Changes in blood glucose level during and after light sedations using propofol-fentanyl and midazolam-fentanyl in diabetic patients who underwent cataract surgery.
Surgeries may trigger the stress response which leads to changes in blood glucose level, and studies suggest that different sedation and anesthesia methods have different effects on blood glucose level. The aim of this study was to investigate changes of blood glucose levels in diabetic patients and compare them in two sedation methods of propofol + fentanyl and midazolam + fentanyl. Totally, 80 diabetic candidates for cataract surgery who had all the inclusion criteria, underwent cataract surgery using two methods of propofol (1 mg/kg/h) + fentanyl (2 μg/kg) (Group P) and midazolam (0.03 mg/kg) + fentanyl (2 μg/kg) (Group M) for light sedation. In the end, 70 patients (Group P n = 35 and Group M n = 35) remained in the study. Patients' blood glucose levels, vital signs, and hemodynamic data were assessed 30 min prior to the surgery, each 15 min during surgery and at the end of surgery. Hemodynamic parameters did not have a statistically significant difference between the two groups mean blood glucose level in Group M was 149.15 mg/dl and in Group P was 149.2 mg/dl, and based on repeated measures analysis of variance test, significant differences were not observed between the two groups (P = 0.99). T-test showed no significant differences in the blood glucose level at any time of the study between the two groups. Light sedation methods of propofol + fentanyl and midazolam + fentanyl did not have any differences in alteration of blood glucose level.


Communities, self-causation and the natural lottery.
This paper examines the various notions of community, and of the 'natural lottery' as well as investigating the role that 'self-causation' plays in communal obligations. In examining community, two opposing views are juxtaposed: (1) the view that community consists merely of persons united by duties of refraining from harm one to another, resulting in autonomy based justice which makes freedom an absolute condition of mortality; and (2) a broader view which sees the concept of community as entailing obligations of beneficence, resulting in beneficence based justice and which, therefore, sees freedom as a value to be cautiously traded with other values. In examining the 'natural lottery' in the light of community, the various consequences of viewing the lottery in various ways and the impact that our view of community has on these consequences, is explored. A third option, the option that the 'natural lottery' as the cause of illness and health is a shaky concept, is offered. Self-causation of illness and its linkage to concepts of community and of the 'natural lottery' is then briefly examined. It is concluded that (1) community implies a social contract which, in order to be conceived in the first place, necessitates more than a minimalist ethic: to come about, a degree of beneficence inspiring trust is presupposed; (2) conceiving community narrowly is neither what we ordinarily do when we think of the term nor, for that matter, workable in our world.(ABSTRACT TRUNCATED AT 250 WORDS)


Tailored novel multifunctional benzyl-functionalized magnetic ionic liquid for rapid and efficient monitoring of trace fluoroquinolones in food samples.
The novel hydrophobic cobalt anion-based benzyl-functionalized magnetic ionic liquid (MIL) was first designed, synthesized, and employed as a multifunctional extractant (for extraction, visual observation, and magnetic separation) for fast dispersive liquid-liquid microextraction of fluoroquinolones (FQs). According to the aromatic structure of FQs, three benzyl-functionalized MILs were customized by introducing various aromatic functional groups (benzyl, paracetyl phenyl, and m-methoxyphenyl) to justify the extraction efficiency and selectivity. In particular, the paracetyl phenyl functionalized MIL showed superior extraction efficiency among others due to its hydrophobicity and strong interactions of hydrogen bonding and π-π stacking. Moreover, under optimal conditions, the limits of detection were as low as 0.47-0.56 μg/L, and the enhancement factors were as high as 88-95. The recoveries were between 90.8 % and 107.8 %, and the relative standard deviation was less than 5.4 %. Ascribed to these outstanding experimental results, the benzyl-functionalized MIL is a potential magnetic extractant for detecting trace FQs in food samples.


A series of 7 cases of patients with narcolepsy with hypocretin deficiency without the HLA DQB1*06:02 allele.
We report data collected from 2 reference European sleep centers on a series of patients with narcolepsy with hypocretin-1 deficiency and absence of the human leukocyte antigens (HLA) DQB1*06:02 allele. Clinical data, HLA DQ markers, and cerebrospinal fluid assessments were collected retrospectively from Caucasian patients with a diagnosis of narcolepsy type 1 with cerebrospinal fluid hypocretin-1 deficiency (< 110 pg/ml) and absence of the HLA DQB1*06:02 allele, with follow-up with at least 1 visit within the last 4 years, consecutively admitted to 2 European sleep centers (Lugano, Switzerland and Montpellier, France). Seven patients (3 of 29 patients in Lugano and 4 of 328 in Montpellier) were diagnosed with narcolepsy with hypocretin-1 deficiency and absence of HLA DQB1*06:02 (ie, 2% of patients with narcolepsy type 1). Regarding the HLA-DQB1 genotyping, 4 cases were positive for HLA DQB1*03:01, 1 for DQB1*03:02, and 3 for DQB1*02:01. Three patients had atypical cataplexy and 1 had no cataplexy. Only 2 patients had both a mean sleep latency of less than 8 minutes and more than 2 sleep onset rapid eye movement periods on the Multiple Sleep Latency Test, indicative of a less severe condition. Although rare, this series of 7 cases confirms that hypocretin-deficient narcolepsy should not be excluded in the absence of HLA DQB1*06:02, especially if patients are carriers of other high-risk HLA-DQB1 alleles (DQB1*03:01, *03:02, *02:01). These data support the hypothesis that narcolepsy type 1 is a wider disease spectrum linked to the loss of hypocretin peptide. Miano S, Barateau L, De Pieri M, et al. A series of 7 cases of patients with narcolepsy with hypocretin deficiency without the HLA DQB1*06:02 allele. J Clin Sleep Med. 2023;19(12):2053-2057.


Deferoxamine ameliorates neurological dysfunction by inhibiting ferroptosis and neuroinflammation after traumatic brain injury.
Traumatic brain injury (TBI) is an important reason of neurological damage and has high morbidity and mortality rates. The secondary damage caused by TBI leads to a poor clinical prognosis. According to the literature, TBI leads to ferrous iron aggregation at the site of trauma and may be a key factor in secondary injury. Deferoxamine (DFO), which is an iron chelator, has been shown to inhibit neuron degeneration; however, the role of DFO in TBI is unclear. The purpose of this study was to explore whether DFO can ameliorate TBI by inhibiting ferroptosis and neuroinflammation. Here, our findings suggest that DFO can reduce the accumulation of iron, lipid peroxides, and reactive oxygen species (ROS) and modulate the expression of ferroptosis-related indicators. Moreover, DFO may reduce NLRP3 activation via the ROS/NF-κB pathway, modulate microglial polarization, reduce neutrophil and macrophage infiltration, and inhibit the release of inflammatory factors after TBI. Additionally, DFO may reduce the activation of neurotoxic responsive astrocytes. Finally, we demonstrated that DFO can protect motor memory function, reduce edema and improve peripheral blood perfusion at the site of trauma in mice with TBI, as shown by behavioral experiments such as the Morris water maze test, cortical blood perfusion assessment and animal MRI. In conclusion, DFO ameliorates TBI by reducing iron accumulation to alleviate ferroptosis and neuroinflammation, and these findings provide a new therapeutic perspective for TBI.


Tocolytic therapy for acute preterm labor.
The pathophysiology leading to preterm labor is not well understood and often multifactorial; initiating factors include intrauterine infection, inflammation, ischemia, overdistension, and hemorrhage. Given these different potential causes, directing therapy for preterm labor has been difficult and suboptimal. To date, no single drug has been identified as successful in treating all of the underlying mechanisms leading to preterm labor. In addition, the methodology of many of the tocolytic studies is limited by lack of sufficient patient numbers, lack of comparison with a placebo, and inconsistent use of glucocorticoids. The limitations in these individual studies make it difficult to evaluate the efficacy of a single tocolytic by meta-analysis. Despite these limitations, the goals for tocolysis for preterm labor are clear: To complete a course of glucocorticoids and secure the appropriate level of neonatal care for the fetus in the event of preterm delivery. The literature demonstrates that many tocolytic agents inhibit uterine contractility. The decision as to which tocolytic agent should be used as first-line therapy for a patient is based on multiple factors, including gestational age, the patient's medical history, common and severe side effects, and a patient's response to therapy. In a patient at less than 32 weeks gestation, indomethacin may be a reasonable first choice based on its efficacy, ease of administration, and minimal side effects. Concurrent administration of magnesium for neuroprotection may be given. At 32 to 34 weeks, nifedipine may be a reasonable first choice because it does not carry the fetal risks of indomethacin at these later gestational ages, is easy to administer, and has limited side effects relative to beta-mimetics. In an effort to review a commonly faced obstetrical complication, this article has provided a summary of the most commonly used tocolytics, their mechanisms of action, side effects, and clinical data regarding their efficacy.


Regioselective synthesis and antimicrobial activities of some novel aryloxyacetic acid derivatives.
Reaction of aryloxyacetic acid hydrazides 1a,b with α-haloketones such as hydrazonoyl chlorides 2a,b; phenacyl bromides 6a,b; and 2-chloro-N-(1,3-thiazol-2-yl)acetamide 10 led to the formation N-(4-halophenyl)-2-[2-(aryloxyacetyl)hydrazinylidene]propanehydrazonoyl chloride 3a-d; (ethene-1,2-diyl)bis-2-(naphthalen-2-yloxy)acetohydrazides 9a,b; and 2-[(2-aryloxyacetyl)hydrazinyl)]-N-(1,3-thiazol-2-yl)acetamides 11a,b; respectively. The nucleophilic substitution reaction of 3a-d with thiophenol and sodium benzenesulfinate furnished the corresponding hydrazinylidenepropanehydrazonothioates 4a-d and sulfones 5a-d, respectively. The antimicrobial activities of the synthesized compounds were evaluated. The obtained data indicated that the majority of the tested compounds exhibited antibacterial activity while all those compounds showed antifungal activity. Sulfone 5d showed greater effect with all tested organism than well known antibacterial and antifungal agents with minimal inhibitory concentration (MIC) ranged between 4.125 and 16.5 μg/mL.


A study of the evaporation of a solvent from a solution--application to writing ink aging.
When writing ink is placed on a substrate, a drying process begins. This process is dependent on the composition of the ink and of the substrate. Lociciro et al. provide an equation that describes the drying process based on models developed by earlier investigators. The work given here develops an equation for the drying process that is based on a different and rather simple model. This model considers the evaporation of a solution in an opened vertical container (e.g., a beaker) and consists of a volatile, non-hygroscopic solvent with a non-volatile solute dissolved in it. Three assumptions are made: (a) the rate of evaporation is proportional to the vapor pressure of the solution and to the solution's exposed surface area, (b) this solution vapor pressure is proportional to the solvent vapor pressure with the proportionality constant being the solvent mole fraction (Raoult's law), and (c) a small fraction of the solvent remains trapped in the solute after evaporation ceases. What results is a differential equation, which, when solved, gives the solvent weight W(t) as an implicit function. What emerges naturally from this treatment is the fact that the function W(t) can have a point of maximum acceleration. Prior to this point the drying process is fast and after this point, the drying process is slow. An approximation to W(t) is taken to be the sum of two exponential functions, one describing the fast drying region and the second describing the subsequent slow drying region. Upon including an additive constant, this approximation turns out to be similar to, but not the same as that provided by Lociciro et al. However, their equivalence is shown and then tested using the two inks examined by Lociciro et al. (the drying of a Bic and a Staedtler blue ballpoint ink). The examples of (solvent+solute) systems ("inks") given here consist of the solvent (2-phenoxyethanol) and a solute such as a dye (crystal violet) or a polymer resin such as synthetic resin SK or polyvinyl butyral. In the case of polymers, the Raoult's law assumption is replaced with one developed by the Flory-Huggins theory of solutions. Saturation and film formation, both of which slow the evaporation rate, are also discussed.


Chronic kidney disease and risk of postoperative cardiovascular events in elderly patients receiving hip fracture surgery.
The long-term risk of cardiovascular events caused by chronic kidney disease (CKD) is well described in the general population. Less is known concerning the risk of postoperative cardiovascular events in geriatric hip fracture patients with CKD. This study involved patients at least 65 years of age who received surgery for acute hip fracture between January 2000 and April 2016. We identified CKD patients with a baseline diagnosis of CKD or an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 at admission. Each CKD patient was matched, for age, gender, fracture type, and year of admission, with 4 control non-CKD patients. The primary endpoint was a compositepostoperative cardiovascular events, including pulmonary embolism, angina pectoris, myocardial infarction, heart failure, arrhythmia, stroke, and death. Conditional logistic regression was used to evaluate the association between CKD and the outcome after adjusting for potential confounders including age, gender, fracture type, body mass index, preexisting comorbidities, history of cardiovascular events, and the Charlson Comorbidity Index (CCI). Three hundred and seventy-five CKD patients were matched with 1,438 non-CKD patients. The mean age of the CKD patients was 81.9 ± 7.0 (mean ± SD), 69.9% were females, and 59.2% had an intertrochanteric fracture. Compared to non-CKD patients, CKD patients had a higher proportion of preexisting comorbidities, including hypertension, coronary heart disease, heart failure, and type 2 diabetes (all p < 0.05). The risk of postoperative cardiovascular events was 125.3 per 1000 persons (95%CI, 91.8-158.8) in CKD patients and 64.7 per 1000 persons (95%CI, 52.0-77.4) in non-CKD patients. A 1.96-fold risk of cardiovascular events after hip fracture surgery was found in CKD patients than those without CKD (adjusted OR, 1.96; 95%CI, 1.23-3.12). Patients with CKD were more likely to have cardiovascular events after hip fracture surgery than those without CKD. Appropriate preoperative cardiovascular risk assessment and corresponding preventive and therapeutic measures should be given to this vulnerable population to mitigate such complications.


Reversal of oliguria and renal cortical ischemia of hemorrhagic shock in the dog with tris (hydroxymethyl) amino methane (THAM). Hemodynamic studies.
We investigated the functional and hemodynamic effects on the kidney of tris (hydroxymethyl) amino methane (THAM) infusion during sustained hemorrhagic hypotension in dogs. The large osmotic load introduced into the vascular compartment during hemorrhagic hypotension resulted in a marked reduction in systemic vascular resistance and a return of cardiac output, total renal blood flow, and the renal arteriographic pattern to normal range. The observed diuresis is probably due to an osmotic effect, because the glomerular filtration rate remains significantly depressed. Anatomical assignment of the mathematical components of the xenon washout curve led to an assessment of intrarenal blood flow distribution that was at variance with the arteriographic pattern and the intrarenal distribution of tagged microspheres.


Posttranslational regulation of coordinated enzyme activities in the Pup-proteasome system.
The proper functioning of any biological system depends on the coordinated activity of its components. Regulation at the genetic level is, in many cases, effective in determining the cellular levels of system components. However, in cases where regulation at the genetic level is insufficient for attaining harmonic system function, posttranslational regulatory mechanisms are often used. Here, we uncover posttranslational regulatory mechanisms in the prokaryotic ubiquitin-like protein (Pup)-proteasome system (PPS), the bacterial equivalent of the eukaryotic ubiquitin-proteasome system. Pup, a ubiquitin analog, is conjugated to proteins through the activities of two enzymes, Dop (deamidase of Pup) and PafA (proteasome accessory factor A), the Pup ligase. As Dop also catalyzes depupylation, it was unclear how PPS function could be maintained without Dop and PafA canceling the activity of the other, and how the two activities of Dop are balanced. We report that tight Pup binding and the limited degree of Dop interaction with high-molecular-weight pupylated proteins results in preferred Pup deamidation over protein depupylation by this enzyme. Under starvation conditions, when accelerated protein pupylation is required, this bias is intensified by depletion of free Dop molecules, thereby minimizing the chance of depupylation. We also find that, in contrast to Dop, PafA presents a distinct preference for high-molecular-weight protein substrates. As such, PafA and Dop act in concert, rather than canceling each other's activity, to generate a high-molecular-weight pupylome. This bias in pupylome molecular weight distribution is consistent with the proposed nutritional role of the PPS under starvation conditions.


An aqueous electrolyte of the widest potential window and its superior capability for capacitors.
A saturated aqueous solution of sodium perchlorate (SSPAS) was found to be electrochemically superior, because the potential window is remarkably wide to be approximately 3.2 V in terms of a cyclic voltammetry. Such a wide potential window has never been reported in any aqueous solutions, and this finding would be of historical significance for aqueous electrolyte to overcome its weak point that the potential window is narrow. In proof of this fact, the capability of SSPAS was examined for the electrolyte of capacitors. Galvanostatic charge-discharge measurements showed that a graphite-based capacitor containing SSPAS as an electrolyte was stable within 5% deviation for the 10,000 times repetition at the operating voltage of 3.2 V without generating any gas. The SSPAS worked also as a functional electrolyte in the presence of an activated carbon and metal oxides in order to increase an energy density. Indeed, in an asymmetric capacitor containing MnO2 and Fe3O4 mixtures in the positive and negative electrodes, respectively, the energy density enlarged to be 36.3 Whkg-1, which belongs to the largest value in capacitors. Similar electrochemical behaviour was also confirmed in saturated aqueous solutions of other alkali and alkaline earth metal perchlorate salts.


Evaluation of the enhanced upper limb therapy programme within the Robot-Assisted Training for the Upper Limb after Stroke trial: descriptive analysis of intervention fidelity, goal selection and goal achievement.
To report the fidelity of the enhanced upper limb therapy programme within the Robot-Assisted Training for the Upper Limb after stroke (RATULS) randomized controlled trial, the types of goals selected and the proportion of goals achieved. Descriptive analysis of data on fidelity, goal selection and achievement from an intervention group within a randomized controlled trial. Out-patient stroke rehabilitation within four UK NHS centres. 259 participants with moderate-severe upper limb activity limitation (Action Research Arm Test 0-39) between one week and five years post first stroke. The enhanced upper limb therapy programme aimed to provide 36 one-hour sessions, including 45 minutes of face-to-face therapy focusing on personal goals, over 12 weeks. 7877/9324 (84%) sessions were attended; a median of 34 [IQR 29-36] per participant. A median of 127 [IQR 70-190] repetitions were achieved per participant per session attended. Based upon the Canadian Occupational Performance Measure, goal categories were: self-care 1449/2664 (54%); productivity 374/2664 (14%); leisure 180/2664 (7%) and 'other' 661/2664 (25%). For the 2051/2664 goals for which data were available, 1287 (51%) were achieved, ranging between 27% by participants more than 12 months post stroke with baseline Action Research Arm Test scores 0-7, and 88% by those less than three months after stroke with scores 8-19. Intervention fidelity was high. Goals relating to self-care were most commonly selected. The proportion of goals achieved varied, depending on time post stroke and baseline arm activity limitation.


Laboratory-based investigation of suspected mumps cases submitted to the German National Reference Centre for Measles, Mumps, and Rubella, 2008 to 2013.
From 2008 to 2013, sample sets from 534 patients displaying clinical symptoms of mumps were submitted to the German Reference Centre for Measles, Mumps and Rubella. Mumps virus infection was confirmed in 216 cases (40%) by PCR and/or serology. Confirmed cases were more frequently seen in male than in female patients (128 vs. 81); the age group predominantly affected was 15 to 29 years old (65%, median age: 26.4 years). The majority of the confirmed cases had a remote history of vaccination with one or two doses of a mumps-containing vaccine (69%). Our results indicate that mumps virus caused two outbreaks in Bavaria in 2008 and 2010/2011 and a third one in Lower Saxony in 2011. Mumps virus genotype G was preponderantly detected from 2008 to 2013. For 107 of the 216 patients with a confirmed mumps infection, we correlated the results from PCR and serology. PCR detected cases during the first week after onset of symptoms (74% positive results). PCR worked best with throat swabs and oral fluids (61% and 60% positive results, respectively). IgM was more reliable with a longer time after onset of symptoms (67%), but indirect IgM serology was of insufficient sensitivity for vaccinated mumps cases (30%); the IgM μ-capture assay detected more cases in this group. Mumps virus is able to initiate an infection in vaccinated patients (secondary vaccine failure, SVF) although it is unclear to what extent. Since SVF does occur in highly vaccinated populations and IgM will not increase to detectable levels in all SVF patients, we strongly recommend using PCR plus serology tests to avoid false-negative diagnoses in vaccinated individuals with clinical signs of mumps.


Identification of tumor-associated MHC class I ligands by a novel T cell-independent approach.
Specific immunotherapy of cancer utilizes tumor-directed cytotoxic T lymphocytes (CTL) that lyse tumor cells presenting MHC class I-associated peptides derived from tumor-associated proteins. Many tumor-associated gene products are known, but corresponding T cell epitopes are only known for relatively few of these. The most commonly used approaches to identify such antigens require pre-existing CTL lines or clones. By using a CTL-independent high performance liquid chromatography mass spectrometry (HPLC MS)-based approach we identified HLA-A2-presented peptides from carcinoembryonic antigen and wild-type p53 with a copy number as low as eight molecules per cell. Potential epitopes were predicted from the sequences of known tumor antigens and the corresponding synthetic peptides were analyzed by nanocapillary HPLC MS. In parallel, peptides were extracted from fresh, solid tumor tissue or tumor cell lines and analyzed in the same way. Upon co-elution of a natural peptide with a predicted peptide of the same mass, the peptide sequence was confirmed by on-line tandem MS. This approach allows rapid screening of large numbers of tumor-associated gene products for naturally processed peptides presented by different MHC class I molecules as a prerequisite for efficient epitope identification and rapid transfer to therapeutic vaccine trials.


Cardioprotective effect of perfluorochemical emulsion for cardiac preservation after six-hour cold storage.
Perfluoro-octyl bromide (PFOB) emulsion is capable of transferring oxygen to tissues even at 4 degrees C, suggesting an application in myocardial preservation. We evaluated the cardioprotective effect of PFOB emulsion added to the storage solution. Guinea pig hearts were isolated (n = 24) and perfused with Krebs-Henseleit solution (KHS) and then cooled and perfused with St. Thomas Hospital II solution (STS). The hearts were stored in three different solutions: STS (STS group), oxygenated (O2) STS (O2 STS group), and O2 STS with PFOB emulsion (30%) (O2 STS + PFOB group) for 6 hours at 4 degrees C. After storage, rewarming was performed, followed by reperfusion with KHS. Left ventricular developed pressure of O2 STS + PFOB group was significantly higher than that of the other groups during reperfusion (p < 0.01). There was no difference among the three groups in O2 extraction and cardiac efficiency; however, cardiac oxygen consumption in the O2 STS + PFOB group significantly improved during reperfusion. In the O2 STS + PFOB group, creatinine kinase, lactate dehydrogenase, and myocardial water content were significantly decreased (p < 0.01). This study suggests that PFOB emulsion is beneficial for the cardioprotection of donor hearts, allowing a prolonged cardiac storage time.


Aerobic glycolysis in the retina of the crab Ocypode ryderi.
Our experiments on the isolated and superfused crab retina reveal that pronounced gradients for PO2 and pH exist in this tissue. The PgO2 profiles and a delayed recovery of the PgO2 after hypoxia seem to be a consequence of the oxygen consumption inside the tissue, as much as both characteristics can be abolished by impairment of electron transport in the respiratory chain after application of antimycin A. The pH profile is obviously created by a production and steady release of lactate, which could be measured in the superfusate. As this lactate release is occurring inspite of a sufficient oxygen supply and consumption, it can be concluded that this tissue performs aerobic glycolysis.


Causal relationships between delirium and Alzheimer's disease: a bidirectional two-sample Mendelian randomization study.
Previous observational studies have reported that delirium has an association with an increased risk of Alzheimer's disease (AD), and that patients with AD have a higher risk of developing delirium. However, due to the limitations of observational study, it is challenging to confirm whether delirium has a causal effect on AD or reverse causation exists. A bidirectional two-sample Mendelian randomization (MR) was performed to investigate the relationship between delirium and AD. Summary statistics from genome-wide association studies of delirium and AD phenotypes were utilized. Inverse-variance weighted (IVW) method was used as the main analysis approach, and additional analyses were performed using MR Egger, weighted median, simple mode and weighted mode to ensure result accuracy. Heterogeneity and horizontal pleiotropy were assessed using Cochran's Q statistics and MR Egger intercept, separately. The MR analyses showed that genetically predicted delirium was not associated with AD (IVW: odds ratio [OR] 0.98, 95% CI 0.91-1.05, P = 0.544; MR Egger: OR 0.98, 95% CI 0.83-1.15, P = 0.780; weighted median: OR 0.96, 95% CI 0.88-1.05, P = 0.323; simple mode: OR 0.91, 95% CI 0.80-1.04, P = 0.212; weighted mode: OR 0.93, 95% CI 0.83-1.05, P = 0.277). However, in the reverse direction, AD was associated with delirium (IVW: OR 1.32, 95% CI 1.13-1.54, P = 3.91E-04; MR Egger: OR 1.42, 95% CI 1.02-1.98, P = 5.60E-02; Weighted median: OR 1.39, 95% CI 1.18-1.63, P = 8.22E-05; Simple mode: OR 1.41, 95% CI 1.10-1.80, P = 1.41E-02; Weighted mode: OR 1.39, 95% CI 1.16-1.67, P = 3.23E-03). Based on the results of our MR study, there is no bidirectional causality between delirium and AD, delirium is not associated with an increased risk of AD, while genetically predicted AD is a potential causal risk factor for delirium.


Positive association of the serotonin 5-HT7 receptor gene with schizophrenia in a Japanese population.
Several lines of evidence suggest that abnormalities in the serotonin system may be related to the pathophysiology of schizophrenia. The 5-HT7 receptor is considered to be a possible schizophrenia-susceptibility factor, based on findings from binding, animal, postmortem, and genomewide linkage studies. In this study, we conducted linkage disequilibrium (LD) mapping of the human 5-HT7 receptor gene (HTR7) and selected four 'haplotype-tagging (ht) SNPs'. Using these four htSNPs, we then conducted an LD case-control association analysis in 383 Japanese schizophrenia patients and 351 controls. Two htSNPs (SNP2 and SNP5) and haplotypes were found to be associated with schizophrenia. A promoter SNP (SNP2) was further assessed in a dual-luciferase reporter assay, but it was not found to have any functional relevance. Although we failed to find an actual susceptibility variant that could modify the function of HTR7, our results support the supposition that HTR7 is a susceptibility gene for schizophrenia in this ethnic group.


Synthesis of carbinoxamine via α-C(sp3)-H 2-pyridylation of O, S or N-containing compounds enabled by non-D-A-type super organoreductants and sulfoxide- or sulfide HAT reagents.
The radical cations of tertiary amines (R3N) have been well-established as the precursors of HAT reagents in photochemical transformations. Similarly, thiols and thioacids bearing SH groups have also been widely applied as HAT reagents. Despite the fact that sulfoxides (R2SO) and sulfides (RSR) also bear lone pairs of electrons, these compounds have been barely reported as HAT reagents in photocatalysis. On the other hand, the α-C-H 4-pyridylation of O or N-containing compounds has been documented, whereas 2-pyridylation remains challenging. However, the antihistamine and anticholinergic agent carbinoxamine is an ether bearing 2-pyridyl, which has not been obtained by the existing α-photoarylation of ether. In this work, we report the discovery of a non-donor-acceptor (D-A) type organic photoreductant CBZ6 and sulfoxide/sulfide synergistically catalyzed general α-C(sp3)-H arylation of ethers, thioethers and amines. By using as low as 1 mol% of CBZ6 as a recyclable organic photoreductant and sulfoxides or sulfides as a new type of HAT reagent, the 2- or 4-pyridylation of O, N, or S-containing compounds has been accomplished. This is the first base-free version of α-C-H 2-/4-pyridylation of O, N, or S-containing compounds. It is the first example of sulfoxides or sulfides working as HAT reagents. It is also the first general method for photocatalytic HAT 2-pyridylation of various ethers, amines or thioethers.


Microbiological aspects of the 1980 national prevalence survey of infections in hospitals.
The records of the 1980 national prevalence survey of infection in hospitals were re-assessed from a microbiological point of view. Of 407 records of Escherichia coli, 71 per cent came from the urinary tract while the commonest source of Staphylococcus aureus was from skin infections. These yielded only 41 per cent of the 303 records. Proteus spp. were recorded 166 times, Pseudomonas spp. 115 times and Klebsiella spp. 101 times. These came mainly from the urinary tract but other sources were important. Streptococcus pneumoniae, Haemophilus influenzae, Mycobacterium tuberculosis and the viruses were associated with community infections while E. coli, Proteus spp., Pseudomonas spp., Klebsiella spp., Str. faecalis and non-aureus staphylococci were associated with hospital-acquired infections. The prevalence of bacteraemia was re-assessed.


The assessment of hypertrophy of nasopharyngeal tonsil by acoustical methods.
The possibilities for using acoustical analysis as a noninvasive measure of the degree of obstruction created by an enlarged pharyngeal tonsil (adenoid) are discussed. The method capitalizes on the relationship which exists between a specific obstruction of the respiratory tract and the resulting respiratory sound. Results indicate that as the adenoid increases in size relative to the size of the nasopharynx, the dominant components of the respiratory sound spectrum shift towards a higher frequency range. Furthermore, the correlation found between the assessments of the obstruction due to various sizes of the adenoid by radiological methods and acoustical analyses supports the theoretical prediction that information on the size of the constriction is carried by the respiratory sound. Therefore, careful analyses of the acoustic patterns in the respiratory sound can assist in identifying constrictions and monitoring the constriction changes in the upper respiratory tract.


Role of intestine in postsurgical complications: involvement of free radicals.
Surgery at any location in the body leads to surgical stress response and alterations in normal body homeostasis. The intestine is extremely sensitive to surgical stress even at remote locations and the gastrointestinal tract plays an important role in the development of postsurgical complications such as sepsis, the systemic immune response syndrome (SIRS), and multiple organ failure syndrome (MOFS). The generation of free radicals and subsequent biochemical alterations at the cellular and subcellular level in the intestine has been suggested to play an important role in this process. These oxidative stress-induced events in the mucosa might act as an initiator of distant organ damage and also facilitate bacterial adherence onto the epithelium and translocation into the systemic circulation. This review attempts to highlight the important role of intestine and oxygen free radicals in initiating post-surgical complications.


Geminicoccus flavidas sp. nov. and Geminicoccus harenae sp. nov., two IAA-producing novel rare bacterial species inhabiting desert biological soil crusts.
Two Gram-staining negative strains (CPCC 101082T and CPCC 101083T) were isolated from biological sandy soil crusts samples collected from Badain Jaran desert, China. Both isolates were heterotrophic phototroph, could produce indole-3-acetic acid. The 16S rRNA gene sequences of these two strains were closely related to the members of the family Geminicoccaceae, showing high similarities with Geminicoccus roseus DSM 18922T (96.9%) and Arboricoccus pini B29T1T (90.1%), respectively. In phylogenetic tree based on 16S rRNA gene sequences, strain CPCC 101082T and CPCC 101083T formed a robust distinct clade with Geminicoccus roseus DSM 18922T within the family Geminicoccaceae, which indicated that these two isolates could be classified into the genus Geminicoccus. The growth of strain CPCC 101082T occurred at 15-42°C and pH 4.0-10.0 (optima at 28-37°C and pH 6.0-8.0). The growth of strain CPCC 101083T occurred at 4-45°C and pH 4.0-10.0 (optima at 25-30°C and pH 6.0-8.0). The major cellular fatty acids of CPCC 101082T and CPCC 101083T contained C18:1 ω7c/C18:1 ω6c, cyclo-C19:0 ω8c, and C16:0. Q-10 was detected as the sole respiratory quinone. Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, an unidentified phospholipid and an unidentified aminolipid were tested in the polar lipids profile. The genomes of the two isolates were characterized as about 5.9 Mbp in size with the G + C content of nearly 68%. The IAA-producing encoding genes were predicated in both genomes. The values of average nucleotide identity were 80.6, 81.2 and 92.4% based on a pairwise comparison of the genomes of strains CPCC 101082T and CPCC 101083T and Geminicoccus roseus DSM 18922T, respectively. On the basis of the genotypic, chemotaxonomic and phenotypic characteristics, the strains CPCC 101082T (=NBRC 113513T = KCTC 62853T) and CPCC 101083T (=NBRC 113514T = KCTC 62854T) are proposed to represent two novel species of the genus Geminicoccus with the names Geminicoccus flavidas sp. nov. and Geminicoccus harenae sp. nov.


Assessment of antibiotic prescribing at different hospitals and primary health care facilities.
In this study, it was aimed to investigate the utilization of antibiotics at various health care facilities. Photocopies of 1250 prescriptions which were containing antibiotics and written out in primary health care facilities (PHCFs), public hospitals (PHs), private hospitals and university hospitals in 10 provinces across Turkey, were evaluated by some drug use indicators. The number of drugs per prescription was 3.23 ± 0.92 and it was highest in PHCFs (3.34 ± 0.84), (p < 0.05). The cost per prescription was 33.3 $, being highest in PHs while being lowest in PHCFs (38.6 $ and 28.2 $ respectively). Antibiotic cost per prescription was 16.7 $ and it was also highest and lowest in PHs and PHCFs respectively (p < 0.05). The most commonly prescribed group of antibiotics was "beta-lactam antibacterials, penicillins" (29.2%) while amoxicillin/clavulanic acid was the most commonly prescribed antibiotic (18.1%). Sixty-one percent of the antibiotics prescribed for acute infections was generics; among facilities being highest in PHCFs (66.5%) and among diagnosis being highest in acute pharyngitis. In general, the duration of antibiotic therapy was approximately 7 days for acute infections. Although much more drugs were prescribed in PHCFs than others, it was found to be in an inverse proportion with both the total cost of prescriptions and the cost of antibiotics. Broad-spectrum antibiotics, beta-lactamase combinations in particular, were considered to be more preferable in all health care facilities is also notable. These results do serve as a guide to achieve the rational use of antibiotics on the basis of health care facilities and indications.


GMP-grade pneumococcal whole-cell vaccine injected subcutaneously protects mice from nasopharyngeal colonization and fatal aspiration-sepsis.
Mucosal immunization with a killed whole-cell pneumococcal vaccine, given with enterotoxin-related adjuvants, has been shown to confer multi-serotype protection against colonization of the nasopharynx and middle ear in mice. However, because novel mucosal immunization strategies may be difficult to implement, here we evaluated subcutaneous injection. Strain RM200 was engineered to be capsule-negative, autolysin-negative, and to express a non-toxic mutant pneumolysoid. Liter-scale and 60-l Good Manufacturing Practice (GMP) cultures were grown in bovine-free soy-based medium, killed with chloroform or beta-propiolactone, and injected into C57Bl/6 mice without or with aluminum adjuvant. The adjuvant Al(OH)(3) strongly increased responses, particularly if pre-treated with phosphate. Protection was found in several tested model infections: nasal colonization with a serotype 6B strain and fatal aspiration-sepsis with strains of serotype 3 and 5. Protection against colonization was mechanistically dependent on the presence of CD4+ T cells at the time of challenge; in contrast, in the type 3 aspiration-sepsis model, CD4+ T cells were not required for protection at the time of challenge, suggesting that antibody alone was sufficient to protect against death in this model. Rabbits receiving sequential intramuscular injections in a pilot toxicity study displayed local reactogenicity at injection sites but no clinical signs. The rabbit antiserum thus produced was active in an in vitro phagocytic killing assay and passively protected mice in the type 3 aspiration-sepsis model. Approval is being sought for human trials of this vaccine.


The utility of endogenous glycochenodeoxycholate-3-sulfate and 4β-hydroxycholesterol to evaluate the hepatic disposition of atorvastatin in rats.
The liver is an important organ for drugs disposition, and thus how to accurately evaluate hepatic clearance is essential for proper drug dosing. However, there are many limitations in drug dosage adjustment based on liver function and pharmacogenomic testing. In this study, we evaluated the ability of endogenous glycochenodeoxycholate-3-sulfate (GCDCA-S) and 4β-hydroxycholesterol (4β-HC) plasma levels to evaluate organic anion-transporting polypeptide (Oatps)-mediated hepatic uptake and Cyp3a-meidated metabolism of atorvastatin (ATV) in rats. The concentration of ATV and its metabolites, 2-OH ATV and 4-OH ATV, was markedly increased after a single injection of rifampicin (RIF), an inhibitor of Oatps. Concurrently, plasma GCDCA-S levels were also elevated. After a single injection of the Cyp3a inhibitor ketoconazole (KTZ), plasma ATV concentrations were significantly increased and 2-OH ATV concentrations were decreased, consistent with the metabolism of ATV by Cyp3a. However, plasma 4β-HC was not affected by KTZ treatment despite it being a Cyp3a metabolite of cholesterol. After repeated oral administration of RIF, plasma concentrations of ATV, 2-OH ATV and 4-OH ATV were markedly increased and the hepatic uptake ratio of ATV and GCDCA-S was decreased. KTZ did not affect plasma concentrations of ATV, 2-OH ATV and 4-OH ATV, but significantly decreased the metabolic ratio of total and 4-OH ATV. However, the plasma level and hepatic metabolism of 4β-HC were not changed by KTZ. The inhibition of hepatic uptake of GCDCA-S by RIF was fully reversed after a 7-d washout of RIF. Plasma concentration and hepatic uptake ratio of GCDCA-S were correlated with the plasma level and hepatic uptake of ATV in rats with ANIT-induced liver injury, respectively. These results demonstrate that plasma GCDCA-S is a sensitive probe for the assessment of Oatps-mediated hepatic uptake of ATV. However, Cyp3a-mediated metabolism of ATV was not predicted by plasma 4β-HC levels in rats.


The impact of financial inclusion on mental health.
This paper examines the impact of financial inclusion on the mental health of heads of household in Nigeria. The study employed data from the 2015/2016 Nigerian General Household Survey (GHS), matched with georeferenced data concerning financial services obtained from the Insight2Impact (i2i) GIS interface. The results indicate that financial inclusion has a strong positive impact on mental health. The study used a robust instrumental variable method, in which a household's distance from the nearest financial institution was used as the instrument for financial inclusion. In addition, it identified the potential channels through which financial inclusion can influence mental health, including: (1) food expenditure; (2) remittances; and (3) risk-coping mechanisms. The findings of this study reinforce growing evidence for the benefits of financial inclusion for alleviating depression symptoms.


Effects of grain refinement on the biocorrosion and in vitro bioactivity of magnesium.
Magnesium is a new class of biodegradable metals potentially suitable for bone fracture fixation due to its suitable mechanical properties, high degradability and biocompatibility. However, rapid corrosion and loss in mechanical strength under physiological conditions render it unsuitable for load-bearing applications. In the present study, grain refinement was implemented to control bio-corrosion demonstrating improved in vitro bioactivity of magnesium. Pure commercial magnesium was grain refined using different amounts of zirconium (0.25 and 1.0 wt.%). Corrosion behavior was studied by potentiodynamic polarization (PDP) and mass loss immersion tests demonstrating corrosion rate decrease with grain size reduction. In vitro biocompatibility tests conducted by MC3T3-E1 pre-osteoblast cells and measured by DNA quantification demonstrate significant increase in cell proliferation for Mg-1 wt.% Zr at day 5. Similarly, alkaline phosphatase (ALP) activity was higher for grain refined Mg. Alloys were also tested for ability to support osteoclast differentiation using RAW264.7 monocytes with receptor activator of nuclear factor kappa-β ligand (RANKL) supplemented cell culture. Osteoclast differentiation process was observed to be severely restricted for smaller grained Mg. Overall, the results indicate grain refinement to be useful not only for improving corrosion resistance of Mg implants for bone fixation devices but also potentially modulate bone regeneration around the implant.


Response surface methodology based on central composite design as a chemometric tool for optimization of dispersive-solidification liquid-liquid microextraction for speciation of inorganic arsenic in environmental water samples.
Dispersive-solidification liquid-liquid microextraction (DSLLME) coupled with electrothermal atomic absorption spectrometry (ETAAS) was developed for preconcentration and determination of inorganic arsenic (III, V) in water samples. At pH=1, As(III) formed complex with ammonium pyrrolidine dithiocarbamate (APDC) and extracted into the fine droplets of 1-dodecanol (extraction solvent) which were dispersed with ethanol (disperser solvent) into the water sample solution. After extraction, the organic phase was separated by centrifugation, and was solidified by transferring into an ice bath. The solidified solvent was transferred to a conical vial and melted quickly at room temperature. As(III) was determined in the melted organic phase while As(V) remained in the aqueous layer. Total inorganic As was determined after the reduction of the pentavalent forms of arsenic with sodium thiosulphate and potassium iodide. As(V) was calculated by difference between the concentration of total inorganic As and As(III). The variable of interest in the DSLLME method, such as the volume of extraction solvent and disperser solvent, pH, concentration of APDC (chelating agent), extraction time and salt effect, was optimized with the aid of chemometric approaches. First, in screening experiments, fractional factorial design (FFD) was used for selecting the variables which significantly affected the extraction procedure. Afterwards, the significant variables were optimized using response surface methodology (RSM) based on central composite design (CCD). In the optimum conditions, the proposed method has been successfully applied to the determination of inorganic arsenic in different environmental water samples and certified reference material (NIST RSM 1643e).


Rechargeable Aqueous Mn-Metal Battery Enabled by Inorganic-Organic Interfaces.
Aqueous batteries that use metal anodes exhibit maximum anodic capacity, whereas the energy density is still unsatisfactory partially due to the high redox potential of the metal anode. Current metal anodes are plagued by the dilemma that the redox potential of Zn is not low enough, whereas Al, Mg, and others with excessively low redox potential cannot work properly in aqueous electrolytes. Mn metal with a suitably low redox potential is a promising candidate, which was rarely explored before. Here, we report a rechargeable aqueous Mn-metal battery enabled by a well-designed electrolyte and robust inorganic-organic interfaces. The inorganic Sn-based interface with a bottom-up microstructure was constructed to preliminarily suppress water decomposition. With this bubble-free interface, the organic interface can be formed via an esterification reaction of sucrose triggered by acyl chloride in the electrolyte, generating a dense physical shield that isolates water while permitting Mn2+ diffusion. Hence, a Mn symmetric cell achieves a superior plating/stripping stability for 200 hours, and a Mn||V2 O5 battery maintains approximately 100 % capacity after 200 cycles. Moreover, the Mn||V2 O5 battery realizes a much higher output voltage than that of the Zn||V2 O5 battery, evidencing the possibility of increasing the energy density through using a Mn anode. This work develops a systematic strategy to stabilize a Mn-metal anode for Mn-metal batteries, opening a new door towards enhanced voltage of aqueous batteries.


The humoral immune response and protective efficacy of vaccination with inactivated split and whole influenza virus vaccines in BALB/c mice.
Recently the urgency of developing a pandemic influenza vaccine has lead to the re-evaluation of the use of whole virus vaccine. We have compared the humoral immune response and the protective efficacy of whole and split influenza virus vaccines in mice. Whole virus vaccine was more immunogenic particularly after the first dose of vaccine, generally eliciting higher numbers of systemic antibody secreting cells and an earlier and higher neutralising antibody response. Immunisation with one dose of whole virus vaccine more effectively reduced viral shedding upon non-lethal homologous viral challenge, but two doses of split virus vaccine was most effective at limiting viral replication and this was correlated with high influenza specific serum IgG concentrations. The two vaccine formulations induced different T helper profiles particularly after one dose of vaccine; split virus vaccine induced a type 2 bias response, whereas whole virus vaccine elicited a dominant type 1 response.


Opiate dependence induces cell type-specific plasticity of intrinsic membrane properties in the rat juxtacapsular bed nucleus of stria terminalis (jcBNST).
Drugs of abuse can alter circuit dynamics by modifying synaptic efficacy and/or the intrinsic membrane properties of neurons. The juxtacapsular subdivision of the bed nucleus of stria terminalis (jcBNST) has unique connectivity that positions it to integrate cortical and amygdala inputs and provide feed-forward inhibition to the central nucleus of the amygdala (CeA), among other regions. In this study, we investigated changes in the synaptic and intrinsic properties of neurons in the rat jcBNST during protracted withdrawal from morphine dependence using a combination of conventional electrophysiological methods and the dynamic clamp technique. A history of opiate dependence induced a form of cell type-specific plasticity characterized by reduced inward rectification associated with more depolarized resting membrane potentials and increased membrane resistance. This cell type also showed a lower rheobase when stimulated with direct current (DC) pulses as well as a decreased firing threshold under simulated synaptic bombardment with the dynamic clamp. Morphine dependence also decreased excitatory postsynaptic potential amplification, suggesting the downregulation of the persistent Na+ current (I NaP). These findings show that a history of morphine dependence leads to persistent cell type-specific plasticity of the passive membrane properties of a jcBNST neuronal population, leading to an overall increased excitability of such neurons. By altering the activity of extended amygdala circuits where they are embedded, changes in the integration properties of jcBNST neurons may contribute to emotional dysregulation associated with drug dependence and withdrawal.


Enantioselective nucleophilic difluoromethylation of aromatic aldehydes with Me3SiCF2SO2Ph and PhSO2CF2H reagents catalyzed by chiral quaternary ammonium salts.
Although the nucleophilic difluoromethylation of aldehydes, ketones, and imines has been realized with PhSO(2)CF(2)H and related reagents, there are still no reports on the enantioselective nucleophilic reactions. With a chiral quaternary ammonium salt as the catalyst and KOH as the base, we describe the first enantioselective difluoromethylation of aromatic aldehydes with PhSO(2)CF(2)H or Me(3)SiCF(2)SO(2)Ph. The enantioselectivity is substrate-dependent and for 2-chlorinated benzaldehyde an ee up to 64% was obtained. These results provide some insights into the enantioselective nucleophilic difluoromethylation chemistry, which will stimulate further progress in this field.


Magnetic particle-linked anti hCG β antibody for immunoassay of human chorionic gonadotropin (hCG), potential application to early pregnancy diagnosis.
The objective of this study was to develop a magnetic particle-linked monoclonal antibody to hCG β for immunosorbent assay of human chorionic gonadotropin (hCG) with improved detection sensitivity. Monoclonal antibody against hCG β was found to be optimally cross-linked to the superparamagnetic particles (SPIO) using EDC and NHS as cross-linking reagents. This superparamagnetic particle-linked monoclonal antibody was able to concentrate hCG from a tested solution for further ELISA assay using horse radish peroxidase-labeled monoclonal antibody against hCG β. This hybrid technique had greatly decreased the detection limit to 0.1 mIU/mL, making an early detection of pregnancy possible. With an improved sensitivity and simple operation, the magnetic particle-linked anti hCG β antibody for immunoassay of human chorionic gonadotropin (hCG) has a great potential to supersede the traditional ELISA for pregnancy diagnosis.


Label Structured Cell Proliferation Models.
We present a general class of cell population models that can be used to track the proliferation of cells which have been labeled with a fluorescent dye. The mathematical models employ fluorescence intensity as a structure variable to describe the evolution in time of the population density of proliferating cells. While cell division is a major component of changes in cellular fluorescence intensity, models developed here also address overall label degradation.


Campylobacter infections. First reports from Red Cross War Memorial Children's Hospital, Cape Town.
We report 10 cases of Campylobacter fetus infection, isolated during a 7-month period, which were all sensitive to erythromycin. The aetiology and epidemiology are discussed.


Building Blocks and COFs Formed in Concert-Three-Component Synthesis of Pyrene-Fused Azaacene Covalent Organic Framework in the Bulk and as Films.
A three-component synthesis methodology is described for the formation of covalent organic frameworks (COFs) containing extended aromatics. Notably, this approach enables synthesis of the building blocks and COF along parallel reaction landscapes, on a similar timeframe. The use of fragmental building block components, namely pyrene dione diboronic acid as aggregation-inducing COF precursor and the diamines o-phenylenediamine (Ph), 2,3-diaminonaphthalene (Naph), or (1R,2R)-(+)-1,2-diphenylethylenediamine (2Ph) as extending functionalization units in conjunction with 2,3,6,7,10,11-hexahydroxytriphenylene, resulted in the formation of the corresponding pyrene-fused azaacene, i.e., Aza-COF series with full conversion of the dione moiety, long-range order, and high surface area. In addition, the novel three-component synthesis was successfully applied to produce highly crystalline, oriented thin films of the Aza-COFs with nanostructured surfaces on various substrates. The Aza-COFs exhibit light absorption maxima in the blue spectral region, and each Aza-COF presents a distinct photoluminescence profile. Transient absorption measurements of Aza-Ph- and Aza-Naph-COFs suggest ultrafast relaxation dynamics of excited-states within these COFs.


Clinical Features and Survival of Single Hormone Receptor-Positive Breast Cancer: A Population-Based Study of 531,605 Patients.
To investigate the prognosis of single hormone receptor-positive (HR+) breast cancer (estrogen receptor [ER] positive and progesterone receptor [PR] negative, and ER-PR+) compared to double HR+ (ER+PR+) and double HR- (ER-PR-) tumors. We included 531,605 cases of invasive breast cancer between 1990 and 2012 from the US Surveillance, Epidemiology, and End Results (SEER) database for study and classified cases into 4 phenotypes according to expression of ER and PR: ER+PR+, ER+PR-, ER-PR+, and ER-PR-. Overall, 66,091 ER+PR- tumors and 9320 ER-PR+ tumors were identified. The clinical characteristics of the ER+PR- group were similar to those of the double HR+ group, while those of the ER-PR+ and double HR- groups were similar. Overall survival of patients with single HR+ tumors was intermediate between that of double HR+ and double HR- tumors. However, we observed no differences in disease-specific survival between ER-PR+ and ER-PR- patients. In multivariate analysis, outcomes were similar. Relative to the double HR+ patient group, risk of death in the ER+PR- group was higher (hazard ratio, 1.422, 95% confidence interval, 1.394-1.452). However, risk of death was comparable between ER-PR+ and ER-PR- patients (hazard ratio, 1.03; 95% confidence interval, 0.98-1.08). Multivariate Cox proportional analysis showed that survival times of patients in the younger age bracket (< 60 years), those positive for human epidermal growth factor receptor 2 (HER2), and patients with tumor stage I-III were longer in the ER-PR+ group. Disease-specific survival of single HR+ tumor cases was longer than that of double HR- tumors but poorer than double HR+ tumors. However, differences in disease-specific survival were not significant between the ER-PR+ and ER-PR- groups.


Paget's disease of the vulva: a clinicopathologic institutional review.
The aim of this study was to assess the clinicopathologic characteristics of patients with Paget's disease of the vulva who were treated by our gynecologic oncology service between 1985 and 2010. Vulvar Paget's disease patient demographics, pathologic diagnosis, treatment and follow-up data were reviewed over a 25-year period. The vulvar Paget's disease patients were primarily (62.5%) treated with a partial simple vulvectomy. Three patients had a history of malignancy, although none of them was intercurrent. Eleven patients had microscopically positive margins, 5 of whom developed progressive disease. Conversely, 5 patients had negative margins, of whom 4 had recurrent disease. There was a significant relationship between the presence of invasive disease and patient progression-free interval (PFI) (p = 0.007), but margin status and lesion size did not correlate with PFI (p > 0.05). Median patient PFI and follow-up was 30 and 53 months, respectively. We found a significant relationship between the presence of invasive disease and patient PFI in vulvar Paget's disease although the presence of microscopic positive margins and lesion size were not prognostic indicators. In patients with high risk factors, prolonged surveillance should be considered an essential component of optimal patient management.


Synovial reaction caused by adjacent malignant tumors: anatomicopathological study of three cases.
Three patients are described, each having a malignant bone tumor associated with inflammatory episodes in the adjacent joint. Two of these were sarcomas of the lower end of the femur, and one a metastatic carcinoma in the distal end of the radius. Histologically, the synovium exhibited moderate and non-specific signs of inflammation near the malignant tissue. These cases illustrate the possibility of diagnostic error, either clinically or on microscopic examination of small specimens, especially in punch biopsies.


Identification of milRNAs and their target genes in Ganoderma lucidum by high-throughput sequencing and degradome analysis.
MicroRNAs (miRNAs in animals and plants or milRNAs in fungi) are endogenous noncoding RNAs that can regulate gene expression. However, little information is known about milRNAs and their target genes in Ganoderma lucidum. Here, we systematically predicted and characterised the milRNAs and their target genes across the three developmental stages of G. lucidum. A total of 168 unique milRNAs were predicted using a small RNA sequencing method. For them, 1612 target sequences corresponding to 1311 unique genes were predicted by degradome sequencing. We selected 42 predicted milRNAs and performed RT-PCR amplification and Sanger sequencing of the products. Five products were found to have sequences similar to those predicted, confirming the presence of milRNAs in G. lucidum, and demonstrating the difficulty in their validation. Among the 168 milRNAs, 111 were found to be significantly differentially expressed across the three developmental stages (q ≤ 0.05). The expression levels of 12 milRNAs were measured by stem-loop quantitative real-time polymerase chain reaction. Eight of them were in line with the sequencing results (r ≥ 0.9, p ≤ 0.05). These 12 milRNAs and their target genes form 16 milRNA-target gene pairs. The expression profiles of 8 of these 16 miRNA-target pairs were negatively correlated, according to real-time quantitative analysis, whereas the other eight pairs were positively correlated. Furthermore, the results of functional enrichment analysis showed that the target genes of milRNAs mapped to the Gene Ontology terms 'GTP binding' and 'FAD binding' were enriched in specific developmental stages. These target genes were related to the biosynthesis of triterpenes and polysaccharides and lignin degradation pathway in G. lucidum. In summary, this study indicates that milRNAs may play crucial regulatory roles in various biological processes of G. lucidum and open up new avenues for research on milRNAs' biosyntheses and functions in basidiomycetes.


Activation of the human complement cascade by bacterial cell walls, peptidoglycans, water-soluble peptidoglycan components, and synthetic muramylpeptides--studies on active components and structural requirements.
Cell walls isolated from 29 strains of 24 gram-positive bacterial species, whose peptidoglycans belong to the group A type of Schleifer and Kandler's classification, with one exception (Arthrobacter sp.), were shown to activate the complement cascade in pooled fresh human serum mainly through the alternative pathway and partly through the classical one. The complement-activating effect of cell walls (5 species) possessing group B type peptidoglycan, except those of Corynebacterium insidiosum, was weaker than that of the walls with group A type peptidoglycan. Preparations of peptidoglycan isolated from cell walls of Staphylococcus aureus, Streptococcus pyogenes, and Lactobacillus plantarum also activated the alternative pathway of the complement cascade, but less effectively than the respective parent cell walls. A water-soluble "polymer" of peptidoglycan subunits (SEPS), which was prepared from Staphylococcus epidermidis peptidoglycans by treatment with a cross-bridge degrading endopeptidase, retained most of the complement-activating ability of the parent cell walls. A peptidoglycan "monomer," SEPS-M, which was obtained by hydrolysis of the glycan chain of SEPS with endo-N-acetylmuramidase to disaccharide units did not activate complement. In conformity with this finding, neither synthetic N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) nor MDP-L-Lys-D-Ala activated the complement cascade. Among several lipophilic derivatives of MDP, 6-O-(3-hydroxy-3-docosylhexacosanoyl)-MDP-L-Lys-D-Ala (BH48-MDP-L-Lys-D-Ala) and 6-O-(2-tetradecylhexadecanoyl)-MDP (B30-MDP) were shown to activate complement through the alternative as well as the classical pathway and exclusively through the classical pathway, respectively. The finding that a D-isoasparagine analog of B30-MDP caused the same effect as the parent molecule strongly suggests that the activation of complement by B30-MDP is different from that caused by cell wall peptidoglycans and a water-soluble "polymer" of peptidoglycan subunits.


X-ray microanalytical histochemistry of human circumpulpar and mantle dentine.
An X-ray microanalytical histochemistry study was carried out, on thick sections observed under scanning electron microscopy, of five freshly extracted human premolars and five molars. In particular the circumpulpar and mantle dentine were examined to determine levels of calcium, phosphorus and sulphur, the basic elements involved in the process of biomineralization. Semiquantitative analysis was subsequently performed after the appropriate ZAF (Z, atomic number; A, absorption; F, secondary fluorescence) correction. Ca/P mass ratio was found to be similar for both regions in molars and slightly higher in circumpulpar dentine in premolars implying that this parameter is independent of the processes of biomineralization in the two dentinal regions. In contrast, statistically significant differences were recorded in sulphur content upon comparing mantle and circumpulpar dentine between premolars and molars (P less than 0.02). If sulphur, which has been associated with sulphated glycosaminoglycans (GAGs) decreases as mineralization progresses it would therefore seem reasonable to posit sulphur-rich areas in both topographical regions of the matrix--more significant in premolars than molars--able to undergo subsequent mineralization if required. The possible application of these findings in remineralization therapies is suggested.


Inspiraling streams of enriched gas observed around a massive galaxy 11 billion years ago.
Stars form in galaxies, from gas that has been accreted from the intergalactic medium. Simulations have shown that recycling of gas-the reaccretion of gas that was previously ejected from a galaxy-could sustain star formation in the early Universe. We observe the gas surrounding a massive galaxy at redshift 2.3 and detect emission lines from neutral hydrogen, helium, and ionized carbon that extend 100 kiloparsecs from the galaxy. The kinematics of this circumgalactic gas is consistent with an inspiraling stream. The carbon abundance indicates that the gas had already been enriched with elements heavier than helium, previously ejected from a galaxy. We interpret the results as evidence of gas recycling during high-redshift galaxy assembly.


Explaining historical change in terms of LHT: A pluralistic causal framework is needed.
Baumard suggests that the advent, through phenotypic plasticity mechanisms, of future-oriented preferences and creative mindsets in eighteenth-century Great Britain explains the wave of innovations that drove the British Industrial Revolution. We argue that, although this approach is promising, Baumard's model would benefit from being supplemented by demographic, economic, and sociological explanations independent of Life History Theory (LHT).


Air pollution involving nitrogen dioxide exposure and wheezing bronchitis in children.
A population-based case-control study was performed in Stockholm to assess the influence of air pollution on the occurrence of severe wheezing bronchitis in children. The study included 197 children aged 4 months to 4 years, who were hospitalized because of breathing difficulties with wheezing, and 350 population controls. Information on potential risk factors for childhood wheezing and a residential history was obtained at home interview with parents. Outdoor nitrogen dioxide (NO2) concentrations at home addresses and day care centres from birth on were estimated from validated models, mainly using data on traffic intensity from municipal registers. The risk of wheezing bronchitis was related to time-weighted mean outdoor NO2 exposure in girls (P = 0.02), but not in boys. A gas stove in the home appeared to be a risk factor primarily for girls. All analyses controlled for parental asthma and maternal smoking, which were independent risk factors for wheezing bronchitis. The results suggest that exposure to combustion products containing NO2 may be of particular importance for the development of wheezing bronchitis in girls.


Integrated imaging of systemic Langerhans cell histiocytosis in an infant.
Langerhans cell histiocytosis (LCH) is a myeloid neoplasm characterized by a clonal proliferation of CD1a+/CD207+ dendritic cells. Although individuals of any age can be affected, the disease is most common in infants younger than 5 years of age, especially males. A wide range of manifestations, from asymptomatic to aggressive, have been described, along with multiorgan involvement. Even though the majority of bone lesions are observed, skin, lymph nodes, brain and lungs can also be involved. The involvement of hematopoietic system, including bone marrow, liver and spleen, is less frequent yet associated with worse prognosis, due to a worse treatment response. Diagnosis of LCH is based on the integration of clinical, laboratory, and radiological data; however, only histopathological examination might confirm it. As far as the spleen involvement is concerned, according to literature, it has been reported in about 15% patients with multisystem involvement, nonetheless only a few cases show parenchymal lesions. The present study reports the case of an infant with LCH with multisystem involvement, including bone, skin, liver, and spleen, with evidence of parenchymal lesions.


Variations in Head and Neck Treatment Plan Quality Assessment Among Radiation Oncologists and Medical Physicists in a Single Radiotherapy Department.
Agreement between planners and treating radiation oncologists (ROs) on plan quality criteria is essential for consistent planning. Differences between ROs and planning medical physicists (MPs) in perceived quality of head and neck cancer plans were assessed. Five ROs and four MPs scored 65 plans for in total 15 patients. For each patient, the clinical (CLIN) plan and two or four alternative plans, generated with automated multi-criteria optimization (MCO), were included. There was always one MCO plan aiming at maximally adhering to clinical plan requirements, while the other MCO plans had a lower aimed quality. Scores were given as follows: 1-7 and 1-2, not acceptable; 3-5, acceptable if further planning would not resolve perceived weaknesses; and 6-7, straightway acceptable. One MP and one RO repeated plan scoring for intra-observer variation assessment. For the 36 unique observer pairs, the median percentage of plans for which the two observers agreed on a plan score (100% = 65 plans) was 27.7% [6.2, 40.0]. In the repeat scoring, agreements between first and second scoring were 52.3% and 40.0%, respectively. With a binary division between unacceptable (scores 1 and 2) and acceptable (3-7) plans, the median inter-observer agreement percentage was 78.5% [63.1, 86.2], while intra-observer agreements were 96.9% and 86.2%. There were no differences in observed agreements between RO-RO, MP-MP, and RO-MP pairs. Agreements for the highest-quality, automatically generated MCO plans were higher than for the CLIN plans. Inter-observer differences in plan quality scores were substantial and could result in inconsistencies in generated treatment plans. Agreements among ROs were not better than between ROs and MPs, despite large differences in training and clinical role. High-quality automatically generated plans showed the best score agreements.


The electrophysiological characteristics of accessory pathways in pediatric patients with intermittent preexcitation.
Accessory pathways (APs) with intermittent preexcitation (IPX) are thought to be of lower risk, but there are reports of IPX patients presenting with rapidly conducted atrial fibrillation. Retrospective study performed on patients with preexcitation who underwent an electro-physiological study (EPS). IPX was defined as loss of the delta wave on electrocardiogram prior to EPS. Patients with IPX were compared with those with persistent preexcitation (PPX) or suppression of the delta wave on exercise test (IPX-ET). Congenital heart disease and prior ablations were excluded. Of 328 patients with preexcitation, 41 (12.5%) had IPX. Patients with IPX or PPX were similar in age (12.9 years vs 13.0 years, P = 0.8) and AP location (left-sided 54% vs 50%, P = 0.7; septal 32% vs 35%, P = 0.4). Testing on isoproterenol was performed in 17 (41%) IPX and 41 (14%) PPX patients. Although IPX patients had a longer median refractory period compared to PPX patients (340 ms vs 310 ms, P = 0.001), the incidence of APs with refractory periods ≤250 ms was similar (10% vs 12%, P = 1.0). Exercise tests were performed on 208 patients and 24 (12%) had IPX-ET. Compared with IPX patients, IPX-ET had similar median AP refractory periods (320 ms, P = 0.4) and incidence of APs with refractory periods ≤250 ms (13%, P = 1.0). Patients with IPX had longer AP refractory periods than those with PPX, but the incidence of pathways with refractory periods ≤250 ms was not significantly different. The finding of IPX on a baseline electrocardiogram does not rule out potentially high-risk pathways.


Cell-surface antigenic modifications with trinitrophenyl sulfonate versus trifluoromethyl-dinitrophenyl sulfonate.
The aim of the work was to justify the use of trifluoromethyl-dinitrobenzene sulfonate (CF3-DNBS) modification rather than trinitrobenzene-sulfonate (TNBS) modification, so as to be able to take advantage of the presence of fluorine atoms in the analogue, which allow the analysis of the hapten-carrier bonds by 19F-NMR nuclear magnetic resonance. Cell-surface antigenic modifications brought about by exposure to TNBS or CF3-DNBS were found to be immunologically cross-reactive, both in cell-mediated lymphocytotoxicity and in indirect immunofluorescence. The extent of haptenic derivatizations was found to be of the same order of magnitude, as appraised both by quantitative-absorption studies or by using radioactive hapten, provided that the less chemically reactive CF3-DNBS was used at the concentration of 10 mM and TNBS at the concentration of 1 mM. However, only TNBS-modified cells were sensitive to destruction by antibody-plus-complement-mediated cytotoxicity.


Low-temperature stopped-flow rapid-scanning spectroscopy: performance tests and use of aqueous salt cryosolvents.
An ultimate goal of enzymology is to determine the structure of intermediates in catalysis in solution. Metalloenzymes provide a unique opportunity in this regard because the metal atom is critical to catalysis. In the case of zinc enzymes, replacement of the zinc by the chromophoric cobalt atom can result in the identification of intermediates in catalysis. This is most easily accomplished by examining the enzyme-catalyzed reaction under rapid-mixing and rapid-scanning subzero conditions. Aqueous salt solutions are particularly useful as cryosolvents whenever hydrophobic forces are important for substrate binding. Rapid-freeze or chemical quenching of these metallointermediates can allow further structural characterization by such approaches as EPR spectroscopy and X-ray absorption fine structure. Such a combination of approaches can bridge the information gained by examining only the structure of the enzyme in the crystalline state by X-ray diffraction and that obtained by examining only steady-state enzymatic activities.


Insect thin films as sun blocks, not solar collectors.
We measured the visible reflectance spectra of whole wing sections from three species of iridescent butterflies and moths, for normal incidence, integrated over all reflected angles. In this manner, we separated the optics of the thin films causing the iridescence from the optics of the rest of the scale. We found that iridescence reduces solar absorption by the wing in all cases, typically by approximately 20% or less, in contrast to claims by Miaoulis and Heilman [Ann. Entomol. Soc. Am. 91, 122 (1998)] that the thin-film structures that produce iridescence act as solar collectors.


Characterisation of gamma-interferon responsive promoters in fish.
Reporter constructs of three interferon (IFN)-gamma-induced rainbow trout genes were generated to examine specificity to type I or type II IFN. Constructs included gammaIP-10, LMP2 and TAP2 and were used to transfect trout fibroblast cells (RTG-2) which were then exposed to rainbow trout rIFNs. The gammaIP-10 construct showed high reporter activity even in the absence of rIFNs. The LMP2 promoter contained one GAS element and two double ISRE elements, of four constructs made, only those with ISRE elements showed significant reporter activity following rIFN-gamma stimulation. The TAP2 regulatory region contained two GAS, two ISRE and one C/EBP element from which four constructs were made. Reporter expression for the construct containing all five elements showed an 11- and 2-fold increase in response to rIFN-gamma and type I rIFN, respectively. Constructs containing only the GAS elements did not respond to rIFNs. The TAP2 construct with two ISRE and the C/EBP gave the greatest dose-dependent reporter response to rIFN-gamma, with no significant response to type I rIFN. These data suggest that the ISRE elements, or elements nearby, are essential for the induction of type II IFN responsive genes in trout. The TAP2 construct is a candidate to develop a IFN-gamma reporter stable cell line.


Deep-reinforcement-learning-based water diversion strategy.
Water diversion is a common strategy to enhance water quality in eutrophic lakes by increasing available water resources and accelerating nutrient circulation. Its effectiveness depends on changes in the source water and lake conditions. However, the challenge of optimizing water diversion remains because it is difficult to simultaneously improve lake water quality and minimize the amount of diverted water. Here, we propose a new approach called dynamic water diversion optimization (DWDO), which combines a comprehensive water quality model with a deep reinforcement learning algorithm. We applied DWDO to a region of Lake Dianchi, the largest eutrophic freshwater lake in China and validated it. Our results demonstrate that DWDO significantly reduced total nitrogen and total phosphorus concentrations in the lake by 7% and 6%, respectively, compared to previous operations. Additionally, annual water diversion decreased by an impressive 75%. Through interpretable machine learning, we identified the impact of meteorological indicators and the water quality of both the source water and the lake on optimal water diversion. We found that a single input variable could either increase or decrease water diversion, depending on its specific value, while multiple factors collectively influenced real-time adjustment of water diversion. Moreover, using well-designed hyperparameters, DWDO proved robust under different uncertainties in model parameters. The training time of the model is theoretically shorter than traditional simulation-optimization algorithms, highlighting its potential to support more effective decision-making in water quality management.


Determination of glyoxal and methylglyoxal in atmospheric fine particulate matter by vortex-assisted micro-solid phase extraction and liquid chromatography-diode array detection.
Determination of α-dicarbonyl compounds, glyoxal (Gly) and methyl glyoxal (Mgly), in atmospheric fine particulate matter PM2.5 (particulate matter with an aerodynamic diameter of less than 2.5 μm) which play vital roles in generating secondary organic aerosols in the ambient air, was carried out by vortex-assisted micro-solid phase extraction (VA-μ-SPE)-liquid chromatography-diode array detection (LC-DAD), with on-sorbent derivatization by 2,4-dinitrophenylhydrazine (DNPH). This is the first time such an approach of combining on-sorbent derivatization and extraction in one step together with LC analysis has been applied to PM2.5. Extraction parameters such as selection of sorbent, extraction time, desorption time and sample volume were optimized using water samples spiked with Gly and Mgly. Under the most favourable conditions, good intra- (1.39%-2.78%) and inter-day (2.29%-6.56%) precision and linearity (ranging between 0.5 and 100 ng mL-1) along with coefficients of determination 0.998 and 0.997, were determined. The limits of detection were determined to be 0.14 ng mL-1 (derivatized Gly) and 0.15 ng mL-1 (derivatized Mgly) whereas the limits of quantification were 0.47 ng mL-1 and 0.50 ng mL-1, respectively. The developed method was successfully employed to the determination of Gly and Mgly associated with PM2.5. The latter was collected on glass fiber filters which were immersed in methanol: water (1:1 v/v) for μ-SPE, which was conducted using a sorbent pre-coated with DNPH. The concentrations of the Gly and Mgly were determined to be 0.38 ng m-3 and 0.41 ng m-3 in the sampled ambient air, with relative recoveries of between 69-97%.


New insights into early recovery after robotic surgery for endometrial cancer.
To assess early recovery of physical health after robotic minimally invasive surgery (RMIS) for early-stage endometrial cancer using the European Organisation of Research and Treatment of Cancer Computer Adaptive Test Core questionnaire (EORTC CAT Core). The EORTC CAT Core provides individualised measurements while maintaining comparability. A hypothesis of individual complete recovery to baseline within three post-surgical weeks was evaluated. Ninety-four women who underwent RMIS for early-stage endometrial cancer were included consecutively. The EORTC CAT Core was distributed before surgery and prospectively every week during the first post-operative month. Repeated measures models were fitted for each of the four domains (physical functioning, role function, fatigue, and pain) and tested for impact of age, ASA score, minor/major surgery, and the individual baseline scores (poorest, intermediate, best). Women with the lowest physical functioning, lowest role function, highest fatigue level, and highest pain level at baseline all recovered within three weeks. Women with the highest physical functioning, highest role function, lowest level of fatigue, and lowest level of pain at baseline did not reach their individual baselines within the first post-operative month but had the most favourable domain-scores three weeks post-operatively. The individual woman's physical health baseline score is predictive for her postoperative recovery following RMIS for early-stage endometrial cancer. Women with the best physical health had the best postoperative functions and lowest level of symptoms; however their recovery to baseline was prolonged. Computer adaptive testing may be a valuable tool for individualised pre-operative information and supportive care during surveillance.


Post Hoc Analyses of a Randomized Controlled Trial for the Effect of Pharmacist Deprescribing Intervention on the Anticholinergic Burden in Frail Community-Dwelling Older Adults.
Anticholinergic burden is detrimental to cognitive health. Multiple studies found that a high anticholinergic burden is associated with an increased risk for dementia, changes to the brain structure, function, and cognitive decline. We performed a post hoc analysis of a randomized controlled deprescribing trial. We compared the effect of the intervention on baseline anticholinergic burden across the treatment and control groups and the time of recruitment before and after a lockdown due to the COVID pandemic with subgroup analyses by baseline frailty index. Randomized controlled trial. We analyzed data from a de-prescribing trial of older adults (>65 years) previously conducted in New Zealand that was focused on reducing the Drug Burden Index (DBI). We used the anticholinergic cognitive burden (ACB) to quantify the impact of the intervention on reducing the anticholinergic burden. Participants not taking anticholinergics at the start of the trial were excluded. The primary outcome for this subgroup analysis was a change in ACB, measured with the ĝHedges statistic describing the difference in standard deviation units of this change between intervention and control. For this analysis, the trial participants were stratified into low, medium, and high frailty and timing into prior- and post-lockdown (public health measures for COVID-19). Among the 295 participants in this analysis, the median (IQR) age was 79 (74, 85), and 67% were women. For the primary outcome ĝHedges = -0.04 (95% CI -0.26 to 0.19) with a -0.23 mean reduction in ACB in the intervention arm and -0.19 in the control arm. Before lockdown ĝHedges = -0.38 (95% CI -0.84 to 0.04) and post-lockdown ĝHedges = 0.07 (95% CI -0.19 to 0.33). The mean change in ACB for each of the frailty strata was as follows: low frailty (-0.02; 95% CI -0.65 to 0.18); medium frailty (0.05; 95% CI -0.28 to 0.38); high frailty (0.08; 95% CI -0.40 to 0.56). The study did not provide evidence for the effect of pharmacist deprescribing intervention on reducing the anticholinergic burden. However, this post hoc analysis examined the impact of COVID on the effectiveness of the intervention, and further research in this area may be warranted.


Survival and prognostic factors for childhood malignant liver tumors: analysis of harmonized clinical data.
Despite overall striking advances in survival of childhood liver tumors, outcomes remain poor for specific patient segments. We aimed to assess overall survival (OS) of this rare disease and evaluate the generalizability of prognostic variables included in international collaborative systems using, for the first time, harmonized clinical data from two geographically different cohorts (Greece and Moscow). Data for children (0-14 years) with liver tumors were retrieved from two Southern-Eastern European areas (Greece; 2001-2019 and Moscow; 2012-2019). Kaplan-Meier curves were constructed, and OS values were derived from Cox proportional models controlling for study variables. A total of 171 newly diagnosed cases (54.4% males) were included. The OS5-year exceeded 80% in patients <5 years, reaching 85% among 133 patients with hepatoblastoma (HBL). By contrast, children with other than HBL histology, especially hepatocellular carcinoma (HCC) had significantly worse prognosis (hazard ratio [HR] HCC: 7.09, 95% confidence intervals [CI]: 2.56-19.65; HR other liver tumors: 5.18; 95%CI: 2.15-12.49). The OS5-year was poorer (40%-60%) in patients with extensive local, metastatic or relapsed disease. By contrast, a significantly lower risk of death was shown in case of microscopically margin-negative resection (HR: 0.06, 95%CI: 0.02-0.17) and liver transplantation (HR: 0.12, 95% CI: 0.02-0.63) compared to the non- operated group. Outcomes of patients with liver tumors registered in two SEE areas were comparable to those reported by major collaborative trials. Ongoing clinical cancer registration could facilitate comparison of outcomes between different study groups in order to shape state of the art of treatment.


3 fraction pencil-beam scanning proton accelerated partial breast irradiation: early provider and patient reported outcomes of a novel regimen.
To report dosimetry and early adverse effects, aesthetic, and patient-reported outcomes of a prospective study of 3-fraction pencil-beam scanning (PBS) proton accelerated partial irradiation (APBI). Eligibility included women age ≥ 50 years with estrogen receptor positive (ER+), sentinel lymph node negative invasive or in-situ breast cancer measuring ≤2.5 cm. The prescription was 21.9 Gy (RBE 1.1) in 3 daily fractions to the post-operative tumor bed with a 1 cm expansion. Toxicities were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, 10-point Linear Analog Scale Assessment, Patient-Reported Outcomes Version of the CTCAE, and the Harvard Breast Cosmesis Scale. Seventy-six women were treated between 2015 and 2017. The median breast volume receiving 50% of prescription or more was 28%. Median mean heart, mean ipsilateral lung, and maximum skin dose were 0 Gy, 0.1 Gy, and 20.6 Gy, respectively. With a median follow-up of 12 months, no treatment-related toxicity grade ≥ 2 has been observed. Most common grade 1 adverse events were dermatitis (68%) and skin hyperpigmentation (18%). At 12 months, the only persistent toxicities were one patient with grade 1 breast edema and one patient with a grade 1 seroma. 90% of patients reported quality of life as ≥7 out of 10 (0 indicating "as bad as it can be" and 10 indicating "as good as it can be") and 98% of patients reported excellent or good cosmesis. 3-fraction PBS proton APBI is well tolerated with low rates of physician and patient reported early adverse effects. Follow-up is ongoing to assess late toxicities and disease control outcomes. Further investigation of this novel adjuvant treatment strategy is warranted.


PAR2 deficiency enhances myeloid cell-mediated immunosuppression and promotes colitis-associated tumorigenesis.
Protease-activated receptor 2 (PAR2) is a member of G-protein coupled receptors, which is widely expressed in intestinal epithelium and immune cells and plays critical roles in intestinal homeostasis. Activation of PAR2 has been implicated in inflammatory process and carcinogenesis. However, it remains unclear whether and how endogenous PAR2 affects colorectal tumorigenesis. Here, we found that PAR2 expression was enhanced in patients with inflammatory bowel disease and colorectal cancer. Intriguingly, PAR2 deficiency significantly aggravated colitis and promoted tumor development in AOM/DSS model. This finding was accompanied with upregulated pro-inflammatory factors IL-6, TNFα, COX2 and NOS2 in tumors of Par2-/- mice. Moreover, PAR2 deficiency reshaped the tumor microenvironment through accumulation of tumor-promoting myeloid cells including tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs) and reduction of anti-tumor T cells, which established an immunosuppressive microenvironment and facilitated tumor progression. Mechanistically, absence of PAR2 in MDSCs directly enhanced their immunosuppressive activity by promoting STAT3-mediated reactive oxygen species production. Our study reveals an unrecognized role of PAR2 in limiting colorectal carcinogenesis by regulating the tumor microenvironment. Specifically targeting PAR2 may be a potential alternative for colorectal cancer immunotherapy.


A novel enzymatic assay for the identification of 4-hydroxyphenylpyruvate dioxygenase modulators.
4-hydroxyphenylpyruvate dioxygenase (HPPD) is a key enzyme involved in the pathogenesis of tyrosinemia III and cancer. Herein, we describe a spectroscopy-based assay to detect HPPD dioxygenase activity in the presence or absence of small-molecule modulators. We describe steps for transformation, expression, and purification of HPPD and preparation of the assay plate. We detail initiation and completion of the enzymatic reaction followed by detection of remaining substrate in the form of enol-HPP/borate complex. This assay is applicable for high-throughput screening. For complete details on the use and execution of this protocol, please refer to Parkins et al.1.


Determination of the lack of a drug interaction between azithromycin and warfarin.
To determine the effect on the international normalized ratio (INR) of adding azithromycin to patients receiving stable dosages of warfarin. Retrospective chart review. Outpatient clinic. Ambulatory patients receiving warfarin and azithromycin concurrently who had a documented therapeutic INR value before the start of azithromycin therapy (pre-INR) and a documented INR value within 30 days after the start of azithromycin therapy (post-INR). Patients given felodipine during long-term warfarin therapy formed a comparative control group. Patient demographics were similar in both treatment groups. Mean age of the azithromycin group (17 patients) was 59 +/- 13 years and of the control group (20 patients) 65 +/- 12 years. All 17 patients in the azithromycin group and 16 of the controls were women. Mean change from pre-INR to post-INR in the azithromycin and control groups, respectively, was 0.14 +/- 0.64 (pre-INR 2.46, post-INR 2.61) and 0.19 +/- 0.54 (pre-INR 2.46, post-INR 2.66) (p = 0.74). A post hoc power analysis based on a pooled standard deviation of 0.60 revealed that the study had 68% power to detect a 0.5 change in the INR value. No interaction between azithromycin and warfarin was observed in ambulatory patients with therapeutic baseline INR values.


The emerging role of immunothrombosis in paediatric conditions.
Immunothrombosis is a physiological process based on the release of neutrophil extracellular traps (NETs) to immobilise, contain and kill bacteria. This is an innate immune response in which the local activation of blood coagulation exerts the critical protective function during microbial infection. In recent years, there has been much interest in the adult literature about the key role of immunothrombosis in pathologic states including thrombosis, cancer, sepsis and trauma. Currently, little research has been done into its role in paediatric conditions. We conducted a literature search of the National Library of Medicine (MEDLINE/PubMed) from the years 2000 to May 2018 and qualitatively identified 24 relevant papers. References of articles included for full-text review were checked for relevant publications. Our aim is to summarise the most relevant evidences regarding an excessive production or defective removal of NETs in paediatric conditions. In particular, we have divided the role of immunothrombosis into acute (sepsis, necrotising enterocolitis, otitis media, neonatal arterial ischaemic stroke, haemolytic anaemic diseases) and chronic (systemic lupus erythematous, type 1 diabetes mellitus, respiratory diseases, graft-versus-host disease) conditions to find important similarities in their pathophysiology. The field of immunothrombosis in paediatric conditions is still in its infancy. We have presented multiple pathways of NET-induced disease together with possible areas of future research and treatments.


Bilateral sagittal split surgery is not a predictable treatment for temporomandibular dysfunction in patients with retrognathia.
A prospective study to clarify the impact of forward bilateral sagittal split osteotomy (BSSO) on temporomandibular dysfunction (TMD). We examined and interviewed patients with BSSO before and at 1 year after surgery to evaluate the changes in TMD symptoms. A well-known TMD index, which incorporated two complementary subindices-the objective functional Helkimo dysfunction index (Di) and the subjective symptomatic anamnestic index (Ai)-was used. Patients with a forward movement of the mandible and osteosynthesis with titanic miniplates were included. Forty patients (26 females and 14 males, mean age of study population 36.9 years) retrognathia completed the study. There was no change in TMD symptoms in 24 patients (60%), as measured by the Di, and 26 (65%), as measured by the Ai. Twelve patients improved (30%), according to the Di scores and 10 (25%) according to the Ai scores. Four patients had more TMD symptoms at follow-up (10%), as measured by both Di and Ai. Surgery for orthognathia is a predictable treatment for improving aesthetics and occlusion but less predictable for alleviating TMD symptoms in patients with retrognathia. TMD symptoms should therefore be treated independently.


Genomic analysis of SARS-CoV-2 variants of concern identified from the ChAdOx1 nCoV-19 immunized patients from Southwest part of Bangladesh.
Bangladesh introduced ChAdOx1 nCoV-19 since February, 2021 and in six months, only a small population (12.8%) received either one or two dose of vaccination like other low-income countries. The COVID-19 infections were continued to roll all over the places although the information on genomic variations of SARS-CoV-2 between both immunized and unimmunized group was unavailable. The objective of this study was to compare the proportion of immune escaping variants between those groups. A total of 4718 nasopharygeal samples were collected from March 1 until April 15, 2021, of which, 834 (18%) were SARS-CoV-2 positive. The minimum sample size was calculated as 108 who were randomly selected for telephone interview and provided consent. The prevalence of SARS-CoV-2 variants and disease severity among both immunized and unimmunized groups was measured. A total of 63 spike protein sequences and 14 whole-genome sequences were performed from both groups and phylogenetic reconstruction and mutation analysis were compared. A total of 40 respondents (37%, N = 108) received single-dose and 2 (2%) received both doses of ChAdOx1 nCoV-19 vaccine, which significantly reduce dry cough, loss of appetite and difficulties in breathing compared to none. There was no significant difference in hospitalization, duration of hospitalization or reduction of other symptoms like running nose, muscle pain, shortness of breathing or generalized weakness between immunized and unimmunized groups. Spike protein sequence assumed 21 (87.5%) B.1.351, one B.1.526 and two 20B variants in immunized group compared to 27 (69%) B.1.351, 5 (13%) B.1.1.7, 4 (10%) 20B, 2 B.1.526 and one B.1.427 variant in unimmunized group. Whole genome sequence analysis of 14 cases identified seven B.1.351 Beta V2, three B.1.1.7 Alpha V1, one B.1.526 Eta and the rest three 20B variants. Our study observed that ChAdOx1 could not prevent the new infection or severe COVID-19 disease outcome with single dose while the infections were mostly caused by B.1.351 variants in Bangladesh.


Parameters to consider for successful medication use in older adults - An AGePOP review.
Older adults are the main users of medicine and due to common multimorbidity they are often confronted with a complex medication management. This review article provides a brief overview on aspects of medication management, i.e., maintaining a stock of the required medicine, understanding and following the instructions for use, coping with the primary and secondary packaging, as well as the preparation prior to use. However, the main focus is on the drug intake itself and the review provides an overview of the current understanding of real life dosing conditions in older adults and geriatric patients. It elaborates the acceptability of dosage forms, in particular solid oral dosage forms as they represent the majority of dosage forms taken by this patient population. An improved understanding of the needs of older adults and geriatric patients, their acceptability of various dosage forms, and the circumstances under which they manage their medications will allow for the design of more patient-centric drug products.