Effects of glycine on hemodynamic responses and visual evoked potentials in the dog.
To study the potential contribution of glycine toxicity in the transurethral resection syndrome, we evaluated hemodynamic and visual evoked potential responses to glycine infusion (1 g/kg) in 22 dogs anesthetized with halothane (1.0-1.2% end tidal. Three dogs received 5% glucose in normal saline without glycine; three received arginine (4 mg/kg) in normal saline without glycine; three received arginine (4 mg/kg) in normal saline without glycine; 10 received glycine (1 g/kg), then arginine (4 mg/kg) 120 min after the completion of glycine infusion; and six received arginine 30 min after the completion of glycine infusion. Arginine was infused to evaluate potential antagonistic effects of glycine toxicity. Blood levels of glycine, ammonia, arginine, urea, and formate were determined after infusions of glycine or arginine. All animals received about 5 ml X kg-1 X hr-1 of normal saline during the 2-4 hr of study. Immediately after glycine infusion, cardiac output increased 57%, whereas systemic vascular resistance and mean arterial pressure decreased 32% and 8%, respectively. Later cardiac output and mean arterial pressure were 41% and 18% less than control levels, whereas systemic vascular resistance returned to control levels. Both amplitude and latency of visual evoked potential waveforms were altered in the animals receiving glycine infusion but not in the control animals. These responses were associated with elevations of blood glycine (149 +/- 5 to 9591 +/- 809 microM/L, mean + SEM) and blood NH3 (10.5 +/- 2.8 to 100.0 +/- 13.6 microM/L), but not with formate levels.(ABSTRACT TRUNCATED AT 250 WORDS)


Controlled expression of lysis gene E by a mutant of the promoter pL of the thermo-inducible λcI857-pL system.
To identify a lambda promoter pL mutant that could extend the thermal stability of the thermo-inducible λcI857-pR/pL system and to evaluate the effects of the modified system for the controlled expression of lysis gene E during the production of bacterial ghosts (BGs). The promoter pL mutant was identified by random mutagenesis and site-directed mutagenesis. The results showed that a T → 35C mutation in the pL promoter was responsible for the phenotype alteration. Under the same induction conditions, the lysis rates of the modified lytic system on Escherichia coli and Salmonella enteritidis were significantly lower than that of the control, while the lysis rates of Escherichia coli with the thermo-inducible lytic system were significantly higher than that of S. enteritidis with the corresponding plasmid (P < 0·05). Increasing the heat stability of the thermo-inducible lytic systems decreased lysis efficiency during the production of BGs. There exist differences in the lysis efficiency of thermo-inducible lytic systems between different bacterial strains. These findings enrich current knowledge about modifications to thermo-inducible systems and provide a reference for the application of these modified systems for the production of BGs and controlled gene expression in bacteria.


Pain relief and local tumour control following percutaneous image-guided cryoablation for spine metastasis: a 12-year single-centre experience.
To assess pain relief and local tumour control retrospectively in spinal metastases undergoing cryoablation. Between May 2008 and September 2020, 46 metastases in 41 consecutive patients (mean age 59.7±4.4 [SD] years; range 27-84) were treated with cryoablation in 42 interventional sessions. Patient demographics, procedural data, complications, pain, and local tumour control were analysed retrospectively. Thirty-one patients (36 spine metastases; 32 sessions) were treated for pain relief and 10 (10 metastases; 10 sessions) for local tumour control. Clinical success was reached in 30/32 (93.8%) interventional palliative sessions. Mean pre-procedural numerical pain rate scale was 6.2±1.7 (SD), and dropped significantly to 3.5±1.8 (SD), 1.9±1.7 (SD), and 1.9±1.8 (SD) at 24-h, 1-month and at the last available follow-up (median 16.5±23.2 [SD] months), respectively. For patients requiring local tumour control, primary clinical success was reached in 6/10 (60%) spinal metastases at median 25-months follow-up. The overall complication rate was 8%, with no secondary fractures or iatrogenic thermal-mediated nerve injuries reported. Percutaneous image-guided cryoablation of spinal metastases is safe and effective in achieving pain relief and local tumour control.


Clinical outcomes of adults and children with cystic fibrosis during the COVID-19 pandemic.
The onset of the COVID-19 pandemic was associated with restricted community movement and limited access to healthcare facilities, resulting in changed clinical service delivery to people with cystic fibrosis (CF). This study aimed to determine clinical outcomes of Australian adults and children with CF in the 12-months following the onset of the COVID-19 pandemic. This longitudinal cohort study used national registry data. Primary outcomes were 12-month change in percent predicted forced expiratory volume in one second (FEV1 %pred), body mass index (BMI) in adults and BMI z-scores in children. A piecewise linear mixed-effects model was used to determine trends in outcomes before and after pandemic onset. Data were available for 3662 individuals (median age 19.6 years, range 0-82). When trends in outcomes before and after pandemic onset were compared; FEV1 %pred went from a mean annual decline of -0.13% (95%CI -0.36 to 0.11) to a mean improvement of 1.76% (95%CI 1.46-2.05). Annual trend in BMI improved from 0.03 kg/m2 (95%CI -0.02-0.08) to 0.30 kg/m2 (95%CI 0.25-0.45) and BMI z-scores improved from 0.05 (95%CI 0.03-0.07) to 0.12 (95%CI 0.09-0.14). Number of hospitalisations decreased from a total of 2656 to 1957 (p < 0.01). Virtual consultations increased from 8% to 47% and average number of consultations per patient increased from median (IQR) of 4(2-5) to 5(3-6) (p < 0.01). In the 12-months following the onset of the COVID-19 pandemic, there was an improvement in the clinical outcomes of people with CF when compared to the pre-pandemic period.


Forecasting COVID-19 Chile' second outbreak by a generalized SIR model with constant time delays and a fitted positivity rate.
The COVID-19 disease has forced countries to make a considerable collaborative effort between scientists and governments to provide indicators to suitable follow-up the pandemic's consequences. Mathematical modeling plays a crucial role in quantifying indicators describing diverse aspects of the pandemic. Consequently, this work aims to develop a clear, efficient, and reproducible methodology for parameter optimization, whose implementation is illustrated using data from three representative regions from Chile and a suitable generalized SIR model together with a fitted positivity rate. Our results reproduce the general trend of the infected's curve, distinguishing the reported and real cases. Finally, our methodology is robust, and it allows us to forecast a second outbreak of COVID-19 and the infection fatality rate of COVID-19 qualitatively according to the reported dead cases.


H-2-restricted graft-versus-host reaction: foreign determinants and restriction elements.
Nylon-wool-purified T cells from radiation chimeras cause a lethal graft-versus-host reaction (GVHR) in irradiated, bone-marrow-protected recipients only if the recipient shares a restriction element with the T-cell donor and also expresses antigens foreign to the donor. Class I molecules (H-2K and H-2D) can act as restriction elements, but restriction to class II molecules could not be demonstrated. However, class II molecules as well as H-2K and some non-H-2 determinants could serve as foreign antigens.


Intestinal-fatty acid binding protein and lipid transport in human intestinal epithelial cells.
Intestinal-fatty acid binding protein (I-FABP) is a 14-15 kDa cytoplasmic molecule highly expressed in the enterocyte. Although different functions have been proposed for various FABP family members, the specific function of I-FABP in human intestine remains unclear. Here, we studied the role of I-FABP in molecularly modified normal human intestinal epithelial cells (HIEC-6). cDNA transfection resulted in 90-fold I-FABP overexpression compared to cells treated with empty pQCXIP vector. The high-resolution immunogold technique revealed labeling mainly in the cytosol and confirmed the marked phenotype abundance of I-FABP in cDNA transfected cells. I-FABP overexpression was not associated with alterations in cell proliferation and viability. Studies using these transfected cells cultured with [14C]oleic acid did not reveal higher efficiency in de novo synthesis or secretion of triglycerides, phospholipids, and cholesteryl esters compared to cells treated with empty pQCXIP vector only. Similarly, the incubation with [35S]methionine did not disclose a superiority in the biogenesis of apolipoproteins (apo) A-I, A-IV, B-48, and B-100. Finally, cells transfected with I-FABP did not exhibit an increased production of chylomicrons, VLDL, LDL, and HDL. Our observations establish that I-FABP overexpression in normal HIEC-6 is not related to cell proliferation, lipid esterification, apo synthesis, and lipoprotein assembly, and, therefore, exclude its role in intestinal fat transport.


Characterization of a ribosomal protein L15 cDNA from Chironomus riparius (Diptera; Chironomidae): transcriptional regulation by cadmium and silver nanoparticles.
A full-length ribosomal protein L15 cDNA from Chironomus riparius (CrRPL15) was identified from the Expressed Sequence Tag (EST) database developed vt 454 pyrosequencing, and expression of the corresponding mRNA was analyzed during different developmental stages and following exposure to Cadmium chloride (Cd) and Silver nanoparticles (AgNPs). The CrRPL15 cDNA contains an open reading frame (ORF) of 615 base pairs (bp) encoding a putative protein of 204 amino acids, with a high level of sequence similarity to RPL15 proteins from other species. The consensus sequence, GXXXXGKS, which is present in other RPL15 proteins, was also present in the putative CrRPL15 protein. The CrRPL15 transcript was present at all life stages, but was most abundant in the eggs. Expression of the CrRPL15 gene was significantly down-regulated in response to exposure to both Cd and AgNPs. In contrast, expression of the heat shock protein 70 (HSP70) gene, a general stress indicator, was significantly up-regulated.


[Morphologic analysis of epiretinal membranes in surgically treated idiopathic macular foramina. Results of light and electron microscopy].
Anteroposterior and tangential traction on the central retina is an important factor in the pathogenesis of idiopathic macular hole formation. Histological studies have shown that macular holes of different stages can be associated with epiretinal membranes. Such membranes can be removed during surgery for macular holes. We investigated such tissue samples of 11 patients with macular holes in stages II-IV. Light microscopically, the tissue consisted of a thin collagen layer mostly covered by a thin layer of cells. Ultrastructural analysis revealed glial cells and macrophages as cellular components. The collagen can be ascribed to vitreous, inner limiting membrane and newly formed collagen. According to the morphological findings a multilayered tissue structure can be assumed. Macrophages were found on the retinal side of the inner limiting membrane and at the vitreal side of the tissue. Therefore, the macrophages probably originate from the retina as well as from the vitreous as so-called resident hyalocytes. Glial cells covered the inner limiting membrane forming pericellular collagen to which outer vitreous collagen fibrils can be attached. The multilayered membrane structure might possibly be the cause for only partial laminar surgical extraction so that contractile or potentially proliferative tissue residues might be one of the reasons for surgical failures after incomplete membrane peeling.


Patient-Reported Outcome Measures to Inform Care of People With Dementia-A Systematic Scoping Review.
Patient-reported outcome measures (PROMs) captures the patient's perspective regarding quality of life, daily functioning, symptom severity, and overall health, and how these may be impacted by health care or other interventions. PROMs are used in clinical quality registries (CQRs) for a number of diseases to assess the patient's perspective of the impact of clinical care on quality-of-life. This scoping review aimed to identify dementia-specific PROMs, determine how the PROMs are being used, and whether they are used within dementia registries. Three electronic databases were searched using Medical Subject Heading terms for dementia, quality of life, and patient-reported outcomes. Data were extracted on the PROMs used and the methods and mode of administering the PROM. Seven dementia-specific PROMs were identified, however none were used in a dementia registry. All the PROMs were used at the patient level to identify patient needs and health service impacts. Three PROMs were also used at a system level to examine difference in care models. The majority of the PROMs were administered via a researcher or clinician and were predominantly completed by a proxy. PROMs provide an opportunity for a patient with dementia to share experiences and perspectives of care. A number of dementia-specific PROMs exist, yet none are used in dementia registries and the majority of studies utilize PROMs via a proxy. The use of PROM for patients with dementia, particularly in the context of dementia registries, requires further exploration and consideration.


Bupivacaine liposomal versus bupivacaine: comparative review.
Bupivacaine liposomal injection was recently approved by the US Food and Drug Administration (FDA) as a local anesthetic for use in management of postsurgical pain in adults. When compared to placebo, bupivacaine liposomal decreases postoperative pain and opioid use. This review examines the efficacy of bupivacaine liposomal when compared to conventional bupivacaine ± epinephrine using published and unpublished data provided to the FDA by the manufacturer.


Isolation of Sporothrix schenckii from the environmental sources of cutaneous sporotrichosis patients in Himachal Pradesh, India: results of a pilot study.
Himachal Pradesh, India is a known endemic area for cutaneous sporotrichosis. No attempt has been made to isolate Sporothrix schenckii, the causative fungus, from environmental sources in this region or in India as such. This prospective study was carried out to isolate Sporothrix schenckii from different environmental samples collected from the vicinity of cutaneous sporotrichosis patients. All patients of cutaneous sporotrichosis diagnosed during March 2005-February 2006 were studied. Twenty-one biopsy specimens and 62 environmental samples of soil, various thorns, corn-stalk, grass-blades and sphagnum moss were subjected to mycologic culture on Sabouraud's glucose agar. Sporothrix schenckii was identified by colony characteristics, lacto-phenol cotton blue mounts and demonstration of temperature dimorphism. These patients (F : M 15 : 6) were between 12 and 72 years of age and had cutaneous lesions for 45 days to 4 years. Lymphocutaneous and fixed cutaneous sporotrichosis was seen in 14 (66.6%) and 7 (33.3%) patients respectively. Extremities were involved in 16 (76.2%); and 5 (23.8%) patients had facial lesions. Ten (47.4%) biopsy specimens and six environmental (three soil, three corn-stalk) samples were culture-positive, which showed morphological characteristics suggesting Sporothrix schenckii. No variation in colony characteristics and mycelial morphology was observed in growth isolates from clinical or environmental samples. Temperature dimorphism was observed in all the 10 isolates obtained from the clinical specimens and in two isolates cultured from corn-stalk. Corn-stalks are evidently important sources of Sporothrix schenckii infection although subsequent contamination of wounds appears more important for development of clinical disease. Culture of Sporothrix schenckii from environmental sources may not be always possible to correlate with profile of injuries.


Morphologic findings in placenta associated with SARS-CoV-2 infection.
SARS-CoV-2 infection in pregnancy can cause a number of serious complications, including fetal growth restriction or intrauterine fetal death. It appears that transplacental transmission of infection is rare and the arising complications are due to damage of placental parenchyma. The aim of this article is to summarize the results of recent publications dealing with placental changes in COVID-19 disease, with special consideration to the morphology of the newly defined SARS-CoV-2 placentitis.


Prevalence of sexually transmitted infections in pregnant urban Aboriginal and Torres Strait Islander women in northern Australia.
To assess the prevalence of sexually transmitted infections (STI) in a cohort of pregnant urban Indigenous women and association of STI with preterm birth, low birthweight birth and perinatal mortality. Prospective intervention program in a cohort of women attending Townsville Aboriginal and Islander Health Services (TAIHS) for shared antenatal care between 1 January 2000 and 31 December 2003 incorporating routine screening for chlamydia, gonorrhoea, trichomoniasis, hepatitis B and syphilis. Townsville is a provincial urban centre with a regional Indigenous population of over 16 000. Four hundred and fifty-six pregnant women who were screened for bacterial STI and other viral infections. Prevalence of STI, associated risk factors and perinatal outcomes. Of the 456 women, 403 (88.4%) were screened for chlamydia, gonorrhoea and trichomonas and 432 (94.7%) were screened for syphilis. A total of 92 cases of STI (20.2%, 95% CI 16.5-23.9) were detected, with 21 concurrent infection(s). The overall prevalence of chlamydia was 14.4%, gonorrhoea 6.1%, trichomoniasis 7.2% and infectious syphilis 2.5%. Predictors for STI were young age, harmful/hazardous alcohol use and unwanted pregnancy. Low birthweight and perinatal death were significantly associated with the presence of STI and infectious syphilis during pregnancy. The prevalence of STI among pregnant women in this urban Indigenous community is high, suggesting that screening for STI should be included in all antenatal care protocols for Indigenous women in Australia. Strategies to reach the whole Indigenous community of child-bearing age, especially those aged less than 25 years, are needed to improve perinatal outcome.


Head injuries at an inner city accident and emergency department.
A prospective study was carried out of 784 adults (aged 13 years and over) with recent head injuries who attended the Accident and Emergency Department of the Glasgow Royal Infirmary during an 11-week period (April-June 1978). One-third were caused by assault and only one-tenth by road traffic accidents. Half the patients had recently ingested alcohol, one-quarter of all patients had at least a brief period of post-traumatic amnesia (PTA). The overall admission rate was 28 per cent. Radiography of the skull was performed in 65 per cent and a fracture seen in 5 per cent of these. One-quarter of the patients had at least one unsatisfactory radiograph. Two patients whose fractures were initially missed on radiography were not admitted. Seven of the 24 patients with fractures had no clinical evidence of brain damage (no PTA, no impaired conscious level, no focal neurological signs or symptoms), but all had wounds of the scalp. One-third of all patients did not have radiography of the skull performed, nor were they admitted to hospital, yet one-quarter of these had some evidence of brain damage.


Direct observations of shifts in the β-sheet register of a protein-peptide complex using explicit solvent simulations.
Using explicit solvent molecular dynamics simulations, we were able to obtain direct observations of shifts in the hydrogen-bonding register of an intermolecular β-sheet protein-peptide complex. The β-sheet is formed between the FHA domain of cancer marker protein Ki67 (Ki67FHA) and a peptide fragment of the hNIFK signaling protein. Potential encounter complexes of the Ki67FHA receptor and hNIFK peptide are misregistered states of the β-sheet. Rearrangements of one of these misregistered states to the native state were captured in three independent simulations. All three rearrangements occurred by a common mechanism: an aromatic residue of the peptide (F263) anchors into a transient hydrophobic pocket of the receptor to facilitate the formation of native hydrogen bonds. To our knowledge, these simulations provide the first atomically detailed visualizations of a mechanism by which nature might correct for errors in the alignment of intermolecular β-sheets.


Regression of cardiomyocyte hypertrophy in SHR following chronic inhibition of the Na(+)/H(+) exchanger.
Experiments were performed to examine the effect of chronic inhibition of the Na(+)/H(+) exchanger isoform-1 (NHE-1) on cardiac hypertrophy of spontaneously hypertensive rats (SHR). SHR were orally treated during 1 month with two different doses (0.3 and 3.0 mg/kg/day) of the NHE-1 inhibitor, cariporide, or nifedipine (10.0 mg/kg/day). The two doses of cariporide did not differ in their effects after 1 month of treatment, since both induced a slight decrease in systolic blood pressure (SBP) of approximately 6 mmHg and regression of the heart weight to body weight ratio (mg/g) from 3.28+/-0.05 to 3.04+/-0.05 (0.3 mg) and 2.99+/-0.10 (3.0 mg, P<0.05). Nifedipine, given for the same period, produced similar reduction in the hypertrophy index (3.03+/-0.05), but with a much greater decrease in arterial pressure (35.6+/-7.4 mmHg). Chronic treatment with cariporide induced a complete regression of the augmented cross sectional area of left ventricular myocytes without significant changes in collagen content, serum procollagen 1 propeptide levels or myocardial distensibility. NHE inhibition represents a novel approach to induce regression of pathological hypertrophy of the heart. The finding can be rationalized mechanistically by previous in vitro studies suggesting a role of the NHE in the development of myocardial hypertrophy.


Perceptions and Experiences of the University of Nottingham Pilot SARS-CoV-2 Asymptomatic Testing Service: A Mixed-Methods Study.
We aimed to explore student and staff perceptions and experiences of a pilot SARS-CoV-2 asymptomatic testing service (P-ATS) in a UK university campus setting. This was a mixed-method study comprised of an online survey, and thematic analysis of qualitative data from interviews and focus groups conducted at the mid-point and end of the 12-week P-ATS programme. Ninety-nine students (84.8% female, 70% first year; 93.9% P-ATS participants) completed an online survey, 41 individuals attended interviews or focus groups, including 31 students (21 first year; 10 final year) and 10 staff. All types of testing and logistics were highly acceptable (virus: swab, saliva; antibody: finger prick) and 94.9% would participate again. Reported adherence to weekly virus testing was high (92.4% completed ≥6 tests; 70.8% submitted all 10 swabs; 89.2% completed ≥1 saliva sample) and 76.9% submitted ≥3 blood samples. Students tested to "keep campus safe", "contribute to national efforts to control COVID-19", and "protect others". In total, 31.3% had high anxiety as measured by the Generalized Anxiety Disorder scale (GAD-7) (27.1% of first year). Students with lower levels of anxiety and greater satisfaction with university communications around P-ATS were more likely to adhere to virus and antibody tests. Increased adherence to testing was associated with higher perceived risk of COVID-19 to self and others. Qualitative findings revealed 5 themes and 13 sub-themes: "emotional responses to COVID-19", "university life during COVID-19", "influences on testing participation", "testing physical and logistical factors" and "testing effects on mental wellbeing". Asymptomatic COVID-19 testing (SARS-CoV-2 virus/antibodies) is highly acceptable to students and staff in a university campus setting. Clear communications and strategies to reduce anxiety are likely to be important for testing uptake and adherence. Strategies are needed to facilitate social connections and mitigate the mental health impacts of COVID-19 and self-isolation.


A Rare Case of Oestrogen Dermatitis.
Oestrogen dermatitis is a rare disorder characterised by cyclical eruptions in association with a woman's menstrual cycle. A 43-year-old woman with an 8-year history of cyclical inguinal dermatitis, with a negative patch test, was tested with intradermal progesterone and oestrogen. Intradermal testing was positive for oestrogen only. In a female patient with cyclical dermatitis, it is important to consider oestrogen or progesterone dermatitis in the differential diagnosis.


An algorithm for diagnosis and treatment of type II endoleaks and endotension after endovascular aneurysm repair.
Endoleak after endoluminal abdominal aortic aneurysm repair is a relatively common occurrence. Depending on the type of endoleak involved, treatment strategies range from continued serial observation to urgent re-intervention. Type II, or branch vessel endoleaks, are often benign in terms of their natural history but can potentially be associated with progressive abdominal aortic aneurysm sac expansion, endograft migration, or even aneurysm rupture. Type V endoleaks, also known as endotension, may represent an undiagnosed type I-IV endoleak or a progressive accumulation of transudate through the interstices of the endograft. Treatment strategies therefore hinge on correctly identifying the etiology of the endotension. We discuss the diagnosis and management of type II and V endoleaks, with a focus on a device-specific approach to endoleak treatment.


Evaluation of 31P NMR spectroscopy as an indicator of chemically induced hepatic toxicity in the rat: comparison with serum enzyme levels and pathology.
The progression of carbon tetrachloride-induced liver damage, determined by 31P NMR spectroscopy, was compared with selected serum enzyme and histological changes in rats. ATP levels declined as early as 8 h post-CCl4 administration, with partial recovery observed at 168 h. The results show that ATP reduction correlates with necrosis. In addition, early decline in ATP occurring prior to significant hepatocellular necrosis indicates abnormal energy metabolism.


Domain shuffling and the increasing complexity of biological networks.
Domains can spread among proteins in a process called domain shuffling and this has been identified as one of the major mechanisms leading to the formation of new proteins throughout evolution. This process has an impact on the topology of protein-protein interaction networks as it may create new hubs and also increase interconnectivity.


Synthesis and characterization of pregabalin lactose conjugate degradation products.
Seven degradation products observed in formulated pregabalin have been characterized. These compounds result from Maillard reactions and Amadori rearrangements. Heating pregabalin in the presence of lactose formed significant quantities of these degradation products. The seven compounds corresponding to the observed degradation products were isolated by preparative liquid chromatography. The synthesis, isolation, and spectral characterization of the degradation products are detailed.


MRI and CT of metastatic hepatocellular carcinoma causing spinal cord compression.
We report the imaging features in five patients with metastatic hepatocellular carcinoma causing spinal cord compression, three of which were biopsy proven and two were in patients with known diagnosis of hepatocellular carcinoma. The radiographic, magnetic resonance imaging (MRI) and computed tomography (CT) features are highlighted. Although the occurrence of metastatic disease in hepatocellular carcinoma is exceedingly rare, it may be increasingly encountered as survival of patients is improved with advancing methods of therapy, both surgical and palliative. It often accompanies local recurrence, and invariably signals a grave prognosis with extremely short life expectancy. Unusually, two of the five patients in this series presented initially with skeletal metastases which led to the diagnosis of hepatocellular carcinoma.


Inactivation of the enveloped virus phi6 with hydrodynamic cavitation.
The COVID -19 pandemic reminded us that we need better contingency plans to prevent the spread of infectious agents and the occurrence of epidemics or pandemics. Although the transmissibility of SARS-CoV-2 in water has not been confirmed, there are studies that have reported on the presence of infectious coronaviruses in water and wastewater samples. Since standard water treatments are not designed to eliminate viruses, it is of utmost importance to explore advanced treatment processes that can improve water treatment and help inactivate viruses when needed. This is the first study to investigate the effects of hydrodynamic cavitation on the inactivation of bacteriophage phi6, an enveloped virus used as a SARS-CoV-2 surrogate in many studies. In two series of experiments with increasing and constant sample temperature, virus reduction of up to 6.3 logs was achieved. Inactivation of phi6 at temperatures of 10 and 20 °C occurs predominantly by the mechanical effect of cavitation and results in a reduction of up to 4.5 logs. At 30 °C, the reduction increases to up to 6 logs, where the temperature-induced increased susceptibility of the viral lipid envelope makes the virus more prone to inactivation. Furthermore, the control experiments without cavitation showed that the increased temperature alone is not sufficient to cause inactivation, but that additional mechanical stress is still required. The RNA degradation results confirmed that virus inactivation was due to the disrupted lipid bilayer and not to RNA damage. Hydrodynamic cavitation, therefore, has the potential to inactivate current and potentially emerging enveloped pathogenic viruses in water at lower, environmentally relevant temperatures.


3-Chloro-N'-(2,4-dichloro-benzyl-idene)benzohydrazide.
The title compound, C(14)H(9)Cl(3)N(2)O, adopts an E configuration about the methyl-idene unit and the two aromatic rings form a dihedral angle of 6.6 (2)°. In the crystal, mol-ecules are linked via N-H⋯O hydrogen bonds, forming C(4) chains propagating in [001]. C-H⋯O inter-actions reinforce the chains.


Prognostic value of the donor-derived cell-free DNA assay in acute renal rejection therapy: A prospective cohort study.
Donor-derived cell-free DNA (dd-cfDNA) is a promising biomarker for monitoring allograft status. However, whether dd-cfDNA can reflect real-time anti-rejection treatment effects remains unclear. We prospectively recruited 28 patients with acute renal rejection, including 5 with ABMR, 12 with type IA or type IB rejection, and 11 with type IIA or IIB rejection. dd-cfDNA levels in peripheral blood were measured using human single nucleotide polymorphism (SNP) locus capture hybridization. The percentage of dd-cfDNA (dd-cfDNA%) declined significantly from 2.566 ± 0.549% to 0.773 ± 0.116% (P < .001) after anti-rejection therapy. The dd-cfDNA% decreased steadily over the course of 3 days with daily methylprednisolone injections, but no significant difference in the dd-cfDNA% was observed between the end of anti-rejection therapy and 2 weeks later. Changes in the dd-cfDNA% (∆dd-cfDNA%) demonstrated a positive correlation with estimated glomerular filtration rates at 1 month (ρ = 2.570, P = .022), 3 months (ρ = 3.210, P = .027), and 6 months (ρ = 2.860, P = .019) after therapy. Thus, the dd-cfDNA assay shows prognostic capabilities in therapy outcome and allograft recovery; however, its ability is inhibited by methylprednisolone regardless of the types of rejection. Additionally, a reassessment of frequency intervals for testing is required.


Discovery of novel N-sulfonamide-tetrahydroisoquinolines as potent retinoic acid receptor-related orphan receptor γt agonists.
Cancer immunotherapy has become a research hotspot in recent years. A variety of targets were developed for small molecule immuno-oncology agents, including retinoic acid-related orphan receptor gamma t (RORγt), chemokine receptor, stimulator of interferon genes (Sting), indoleamine 2,3-dioxygenase (IDO), toll-like receptors (TLR), etc. Among them, the retinoic acid receptor-related orphan receptor γt (RORγt) has gradually attracted more attention in these years. In particular, LYC-55716 (cintirorgon), a small molecule RORγt agonist developed by Lycera, has entered the phase II clinical study. In this work, starting from compound 7, compound 28 was obtained after 4 rounds of compound design, synthesis and SAR studies, which had an EC50 of 0.021 ± 0.002 μM in dual Fluorescence Resonance Energy Transfer (dual-FRET) assay and an EC50 of 0.021 ± 0.002 μM in mouse Th17 cell differentiation assay. It indicated that compound 28 had excellent RORγt agonistic activity and was expected to be developed as a new type of small molecule drug for cancer immunotherapy. The molecular dynamic simulation revealed that the agonist 28 formed a strong HYF triplet intramolecular interaction to stabilize H12, which helped RORγt to form the protein-binding site and therefore made the receptor ready to recruit coactivator. When the inverse agonist s27 bound with RORγt, the steric hindrance between s27 and H479 caused the destruction of the HYF triplet, leading to the collapse of H12, thus the transcription function of RORγt was interrupted due to the failure of recruiting a coactivator molecule. The triplet HYF in RORγt and the rigidity of 28 and s27 were identified to be the structural determinants for the functional switch of RORγt.


N-Nitrosocarbaryl-induced mutagenesis in Haemophilus influenzae strains deficient in repair and recombination.
Mutagenesis was studied in repair- and recombination-deficient strains of Haemophilus influenzae after treatment with N-nitrosocarbaryl (NC). Three different strains of H. influenzae carrying mutations affecting excision-repair of UV-induced pyrimidine dimers exhibited normal repair of premutational lesions (as detected by decreased mutation yield resulting from post-treatment DNA synthesis delay) and normal nonreplicative mutation fixation. This indicated that neither of these phenomena are caused by the smae repair mechanism that removes UV-induced pyrimidine dimers from the DNA. The recombination-deficient mutant recI is apparently deficient in the replication-dependent mode of NC-induced mutation fixation. This conclusion is based on the following results: (I) NC-induced mutagenesis is lower in the recI strain than in rec+ cells. (2) Repair of premutational lesions (which depends on the existence of replication-dependent mutation fixation for its detection) was not detected in the recI strain. (3) When nonreplicative mutation fixation and final mutation frequency were measured in the same experiment, about I/4 to I/3 of the final mutation yield could be accounted for by nonreplicative mutation fixation in the rec+ strain, whereas all of the mutation could be accounted for in the recI strain by the nonreplicative mutation fixation. (4) When mutation fixation in strain dna9 recI was followed at the permissive (36 degrees) and nonpermissive (41 degrees) temperatures, it became apparent that in the recI strain replication-dependent mutation fixation occurs at early times, but these newly fixed mutations are unstable and disappear at later times, leaving only the mutations fixed by the nonreplicative process. The recI strain exhibits normal repair of NC-induced single-strand breaks or alkali-labile bonds in the DNA labeled before treatment, but is slow in joining discontinuties present in DNA synthesized after treatment. The results are consistent with the idea that in NC-treated H. influenzae cells the replication-dependent mode of mutation fixation occurs by error-prone joining of interruptions present in the DNA synthesized after treatment. The possibility still exists, however, that during DNA replication mispairing occurs opposite certain alkylation-induced lesions and that mutations arising during replication of strain recI later disappear as a result of degradation of newly synthesized DNA, which is excessive in this strain.


Cytokine gene expression profile in monocytic cells after a co-culture with epithelial cells.
Epithelial cells represent an important source of cytokines that may modulate the influx and functions of mononuclear phagocytes. The aim of our study was to characterize changes in the gene expression of selected cytokines in human macrophages co-cultured with respiratory epithelial cells. The A549 alveolar type II-like cell line was co-cultured with THP-1 cells (monocyte/macrophage cell line) in filter-separated mode to avoid their cell-cell contact. At different time-points (0, 4, 8, 12 and 24 h), the cells were harvested separately to evaluate their gene and protein expression (IL-1 beta, IL-6, IL-8, IL-10 and GM-CSF). Quantitative RT-PCR analysis showed prominent changes in the THP-1 cytokine gene expression induced by a co-culture with A549 cells. Fourfold upregulation of mRNA expression has been found in 12 genes and 4-fold downregulation in 5 genes as compared to the unstimulated control sample with a p value smaller than 0.05. The induction of inhibin beta A and IL-1 beta mRNA after 12 h and the expression of IL-1 alpha and GM-CSF mRNA after 24 h were the most prominent. When looking at the cytokine levels in culture supernatants, IL-1 beta and IL-8 were induced early (at 8 h) as compared to the release of IL-6 and GM-CSF (at 24 h). We conclude that respiratory epithelial cells constitutively regulate the cytokine gene expression of macrophages located in their environment and might further modulate the release of cytokines by posttranslational pathways.


The evaluation of three treatment protocols using oral prednisone and oral meloxicam for therapy of canine idiopathic lymphoplasmacytic rhinitis: a pilot study.
Idiopathic lymphoplasmacytic rhinitis (LPR) is a common inflammatory disorder of the nasal cavity in dogs due to unknown etiology. It is characterised by non-specific clinical signs, including nasal discharge, epistaxis and breathing problems. Diagnosis is usually based on the histopathologic identification of infiltrating plasmocytes and lymphocytes in the nasal mucosa and the exclusion of other underlying diseases. Treatment strategies include glucocorticoids, non-steroidal anti-inflammatory drugs, antibiotics and antifungal medications. The aim of this study was to evaluate the efficacy of various therapeutic protocols for managing canine lymphoplasmacytic rhinitis based on the results of clinical, endoscopic and histological examinations, and to determine the relapse rate for LPR in dogs.Twenty dogs of different breeds and both sexes, aged 1 to 14 years, were divided into four groups, each consisting of five dogs, including three experimental groups diagnosed with LPR and a control group.The dogs from the first experimental group were administered prednisone orally at 1 mg/kg/day in the first 4 weeks and 0,5 mg/kg/day in the following 2 weeks. The second group of dogs was administered meloxicam orally at 0,1 mg/kg/day in the first 3 weeks, followed by prednisone at 1 mg/kg/day in the following 2 weeks and 0,5 mg/kg/day in the last week of the treatment. The dogs from the third experimental group were administered meloxicam orally at 0,1 mg/kg/day for 6 weeks. The control group of dogs was administered empty gelatin capsules (placebo) orally for 6 weeks. Clinical signs, endoscopic and histopathologic lesions were scored before and after treatment. Groups were compared using Chi- squared statistics in a 2 × 2 table for pre- versus post-treatment scores. Clinical signs persisted in the group treated with meloxicam and were mostly resolved in prednisone-treated dogs. However, endoscopic and histological changes were still observed in these two groups after treatment. The severity of all diagnostic features was reduced in the group treated with meloxicam for 3 weeks followed by prednisone for 3 weeks. The significant differences (p < 0.05) were noted between experimental and control groups. The dogs showed a statistically significant reduction in characteristics of the LPR before and after treatment, as measured by clinical signs (Group 1vs.4 p = 0.00, group 2 vs 4 p = 0.00, group 3 vs 4 p = 0,01), by endoscopy (1 vs 4 p = 0,01, 2 vs 4 p = 0,00, 3 vs 4 p = 0,03), and by histopathology (groups 1 vs 4 p = 0,00, 2 vs 4 p = 0,00, 3 vs 4 p = 0,03). The significant differences were noted between experimental groups, as measured by endoscopy (group 2vs 3 p = 0,04), and by relapse rate (groups 1 and 2 p = 0,03, groups 2 and 3 p = 0,01). The three treatment protocols administered to dogs improved clinical, endoscopic and histological status. However, oral administration of meloxicam for 3 weeks, followed by prednisone for 3 weeks, appeared to be the most successful treatment. These patients remained asymptomatic for 6 months.


Establishment and characterization of an embryonic cell line from Gampsocleis gratiosa (Orthoptera: Tettigoniidae).
The first continuous cell line from the embryo of Gampsocleis gratiosa (Orthoptera: Tettigoniidae), designated as RIRI-GG1, was established. This cell line was serially subcultured in modified Grace medium. The cells were grown adherent to a culture flask and had spindle-like and polygonal shapes. The chromosome number ranged from 26 to 79 at the 50th passage, and 68% of cells had a diploid chromosome number. The growth rate was determined at the 53rd passage, and the population doubling time was calculated to be 122.1 h. The rDNA internal transcribed spacer and the mitochondrial cytochrome c oxidase subunit I gene sequence analysis indicated that the RIRI-GG1 cell line was derived from G. gratiosa. This cell line had no apparent susceptibility to Autographa californica nucleopolyhedrovirus and Bombyx mori nucleopolyhedrovirus.


Discovery of 3-pyrazolyl-substituted pyrazolo[1,5-a]pyrimidine derivatives as potent TRK inhibitors to overcome clinically acquired resistance.
Several secondary tropomyosin receptor kinase (TRK) mutations located in the solvent front, xDFG, and gatekeeper regions, are a common cause of clinical resistance. Mutations in the xDFG motif in particular limit sensitivity to second-generation TRK inhibitors, which represent an unmet clinical need. We designed a series of 3-pyrazolyl-substituted pyrazolo[1,5-a]pyrimidine derivatives toward these secondary mutations using ring-opening and scaffold-hopping strategies. Compound 5n was the most potent, with IC50 values of 2.3 nM, 0.4 nM, and 0.5 nM against TRKAG667C, TRKAF589L, and TRKAG595R, compared to selitrectinib with IC50 values of 12.6 nM, 5.8 nM, and 7.6 nM, respectively (approximately 5.4, 14.5, and 15.2-fold increases). Furthermore, 5n displayed favorable pharmacokinetic properties and satisfactory antitumor efficacy (tumor growth inhibition of 97% at 30 mg/kg and 73% at 100 mg/kg) in TRKAWT and TRKAG667C xenograft mouse models. Collectively, 5n is a promising TRK inhibitor lead compound for overcoming clinically acquired resistance to second-generation inhibitors, particularly for resistant tumors harboring the TRKAG667C mutation in the xDFG motif.


Treatment of high-renin hypertension with propranolol in children after renal transplantation.
Ten children with hypertension poorly controlled with other drugs and high peripheral plasma renin activity after renal transplantation were treated with propranolol. The mean systolic pressure decreased from 139 to 127 mm Hg (p less than 0.05) and the mean diastolic pressure from 98 to 83 mm Hg (p less than 0.01). Eight children had an antihypertensive response; two did not respond. The maximum dose of propranolol in responders varied from 1.0 to 6.2 mg/kg/day and duration of treatment until response varied from four to 49 days. PRA, repeated in seven responders, decreased in all (p less than 0.01). There was no correlation between changes in PRA and blood pressure. Propranolol was well tolerated and was a valuable antihypertensive drug in these children.


Self-report versus clinician-ratings in the assessment of aggression in violent offenders.
The construct of aggression is central to work with violent offenders, but it is a broad construct that can be assessed by many different methods and instruments. Its measurement may, however, have profound implications for treatment planning. We need more knowledge about how different methods for assessing aggression relate to each other. Our aims were to investigate, first, the convergence and concordance of two methods of assessing aggression: self-report and clinical assessment and, second, to determine the degree to which aggression can be discriminated from neighbouring constructs, such as hostility, anger and criminal behaviour. A nationally representative Swedish cohort of 269 18-25-year-old incarcerated violent offenders was recruited. Data were collected through structured self-reports of aggression, anger and hostility traits (Aggression Questionnaire-Revised Swedish Version) and clinical assessments of lifetime prevalence of aggressive and antisocial behaviours (Life History of Aggression). Criminal records were retrieved from the Swedish National Crime Register. Self-ratings and clinician-ratings of aggression were highly convergent and concordant, especially regarding physical aggression. Violent offence records were weakly, if at all, correlated, while self-reported hostility was weakly, or not at all, correlated with self-reported or with clinician-rated aggression. There was an inverse relationship between aggression and criminal records of sexual offences. Even though a combination of self-reports and clinician-ratings may provide a better overview of an individual's aggressive behaviours, our results indicate that they yield such similar information that either alone would be sensitive enough. Our results do not, however, support using one of these methods as a proxy for the other since choice of measure and accepted concordance between them depend on the context within which the assessment is conducted. We reconfirmed that official records of violent offending are unlikely to be adequate measures of outcome after interventions to reduce aggressive behaviours.


Inter-individual response differences on resting blood pressure as a result of qigong in adults: An ancillary meta-analysis of randomized trials.
Conduct an ancillary meta-analysis to determine whether true inter-individual response differences (IIRD) exist with respect to the effects of qigong on resting systolic blood pressure (SBP) and diastolic blood pressure (DBP) in adults. Data from a meta-analysis representing 370 participants (181 qigong, 189 control) from 7 randomized trials on qigong and resting SBP and DBP in men and women were included. Qigong and control group change outcome standard deviations treated as point estimates for both resting SBP and DBP were used to calculate true IIRD from each study. The inverse variance heterogeneity (IVhet) model was used to pool results. For participants with essential hypertension, statistically significant and clinically important reductions in resting SBP (X̅, -18.2 mmHg, 95% CI, -21.3 to -15.2 mmHg) and DBP (X̅, -11.7 mmHg, 95% CI, -17.0 to -6.3 mmHg) were found. However, true IIRD were neither significant nor clinically important for either SBP (X̅, -6.0 mmHg, 95% CI, -9.1 to 3.5 mmHg) or DBP (X̅, 2.8 mmHg, 95% CI, -3.4 to 5.2 mmHg). The 95% prediction interval for true IIRD was - 11.9 to 8.4 mmHg for SBP and - 5.8 to 7.0 mmHg for DBP. While qigong is associated with reductions in resting SBP and DBP in adults with essential hypertension, a lack of true IIRD exists, suggesting that other external factors are responsible for any variation.


Buspirone metabolite structure profile using a standard liquid chromatographic-mass spectrometric protocol.
A rapid and systematic LC-MS protocol is utilized to profile buspirone metabolites. Analysis of rat bile, urine and liver S9 samples using a standard LC-MS method provides structural information for 25 metabolites. The resulting buspirone metabolite structure database contains characteristic retention time, molecular mass and MS-MS product ion information for each compound. Metabolites are categorized according to profile groups, which illustrate that substitution reactions are primarily associated with the azaspirone decane dione and pyrimidine substructures. Structures of new buspirone metabolites are reported and include the despyrimidinyl, despyrimidinylpiperazine, glucuronide, hydroxyglucuronide (four isomers), methoxyglucuronide and hydroxymethoxyglucuronide (two isomers) buspirone metabolites.


Population dynamics and drug resistance mutations in Plasmodium falciparum on the Bijagós Archipelago, Guinea-Bissau.
Following integrated malaria control interventions, malaria burden on the Bijagós Archipelago has significantly decreased. Understanding the genomic diversity of circulating Plasmodium falciparum malaria parasites can assist infection control, through identifying drug resistance mutations and characterising the complexity of population structure. This study presents the first whole genome sequence data for P. falciparum isolates from the Bijagós Archipelago. Amplified DNA from P. falciparum isolates sourced from dried blood spot samples of 15 asymptomatic malaria cases were sequenced. Using 1.3 million SNPs characterised across 795 African P. falciparum isolates, population structure analyses revealed that isolates from the archipelago cluster with samples from mainland West Africa and appear closely related to mainland populations; without forming a separate phylogenetic cluster. This study characterises SNPs associated with antimalarial drug resistance on the archipelago. We observed fixation of the PfDHFR mutations N51I and S108N, associated with resistance to sulphadoxine-pyrimethamine, and the continued presence of PfCRT K76T, associated with chloroquine resistance. These data have relevance for infection control and drug resistance surveillance; particularly considering expected increases in antimalarial drug use following updated WHO recommendations, and the recent implementation of seasonal malaria chemoprevention and mass drug administration in the region.


Prolongation of liver xenograft survival by adenovirus vector-mediated CTLA-4Ig gene transfer.
Cytotoxic T lymphocyte-associated antigen-4/immunoglobulin fusion products (CTLA-4Ig), a structural homologue of CD28, has been shown to inhibit cellular and humoral immune responses. In this study, we investigated the efficacy of an adenovirus vector containing the CTLA-4Ig gene (AdCTLA-4Ig) on recipient survival after hamster-to-rat liver xenografting. AdCTLA-4Ig was administrated intravenously immediately after grafting. Gene expression was achieved a maximum of 7 days after vector injection and continued for more than 4 weeks. The proportion of CD25(+) T-cells in recipient lymph nodes was significantly reduced 7 days after administration of AdCTLA-4Ig, compared to a group given an adenoviral vector containing LacZ gene (AdLacZ) or to an untreated control group. AdCTLA-4Ig markedly reduced CD2(+) T-cell infiltration into the graft and significantly prolonged recipient survival time (9.2+/-4.12 days), compared to the untreated group (5.4+/-0.78 days) (P<0.001) and the AdLacZ-treated group (5.2+/-0.28 days) (P<0.001). These results indicate that a blockade of T-cell co-stimulation by AdCTLA-4Ig inhibited T-cell activation and attenuated CD2(+) T-cell infiltration into the xenograft, resulting in significant prolongation of recipient survival time. Thus, AdCTLA-4Ig therapy may provide a novel approach to immune regulation.


Absenteeism control programs. Results of a national survey of certified occupational health nurses.
An absenteeism control program can reduce employee absenteeism, thereby reducing company expenses, improving productivity, and bringing workers back to work sooner. A survey of Cohn's suggests that many companies in the United States lack absenteeism control programs, and those firms that have such programs are unlikely to have all the elements of a good program in place. Placing the occupational health nurse in charge of a comprehensive program will provide needed leadership, responsibility, expertise, and control.


[Somatic hybridization and oncogenesis: induction of tumors in mice by administration of mixtures of cells of the homologous organs and their hybrids].
The 2 months old C57BL/6J mice were injected with the mixtures of kidney and spleen cells from mice of the same strain or of the same cells following the hybridization induced by Sendai virus. The tumours of liver, kidney and lymphoid system appeared in 25% of recipients within 12--14 months. The result obtained is predicted by the general theory of oncogenesis proposed early by L. B. Mekler.


Large Drosophila germline piRNA clusters are evolutionarily labile and dispensable for transposon regulation.
PIWI proteins and their guiding Piwi-interacting small RNAs (piRNAs) are crucial for fertility and transposon defense in the animal germline. In most species, the majority of piRNAs are produced from distinct large genomic loci, called piRNA clusters. It is assumed that germline-expressed piRNA clusters, particularly in Drosophila, act as principal regulators to control transposons dispersed across the genome. Here, using synteny analysis, we show that large clusters are evolutionarily labile, arise at loci characterized by recurrent chromosomal rearrangements, and are mostly species-specific across the Drosophila genus. By engineering chromosomal deletions in D. melanogaster, we demonstrate that the three largest germline clusters, which account for the accumulation of >40% of all transposon-targeting piRNAs in ovaries, are neither required for fertility nor for transposon regulation in trans. We provide further evidence that dispersed elements, rather than the regulatory action of large Drosophila germline clusters in trans, may be central for transposon defense.


Two-way mobile phone intervention compared with standard-of-care adherence support after second-line antiretroviral therapy failure: a multinational, randomised controlled trial.
Antiretroviral therapy (ART) non-adherence causes HIV treatment failure. Past behaviour might predict future behaviour; failing second-line ART could indicate ongoing risk for subsequent non-adherence. We aimed to find out whether a two-way mobile phone-based communication intervention would increase HIV treatment success by improving medication adherence. We did a multinational, randomised controlled trial of patients at 17 sites in nine lower-income and middle-income countries in Africa, Asia, and the Americas. Patients aged 18 years and older, with HIV infection, and on second-line protease-inhibitor-based antiretroviral regimens, were randomly assigned (1:1) to either two-way mobile phone intervention plus standard of care (MPI + SOC) adherence support or standard-of-care alone (SOC). Our study was nested within a strategy study of ART after second-line ART failure (the main study, A5288). The main study had four cohorts, which were assigned regimens according to ART history and real-time genotype. Randomisation was stratified by the main study cohort with dynamic institutional balancing. Only the clinical management committee was masked, not the participants or site personnel. Text messages were sent over 48 weeks starting once a day and tapering down to once per week; participants were to respond once to each message if taking ART without issues. Repeated non-response to three messages over a 2-week period for the first 8 weeks, and then two messages over a 2-week period for the remainder of the study, triggered problem-solving counselling by staff. For this study, the primary endpoint was plasma HIV-1 RNA 200 copies per mL or less at 48 weeks and the secondary endpoint was virological failure (two consecutive HIV-1 RNA ≥1000 copies per mL) at 24 or more weeks. Prespecified intention-to- treat analyses were adjusted for cohort. Follow-up continued until the last participant had reached 48 weeks, with a median follow-up time of 72 weeks. The trial is registered with ClinicalTrials.gov, number . Enrolment began on Feb 22, 2013, and ended on Dec 21, 2015, with the last participant completing follow-up on Feb 13, 2017. Of 545 participants in the main study, 521 (96%) were enrolled and randomly assigned to MPI + SOC (n=257) or SOC alone (n=264). 52% of patients were men and the median HIV-1 RNA 4-4 log10 copies per mL (IQR 3.5 to 5-2). At week 48, HIV-1 RNA 200 copies per mL or less was reached in 169 (66%) of 257 patients in the MPI + SOC group and 164 (62%) of 264 patients in the SOC group (estimated difference 3-6% [95% CI -4-6% to 11-9%]; p=0-39). The adjusted odds ratio comparing MPI + SOC and SOC was 1-23 (0-82 to 1-84; p=0-32). Virological failure occurred in 66 (26%) patients in the MPI + SOC group and 89 (34%) patients in the SOC group during the median 72 weeks follow-up (adjusted p=0-027). Observed difference in virological failure favoured MPI + SOC in all cohorts. 23 (4%) participants died, 11 (4%) in the MPI + SOC group and 12 (5%) in the SOC group (p=0-89), with none of the deaths ascribed to ART, the MPI, or study procedures. Two-way MPI did not significantly improve week 48 suppression, but it did modestly affect virological failure. People failing second-line ART might not achieve benefits from phone-based triggers or enhanced adherence support (or both). More effective strategies are needed.


Prediction of the molecular mechanism of eucommiae Cortex - Achyranthis bidentatae radix in the treatment of osteoarthritis: network pharmacology and molecular docking.
To retrieve the core drug of osteoarthritis in clinic using Data Mining, predict the drug molecular action target through the Network Pharmacology, identify the key nodes of the interaction by combining with the related targtes of osteoarthritis, explore the pharmacological mechanism of Traditional Chinese Medicine against osteoarthritis and other possible mechanisms of actions. to retrieve the commonly used therapeutic formulations for osteoarthritis patients in clinical with PubMed, CNKI, VIP, CBM, Wan Fang Database and other databases, and screen out the core drugs through the Ancient and Modern Medical Case Cloud Platform and software Gephi, filter out the core drug molecules and targets combined with TCMSP database and the targets of osteoarthritis in Genecard and OMIM database, plunge those data into R project and Cytoscape to construct the intersection model of Drug molecule-osteoarthritis, establish PPI network and GO and conduct KEGG enrichment analysis with String database. Vina molecular docking was finally implemented to draw molecular docking diagram, and the results were analyzed after comprehensive analysis. The core drug pairs were identified as 'Eucommiae Cortex - Achyranthis Bidentatae Radix' through correlation analysis, complex network analysis based on the coefficient. 'Eucommiae Cortex - Achyranthis Bidentatae Radix' can intervene cell behavior through multiple pathways and regulate cell metabolism, cytokine synthesis, oxidative and cellular immunity with the help of topology analysis in String Database. The core molecules of Quercetin and Kaempferol derived from 'Eucommia bark - achyranthes' can change the spatial conformation of PTGSs by hydrogen bonding with PTGSs, the hydrophobic bonds and van der Waals forces generated by Baicalein, Wogonin and β-carotene, thereby changing the activity of PTGSs and affecting bone properties the process of osteoarthritis.


In vivo spatially localized high resolution 1H MRS via intermolecular single-quantum coherence of rat brain at 7 T.
To compare the conventional localized point-resolved spectroscopy (PRESS) with localized 2D intermolecular single-quantum coherence (iSQC) magnetic resonance spectroscopy (MRS) and obtain in vivo MRS spectrum of rat brain using the latter technique. A brain phantom, an intact pig brain tissue, and mature Sprague-Dawley rat were studied by PRESS, Nano magic-angle spinning spectroscopy, and iSQC MRS. Using PRESS, high-resolution MRS can be obtained from the brain phantom and pig brain tissue with a small voxel in a relatively homogeneous field. When a large voxel is selected, the field homogeneity is distinctly reduced. No useful information is obtained from the PRESS spectra. However, using the iSQC MRS, high-resolution spectra can be obtained from the two samples with a relatively large voxel. In the same way, an iSQC MRS spectrum can be obtained from a relatively large voxel of in vivo rat brain with a comparable resolution to the PRESS spectrum with a small voxel. Compared to PRESS, the iSQC MRS may be more feasible and promising for detection of strongly structured tissues with relatively large voxels.


Successful pre-emptive emergency management of a compromised airway with a Proseal™ Laryngeal Mask Airway followed by tracheostomy.
Following hemi-glossectomy and right neck dissection a 63-year-old female patient presented as an emergency with a large neck hematoma. There were significant concerns over difficulty in intubation and mask ventilation leading to deterioration into a cannot intubate cannot ventilate (CICV) situation. After careful discussion and planning with the surgical team, who planned a tracheostomy, the situation was salvaged using a ProSealTM Laryngeal Mask Airway (PLMA). The PLMA enabled rapid establishment of a clear airway early in anesthetic induction, controlled ventilation and safe airway maintenance during a difficult tracheostomy.


What do attending physicians contribute in a house officer-based ambulatory continuity clinic?
To study the educational contributions of attending physicians in an internal medicine house staff ambulatory clinic. Cross-sectional, self-administered survey. University-affiliated general internal medicine practice. Internal medicine residents and attendings. Attending and resident perceptions of whether attendings made contributions to teaching points, diagnosis (DX), therapy (RX), and health care maintenance (HCM) were assessed in 428 patient encounters. Resident assessments significantly exceeded attending self-assessments of contributions to teaching points (82% vs 74%, P=.001), DX (44% vs 34%, P=.001), RX (61% vs 55%, P=.02), and HCM (19% vs 15%, P=.04). Both residents and attendings perceived that contributions declined progressively with increasing resident year (P<.05). Primary care and categorical residents assessed attending contributions comparably. However, attendings perceived contributing more to RX and HCM for categorical residents than primary care (P<.05). Male and female residents assessed attending contributions comparably. However, attendings perceived contributing generally more to DX in male residents than female (P=.003). In 8% of encounters, either residents or attendings felt that patient evaluation by the attending was needed. In these encounters with personal patient evaluation by attendings, both residents and attendings felt that attendings made more contributions to DX (P=.001) and teaching points than in other encounters. Attending physicians consistently underestimate their perceived contributions to house officer ambulatory teaching. Their personal patient evaluation increases assistance with DX and teaching points. Given perceived declining contributions by training year, attendings may need to identify other teaching strategies for interactions with senior residents.


Molecular requirements for peroxisomal targeting of alanine-glyoxylate aminotransferase as an essential determinant in primary hyperoxaluria type 1.
Alanine-glyoxylate aminotransferase is a peroxisomal enzyme, of which various missense mutations lead to irreversible kidney damage via primary hyperoxaluria type 1, in part caused by improper peroxisomal targeting. To unravel the molecular mechanism of its recognition by the peroxisomal receptor Pex5p, we have determined the crystal structure of the respective cargo-receptor complex. It shows an extensive protein/protein interface, with contributions from residues of the peroxisomal targeting signal 1 and additional loops of the C-terminal domain of the cargo. Sequence segments that are crucial for receptor recognition and hydrophobic core interactions within alanine-glyoxylate aminotransferase are overlapping, explaining why receptor recognition highly depends on a properly folded protein. We subsequently characterized several enzyme variants in vitro and in vivo and show that even minor protein fold perturbations are sufficient to impair Pex5p receptor recognition. We discuss how the knowledge of the molecular parameters for alanine-glyoxylate aminotransferase required for peroxisomal translocation could become useful for improved hyperoxaluria type 1 treatment.


Quality of Life in Caregivers of Type 2 Diabetes Patients After Patient's Surgery: a Path Analysis.
Type 2 diabetes Mellitus is a chronic disease, and one of its complications may result in amputation. The goal of this study was to evaluate the impact of psychosocial variables, over time, on quality of life (QoL) of caregivers of patients (N = 110) who had undergone a recent amputation. A longitudinal design was employed: (T1) 1 month after the patient's surgery; (T2) 7 months after; and (T3) 10 months after. Burden Assessment Scale, Family Assessment Device, Revised Impact of Events Scale, Family Disruption from Illness Scale, and Short Form Health Survey were used. A path analysis model was tested. Burden, perception of family functioning, and traumatic symptoms at T1 showed a positive impact on the perception of family functioning, at T2. Traumatic symptoms, at T1, predicted traumatic symptoms at T2 being also a mediator between those symptoms (T1) and physical QoL (T3). Physical and traumatic symptoms, at T1 predicted physical symptoms, at T2 affecting both mental and physical QoL (T3), being also a mediator in these relationships. Burden (T1) also had a direct effect on mental QoL (T3) and at T2 had an impact on physical QoL (T3) mediating also the relationship between burden/physical symptoms at T1 and physical QoL, at T3. Intervention should focus on physical and traumatic symptoms as well as burden since they were both mediators regarding mental and physical QoL.


Essential oil toxicity on biological and reproductive parameters of Alabama argillacea (Hübner) (Lepidoptera: Erebidae).
Several studies have demonstrated the effects of essential oils on insect pests. These effects vary and affect fundamental parameters for the survival of these organisms. However, there is a scarcity of research on the effect of these substances on Alabama argillacea (Hübner) (Lepidoptera: Erebidae), the main defoliating pest of cotton (Gossypium hirsutum L.). Thus, the present study aimed to evaluate the activity of essential oils from Litsea cubeba (Lour.) Pers., Melaleuca alternifolia Cheel, Juniperus virginiana L., and Mentha spicata L., on the biological and reproductive parameters of A. argillacea and the consequent effects on the gonads of both males and females of this pest. All essential oils presented toxicity by contact in third instar larvae of A. argillacea, causing a reduction in the weight of larvae and pupae, as well as affecting the number and viability of eggs. These essential oils changed the histochemistry of the testicles, and M. alternifolia, J. virginiana, and M. spicata also affected their morphology. The histochemistry of the ovarioles was altered by the essential oils from M. alternifolia, J. virginiana, and L. cubeba. Thus, the essential oils tested in the present work are promising for the control of A. argillacea, as they are toxic and affect the development and reproduction of this key pest of cotton.


Diagnostic value of intraoperative tap test for acute deltoid ligament injury.
Deltoid ligament injuries appear with isolated or even no displacement of the lateral malleolus fracture which could easily lead to misdiagnosis, which frequently brings about ankle medial instability and talus shift that eventually lead to the occurrence of ankle osteoarthritis. This study is aimed to investigate the value of the tap test for assessing the integrity of the deltoid ligament intraoperatively. Ninety-two patients with malleolar fractures and possible acute deltoid ligament injury treated in our hospital from March 2013 to May 2016 were enrolled in this prospective study. The gravity stress test and tap test were performed preoperatively by three physicians independently before and after fixation of the fibula. The sensitivity, specificity, positive and negative predictive values, and false-positive and false-negative rates of both tests were determined based on medial malleolus exploration for the integrity of the deltoid ligament. The inter-observer consistency was also analyzed. Forty seven (51.1%) versus fifty two (56.5%) of the 92 patients tested positive for deltoid ligament injury according to the preoperative gravity stress test or the subsequent tap test. Forty-eight cases (52.2%) were confirmed during surgery. The sensitivity of gravity stress test was lower than that of tap test (95.8% vs 100%), and specificity of gravity stress test was the same as tap test (97.7% vs 97.7%). Between gravity stress test and tap test, the positive and negative predictive values were 97.9% vs 92.3% and 95.6% vs 100%, and the false-positive and false-negative rates were 2.3% vs 9.09% and 4.2% vs 0%, respectively. Between the two tests results, the percentage of inter-observer agreement was > 90% (kappa coefficient > 0.80). The tap test has the advantages of high sensitivity, simple operation, and less radiation exposure, suggesting that it is of high diagnostic value for assessing the integrity of the acute deltoid ligament.


Mammary analog secretory carcinoma of salivary glands: a report of 2 cases in the lips.
This study presents 2 cases of labial mammary analog secretory carcinoma (MASC) including diagnostic criteria and a review of literature. MASC has not been previously described in the dental literature. Two cases of MASC and 1 case of acinic cell carcinoma (ACC) of the lips were reviewed for their microscopic and immunohistochemical features. Fluorescence in situ hybridization (FISH) for the ETV6-NTRK3 translocation was performed. The clinical features of 65 cases previously described in the medical literature are reviewed. MASCs had hematoxylin and eosin features similar to those of ACC but demonstrated larger, globular periodic acid-Schiff positive deposits, whereas ACC had finer granular deposits. MASCs were strongly positive for S100, vimentin, and mammaglobin, whereas ACC was negative for S100 and vimentin and only focally mammaglobin positive. FISH demonstrated that MASCs were positive for ETV6 disruption. MASCs are newly described, can occur in a wide age range, favor males, and can be misinterpreted as ACC or adenocarcinoma not otherwise specified by routine microscopy.


Investigation on a focus of human trichinellosis revealed by an atypical clinical case: after wild-boar (Sus scrofa) pork consumption in northern Italy.
Trichinellosis is one of the most serious foodborne parasitic zoonoses in Europe. Wild carnivorous and omnivorous hosts are the main reservoirs of Trichinella spp. nematodes in nature. In the winter of 2008-2009, an atypical clinical case of trichinellosis occurred for the consumption of pork from a wild boar (Sus scrofa) hunted in southwestern Alps in Italy. The symptomatic individual showed delayed development of oedemas in the lower limbs and eosinophilia, which appeared three months after infection. Muscle samples harboured 3.8 larvae/g, which were identified as Trichinella britovi. During the epidemiological investigation, anti-Trichinella IgG were detected in five hunters.


Knowledge of Palestinian women about cervical cancer warning signs: a national cross- sectional study.
Timely presentation and diagnosis of cervical cancer (CC) are crucial to decrease its mortality especially in low- and middle-income countries like Palestine. This study aimed to evaluate the knowledge of Palestinian women about CC warning signs and determine the factors associated with good knowledge. This was a national cross-sectional study conducted between July 2019 and March 2020 in Palestine. Stratified convenience sampling was used to recruit adult women from hospitals, primary healthcare centers, and public spaces of 11 governorates. A translated-into-Arabic version of the validated CC awareness measure (CeCAM) was used to assess women's knowledge of 12 CC warning signs. Of 8086 approached, 7223 participants completed the CeCAM (response rate = 89.3%). A total of 7058 questionnaires were included in the analysis: 2655 from the Gaza Strip and 4403 from the West Bank and Jerusalem (WBJ). The median age [interquartile range] for all participants was 34.0 [24.0, 42.0] years. Participants recruited from the WBJ were older, getting higher monthly income, and having more chronic diseases than those recruited from the Gaza Strip. The most frequently identified warning sign was 'vaginal bleeding after menopause' (n = 5028, 71.2%) followed by 'extreme generalized fatigue' (n = 4601, 65.2%) and 'unexplained weight loss' (n = 4578, 64.9%). Only 1934 participants (27.4%) demonstrated good knowledge of CC warning signs. Participants from the Gaza Strip were slightly more likely than participants from the WBJ to have a good level of knowledge. Factors associated with having good knowledge included having a bachelor or postgraduate degree, being married, divorced, or widowed as well as knowing someone with cancer. The overall awareness of CC warning signs was low. Educational interventions are needed to increase Palestinian women's awareness of CC warning signs.


Correlation analysis between heart rate variability, epicardial fat thickness, visfatin and AF recurrence post radiofrequency ablation.
The aim of the present study is to investigate the possible correlation between heart rate variability (HRV), epicardial fat thickness (EFT), visfatin and AF recurrence post radiofrequency ablation. Data of 337 AF patients to whom radiofrequency ablation therapy had been initiated at our hospital over the past three years were evaluated. The patients enrolled were divided into the non-recurrence group (102 patients) and the recurrence group (235 patients) according to AF recurrence in the preceding 12 months. General data in the two groups were collected and HRV, EFT, and visfatin levels were comprehensively compared for each patients of the two groups. The recurrence group showed significantly higher results in rMSSD, PNN50, HF, total EFT, and visfatin but with evidently lower results in LF/HF when comparing the non-recurrence group (P < 0.05). The significantly different general variables in the general data and laboratory parameters, rMSSD, PNN50, HF, total EFT, visfatin, LF/HF were used as independent variables, and AF recurrence post radiofrequency ablation was used as dependent variables. Logistic regression analysis revealed that the risk factors of AF recurrence post radiofrequency ablation were rMSSD, PNN50, HF, total EFT, visfatin, and LF/HF, and the difference was statistically significant (P < 0.05). HRV, EFT, visfatin appear to show high association with AF recurrence post radiofrequency ablation.


Effects of phytase supplementation and increased nutrient density on growth performance, carcass characteristics, and hypothalamic appetitive hormone expression and catecholamine concentrations in broilers from 1 to 43 days of age.
Two experiments were conducted to evaluate extra-phosphoric effects of phytase and nutrient density on growth performance, meat yield, and hypothalamic appetitive hormone expression and catecholamine concentrations of broilers. Experiment 1 determined differences of digestible amino acid concentrations and AMEn using 256 Yield Plus × Ross 708 broilers (32 cages, 8 birds/cage) fed diets without or with 4,500 phytase units (FTU)/kg inclusion (16 reps/treatment). In Experiment 2, 832 Yield Plus × Ross 708 broilers (32 pens; 26 birds/pen) were provided diets in a 2 × 2 factorial arrangement consisting of 2 nutrient contents (without or with increased density) and 2 phytase inclusions (0 or 4,500 FTU/kg). Increased nutrient density was formulated to contain 0.007, 0.015, 0.013, 0.021, 0.024%, and 61 kcal/kg higher digestible SAA, Lys, Thr, Val, Ile, and AMEn (from Experiment 1) respectively, compared with the control diet. Growth performance was determined at 14, 28, and 40 d of age and carcass characteristics at 41 d of age. At 43 d of age, plasma inositol, hypothalamic appetitive hormone expression, and catecholamine concentrations were determined from 4 birds/pen. Additive effects of phytase inclusion and increased nutrient density resulted in the lowest (P < 0.05) feed conversion from 1 to 40 d of age and the heaviest (P < 0.01) breast meat weights among dietary treatments. Phytase addition numerically increased feed intake (P = 0.06) and BW gain (P = 0.051) compared with birds fed diets without phytase from 1 to 40 d of age. Plasma inositol and dopamine concentrations were 2.3- and 1.2-fold higher (P < 0.01), respectively, in broilers fed phytase-added diets than birds fed diets without phytase inclusion. However, mRNA expression of neuropeptide Y, agouti-related peptide, proopiomelanocortin, cholecystokinin A receptor, ghrelin, and serotonin concentration were not different (P > 0.05) among treatments. These data indicated additive effects of phytase supplementation and increased nutrient density on growth performance and meat accretion of broilers. However, the influence of phytase on feed intake warrants future research.


Functional assay for assessment of pathogenicity of BAP1 variants.
Pathogenic germline variants in BRCA1-Associated Protein 1 (BAP1) cause BAP1 tumor predisposition syndrome (BAP1-TPDS). Carriers run especially a risk of uveal (UM) and cutaneous melanoma, malignant mesothelioma, and clear cell renal carcinoma. Approximately half of increasingly reported BAP1 variants lack accurate classification. Correct interpretation of pathogenicity can improve prognosis of the patients through tumor screening with better understanding of BAP1-TPDS. We edited five rare BAP1 variants with differing functional characteristics identified from patients with UM in HAP1 cells using CRISPR-Cas9 and assayed their effect on cell adhesion/spreading (at 4 h) and proliferation (at 48 h), measured as cell index (CI), using xCELLigence real-time analysis system. In BAP1 knockout HAP1 cultures, cell number was half of wild type (WT) cultures at 48 h (p = 0.00021), reaching confluence later, and CI was 78% reduced (p < 0.0001). BAP1-TPDS-associated null variants c.67+1G>T and c.1780_1781insT, and a likely pathogenic missense variant c.281A>G reduced adhesion (all p ≤ 0.015) and proliferation by 74%-83% (all p ≤ 0.032). Another likely pathogenic missense variant c.680G>A reduced both by at least 50% (all p ≤ 0.032), whereas cells edited with likely benign one c.1526C>T grew similarly to WT. BAP1 is essential for optimal fitness of HAP1 cells. Pathogenic and likely pathogenic BAP1 variants reduced cell fitness, reflected in adhesion/spreading and proliferation properties. Further, moderate effects were quantifiable. Variant modelling in HAP1 with CRISPR-Cas9 enabled functional analysis of coding and non-coding region variants in an endogenous expression system.


Accuracy of 4 Free Online Dosing Calculators in Predicting the Vancomycin Area Under the Concentration-Time Curve Calculated Using a 2-Point Pharmacokinetic Approach.
Free online adaptive vancomycin dosing calculators are available to estimate area under the concentration-time curve (AUC), but the accuracy of predicting vancomycin AUC using these calculators compared with using a 2-point pharmacokinetic approach has not been described. To evaluate the accuracy of calculator-predicted AUC (cpAUC) using 4 free online calculators compared with reference AUC (rAUC), and to assess pharmacists' impressions of the ease of use. Vancomycin AUC was estimated using (1) the reference method via the Sawchuk-Zaske method and linear-logarithmic trapezoidal rule using 2 steady-state postdistributional vancomycin serum concentrations and (2) 4 free online vancomycin dosing calculators including ClinCalc, VancoPK, TDMx, and DMC. Accuracy was calculated by dividing cpAUC by rAUC. Ease of cpAUC estimation was determined by using a 10-point Likert scale. All 4 calculators had a median cpAUC accuracy ranging from 89% to 110%. Concordance between cpAUC and rAUC determinations of AUC <400 and > 600 mg·h/L occurred 63.3% to 71.4% and 74.5% to 78.6% of the time, respectively. Pharmacist investigators agreed that ClinCalc and VancoPK calculators were easiest to use. cpAUC accuracy varied among the 4 calculators, but all consistently identified patients with an rAUC <400 mg·h/L and an rAUC > 600 mg·h/L at comparable frequencies. All 4 calculators demonstrated some imprecision based on their wide 95% CIs and potential inaccuracies in predicting an rAUC <400 mg·h/L or an rAUC > 600 mg·h/L. Clin Calc and VancoPK were most user friendly based on our pharmacists' impressions.


Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants.
KRAS is the most frequently mutated oncogene, harboring mutations in approximately one in seven cancers. Allele-specific KRASG12C inhibitors are currently changing the treatment paradigm for patients with KRASG12C-mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive KRAS allele has fueled drug discovery efforts for all KRAS mutants. Pan-KRAS drugs have the potential to address broad patient populations, including KRASG12D-, KRASG12V-, KRASG13D-, KRASG12R-, and KRASG12A-mutant or KRAS wild-type-amplified cancers, as well as cancers with acquired resistance to KRASG12C inhibitors. Here, we review actively pursued allele-specific and pan-KRAS inhibition strategies and their potential utility. Mutant-selective KRASG12C inhibitors target a fraction (approximately 13.6%) of all KRAS-driven cancers. A broad arsenal of KRAS drugs is needed to comprehensively conquer KRAS-driven cancers. Conceptually, we foresee two future classes of KRAS medicines: mutant-selective KRAS drugs targeting individual variant alleles and pan-KRAS therapeutics targeting a broad range of KRAS alterations.


Healthcare workers' burn-out, hopelessness, fear of COVID-19 and perceived social support levels.
During the pandemic, all healthcare workers have tried to cope with mental challenges. This study evaluated the healthcare workers' levels of burn-out, hopelessness, fear of COVID-19 and perceived social support, the relation between these factors, and other possible related components. Four hundred and fifty-one HCW (healthcare workers) all across Turkey were included in the study. Sociodemographic information form, Maslach Burn-out Inventory, Beck Hopelessness Scale, Multidimensional Scale of Perceived Social Support, and the Fear of COVID-19 Scale were given to the participants. This was a cross-sectional study via various online platforms. The participants who were on duty in the COVID-19 clinic, complaining about the low salary or not having enough time for themselves or their own family, had significantly higher scores on three subscales of burn-out scale, and hopelessness scale. Working at governmental hospitals, working at departments containing a high risk of COVID-19 infection, and having a history of COVID-19 infection were found to be significantly associated with emotional exhaustion, depersonalization, and hopelessness. Feeling control of your profession and getting social support from others were the two factors that tackle burnout in HCW. Family support is the only support that tackles all 3 subscales of burn-out and hopelessness. The findings emphasized that to tackle the burn-out and hopelessness of HCW, it is important for HCW to receive financial compensation for their hard work, to work under improved conditions, and to receive adequate social support.


Subfoveal choroidal thickness and peripapillary retinal nerve fiber layer thickness in young obese males.
Regarding the effect of obesity on subfoveal choroidal thickness (CT) and peripapillary retinal nerve fiber layer (RNFL) thickness, controversial results have been reported in different patient groups. This study aimed to evaluate the effect of obesity on these parameters among young male subjects in comparison with age-matched non-obese healthy males. This prospective, cross-sectional study included both eyes of 50 obese young males and 50 healthy non-obese young males. The obese and the non-obese groups included subjects with a BMI of ⩾30 and ⩽25 kg/m², respectively. Subfoveal choroidal thickness and RNFL analyses were conducted by spectral domain optical coherence tomography (SD-OCT). Subfoveal choroidal thickness (321.0 ± 46.7 vs 338.4±35.3, p = 0.002) and RNFL thickness at temporal quadrant (73.4 ± 9.9 vs 76.4 ± 9.3, p = 0.008) was significantly lower in the obese group when compared to the non-obese group. The groups did not differ regarding peripapillary RNFL thickness at other quadrants (superior, inferior, or nasal) or regarding mean peripapillary RNFL thickness. Findings of this study demonstrated a negative correlation of obesity with subfoveal choroidal thickness and temporal quadrant peripapillary RNFL thickness. Larger studies on different patient groups with longer-term follow-up are warranted to better elucidate the ophthalmological effects of obesity.


Spatial regulation of controlled bioactive factor delivery for bone tissue engineering.
Limitations of current treatment options for critical size bone defects create a significant clinical need for tissue engineered bone strategies. This review describes how control over the spatiotemporal delivery of growth factors, nucleic acids, and drugs and small molecules may aid in recapitulating signals present in bone development and healing, regenerating interfaces of bone with other connective tissues, and enhancing vascularization of tissue engineered bone. State-of-the-art technologies used to create spatially controlled patterns of bioactive factors on the surfaces of materials, to build up 3D materials with patterns of signal presentation within their bulk, and to pattern bioactive factor delivery after scaffold fabrication are presented, highlighting their applications in bone tissue engineering. As these techniques improve in areas such as spatial resolution and speed of patterning, they will continue to grow in value as model systems for understanding cell responses to spatially regulated bioactive factor signal presentation in vitro, and as strategies to investigate the capacity of the defined spatial arrangement of these signals to drive bone regeneration in vivo.


Tryptophan metabolites modify brain Aβ peptide degradation: A role in Alzheimer's disease?
Among several processes, a decrease in amyloid-beta (Aβ) peptide elimination is thought to be one of the major pathophysiological factors in Alzheimer's disease (AD). Neprilysin (NEP) is a key metalloproteinase controlling the degradation and clearance of Aβ peptides in the brain. NEP is induced by several pharmacological substances, amyloid deposits and somatostatin, but the physiological regulation of its expression remains unclear. This situation hampers the exploitation of NEP regulatory factors/mechanisms to develop effective strategies against Aβ peptide accumulation-induced brain toxicity. Based on recent data aimed at elucidating this major question, the present paper addresses and critically discusses the role of 5-hydroxyindole-acetic acid (5-HIAA) and kynurenic acid (KYNA) in the regulation of NEP activity/expression in the brain. Both 5-HIAA and KYNA are endogenous metabolites of tryptophan, an essential amino-acid obtained through diet and gut microbiome. By interacting with the aryl hydrocarbon receptor, various tryptophan metabolites modulate several metalloproteinases regulating brain Aβ peptide levels under normal and pathological conditions such as AD. In particular, interesting data reviewed here show that 5-HIAA and KYNA stimulate NEP activity/expression to prevent Aβ peptide-induced neurotoxicity. These data open promising perspectives for the development of tryptophan metabolite-based therapies against AD.


Chemical Treatments for Mobilizing Arsenic from Contaminated Aquifer Solids to Accelerate Remediation.
Arsenic is a prevalent contaminant at US Superfund sites where remediation by pump and treat systems is often complicated by slow desorption of As from Fe and Al (hydr)oxides in aquifer solids. Chemical amendments that either compete with As for sorption sites or dissolve Fe and Al (hydr)oxides can increase As mobility and improve pump and treat remediation efficiency. The goal of this work was to determine optimal amendments for improving pump and treat at As contaminated sites such as the Vineland Chemical Co. Superfund site in southern New Jersey. Extraction and column experiments were performed using As contaminated aquifer solids (81 ± 1 mg/kg), site groundwater, and either phosphate (NaH(2)PO(4)·H(2)O) or oxalic acid (C(2)H(2)O(4)·2H(2)O). In extraction experiments, phosphate mobilized between 11% and 94% of As from the aquifer solids depending on phosphate concentration and extraction time (1 mM-1 M; 1-24 h) and oxalic acid mobilized between 38 and 102% depending on oxalic acid concentration and extraction time (1-400 mM; 1-24 h). In column experiments, phosphate additions induced more As mobilization in the first few pore volumes but oxalic acid was more effective at mobilizing As overall and at lower amendment concentrations. At the end of the laboratory column experiments, 48% of As had been mobilized from the aquifer sediments with 100 mM phosphate and 88% had been mobilized with 10 mM oxalic acid compared with 5% with ambient groundwater alone. Furthermore, simple extrapolations based on pore volumes suggest that chemical treatments could lower the time necessary for clean up at the Vineland site from 600 a with ambient groundwater alone to potentially as little as 4 a with 10 mM oxalic acid.


A new method for robust mixture regression.
Finite mixture regression models have been widely used for modelling mixed regression relationships arising from a clustered and thus heterogenous population. The classical normal mixture model, despite its simplicity and wide applicability, may fail in the presence of severe outliers. Using a sparse, case-specific, and scale-dependent mean-shift mixture model parameterization, we propose a robust mixture regression approach for simultaneously conducting outlier detection and robust parameter estimation. A penalized likelihood approach is adopted to induce sparsity among the mean-shift parameters so that the outliers are distinguished from the remainder of the data, and a generalized Expectation-Maximization (EM) algorithm is developed to perform stable and efficient computation. The proposed approach is shown to have strong connections with other robust methods including the trimmed likelihood method and M-estimation approaches. In contrast to several existing methods, the proposed methods show outstanding performance in our simulation studies.


Molecular characterization of dissolved organic nitrogen during anoxic/oxic and anammox processes using ESI FT-ICR MS.
Dissolved organic nitrogen (DON) is a component of wastewater with a negative influence on the environment. The removal of DON is conducted through the anoxic/oxic (A/O) and anammox processes. However, the mechanisms and chemical preferences in the removal of DON compounds have not been understood and compared so far. This study, for the first time, comparatively investigated the molecular-level characteristics of DON during both processes by using FT-ICR MS (Fourier transform ion cyclotron resonance mass spectrometry). The results indicated that the number of DON formulas increased from 1844 to 1935 during A/O process, and from 2784 to 3242 during anammox process, highlighting the increase in complexity of DON after undergoing both processes. DON with high saturation and aliphatic structures was removed by A/O process, whereas highly unsaturated and aromatic structures were removed by anammox process. For DON without S atom, Lignin-like and tannin-like ones were resistant to both processes and protein-like and condensed aromatic structures were resistant to anammox process. The complementarity of these two processes provided a sequential combination with sufficient theoretical support to improve DON removal efficiency. PRACTITIONER POINTS: Molecular components of dissolved organic nitrogen characterized by ESI FT-ICR MS. DON removal preferences of A/O and anammox processes evaluated. A/O and anammox processes are effective to remove aliphatic and aromatic DON, respectively. Complementarity in removal preferences of A/O and anammox processes can remove recalcitrant DON of each other. Sequential A/O and anammox processes can improve DON removal.


The effects of polymorphisms in CYP2C19, ATP-binding cassette transporter B1, and paraoxonase-1 on clopidogrel treatment of Uygur patients following percutaneous coronary intervention.
Acute coronary syndrome (ACS) carries a high mortality in Uygur populations. Percutaneous coronary intervention (PCI) is a safe treatment for patients with ACS. Clopidogrel reduces the risk for recurrent cardiovascular events after PCI; however, its activity is influenced by cytochrome P450 (CYP450), ATP-binding cassette transporter B1 (ABCB1), and paraoxonase-1 (PON1). To assess the effects of genetic polymorphisms CYP2C19*2, *3, *17, ABCB1 C3435T, and PON1 Q192R along with clinical and demographic factors on variations in responses in Uygur patients following PCI. We enrolled 281 patients with PCI who were treated with clopidogrel and aspirin for at least 12 months and recorded major adverse cardiovascular events (MACE) or bleeding within 1 year. Approximately, 2 mL of peripheral venous blood samples were used for genotype detection. Binary logistic regression with likelihood ratio forward stepwise analysis and redundancy analysis were carried out to identify factors associated with MACE. We analyzed risk factors including age, body mass index, smoking, hypertension, dyslipidemia, gender, alcohol consumption, diabetes mellitus, carriers of ABCB1 C3435T T allele, carriers of PON1 Q192R A allele, metabolizer phenotype of CYP2C19, number of targeted vessels, and number of stents. The CYP2C19 IMs (OR 3.546, 95% CI 1.972-6.375, P = 0.001), CYP2C19 PMs (OR 7.038, 95% CI 1.658-29.880, P = 0.008), and number of targeted vessels (OR 2.033, 95% CI 1.078-3.648, P = 0.026) were significantly associated with MACE. The CYP2C19 IMs, PMs, and the number of targeted vessels are essential factors associated with MACE risk in dual clopidogrel-treated Uygur population with ACS following PCI. These data provide valuable insights into the genetic polymorphisms affecting clopidogrel response among minority groups in China.


A g-C3N4 self-templated preparation of N-doped carbon nanosheets@Co-Co3O4/Carbon nanotubes as high-rate lithium-ion batteries' anode materials.
A novel N-doped graphene-like carbon nanosheets (CNs) and carbon nanotubes (CNTs)-encapsulated Co-Co3O4 nanoparticles (NPs) (CN@Co-Co3O4/CNTs) were synthesized successfully by a simple hydrothermal and annealing method with graphite carbon nitride (g-C3N4) as self-template. By annealing Co2+/g-C3N4 under N2 atmosphere, g-C3N4 was transformed into CN/CNTs, and Co2+ was reduced into CoNPs which were embedded in CNs. Further annealing in air, a shell of Co3O4 was formed around CoNPs. The amount of CNs, CNTs, and CoNPs can be adjusted by changing the ratio of Co2+ in Co2+/g-C3N4. The graphene-like CNs provided a large number of active sites and a large specific surface area for loading lots of small CoNPs uniformly. The CNTs with a diameter of 100 nm could not only improve the conductivity but also provide a buffer space for the aggregation and volume expansion of Co3O4. CNTs also enlarged the interlayer distance of CNs, which prevented the re-stacking of CNs and provided great convince for the intercalation and de-intercalation of Li+. When applied for anode material of lithium-ion batteries, CN@Co-Co3O4/CNTs exhibited a high discharge capacity of 460.0 mAh g-1 at 5000 mA g-1 after 300 cycles with a Coulombic efficiency of 98% and excellent higher-rate capacity (401.0 mAh g-1 at 2000 mA g-1 and 329.0 mAh g-1 at 5000 mA g-1).