EcoRI cleavage and methylation of DNAs containing modified pyrimidines in the recogintion sequence.
The effects of substituents at position 5 in the pyrimidine ring of a variety of phage DNAs upon EcoRI endonuclease and methylase activities have been examined. The replacement of cytidine in DNA with glucosylated hydroxymethylcytidine confers resistance to cleavage by the EcoRI endonuclease. Substitution of thymidine in DNA by hydroxy-methyluridine(a change in the methyl at position 5 of thymidine for a hydroxymethyl) lowers the maximal velocity of endonucleolytic cleavage 20-fold, but has no detectable effect upon the Km. Substitution of thymidine in DNA by uridine (a change in the methyl at position 5 of thymidine for a hydrogen atom) has no effect upon either the maximal velocity or the Km. The effect of these modifications upon EcoRI methylase activity was markedly different. DNA containing glucosylated hydroxymethylcytidine is methylated as well as normal DNA. DNA containing uridine or hydroxy-methyluridine, in place of thymidine, is much more poorly methylated than normal DNA. These different sensitivities of the EcoRI endonuclease and methylase to modifications in the pyrimidine rings of DNA suggest there are significant differences in the manner by which these enzymes recognize and bind to the canonical EcoRI sequence.


Antibiotic Prophylaxis Against Infective Endocarditis Before Invasive Dental Procedures.
Antibiotic prophylaxis (AP) before invasive dental procedures (IDPs) is recommended to prevent infective endocarditis (IE) in those at high IE risk, but there are sparse data supporting a link between IDPs and IE or AP efficacy in IE prevention. The purpose of this study was to investigate any association between IDPs and IE, and the effectiveness of AP in reducing this. We performed a case-crossover analysis and cohort study of the association between IDPs and IE, and AP efficacy, in 7,951,972 U.S. subjects with employer-provided Commercial/Medicare-Supplemental coverage. Time course studies showed that IE was most likely to occur within 4 weeks of an IDP. For those at high IE risk, case-crossover analysis demonstrated a significant temporal association between IE and IDPs in the preceding 4 weeks (OR: 2.00; 95% CI: 1.59-2.52; P = 0.002). This relationship was strongest for dental extractions (OR: 11.08; 95% CI: 7.34-16.74; P < 0.0001) and oral-surgical procedures (OR: 50.77; 95% CI: 20.79-123.98; P < 0.0001). AP was associated with a significant reduction in IE incidence following IDP (OR: 0.49; 95% CI: 0.29-0.85; P = 0.01). The cohort study confirmed the associations between IE and extractions or oral surgical procedures in those at high IE risk and the effect of AP in reducing these associations (extractions: OR: 0.13; 95% CI: 0.03-0.34; P < 0.0001; oral surgical procedures: OR: 0.09; 95% CI: 0.01-0.35; P = 0.002). We demonstrated a significant temporal association between IDPs (particularly extractions and oral-surgical procedures) and subsequent IE in high-IE-risk individuals, and a significant association between AP use and reduced IE incidence following these procedures. These data support the American Heart Association, and other, recommendations that those at high IE risk should receive AP before IDP.


Patient selection and patient satisfaction.
Patient selection is difficult. Modern-day plastic surgeons are becoming increasingly aware that patient selection is an important aspect of a successful surgical practice. Evaluation of the patient as a whole rather than just the deformity is necessary to avoid dissatisfied patients. Surgeons should, during the initial interview, consider the acronym SAFE, asking open-ended questions and evaluating the patient. Patient selection rules for outpatient facilities are an extension of patient selection in general. Either patient or surgeon may have reasons for choosing the hospital over the outpatient facility for the procedure. The importance of patient selection extends to patient management as a whole. Appropriate management is even more important in the office-based setting because the stress may have more of an impact on the patient than for hospitalized procedures. Awareness of the stress state in surgery and the patient's personality style allows for a knowledgeable surgeon and staff to anticipate behaviors and emotions and use appropriately their power and nurturance to lead the patient to the ultimate goal, a feeling of satisfaction with the surgical result.


Warning labels on alcoholic beverage containers: a pilot randomized experiment among young adults in Mexico.
Little is known about the potential impacts of visible and up-to-date health warning labels on alcoholic beverage containers on a range of outcomes in low- and middle-income countries. We conducted an experimental study to test the potential impacts of visible health warning labels (on the principal panel of the package) on thinking about health risks, product attractiveness, visual avoidance, and intention to change alcohol use among students in Mexico aged 18-30 years. A double-blind, parallel-group, online randomized trial was conducted from November 2021 to January 2022 in 11 states in Mexico. In the control group, participants were presented with the image of a conventional beer can with a fictional design and brand. In the intervention groups, the participants observed pictograms with a red font and white backgrounds (health warning label in red-HWL red) or with a black font and yellow backgrounds (health warning label in yellow-HWL yellow), located at the top, covering around one-third of the beer can. We used Poisson regression models -unadjusted and adjusted for covariates- to assess differences in the outcomes across study groups. Using intention-to-treat analysis (n = 610), we found more participants in groups HWL red and HWL yellow thought about the health risks from drinking beer compared to the control group [Prevalence Ratio (PR) = 1.43, CI95%:1.05,1.93 for HWL red; PR = 1.25, CI95%: 0.91, 1.71 for HWL yellow]. A lower percentage of young adults in the interventions vs control group considered the product attractive (PR 0.74, 95%CI 0.51, 1.06 for HWL red; PR 0.56, 95%CI 0.38, 0.83 for HWL yellow). Although not statistically significant, a lower percentage of participants in the intervention groups considered buying or consuming the product than the control group. Results were similar when models were adjusted for covariates. Visible health warning labels could lead individuals to think about the health risks of alcohol, reducing the attractiveness of the product and decreasing the intention to purchase and consume alcohol. Further studies will be required to determine which pictograms or images and legends are most contextually relevant for the country. The protocol of this study was retrospectively registered on 03/01/2023: ISRCTN10494244.


A study on the biochemical and biological behavior of methylmercury.
The biochemical and biological behavior of methylmercury (MeHg) was investigated by measurement of MeHg release rate from erythrocytes (RBC) of selected animal strains and species, by measurement of the intracellular distribution of MeHg in RBC, and by measurement of the binding affinity of hemoglobin (Hb) for MeHg. Methylmercury chloride was used throughout the experiments. Significant strain and species differences were found in the release rate of MeHg from RBC of mice, rats, and man and in the distribution of MeHg in RBC. Significant correlations were found between the above two indexes and the brain/blood ratio of mercury concentration 24 hr after MeHg injection, ip. The affinity of Hb for MeHg was examined by ultrafiltration techniques and Scatchard plots. There were Hbs with only one type of binding site and others with two types of binding sites. Both sites were considered to be cysteinyl residues. Primary sites involved cysteinyl residues oriented externally at the outside of the alpha 1 beta 1 contact junction and cysteinyl residues in the junction, while secondary sites involved only cysteinyl residues in the junction.


Higher levels of consultation services increase patient satisfaction.
Satisfaction of patients with pharmacist consultation was studied in 360 pharmacist-patient interactions in 12 pharmacies. Personal interviews conducted when patients exited pharmacies provided 304 (84%) usable responses. Patients who received longer consultations and were provided with more types of information during consultation were more likely to report that their expectations were exceeded. Patients who received more consultation than they expected reported the highest satisfaction with the service, on average. Exceeding patients' expectations for pharmacist consultation appears to be a key component of patient satisfaction with this service.


Silicone intraocular lens implants and circular anterior capsulotomy (capsulorhexis).
Anterior circular capsulorhexis is used to guarantee accurate placement and stability for the flexible silicone intraocular lens. The smaller wound needed for this procedure allows for immediate postoperative bending by the patient. The visual results achieved with this implant are excellent.


Purification and partial characterization of a new lectin from Parkia panurensis Benth. ex H.C. Hopkins seeds (Leguminosae family; Mimosoideae subfamily) and evaluation of its biological effects.
Lectins are proteins that have as one of their main characteristics recognizing and reversibly binding to carbohydrates. In this work, it was possible to purify and characterize a lectin from Parkia panurensis (Leguminosae family; Mimosoideae subfamily) seeds by a combination of the techniques: protein precipitation, along with affinity and then ion exchange chromatography using the Sepharose-mannose and diethylaminoethyl matrices, respectively. The pure lectin, called PpaL, has affinity by D-mannose, D-glucose and derivatives. PpaL was stable over a wide range of temperature and pH, and it showed an SDS-PAGE profile of only one protein band with apparent mass of 45 kDa, subsequently confirmed by mass spectrometry, and presented a molecular mass of 50,566 ± 1 Da. PAGE analysis and molecular exclusion chromatography demonstrated that PpaL is presented as a dimer in solution. Partial sequencing of the primary structure resulted in a total of 334 amino acid residues with approximately 97% similarity to Parkia biglobosa and Parkia platycephala seed lectins. PpaL was shown to be toxic against Artemia nauplii and had an LC50 of 20 µg/mL. The effects of biological activities presented by these proteins make them important biotechnological tools, demonstrating the importance of bioprospection of new lectins.


High-volume continuous venovenous hemodiafiltration plus resin hemoperfusion improves severe metformin-associated toxicity.
We present the case of a 42-year-old female patient who attempted suicide by taking approximately 100 tablets of metformin (500 mg). Laboratory tests revealed severe lactic acidosis with lactate levels of 24 mmol/L and pH of 7.09. The patient was treated with high-volume continuous venovenous hemodiafiltration (CVVH) and resin-sorbent hemoperfusion. Metformin concentrations were measured by high-performance liquid chromatography during CVVH and hemoperfusion treatment. Before extracorporeal treatment, the plasma metformin concentration was 208.5 mg/L. After CVVH treatment for 24 h, the plasma metformin concentration had decreased to 13.9 mg/L. Resin-based sorbent hemoperfusion plus CVVH treatment had reduced the metformin plasma concentration by 61.8% after 3 h. After 7 days, the patient's laboratory tests and clinical syndrome were improved, and she was discharged from hospital. We provide evidence that CVVH plus hemoperfusion is effective in eliminating metformins and metabolic products.


Allergens of hymenopteran venoms.
Venoms of the Hymenoptera are mixtures of several antigens with nonimmunogenic small peptides and vasoactive amines. Limited local toxicity occurs with stings; systemic reactions to venoms are mediated by IgE antibodies and can be prevented by immunization with the appropriate venom. Skin testing with venoms detects the sensitized state, and a positive test predicts a 50 to 60% risk of an allergic response to a future sting. Because considerable crossreactivity exists between vespid venom allergens, choice of correct venom(s) for immunotherapy will not always be indicated by skin-testing with whole, unfractionated venom. Further efforts at skin testing with individual venom antigens may help to resolve problems regarding choice of venoms for immunotherapy.


Water as a structural element in a channel: gating in the Kcsa channel, and implications for voltage-gated ion channels.
Water is becoming understood as a structural element in proteins. Here we are concerned with one particular type of protein, ion channels. The S. Lividans KcsA K(+) channel, the X-ray structure of which is known, is gated by protons (i.e, by a drop in pH). Ab initio calculations suggest that an H(5)O(2) group, partially charged, connects the E118 residues in the gating region, when the four residues have a -2 net charge, but that the hydrogen bonding is not strong enough to do this when the charge becomes -1. The H(5)O(2) group would block the channel, in the -2 state, and prevent motion of the four transmembrane (TM) segments of the protein, by binding them. With the weaker bond in the -1 state, the TM segments would be able to separate (as they have been found to do experimentally, opening the channel. Voltage gated channels have four additional TM segments for each of the four domains of the channel protein. These appear to allow motion of protons; in fact there is evidence that the initial step in gating must be the transfer of a proton. We have earlier shown that the transfer of a single proton between two methylamines under the influence of a field is possible, as proton tunneling. Subsequent steps are hypothesized to result from four proton transfer cascades of about three protons each, triggered by the initial proton transfer. We suggest that the extra 4 TM segments of the voltage gated channel act as a voltage to proton-current transducer. Water, held by hydrogen bonds, is also suggested as the source of the accessibility data found with MTS reagents, based largely on simulations, our earlier Monte Carlo simulations as well as molecular dynamics studies reported by others. These waters may also play a structural role in the protein.


Operationalizing value-based pricing of medicines : a taxonomy of approaches.
The UK Government is proposing a novel form of price regulation for branded medicines, which it has dubbed 'value-based pricing' (VBP). The specifics of how VBP will work are unclear. We provide an account of the possible means by which VBP of medicines might be operationalized, and a taxonomy to describe and categorize the various approaches. We begin with a brief discussion of the UK Government's proposal for VBP and proceed to define a taxonomy of approaches to VBP. The taxonomy has five main dimensions: (1) what is identified as being of value, (2) how each element is measured, (3) how it is valued, (4) how the different elements of value are aggregated, and (5) how the result is then used to determine the price of a medicine. We take as our starting point that VBP will include a measure of health gain and that, as proposed by the UK Government, this will be built on the QALY. Our principal interest is in the way criteria other than QALYs are taken into account, including severity of illness, the extent of unmet need, and wider societal considerations such as impacts on carers. We set out to: (1) identify and describe the full range of alternative means by which 'value' might be measured and valued, (2) identify and describe the options available for aggregating the different components of value to establish a maximum price, and (3) note the challenges and relative advantages associated with these approaches. We review the means by which aspects of VBP are currently operationalized in a selection of countries and place these, and proposals for the UK, in the context of our taxonomy. Finally, we give an initial assessment of the challenges, pros and cons of each approach. We conclude that identifying where VBP should lie on each of the five dimensions entails value judgements: there are no simple 'right or wrong' solutions. If a wider definition of value than incremental QALYs gained is adopted, as is desirable, then a pragmatic way to aggregate the different elements of value, including both QALYs and benefits unrelated to QALYs, is to use a multi-criteria decision analysis (MCDA) approach. All approaches to VBP ultimately require the conversion of value, however assessed, into a monetary price. This requires assessment of the marginal values of all types of benefit, not just of QALYs. All stages of the VBP process are subject to uncertainty and margins of error. Consequently, the assessment of overall value can provide bounds to a price negotiation but cannot be expected to identify a precise value-based price.


At home in hospital? Interaction and stigma in people affected by cancer.
Social research conducted in cancer hospitals has tended to focus on interaction between patients and staff, and studies of interaction amongst people with cancer often centre on group therapy and patient-patient support mediated by health professionals. Informal interaction between patients and fellow patients, and their carers/visitors, occurs in cancer hospitals every day but has remained largely unanalysed, particularly in the case of visitors. In this paper, based on data from 71 in-depth interviews, we compare patient and carer perceptions of interacting with fellow patients/visitors in a cancer centre with their perceptions of interacting in the outside world. We apply Erving Goffman's theories on stigma to the data and argue that these theories have both relevance and currency. The outside world can be seen as a 'civil place' where people with cancer often encountered difficulties such as undue admiration, uneasiness, avoidance and lack of tact, whereas the cancer centre appears to have been a 'back place' where, for most patients, stigmatisation was not an issue, and they could 'get on with it' in the company of fellow patients and their visitors. However, some groups of patients experienced social isolation in the hospital or seemed to be assigned to the lower strata of cancer patient society. We conclude that patients who are outside the informal support system in cancer hospitals may have psychosocial difficulties that might be recognised and addressed by healthcare staff, and that patients and their carers might benefit from enhanced support following discharge from hospital.


[Response and progression-free survival in T2 to T4 bladder tumors treated with trimodality therapy with bladder preservation].
To evaluate the response and the free-survival progression in patients diagnosed of invasive bladder cancer who have been treated with transurethral resection, chemotherapy and radiotherapy. This multimodal treatment is compared with a not random serie of patients treated by radical cistectomy. Retrospective analysis of 43 cases of invasive bladder cancer treated with two schemes of bladder preservation between 1994-2007. They are compared with 145 cases treated with radical cistectomy in the same period of time. Pronostic variables included in the study are clinical stage, grade of differentiation, presence of ureteral obstruction, chemotherapy modality, radiotherapy doses and p53 and ki-67 expression. Mean and median time are 51 and 39 months in patients with multimodal treatment. Complete response is achieved in 72% of cases treated with bladder preservation. Ureteral obstruction is a prognostic factor (OR: 7,3;p:0,02). 72% patients with complete response mantain it at the end of the study. None of analyzed variables are predictors of maintenance of the response. Survival rates with a intact bladder were 69±7% and 61±7% at three and five years. Radiotherapy doses greater than 60Gy (OR: 6,1; p<0,001) and the absence of ureteral obstruction (OR: 7,5; p<0,002) were pronostic variables. Free-survival in patients with complete response was 80±7% and 58±10% at three and five years. At the end of the study, 53,5% of patients had a intact bladder and free-disease.In the same period of time, 145 radical cistectomies were performed due to muscle invasive bladder cancer. Mean and median time in this group were 29 and 18 months respectively. Stadistical analysis reveals a worse clinical stage in the group of patients treated with multimodal treatment (p:0.01). Free-survival was 72±5% and 63±7% at 3 and 5 years in the group of radical cistectomies. There was not statistical significant differences between cistectomies and bladder preservation. Patients treated with bladder preservation have a free-survival similar to those treated with radical cistectomy. Radiotherapy doses greater than 60Gy and absence of ureteral obstruction were free-survival prognostic variables.


Comprehensive analysis of polymorphisms throughout GAD1 gene: a family-based association study in schizophrenia.
Studies suggest that GAD1 gene is a functional candidate susceptibility gene for schizophrenia. In order to investigate the contribution of GAD1 gene to the etiology of schizophrenia in Chinese, we carried out a family-based association study between GAD1 gene and schizophrenia in 235 Chinese Han family trios. The GAD1 gene is comprehensively analyzed using a systematic mutation scan and the following-up association studies between common SNPs and schizophrenia in both single-locus and haplotype levels. Altogether, we have found 17 variants including 10 SNPs in 5'-flanking regions, 4 SNPs and one novel in-del in intronic regions and 2 SNPs (one novel SNP) in the 3'-untranslated region (UTR). Using the transmission disequilibrium test of the 9 common SNPs out of 17 variants, Significant evidence of SNP rs3791878-G allele in 5'-flanking region of GAD1 was preferentially transmitted to both the all offsprings of the trios (P = 0.0063, respectively; odds ratio = 1.83; 95% confidence interval: 1.26-2.65) and the male offsprings the trios (P = 0.0045, respectively; odds ratio = 2.21; 95% confidence interval: 1.37-3.56). Haplotype analysis suggested that rs3762556(C)-rs3791878(G)-rs6755102(C) is the major risky haplotype preferentially transmitted in both all the trios and male-offspring trios (Global P = 0.016 and 0.012, respectively). The gender-dependent of the risk of SNP rs3791878 suggest the complexity of GAD1 gene in schizophrenia. Given that the switch from G to T in SNP rs3791878 might cause the loss of ARNT and XBP1 transcriptional factor binding sites using a bioinformatics approach, our positive findings of this SNP support the hypothesis that the abruption of GAD1 gene is important to the risk of schizophrenia.


Preventing Airborne Transmission of SARS-CoV-2 in Hospitals and Nursing Homes.
The first case of the coronavirus disease 2019 (COVID-19), the novel contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was reported in Wuhan, China in December 2019 [...].


Comprehensive Review on Neuro-degenerative Type 3 DM.
According to research, Alzheimer's disease (AD) is considered a metabolic illness caused by defective insulin signaling, insulin resistance, and low insulin levels in the brain. Type 3 diabetes has been postulated for AD because reduced insulin signaling has molecular and physiological consequences that are comparable to type I and type 2 diabetes mellitus, respectively. The similarities between type 2 diabetes and Alzheimer's disease suggest that these clinical trials might yield therapeutic benefits. However, it is important to note that lowering your risk of Alzheimer's dementia, whether you have diabetes or not, is still a multidimensional process involving factors like exercise, smoking, alcohol, food, and mental challenges. The current aim is to show that the relationship between T3D and AD is based on both the processing of amyloid-β (Aβ) precursor protein toxicity and the clearance of Aβ, which are the results of impaired insulin signaling. The brain's metabolism, with its high lipid content and energy needs, places excess demands on mitochondria and appears more susceptible to oxidative damage than the rest of the body. Current data suggests that increased oxidative stress relates to amyloid-β (Aβ) pathology and the onset of AD.


A thermoresistant strain of feline immunodeficiency virus (FIV) with an altered cytopathic effect and a restricted cell tropism.
A thermoresistant strain, designated m41, of feline immunodeficiency virus (FIV) was selected after 31 successive passages of chronically infected IRC4 cells at 41 degrees C. The wild-type virus (wt) which served as a control was cultivated the same number of times at 37 degrees C. In Crandell feline kidney cells (CrFK), the replication of m41 was similar at 37 degrees C and 41 degrees C, whereas wt multiplied only at 37 degrees C. Furthermore, m41 was more resistant than the wt strain at temperatures ranging from 37 to 56 degrees C. Syncytia formation was observed with m41 when the CrFK were incubated at 41 degrees C whereas neither m41 nor wt produced syncytia at 37 degrees C. The level of replication of wt and m41 on feline lymphoid primary cells at 37 degrees C was similar. In contrast to wt, m41 was unable to infect bone marrow macrophages. Since one or several mutations in the envelope (env) gene could be involved in changes of cell fusion properties and of cellular tropism, the nucleotide sequence of the env gene derived from wt and m41 respectively was determined. Ten mutations were found in the env gene of m41, thus leading to 9 amino acid modifications in the envelope glycoproteins. These results suggest that structural modifications of the viral envelope proteins are prerequisites for the replication of a thermoresistant FIV strain at elevated temperature and are correlated with the newly acquired viral phenotype.


Effects of Opioids on Immune and Endocrine Function in Patients with Cancer Pain.
Opioids are an important treatment in managing cancer pain. Uncontrolled pain can be detrimental to function and quality of life. Common adverse effects of opioids such as sedation, constipation and nausea are well recognised, but opioid effects on the endocrine and immune systems are less apparent. The evidence for the immunomodulatory effects of opioids suggest that some opioids might be immunosuppressive and that their use might be associated with reduced survival and increased rates of infection in patients with cancer. However, the quality of this evidence is limited. Opioid-induced endocrinopathies, in particular opioid-induced hypogonadism, may also impact cancer survival and impair quality of life. But again, evidence in patients with cancer is limited, especially with regard to their management. There are some data that different opioids influence immune and endocrine function with varying outcomes. For example, some opioids, such as tramadol and buprenorphine, demonstrate immune-sparing qualities when compared to others. However, most of this data is preclinical and without adequate clinical correlation; thus, no opioid can currently be recommended over another in this context. Higher opioid doses might have more effect on immune and endocrine function. Ultimately, it is prudent to use the lowest effective dose to control the cancer pain. Clinical presentations of opioid-induced endocrinopathies should be considered in patients with cancer and assessed for, particularly in long-term opioid users. Hormone replacement therapies may be considered where appropriate with support from endocrinology specialists.


Suspected drug-induced liver fatalities reported to the WHO database.
World Health Organisation drug monitoring started in 1968. No systematic investigation has been carried out using this database of adverse drug reactions with liver injury associated with fatalities. All reports of suspected hepatic adverse drug reactions with a fatal outcome received by the WHO Collaborating Centre for International Drug Monitoring in Uppsala Sweden from 1968 to 2003 were screened. Only those drugs associated with at least 50 suspected cases were analysed. A total of 4,690 reports of suspected drug-induced liver injury associated with fatal outcome were found in the database. The median age of the patients was 45 years and 50.4% were females. A total of 21 drugs were suspected to have caused at least 50 fatalities each. Among these 1,808 adverse drug reactions, the reporting country in 1,598 (88.3%) of the cases was the United States. The most common drugs associated with fatalities were acetaminophen, troglitazone, valproate, stavudine, halothane, lamivudine, didanosine, amiodarone, nevirapine and sulfamethoxazole/trimethoprim. The most common drug types found were analgesics, drugs against human immunodeficiency virus, anticonvulsants and antibacterial drugs. A wide range of different drugs were suspected to have caused fatal liver injury. Analgesics, drugs against infectious diseases and anticonvulsants were the drug types most commonly associated with fatalities.


Healthcare utilization and costs of pediatric home mechanical ventilation in Canada.
Children using home mechanical ventilation (HMV) live at home with better quality of life, despite financial burden for their family. Previous studies of healthcare utilization and costs have not considered public and private expenditures, including family caregiver time. Our objective was to examine public and private healthcare utilization and costs for children using HMV, and variables associated with highest costs. Longitudinal, prospective, observational cost analysis study (2012-2014) collecting data on public and private (out-of-pocket, third-party insurance, and caregiving) costs every 2 weeks for 6 months using the Ambulatory Home Care Record. Functional Independence Measure (FIM), WeeFIM, and Caregiving Impact Scale (CIS) were measured at baseline and study completion. Regression modeling examined a priori selected variables associated with monthly costs using Andersen and Newman's framework for healthcare utilization, relevant literature, and clinical expertise. Data are reported in 2015 Canadian dollars ($1CAD = $0.78USD). Forty two children and their caregivers were enrolled. Overall median (interquartile range) monthly healthcare cost was $12 131 ($8159-$15 958) comprising $9929 (89%) family caregiving hours, $996 (9%) publicly funded, and $252 (2%) out-of-pocket (<1% third-party insurance) costs. With higher FIM score (lower dependency), median costs were reduced by 4.5% (95% confidence interval: 8.3%-0.5%), adjusted for age, sex, tracheostomy, and daily ventilation duration. Note: since the three cost categories did not sum to the total statistically derived median cost, the percentage of each category used the sum of median public + caregiver lost time + private out-of-pocket + third-party insurance as the denominator. For HMV children, most healthcare costs were due to family caregiving costs. More dependent children incur highest costs. The financial burden to family caregivers is substantial and needs to considered in future policy decisions related to pediatric HMV.


Long non coding RNAs reveal important pathways in childhood asthma: a future perspective.
Asthma is a long-term inflammatory disease of the airways of the lungs refers changes that occur in conjunction with, or as a result of, chronic airway inflammation. Airway remodeling the subsequent of inflammation constitutes cellular and extracellular matrix changes in the wall airways, epithelial-to-mesenchymal-transition and airway smooth muscle cell proliferation. Diseases often begin in childhood and despite extensive research, causative pathogenic mechanisms still remain unclear. Transcriptome analysis of childhood asthma reveals distinct gene expression profiles of Long noncoding RNAs which have been reported to play a central regulatory role in various aspects of pathogenesis, clinical course and treatment of asthma. We briefly review current understanding of lnc-RNA dysregulation in children with asthma, focusing on their complex role in the inflammation, cell proliferation and remodeling of airway to guide future researches. We found that the lnc-RNAs increases activity of several oncogenes such c-Myc, Akt, and ERK and various signaling pathways such as MAPK (PI3K, Ras, JNK and p38), NF-κB and Wnt and crosstalk between these pathways by TGFβ, β-catenin, ERK and SKP2. Moreover, two different signal transduction pathways, Wnt and Notch1, can be activated by two lnc-RNAs through sponging the same miRNA for exacerbation cell proliferation.


Implantable arterial doppler efficacy in free flap reconstruction: A systematic review and meta-analysis.
The implantable arterial doppler (IAD) is frequently used to postoperatively monitor free flaps with high accuracy, but there are no guidelines for its use. Bedside exam is used adjunctively to determine necessary intervention. This systematic review seeks to discover why the doppler is used adjunctively despite its established record of accuracy. Criteria for inclusion and exclusion were established. In total, 280 articles were found on PubMed and Web of Science, then screened accordingly. Data from 22 articles were analyzed using a bivariate hierarchical random effects model. Twenty-two studies yielded 2996 total patients undergoing 3127 free flap procedures. The meta-analysis found a high sensitivity of 0.809 (95% CI = 0.709, 0.880) and specificity of 0.966 (95% CI = 0.947, 0.979). False-positive rate was found to be 0.034 (95% CI = 0.021, 0.053). Positive and negative predictive values were 0.711 (95% CI = 0.581, 0.817) and 0.979 (95% CI = 0.966, 0.988). Positive and negative likelihood ratios were 24.7 (95% CI = 14.5, 39.5) and 0.20 (95% CI = 0.12, 0.30). The established efficacy of the IAD is supported by this study. Clinical exams may remain as the final adjunct due to the risks of inaccurate IAD signals. Further studies are warranted to optimize its use for future practice guidelines.


Space-time scan statistics of 2007-2013 dengue incidence in Cimahi City, Indonesia.
Four dengue serotypes threatened more than 200 million people and has spread to over 400 districts in Indonesia. Furthermore, 26 districts in most densely populated province, West Java, have been declared as hyperendemic areas. Cimahi is an endemic city with the highest population (14,969 people per square kilometer). Evidence on distribution pattern of dengue cases is required to discover the spread of dengue cases in Cimahi. A study has been conducted to detect clusters of dengue incidence during 2007-2013. A temporal spatial analysis was performed using SaTScan™ software incorporated confirmed dengue monthly data from the Municipality Health Office and population data from a local Bureau of Statistics. A retrospective space-time analysis with a Poisson distribution model and monthly precision was performed. Our results revealed a significant most likely cluster (p<0.001) throughout period of study. The most likely cluster was detected in the centre of the city and moved to the northern region of Cimahi. Cimahi, Karangmekar, and Cibabat village were most likely cluster in 2007-2010 (p <0.001; RR = 2.16-2.98; pop at risk 12% total population); Citeureup were detected as the most likely cluster in 2011-2013 (p <0.001; RR 5.77), respectively. Temporaly, clusters were detected in the first quarter of each year each. In conclusion, a dynamic spread of dengue initiated from the centre to its surrounding areas during the period 2007-2013. Our study suggests the use of GIS to strengthen case detection and surveillance. An in-depth investigation to relevant risk factors in high-risk areas in Cimahi city is encouraged.


Inhibition of EZH2 alleviates SAHA-induced senescence-associated secretion phenotype in small cell lung cancer cells.
Chemotherapy has been widely used in small cell lung cancer (SCLC) treatment in the past decades. However, SCLC is easy to recur after chemotherapy. The senescence of cancer cells during chemotherapy is one of the effective therapeutic strategies to inhibit the progression of cancer. Nevertheless, the senescence-associated secretion phenotype (SASP) promotes chronic inflammation of the cancer microenvironment and further accelerates the progression of tumors. Therefore, inducing the senescence of cancer cells and inhibiting the production of SASP factors during anticancer treatment have become effective therapeutic strategies to improve the anticancer effect of drugs. Here we reported that SCLC cells treated with an FDA-approved HDAC inhibitor SAHA underwent senescence and displayed remarkable SASP. In particular, SAHA promoted the formation of cytoplasmic chromatin fragments (CCFs) in SCLC cells. The increased CCFs in SAHA-treated SCLC cells were related to nuclear porin Tpr, which activated the cGAS-STING pathway, and promoted the secretion of SASP in cancer cells. Inhibition of EZH2 suppressed the increase of CCFs in SAHA-treated SCLC cells, weakened the production of SASP, and increased the antiproliferative effect of SAHA. Overall, our work affords new insight into the secretion of SASP in SCLC and establishes a foundation for constructing a new therapeutic strategy for SCLC patients.


What's in a prick? Vaccines and the cardiovascular system.
Evidence suggests a crucial role for vaccines in cardiovascular disease, mediated not only by disease prevention but also by immunomodulatory effects. This review attempts to briefly present the effects of pathogens and vaccines on the cardiovascular system and potential mechanisms for the development of vaccines against cardiovascular diseases per se. Current epidemiological evidence regarding vaccine effectiveness in different categories of heart disease is discussed, as well as current international guidelines' recommendations. In summary, cardiologists should strive to promote vaccination against specific pathogens with proven beneficial effects on cardiovascular diseases.


Coregionalization analysis of heavy metals in the surface soil of Inner Mongolia.
Due to potential problems associated with their deficiencies or toxicities, heavy metals in soils are of great environmental concern. To evaluate heavy metal contents and their relationships in the surface soil of Inner Mongolia, soil samples were collected from 344 sites and contents of copper, lead, zinc, cadmium, nickel, chromium, mercury, cobalt, vanadium and manganese were determined. In this article, coregionalization of these ten heavy metals is investigated using factorial kriging. Vegetation type, parent material type and soil pH, with respective characteristic ranges of 200, 400 and over 1000 km, are identified as the primary factors that control the spatial distribution of soil heavy metals. At the scale of 200 km, heavy metal relationships mainly reflect the result of biocycling. Their relationships at the intermediate scale (400 km) are thought to be derived from the atomic substitution of metals in the parent materials. Effects of soil pH on the adsorption of heavy metals by soil organic materials could explain their relationships at the large spatial scale (over 1000 km).


Cavernous angiomas of the brain. Account of fourteen personal cases and review of the literature.
Fourteen cases of cerebral cavernous angiomas are reported and the literature pertaining to the subject is reviewed. Some of these rare malformations remain asymptomatic throughout life, some give rise to symptoms (epileptic seizures with or without haemorrhage or slowly evolving focal nervous deficits) which usually appear in adult life. Precise pre-operative diagnosis is difficult, as at angiography they most often appear as avascular space-occupying lesions. Surgical removal is easy in most cases, and the operative outcome is good.


Retinal axonal loss in very early stages of multiple sclerosis.
The lack of surrogates of clinical progression has limited the design of neuroprotection trials in multiple sclerosis (MS). Our aim was to study the association between time-domain optical coherence tomography measures and clinical and magnetic resonance imaging outcomes in early MS. Forty-three relapsing-remitting MS patients within 1 year of onset were followed for up to 3 years. The peripapillary retinal nerve fiber layer (RNFL) decreased annually by 2 μm (95% confidence interval -3.89, -0.11; P = 0.038). The RNFL tended to be associated with normalized normal appearing white matter volume in cross-sectional (P = 0.08) and longitudinal analyses (P = 0.06). There is substantial RNFL loss even in very early MS. Our data suggest that retinal axonal atrophy is associated with atrophy in global white matter volume in early MS.


Inteurleukin-8 gene variations and the susceptibility to schizophrenia.
The relevance of Interleukin-8 (IL-8) cytokine alteration in the peripheral and central system has been widely shown in psychosis while variation in the IL-8 gene remains largely unexplored and to the best of our knowledge, IL-8 polymorphisms have never been specifically targeted in Schizophrenia (Scz). Thus, we set out to search a potential correlation between rs4073, rs2227306 and rs1126647 polymorphisms in IL-8 gene and the development of Scz in a sample of the Tunisian population in a candidate gene approach. Targeted polymorphisms were analysed in 206 patients and 195 controls using PCR-RFLP method. Among all analysed polymorphisms, only rs1126647 showed a significant risk for Scz. After stratification analysis, we noted a significant association of TT genotype and T allele at rs1126647 with paranoid form, and more specifically with female sex. We find that the rare haplotypes at rs4073-rs2227306-rs1126647 of TTT, ACT and TCT, each containing the risk allele rs1126647T, were associated with increased risk for paranoid Scz while only the TCT combination constituted a risk factor for Scz more generally. Our findings support that IL-8 gene may be involved in susceptibility to Scz but this still preliminary and needs to be strengthened by further independent analyses.


Integrated metabolomics and transcriptomics study of traditional herb Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao reveals global metabolic profile and novel phytochemical ingredients.
Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao is one of the most common herbs widely used in South and East Asia, to enhance people's health and reinforce vital energy. Despite its prevalence, however, the knowledge about phytochemical compositions and metabolite biosynthesis in Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao is very limited. An integrated metabolomics and transcriptomics analysis using state-of-the-art UPLC-Q-Orbitrap mass spectrometer and advanced bioinformatics pipeline were conducted to study global metabolic profiles and phytochemical ingredients/biosynthesis in Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao. A total of 5435 metabolites were detected, from which 2190 were annotated, representing an order of magnitude increase over previously known. Metabolic profiling of Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao tissues found contents and synthetic enzymes for phytochemicals were significantly higher in leaf and stem in general, whereas the contents of the main bioactive ingredients were significantly enriched in root, underlying the value of root in herbal remedies. Using integrated metabolomics and transcriptomics data, we illustrated the complete pathways of phenylpropanoid biosynthesis, flavonoid biosynthesis, and isoflavonoid biosynthesis, in which some were first reported in the herb. More importantly, we discovered novel flavonoid derivatives using informatics method for neutral loss scan, in addition to inferring their likely synthesis pathways in Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao. The current study represents the most comprehensive metabolomics and transcriptomics analysis on traditional herb Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao. We demonstrated our integrated metabolomics and transcriptomics approach offers great potentials in discovering novel metabolite structure and associated synthesis pathways. This study provides novel insights into the phytochemical ingredients, metabolite biosynthesis, and complex metabolic network in herbs, highlighting the rich natural resource and nutritional value of traditional herbal plants.


Structural repeats in cyclosporin A.
The conformation of various dipeptides of free and cyclophilin A-bound cyclosporin A were compared. Cyclosporin A was shown to contain in both states conformationally duplicated fragments in the putative binding sites for cyclophilin A and phosphatase calcineurin.


A current perspective of suicide and attempted suicide.
Suicide and suicide attempts are a major cause of death and morbidity worldwide. Suicide is generally a complication of a psychiatric disorder, but it requires additional risk factors because most psychiatric patients never attempt suicide. This review includes a hypothesized stress-diathesis model, which has implications for detection of high-risk patients and treatment interventions, and discusses promising treatment approaches that have been recently identified.


Purification and identification of the essential ionizable groups of honeybee, Apis mellifera L., trehalase.
Trehalase (EC 188.8.131.52) of the bound type was purified as an electrophoretically homogeneous protein from adult honeybees by fractionation with ammonium sulfate, hydrophobic chromatography, and DEAE-Sepharose CL-6B, CM-Sepharose CL-6B, butyl-Toyopearl 650M, and p-aminophenyl beta-glucoside Sepharose 4B column chromatographies. The enzyme preparation was confirmed to be a monomeric protein containing 3.1% carbohydrate. The molecular weight was estimated to be approximately 69,000, and the optimum pH was 6.7. The Michaelis constant (Km) was 0.66 mM, and the molecular activity (k0) was 86.2 s(-1). The enzyme was an "inverting" type which produced beta-glucose from alpha, alpha-trehalose. Dependence of the V and Km values on pH gave values for the ionization constants, pKe1 and pKe2, of essential ionizable groups 1 and 2 of the free enzyme of 5.3 and 8.5, respectively. When the dielectric constant of the reaction mixture was decreased, pKe1, and pKe2 were shifted to higher values of + 0.2 and + 0.5 pH unit, respectively. The ionization heat (deltaH) of ionizable group 1 was estimated to be + 1.8 kcal/mol, and the deltaH value of group 2 was + 1.5 kcal/mol. These findings strongly support the notion that the essential ionizable groups of honeybee trehalase are two kinds of carboxyl groups, one being a dissociated type (-COO(-), ionizable group 1) and the other a protonated type (-COOH, ionizable group 2), although the pKe2 value is high.


In Silico Prediction Method for Protein Asparagine Deamidation.
In silico prediction methods were developed to predict protein asparagine (Asn) deamidation. The method is based on understanding deamidation mechanism on structural level with machine learning. Our structure-based method is more accurate than the sequence-based method which is still widely used in protein engineering process. In addition, molecular dynamics simulation was applied to study the time occupancy of nucleophilic attack distance, which is hypothesized as the most important step toward the rate-limiting succinimide intermediate formation. A more accurate prediction method for distinguishing potentially liable amino acid residues would allow their elimination or reduction as early as possible in the drug discovery process. It is possible that such quantitative protein structure-property relationship tools can also be applied to other protein hotspot predictions.


Brain imaging in normal kids: a community-based MRI study in Malawian children.
To collect normative MRI data for effective clinical and research applications. Such data may also offer insights into common neurological insults. We identified a representative, community-based sample of children aged 9-14 years. Children were screened for neurodevelopmental problems. Demographic data, medical history and environmental exposures were ascertained. Eligible children underwent the Neurologic Examination for Subtle Signs (NESS) and a brain MRI. Descriptive findings and analyses to identify risk factors for MRI abnormalities are detailed. One hundred and two of 170 households screened had age-appropriate children. Two of 102 children had neurological problems - one each with cerebral palsy and epilepsy. Ninety-six of 100 eligible children were enrolled. Mean age was 11.9 years (SD 1.5), and 43 (45%) were boys. No acute MRI abnormalities were seen. NESS abnormalities were identified in 6 of 96 children (6%). Radiographic evidence of sinusitis in 29 children (30%) was the most common MRI finding. Brain abnormalities were found in 16 (23%): mild diffuse atrophy in 4 (4%), periventricular white matter changes/gliosis in 6 (6%), multifocal punctuate subcortical white matter changes in 2 (2%), vermian atrophy in 1 (1%), empty sella in 3 (3%) and multifocal granulomas with surrounding gliosis in 1 (1%). Having an abnormal MRI was not associated with age, sex, antenatal problems, early malnutrition, febrile seizures, an abnormal neurological examination or housing quality (all P values >0.05). No predictors of radiographic sinusitis were identified. Incidental brain MRI abnormalities are common in normal Malawian children. The incidental atrophy and white matter abnormalities seen in this African population have not been reported among incidental findings from US populations, suggesting Malawi-specific exposures may be the cause.


Low lipoprotein lipase mass in preheparin serum of type 2 diabetes mellitus patients and its recovery with insulin therapy.
There exists lipoprotein lipase mass in preheparin serum, even though the activity is scarcely found. We studied the preheparin serum lipoprotein lipase mass levels (prehaparin LPL mass) in type 2 diabetes mellitus patients and the effect of insulin therapy on the levels of preheparin LPL mass. In 40 type 2 diabetes mellitus patients, preheparin LPL mass were measured by the sandwich enzyme-linked immunosorbent assay (ELISA), and were compared with those of non-diabetic healthy control. The correlation between preheparin LPL mass and Hemoglobin A(1c) (HbA(1c)), serum lipids were studied. Preheparin LPL mass were measured before and after insulin therapy. Preheparin LPL mass of type 2 diabetes mellitus patients was significantly lower than that of non-diabetic healthy control. In diabetic patients, preheparin LPL mass were negatively correlated with HbA(1c). Fifteen patients started to take insulin therapy. Preheparin LPL mass increased significantly at 4th week, when fasting blood glucose decreased. These results suggested that preheparin LPL mass was greatly regulated by insulin action.


Coronary flow distribution and dynamics during continuous and pulsatile extracorporeal circulation in the pig.
Four extracorporeal perfusion conditions (continuous beating, continuous fibrillating, pulsatile beating, and pulsatile fibrillating) were tested for 15 minutes each in pigs. Coronary flow, endocardial-epicardial flow ratio, phasic coronary flow, myocardial oxygen consumption, and myocardial lactate extraction were measured. No significant differences in any of these variables were found between pulsatile and continuous flow states in either fibrillating or beating hearts (p greater than 0.05). In both fibrillating conditions, significant elevations of myocardial oxygen consumption and decreases in endocardial-epicardial flow ratios were found (p less than 0.05). Lactate extraction occurred in all conditions, and phasic coronary flows were similar in both beating conditions. These data suggest caution in the expectation that pulsatile perfusion will reverse the coronary flow and myocardial oxygen consumption changes seen with fibrillation.


Myocardial creep and cardiorespiratory motion correction improves diagnostic accuracy of Rubidium-82 cardiac positron emission tomography.
To evaluate the feasibility of retrospectively detecting and correcting periodical (cardiac and respiratory motion) and non-periodical shifts of the myocardial position (myocardial creep) using only the acquired Rubidium-82 positron emission tomography raw (listmode) data. This study comprised 25 healthy participants (median age = 23 years) who underwent repeat rest/adenosine stress Rubidium-82 myocardial perfusion imaging (MPI) and 53 patients (median age = 64 years) considered for revascularization who underwent a single MPI session. All subjects were evaluated for myocardial creep during MPI by assessing the myocardial position every 200 ms. A proposed motion correction protocol, including corrections for cardiorespiratory and creep motion (3xMC), was compared to a guideline-recommended protocol (StandardRecon). For the volunteers, we report test-retest repeatability using standard error of measurements (SEM). For the patient cohort, we evaluated the area under the receiver operating curve (AUC) for both stress and ischemic total perfusion deficits (sTPD and iTPD, respectively) using myocardial ischemia defined as fractional flow reserve values < 0.8 in the relevant coronary segment as the gold standard. Test-retest repeatability was significantly improved following corrections for myocardial creep (SEM; sTPD: StandardRecon = 2.2, 3xMC = 1.8; iTPD: StandardRecon = 1.6, 3xMC = 1.2). AUC analysis of the ROC curves revealed significant improvements for iTPD measurements following 3xMC [sTPD: StandardRecon = 0.88, 3xMC = 0.92 (P = .21); iTPD: StandardRecon = 0.88, 3xMC = 0.95 (P = .039)]. 3xMC has the potential to improve the diagnostic accuracy of myocardial MPI obtained from positron emission tomography. Therefore, its use should be considered both in clinical routine and large-scale multicenter studies.


Quantitation of helper factor activity. II. Inhibition of antibody binding.
A sensitive direct assay has been developed to quantitate antigen specific helper factors (ThF). The assay depends on the ability of ThF to block the binding of free antibody to immobilized antigen. It has been used to follow the course of purification of ThF produced in short-term cultures of in vitro primed helper cells and purified by affinity chromatography on antibody and antigen immunoabsorbents. The identity of the ThF was confirmed by assaying its biological activity and by its reactivity with anti-Ia antibody and with a monoclonal anti-ThF.


Prolonged ventricular pause associated with ticagrelor use: A case report.
We report a case of a 76-year-old female who presented with non-ST elevation myocardial infarction and developed a 22-second ventricular pause with ticagrelor that did not recur after shifting to clopidogrel. Based on the Naranjo algorithm, the likelihood that our patient's prolonged ventricular pause was due to ticagrelor exposure was probable. Ticagrelor use is associated with prolonged ventricular pauses, warranting close monitoring, particularly during the first week of therapy.


Sequence-based bioprospecting of myo-inositol oxygenase (Miox) reveals new homologues that increase glucaric acid production in Saccharomyces cerevisiae.
myo-Inositol oxygenase (Miox) is a rate-limiting enzyme for glucaric acid production via microbial fermentation. The enzyme converts myo-inositol to glucuronate, which is further converted to glucaric acid, a natural compound with industrial uses that range from detergents to pharmaceutical synthesis to polymeric materials. More than 2,000 Miox sequences are available in the Uniprot database but only thirteen are classified as reviewed in Swiss-Prot (August 2019). In this study, sequence similarity networks were used to identify new homologues to be expressed in Saccharomyces cerevisiae for glucaric acid production. The expression of four homologues did not lead to product formation. Some of these enzymes may have a defective "dynamic lid" - a structural feature important to close the reaction site - which might explain the lack of activity. Thirty-one selected Miox sequences did allow for product formation, of which twenty-five were characterized for the first time. Expression of Talaromyces marneffei Miox led to the accumulation of 1.76 ± 0.33 g glucaric acid/L from 20 g glucose/L and 10 g/L myo-inositol. Specific glucaric acid titer with TmMiox increased 44 % compared to the often-used Arabidopsis thaliana variant AtMiox4 (0.258 vs. 0.179 g glucaric acid/g biomass). AtMiox4 activity decreased from 12.47 to 0.40 nmol/min/mg protein when cells exited exponential phase during growth on glucose, highlighting the importance of future research on Miox stability in order to further improve microbial production of glucaric acid.


Discovery of a potent microtubule-targeting agent: Synthesis and biological evaluation of water-soluble amino acid prodrug of combretastatin A-4 derivatives.
Amino acid prodrugs are known to be very useful for improving the aqueous solubility of sparingly water soluble drugs (Drug Discovery Today 2013, 18, 93). Therefore, we synthesized eleven novel combretastatin A-4 amino acid derivatives and evaluated their anti-tumor activities in vitro and in vivo. Among them, compound 15 (valine attached to compound 3, which was shown to be a potent tubulin polymerization inhibitor in our previous study) exhibited high efficacy in tumor-bearing mice, and pharmacokinetic analysis in rats indicated that compound 15 was an effective prodrug as well. Besides, compound 15 significantly inhibited tubulin polymerization in vitro and in vivo by binding to the colchicine binding site. In addition, compound 15 induced cell cycle arrest in the G2/M phase and triggered apoptosis in a caspase-dependent manner. In conclusion, our study showed that compound 15 could have significant anti-tumor activity as a novel microtubule polymerization disrupting agent with improved aqueous solubility.


Particle-bound organic and elemental carbons for source identification of PM < 0.1 µm from biomass combustion.
Atmospheric nanoparticles (PM < 0.1 µm) are a major cause of environmental problems and also affect health risk. To control and reduce these problems, sources identification of atmospheric particulates is necessary. Combustion of bituminous coal and biomass including rubber wood, palm kernel, palm fiber, rice stubble, rice straw, maize residue, sugarcane leaves and sugarcane bagasse, which are considered as sources of air quality problems in many countries, was performed. Emissions of particle-bound chemical components including organic carbon (OC), elemental carbon (EC), water-soluble ions (NH4+, Cl-, NO3-, SO42-), elements (Ca, K, Mg, Na) and heavy metals (Cd, Cr, Ni, Pb) were investigated. The results revealed that PM < 0.1 µm from all samples was dominated by the OC component (>50%) with minor contribution from EC (3%-12%). The higher fraction of carbonaceous components was found in the particulates with smaller sizes, and lignin content may relate to concentration of pyrolyzed organic carbon (PyOC) resulting in the differences of OC/EC values. PM emitted from burning palm fiber and rice stubble showed high values of OC/EC and also high PyOC. Non-carbonaceous components such as Cl-, Cr, Ca, Cd, Ni, Na and Mg may be useful as source indicators, but they did not show any correlation with the size of PM.


Fasting ghrelin levels after gastric bypass and vertical sleeve gastrectomy: An analytic cohort study.
Neuronal populations involved in the regulation of food intake, particularly the orexigenic (appetite-stimulating) hormone ghrelin, are found in the hypothalamus. Changes in plasma ghrelin levels have been observed following different bariatric surgery procedures, but the results from different studies are contradictory. Much remains unknown regarding the role of ghrelin in the weight loss process following bariatric surgery. Our objective was to describe the behaviour of fasting ghrelin levels, comparing the changes occurring between 2 different surgical techniques (gastric bypass versus vertical sleeve gastrectomy) and their correlation with weight loss. A prospective, observational, analytic cohort study of 54 patients (27 for each surgical technique) with a 12-month follow-up period. We analysed demographic data, anthropometric data, comorbidities, weight loss and evolution of fasting ghrelin. The behaviour of acylated ghrelin was similar with the 2 surgical techniques, with no significant differences between gastric bypass and vertical sleeve gastrectomy. With both procedures, there was an increase in acylated ghrelin on day 5 and a subsequent decrease, and levels then gradually increased to reach values at 12 months that were higher than those reported preoperatively. This increase in ghrelin levels did not affect weight loss, since one year post-surgery, 30% weight loss was achieved with both types of surgery. We observed an increase in fasting acylated ghrelin levels at one year of follow-up with both surgical techniques, with 30% weight loss.


Roles, outcomes, and enablers within research partnerships: A rapid review of the literature on patient and public involvement and engagement in health research.
Recent studies mention a need to investigate partnership roles and dynamics within patient and public involvement and engagement (PPIE) in health research, and how impact and outcomes are achieved. Many labels exist to describe involvement processes, but it is unknown whether the label has implications on partnerships and outcomes. This rapid review investigates how roles between patients, relatives and researchers in a broad variety of PPIE activities in health research are described in peer reviewed papers and explores what enables these partnerships. Rapid review of articles published between 2012 and February 2022 describing, evaluating, or reflecting on experiences of PPIE in health research. All research disciplines and research areas were eligible. Four databases (Medline, Embase, PsychInfo and CINAHL) were searched between November 2021 and February 2022. We followed PRISMA guidelines and extracted descriptive factors: year, origin, research area and discipline, study focus, framework used and co-authorship. On a selection of articles, we performed a narrative analysis of partnership roles using Smits et al.'s. Involvement Matrix. Lastly, we performed a meta synthesis of reported enablers and outcomes of the partnerships. Patients and Relatives (PRs) have been involved in the whole rapid review process and are co-authors of this article. Seventy articles from various research disciplines and areas were included. Forty articles were selected for a narrative analysis of the role description of PRs and researchers, and a meta synthesis of enablers and outcomes. Most articles described researchers as decision-makers throughout the research cycle. PRs most often were partners when they were included as co-authors; they were mostly partners in the design, analysis, write-up, and dissemination stages. Enablers of partnerships included: PR training, personality of PRs and communication skills, trust, remuneration and time. Researchers' decision-making roles gives them control of where and when to include PRs in their projects. Co-authorship is a way of acknowledging patients' contributions which may lead to legitimation of their knowledge and the partnership. Authors describe common enablers, which can help future partnership formation.


PCR detection of colostrum-associated Maedi-Visna virus (MVV) infection and relationship with ELISA-antibody status in lambs.
A recent large-scale experimental study showed that bottle-feeding ovine colostrum from seropositive ewes results in high MVV-seroconversion in lambs. In contrast, relatively few lambs that naturally suckled colostrum from seropositive dams seroconverted as a result of it. Furthermore, lambs fed uninfected bovine colostrum readily seroconverted when mixed with ovine-colostrum lambs indicating that horizontal MVV transmission between lambs was efficient. MVV-infection was further investigated in the same samples using two PCR tests targeting sequences in the long-terminal repeats (LTR) and POL MVV genes. PCR-tests confirmed previous serological findings. However, the LTR-PCR was more sensitive and allowed detecting infection earlier than the other tests, including 5-8% of new-born lambs from seropositive dams, providing more evidence that prenatal MVV-infection may be more important than considered. The degree of agreement between PCR and antibody tests in individual samples was low up to 6 months of age and moderate at 10 months-old. Nine percent of lambs were always PCR-negative but seroconverted and 19% of lambs were PCR-positive at least once and did not seroconvert. However, seroconversion was associated with increasing number of times lambs were PCR-positive and ovine colostrum-fed lambs were more frequently PCR-positive than other lambs. The significance of these findings in terms of MVV-infection, epidemiology and control is discussed.


The many faces of the zinc finger protein 335 in brain development and immune system.
Zinc finger protein 335 (ZNF335) plays a crucial role in the methylation and, consequently, regulates the expression of a specific set of genes. Variants of the ZNF335 gene have been identified as risk factors for microcephaly in a variety of populations worldwide. Meanwhile, ZNF335 has also been identified as an essential regulator of T-cell development. However, an in-depth understanding of the role of ZNF335 in brain development and T cell maturation is still lacking. In this review, we summarize current knowledge of the molecular mechanisms underlying the involvement of ZNF335 in neuronal and T cell development across a wide range of pre-clinical, post-mortem, ex vivo, in vivo, and clinical studies. We also review the current limitations regarding the study of the pathophysiological functions of ZNF335. Finally, we hypothesize a potential role for ZNF335 in brain disorders and discuss the rationale of targeting ZNF335 as a therapeutic strategy for preventing brain disorders.


Psychophysiological responses to drug-associated stimuli in chronic heavy cannabis use.
Due to learning processes originally neutral stimuli become drug-associated and can activate an implicit drug memory, which leads to a conditioned arousing 'drug-seeking' state. This condition is accompanied by specific psychophysiological responses. The goal of the present study was the analysis of changes in cortical and peripheral reactivity to cannabis as well as alcohol-associated pictures compared with emotionally significant drug-unrelated and neutral pictures in long-term heavy cannabis users. Participants were 15 chronic heavy cannabis users and 15 healthy controls. Verbal reports as well as event-related potentials of the electroencephalogram and skin conductance responses were assessed in a cue-reactivity paradigm to determine the psychophysiological effects caused by drug-related visual stimulus material. The evaluation of self-reported craving and emotional processing showed that cannabis stimuli were perceived as more arousing and pleasant and elicited significantly more cannabis craving in cannabis users than in healthy controls. Cannabis users also demonstrated higher cannabis stimulus-induced arousal, as indicated by significantly increased skin conductance and a larger late positivity of the visual event-related brain potential. These findings support the assumption that drug-associated stimuli acquire increased incentive salience in addiction history and induce conditioned physiological patterns, which lead to craving and potentially to drug intake. The potency of visual drug-associated cues to capture attention and to activate drug-specific memory traces and accompanying physiological symptoms embedded in a cycle of abstinence and relapse--even in a 'so-called' soft drug--was assessed for the first time.


Formoguanamine-induced inhibition of deprivation myopia in chick is accompanied by choroidal thinning while retinal function is retained.
Twenty hatchling chickens were injected intravitreally every 4 days from day 2 to day 16 with dimethyl sulphoxide (DS) in one eye and DS or formoguanamine dissolved in DS (FG.DS) with or without occlusion in the other (FG.DS.MD, DS.MD, FG.DS). At day 16, the FG.DS.MD eyes failed to show the high refractive myopia and showed less axial elongation than that developed by the DS.MD eyes. Electroretinograms indicated that at the dosage used, FG.DS does not eliminate phototransduction. Light microscopy showed choroidal and retinal thinning in DS.MD and FG.DS.MD eyes but less than in FG.DS eyes, suggesting that change in choroidal thickness is unlikely to be the primary cause of form deprivation myopia.


[The effect of adequate stimulation of the vestibular apparatus on evoked rhythmic activity in the nerves of the forelimbs in the immobilized guinea pig].
The influence of adequate vestibular stimulation on the rhythmical activity of forelimb nerves evoked by electrical stimulation of the mesencephalic locomotor region in combination with DOPA administration was registered in an immobilized guinea pig. Rhythmical activity was mainly registered in the flexor nerve. Intensity of the activity changed with animal tilting, decreasing during an ipsilateral incline and increasing during a contralateral one. These changes revealed a phase lag of -110 divided by -150 degrees relative to angular acceleration during cyclic tilting about a longitudinal axis with frequencies of 0.02-0.4 Hz.


Granulomatosis with polyangiitis diagnosed during the treatment of otitis media with prednisolone in a patient with anti-neutrophil cytoplasmic antibody-associated vasculitis: A case report.
A 78-year-old woman with severe auditory disturbance was referred to our hospital and was diagnosed with otitis media with anti-neutrophil cytoplasmic antibody -associated vasculitis (OMAAV). The auditory disturbance improved moderately with prednisolone 40 mg/day, but multiple pulmonary masses were detected on chest computed tomography six months later. Transbronchial lung biopsy revealed granulomatosis with polyangiitis (GPA). Administration of prednisolone 50 mg/day and cyclophosphamide 500 mg once every two weeks for 12 weeks improved the lung lesions, but no further improvement in the hearing ability was observed. Prednisolone monotherapy was not able to prevent progression of OMAAV to GPA.


Synthesis of new chiral cis-3-hydroxyazetidines and their application in diethylzinc addition to aldehydes.
A new series of chiral cis-3-hydroxyazetidines have been prepared from (R)-1-phenylethylamine. They have excellent catalytic activities and enantiomeric selectivities in asymmetric addition of diethylzinc to aromatic aldehydes.


Multi-AI competing and winning against humans in iterated Rock-Paper-Scissors game.
Predicting and modeling human behavior and finding trends within human decision-making processes is a major problem of social science. Rock Paper Scissors (RPS) is the fundamental strategic question in many game theory problems and real-world competitions. Finding the right approach to beat a particular human opponent is challenging. Here we use an AI (artificial intelligence) algorithm based on Markov Models of one fixed memory length (abbreviated as "single AI") to compete against humans in an iterated RPS game. We model and predict human competition behavior by combining many Markov Models with different fixed memory lengths (abbreviated as "multi-AI"), and develop an architecture of multi-AI with changeable parameters to adapt to different competition strategies. We introduce a parameter called "focus length" (a positive number such as 5 or 10) to control the speed and sensitivity for our multi-AI to adapt to the opponent's strategy change. The focus length is the number of previous rounds that the multi-AI should look at when determining which Single-AI has the best performance and should choose to play for the next game. We experimented with 52 different people, each playing 300 rounds continuously against one specific multi-AI model, and demonstrated that our strategy could win against more than 95% of human opponents.


Lipid peroxides in the free radical pathophysiology of brain diseases.
1. Polyunsaturated fatty acids are essential for normal cell membrane functioning because many membrane properties, such as fluidity and permeability, are closely related to the presence of unsaturated and polyunsaturated side chains. Lipid peroxidation results in loss of membrane polyunsaturated fatty acids and oxidized phospholipids as polar species contributing to increased membrane rigidity. 2. Polyunsaturated fatty acids are released from membrane phospholipids by a number of enzymic mechanisms involving the receptor-mediated stimulation of phospholipase A2 and phospholipase C/diacylglycerol lipase pathways. 3. The overstimulation of excitatory amino acid (EAA) receptors stimulates the activities of lipases and phospholipases, and this stimulation produces changes in membrane phospholipid composition, permeability, and fluidity, thus decreasing the integrity of plasma membranes. 4. Alterations in properties of plasma membranes may be responsible for the degeneration of neurons seen in neurodegenerative diseases. Two major processes may be involved in neuronal injury caused by the overstimulation of EAA receptors. One is a large Ca2+ influx and the other is an accumulation of free radicals and lipid peroxides as a result of neural membrane phospholipid degradation. It is suggested that calcium and free radicals act in concert to induce neuronal injury in acute trauma (ischemia and spinal cord injury) and in neurodegenerative diseases.


QTc interval prolongation in children with Ulrich-Turner syndrome.
The Ullrich-Turner-Syndrome (UTS) is the most commonly occurring sex chromosome abnormality in females. Cardiac malformations are well known, but no data exist on specific electrocardiogram (ECG) patterns in children and adolescents. A prolongation of the QT interval on the ECG has been correlated to an increased risk for sudden cardiac death, and medical treatment is warranted in patients with long QT syndrome (LQTS). Moreover, several drugs of common use are contraindicated in LQTS because of their effects on myocardial repolarization. The ECG tracings of 86 UTS patients [mean age (+/-SD): 11.0+/-3.6 years; mean height-SD: -2.6+/-1.0] were analyzed and compared to age-matched control groups of 75 boys (mean age: 11.3+/-3.5 years; mean height-SD: -1.9+/-1.0) and 62 girls (mean age: 10.1+/-3.2 years; mean height-SD: -2.5+/-0.9) with short stature. Eighteen UTS patients (20.9%) had an abnormally prolonged QTc >0.45 s in contrast to only one control subject (0.9%). The QTc interval of UTS patients was significantly prolonged compared to that of the controls (p<0.01) and normal values. There is an increased prevalence of a long QT interval among UTS patients. This should be taken into account for the cardiovascular screening of such patients. Patients with UTS have an intrinsically prolonged QT interval and as such may be at higher risk for arrhythmias in the context of a QT-prolonging medication.


Anticoagulation in patients with isolated distal deep vein thrombosis: a meta-analysis.
Essentials The optimal management of isolated distal deep vein thrombosis (IDDVT) is undefined. This meta-analysis aimed to assess the clinical benefit of anticoagulation for IDDVT. Anticoagulation reduced the rate of pulmonary embolism without increasing major bleeding risk. Recurrent thromboembolism was less common with more than 6 weeks vs. 6 weeks of anticoagulation. Background The optimal management of patients with isolated distal deep vein thrombosis (IDDVT), concerning both the need for anticoagulation and its duration, is undefined. Objectives We performed a meta-analysis of randomized and cohort studies in patients with IDDVT to assess the clinical benefit of: (i) anticoagulation versus no anticoagulation; and (ii) anticoagulant treatment for 6 weeks versus for > 6 weeks. Methods The primary outcome of this analysis was recurrent venous thromboembolism (proximal propagation, recurrence of deep vein thrombosis, and pulmonary embolism). Data were pooled and compared by the use of odds ratio (OR) and 95% confidence interval (CI). Results A reduction in the rate of recurrent venous thromboembolism was observed in patients who received anticoagulation relative to those who did not receive anticoagulation (either therapeutic or prophylactic) (20 studies, 2936 patients; OR 0.50, 95% CI 0.31-0.79), without an increase in the risk of major bleeding (OR 0.64, 95% CI 0.15-2.73). The rate of pulmonary embolism was lower in anticoagulant-treated patients than in controls (15 studies, 1997 patients; OR 0.48, 95% CI 0.25-0.91). A lower rate of recurrent venous thromboembolism was observed in patients who received > 6 weeks of anticoagulant therapy than in those who received 6 weeks of anticoagulant therapy (four studies, 1136 patients; OR 0.39, 95% CI 0.17-0.90). Conclusions In patients with IDDVT, anticoagulation (both therapeutic and prophylactic) reduces the rate of recurrent venous thromboembolism and the incidence of pulmonary embolism as compared with no anticoagulation, without an increased risk of major bleeding. Anticoagulation for > 6 weeks should be preferred over shorter durations.


Anaerobic bacterial meningitis.
Anaerobic meningitis occurred in four patients in whom anaerobic bacteria had not been suspected as a possible cause. The predisposing conditions were typical of those seen in patients previously reported to have this infection and included chronic otitis media with mastoiditis, chronic sinusitis, recent craniotomy and abdominal trauma. Two of the patients had undergone immunosuppression (immunosuppressed patients); a compromised immune system may facilitate the development of anaerobic meningitis in patients with the appropritate underlying conditions. Head and neck neoplasms, head trauma, suppurative pharyngitis and laminectomy wounds are additional situations in which anaerobic meningitis occurs. Anaerobic bacterial meningitis probably occurs more often than is recognized. The cerebrospinal fluid should be transported and cultured anaerobically when meningitis develops in a patient with a predisposing condition.


Structural-functional characterization of recombinant Apolipoprotein A-I fromLabeo rohitademonstrates heat-resistant antimicrobial activity.
Apolipoprotein A-I is an anti-inflammatory, antioxidative, cardioprotective, anti-tumorigenic, and anti-diabetic in mammals. Apolipoprotein A-I also regulates innate immune defense mechanisms in vertebrates and invertebrates. Apolipoproteins A-I from mammals and several teleosts display antibacterial activities against Gram negative and Gram positive bacteria. The present study describes strategies to obtain high amounts of soluble purified recombinant Apolipoprotein A-I of Labeo rohita, an Indian major carp (rLrApoA-I). The study also reports its detailed structural and functional characterization i.e. antimicrobial activity against a number of important marine and fresh water bacterial pathogens. The rLrApoA-I was expressed in Escherichia coli BL21(DE3) pLysS expression host as a soluble protein under optimized conditions. The yield of purified rLrApoA-I was ~ 75 mg/L from soluble fraction using metal ion affinity chromatography. The authenticity of the rLrApoA-I was confirmed by MALDI-TOF-MS analysis. The secondary structure analysis showed rLrApoA-I to be predominantly alpha helical, an evolutionary conserved characteristic across mammals and teleosts. The purified rLrApoA-I exhibited antimicrobial activity as evident from inhibition of growth of a number of bacteria namely Aeromonas hydrophila, A. liquefaciens, A. culicicola, A. sobria, Vibrio harveyi, V. parahaemolyticus and Edwardsiella tarda in a dose-dependent manner. Minimum bactericidal concentration for A. liquefaciens, A. culicicola, and A. sobria, was determined to be 25 μg/ml or 0.81 μM whereas for A. hydrophila, E. tarda, V. parahaemolyticus and V. harveyi, it was determined to be 100 μg/ml or 3.23 μM. These data strongly suggest that recombinant ApoA-I from Labeo rohita could play a role in primary defense against fish pathogen. Further, at temperature ≥ 55 °C, though a loss in secondary structure was observed, no effect on its antibacterial activity was observed. This is of significance as the antibacterial activity is not likely to be lost even if the protein is subjected to high temperatures during transport.


Phosphorylation negatively regulates exosome mediated secretion of cryAB in glioma cells.
Exosomes mediate secretion of crystallin alphaB (cryAB), a well characterized molecular chaperone with anti-apoptotic activity. However, the mechanisms governing its packaging and secretion remained unexplored. In glioma cells, notwithstanding extensive phosphorylation of cryAB at Ser59 followed by Ser45 (Ser19 is largely unphosphorylated), we discovered that the majority of secreted exosomal cryAB is nonphosphorylated. Transient ectopic expression of a yellow fluorescent protein (YFP) tagged triple phosphomimic (3-SD) cryAB construct in cryAB absent glioma cells led to the formation of large cytosolic inclusions. Our findings demonstrate that mimicking phosphorylation significantly reduces cryAB secretion via exosomes. Moreover, decreased colocalization of 3-SD YFP-cryAB with multivesicular endosome (MVE) and exosome marker, CD63 or Rab27, a small GTPase regulating exocytosis of MVEs, suggests that phosphorylation deters packaging of cryAB in vesicles bound for secretion as exosomes. Additionally, we found that preventing O-GlcNAcylation on cryAB also curtailed its colocalization with CD63 and Rab27 resulting in reduced exosomal secretion. Thus, our study points to O-GlcNAcylation and lack of phosphorylation as being the selective processes involved in the packaging and secretion of cryAB via exosomes.


PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts.
PARP inhibitors niraparib and talazoparib are FDA approved for special cases of breast cancer. PARP is an interesting repair protein which is frequently affected in cancer cells. We studied the combined action of talazoparib or niraparib with ionizing radiation in melanoma cells and healthy fibroblasts. Homologous recombination (HR) status in six different melanoma cell lines and healthy fibroblasts was assessed. Cell cultures were treated with PARP inhibitors talazoparib or niraparib and ionizing radiation (IR). Apoptosis, necrosis and cell cycle distribution was analyzed via flow cytometry. Cell migration was studied by scratch assays. Studied melanoma cell cultures are HR deficient. Studied healthy fibroblasts are HR proficient. Talazoparib and niraparib have congruent effects within the same cell cultures. In all cell cultures, combined treatment increases cell death and G2/M arrest compared to IR. Combined treatment in melanoma cells distinctly increases G2/M arrest. Healthy fibroblasts are less affected by G2/M arrest. Treatment predominantly decelerates or does not modify migration. In two cell cultures migration is enhanced under the inhibitors. Although the two PARP inhibitors talazoparib and niraparib appear to be suitable for a combination treatment with ionizing radiation in our in vitro studies, a combination treatment cannot generally be recommended. There are clear interindividual differences in the effect of the inhibitors on different melanoma cells. Therefore, the effect on the cancer cells should be studied prior to a combination therapy. Since melanoma cells increase more strongly than fibroblasts in G2/M arrest, the fractional application of combined treatment should be further investigated.


The fabrication of nurse--patient relationships.
This paper argues that until about 10 years ago the caring role of the nurse was restricted primarily to the biological functioning of the patient. The more recent concern with communication and patient 'psychology' in the nursing literature suggests that nursing has succeeded, through this analysis, in constituting a new identity for the patient.


Acute cylindrospermopsin exposure: Pulmonary and liver harm and mitigation by dexamethasone.
Cylindrospermopsin (CYN) is a cyanotoxin of increasing worldwide environmental importance as it can harm human beings. Dexamethasone is a steroidal anti-inflammatory agent. Thus, we aimed at evaluating the pulmonary outcomes of acute CYN intoxication and their putative mitigation by dexamethasone. Male BALB/c mice received intratracheally a single dose of saline or CYN (140 μg/kg). Eighteen hours after exposure, mice instilled with either saline solution (Ctrl) or CYN were intramuscularly treated with saline (Tox) or 2 mg/kg dexamethasone (Tox + dexa) every 6 h for 48 h. Pulmonary mechanics was evaluated 66 h after instillation using the forced oscillation technique (flexiVent) to determine airway resistance (RN), tissue viscance (G) and elastance (H). After euthanasia, the lungs were removed and separated for quantification of CYN, myeloperoxidase activity and IL-6 and IL-17 levels plus histological analysis. CYN was also measured in the liver. CYN increased G and H, alveolar collapse, PMN cells infiltration, elastic and collagen fibers, activated macrophages, peroxidase activity in lung and hepatic tissues, as well as IL-6 and IL-17 levels in the lung. Tox + Dexa mice presented total or partial reversion of the aforementioned alterations. Briefly, CYN impaired pulmonary and hepatic characteristics that were mitigated by dexamethasone.


Determination of glycosylated adult and foetal haemoglobins by affinity chromatography.
Estimation of adult glycosylated haemoglobin by affinity chromatography was found to be quick and less dependent on ionic strength, pH and temperature than ion-exchange chromatography. Results obtained by both procedures correlated strongly (r = 0.96) but the range for normal subjects was smaller with the affinity assay. The affinity method correlated equally well with the colorimetric assay (r = 0.95). However, the method did not measure all the glycosylated forms, and only half of the glycosylated species isolated by ion-exchange chromatography was bound to the affinity resin. It also showed that the amount of glycosylated haemoglobin in cord blood is less than in adult blood.


Ultrasonographic Evaluation of Peripheral Nerves.
There are a variety of imaging modalities for evaluation of peripheral nerves. Of these, ultrasonography (US) is often underused. There are several advantages of this imaging modality, including its cost-effectiveness, time-efficient assessment of long segments of peripheral nerves, ability to perform dynamic maneuvers, lack of contraindications, portability, and noninvasiveness. It can provide diagnostic information that cannot be obtained by electrophysiologic or, in some cases, magnetic resonance imaging studies. Ideally, the neurosurgeon can use US as a diagnostic adjunct in the preoperative assessment of a patient with traumatic, neoplastic, infective, or compressive nerve injury. Perhaps its most unique use is in intraoperative surgical planning. In this article, a brief description of normal US nerve anatomy is presented followed by a description of the US appearance of peripheral nerve disease caused by trauma, tumor, infection, and entrapment.


Cerebral function monitoring on a general paediatric ward: feasibility and potential.
Cerebral function monitoring is widely used in neonatal intensive care, but its potential role in assessment of older infants is scarcely reported. We reviewed the use of cerebral function monitoring on a general paediatric ward in a series of young infants admitted with abnormal movements. Review of the amplitude-integrated EEG obtained by cerebral function monitoring revealed electrographic seizures in four of seven infants monitored. We also surveyed general paediatric wards in hospitals in our region of the UK to ask about current use of cerebral function monitoring and local availability of formal electroencephalography services. Cerebral function monitoring was not being used in the 16 other paediatric departments surveyed, and there was very limited provision for obtaining a full-array electroencephalogram out-of-hours. With adequate training and education, it is feasible to undertake cerebral function monitoring on a general paediatric ward. Continuous cerebral function monitoring is a tool that has potential use for detecting clinical seizures and augmenting clinical neuro-observations of young children admitted to a general paediatric ward. • In intensive care settings, cerebral function monitoring (CFM) has long been used for the continuous bedside monitoring of brain function in critically ill neonates, children and adults. • Very few studies have looked at the use of CFM outside of the intensive care setting, and it is presently unclear if CFM is used in the general paediatric ward. What is new: • CFM is presently not widely used in the general paediatric setting. • With appropriate training and support, CFM can be successfully introduced to the general paediatric ward with the potential to enhance the clinical monitoring of young infants admitted with abnormal movements.


A computer-aided diagnosis system for the classification of COVID-19 and non-COVID-19 pneumonia on chest X-ray images by integrating CNN with sparse autoencoder and feed forward neural network.
Several infectious diseases have affected the lives of many people and have caused great dilemmas all over the world. COVID-19 was declared a pandemic caused by a newly discovered virus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by the World Health Organisation in 2019. RT-PCR is considered the golden standard for COVID-19 detection. Due to the limited RT-PCR resources, early diagnosis of the disease has become a challenge. Radiographic images such as Ultrasound, CT scans, X-rays can be used for the detection of the deathly disease. Developing deep learning models using radiographic images for detecting COVID-19 can assist in countering the outbreak of the virus. This paper presents a computer-aided detection model utilizing chest X-ray images for combating the pandemic. Several pre-trained networks and their combinations have been used for developing the model. The method uses features extracted from pre-trained networks along with Sparse autoencoder for dimensionality reduction and a Feed Forward Neural Network (FFNN) for the detection of COVID-19. Two publicly available chest X-ray image datasets, consisting of 504 COVID-19 images and 542 non-COVID-19 images, have been combined to train the model. The method was able to achieve an accuracy of 0.9578 and an AUC of 0.9821, using the combination of InceptionResnetV2 and Xception. Experiments have proved that the accuracy of the model improves with the usage of sparse autoencoder as the dimensionality reduction technique.


Comparison of physical and mental health status between cancer survivors and the general population: a Korean population-based survey (KNHANES II-IV).
To compare the physical and mental health status of the general population with that of cancer survivors in South Korea. We analyzed 19,035 subjects (age ≥40 years), who participated in the 2001-2009 Korea National Health and Nutrition Examination Survey II-IV. We compared metabolic syndrome components, health behaviors, and mental health outcomes between cancer survivors and non-cancer controls. Cancer survivors accounted for 1.68 % (n = 316) of total population. Cancer survivors did not show low occurrence of hypertension and diabetes compared to the control group. Both cancer survivors and the general population had high risks of physical inactivity (75.4 % and 75.5 %, respectively) and inadequate sleep (52.5 % and 60.7 %, respectively). In the unadjusted model, depression was more common in cancer survivors (odds ratio [OR], 1.61; 95 % CI, 1.22-2.74), so was suicidal ideation (OR, 1.51; 95 % CI, 0.16-1.96) than non-cancer controls. After adjustment for attributable socioeconomic factors, the elevated adjusted odds ratios (aORs) among cancer survivors were reduced by 23 % in depression and 45 % in suicidal thought. Cancer survivors at <5 years from diagnosis showed a high occurrence of depression (aOR, 1.77; 95 % CI, 1.09-2.85) while the magnitude of aOR decreases after ≥5 years from cancer diagnosis (aOR, 1.38; 95 % confidence interval, 0.97-1.98, respectively). The physical and mental health of South Korean cancer survivors was not optimal. Their control rates of modifiable risk factors were similar or even lower than those for the non-cancer groups. Depression was highly prevalent in cancer survivors which can be ascribed, at least in part, to socioeconomic environment. A better-targeted intervention to improve the health of this population may be needed.


Novel approaches to retard ventricular remodeling in heart failure.
While the etiologies of congestive heart failure (CHF) are diverse, a common event in the progression of this disease process is LV remodeling, increased wall stress, and subsequent pump dysfunction. Therapeutic approaches for CHF have been focused upon reducing LV afterload through vasodilator therapy, or by blocking/interrupting the effects of neurohormonal stimuli. However, another therapeutic approach would be to directly intervene in the LV remodeling process with CHF. An important determinant in the maintenance of myocyte shape, alignment and transduction of myocyte shortening into an overall ejection is the structural support provided by the fibrillar collagen matrix. As in most tissue remodeling processes, LV myocardial remodeling with CHF is accompanied by changes in the structure and composition of the collagen matrix. Matrix metalloproteinases (MMPs) are an endogenous family of zinc-dependent enzymes which have been identified to be responsible for matrix remodeling and alterations in MMP expression and activity have been identified in clinical and animal models of CHF. Moreover, alterations in the tissue inhibitors of MMPs (TIMPs) have also been identified to occur in the end-stage CHF myocardium. Thus, it is very likely that increased MMP activity and reduced inhibitory control of the TIMPs contribute to the LV remodeling process with CHF. A number of bioactive peptides and cytokines influence MMP and TIMP expression and activity. In addition, pharmacologically active MMP inhibitors have been synthesized and are currently under study. Accordingly, the control of MMP and TIMP expression and activity within the failing myocardium represents a new and potentially significant therapeutic target for CHF.


Practitioner Review: On the trustworthiness of clinical practice guidelines - a systematic review of the quality of methods used to develop guidelines in child and youth mental health.
Numerous practice guidelines (PGs) relevant to child and youth mental health (CYMH) are available, but their quality is uncertain. We used systematic review methodology to identify the methods employed to develop PGs in CYMH and assess whether they align with international quality standards. We used prespecified inclusion criteria to search for CYMH PGs (2009-2014) in journals of professional associations or websites of organizations who produce or house PGs. Eligible PGs and organization websites were screened to identify PG development methods. Two reviewers assessed the alignment of the PG development methods with PG quality criteria using the Appraisal of Guidelines for Research and Evaluation (AGREE II) domains and Institute of Medicine (IOM) standards. Five sets of eligible development methods were identified in 70 eligible PGs. Three sets adhered to all (National Institute for Health and Care Excellence; Scottish Intercollegiate Guidelines Network) or most (U.S. Preventive Services Task Force) AGREE II domains and IOM standards, and were used to develop 31.4% of PGs. The two remaining sets of development methods had important weaknesses (e.g. lack of mandatory rigorous systematic reviews, multidisciplinary development groups, or transparent conflict of interest methods) and were associated with 21.4% of PGs. No development methods could be identified in 40.0% of PGs; ineligible development methods were referenced in 7.1% of PGs. Up to 69% of available CYMH PGs may have been developed using methods that do not align with AGREE II quality criteria or IOM standards. The quality of available CYMH PGs needs to be assessed, and strategies designed to guide practitioners to high quality PGs and facilitate adherence by PG developers to international quality standards are needed.


Rutaecarpine alleviates migraine in nitroglycerin-induced mice by regulating PTEN/PGK1 signaling pathway to activate NRF2 antioxidant system.
Due to its widespread prevalence, migraine is a common neurovascular condition that has a major impact on people's health and quality of life. Rutaecarpine (RUT) is one of the main effective components of Evodia rutaecarpa, which has a wide range of biological activities. However, the exact mechanism by which RUT improves migraine remain unknown. The purpose of this study was to investigate whether RUT improves migraine by inhibiting oxidative stress via activating the Nrf2 antioxidant system through the PTEN/PGK1 signaling pathway. In vivo, a mouse model of chronic migraine (CM) was established by repeated intraperitoneal injection of nitroglycerin (NTG). After treatment with RUT and Sumatriptan, behavioral tests were performed, followed by measurements of oxidative stress-related indicators in the trigeminal nucleus caudalis, expression of proteins associated with the Nrf2 antioxidant system, and the PTEN/PGK1 pathway. In vitro, PC12 cells were stimulated by 100 μM H2O2 for 24 h to induce oxidative stress, which was then treated with RUT. Furthermore, the role of PTEN in antioxidant stress of RUT was elucidated by knockout of the PTEN gene. The results showed that RUT treatment improved NTG-induced migraine in mice by inhibiting oxidative stress. Importantly, RUT inhibited oxidative stress in NTG-induced mice or H2O2-induced PC12 cells via activating the Nrf2 antioxidant system by inhibiting PGK1 activity through PTEN. These results provide evidence that RUT improves migraine by activation of the Nrf2 antioxidant system through the PTEN/PGK1 pathway and provide new insights into the potential use of RUT as an effective drug development candidate for migraine.