Ethical concerns around use of artificial intelligence in health care research from the perspective of patients with meningioma, caregivers and health care providers: a qualitative study.
As artificial intelligence (AI) approaches in research increase and AI becomes more integrated into medicine, there is a need to understand perspectives from members of the Canadian public and medical community. The aim of this project was to investigate current perspectives on ethical issues surrounding AI in health care. In this qualitative study, adult patients with meningioma and their caregivers were recruited consecutively (August 2018-February 2019) from a neurosurgical clinic in Toronto. Health care providers caring for these patients were recruited through snowball sampling. Based on a nonsystematic literature search, we constructed 3 vignettes that sought participants' views on hypothetical issues surrounding potential AI applications in health care. The vignettes were presented to participants in interviews, which lasted 15-45 minutes. Responses were transcribed and coded for concepts, frequency of response types and larger concepts emerging from the interview. We interviewed 30 participants: 18 patients, 7 caregivers and 5 health care providers. For each question, a variable number of responses were recorded. The majority of participants endorsed nonconsented use of health data but advocated for disclosure and transparency. Few patients and caregivers felt that allocation of health resources should be done via computerized output, and a majority stated that it was inappropriate to delegate such decisions to a computer. Almost all participants felt that selling health data should be prohibited, and a minority stated that less privacy is acceptable for the goal of improving health. Certain caveats were identified, including the desire for deidentification of data and use within trusted institutions. In this preliminary study, patients and caregivers reported a mixture of hopefulness and concern around the use of AI in health care research, whereas providers were generally more skeptical. These findings provide a point of departure for institutions adopting health AI solutions to consider the ethical implications of this work by understanding stakeholders' perspectives.


Nursing home care trajectories for older adults following in-hospital palliative care consultation.
Palliative care consultation (PCC) during hospitalization is increasingly common for older adults with life-limiting illness discharged to nursing homes. The objective of this qualitative descriptive study was to describe the care trajectories and experiences of older adults admitted to a nursing home following a PCC during hospitalization. Twelve English-speaking adults, mean age 80 years, who received a hospital PCC and discharge to a nursing home without hospice. Data were collected from medical records at five time points from hospital discharge to 100 days after nursing home admission and care trajectories were mapped. Interviews (n = 15) with participants and surrogates were combined with each participant's medical record data. Content analysis was employed on the combined dataset. All PCC referrals were for goals of care conversations during which the PCC team discussed poor prognosis. All participants were admitted to a nursing home under the Medicare skilled nursing facility benefit. Seven were rehospitalized; six of the 12 died within 6 weeks of initial nursing home admission. The two care trajectories were Focus on Rehabilitative Care and Comfort Care Continuity. There was a heavy emphasis on recovering functional status through rehabilitation and skilled nursing care, despite considerable symptom burden and poor prognosis. Regardless of PCC with recommendations for palliative interventions, frail older adults with limited life expectancy and their family caregivers often perceive that rehabilitation will improve physical function. This perception may contribute to inappropriate, ineffective care. More emphasis is needed to coordinate care between PCC recommendations and post-acute care.


Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study.
There is a need for effective and safe treatment during pregnancy in women with chronic inflammatory diseases. This study evaluated placental transfer of certolizumab pegol (CZP), an Fc-free anti-tumour necrosis factor drug, from CZP-treated pregnant women to their infants. CRIB was a pharmacokinetic (PK) study of women ≥30 weeks pregnant receiving commercial CZP for a locally approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords and infants at delivery, and infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 μg/mL). Sixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0-49.4] μg/mL). Of the 16 infants, 2 were excluded from the per-protocol set: 1 due to missing data at birth and 1 due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth (<0.032 μg/mL), and 1 had a minimal CZP level of 0.042 μg/mL (infant/mother plasma ratio 0.0009); no infants had quantifiable CZP levels at weeks 4 and 8. Of 16 umbilical cord samples, 1 was excluded due to missing data; 3/15 had quantifiable CZP levels (maximum 0.048 μg/mL). There was no to minimal placental transfer of CZP from mothers to infants, suggesting lack of in utero foetal exposure during the third trimester. These results support continuation of CZP treatment during pregnancy, when considered necessary. NCT02019602; Results.


Perioperative antimicrobial prophylaxis in pediatric patients in Greece: Compliance with guidelines and impact of an educational intervention.
Appropriate antimicrobial prophylaxis (PAP) prevents surgical site infections (SSI). The aim of this study was to evaluate the effectiveness of an educational intervention to improve adherence to PAP guidelines in pediatric patients. A three-phase prospective study with a pre-post design was conducted from April 2013 to December 2014. All patients who underwent one or more surgical procedures were enrolled. A modified Centers for Disease Control's (CDC) Denominator for Procedure form was used to collect clinical and PAP data. The educational intervention was targeted at all pediatric surgeons in the department. Outcomes assessed were the appropriateness of the agent selected for PAP (according to international guidelines) and appropriate termination of PAP within 24h of surgery completion. SSI rates were calculated before and after the intervention. During the study period 889 children were enrolled (219 in the preintervention and 670 in the postintervention period). The percentage of patients receiving appropriate PAP improved from 6.2% to 77.1% after the educational intervention (p<0.001). The median duration of PAP was reduced from 5 to 1days in preintervention and postintervention period, respectively. There was no increase in the rate of SSIs (0.93% and 0.92%, p=0.992, in preinterventionand postintervention, respectively). An educational intervention targeted at pediatric surgeons improved the selection of agent and timely discontinuation of PAP.


"Open-top" microfluidic device for in vitro three-dimensional capillary beds.
We introduce a novel microfluidic device to co-culture a blood vessel network and cell tissues in an in vivo-like niche. Our "open-top" microfluidic device is composed of microchannels with micropores in the ceiling, which provides direct fluid access from reservoir to microchannel. Fluid connections through micropores afford novel advantages, including: i) the long-term culture of large-scale microvessel network, ii) access of different fluids to inner and exterior sides of the microvessel, and iii) co-culturing of the microvessel network and small cell tissue. In this study, we have successfully assembled microvessels with 5 mm channel widths. We were also able to mimic capillary bed conditions by co-culturing microvessels with cancer spheroids. Intimate contact between the cancer spheroid and microvessel caused vessel recruitment and an increase in vessel formation, and affected vessel morphology. We expect this device to be used as a novel platform for vascularized tissue models.


Multiple Cranial Neuropathies as the Initial Presentation of Primary Ductal Adenocarcinoma of the Lacrimal Gland.
Primary ductal adenocarcinoma of the lacrimal gland is a rare, aggressive malignancy that clinically and histologically resembles salivary duct carcinoma. Similar to other malignant epithelial lacrimal gland tumors, ductal adenocarcinoma typically presents with unilateral proptosis, pain, upper eyelid swelling, palpable mass, diplopia, ptosis, and blurred or decreased vision. Rarely, primary malignant epithelial lacrimal gland tumors may first present with multiple cranial neuropathies due to occult spread to the cavernous sinus, as in this case. With such a vast differential diagnosis, a practical yet systematic approach to multiple cranial neuropathies, as guided by clinical history, exam, and neuroimaging, allows for a more targeted diagnostic evaluation, especially when multiple diagnostic tests and interventions return unrevealing. A repeat biopsy or complete excision of the lacrimal gland may be necessary to yield the correct diagnosis.


Multilevel modeling of single-case data: A comparison of maximum likelihood and Bayesian estimation.
The focus of this article is to describe Bayesian estimation, including construction of prior distributions, and to compare parameter recovery under the Bayesian framework (using weakly informative priors) and the maximum likelihood (ML) framework in the context of multilevel modeling of single-case experimental data. Bayesian estimation results were found similar to ML estimation results in terms of the treatment effect estimates, regardless of the functional form and degree of information included in the prior specification in the Bayesian framework. In terms of the variance component estimates, both the ML and Bayesian estimation procedures result in biased and less precise variance estimates when the number of participants is small (i.e., 3). By increasing the number of participants to 5 or 7, the relative bias is close to 5% and more precise estimates are obtained for all approaches, except for the inverse-Wishart prior using the identity matrix. When a more informative prior was added, more precise estimates for the fixed effects and random effects were obtained, even when only 3 participants were included. (PsycINFO Database Record


Clinicopathologic Features of Varicella Zoster Virus Infection of the Upper Gastrointestinal Tract.
Reactivation of latent varicella zoster virus (VZV) may be limited to a dermatome or involve multiple organs, including the gastrointestinal tract. Although gastrointestinal manifestations of disseminated zoster have been likened to those of herpes simplex virus (HSV), histologic features of VZV-related injury to the tubular gut are not well-documented. We performed this study to describe the clinicopathologic features of VZV-related gastrointestinal injury. We identified 6 such patients with VZV infection. All involved the upper gastrointestinal tract, affecting the esophagus (n=3), stomach (n=2), or both (n=1). All patients were immunocompromised adults with hematologic malignancies (n=5) or a heart transplant (n=1); 3 with hematologic malignancies had received stem cell transplants. Five patients had cutaneous and gastrointestinal zoster; 1 had gastrointestinal disease alone. When compared with 14 HSV-related esophagitis controls, there were several notable differences. VZV caused hemorrhagic ulcers with nodularity or erythema, whereas HSV produced round, shallow ulcers on a background of nearly normal mucosa (P=0.01). VZV-related ulcers featured fibrin-rich, pauci-inflammatory exudates compared with the macrophage-rich exudates of HSV (P=0.003). The cytopathic changes of VZV were present at all levels of the squamous epithelium, especially in a peripapillary distribution. In contrast, HSV inclusions were located in the superficial layers (P=0.003) and detached keratinocytes. Unlike HSV, VZV involved the stomach, producing hemorrhage accompanied by striking apoptosis in the deep glands. We conclude that VZV produces unique patterns of gastrointestinal injury that facilitate its diagnosis. Recognition of gastrointestinal VZV infection is important because it heralds potentially life-threatening disseminated disease.


Outcome of Chiari-associated syringomyelia after hindbrain decompression in children: analysis of 49 consecutive cases.
Chiari I malformation is complicated by syringomyelia in many cases. Hindbrain decompression remains first-line surgical treatment; however, the incidence, time course, and predictors of syrinx resolution remain unclear. We set out to determine predictors of syrinx improvement after hindbrain decompression for Chiari I- associated syringomyelia. Forty-nine consecutive pediatric patients undergoing posterior fossa decompression for Chiari I-associated syringomyelia were followed with serial magnetic resonance imaging evaluations postoperatively. Clinical, radiological, and operative variables were assessed as predictors of syrinx improvement as a function of time using Kaplan-Meier plots and log-rank analysis. Mean patient age was 11 +/- 5 years. Syringomyelia was symptomatic in 39 (80%) and asymptomatic in 10 (20%) cases. Twenty-one (54%) patients experienced symptom resolution (median, 4 mo postoperatively). Twenty-seven (55%) patients experienced radiographic improvement in syringomyelia (median, 14 mo postoperatively). After hindbrain decompression, motor symptoms were associated with a 2.35 increased hazard ratio for symptom improvement (P = 0.031) versus all other symptoms. Among patients with sensory deficits, dysesthesia was associated with a 3.12 increased hazard ratio for symptom improvement (P = 0.032) versus symptoms of paresthesia or anesthesia. In our experience, just more than one-half of patients with Chiari- associated syringomyelia demonstrated clinical and radiographic improvement after hindbrain decompression. Median time to radiographic improvement lagged behind clinical improvement by 10 months. Motor symptoms were more likely to improve with hindbrain decompression. Paresthesia or anesthesia symptoms were less likely to improve with hindbrain decompression. These findings may help guide surgical decision making and aid in patient education.


Frequency-domain near-infrared photo diffusion imaging: initial evaluation in multitarget tissuelike phantoms.
In this paper, an initial evaluation of our finite element based frequency-domain image reconstruction algorithm is performed for experiments where multiple millimeter-sized heterogeneities are embedded within a tissue-equivalent (optically) background medium having multicentimeter dimensions. The cases considered consist of several interesting geometry and optical property contrast combinations including (i) two different-sized targets with the same contrast at three different separation distances; (ii) two different-sized targets with different contrasts at two different separation distances; and (iii) three targets with the same and different sizes and contrasts, respectively. The reconstruction algorithm that has been used is an enhanced version of our originally developed regularized least squares approach that now includes total variation minimization, dual meshing, and spatial low-pass filtering. Quantitative measures of image quality including the size, location, and shape of the embedded heterogeneities along with errors in their recovered optical property values are presented. The results show that multiple targets can be clearly detected for all combinations of locations, sizes, and contrast levels considered, but the quantitative nature of this detection is influenced by these parameters.


EphA2-derived peptide vaccine with amphiphilic poly(gamma-glutamic acid) nanoparticles elicits an anti-tumor effect against mouse liver tumor.
The prognosis of liver cancer remains poor, but recent advances in nanotechnology offer promising possibilities for cancer treatment. Novel adjuvant, amphiphilic nanoparticles (NPs) composed of L: -phenylalanine (Phe)-conjugated poly(gamma-glutamic acid) (gamma-PGA-Phe NPs) having excellent capacity for carrying peptides, were found to have the potential for use as a peptide vaccine against tumor models overexpressing artificial antigens, such as ovalbumin (OVA). However, the anti-tumor potential of gamma-PGA-Phe NPs vaccines using much less immunogenic tumor-associated antigen (TAA)-derived peptide needs to be clarified. In this study, we evaluated the effectiveness of immunization with EphA2, recently identified TAA, derived peptide-immobilized gamma-PGA-Phe NPs (Eph-NPs) against mouse liver tumor of MC38 cells (EphA2-positive colon cancer cells). Immunization of normal mice with Eph-NPs resulted in generation of EphA2-specific type-1 CD8+ T cells. Immunization with Eph-NPs tended to provide a degree of anti-MC38 liver tumor protection more than that observed for immunization with the mixture of EphA2-derived peptide and complete Freund's adjuvant (Eph + CFA). Neither Eph-NPs nor Eph + CFA vaccines inhibited tumor growth of BL6, EphA2-negative melanoma cells. Splenocytes isolated from MC38-bearing mice treated with Eph-NPs showed strong and specific cytotoxic activity against MC38 cells. Immunization with Eph + CFA induced liver damage as evidenced by elevation of serum alanine aminotransferase, while Eph-NPs vaccination did not exhibit any toxic damage to the liver. These results demonstrated that immunization with Eph-NPs displayed anti-tumor effects against liver tumor by generating acquired immunity equivalent to the toxic adjuvant CFA, suggesting that safe gamma-PGA-Phe NPs could be applied clinically for the vaccine treatment of liver cancer.


Oral condyloma acuminatum.
Oral condyloma acuminatum is a papillomatous lesion that is transmitted sexually and associated with the human papilloma virus. Condyloma acuminatum generally appears one to three months after exposure to an infected partner and presents in multiple form in the oral cavity.


UV photodissociation spectroscopy of cryogenically cooled gas phase host-guest complex ions of crown ethers.
The geometric and electronic structures of cold host-guest complex ions of crown ethers (CEs) in the gas phase have been investigated by ultraviolet (UV) fragmentation spectroscopy. As host CEs, we chose 15-crown-5 (15C5), 18-crown-6 (18C6), 24-crown-8 (24C8), and dibenzo-24-crown-8 (DB24C8), and as guests protonated-aniline (aniline·H(+)) and protonated-dibenzylamine (dBAM·H(+)) were chosen. The ions generated by an electrospray ionization (ESI) source were cooled in a quadrupole ion-trap (QIT) using a cryogenic cooler, and UV spectra were obtained by UV photodissociation (UVPD) spectroscopy. UV spectroscopy was complemented by quantum chemical calculations of the most probable complex structures. The UV spectrum of aniline·H(+)·CEs is very sensitive to the symmetry of CEs; aniline·H(+)·18C6 shows a sharp electronic spectrum similar to aniline·H(+), while aniline·H(+)·15C5 shows a very broad structure with poor Franck-Condon factors. In addition, a remarkable cage effect in the fragmentation process after UV excitation was observed in both complex ions. In aniline·H(+)·CE complexes, the cage effect completely removed the dissociation channels of the aniline·H(+) moiety. A large difference in the fragmentation yield between dBAM·H(+)·18C6 and dBAM·H(+)·24C8 was observed due to a large barrier for releasing dBAM·H(+) from the axis of rotaxane in the latter complex.


Examining the impacts of health literacy on healthcare costs. An evidence synthesis.
Scholars and practitioners share a significant concern about rising healthcare costs. Health literacy is widely presented as a solution to this momentous issue, paving the way for a more appropriate access to care and therefore, for cost savings. However, to date little is still known about the ultimate effects of better health literacy on healthcare costs. Drawing from the findings of a systematic literature review which ultimately involved 29 papers retrieved from Scopus-Elsevier and PubMed. This manuscript is aimed at shedding light on the relationship between health literacy and healthcare costs. The inadequate ability of patients to understand health information and to navigate the healthcare system was found to be an important predictor of inappropriateness in the access to health care. In addition, people living with problematic health literacy are discouraged to be engaged in the provision of health services and are expected to show poor self-efficacy in dealing with their health-related conditions. From this point of view, poor health literate patients are assumed to be at high risk of exacerbation of their health problems, which in turn contributes in rising healthcare costs. In spite of these findings, both policy makers and practitioners seem to overlook the importance of health literacy. Eventually, the joint intervention on laws, policies, organizational strategies, and practices is crucial to handle the challenges related to limited health literacy.


Meeting report: American Aging Association 40th Annual Meeting, Raleigh, North Carolina, June 3-6, 2011.
The focus of the 2011 American Aging Association meeting was emerging concepts in the mechanisms of aging. Many of the usual topics in aging were covered, such as dietary restriction (DR), inflammation, stress resistance, homeostasis and proteasome activity, sarcopenia, and neural degeneration. There was also discussion of newer methods, such as microRNAs and genome sequencing, that have been employed to investigate gene expression variance with aging and genetic signatures of longevity. Aging as a field continues to mature, including the following areas: Using a systems approach to tracing conserved pathways across organisms; sharpening definitions of sarcopenia, frailty, and health span; and distinguishing interventions by age tier (early-onset versus late-onset). A preconference session on late-onset intervention concluded that there are numerous benefits to deriving such interventions. Conference talks applied the biology of aging in a translational manner to intervention development. Using an individual's own stem cells to regenerate organs for transplantation and as a cell source for cellular therapies could be a powerful near-term solution to disease. Several proposed interventions were pharmaceutical, myostatin inhibition, losartan, Janus kinase (JAK) pathway inhibitors, and enalapril for frailty and sarcopenia, and metformin to promote the Nrf2 antiinflammation response. In DR, protein restriction was found to be better than general calorie restriction. Short-term fasting may be helpful in chemotherapy, surgery, and acute stress, simultaneously increasing the killing of cancer cells by chemotherapy, while improving the survival of normal cells. Immune system interventions remain elusive, although statins may help to improve cellular senescence promoted bacterial infection. Engineered enzymes may be useful in lysosomal catabolism. Dietary restriction mimetics, most promisingly involving target of rapamycin (TOR; TORC1 inhibition and rapamycin), may be more feasible than dietary restriction.


In vitro and in vivo inhibitory activities of four Indian medicinal plant extracts and their major components on rat aldose reductase and generation of advanced glycation endproducts.
The polyol enzyme aldose reductase (AR) and advanced glycation endproducts (AGEs) play an important role in diabetic complications such as cataracts. The purpose of this study was to investigate four standardized plant extracts used for the treatment of diabetes and related diseases, and their principal components for AR inhibitory activity and to find out their influence in diabetic complications. Thus, Boswellia serrata Triana & Planch. (Burseraceae), Lagerstroemia speciosa (L.) Pers. (Lythraceae), Ocimum gratissimum (L.) (Lamiaceae) and Syzygium cumin (L.) Skeels. (Myrthaceae) and their respective major constituents, boswellic acid, corosolic acid, ursolic acid and ellagic acid, were studied for their inhibitory activity against rat lens AR, rat kidney AR, human recombinant AR and generation of AGEs. In addition, in vivo inhibition of lens galactitol accumulation by the major constituents of the plants in galactose-fed rat has been studied. The results revealed that all the tested extracts and their active ingredients possess significant AR inhibitory actions in both in vitro and in vivo assays with urosolic acid showing the most potent effect. Furthermore, the study indicates the potential of the studied plants and their major constituents as possible protective agents against long-term diabetic complications.


Radical chemoradiotherapy for adenocarcinoma of the distal oesophagus and oesophagogastric junction: what planning margins should we use?
Distal oesophageal and Type I-II oesophagogastric junctional adenocarcinomas have a poor prognosis. In radical chemoradiotherapy, consensus is lacking on radiotherapy margins. Here, we review the effect of common imaging modalities on the extent of the gross tumour volume (GTV) and the evidence for margins. To do this, papers were identified from PubMed, and geometric uncertainties were combined using the British Institute of Radiology formula. CT and endoscopic ultrasound were best for GTV delineation, but the role of positron emission tomography is uncertain. Evidence suggests 3 cm proximal and 5 cm distal GTV-CTV (clinical target volume) margins (along the mucosa) for advanced tumours, but is lacking for early tumours and radial margins. Nodal spread, present in most pT2 tumours, is strongly prognostic and is initially to regional nodes (not wholly covered by typical radiotherapy). Calculated CTV-PTV (planning target volume) margins for three-dimensional conformal radiotherapy using literature estimates of tumour motion and set-up errors with bony online set-up correction, ignoring delineation errors, are 2.2 cm superiorly (sup) and inferiorly (inf) and 1.2-1.3 cm radially (1.3 cm sup-inf; 0.8 cm radially if the tumour's mid-position is known). As these margins may risk excessive toxicity, we propose treating microscopic disease for potentially curable tumours (cT2N0, some cT3N0), but gross disease only for advanced tumours. Recommended GTV-CTV margins are a maximum of 3 cm proximally and 5 cm distally up to cT2N0; 3 cm proximally and 5 cm distally for cT3N0 if anticipated toxicity allows; and 0 cm for cT4 and most node-positive tumours. The CTV-PTV margins above must be added to this for all stages. Methods of including elective nodal areas close to the GTV should be researched, e.g. nodal maps and intensity-modulated radiotherapy.


Templated preparation of porous magnetic microspheres and their application in removal of cationic dyes from wastewater.
Porous magnetic microspheres with large particle size (350-450 microm) were prepared with sulfonated macroporous polydivinylbenzene as a template. The preparation process included ferrous ion exchange and following oxidation by hydrogen peroxide. The results showed that the weight fraction of magnetic nanoparticles exceeded 20 wt% in microspheres after the preparation process was repeated three times. X-ray diffraction profiles indicated that the crystalline phase of as-formed magnetic nanoparticles was magnetite (Fe(3)O(4)). TEM images revealed rod-like magnetite crystal after the first oxidation cycle, however, the crystal morphologies were transferred into random shape after more oxidation cycles. The applicability of porous magnetic microspheres for removal of cationic dyes from water was also explored. The results exhibited that basic fuchsin and methyl violet could be quickly removed from water with high efficiency. More importantly, the magnetic microspheres could be easily regenerated and repeatedly employed for wastewater treatment. Therefore, a novel methodology was provided for fast removal cationic dyes from wastewater.


Inequalities in assisted reproduction technology utilisation between the G20 countries.
Large global inequalities in assisted reproduction technology (ART) utilisation have existed ever since the introduction of ART. The reasons for these inequalities are multifactorial and include national wealth and affordability, pronatalist policies, regulatory differences in provision, and sociocultural components such as racial, gender and educational inequalities. Examining ART utilisation across the largest world economies (G20 countries) in 2016 (the most recent year with publically available data) reveals significant inequality, which is highly correlated to gross domestic product per capita, a measure of national wealth, and to provision of government funding and/or insurance coverage for in vitro fertilisation and intracytoplasmic sperm injection. A strong negative correlation with the Gender Inequality Index is also noted. The gap in ART utilisation rate will only begin to close once the majority of nations introduce more affordable ART treatment, instigate pronatalist policies, and implement changes in education, attitudes and behaviours to minimise racial and gender inequalities; however, achieving all of these changes may be a very difficult target to attain for many poorer economies, regardless of their size.


TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer.
Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25-75 mg p.o. twice a day; continuous or intermittent), savolitinib (600-800 mg p.o. once a day), or durvalumab (3-10 mg/kg intravenous every 2 weeks). At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm-diarrhea (75%), rash (58%), nausea (47%); savolitinib arm-nausea (67%), rash (56%), vomiting (50%); durvalumab arm-rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. NCT02143466.


[Changes in the cytochrome P-450 content of the liver of congenic resistant mouse strains during chronic alcoholization].
Differences were found in the levels of alcohol consumption in two pairs of congenic resistant mice (BI0.RI07, BI0.RIII and A/Sn, A.SW). BI0.RI07 and A/Sn mice were characterized as "drinking" compared to their congenic resistant partners BI0.R and A.SW. The concentration of cytochrome P-450 in the animal liver was measured at different periods of alcoholization. Certain correlation was found between the time-course of hemoprotein changes and the levels of alcohol consumption. The contribution of the major histocompatibility mouse system (H-2) to the correlations found is discussed.


Effect of Extra-abdominal Vein Varix on the Stress Distribution in Umbilical Cord: A Simulation Study.
The umbilical cord is a critical structure linking the fetus to the placenta and is surrounded by the amniotic fluid. It is composed of a vein, two arteries coiled around the vein, and Wharton's jelly surrounding the blood vessels. In this study, the stress distribution of the arteries, vein, and Wharton's jelly of an umbilical cord with extra-abdominal umbilical vein varix is analyzed for varying amniotic pressure using finite element analysis. Four diameters are considered for the umbilical vein, 6.5 mm, 11 mm, 15.5 mm, and 20 mm, with 6.5 mm corresponding to the normal vein diameter. The amniotic pressure is varied from 15-105 mmHg in steps of 15 mmHg, to simulate contractions during labour. Stress distribution is obtained and the peak stresses are analyzed. According to the results, the peak stress in the Wharton's jelly and the umbilical vein increases nonlinearly with increasing amniotic pressure. The peak stress in umbilical arteries initially decreases till the amniotic pressure reaches 45 mmHg and thereafter increases. This might be due to asymmetric deformation of the Wharton's jelly at the pressure range below arterial pressure.Clinical Relevance- This study could be useful in understanding the fundamental mechanics of extra-abdominal umbilical vein varix and help in development of better treatment protocols.


Study of calcaneal articular facets in human tali.
Aim of the present study is to know the presence and their percentages of incidences of various patterns of calcaneal articular facets in human tali. PLACE OF STUDY: Department of Anatomy of Sree Dev Raj Urs Medical College, Tamaka, Kolar, Karnataka, India. It is a study of two years of 1996-97 and 1997-98 batches of students. Two hundred and forty unknown, dry human tali possessed from the bone sets of students of above batches constituted the materials for the study during the above period. They were carefully examined for articular facets and classified into five groups. The present study on human tali revealed five types articular facets . They are Type-1 were observed in 10% (in 24 tali), similarly Type-2 in 50% (120 tali), Type-3 in 16.66% (40 tali), Type-4 in 5.00% (12 tali), Type-5 in 18.41% (44 tali). Later they were well compared and correlated with available literatures. This study on human tali has revealed the type of gait, and walking habits and weight bearing bone that has given rise to various articular facets. Hence it has been studied and reported.


Rapid ELISA for the diagnosis of rotavirus.
Rotavirus is the major cause of gastroenteritis in infants and young children all over the world. The objective of the study was to develop a rapid ELISA for the diagnosis of rotavirus infection in children hospitalised with diarrhoea. Immune serum was raised in rabbits by inoculating semipurified rotavirus, SA-11 strain. Immunoglobulins were conjugated to horse radish peroxidase and a rapid ELISA for rotavirus diagnosis was developed. The rapid ELISA was compared with routine ELISA, developed earlier at NIV. Of the 155 faecal samples from patients with diarrhoea, 96 were positive by rapid ELISA and 95 in routine NIV ELISA. OD values were higher in rapid ELISA. The rapid ELISA takes only 4 h to complete. Rotavirus diagnosis by rapid ELISA is simple and easy to perform. This may lead to a significant reduction in the unnecessary usage of antibiotics, which cannot control infection due to rotavirus. This technology is being commercialized.


Persons with disabilities as an unrecognized health disparity population.
Disability is an emerging field within public health; people with significant disabilities account for more than 12% of the US population. Disparity status for this group would allow federal and state governments to actively work to reduce inequities. We summarize the evidence and recommend that observed differences are sufficient to meet the criteria for health disparities: population-level differences in health outcomes that are related to a history of wide-ranging disadvantages, which are avoidable and not primarily caused by the underlying disability. We recommend future research and policy directions to address health inequities for individuals with disabilities; these include improved access to health care and human services, increased data to support decision-making, strengthened health and human services workforce capacity, explicit inclusion of disability in public health programs, and increased emergency preparedness.


Programming effects of short prenatal exposure to cortisol.
Recent studies have linked fetal exposure to a suboptimal intrauterine environment with adult hypertension. The aims of this study were twofold: 1) to see whether cortisol treatment administered to the ewe for 2 days at 27 days of gestation (term approximately 150 days) resulted in high blood pressure in offspring; 2) to study the effect of the same treatment on gene expression in the brain at 130 days of gestation and in lambs at 2 months of age. Mean arterial pressure was significantly higher in the adult female and male offspring of sheep treated with cortisol than in the control group (females: 89+/-2 mmHg vs. 81+/-2; P<0.05 and males: 102+/-4 mmHg vs. 91+/-3; P<0.05). Prenatal cortisol treatment led to up-regulation of angiotensinogen, AT1, MR, and GR mRNA in the hippocampus in fetuses at 130 days of gestation but not in the animals at 2 months of age. This is the first evidence that short prenatal exposure to cortisol programmed high blood pressure in the adult female and male offspring of sheep. Altered gene expression in the hippocampus could have a significant effect on the development of the hippocampus, and on postnatal behavior.


A circadian oscillator in Aspergillus spp. regulates daily development and gene expression.
We have established the presence of a circadian clock in Aspergillus flavus and Aspergillus nidulans by morphological and molecular assays, respectively. In A. flavus, the clock regulates an easily assayable rhythm in the development of sclerotia, which are large survival structures produced by many fungi. This developmental rhythm exhibits all of the principal clock properties. The rhythm is maintained in constant environmental conditions with a period of 33 h at 30 degrees C, it can be entrained by environmental signals, and it is temperature compensated. This endogenous 33-h period is one of the longest natural circadian rhythms reported for any organism, and this likely contributes to some unique responses of the clock to environmental signals. In A. nidulans, no obvious rhythms in development are apparent. However, a free running and entrainable rhythm in the accumulation of gpdA mRNA (encoding glyceraldehyde-3-phosphate dehydrogenase) is observed, suggesting the presence of a circadian clock in this species. We are unable to identify an Aspergillus ortholog of frequency, a gene required for normal circadian rhythmicity in Neurospora crassa. Together, our data indicate the existence of an Aspergillus circadian clock, which has properties that differ from that of the well-described clock of N. crassa.


Chronic ethanol administration causes oxidative stress in the rat pancreas.
There is increasing evidence implicating oxidative stress in the pathogenesis of both acute and chronic pancreatitis. Because ethanol is a major cause of pancreatitis in Western society, the aim of this study was to determine whether chronic ethanol administration results in oxidative stress in the pancreas. Twelve pairs of rats were fed a diet containing ethanol as 36% of calories or an isocaloric control diet for 4 weeks. Ethanol feeding resulted in a 46% increase in pancreatic malondialdehyde (p=0.006). In addition, total pancreatic glutathione was increased by 22% (p=0.005). These biochemical changes occurred in the absence of histologic evidence of inflammation or necrosis, implying that the observed oxidative stress is a primary phenomenon rather than part of an inflammatory response.


Hemophilic bleeding evaluated by blood pool scanning.
The technique of blood pool scanning was used to examine 15 hemophilic subjects. Employing an in vivo method for erythrocyte labeling with Technetium-99 m, a dynamic perfusion sequence is obtained using a scintillation camera positioned over the area to be examined. This demonstrates the vascularity of the tissue. Subsequently, equilibrium blood pool images of the area are obtained and analyzed with a densitometer to assess relative regional blood volume. In patients who were not bleeding but had chronic arthropathy, vascularity was not increased, and the blood volume of comparable joints was similar. By contrast, marked increases in vascularity and image density were observed in studies of acutely bleeding joints. Chronic hemarthroses were associated with persistent, but less marked increases in joint perfusion. Transient increases in joint vascularity were demonstrated after insertion of knee prostheses. In a patient with a thigh hematoma, the dimensions of the hemorrhage were clearly delineated. Since only a tracer dose of nuclide is infused intravenously, there are no allergic reactions or other side effects of the procedure. Blood pool scanning is a safe, non-invasive technique that augments clinical and radiographic evaluations, and provides a new dimension in the assessment of the hemophilic patient.


Single Port and Conventional Laparoscopy in Colorectal Surgery: Comparison of Two Techniques.
Single-incision laparoscopic surgery (SILS) was introduced to further the enhanced outcome of conventional multiport laparoscopy (CML). We compared their short- and long-term outcomes in colorectal surgery. Retrospective review of patients who underwent elective laparoscopic colorectal surgery during 3-year period. Patients' data, surgery outcomes, and oncological results were compared. Sixty-one patients (33 male, 28 female), mean age 67.4 years, underwent laparoscopic colonic resections: 28 SILS and 33 CML. Twenty-three (37.7%) patients had previous abdominal surgery. There were 19 (31.2%) right, 9 (14.7%) left, and 2 (3.3%) total colectomies, 16 (26.2%) sigmoidectomies, 13 (21.3%) anterior and 2 (3.3%) abdominoperineal resections. Colonic malignancy was a main indication for the surgery in 51 (83.6%) patients. Mean surgery time and postoperative stay were 92.0 minutes and 9 days, respectively. Pathological examination revealed stage I colon cancer in 16 (32%), stage II in 22 (44%), stage III in 10 (20%), and stage IV in 2 (4%) patients. Mean number of retrieved lymph nodes was 19 ± 13.5. No differences were found between groups in demographic data, type of surgery, surgery time and hospital stay, pathological results and tumor staging, and disease-free and overall survivals. In the SILS group, placement of additional trocar was required in 7 (25%) and conversion in 3 (10.7%) cases compared with 1 (3%) case of conversion to formal laparotomy in the CML group. Overall postoperative morbidity was 16.4%. There was no mortality in both the groups. During the study period, 3 patients from the CML group had cancer recurrence. SILS is a feasible and safe technique compared with CML in terms of surgical and oncological outcomes.


Rejecting impulsivity as a psychological construct: A theoretical, empirical, and sociocultural argument.
We demonstrate through theoretical, empirical, and sociocultural evidence that the concept of impulsivity fails the basic requirements of a psychological construct and should be rejected as such. Impulsivity (or impulsiveness) currently holds a central place in psychological theory, research, and clinical practice and is considered a multifaceted concept. However, impulsivity falls short of the theoretical specifications for hypothetical constructs by having meaning that is not compatible with psychometric, neuroscience, and clinical data. Psychometric findings indicate that impulsive traits and behaviors (e.g., response inhibition, delay discounting) are largely uncorrelated and fail to load onto a single, superordinate latent variable. Modern neuroscience has also failed to identify a specific and central neurobehavioral mechanism underlying impulsive behaviors and instead has found separate neurochemical systems and loci that contribute to a variety of impulsivity types. Clinically, these different impulsivity types show diverging and distinct pathways and processes relating to behavioral and psychosocial health. The predictive validity and sensitivity of impulsivity measures to pharmacological, behavioral, and cognitive interventions also vary based on the impulsivity type evaluated and clinical condition examined. Conflation of distinct personality and behavioral mechanisms under a single umbrella of impulsivity ultimately increases the likelihood of misunderstanding at a sociocultural level and facilitates misled hypothesizing and artificial inconsistencies for clinical translation. We strongly recommend that, based on this comprehensive evidence, psychological scientists and neuroscientists reject the language of impulsivity in favor of a specific focus on the several well-defined and empirically supported factors that impulsivity is purported to cover. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Indoleamine 2,3-dioxygenase (IDO) induced by Leishmania infection of human dendritic cells.
Dendritic cells (DC) play a pivotal role in regulating immunity, establishing immunologically privileged tissue microenvironments and maintaining homoeostasis. It is becoming increasingly clear that one key mechanism that mediates many DC functions is production of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). For pathogens that cause chronic infection, exploitation of host DCs is a solution to establish and persist within a host. Leishmania parasites cause a range of clinical manifestations, all involving chronic infection, and are proficient at avoiding immune responses. We demonstrate here that infection of human myeloid-derived DC with L. major and L. donovani induces IDO expression using a mechanism that involves autocrine or paracrine stimulation with a DC-secreted factor. Leishmania-induced IDO suppresses allogeneic and tetanus toxoid-specific lymphocyte proliferation, an inhibition that is reversed with the IDO inhibitor, 1-methyl tryptophan (1-MT). Furthermore, IDO expression by human DC does not require live Leishmania infection, as parasite lysates also up-regulate IDO mRNA production. Our data suggest that one mechanism Leishmania parasites utilize to circumvent immune clearance may be to promote the induction of IDO among host DC within the infection microenvironment.


Intestinal capillariasis: indigenous cases from Chiang Mai and Phayao provinces, Thailand.
Two cases of intestinal capillariasis were presented from new locations in northern Thailand, i.e., Phayao and Chiang Mai provinces. Both of them had chronic voluminous diarrhea and malabsorption. It was believed that they acquired the infection indigenously. Both adult worms and their eggs, presented in the feces, were identified as Capillaria philippinensis but with morphological variation. The infection was treated effectively with a prolonged administration of mebendazole.


Validity of caregiver-report measures of language skill for Wolof-learning infants and toddlers living in rural African villages.
Valid indigenous language assessments are needed to further our understanding of how children learn language around the world. We assessed the psychometric properties and performance of two caregiver-report measures of Wolof language skill (language milestones achieved and vocabulary knowledge) for 500 children (ages 0;4 to 2;6) living in rural Senegal. Item response models (IRM) evaluated instrument- and item-level performance and differential function by gender. Both caregiver-report measures had good psychometric properties and displayed expected age and socioeconomic effects. Modest concurrent validity was found by comparing the caregiver-report scores to transcribed child language samples from a naturalistic play session. The caregiver-report method offers a valid alternative to more costly tools, such as direct behavioral assessments or language sampling, for measuring early language development in non-literate, rural African communities. Recommendations are made to further improve the performance of caregiver-report measures of child language skill in these settings.


Factors associated with uptake of pandemic influenza vaccine among general practitioners and practice nurses in Shropshire, UK.
At the time of the 2009-10 influenza pandemic there was considerable unease about vaccination. Early surveys suggested that the intention to be vaccinated amongst healthcare workers was low. To determine what influenced vaccination uptake among general practice healthcare workers in Shropshire County Primary Care Trust in the UK. A cross-sectional survey was distributed to all frontline healthcare workers in Shropshire County's general practices in June 2010. All 45 practices participated. Questionnaires were distributed by practice managers to frontline staff and returned by post. Practices with the lowest return rates were reminded by telephone after 3 months. 205 valid replies were received, giving a response rate of 48.0%. 10.0% reported being infected with the pandemic H1N1 strain by the time they received the questionnaire. 172 (83.9%) respondents reported that they had been vaccinated against H1N1. Influenza infection prior to vaccination had a negative impact on uptake (adjusted OR 0.17, 95% CI 0.05 to 0.56) and previous vaccination against seasonal influenza was associated with increased uptake (adjusted OR 4.07, 95% CI 1.62 to 10.24). Those who received the pandemic vaccine were seven times more likely to accept future vaccines (adjusted OR 7.04, 95% CI 2.70 to 18.37). Vaccination uptake was significantly higher than the national (40.3%), regional (40.9%), and county averages (49.3%). Motivation for and against vaccination was very similar to that for seasonal vaccination, with previous vaccination having the greatest influence. Ensuring healthcare workers receive vaccination early in their career is likely to set a precedent for future vaccination. This is the first detailed study purely in general practice in England.


Transduction of Gal+ by coliphage T1. I. Role of hybrids of bacterial and prophage lambda deoxyribonucleic acid.
Hybrids of lambda and adjacent bacterial deoxyribonucleic acid carried in T1 particles were able to transduce Gal(+) with a greatly increased efficiency to strains which were not immune to lambda compared to immune strains. The enhanced transduction was dependent on a functional recA(+) gene in the recipient. Mutations of the donor's lambda prophage which abolished the function of either the cI, O, or P genes in the recipients led to a further enhancement of transduction. The rate of transduction of a nonlysogenic recipient such as W3350 by the hybrid particles may be as much as 140 times greater than transduction of the lysogenic recipient W3350(lambda). In addition to the effect of lambda immunity in blocking enhanced transduction, mutations of the N gene of the donor's lambda prophage abolished enhanced transduction. Mutations in the red, int, xis, and Q genes of the donor's prophage had no significant effect on transduction. The hybrids which mediated the enhanced transduction are called (lambda-gal)T1.


Seasonal changes in bovine fertility: relation to developmental competence of oocytes, membrane properties and fatty acid composition of follicles.
Follicle dynamics and oocyte viability in Holstein primiparous and multiparous cows and the relationships between fertility and the biochemical and physical properties of oocyte membranes with season were examined. The conception rates of primiparous (n = 70 885) and multiparous (n = 143 490) cows differed, peaking in the winter and decreasing in the summer. The number of follicles 3-8 mm in diameter per ovary was higher in winter (19.6) compared with summer (12.0). However, in winter the percentage of ovaries with fewer than ten follicles per ovary was 16%, in contrast to 50% in summer. After aspiration of follicles, 7.5 oocytes per ovary were found in winter and 5.0 oocytes per ovary in summer. Cleavage to the two- to four-cell stage after chemical activation was greater in winter than in summer; this was enhanced at the morula stage and embryo development to the blastocyst stage was significantly higher in winter than in summer. Determination of the lipid phase transition in oocyte membranes revealed a shift of 6 degrees C between summer and winter. Fatty acid composition of phospholipids from follicular fluid, granulosa cells and oocytes indicated that there was a higher percentage of saturated fatty acids during the summer and that the percentages of mono-unsaturated and polyunsaturated fatty acids were higher in oocytes and granulosa cells during the winter. Oocytes and granulosa cells had similar fatty acid compositions, in contrast to follicular fluid. These results may explain the differences in the ability of oocytes to develop to the blastocyst stage at different seasons. Thus, temperature changes may lead to changes in membrane properties, which, in turn, can influence oocyte function and fertility.


The Impact of Conflict on Immunisation Coverage in 16 Countries.
Military conflict has been an ongoing determinant of inequitable immunisation coverage in many low- and middle-income countries, yet the impact of conflict on the attainment of global health goals has not been fully addressed. This review will describe and analyse the association between conflict, immunisation coverage and vaccine-preventable disease (VPD) outbreaks, along with country specific strategies to mitigate the impact in 16 countries. We cross-matched immunisation coverage and VPD data in 2014 for displaced and refugee populations. Data on refugee or displaced persons was sourced from the United Nations High Commissioner for Refugees (UNHCR) database, and immunisation coverage and disease incidence data from World Health Organization (WHO) databases. Demographic and Health Survey (DHS) databases provided additional data on national and sub-national coverage. The 16 countries were selected because they had the largest numbers of registered UNHCR "persons of interest" and received new vaccine support from Global Alliance for Vaccine and Immunisation (GAVI), the Vaccine Alliance. We used national planning and reporting documentation including immunisation multiyear plans, health system strengthening strategies and GAVI annual progress reports (APRs) to assess the impact of conflict on immunisation access and coverage rates, and reviewed strategies developed to address immunisation program shortfalls in conflict settings. We also searched the peer-reviewed literature for evidence that linked immunisation coverage and VPD outbreaks with evidence of conflict. We found that these 16 countries, representing just 12% of the global population, were responsible for 67% of global polio cases and 39% of global measles cases between 2010 and 2015. Fourteen out of the 16 countries were below the global average of 85% coverage for diphtheria, pertussis, and tetanus (DPT3) in 2014. We present data from countries where the onset of conflict has been associated with sudden drops in national and sub-national immunisation coverage. Tense security conditions, along with damaged health infrastructure and depleted human resources have contributed to infrequent outreach services, and delays in new vaccine introductions and immunisation campaigns. These factors have in turn contributed to pockets of low coverage and disease outbreaks in sub-national areas affected by conflict. Despite these impacts, there was limited reference to the health needs of conflict affected populations in immunisation planning and reporting documents in all 16 countries. Development partner investments were heavily skewed towards vaccine provision and working with partner governments, with comparatively low levels of health systems support or civil partnerships. Global and national policy and planning focus is required on the service delivery needs of conflict affected populations, with increased investment in health system support and civil partnerships, if persistent immunisation inequities in conflict affected areas are to be addressed.


Comparative assessment of the environmental sustainability of existing and emerging perchlorate treatment technologies for drinking water.
Environmental impacts of conventional and emerging perchlorate drinking water treatment technologies were assessed using life cycle assessment (LCA). Comparison of two ion exchange (IX) technologies (i.e., nonselective IX with periodic regeneration using brines and perchlorate-selective IX without regeneration) at an existing plant shows that brine is the dominant contributor for nonselective IX, which shows higher impact than perchlorate-selective IX. Resource consumption during the operational phase comprises >80% of the total impacts. Having identified consumables as the driving force behind environmental impacts, the relative environmental sustainability of IX, biological treatment, and catalytic reduction technologies are compared more generally using consumable inputs. The analysis indicates that the environmental impacts of heterotrophic biological treatment are 2-5 times more sensitive to influent conditions (i.e., nitrate/oxygen concentration) and are 3-14 times higher compared to IX. However, autotrophic biological treatment is most environmentally beneficial among all. Catalytic treatment using carbon-supported Re-Pd has a higher (ca. 4600 times) impact than others, but is within 0.9-30 times the impact of IX with a newly developed ligand-complexed Re-Pd catalyst formulation. This suggests catalytic reduction can be competitive with increased activity. Our assessment shows that while IX is an environmentally competitive, emerging technologies also show great promise from an environmental sustainability perspective.


Statistical analysis of temporal evolution in single-neuron firing rates.
A fundamental methodology in neurophysiology involves recording the electrical signals associated with individual neurons within brains of awake behaving animals. Traditional statistical analyses have relied mainly on mean firing rates over some epoch (often several hundred milliseconds) that are compared across experimental conditions by analysis of variance. Often, however, the time course of the neuronal firing patterns is of interest, and a more refined procedure can produce substantial additional information. In this paper we compare neuronal firing in the supplementary eye field of a macaque monkey across two experimental conditions. We take the electrical discharges, or 'spikes', to be arrivals in a inhomogeneous Poisson process and then model the firing intensity function using both a simple parametric form and more flexible splines. Our main interest is in making inferences about certain characteristics of the intensity, including the timing of the maximal firing rate. We examine data from 84 neurons individually and also combine results into a hierarchical model. We use Bayesian estimation methods and frequentist significance tests based on a nonparametric bootstrap procedure. We are thereby able to conclude that a substantial fraction of the neurons exhibit important temporal differences in firing intensity across the two conditions, and we quantify the effect across the population of neurons.


A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo.
Amyloid deposits, neurofibrillary tangles, and neuronal cell death in selectively vulnerable brain regions are the chief hallmarks in Alzheimer's (AD) brains. Glycogen synthase kinase-3 (GSK-3) is one of the key kinases required for AD-type abnormal hyperphosphorylation of tau, which is believed to be a critical event in neurofibrillary tangle formation. GSK-3 has also been recently implicated in amyloid precursor protein (APP) processing/Abeta production, apoptotic cell death, and learning and memory. Thus, GSK-3 inhibition represents a very attractive drug target in AD and other neurodegenerative disorders. To investigate whether GSK-3 inhibition can reduce amyloid and tau pathologies, neuronal cell death and memory deficits in vivo, double transgenic mice coexpressing human mutant APP and tau were treated with a novel non-ATP competitive GSK-3beta inhibitor, NP12. Treatment with this thiadiazolidinone compound resulted in lower levels of tau phosphorylation, decreased amyloid deposition and plaque-associated astrocytic proliferation, protection of neurons in the entorhinal cortex and CA1 hippocampal subfield against cell death, and prevention of memory deficits in this transgenic mouse model. These results show that this novel GSK-3 inhibitor has a dual impact on amyloid and tau alterations and, perhaps even more important, on neuronal survival in vivo further suggesting that GSK-3 is a relevant therapeutic target in AD.


The Binding of Platinum (II) Complexes to Rabbit Skeletal Muscle G-Actin Induces Conformation Changes.
The binding of cis-diamminedichloroplatinum (DDCP) and cis-diaquodiammine platinum (DADP) to rabbit skeletal muscle G-actin and the consequent conformation changes were studied as the function of the Pt/actin molar ratio (R) and time by intrinsic and NPM labeled fluorescence, CD spectra as well as gelfiltration chromatography. The results indicated that the unhydrolyzed DDCP can react with G-actin in presence of Cl(-) ion. The reaction differs from that of its hydrolysis product DADP in a higher specificity and a lower capacity. Both of them induced exposure of the tryptophane residues and labeled Cys374 and the increase in alpha-helix content depending on R, but the conformation changes caused by DADP are more significant than DDCP at the same R. These are related to the binding of DADP to groups other than thiols. The rate constants of conformation change suggested that DADP quenched the intrinsic fluorescence more rapid. The temporal change in fluorescence of NPM labeled actin has a biphasic feature: in the first 16 minutes, the fluorescence was quenched, then it recovered slowly, indicating a multi-step reaction including high affinity platinum binding --> labeled Cys374 moving to hydrophilic environment --> low affinity platinum binding --> Cys374-related conformation compacting in sequence.


Characterization of the Arc two-component signal transduction system of the capnophilic rumen bacterium Mannheimia succiniciproducens.
The ArcB/A two-component signal transduction system of Escherichia coli modulates the expression of numerous operons in response to redox conditions of growth. We demonstrate that the putative arcA and arcB genes of Mannheimia succiniciproducens MBEL55E, a capnophilic (CO2-loving) rumen bacterium, encode functional proteins that specify a two-component system. The Arc proteins of the two bacterial species sufficiently resemble each other that they can participate in heterologous transphosphorylation in vitro, and the arcA and arcB genes of M. succiniciproducens confer toluidine blue resistance to E. coli arcA and arcB mutants. However, neither the quinone analogs (ubiquinone 0 and menadione) nor the cytosolic effectors (d-lactate, acetate, and pyruvate) affect the net phosphorylation of M. succiniciproducens ArcB. Our results indicate that different types of signaling molecules and distinct modes of kinase regulation are used by the ArcB proteins of E. coli and M. succiniciproducens.


Serum neuron-specific enolase: a serum marker for nonfunctioning pancreatic islet cell carcinoma.
The isoenzyme, neuron-specific enolase (NSE) was evaluated as a serum marker for nonfunctioning pancreatic islet cell carcinoma. Serum NSE was measured by radioimmunoassay in 6 patients with islet cell cancer and in 22 healthy adults. Mean serum NSE in control subjects was 5 ng/ml (range 3.2 to 8.4 ng/ml). Three of six patients had clearly elevated serum NSE with values that ranged from 22 to 44 ng/ml. One patient had an equivocally elevated serum NSE of 9.2 ng/ml while receiving chemotherapy. When relapse occurred, the NSE level increased to 44 ng/ml. One of two patients with normal serum NSE had undergone radical pancreatectomy and had no evidence of disease when studied. Elevated serum NSE returned to normal limits after removal of all gross tumor in the only patient from whom a preoperative measurement was obtained. Results of this preliminary study suggest that serum NSE levels can aid in the diagnosis and monitoring of the course of nonfunctining islet cell carcinoma.


Dynamics of equilibrium-linked colloidal networks.
Colloids that attractively bond to only a few neighbors (e.g., patchy particles) can form equilibrium gels with distinctive dynamic properties that are stable in time. Here, we use a coarse-grained model to explore the dynamics of linked networks of patchy colloids whose average valence is macroscopically, rather than microscopically, constrained. Simulation results for the model show dynamic hallmarks of equilibrium gel formation and establish that the colloid-colloid bond persistence time controls the characteristic slow relaxation of the self-intermediate scattering function. The model features re-entrant network formation without phase separation as a function of linker concentration, centered at the stoichiometric ratio of linker ends to nanoparticle surface bonding sites. Departures from stoichiometry result in linker-starved or linker-saturated networks with reduced connectivity and shorter characteristic relaxation times with lower activation energies. Underlying the re-entrant trends, dynamic properties vary monotonically with the number of effective network bonds per colloid, a quantity that can be predicted using Wertheim's thermodynamic perturbation theory. These behaviors suggest macroscopic in situ strategies for tuning the dynamic response of colloidal networks.


Hepatoprotective effects of red beetroot-based beverages against CCl4 -induced hepatic stress in Sprague Dawley rats.
Red beetroot (Beta vulgaris L.) is considered important to improve hepatic health but its use is primarily limited to fresh salads in Pakistan. This study was aimed at exploring prophylactic role of red beetroot-based beverages against carbon tetrachloride (CCl4 )-induced hepatic stress. Purposely, red beetroot-based beverages (8 ml/kg b.w. per day) were administered to normal and hepatotoxicity-induced rats for 8 weeks. The biochemical analyses revealed significantly higher levels of superoxide dismutase (25%-28%), catalase (21%-24%), and hepatic enzymes (15%-19%) alongside reduced lipid peroxidation (27%-32%) in liver tissues of hepatotoxicity-induced rats treated with beetroot-based beverages compared to control. Similarly, hepatic injury was reduced by 19%-26% as indicated by concentrations of serum hepatic health biomarkers. Moreover, histological architecture of hepatocytes also portrayed promising effects of beetroot-based beverages to preserve hepatocellular portfolio. It was concluded that red beetroot-based beverages considerably assuage negative impacts of hepatic stress. PRACTICAL APPLICATIONS: Functional foods and nutraceuticals are considered vital in controlling the oxidative stress-mediated metabolic disorders as safer alternatives to pharmaceutical agents. The current research explored the protective effects of red beetroot-based beverages which can be utilized as an effective approach to prevent liver injuries. Also, the outcomes of this research endorsed the defensive role of these beverages against oxidative stress-induced hepatic stress, so dietary supplementation of such products can be synchronized in clinical practices to alleviate oxidative stress. However, there is a need to further explore the safety aspects of such products in their long-term usage before implementing this module in humans for disease prevention/cure.


AIR12 confers cold tolerance through regulation of the CBF cold response pathway and ascorbate homeostasis.
Auxin induced in root culture (AIR12) is a single gene in Arabidopsis and codes for a mono-heme cytochrome b, but it is unknown whether plant AIR12 is involved in abiotic stress responses. MfAIR12 was identified from Medicago falcata that is legume germplasm with great cold tolerance. Transcript levels of MfAIR12 and its homolog MtAIR12 from Medicago truncatula was induced under low temperature. Overexpression of MfAIR12 led to the accumulation of H2 O2 in apoplast and enhanced cold tolerance, which was blocked by H2 O2 scavengers, indicating that the increased cold tolerance was dependent upon the accumulated H2 O2 . In addition, declined cold tolerance was observed in Arabidopsis mutant air12, which could be restored by expressing MfAIR12. Compared to the wild type, higher levels of ascorbic acid and ascorbate redox state, as well as transcripts of the C repeat/dehydration responsive element-binding factor (CBF) transcription factors and their downstream cold-responsive genes, were observed in MfAIR12 transgenic lines, but lower levels of those in air12 mutant. It is suggested AIR12 confers cold tolerance as a result of the altered H2 O2 in the apoplast that is signaling in the regulation of CBF cold response pathway and ascorbate homeostasis.


Confirming persistence of gluten intolerance in children diagnosed as having coeliac disease in infancy.
In young infants the clinical and investigative features of coeliac disease (CD) may be mimicked by other conditions such as cow's milk intolerance or secondary disaccharidase deficiency. It is therefore especially important to confirm a diagnosis of CD by later gluten challenge in such infants. Sixteen children in whom the diagnosis of CD had been made before the age of 12 months had an oral gluten challenge, after being treated with a gluten-free diet for periods of one month to 5 years. In 15 we showed intestinal xylose malabsorption by the one-hour blood xylose level within 1-28 days of starting ingestion of gluten. One child, with a persistently normal one-hour blood xylose test after gluten challenge for 3 months, had normal absorption and normal jejunal histology after 18 months on a gluten-containing diet; she is considered not to have CD. The one-hour blood xylose test before and after gluten challenge can help to confirm the diagnosis in coeliac patients diagnosed in infancy.


A Comparison of Mortality Following Emergency Laparotomy Between Populations From New York State and England.
The aim of this study was to compare mortality following emergency laparotomy between populations from New York State and England. Mortality following emergency surgery is a key quality improvement metric in both the United States and UK. Comparison of the all-cause 30-day mortality following emergency laparotomy between populations from New York State and England might identify factors that could improve care. Patient demographics, in-hospital, and 30-day outcomes data were extracted from Hospital Episode Statistics (HES) in England and the New York Statewide Planning and Research Cooperative System (SPARCS) administrative databases for all patients older than 18 years undergoing laparotomy for emergency open bowel surgery between April 2009 and March 2014. The primary outcome measure was all-cause mortality within 30 days of the index laparotomy. Mixed-effects logistic regression was performed to model independent demographic variables against mortality. A one-to-one propensity score matched dataset was created to compare the odd ratios of mortality between the 2 populations. Overall, 137,869 patient records, 85,286 (61.9%) from England and 52,583 (38.1%) from New York State, were extracted. Crude 30-day mortality for patients was significantly higher in the England compared with New York State [11,604 (13.6%) vs 3633 (6.9%) patients, P < 0.001]. Patients undergoing emergency laparotomy in England had significantly higher risk of mortality compared with those in New York State (odds ratio 2.35, confidence interval 2.24-2.46, P < 0.001). The risk of mortality at 30 days is higher following emergency laparotomy in England as compared with New York State despite similar patient groups.


Anaerobic co-digestion of sludge with other organic wastes and phosphorus reclamation in wastewater treatment plants for biological nutrients removal.
This paper deals with the performances obtained in full scale anaerobic digesters co-digesting waste activated sludge from biological nutrients removal wastewater treatment plants, together with different types of organic wastes (solid and liquid). Results showed that the biogas production can be increased from 4000 to some 18,000 m3 per month when treating some 3-5 tons per day of organic municipal solid waste together with waste activated sludge. On the other hand, the specific biogas production was improved, passing from 0.3 to 0.5 m3 per kgVS fed the reactor, when treating liquid effluents from cheese factories. The addition of the co-substrates gave minimal increases in the organic loading rate while the hydraulic retention time remained constant. Further, the potentiality of the struvite crystallisation process for treating anaerobic supernatant rich in nitrogen and phosphorus was studied: 80% removal of phosphorus was observed in all the tested conditions. In conclusion, a possible layout is proposed for designing or upgrading wastewater treatment plants for biological nutrients removal process.


Entropy Hotspots for the Binding of Intrinsically Disordered Ligands to a Receptor Domain.
Proline-rich motifs (PRMs) are widely used for mediating protein-protein interactions with weak binding affinities. Because they are intrinsically disordered when unbound, conformational entropy plays a significant role for the binding. However, residue-level differences of the entropic contribution in the binding of different ligands remain not well understood. We use all-atom molecular dynamics simulation and the maximal information spanning tree formalism to analyze conformational entropy associated with the binding of two PRMs, one from the Abl kinase and the other from the nonstructural protein 1 of the 1918 Spanish influenza A virus, to the N-terminal SH3 (nSH3) domain of the CrkII protein. Side chains of the stably folded nSH3 experience more entropy change upon ligand binding than the backbone, whereas PRMs involve comparable but heterogeneous entropy changes among the backbone and side chains. In nSH3, two conserved nonpolar residues forming contacts with the PRM experience the largest side-chain entropy loss. In contrast, the C-terminal charged residues of PRMs that form polar contacts with nSH3 experience the greatest side-chain entropy loss, although their "fuzzy" nature is attributable to the backbone that remains relatively flexible. Thus, residues that form high-occupancy contacts between nSH3 and PRM do not reciprocally contribute to entropy loss. Furthermore, certain surface residues of nSH3 distal to the interface with PRMs gain entropy, indicating a nonlocal effect of ligand binding. Comparing between the PRMs from cAbl and nonstructural protein 1, the latter involves a larger side-chain entropy loss and forms more contacts with nSH3. Consistent with experiments, this indicates stronger binding of the viral ligand at the expense of losing the flexibility of side chains, whereas the backbone experiences less entropy loss. The entropy "hotspots" as identified in this study will be important for tuning the binding affinity of various ligands to a receptor.


Urinary symptoms and female sexual dysfunction in women with type 1 diabetes: the role of depression.
Some reports suggest that women with type 1 diabetes (T1D) have a greater burden of female sexual dysfunction (FSD) than women without T1D, but the etiology of this elevated risk is poorly understood. To examine the associations between FSD and urinary incontinence/lower urinary tract symptoms (UI/LUTS) in women with T1D and to evaluate how depression may mediate these relationships. LUTS and UI symptoms were assessed in women with T1D who participated in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study. Multivariable logistic regression models estimated associations between FSD and UI/LUTS (overall and specific domains) and the impact of depression on these associations. FSD was measured with the Female Sexual Function Index-Reduced. In total, 499 self-reported sexually active women completed validated assessments of sexual and urinary function (mean ± SD age, 47.7 ± 7.6 years; T1D duration, 23.4 ± 5.15 years). FSD was reported in 232 (46%) responders. The frequency of UI and LUTS was 125 (25.1%) and 96 (19.2%), respectively. Neither UI nor its subcategories (urge, stress) were associated with FSD. Although LUTS (odds ratio [OR], 1.75; 95% CI, 1.09-2.77) and its symptoms of urgency (OR, 1.99; 95% CI, 1.09-3.61) and incomplete emptying (OR, 2.44; 95% CI, 1.23-4.85) were associated with FSD, these associations were attenuated following adjustment for depression and antidepressant medication use. Depression indicators were independently associated with FSD overall and across domains. The complex interplay of voiding dysfunction, mental health, and sexual function warrants further investigation to understand the potential implications for patient assessment, goal setting, treatment, and care planning. Data are from a prospective study of individuals with T1D. These results are unable to explore cause-and-effect relationships among LUTS, UI, depression, and FSD. The sample may not be representative of the general population of women with T1D. Because participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study are mostly White, generalizing the findings to other races and to type 2 diabetes may not be appropriate. While exclusion of sexually inactive women likely biases our findings toward the null, this design element permitted study of LUTS and UI in relation to aspects of FSD, the primary objective of this study. The significant associations between LUTS/UI and FSD among middle-aged women with T1D were greatly attenuated when depression was considered a mediating factor.


Hybrid multimodal contrast agent for multiscale in vivo investigation of neuroinflammation.
Neuroinflammation is a process common to several brain pathologies. Despites its medical relevance, it still remains poorly understood; there is therefore a need to develop new in vivo preclinical imaging strategies to monitor inflammatory processes longitudinally. We here present the development of a hybrid imaging nanoprobe named NP3, that was specifically designed to get internalized by phagocytic cells and imaged in vivo with MRI and bi-photon microscopy. NP3 is composed of a 16 nm core of gadolinium fluoride (GdF3), coated with bisphosphonate polyethylene glycol (PEG) and functionalized with a Lemke-type fluorophore. It has a hydrodynamic diameter of 28 ± 8 nm and a zeta potential of -42 ± 6 mV. The MR relaxivity ratio at 7 T is r1/r2 = 20; therefore, NP3 is well suited as a T2/T2* contrast agent. In vitro cytotoxicity assessments performed on four human cell lines revealed no toxic effects of NP3. In addition, NP3 is internalized by macrophages in vitro without inducing inflammation or cytotoxicity. In vivo, uptake of NP3 has been observed in the spleen and the liver. NP3 has a prolonged vascular remanence, which is an advantage for macrophage uptake in vivo. The proof-of-concept that NP3 may be used as a contrast agent targeting phagocytic cells is provided in an animal model of ischemic stroke in transgenic CX3CR1-GFP/+ mice using three complementary imaging modalities: MRI, intravital two-photon microscopy and phase contrast imaging with synchrotron X-rays. In summary, NP3 is a promising preclinical tool for the multiscale and multimodal investigation of neuroinflammation.


Multiple primary tumors involving cancer of the brain and central nervous system as the first or subsequent cancer.
This study was undertaken to determine whether cancer of the brain and central nervous system (CNS) occurs together with other types of cancer more often or less often than would be expected due to chance. The study was based on data collected by the Surveillance, Epidemiology, and End Results (SEER) Program for cancers diagnosed in the U.S. between 1973 and 1998. The standardized incidence ratio (SIR) for new malignancies was estimated as the number of patients diagnosed with a particular type of cancer (observed), divided by the number of diagnoses expected based on person-years of follow-up and incidence rates for SEER cancer registries. Among patients who were diagnosed first with cancer of the brain or CNS, statistically significant excesses were observed for cancers of bone (SIR = 14.4), soft tissue (SIR = 4.6), brain and CNS (SIR = 5.9), salivary gland (SIR = 5.1), and thyroid gland (SIR = 2.7) in addition to acute myelocytic leukemia (SIR = 4.1) and melanoma of the skin (SIR = 1.7). Excess risk of new malignancies was markedly greater after first cancers of the brain or CNS diagnosed in childhood compared with similar diagnoses in adulthood. In reverse associations, significant excesses of cancer of the brain and CNS were observed only after diagnoses of acute lymphocytic leukemia (SIR = 7.4) and cancer of the testis (SIR = 1.8) or the thyroid gland (SIR = 1.7). Cancer treatment appears to have been the major factor underlying most of the positive associations between brain cancer and primary cancers of other types, with a probable lesser contribution from shared genetic susceptibility. Results provide little or no evidence that brain cancer shares important etiologic factors with the common cancers of adulthood.


Identification of a novel non-retinoid pan inverse agonist of the retinoic acid receptors.
Retinoids are potent forms of vitamin A and are involved in a broad range of physiological processes and the pharmacological effects of retinoids are primarily mediated by the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Several natural and synthetic RAR modulators have proven to be clinically useful for a number of therapeutic indications including cancer, psoriasis, and diabetes. Unfortunately, these agents lead to a number of significant side effects. Most synthetic retinoid ligands are based on the retinoid scaffold and thus have similarities to the natural ligand with all previously disclosed RAR ligands having a carboxylic acid that makes a critical ionic bridge within the ligand binding domain of the receptors. The potential therapeutic value offered from RAR modulation provides the impetus to identify novel ligands based on unique scaffolds that may offer improved toxicity and pharmacokinetic profiles. Here we describe the identification of an atypical RAR inverse agonist that represents the first non-acid, non-retinoid direct modulator of RAR receptor subfamily. SR-0065 functions as a pan-RAR inverse agonist suppressing the basal activity of RARα, RARβ, and RARγ, as well as inhibiting agonist-induced RAR activity. SR-0065 treatment enhanced receptor interaction with a peptide representative of the corepressor SMRT, and in cells SR-0065 enhances recruitment of SMRT to the promoter of the RARγ dependent gene, Cyp26A1. The acid form of SR-0065, SR-1758, was inactive in all assays. Thus, SR-0065 represents a new class of non-acid, non-retinoid RAR modulator that may be used as a point to initiate development of improved RAR-targeted drugs.


Structural basis of telomeric nucleosome recognition by shelterin factor TRF1.
Shelterin and nucleosomes are the key players that organize mammalian chromosome ends into the protective telomere caps. However, how they interact with each other at telomeres remains unknown. We report cryo-electron microscopy structures of a human telomeric nucleosome both unbound and bound to the shelterin factor TRF1. Our structures reveal that TRF1 binds unwrapped nucleosomal DNA ends by engaging both the nucleosomal DNA and the histone octamer. Unexpectedly, TRF1 binding shifts the register of the nucleosomal DNA by 1 bp. We discovered that phosphorylation of the TRF1 C terminus and a noncanomical DNA binding surface on TRF1 are critical for its association with telomeric nucleosomes. These insights into shelterin-chromatin interactions have crucial implications for understanding telomeric chromatin organization and other roles of shelterin at telomeres including replication and transcription.


The environment and childhood asthma (ECA) study in Oslo: ECA-1 and ECA-2.
An observed increase in asthma admissions in Oslo during the 1980s prompted a prospective birth cohort study to ask the following question: was air pollution (outdoor and indoor) (in a broad sense) associated with asthma development in young children? During 12 months from 1 January 1992, 3,754 children (birth weight > or = 2,000 g) in Oslo were enrolled at birth into the Environment and Childhood Asthma (ECA) study and followed to 2 years of age (ECA-part I). Cord blood, a detailed questionnaire (family and pregnancy history of disease, environmental exposures, socio-economic status) completed by the mother and lung function measurements (n = 803) were collated at birth. Detailed questionnaires completed every 6 months for 2 years included the child's disease history, feeding habits and environmental exposures. A nested case-control study comprised 306 children with confirmed minimum two episodes of bronchial obstruction (rBO) and 306 controls (without lower respiratory tract disease) with clinical investigations (including tidal breathing lung function, beta-2 responsiveness and allergy assessment) and environmental exposure assessments (indoor and outdoor). Home dampness and low ventilation, as well as maternal smoking in pregnancy, but not outdoor air pollution increased the risk of rBO. Lung function at birth was decreased among newborns whose mother smoked during pregnancy. To understand better the early risk factors for asthma and allergy development, a follow-up study started (in 2001; ECA-part II) of all cases and controls, and those with lung function measured at birth (total 1,230 invited) (9-10 years of age). This involved clinical investigation, allergy assessments, lung function, airway hyper responsiveness measures, exhaled nitric oxide and immunological as well as allergen exposure investigations.


Prognostic impact of cancer genomic profile testing for advanced or metastatic solid tumors in clinical practice.
Cancer genomic profile (CGP) testing, which is covered by the national health insurance system in Japan, has been introduced as a routine clinical practice. However, the effects of CGP testing on prognoses remain unclear. Drug accessibility rates and prognoses after CGP testing were retrospectively investigated in 713 patients who underwent CGP testing examined by our molecular tumor board between November 2019 and October 2022,. Overall survival (OS) was examined using the log-rank test and the Kaplan-Meier method. The median age of patients (326 males and 387 females) was 58 years (12-85 years). CGP testing revealed one or more gene mutations in 681 cases (95.5%), among which actionable gene mutations were detected in 439 (61.6%). Although treatment options were recommended for 285 cases (40.0%) by the molecular tumor board, only 45 received treatment based on their gene mutations. During the median observation period of 8.6 months, 351 (49.2%) patients died of the exacerbation of existing diseases. No significant differences were observed in OS between patients treated with and without genomically matched therapy (p = 0.285). According to clinical responses to treatment based on gene mutations, median OS was significantly longer in patients who achieved partial response and stable disease (26.5 months; 95% CI 14.4-38.6) than in those with progressive disease and not evaluated (9.8 months; 95% CI 5.8-13.8, p = 0.013). Responses to treatment based on gene mutations may improve prognoses, and it is important to increase the drug accessibility rate after CGP testing.


Ab initio studies of phoshorene island single electron transistor.
Phosphorene is a newly unveiled two-dimensional crystal with immense potential for nanoelectronic and optoelectronic applications. Its unique electronic structure and two dimensionality also present opportunities for single electron devices. Here we report the behaviour of a single electron transistor (SET) made of a phosphorene island, explored for the first time using ab initio calculations. We find that the band gap and the charging energy decrease monotonically with increasing layer numbers due to weak quantum confinement. When compared to two other novel 2D crystals such as graphene and MoS2, our investigation reveals larger adsorption energies of gas molecules on phosphorene, which indicates better a sensing ability. The calculated charge stability diagrams show distinct changes in the presence of an individual molecule which can be applied to detect the presence of different molecules with sensitivity at a single molecular level. The higher charging energies of the molecules within the SET display operational viability at room temperature, which is promising for possible ultra sensitive detection applications.


Trace metal sorption ability of insolubilized humic acids.
The objective of this work was to study the trace metal sorption ability of Insolubilized Humic Acids (IHA) in comparison with regular Humic Acids (HA). IHA were prepared from HA by heating at 330 degrees C for one hour under a nitrogen atmosphere. A solubility study was carried out at different pH values in NaNO3 (0.1 M) as a background electrolyte. It showed that IHA were insoluble until pH 10 whereas the solubility of HA increased with pH in one main step in the pH range 4-5 over which the soluble fraction of humic acids increased from 10% to 90%. We observed that trace metal sorption was dramatically influenced by these solubility properties. Indeed this study showed that above pH 5-6, HA and IHA may have opposite effects in terms of trace metal sorption. Solubilization of HA made possible the formation of soluble metal-humic complexes, retaining metal in solution even for pH at which hydroxide can form. Under such pH conditions, which very numerous soils show, HA could be involved in the transport and uptake of trace metals in the plant-soil system. In terms of remediation, HA are not a suitable binding phase. On the contrary IHA were not solubilized at neutral and alkaline pH, avoiding then the solubilization of sorbed trace metals. They appeared to be a suitable binding additive phase for future remediation trials.


Prolonged intralymphatic delivery of dendritic cells through implantable lymphatic ports in patients with advanced cancer.
The currently-used modes of administration of immunotherapeutic agents result in their limited delivery to the lymph nodes and/or require repetitive ultrasound-guided nodal injections or microsurgical lymphatic injections, limiting their feasibility. Here, we report on the feasibility and safety of a new method of long-term repetitive intralymphatic (IL) infusion of immune cells, using implantable delivery ports. Nine patients with stage IV recurrent colorectal cancer underwent complete resection and received autologous dendritic cells (DCs) loaded with killed autologous tumor cells, KLH and PADRE, for up to four monthly cycles. Leg lymphatic vessels were cannulated, connected to 6.6Fr low-profile implantable subcutaneous delivery ports, and used to infuse 12 doses of DC over each 72 h-long cycle (every 6 h), followed by heparin flushes of the cannula-port system (one 72 h-long cycle per month). The patients who opted for alternative route of vaccine administration (2 patients) or whose ports became non-functional between cycles, continued treatment via intranodal (one injection/cycle) or intradermal (four injections/cycle) routes. A total of nine lymphatic cannulations and implantations of subcutaneous delivery ports were attempted in seven patients, with a success rate of eight out of nine (89 %). The average patency of the IL delivery system was 7.5 (±3.2) weeks. All six patients with IL ports successfully completed at least one complete 72 h-long DC infusion cycle (12 injections). Five patients (56 %) completed two full IL cycles (24 IL injections). No patients received more than two IL cycles without replacement of the IL port, due to catheter occlusion and/or local side effects: cellulitis and hematoma. Intranodal and intradermal backup options were used in, respectively, one and two patients. Overall cohort survival was >28 (±25) months. One patient with aggressive recurrent carcinomatosis, who received DC vaccines by intranodal route is alive at > 90 months, without evidence of disease. We conclude that an intermediate-duration IL delivery of multiple doses of immunotherapeutic factors using implantable delivery ports is feasible, highly-tolerable and can be reproducibly performed in cancer patients to administer immune cells, or potentially, other immune factors. However, long-term IL port placement (>7.5 weeks), is not a currently-feasible option. NCT00558051, registered Nov. 13, 2007.


Effect of preoperative cannabis use on perioperative outcomes: a retrospective cohort study.
The reported use of cannabis within surgical population is increasing. Cannabis use is potentially associated with increased harms and varied effects on pain control. These have important implications to perioperative care. We conducted a retrospective cohort study comparing surgical patients reporting cannabis use preoperatively to control patients with no cannabis exposure, in a 1:2 ratio. To control for confounding, we used a propensity score-matched analysis to assess the adjusted association between cannabis use and study outcomes. Our primary outcome was a composite of (1) respiratory arrest or cardiac arrest, (2) intensive care admission, (3) stroke, (4) myocardial infarction and (5) mortality during this hospital stay. Secondarily, we assessed the effects on pain control, opioid usage, induction agent dose and nausea-vomiting. Between January 2018 and March 2019, we captured 1818 patients consisting of cannabis users (606) and controls (1212). For propensity score-matched analyses, 524 cannabis patients were compared with 1152 control patients. No difference in the incidence of composite outcome was observed (OR 1.06, 95% CI 0.23 to 3.98). Although a higher incidence of arrhythmias (2.7% vs 1.6%) and decreased incidence of nausea-vomiting needing treatment (9.6% vs 12.6%) was observed with cannabis users vs controls, results were not statistically significant. No significant differences were observed with other secondary outcomes. Our results do not demonstrate a convincing association between self-reported cannabis use and major surgical outcomes or pain management. Perioperative decisions should be made based on considerations of dose, duration, and indication.


Bone mineral status in ambulatory pediatric patients on long-term anti-epileptic drug therapy.
For ambulatory pediatric outpatients,reports of abnormalities of bone metabolism associated with anti-epileptic drugs are inconsistent and may be difficult to interpret. The effects of long-term anti-epileptic therapy (mainly valproic acid and/or carbamazepine) on bone mineral status were evaluated in ambulatory epileptic patients(seven males and 11 females) aged 5.5-15.9 years. Bone mineral density (BMD) at the lumbar spine was measured by dual-energy X-ray absorptiometry and markers of bone and mineral metabolism were determined. The mean BMD was decreased by 9% in our patients relative to the control, and five patients (all males)showed osteopenia, defined as BMD SD scores less than - 1.5. Serum levels of minerals, intact parathyroid hormone and 1alpha,25(OH)2 vitamin D were within the normal ranges. In most patients, serum levels of intact osteocalcin, carboxyterminal propeptide of type I procollagen and pyridinoline cross-linked telopeptide of type I collagen were reduced relative to the corresponding mean control values. The BB genotype by BsmI restriction fragment length polymorphism, associated with low BMD, was not found in our patients. The dietary calcium intake in the osteopenic patients was significantly lower than that of the non-osteopenic patients. Our results indicate that long-term anti-epileptic treatment induces a state of decreased bone turnover in children, resulting in osteopenia preferentially in males. The alterations may be due, at least in part, to direct effects of the drugs on bone cells; and that low calcium intake could be an aggravating factor for anti-epileptic-associated osteopenia.