Besides hospitals, also retirement homes were found to be responsible for high levels of ARG discharges compared to housing area sewer systems. The monitoring combines qPCR-based quantifications, flow volume-based analyses, and multiple antibiotic resistance analyses of isolates. As result of the study, local actions at identified critical control points could help to prevent contaminations of larger volumes of wastewaters. This strategy will support a more cost-effective treatment compared to central actions at WWTPs, only. A polluter-pays principle should be applied by this monitoring strategy.


Unraveling the mechanisms of S-doped carbon nitride for photocatalytic oxygen reduction to H2O2.
An in-depth understanding of the microscopic reaction mechanism on a nonmetal-doped catalytic system at the atomic level is one of the critical approaches to developing new efficient catalysts. Herein, the effects of S-doping on melon-based carbon nitride (CN) for the photocatalytic selective oxygen reduction reaction (ORR) have been comprehensively investigated by first-principles calculations. The configurations, electronic properties, optical properties, and the reaction performance of the S-doped melon-based CN have been studied and discussed. The results demonstrate that the decoration with S atoms exhibited substantial effects, involving the redistribution of the charge density and tuning of the bandgap, which promote the photocatalytic selective ORR activity. Accordingly, O2 is activated on the S-doped system with about 0.4 e of charge obtained from catalytic surfaces, leading to the thermodynamically feasible H2O2 and H2O formation, which is in good agreement with the experimental results. Our results provide theoretical insights into the design and development of polymeric carbon nitride (PCN) as well as other metal-free photocatalysts for the selective ORR.


Subclinical diabetic neuropathy: similarities between electrophysiological results of patients with type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus.
Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients share many clinical and biochemical characteristics. However, sural nerve biopsies from patients with advanced and chronic neuropathy show ultrastructural differences between these two groups. We investigated whether at a subclinical stage of the illness, when Type 1 and Type 2 diabetic patients are clinically uniform and the histopathological nerve alterations are not advanced, comparison between the two diabetes groups might show differences in nerve fibre involvement related to the different pathogeneses of the neuropathies. A total of 88 diabetic patients (52 Type 1 and 36 Type 2), with a subclinical form of polyneuropathy were selected. The clinical neurophysiological examination consisted of motor and sensory nerve conduction studies, Hoffmann (H)-reflex, single fibre electromyography and static as well as dynamic pupillometry. With regard to clinical neurophysiological abnormalities, the severity of the polyneuropathy appeared to be equal in both groups. Despite the absence of clinical symptoms the neurophysiological abnormalities were pronounced and it was impossible to differentiate Type 1 diabetic patients from Type 2 diabetic patients on a clinical neurophysiology basis when correcting for differences in age, height, and duration of illness. In the Type 1 diabetic group as well as in the Type 2 diabetic group the autonomic nerve fibres and nerves in the legs were more frequently affected than the thick myelinated nerves in the arms. These findings do not support the assumption that there is a difference in the manifestation of polyneuropathy between Type 1 and Type 2 diabetic patients.


Mycotic aneurysm: a rare complication of vertebral osteomyelitis.
We report the case of a 49-year-old man that presented with persistent low back pain after being treated for vertebral osteomyelitis. An abdominopelvic CT scan with intravenous contrast showed a mycotic aneurysm of the abdominal aorta. The patient was taken to the operating room where a bypass reconstruction surgery was successfully performed. The history, pathophysiology, most common organisms, risk factors, and clinical presentation of mycotic aneurysms are discussed. The importance of a high index of suspicion for prompt and proper diagnosis and treatment, is emphasized to create awareness about this dreadful complication of vertebral osteomyelitis.


Temporomandibular disorders: A position paper of the International College of Cranio-Mandibular Orthopedics (ICCMO).
Two principal schools of thought regarding the etiology and optimal treatment of temporomandibular disorders exist; one physical/functional, the other biopsychosocial. This position paper establishes the scientific basis for the physical/functional. THE ICCMO POSITION: Temporomandibular disorders (TMD) comprise a group of musculoskeletal disorders, affecting alterations in the structure and/or function of the temporomandibular joints (TMJ), masticatory muscles, dentition and supporting structures. The initial TMD diagnosis is based on history, clinical examination and imaging, if indicated. Diagnosis is greatly enhanced with physiologic measurement devices, providing objective measurements of the functional status of the masticatory system: TMJs, muscles and dental occlusion. The American Alliance of TMD organizations represent thousands of clinicians involved in the treatment of TMD. The ten basic principles of the Alliance include the following statement: Dental occlusion may have a significant role in TMD; as a cause, precipitant and/or perpetuating factor. Therefore, it can be stated that the overwhelming majority of dentists treating TMD believe dental occlusion plays a major role in predisposition, precipitation and perpetuation. While our membership believes that occlusal treatments most frequently resolve TMD, it is recognized that TMD can be multi faceted and may exist with co-morbid physical or emotional factors that may require therapy by appropriate providers. The International College of Cranio-Mandibular Orthopedics (ICCMO), composed of academic and clinical dentists, believes that TMD has a primary physical/functional basis. Initial conservative and reversible TMD treatment employing a therapeutic neuromuscular orthosis that incorporates relaxed, healthy masticatory muscle function and a stable occlusion is most often successful. This is accomplished using objective measurement technologies and ultra low frequency transcutaneous electrical neural stimulation (TENS). Extensive literature substantiates the scientific validity of the physical/functional basis of TMD, efficacy of measurement devices and TENS and their use as aids in diagnosis and in establishing a therapeutic neuromuscular dental occlusion. A scientifically valid basis for TMD diagnosis and treatment is presented aiding in therapy.


Endotoxn-induced nonthyroidal illness in dogs.
To determine the effects of endotoxin administration on thyroid function test results and serum tumor necrosis factor-alpha (TNF-alpha) activity in healthy dogs. 6 healthy adult male dogs. Serum concentrations of thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3'5'-triiodothyronine (rT3), free T4 (fT4), and endogenous canine thyroid stimulating hormone (TSH), and TNF-alpha activity were measured before (day-1; baseline), during (days 0 to 3), and after (days 4 to 24) IV administration of endotoxin every 12 hours for 84 hours. Compared with baseline values, serum T3 concentration decreased significantly, whereas rT3 concentration increased significantly 8 hours after initial endotoxin administration. Serum T4 concentration decreased significantly at 8 and 12 hours after initiating endotoxin administration. Serum T4 concentration returned to reference range limits, then decreased significantly on days 6 to 12 and 16 to 20. Serum fT4 concentration increased significantly at 12, 24, and 48 hours after cessation of endotoxin treatment, compared with baseline values. Serum rT3 concentration returned to reference range, then decreased significantly days 5 and 7 after stopping endotoxin treatment. Serum TNF-alpha activity was significantly increased only 4 hours after initial endotoxin treatment, compared with baseline activity. Endotoxin administration modeled alterations in thyroid function test results found in dogs with spontaneous nonthyroidal illness syndrome. A decrease in serum T4 andT3 concentrations and increase in serum rT3 concentration indicate impaired secretion and metabolism of thyroid hormones. The persistent decrease in serum T4 concentration indicates that caution should be used in interpreting serum T4 concentrations after resolution of an illness in dogs.


Origin and genetic diversity of diploid parthenogenetic Artemia in Eurasia.
There is wide interest in understanding how genetic diversity is generated and maintained in parthenogenetic lineages, as it will help clarify the debate of the evolution and maintenance of sexual reproduction. There are three mechanisms that can be responsible for the generation of genetic diversity of parthenogenetic lineages: contagious parthenogenesis, repeated hybridization and microorganism infections (e.g. Wolbachia). Brine shrimps of the genus Artemia (Crustacea, Branchiopoda, Anostraca) are a good model system to investigate evolutionary transitions between reproductive systems as they include sexual species and lineages of obligate parthenogenetic populations of different ploidy level, which often co-occur. Diploid parthenogenetic lineages produce occasional fully functional rare males, interspecific hybridization is known to occur, but the mechanisms of origin of asexual lineages are not completely understood. Here we sequenced and analysed fragments of one mitochondrial and two nuclear genes from an extensive set of populations of diploid parthenogenetic Artemia and sexual species from Central and East Asia to investigate the evolutionary origin of diploid parthenogenetic Artemia, and geographic origin of the parental taxa. Our results indicate that there are at least two, possibly three independent and recent maternal origins of parthenogenetic lineages, related to A. urmiana and Artemia sp. from Kazakhstan, but that the nuclear genes are very closely related in all the sexual species and parthenogegetic lineages except for A. sinica, who presumable took no part on the origin of diploid parthenogenetic strains. Our data cannot rule out either hybridization between any of the very closely related Asiatic sexual species or rare events of contagious parthenogenesis via rare males as the contributing mechanisms to the generation of genetic diversity in diploid parthenogenetic Artemia lineages.


Women's Experiences of Fetal Movements before the Confirmation of Fetal Death--Contractions Misinterpreted as Fetal Movement.
Decreased fetal movement often precedes a stillbirth. The objective of this study was to describe women's experiences of fetal movement before the confirmation of fetal death. Data were collected through a Web-based questionnaire. Women with stillbirths after 28 gestational weeks were self-recruited. Content analysis was used to analyze the answers to one open question. The statements from mothers of a stillborn, born during gestational weeks 28 to 36 were compared with those of a stillborn at term. The women's 215 answers were divided into three categories: decreased, weak, and no fetal movement at all; 154 (72%) of the descriptions were divided into three subcategories: decreased and weak movement (106; 49%), no movement at all (35; 16%), and contraction interpreted as movement (13; 6%). The category fetal movement as normal includes 39 (18%) of the descriptions. The third category, extremely vigorous fetal activity followed by no movement at all, includes 22 (10%) of the descriptions. Eight (15%) of the women with stillbirths in gestational weeks 28 to 36 interpreted contractions as fetal movement as compared to 5 (5%) of the women with stillbirths at term. Uterine contractions can be interpreted as fetal movement. A single episode of extremely vigorous fetal activity can precede fetal death. The majority of the women experienced decreased, weaker, or no fetal movement at all 2 days before fetal death was diagnosed. Mothers should be educated to promptly report changes in fetal movement to their health care providers. Using fetal movement information to evaluate possible fetal distress may lead to reductions in stillbirths.


Ventriculoperitoneal shunt surgery outcome in adult transition patients with pediatric-onset hydrocephalus.
Ventriculoperitoneal shunting remains the most widely used neurosurgical procedure for the management of hydrocephalus, albeit with many complications. To review and assess the long-term clinical outcome of ventriculoperitoneal shunt surgery in adult transition patients with pediatric-onset hydrocephalus. Patients 17 years or older who underwent ventriculoperitoneal shunt placement for hydrocephalus during their pediatric years (younger than 17 years) were included. Medical charts, operative reports, imaging studies, and clinical follow- up evaluations were reviewed and analyzed retrospectively. A total of 105 adult patients with pediatric-onset hydrocephalus were included. The median age of the patients was 25.9 years. The median age at the time of the initial ventriculoperitoneal shunt placement was 1.0 year. The median follow-up time for all patients was 17.7 years. The incidence of shunt failure at 6 months was 15.2%, and the overall incidence of shunt failure was 82.9%. Single shunt revision occurred in 26.7% of the patients, and 56.2% had multiple shunt revisions. The cause of hydrocephalus was significantly associated with shunt survival for patients who had shunt failure before the age of 17 years. Being pediatric at first shunt revision, infection, proximal shunt complication, and other causes were independently associated with multiple shunt failures. The findings of this retrospective study show that the long-term ventriculoperitoneal shunt survival remains low in adult transition patients with pediatric-onset hydrocephalus.


Phase II study of erlotinib in patients with advanced biliary cancer.
Epidermal growth factor receptor/human epidermal growth factor receptor 1 and ligand expression is common in biliary cancers (BILI) and may be associated with worse outcome. The primary objective of this study was to determine the proportion of patients with advanced BILI who were progression-free at 6 months. Patients with either unresectable or metastatic disease were studied. Only one prior systemic or locoregional therapy was allowed. Erlotinib was administered continuously at a dose of 150 mg per day orally. Forty-two patients with BILI were enrolled. The median age was 67 years (range, 33 to 82 years). Fifty-two percent of patients had Eastern Cooperative Oncology Group performance status of 1. Fifty-seven percent of patients had received prior chemotherapy for advanced BILI. HER1/EGFR expression by immunohistochemistry in tumor cells was detected in 29 (81%) of the 36 assessable patients. Seven of the patients (17%; 95% CI, 7% to 31%) were progression free at 6 months. Three patients had partial response by Response Evaluation Criteria in Solid Tumors Group classification of duration 4, 4, and 14 months, respectively. All responding patients had mild (grade 1/2) skin rash and two patients had positive tumoral HER1/EGFR expression. Three patients (7%) had toxicity-related dose reductions of erlotinib due to grade 2/3 skin rash. Results suggest a therapeutic benefit for EGFR blockade with erlotinib in patients with biliary cancer. Additional studies with erlotinib as a single agent and in combination with other targeted agents are warranted in this disease.


Melanoblasts on the move: Rac1 sets the pace.
Cell migration is fundamental to development and many cell types have a migratory phase during embryonic development when tissues and body structures are forming. Cancer metastasis is in many ways thought to be analogous to embryonic development. Some of the mechanisms that tumor cells use to hijack the adult body are thought to derive from their abilities to reactivate embryonic signaling and motility pathways and thus enhance their growth and motility. Melanomas are notorious for their ability to become highly invasive and metastatic if not removed early. While adult melanin producing cells, melanocytes, have limited mobility, melanoblasts are highly motile cells that move through the dermis and epidermis during embryogenesis and could serve as a useful paradigm for some aspects of melanoma invasion and metastasis. Recent findings from our laboratory using ex-vivo imaging of mouse melanoblast migration in the epidermis provide the first insights into the role of Rac1 in developing mouse melanoblasts in vivo. Melanoblasts do not move as a collective group, or use an invasive or blebbing mode of migration as revealed by other in vivo systems, but rather they extend short and long dynamic pseudopodia and squeeze between epidermal keratinocytes using myosin motors. Melanoblasts can initiate short actin-based protrusions independently of Rac1. Rac1 is required to control the rate of formation of long actin-based protrusions for effective translocation in skin. Our results reveal a novel mode of in vivo migration controlled by Rac1 that is important for normal development and likely in melanoma.


Application of Hyperspectral Imaging to Underwater Habitat Mapping, Southern Adriatic Sea.
Hyperspectral imagers enable the collection of high-resolution spectral images exploitable for the supervised classification of habitats and objects of interest (OOI). Although this is a well-established technology for the study of subaerial environments, Ecotone AS has developed an underwater hyperspectral imager (UHI) system to explore the properties of the seafloor. The aim of the project is to evaluate the potential of this instrument for mapping and monitoring benthic habitats in shallow and deep-water environments. For the first time, we tested this system at two sites in the Southern Adriatic Sea (Mediterranean Sea): the cold-water coral (CWC) habitat in the Bari Canyon and the Coralligenous habitat off Brindisi. We created a spectral library for each site, considering the different substrates and the main OOI reaching, where possible, the lower taxonomic rank. We applied the spectral angle mapper (SAM) supervised classification to map the areal extent of the Coralligenous and to recognize the major CWC habitat-formers. Despite some technical problems, the first results demonstrate the suitability of the UHI camera for habitat mapping and seabed monitoring, through the achievement of quantifiable and repeatable classifications.


Literature-based compound profiling: application to toxicogenomics.
To reduce continuously increasing costs in drug development, adverse effects of drugs need to be detected as early as possible in the process. In recent years, compound-induced gene expression profiling methodologies have been developed to assess compound toxicity, including Gene Ontology term and pathway over-representation analyses. The objective of this study was to introduce an additional approach, in which literature information is used for compound profiling to evaluate compound toxicity and mode of toxicity. Gene annotations were built by text mining in Medline abstracts for retrieval of co-publications between genes, pathology terms, biological processes and pathways. This literature information was used to generate compound-specific keyword fingerprints, representing over-represented keywords calculated in a set of regulated genes after compound administration. To see whether keyword fingerprints can be used for assessment of compound toxicity, we analyzed microarray data sets of rat liver treated with 11 hepatotoxicants. Analysis of keyword fingerprints of two genotoxic carcinogens, two nongenotoxic carcinogens, two peroxisome proliferators and two randomly generated gene sets, showed that each compound produced a specific keyword fingerprint that correlated with the experimentally observed histopathological events induced by the individual compounds. By contrast, the random sets produced a flat aspecific keyword profile, indicating that the fingerprints induced by the compounds reflect biological events rather than random noise. A more detailed analysis of the keyword profiles of diethylhexylphthalate, dimethylnitrosamine and methapyrilene (MPy) showed that the differences in the keyword fingerprints of these three compounds are based upon known distinct modes of action. Visualization of MPy-linked keywords and MPy-induced genes in a literature network enabled us to construct a mode of toxicity proposal for MPy, which is in agreement with known effects of MPy in literature. Compound keyword fingerprinting based on information retrieved from literature is a powerful approach for compound profiling, allowing evaluation of compound toxicity and analysis of the mode of action.


Changes in barrier function of a model intestinal epithelium by intraepithelial lymphocytes require new protein synthesis by epithelial cells.
Elements of the mucosal immune system may play an important part in regulating epithelial barrier function in the intestinal tract. Intraepithelial lymphocytes (IELs) represent a subtype of immunocyte which is strategically placed to regulate epithelial function at most mucosal sites. An IEL derived cell line (SC1) was used to examine its effects on the model epithelium T84--a tumour derived cell line which retains the phenotype of colonic crypt cells. Transepithelial electrical resistance (TER) was used as a marker of epithelial integrity. Coculture of T84 cells with SC1 produced a significant fall in TER as did exposure of T84 monolayers to IEL derived supernatant. Recombinant interferon-gamma (rIFN gamma) also reduced TER in T84 monolayers. Cycloheximide prevented the effects of IEL supernatant and of rIFN gamma on TER. The fall in TER in response to rIFN gamma was attenuated by blocking antibodies, which did not alter the fall in resistance induced by IEL supernatant. Fractions of IEL supernatant, separated on the basis of size, evoked temporally distinct changes in TER. Ultrastructural studies support the hypothesis that the slow onset but severe fall in TER indicates catastrophic effects on the monolayer. The more rapid onset fall in TER was not associated with gross changes in monolayer morphology. Reduction of TER by IEL supernatant was not influenced by inhibitors of tyrosine phosphatase or of protein kinase C. Although herbimycin did reduce the rapid onset change in TER, the tyrosine kinase inhibitor genistein did not alter responses to IEL supernatant. Mucosal T cells may influence barrier function by a process involving new protein synthesis by epithelial cells. This model may have relevance in some inflammatory conditions of the gastrointestinal tract.


Takayasu arteritis with multiple intracranial aneurysms. A case report.
A rare case of multiple cerebral aneurysms associated with Takayasu aortitis is reported. Only seven cases have been reported so far, all of which are from Japan. This is the first case with this association being reported from India. A 50-year-old hypertensive woman developed sudden onset severe headache and loss of consciousness. CT scan revealed subarachnoid haemorrhage in the suprasellar cisterns and mild hydrocephalus. The patient on admission had a rebleed producing a massive subarachnoid haemorrhage. Angiogram revealed occlusion of bilateral vertebral arteries and right common carotid artery. The left carotid artery was ectatic with saccular aneurysms in the ophthalmic segment and communicating segment. Aortogram showed the radiological picture of Takayasu arteritis Type III. Surgical clipping of the aneurysms was performed. However, the patient developed a massive right cerebral infarct in the postoperative period following which she expired. Abnormal haemodynamics in the overloaded cerebral circulation rather than primary arteritic involvement of intracranial vessels appears to be the cause of aneurysm formation.


Using Smart City Technology to Make Healthcare Smarter.
Smart cities use information and communication technologies (ICT) to scale services include utilities and transportation to a growing population. In this article we discuss how smart city ICT can also improve healthcare effectiveness and lower healthcare cost for smart city residents. We survey current literature and introduce original research to offer an overview of how smart city infrastructure supports strategic healthcare using both mobile and ambient sensors combined with machine learning. Finally, we consider challenges that will be faced as healthcare providers make use of these opportunities.


Targeting CGRP for the Prevention of Migraine and Cluster Headache: A Narrative Review.
Calcitonin-gene-related peptide (CGRP), a neuropeptide broadly distributed in neuronal and non-neuronal regions throughout the body, plays a fundamental role in migraine and cluster headache (CH) pathophysiology. CGRP functional blockade alleviates neurogenic inflammation and reduces pain pathway sensitization. Two types of CGRP function-blocking modalities, monoclonal antibodies (MAbs), and small molecules (gepants), have been designed to target the CGRP ligands and CGRP receptors. In this narrative review, we summarized the latest clinical trials on gepants and CGRP function-blocking MAbs for migraine and CH prevention. At the time of writing, newer gepants are currently under Federal Drug Administration (FDA) review for migraine management, but there is no study yet on the usage of gepants for CH. Erenumab, fremanezumab, and galcanezumab have been approved by the FDA for migraine prevention while eptinezumab is under FDA review. CGRP MAbs are as effective as and more tolerable than conventional migraine preventives. For CH prevention, galcanezumab has shown some promising findings and was recently approved for use in episodic cluster prevention. CGRP function-blocking therapy not only demonstrates high efficacy and superior safety profile, but also improves headache frequency and quality of life. Convenient monthly dosing for the MAbs can further improve medication adherence, hence better headache control. With CGRP function-blocking therapy showing efficacy even in individuals who failed other preventives, it has become an exciting new therapeutic option in the field of migraine and CH.


Allosteric regulation and communication between subunits in uracil phosphoribosyltransferase from Sulfolobus solfataricus.
Uracil phosphoribosyltransferase (UPRTase) catalyzes the conversion of 5-phosphate-alpha-1-diphosphate (PRPP) and uracil to uridine 5'-monophosphate (UMP) and diphosphate. The UPRTase from Sulfolobus solfataricus has a unique regulation by nucleoside triphosphates compared to UPRTases from other organisms. To understand the allosteric regulation, crystal structures were determined for S. solfataricus UPRTase in complex with UMP and with UMP and the allosteric inhibitor CTP. Also, a structure with UMP bound in half of the active sites was determined. All three complexes form tetramers but reveal differences in the subunits and their relative arrangement. In the UPRTase-UMP complex, the peptide bond between a conserved arginine residue (Arg80) and the preceding residue (Leu79) adopts a cis conformation in half of the subunits and a trans conformation in the other half and the tetramer comprises two cis-trans dimers. In contrast, four identical subunits compose the UPRTase-UMP-CTP tetramer. CTP binding affects the conformation of Arg80, and the Arg80 conformation in the UPRTase-UMP-CTP complex leaves no room for binding of the substrate PRPP. The different conformations of Arg80 coupled to rearrangements in the quaternary structure imply that this residue plays a major role in regulation of the enzyme and in communication between subunits. The ribose ring of UMP adopts alternative conformations in the cis and trans subunits of the UPRTase-UMP tetramer with associated differences in the interactions of the catalytically important Asp209. The active-site differences have been related to proposed kinetic models and provide an explanation for the regulatory significance of the C-terminal Gly216.


Fungi: Friend or Foe? A Mycobiome Evaluation in Children With Autism and Gastrointestinal Symptoms.
Gastrointestinal (GI) symptoms often affect children with autism spectrum disorders (ASD) and GI symptoms have been associated with an abnormal fecal microbiome. There is limited evidence of Candida species being more prevalent in children with ASD. We enrolled 20 children with ASD and GI symptoms (ASD + GI), 10 children with ASD but no GI symptoms (ASD - GI), and 20 from typically developing (TD) children in this pilot study. Fecal mycobiome taxa were analyzed by Internal Transcribed Spacer sequencing. GI symptoms (GI Severity Index [GSI]), behavioral symptoms (Social Responsiveness Scale -2 [SRS-2]), inflammation and fungal immunity (fecal calprotectin and serum dectin-1 [ELISA]) were evaluated. We observed no changes in the abundance of total fungal species (alpha diversity) between groups. Samples with identifiable Candida spp. were present in 4 of 19 (21%) ASD + GI, in 5 of 9 (56%) ASD - GI, and in 4 of 16 (25%) TD children (overall P = 0.18). The presence of Candida spp. did not correlate with behavioral or GI symptoms (P = 0.38, P = 0.5, respectively). Fecal calprotectin was normal in all but one child. Finally, there was no significance in serum dectin-1 levels, suggesting no increased fungal immunity in children with ASD. Our data suggest that fungi are present at normal levels in the stool of children with ASD and are not associated with gut inflammation.


Radioadaptive response in human lymphocytes in vitro.
Exposure to low doses of radiation and/or chemicals can prime an organism to withstand the stress of a subsequent exposure to higher doses of the same agent. In the case of radiation, this phenomenon has been called radioadaptive response. Cytogenetic studies have been undertaken in human lymphocytes to investigate adaptive response (AR) to ionizing radiation, in particular to seek the role of variables such as priming dose, cell cycle stage, and age and gender of the donor. We demonstrated that pre-exposure of lymphocytes in whole blood cultures to very low doses in the range of about 1 cGy (priming or adaptive dose [AD]) reduced the frequency of micronuclei in binucleated cells induced by 100 cGy--that is, produced an AR in these cells in vitro. However, pre-exposure of cells to 10.0 cGy did not reduce the chromosomal damage (micronuclei) induced by the challenging dose (CD) of 100 cGy under the same protocol, thus exhibiting an inverse dose-response relationship. There was marked variability in the AR among the individuals investigated in the study. The extent of AR also depended on the stage of cell cycle exposed to the CD of radiation. Maximum AR was observed when CD of 100 cGy was given 4 hours after AD, 30 hours following the mitogenic stimulation of lymphocytes. The least AR was observed when CD was given 48 hours after stimulation. Interestingly, AR was also found to be dependent on the age of the donor, a decrease in AR being observed with an increasing age. No significant difference in AR was observed between male and female donors. To understand the molecular events underlying AR, protein synthesis patterns were studied in human lymphocytes subjected to mitogen, heat, or radiation stress. Heat shock (45 degrees C, for 15 min) induced 7 proteins with molecular weights ranging from 40 to 80 kDa, while treatment with phytohemagglutinin (40 microg/mL) showed induction of 2 proteins of molecular weights 38 and 48 kDa, respectively. However, exposure of human lymphocyte cultures to gamma radiation did not significantly induce synthesis of any protein, up to 800 cGy dose. Lack of induction of proteins by gamma radiation in human lymphocytes contrasts with the previous reports showing X-ray radiation-enhanced gene expression in melanoma cells and/or human tumor fibroblasts.


Characterisation of aroma profiles of commercial sufus by odour activity value, gas chromatography-olfactometry, aroma recombination and omission studies.
Sufu is a solid-state fermented product made from soya beans. For the sake of quality control and regulation purposes, it is essential to be able to identify key odorants of various commercial sufus. To identify the aroma-active compounds in sufus, gas chromatography-olfactometry/aroma extract dilution analysis (GC-O/AEDA) was performed, and odour activity value (OAV) was estimated. The correlations between aroma profiles and identified aroma-active compounds were also investigated by principal component analysis. Results showed that 35 aroma-active compounds were detected through OAV calculation, while 28 compounds were identified by using GC-O/AEDA. Quantitative descriptive analysis revealed that aroma recombination model based on OAV calculation was more similar to original sufu in terms of aroma comparing to aroma recombination model based on GC-O/AEDA. Omission experiments further confirmed that the aroma compounds, such as ethyl butanoate, ethyl 2-methylbutanoate, ethyl hexanoate, (E,E)-2,4-decadienal and 2,6-dimethylpyrazine, contributed most significantly to the characteristic aroma of a commercial sufu.


Immunogenicity of the UK group B meningococcal vaccine (4CMenB) schedule against groups B and C meningococcal strains (Sched3): outcomes of a multicentre, open-label, randomised controlled trial.
The use of the multicomponent meningococcal vaccine 4CMenB in the UK schedule at 2, 4, and 12 months of age has been shown to be 59·1% effective at preventing invasive group B meningococcal disease. Here, we report the first data on the immunogenicity of this reduced-dose schedule to help to interpret this effectiveness estimate. In this multicentre, parallel-group, open-label, randomised clinical trial, infants aged up to 13 weeks due to receive their primary immunisations were recruited via child health database mailouts in Oxfordshire and via general practice surgeries in Gloucestershire and Hertfordshire. Infants were randomly assigned (1:1) with permuted block randomisation to receive a 2 + 1 (2, 4, and 12 months; group 1) or 1 + 1 (3 and 12 months; group 2) schedule of the 13-valent pneumococcal conjugate vaccine (PCV13). All infants also received 4CMenB at 2, 4, and 12 months of age, and had blood samples taken at 5 and 13 months. Participants and clinical trial staff were not masked to treatment allocation. Proportions of participants with human complement serum bactericidal antibody (hSBA) titres of at least 4 were determined for group B meningococcus (MenB) reference strains 5/99 (Neisserial Adhesin A [NadA]), NZ98/254 (porin A), and 44/76-SL (factor H binding protein [fHbp]). Geometric mean titres (GMTs) with 95% CIs were also calculated, and concomitant vaccine responses (group C meningococcus [MenC], Haemophilus influenzae b [Hib], tetanus, diphtheria, and pertussis) were compared between groups. The primary outcome was PCV13 immunogenicity, with 4CMenB immunogenicity and reactogenicity as secondary outcomes. All individuals by randomised group with a laboratory result were included in the analysis. The study is registered on the EudraCT clinical trials database, 2015-000817-32, and ClinicalTrials.gov, NCT02482636, and is complete. Between Sept 22, 2015, and Nov 1, 2017, of 376 infants screened, 213 were enrolled (106 in group 1 and 107 in group 2). 204 samples post-primary immunisation and 180 post-boost were available for analysis. The proportion of participants with hSBA of at least 4 was similar in the two study groups. For strain 5/99, all participants developed hSBA titres above 4 in both groups and at both timepoints. For strain 44/76-SL, these proportions were 95·3% (95% CI 88·5-98·7) or above post-priming (82 of 86 participants in group 1), and 92·4% (84·2-97·2) or above post-boost (73 of 79 participants in group 1). For strain NZ98/254, these proportions were 86·5% (78·0-92·6) or above post-priming (83 of 96 participants in group 2) and 88·6% (79·5-94·7) or above post-boost (70 of 79 participants in group 1). The MenC rabbit complement serum bactericidal antibody (rSBA) titre in group 1 was significantly higher than in group 2 (888·3 vs 540·4; p=0·025). There was no significant difference in geometric mean concentrations between groups 1 and 2 for diphtheria, tetanus, Hib, and pertussis post-boost. A very small number of children did not have a protective response against 44/76-SL and NZ98/254. Local and systemic reactions were similar between the two groups, apart from the 3 month timepoint when one group received an extra dose of PCV13 and recorded more systemic reactions. These data support the recent change to the licensed European schedule for 4CMenB to add an infant 2 + 1 schedule, as used in the routine UK vaccine programme with an effectiveness of 59·1%. When compared with historical data, our data do not suggest that effectiveness would be higher with a 3 + 1 schedule, however a suboptimal boost response for bactericidal antibodies against vaccine antigen fHbp suggests a need for ongoing surveillance for vaccine breakthroughs due to fHbp-matched strains. Changing from a 2 + 1 to a 1 + 1 schedule for PCV13 for the UK is unlikely to affect protection against diphtheria, tetanus, and Hib, however an unexpected reduction in bactericidal antibodies against MenC seen with the new schedule suggests that ongoing surveillance for re-emergent MenC disease is important. Bill & Melinda Gates Foundation and the National Institute for Health Research.


To absorb fat - supersize my lipid droplets.
Lipins play important roles in adipogenesis, insulin sensitivity, and gene regulation, and mutations in these genes cause lipodystrophy, myoglobinuria, and inflammatory disorders. While all lipins (lipin 1, 2, and 3) act as phosphatidic acid phosphatase (PAP) enzymes, which are required for triacylglycerol (TAG) synthesis from glycerol 3-phosphate, lipin 1 has been the focus of most of the lipin-related research. In the current issue of the JCI, Zhang et al. show that while lipin 2 and 3 are expendable for the incorporation of dietary fatty acids into triglycerides, lipin 2/3 PAP activity has a critical role in phospholipid homeostasis and chylomicron assembly in enterocytes.


Cold assessment criteria and prediction of cooling risk in humans: the Russian perspective.
Protection of humans working in open areas during a cold period is of great importance. Cold influences human heat state, health and functional capacity. The assessment criteria for optimal permissible heat state during work time and maximum permissible heat state demanding regulation of cold exposure time are described. They form the basis for estimation and forecast of cold risk. Classification of cooling risk is made on the basis of factors such as mean skin temperature, heat deficit, strain of thermo regulative reactions, thermal sensation, and occupational conditions. Cooling risk is also dependent on human factors such as metabolic rate and clothing thermal insulation and ambient conditions such as air temperature, wind velocity, and exposure time. For evaluation of the cooling risk a regression equation is presented for determination of the integral index of cooling conditions (IICC). On basis of the IICC value, presented in a nomogram it is possible to predict the probability of cooling risk of various rates. In consideration of the shifting climate conditions of Russia, requirements for thermal insulation of protective clothing for four major climate regions of the country are presented.


An ultrathin terahertz quarter-wave plate using planar babinet-inverted metasurface.
Metamaterials promise an exotic approach to artificially manipulate the polarization state of electromagnetic waves and boost the design of polarimetric devices for sensitive detection, imaging and wireless communication. Here, we present the design and experimental demonstration of an ultrathin (0.29λ) terahertz quarter-wave plate based on planar babinet-inverted metasurface. The quarter-wave plate consisting of arrays of asymmetric cross apertures reveals a high transmission of 0.545 with 90 degrees phase delay at 0.870 THz. The calculated ellipticity indicates a high degree of polarization conversion from linear to circular polarization. With respect to different incident polarization angles, left-handed circular polarized light, right-handed circular polarized light and elliptically polarized light can be created by this novel design. An analytical model is applied to describe transmitted amplitude, phase delay and ellipticitiy, which are in good agreement with the measured and simulated results. The planar babinet-inverted metasurface with the analytical model opens up avenues for new functional terahertz devices design.


Metacognitive therapy (MCT+) in patients with psychosis not receiving antipsychotic medication: A case study.
Psychotherapies for psychosis typically aim to develop an awareness of the implausible content of a delusion or target the underlying cognitive biases (i.e., problematic thinking styles, such as hasty decisions and illusory control) that foster and maintain delusional beliefs. A recently designed individual-based treatment entitled metacognitive therapy (MCT+) combines these two approaches. Emerging evidence suggests individualized MCT+, when used concurrently with antipsychotic medication, may be an effective psychological treatment for reducing delusional symptoms. However, it remains to be tested whether MCT+ can be effective in patients with active delusions who are not currently receiving psychotropic drugs. We present two cases (one patient with schizophrenia and the other with delusional disorder) experiencing active delusions who underwent 4-weeks of intensive MCT+, without concurrent antipsychotic medication (minimum 6-months unmedicated). Baseline and 6-week follow-up data are presented on a variety of measures assessing delusion symptom severity (i.e., PANSS, PSYRATS, SAPS), clinical insight, and cognitive bias propensity. After 4-weeks of MCT+, both patients showed substantial reduction in delusional symptoms, reported improved clinical insight, and were less prone to making illusory correlations. The presented case studies provide preliminary evidence for the feasibility of MCT+ in treating patients not taking, or resistant to, antipsychotic medication.


Three scleral ossicles in the West African Denticle herring Denticeps clupeoides (Clupeiformes: Denticipitidae).
The eyes of teleostean fishes typically exhibit two ossifications, the anterior and posterior sclerotics, both associated with the scleral cartilage. The West African Denticle herring Denticeps clupeoides has three scleral ossifications, including the typical two associated with the scleral cartilage (anterior and posterior sclerotic) and a third ossification (Di Dario's ossicle), spatially separated from the scleral cartilage and located within the anteromedial wall of the sclera. The medial rectus muscle inserts on the medial surface of Di Dario's ossicle, suggesting that this third sclerotic may play a role in forward rotation of the eye in this surface feeding fish.


Reconstruction of the Shallow Acetabulum With a Combination of Autologous Bulk and Impaction Bone Grafting Fixed by Cement.
Acetabular bone deficiency, especially proximal and lateral deficiency, is a difficult technical problem during primary total hip arthroplasty (THA) in developmental dysplasia of the hip (DDH). We report a new reconstruction method using a medial-reduced cemented socket and additional bulk bone in conjunction with impaction morselized bone grafting (additional bulk bone grafting method). In a population of patients with acetabular dysplasia undergoing THA using a medial-reduced cemented socket and additional bulk bone with impacted morselized bone grafting, we evaluated (1) the radiographic appearance of bone graft; (2) the proportion of cups that developed loosening and subsequent revision; and (3) clinical results (outcome scores and complications). Forty percent of 330 THAs for DDH performed at one center between 1999 and 2009 were defined as shallow dysplastic hips. The additional bulk bone grafting method was performed on 102 THAs with shallow acetabulum (31% for DDH) at one center between 1999 and 2009. We used this approach and technique for shallow acetabuli when a cup protruded from the lateral acetabular edge in preoperative templating. The other 132 dysplastic hips without bone grafting had THA performed at the same periods and served as a control. Acetabuli were defined as shallow when the depth was less than or equal to one-fifth of the pelvic height (cranial-caudal length on radiograph). The additional bulk bone grafting technique was as follows: the resected femoral head was sectioned at 1 to 2 cm thickness, and a suitable size of the bulk bone graft was placed on the lateral iliac cortex and fixed by poly-L-lactate absorbable screws. Autologous impaction morselized bone grafting, with or without hydroxyapatite granules, was performed along with the implantation of a medial-reduced cemented socket. We defined an "incorporated" graft as remodeling and trabeculation including rounding off of the protruding edge of a graft beyond the socket. Radiographic criteria used for determining loosening were migration or a continuous radiolucent zone between the prosthesis/bone cement and host bone. Clinical outcomes were assessed using the Japanese Orthopaedic Association (JOA) and the Merle d'Aubigne and Postel score; complications were tallied from chart review. The followup was 10 ± 3 years (range, 6-15 years). One acetabular component (1%) with severe shallow and steep acetabuli showed definite radiographic evidence of loosening and was revised. Clinically, the mean JOA score for the hips treated with additional bulk bone grafting THA in this study improved from 39 ± 10 points preoperatively to 95 ± 5 points postoperatively (p < 0.05, paired t-test). The mean Merle d'Aubigne and Postel score for the hips improved from 7 ± 2 points to 17 ± 1 points (p < 0.05, paired t-test). Complications included a Trendelenburg sign in one hip, dislocation in one, and transient partial sciatic nerve palsy in one. Within 3 years 6 months postoperatively, 101 of 102 additional bulk bone grafting cases showed successful bone remodeling and bone graft reorientation without collapse on radiographs. Partial resorption of the additional bone graft on the lateral side was observed in two hips (2%) with socket abduction angles of < 35°. Achieving stable acetabular fixation is often challenging in the dysplastic hip, especially shallow acetabulum, and a variety of techniques have been described. Early results of combining bulk graft with impaction of morselized graft are promising. Although each surgical technique was well established, further investigation for clinical results of a combination of these techniques might be necessary to confirm longer term outcomes. Level IV, therapeutic study.


The dyad gene is required for progression through female meiosis in Arabidopsis.
In higher plants the gametophyte consists of a gamete in association with a small number of haploid cells, specialized for sexual reproduction. The female gametophyte or embryo sac, is contained within the ovule and develops from a single cell, the megaspore which is formed by meiosis of the megaspore mother cell. The dyad mutant of Arabidopsis, described herein, represents a novel class among female sterile mutants in plants. dyad ovules contain two large cells in place of an embryo sac. The two cells represent the products of a single division of the megaspore mother cell followed by an arrest in further development of the megaspore. We addressed the question of whether the division of the megaspore mother cell in the mutant was meiotic or mitotic by examining the expression of two markers that are normally expressed in the megaspore mother cell during meiosis. Our observations indicate that in dyad, the megaspore mother cell enters but fails to complete meiosis, arresting at the end of meiosis 1 in the majority of ovules. This was corroborated by a direct observation of chromosome segregation during division of the megaspore mother cell, showing that the division is a reductional and not an equational one. In a minority of dyad ovules, the megaspore mother cell does not divide. Pollen development and male fertility in the mutant is normal, as is the rest of the ovule that surrounds the female gametophyte. The embryo sac is also shown to have an influence on the nucellus in wild type. The dyad mutation therefore specifically affects a function that is required in the female germ cell precursor for meiosis. The identification and analysis of mutants specifically affecting female meiosis is an initial step in understanding the molecular mechanisms underlying early events in the pathway of female reproductive development.


Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension.
Hypertension is a leading cause of cardiovascular, cerebral, and renal disease morbidity and mortality. Here we show that disruption of the Cyp 4a14 gene causes hypertension, which is, like most human hypertension, more severe in males. Male Cyp 4a14 (-/-) mice show increases in plasma androgens, kidney Cyp 4a12 expression, and the formation of prohypertensive 20-hydroxyarachidonate. Castration normalizes the blood pressure of Cyp 4a14 (-/-) mice and minimizes Cyp 4a12 expression and arachidonate omega-hydroxylation. Androgen replacement restores hypertensive phenotype, Cyp 4a12 expression, and 20-hydroxy-arachidonate formation. We conclude that the androgen-mediated regulation of Cyp 4a arachidonate monooxygenases is an important component of the renal mechanisms that control systemic blood pressures. These results provide direct evidence for a role of Cyp 4a isoforms in cardiovascular physiology, establish Cyp 4a14 (-/-) mice as a monogenic model for the study of cause/effect relationships between blood pressure, sex hormones, and P450 omega-hydroxylases, and suggest the human CYP 4A homologues as candidate genes for the analysis of the genetic and molecular basis of human hypertension.


Insulator dysfunction and oncogene activation in IDH mutant gliomas.
Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes catalyse a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear. Here we show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.


A Phospholipid-Protein Complex from Krill with Antioxidative and Immunomodulating Properties Reduced Plasma Triacylglycerol and Hepatic Lipogenesis in Rats.
Dietary intake of marine omega-3 polyunsaturated fatty acids (n-3 PUFAs) can change the plasma profile from atherogenic to cardioprotective. In addition, there is growing evidence that proteins of marine origin may have health benefits. We investigated a phospholipid-protein complex (PPC) from krill that is hypothesized to influence lipid metabolism, inflammation, and redox status. Male Wistar rats were fed a control diet (2% soy oil, 8% lard, 20% casein), or diets where corresponding amounts of casein and lard were replaced with PPC at 3%, 6%, or 11% (wt %), for four weeks. Dietary supplementation with PPC resulted in significantly lower levels of plasma triacylglycerols in the 11% PPC-fed group, probably due to reduced hepatic lipogenesis. Plasma cholesterol levels were also reduced at the highest dose of PPC. In addition, the plasma and liver content of n-3 PUFAs increased while n-6 PUFAs decreased. This was associated with increased total antioxidant capacity in plasma and increased liver gene expression of mitochondrial superoxide dismutase (Sod2). Finally, a reduced plasma level of the inflammatory mediator interleukin-2 (IL-2) was detected in the PPC-fed animals. The present data show that PPC has lipid-lowering effects in rats, and may modulate risk factors related to cardiovascular disease progression.


Structural insights into the autoregulation and cooperativity of the human transcription factor Ets-2.
Ets-2, like its closely related homologue Ets-1, is a member of the Ets family of DNA binding transcription factors. Both proteins are subject to multiple levels of regulation of their DNA binding and transactivation properties. One such regulatory mechanism is the presence of an autoinhibitory module, which in Ets-1 allosterically inhibits the DNA binding activity. This inhibition can be relieved by interaction with protein partners or cooperative binding to closely separated Ets binding sites in a palindromic arrangement. In this study we describe the 2.5 Å resolution crystal structure of a DNA complex of the Ets-2 Ets domain. The Ets domain crystallized with two distinct species in the asymmetric unit, which closely resemble the autoinhibited and DNA bound forms of Ets-1. This discovery prompted us to re-evaluate the current model for the autoinhibitory mechanism and the structural basis for cooperative DNA binding. In contrast to Ets-1, in which the autoinhibition is caused by a combination of allosteric and steric mechanisms, we were unable to find clear evidence for the allosteric mechanism in Ets-2. We also demonstrated two possibly distinct types of cooperative binding to substrates with Ets binding motifs separated by four and six base pairs and suggest possible molecular mechanisms for this behavior.


Vaccination with the Staphylococcus aureus secreted proteins EapH1 and EapH2 impacts both S. aureus carriage and invasive disease.
There is a need for an efficacious vaccine reducing infections due to Staphylococcus aureus, a common cause of community and hospital infection. Infecting organisms originate from S. aureus populations colonising the nares and bowel. Antimicrobials are widely used to transiently reduce S. aureus colonisation prior to surgery, a practice which is selecting for resistant S. aureus isolates. S. aureus secretes multiple proteins, including the protease inhibitors extracellular adhesion protein homologue 1 and 2 (EapH1 and EapH2). Mice were vaccinated intramuscularly or intranasally with Adenovirus serotype 5 and Modified Vaccinia Ankara viral vectors expressing EapH1 and EapH2 proteins, or with control viruses. Using murine S. aureus colonisation models, we monitored S. aureus colonisation by sequential stool sampling. Monitoring of S. aureus invasive disease after intravenous challenge was performed using bacterial load and abscess numbers in the kidney. Intramuscular vaccination with Adenovirus serotype 5 and Modified Vaccinia Ankara viral vectors expressing EapH1 and EapH2 proteins significantly reduces bacterial recovery in the murine renal abscess model of infection, but the magnitude of the effect is small. A single intranasal vaccination with an adenoviral vaccine expressing these proteins reduced S. aureus gastrointestinal (GI) tract colonisation. Vaccination against EapH1 / EapH2 proteins may offer an antibiotic independent way to reduce S. aureus colonisation, as well as contributing to protection against S. aureus invasive disease.


A multicenter phase II study of a five-day regimen of oral 5-fluorouracil plus eniluracil with or without leucovorin in patients with metastatic colorectal cancer.
To evaluate the safety and efficacy of a five-day regimen of oral 5-fluorouracil (5-FU) plus eniluracil (776C85) in patients with metastatic colorectal cancer (CRC). Seventy-five patients with metastatic CRC that was previously untreated or refractory to 5-FU-leucovorin (LV) were enrolled and divided into two strata based upon their treatment history. Twenty-four had not previously received chemotherapy or had received adjuvant chemotherapy that ended > 6 months prior to enrollment on study (previously untreated stratum). Fifty-one patients had disease refractory to intravenous (i.v.) 5-FU-LV (previously treated stratum). All patients received seven consecutive daily doses of eniluracil (20 mg/day) with once daily oral 5-FU given on days 2-6, repeated every four weeks. One-half of the patients in each stratum also received 50 mg/day oral LV on days 2-6. The 5-FU dose was 25 mg/m2 when administered without LV and 20 mg/m2 when administered with LV. Partial response (PR) was noted in 2 of 12 patients receiving eniluracil-5-FU and in 3 of 12 patients receiving eniluracil-5-FU-LV in the previously untreated stratum. No responses were observed in the refractory disease stratum, however, 15 patients (30%) demonstrated stable disease over 2-18+ courses of therapy. Non-hematologic toxicities were mild; only 7% of patients experienced grade 3 diarrhea. Myelosuppression was frequent and dose limiting. Neutropenic sepsis was reported in 13.5% of patients. Eniluracil with 5-FU administered orally with or without LV on a five-day schedule is active and well tolerated when given as primary therapy to patients with metastatic CRC.


MicroRNA-204-5p mediates sevoflurane-induced cytotoxicity in HT22 cells by targeting brain-derived neurotrophic factor.
Sevoflurane is widely used as an inhalational anesthetic in clinical practice. However, sevoflurane can cause cytotoxicity and induce learning capacity decline in patients. A previous publication indicated that miR-204-5p might have a close relationship with sevoflurane-induced neurotoxicity. When exposed to sevoflurane, the expression of miR-204-5p in neonatal hippocampus of rats was significantly increased. Hence, we aimed to investigate the role of miR-204-5p in sevoflurane-induced neurotoxicity using a mouse hippocampal neuronal cell line (HT22). The levels of miR-204-5p in HT22 cells were detected by RT-qPCR. In addition, the effects of miR-204-5p on cell viability, apoptosis and proliferation were evaluated by CCK-8, flow cytometric, and immunofluorescence assay, respectively. Western blotting was used to detect expressions of Bax, Bcl-2, active caspase 3, BDNF, TrkB, p-TrkB, Akt and p-Akt in HT22 cells. ELISA assay was used to examine the levels of total superoxide dismutase (SOD), reduced glutathione (GSH), malondialdehyde (MDA) and reactive oxygen species (ROS) in cells. Meanwhile, the dual luciferase reporter system assay was employed to explore the interaction of miR-204-5p and BDNF in cells. The level of miR-204-5p was increased in sevoflurane-treated HT22 cells. Moreover, downregulation of miR-204-5p inhibited sevoflurane-induced apoptosis and promoted cell proliferation by upregulating the proteins of Bcl-2 and downregulating the expressions of Bax and active caspase-3 in HT22 cells. In addition, inhibition of miR-204-5p alleviated sevoflurane-induced oxidative injuries in HT22 cells via decline of ROS and MDA and upregulation of SOD and GSH. Furthermore, bioinformatics and dual luciferase assay demonstrated that miR-204-5p can inhibit the TrkB/Akt pathway by targeting BDNF. Our findings indicated that downregulation of miR-204-5p can decrease oxidative status in HT22 cells and alleviate sevoflurane-induced cytotoxicity through stimulating the BDNF/TrkB/Akt pathway. Therefore, miR-204-5p might be a potential biomarker and therapeutic target for the treatment of sevoflurane-induced neurotoxicity.


Human taeniasis/cysticercosis: a potentially emerging parasitic disease in Europe.
Taenia saginata (T. saginata)/Taenia solium (T. solium) taeniasis/cysticercosis disease complexes remain a significant challenge for food safety and public health. Human taeniasis is an infectious disease caused by the ingestion of the metacestode larval stage, the cysticerci of T. saginata in beef or T. solium in pork. Humans can also become infected via the ingestion of T. solium eggs. In this case, the cysticerci can establish in the central nervous system, causing the infection called neurocysticercosis. T. solium is of higher importance than T. saginata because the former species can cause neurocysticercosis in humans, a major cause of neurological morbidity in the world. The taeniasis/cysticercosis complex is included in the list of neglected zoonotic diseases by the World Health Organization and Food and Agriculture Organization, with T. solium being the number one foodborne parasite; it occurs mostly in developing countries, such as regions of Asia, Africa and Latin America, where the disease remains endemic. Long absent in Western Europe and other developed countries, cysticercosis has been recently re-emerged as a result of immigration, travel and commerce. In this review, cysticercosis is presented with special emphasis on some aspects of this neglected disease: the main clinical manifestations, risk factors and epidemiology. In addition, any recent advances in diagnostic approaches and treatment are discussed. Finally, the complexities involved in the control of the disease and the need to revise current management strategies are highlighted.


Neurocognitive and Psychiatric Issues Post Cardiac Surgery.
Neurocognitive and psychiatric complications are common following cardiac surgery and impact on patient quality of life, recovery from surgery, participation in rehabilitation and long-term mortality. Postoperative cognitive decline, depressive disorders, post-traumatic stress disorder and neurocognitive impairment related to silent brain infarcts have all been linked to the perioperative period of cardiac surgery, and potentially have serious consequences. The accurate assessment of these conditions, particularly in determining the aetiology, and impact on patients is difficult due to the poorly recognised nature of these complications as well as similarities in presentation with postoperative delirium. This review aims to summarise current understanding surrounding psychiatric disturbances following cardiac surgery including the impact on patient quality of life and long-term outcomes.


Magnetic Printing of Liquid Metal for Perceptive Soft Actuators with Embodied Intelligence.
Soft actuators with perception capability are essential for robots to intelligently interact with humans and the environment. However, existing perceptive soft actuators require complex integration and coupling between the discrete functional units to achieve autonomy. Here, we report entirely soft actuators with embodied sensing, actuation, and control at the single-unit level. This is achieved by synergistically harnessing the mechanosensing and electrothermal properties of liquid metal (LM) to actuate the thermally responsive liquid crystal elastomer (LCE). We create multifunctional LM circuits on the LCE surface using a simple and facile methodology based on magnetic printing. The fluidic LM circuit can not only be utilized as a conformable resistive heater but also as a sensory skin to perceive its own deformation. Moreover, the rational design of the LM circuits makes it possible to achieve biomimetic autonomous actuation in response to mechanical stimuli such as pressure or strain. In addition, the intrinsic stretchability of LM allows us to create 3D spring-like actuators via a simple prestretch step, and complex helical motions can be obtained upon mechanical stimulation. This work provides a unique and simple design for autonomous soft robotics with embodied intelligence.


Synthesis, screening and docking analysis of hispolon analogs as potential antitubercular agents.
A series of 20 hispolons/dihydrohispolons were synthesized and characterized by spectral data. These compounds were subjected to in vitro antitubercular activity screening against Mycobacterium tuberculosis (H37Rv) strain. The synthesized compounds showed varied antitubercular activity ranging from 100 to 1.6μg/mL. Among the screened compounds, four compounds (H1, H2, H3 and H15) have shown moderate activity with MIC 25μg/mL. Potent activities were observed for the dihydrohispolon derivative H14 (MIC 1.6μg/mL) followed by H13 (6.25μg/mL) and H17 (12.5μg/mL), H19 (3.125μg/ML). Docking simulations gave good insights on the possible interactions between the tested compounds and β-keto acyl synthase enzyme (mtbFabH). Drug-inhibitor combination studies showed no synergism with the drugs targeting mycolic acid biosynthesis (isoniazid, ethambutol and thiolactomycin, a specific inhibitor of KAS-B enzyme) but showed significant synergism with other drugs including rifampicin and ciprofloxacin ascertaining the drug target for hispolons as inhibition of mycolic acid biosynthesis, probably via mtbFabH.


High molecular weight glutenin gene diversity in Aegilops tauschii demonstrates unique origin of superior wheat quality.
Central to the diversity of wheat products was the origin of hexaploid bread wheat, which added the D-genome of Aegilops tauschii to tetraploid wheat giving rise to superior dough properties in leavened breads. The polyploidization, however, imposed a genetic bottleneck, with only limited diversity introduced in the wheat D-subgenome. To understand genetic variants for quality, we sequenced 273 accessions spanning the known diversity of Ae. tauschii. We discovered 45 haplotypes in Glu-D1, a major determinant of quality, relative to the two predominant haplotypes in wheat. The wheat allele 2 + 12 was found in Ae. tauschii Lineage 2, the donor of the wheat D-subgenome. Conversely, the superior quality wheat allele 5 + 10 allele originated in Lineage 3, a recently characterized lineage of Ae. tauschii, showing a unique origin of this important allele. These two wheat alleles were also quite similar relative to the total observed molecular diversity in Ae. tauschii at Glu-D1. Ae. tauschii is thus a reservoir for unique Glu-D1 alleles and provides the genomic resource to begin utilizing new alleles for end-use quality improvement in wheat breeding programs.


Cuticle Biosynthesis in Tomato Leaves Is Developmentally Regulated by Abscisic Acid.
The expansion of aerial organs in plants is coupled with the synthesis and deposition of a hydrophobic cuticle, composed of cutin and waxes, which is critically important in limiting water loss. While the abiotic stress-related hormone abscisic acid (ABA) is known to up-regulate wax accumulation in response to drought, the hormonal regulation of cuticle biosynthesis during organ ontogeny is poorly understood. To address the hypothesis that ABA also mediates cuticle formation during organ development, we assessed the effect of ABA deficiency on cuticle formation in three ABA biosynthesis-impaired tomato mutants. The mutant leaf cuticles were thinner, had structural abnormalities, and had a substantial reduction in levels of cutin. ABA deficiency also consistently resulted in differences in the composition of leaf cutin and cuticular waxes. Exogenous application of ABA partially rescued these phenotypes, confirming that they were a consequence of reduced ABA levels. The ABA mutants also showed reduced expression of genes involved in cutin or wax formation. This difference was again countered by exogenous ABA, further indicating regulation of cuticle biosynthesis by ABA. The fruit cuticles were affected differently by the ABA-associated mutations, but in general were thicker. However, no structural abnormalities were observed, and the cutin and wax compositions were less affected than in leaf cuticles, suggesting that ABA action influences cuticle formation in an organ-dependent manner. These results suggest dual roles for ABA in regulating leaf cuticle formation: one that is fundamentally associated with leaf expansion, independent of abiotic stress, and another that is drought induced.


The Genetic Diversity of Influenza A Viruses in Wild Birds in Peru.
Our understanding of the global ecology of avian influenza A viruses (AIVs) is impeded by historically low levels of viral surveillance in Latin America. Through sampling and whole-genome sequencing of 31 AIVs from wild birds in Peru, we identified 10 HA subtypes (H1-H4, H6-H7, H10-H13) and 8 NA subtypes (N1-N3, N5-N9). The majority of Peruvian AIVs were closely related to AIVs found in North America. However, unusual reassortants, including a H13 virus containing a PA segment related to extremely divergent Argentinian viruses, suggest that substantial AIV diversity circulates undetected throughout South America.


Develop a 3D neurological disease model of human cortical glutamatergic neurons using micropillar-based scaffolds.
Establishing an effective three-dimensional (3D) in vitro culture system to better model human neurological diseases is desirable, since the human brain is a 3D structure. Here, we demonstrated the development of a polydimethylsiloxane (PDMS) pillar-based 3D scaffold that mimicked the 3D microenvironment of the brain. We utilized this scaffold for the growth of human cortical glutamatergic neurons that were differentiated from human pluripotent stem cells. In comparison with the 2D culture, we demonstrated that the developed 3D culture promoted the maturation of human cortical glutamatergic neurons by showing significantly more MAP2 and less Ki67 expression. Based on this 3D culture system, we further developed an in vitro disease-like model of traumatic brain injury (TBI), which showed a robust increase of glutamate-release from the neurons, in response to mechanical impacts, recapitulating the critical pathology of TBI. The increased glutamate-release from our 3D culture model was attenuated by the treatment of neural protective drugs, memantine or nimodipine. The established 3D in vitro human neural culture system and TBI-like model may be used to facilitate mechanistic studies and drug screening for neurotrauma or other neurological diseases.


Event-related repetitive transcranial magnetic stimulation of posterior superior temporal sulcus improves the detection of threatening postural changes in human bodies.
Perceiving others' emotions through their body movements and postures is crucial for successful social interaction. While imaging studies indicate that perceiving body emotions relies upon a wide network of subcortico-cortical neural regions, little is known on the causative role of different nodes of this network. We applied event-related repetitive transcranial magnetic stimulation (rTMS) over nonfacial, body- and action-related extrastriate (EBA), temporal (pSTS), and premotor (vPM) cortices to test their active contribution in perceiving changes between two successive images of either threatening or neutral human body or animal postures. While stimulation of EBA and vPM showed no selective effect on threatening stimuli with respect to neutral ones, rTMS over pSTS selectively impaired neutral posture detection and increased the accuracy in detecting changes of threatening human postures with respect to all other experimental conditions. No such effect was found for animal stimuli. These results support the notion that pSTS is crucially devoted to the detection of socially relevant information concerning others' actions, fostering the notion that amygdalo-temporo-cortical modulatory connections mediate perception of emotionally salient body postures.