The C-reactive Protein to Albumin Ratio Predicts Long-Term Outcomes in Patients with Pancreatic Cancer After Pancreatic Resection.
The C-reactive protein to albumin (CRP/Alb) ratio, a novel inflammation-based prognostic score, is associated with outcomes in septic patients. The prognostic value of CRP/Alb ratio has not been established in cancer patients. The aim of this study is to evaluate the significance of CRP/Alb ratio in therapeutic outcome after pancreatic resection for pancreatic cancer. The study comprised 113 patients who had undergone pancreatic resection for pancreatic cancer between April 2001 and December 2011. We retrospectively investigated the relation between CRP/Alb ratio and disease-free as well as overall survival. The optimal cut-off level of the CRP/Alb ratio was 0.03. For disease-free survival, preoperative biliary drainage (p = 0.011), advanced tumor-node-metastasis (TNM) classification (p = 0.002), and higher CRP/Alb ratio (p = 0.049) by univariate analysis, and advanced TNM classification (p = 0.003) by multivariate analysis, were independent and significant predictors of cancer recurrence. For overall survival, preoperative biliary drainage (p = 0.012), advanced TNM classification (p = 0.001), and higher CRP/Alb ratio (p = 0.023) by univariate analysis, and advanced TNM classification (p = 0.003) and higher CRP/Alb ratio (p = 0.035) by multivariate analysis, were independent and significant predictors of poor patient outcome. The CRP/Alb ratio may be an independent and significant indicator of poor long-term outcomes in patients with pancreatic cancer after pancreatic resection.


Correction to: Implication of OPRM1 A118G Polymorphism in Opioids Addicts in Pakistan: In vitro and In silico Analysis.
The original version of this article is missing the Acknowledgments section.


3D Printing Hierarchically Nano-Ordered Structures.
Natural materials are composed of a limited number of molecular building blocks and their exceptional properties are governed by their hierarchical structure. However, this level of precision is unattainable with current state-of-the-art materials for 3D printing. Herein, new self-assembled printable materials based on block copolymers (BCPs) enabling precise control of the nanostructure in 3D are presented. In particular, well-defined BCPs consisting of poly(styrene) (PS) and a polymethacrylate-based copolymer decorated with printable units are selected as suitable self-assembled materials and synthesized using controlled radical polymerization. The synthesized library of BCPs are utilized as printable formulations for the fabrication of complex 3D microstructures using two-photon laser printing. By fine-tuning the BCP composition and solvent in the formulations, the fabrication of precise 3D nano-ordered structures is demonstrated for the first time. A key point of this work is the achievement of controlled nano-order within the entire 3D structures. Thus, imaging of the cross-sections of the 3D printed samples is performed, enabling the visualization also from the inside. The presented versatile approach is expected to create new avenues for the precise design of functional polymer materials suitable for high-resolution 3D printing exhibiting tailor-made nanostructures.


Novel anticoagulants versus vitamin K antagonists for cardioversion of non- valvular atrial fibrillation - a meta-analysis of more than 17000 patients.
Non-vitamin K antagonist oral anticoagulants (NOACs) have proven a favorable risk-benefit profile compared to vitamin K antagonists (VKAs) for preventing stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF), but actual data are not sufficiently powered to extend this profile on patients with AF that undergo cardioversion. We aimed to compare outcomes after cardioversion of AF under NOACs vs. VKAs. We systematically searched Pubmed, Cochrane, SCOPUS, and Web of Science databases for studies published until October 2017. A total of 17506 patients from 11 studies were included. Treatment with NOACs was associated with similar relative risks (RR) of stroke and systemic embolism, hemorrhagic stroke, myocardial infarction, cardiovascular death, and all cause death compared to VKAs treatment. The RR of ischemic stroke was lower in the NOACs group. The risk of major bleeding was similar across treatment groups. Treatment with NOACs in patients with non-valvular AF that undergo cardioversion seems to be as safe and effective as the use of classical VKAs, with a better profile for ischemic stroke. Clinical Trial Registration: PROSPERO Registry, CRD42018086181 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID = 86181 .


SOdium-glucose CO-transporter inhibition in patients with newly detected Glucose Abnormalities and a recent Myocardial Infarction (SOCOGAMI).
Established dysglycaemia (impaired glucose tolerance [IGT] or type 2 diabetes [T2DM]) is a risk factor for further cardiovascular events in patients with coronary artery disease. Sodium-glucose cotransporter 2 inhibitors reduce this risk. The aim of the present investigation was to test the hypothesis that empagliflozin exerts beneficial effects on myocardial function in patients with a recent acute coronary syndrome and newly detected dysglycaemia. Forty-two patients (mean age 67.5 years, 81 % male) with recent myocardial infarction (n = 36) or unstable angina (n = 6) and newly detected IGT (n = 27) or T2DM (n = 15) were randomised to 25 mg of empagliflozin daily (n = 20) or placebo (n = 22) on top of ongoing therapy. They were investigated with oral glucose tolerance tests, stress-perfusion cardiac magnetic resonance imaging (CMR) and echocardiography at three occasions: before randomisation, after seven months on study drug and three months following cessation of such drug. Primary outcome was a change in left ventricular (LV) end-diastolic volume (LVEDV) and secondary outcomes were a change in a) systolic and diastolic LV function; b) coronary flow reserve; c) myocardial extracellular volume (ECV) in non-infarcted myocardium; d) aortic pulse wave velocity. Empagliflozin induced a significant decrease in fasting and post load glucose (p < 0.05) and body weight (p < 0.01). Empagliflozin did not influence LVEDV, LV systolic or mass indexes, coronary flow reserve, ECV or aortic pulse wave velocity. Echocardiographic indices of LV diastolic function (E/e' and mitral E/A ratio) were not influenced. No safety concerns were identified. Empagliflozin had predicted effects on the dysglycaemia but did not influence variables expressing LV function, coronary flow reserve and ECV. An explanation may be that the LV function of the patients was within the normal range.


Synthesis of aminoglycoside-DNA conjugates.
Development of aminoglycoside-nucleic acid conjugates is presented. Synthesis of a DNA dimer covalently linked to kanamycin and neomycin isothiocyanates has been carried out. The development of such conjugates will help couple the sequence specificity of nucleic acids to the electrostatic/shape complementarity of aminoglycoside antibiotics in binding nucleic acid targets.


[Results of subinguinal microsurgical varicocelectomy].
The subinguinal microsurgical varicocelectomy is considered as the gold standard surgical technique for the treatment of varicocele. The objective of this study is to evaluate the results of this technique on the resolution of pain and the parameters of sperm analysis. Single-center, retrospective study that includes 22 patients who have been operated over a period of six months for a clinically palpable varicocele via the microsurgical subinguinal technique. Nine patients were operated for pain and 13 patients for infertility with an abnormality of their sperm analysis. All the patients operated for pain had a complete resolution of pain at the postoperative follow-up (3 months). Concerning the patients operated for infertility, 76.92% of the patients had a normal sperm analysis, 7.69% of the patients presented a partial improvement, and 15.39% of the patients without any improvement. Analysis of sperm's parameters at 3 months showed a significant improvement in the morphology (4.3% vs 6.69% of typical forms according to Kruger ; P<0.05) and mobility (progressive mobility 15.6% vs 23% postoperatively; P<0.01). A non-significant improvement (low sample) in the concentration was noted (21.58 million/mL preoperative vs 34.9 million/mL postoperative, P=0.08). Pregnancies are noted in 38.5% of patients. A postoperative complication was noted with surgical site infection resolved with antibiotics. This single-center study confirms that the treatment of varicocele by subinguinal microsurgical route is an effective therapeutic strategy on symptomatic varicocele and in infertile men. This technique is associated with few complications.


The relationship between Bcl-gene expression and learning and memory impairment in chronic aluminum-exposed rats.
Aluminum (Al), a known neurotoxin, has been implicated in Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Parkinsonism Dementia Complex, etc., and it causes extensive damage to the nervous system, including the impairment of learning and memory. However, to date, the mechanism of Al neurotoxicity has not been fully elucidated. Neuronal apoptosis has become a focus of interest, as it has been reported to play a key role in the impairment of learning and memory processes (Thompson, Science 267:1456, 1995). The Bcl-2 gene acts as an important effector for inhibiting apoptosis. In the present study we observe neuronal apoptosis in association with learning and memory impairment, as well as regional brain alterations in Bcl-2 expression in rats chronically exposed to Al. The chronic Al-intoxicated model was established by i.p. injection of AlCl3 in adult Sprague Dawley rats for 3 successive days, with one-day intervals, for 60 days. After exposure, the step-down test was performed to examine the behavioral reaction of the rats. Neuronal apoptosis and Bcl-2 protein expression in different regions of rat brain were then assessed by an immunohistochemical method. In the step-down test, the latency of Al-exposed rats was significantly lower than that of controls. Also, the number of performance errors in 5 minutes of exposure was significantly higher than that of controls. Neuronal apoptosis was extensive in the brain of Al-exposed groups, and the expressions of Bcl-2 protein in frontal cortex, cerebellum and hippocampus of Al-exposed rats was stronger. In conclusion, chronic Al-exposure in rats is associated with neuronal apoptosis in brain, and impaired learning and memory. Augmented Bcl-2 protein expression may be a stimulated compensatory mechanism.


Simultaneous visualization of vascular permeability change and leukocyte egress in the central nervous system during autoimmune encephalomyelitis.
An unresolved issue in the study of demyelinating disease is whether blood-brain barrier damage is dependent upon the migration of inflammatory cells into the central nervous system (CNS). In a study of experimental autoimmune encephalomyelitis (EAE) in rabbits, a freeze-dried, paraffin-embedded tissue technique was exploited to enable (1) the immobilization of intravenously injected sodium fluorescein tracer, as an index of vascular permeability; and (2) an effective labeling by monoclonal antibodies of both T-lymphocytes and mononuclear phagocytes in "unfixed" neural tissue. Using these newly combined methods, evidence was found that increased vascular permeability in the CNS during EAE occurs concomitantly with, and not prior to, infiltration by mononuclear phagocytes.


Sleep loss due to worry and future risk of cardiovascular disease and all-cause mortality: the Scottish Health Survey.
The association between specific sleeping disorders and risk of cardiovascular disease (CVD) is unclear. We assessed the association between sleep loss due to worry and future risk of CVD and death in a representative sample of community dwelling adults. A cohort of 11,905 adults (aged 53.4 ± 12.2 years, 42.2% male) without known history of CVD were drawn from the Scottish Health Surveys. Self-reported sleep disturbance was measured using a single item from the General Health Questionnaire. Incident CVD events (comprising CVD death, nonfatal myocardial infarction, coronary surgical procedures, stroke, and heart failure) over 8-year follow up were ascertained by a linkage to national registers; a total of 1448 CVD events and 1249 all-cause deaths were recorded. 15.6% of the sample reported 'rather more' or 'much more than usual' sleep loss due to worry over the prior 4 weeks. Sleep loss due to worry (much more than usual) was associated with elevated risk of CVD [age- and sex-adjusted hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.35-2.25] and all-cause mortality (age- and sex-adjusted HR 2.02, 95% CI 1.57-2.61). Adjustment for a range of psychosocial, behavioural, and clinical risk factors partly attenuated the association, and in particular health behaviours (smoking, alcohol, physical inactivity) accounted for approximately 40% of the sleep-CVD relation. Sleep loss due to worry was associated with a greater risk of CVD and all-cause mortality, but the association can be largely explained by intermediate risk factors such as health behaviours.


Biochemical analyses of tau and other neuronal markers in the submandibular gland and frontal cortex across stages of Alzheimer disease.
Hyperphosphorylation of the microtubule-associated protein tau is hypothesized to lead to the development of neurofibrillary tangles in select brain regions during normal aging and in Alzheimer disease (AD). The distribution of neurofibrillary tangles is staged by its involvement starting in the transentorhinal regions of the brain and in final stages progress to neocortices. However, it has also been determined neurofibrillary tangles can extend into the spinal cord and select tau species are found in peripheral tissues and this may be depended on AD disease stage. To further understand the relationships of peripheral tissues to AD, we utilized biochemical methods to evaluate protein levels of total tau and phosphorylated tau (p-tau) as well as other neuronal proteins (i.e., tyrosine hydroxylase (TH), neurofilament heavy chain (NF-H), and microtubule-associated protein 2 (MAP2)) in the submandibular gland and frontal cortex of human cases across different clinicopathological stages of AD (n = 3 criteria not met or low, n = 6 intermediate, and n = 9 high likelihood that dementia is due to AD based on National Institute on Aging-Reagan criteria). We report differential protein levels based on the stage of AD, anatomic specific tau species, as well as differences in TH and NF-H. In addition, exploratory findings were made of the high molecular weight tau species big tau that is unique to peripheral tissues. Although sample sizes were small, these findings are, to our knowledge, the first comparison of these specific protein changes in these tissues.


Accumulation of organic air constituents by plant surfaces. Spruce needles for monitoring airborne chlorinated hydrocarbons.
The needles of the spruce (Picea abies) were used to monitor ambient air for organic trace substances. Analyses of spruce needles in an industrialized area demonstrated that the concentrations of these substances were much higher than those in a nonindustrialized area.


Systemic growth hormone deficiency causes mechanical and thermal hypersensitivity during early postnatal development.
Injury during early postnatal life causes acute alterations in afferent function and DRG gene expression, which in addition to producing short-term sensitivity has the potential to influence nociceptive responses in adulthood. We recently discovered that growth hormone (GH) is a key regulator of afferent sensitization and pain-related behaviors during developmental inflammation of the skin. Peripheral injury caused a significant reduction in cutaneous GH levels, which corresponded with the observed hypersensitivity. However, it has yet to be determined whether GH deficiency (GHD) is sufficient to drive peripheral sensitization in uninjured animals. Here, we found that systemic GHD, induced by knockout of the GH release hormone receptor (GHRHr), was able to induce behavioral and afferent hypersensitivity to peripheral stimuli specifically during early developmental stages. GHD also produced an upregulation of many receptors and channels linked to nociceptive processing in the DRGs at these early postnatal ages (P7 and P14). Surprisingly, P21 GHRHr knockouts also displayed significant alterations in DRG gene expression even though behavioral and afferent hypersensitivity resolved. These data support previous findings that GH is a key modulator of neonatal hypersensitivity. Results may provide insight into whether GH treatment may be a therapeutic strategy for pediatric pain.


Effects of uridine on kindling.
The anticonvulsant effect of the nucleoside uridine has been studied for several decades with controversial results. One of its attractive properties is that as a natural endogenous molecule, it lacks the serious side effects of common antiepileptic drugs used today. In the current study, we examined the potential antiepileptogenic effect of uridine in the hippocampal kindling model, using once-daily stimulations. Uridine was administered once or three times daily; levetiracetam was administered as a positive control; and normal saline was used as a negative control. Rats receiving uridine or levetiracetam had slower kindling rates and shorter afterdischarge durations than the normal saline controls. These results are consistent with previous work using a rapid kindling model and suggest that uridine has antiepileptogenic properties. Because of its combination of low toxicity and efficacy, uridine is a possible candidate for the treatment of epilepsy.


Peri-procedural Management of Implanted Spinal Cord Stimulators in Patients Undergoing Radiofrequency Ablation: A Case Report and Manufacturer-Specific Recommendations.
Radiofrequency ablation (RFA) and spinal cord stimulation (SCS) are 2 common modalities used in management of various pain conditions. RFA generates heat and an electromagnetic field that can theoretically interfere with the functionality and longevity of the SCS device. This is problematic for patients who need RFA and have previously undergone implantation of an SCS device. We present a case highlighting the safe use of bipolar RFA in a patient who had previously undergone implantation of a cervical SCS device. We also present device-specific industry guidelines and recommendations for performing RFA in patients following SCS device implantation.


Highly selective colorimetric detection of spermine in biosamples on basis of the non-crosslinking aggregation of ssDNA-capped gold nanoparticles.
The selective adsorption of single-stranded oligonucleotides (ssDNA) on gold nanoparticles (AuNPs) is well known for stabilizing the AuNPs against aggregation even at high salt concentrations. Our investigation shows that the non-crosslinking aggregation of arbitrary ssDNA-capped AuNPs occurs due to their interaction with the cationic polyamine, spermine (Spm), even without any addition of NaCl. The non-crosslinking aggregation mechanism is that the Spm, served as multivalent counterions, plays the dual roles of charge shielding and ion bridging among the ssDNA-capped AuNPs, which jointly result in the aggregation of the ssDNA-capped AuNPs. Therefore, a sensitive and highly selective colorimetric method for the detection of Spm was developed. To the best of our knowledge, it is the first successful case as to the efforts towards the development of optical assays for cationic polyamine, showing neither natural UV absorption nor fluorescence. Compared with the traditional methods of chromatography and capillary electrophoresis, the approach described here would provide a convenient alternative and new train of thought for the specific detection of Spm in both biological fluid and fermented products.


Toxicity and physiological effects of brominated flame retardant PBDE-47 on two life stages of grass shrimp, Palaemonetes pugio.
This study examined the effects of a polybrominated diphenyl ether (PBDE) compound, PBDE-47, on adult and larval stages of the estuarine grass shrimp (Palaemonetes pugio). The 96-h LC50 test resulted in an estimate of 23.60 microg/L (95% confidence interval=14.51-38.37 microg/L) for larval shrimp. Adult shrimp had a higher 96-h LC50 of 78.07 microg/L (95% CI=65.1-93.63 microg/L). Four physiological biomarkers glutathione (GSH), lipid peroxidation (LPx), cholesterol (CHL) and acetylcholinesterase (AChE) were then assessed to study the sublethal effects of PBDE-47 exposure. GSH, LPx and AChE levels in both adults and larvae were not affected by PBDE-47 at concentrations up to 50 microg/L for 96 h. CHL levels were elevated in adults and larvae at the lowest exposure concentrations tested, but significant differences were found only in adult exposures. Effects associated with PBDE-47 aqueous exposures were observed at levels well above those reported in the environment.


Prehabilitation.
The rehabilitation of an athletic injury may represent the greatest challenge of an athlete's career. The challenge to the sports medicine professional is to provide the most up to date and best care possible. Prehabilitation is one part of that care. Management of the acute injury, conditioning the athlete, and preventing unnecessary atrophy are all steps in helping the athlete to meet his or her challenge.


Remote Speech Analysis in the Evaluation of Hospitalized Patients With Acute Decompensated Heart Failure.
This study assessed the performance of an automated speech analysis technology in detecting pulmonary fluid overload in patients with acute decompensated heart failure (ADHF). Pulmonary edema is the main cause of heart failure (HF)-related hospitalizations and a key predictor of poor postdischarge prognosis. Frequent monitoring is often recommended, but signs of decompensation are often missed. Voice and sound analysis technologies have been shown to successfully identify clinical conditions that affect vocal cord vibration mechanics. Adult patients with ADHF (n = 40) recorded 5 sentences, in 1 of 3 languages, using HearO, a proprietary speech processing and analysis application, upon admission (wet) to and discharge (dry) from the hospital. Recordings were analyzed for 5 distinct speech measures (SMs), each a distinct time, frequency resolution, and linear versus perceptual (ear) model; mean change from baseline SMs was calculated. In total, 1,484 recordings were analyzed. Discharge recordings were successfully tagged as distinctly different from baseline (wet) in 94% of cases, with distinct differences shown for all 5 SMs in 87.5% of cases. The largest change from baseline was documented for SM2 (218%). Unsupervised, blinded clustering of untagged admission and discharge recordings of 9 patients was further demonstrated for all 5 SMs. Automated speech analysis technology can identify voice alterations reflective of HF status. This platform is expected to provide a valuable contribution to in-person and remote follow-up of patients with HF, by alerting to imminent deterioration, thereby reducing hospitalization rates. (Clinical Evaluation of Cordio App in Adult Patients With CHF; NCT03266029).


ROC steady: a receiver operating characteristic curve that is invariant relative to selection bias.
This paper describes a simple method for constructing receiver operating characteristic (ROC) curves based on boundary conditions that restrict its theoretical shape. The resultant curve is identical to that for logistic distributions with equal variance. Although the underlying assumptions are highly restrictive, this method nevertheless possesses several attractive properties which are illustrated by its application to 2,567 patients undergoing a variety of noninvasive diagnostic tests for coronary artery disease: 1) the area under the curve is defined by a single parameter; 2) the associated standard deviation is analytically defined and readily computed; 3) the curve is completely invariant with respect to selection bias.


The Relation between the Dynamization of Hexapod Circular External Fixator and Tibial Mechanical Properties.
Dynamization of the external fixator, defined as gradually decreasing construct-stability of the fixator, is widely accepted as a method for treatment during the late phase of the bone healing process. However, the dynamization is mostly based on the subjective experience of orthopaedists at present, without unified standards and a clear theoretical basis. The objective of the study is to investigate the influence of the dynamization operations on the tibial mechanical properties with a hexapod circular external fixator and standardize the dynamization process. A 3D-printed tibial defects model with Young's modulus of 10.5 GPa and Poisson's ratio of 0.32 simulated the clinically fractured bone. A 10 × ∅ 45 mm silicone sample with Young's modulus of 2.7 MPa and Poisson's ratio of 0.32 simulated the callus in the fracture site. Furthermore, a hexapod circular external fixator whose struts were coded from #1 to #6 was fixed on the model with six half-pins (5 mm diameter). Corresponding to the action of removing and loosening the struts, 17 dynamization operations are designed. For each construct after different dynamization operations, the mechanical environment changes in the fracture site were recorded by a triaxle forces sensor under gradually increasing external load from 0 to 500 N. The results show that the bone axial load-sharing ratio of each construct in the removal group was generally higher than that in the loosening group. The ratio increased from 92.51 ± 0.74% to 102.68 ± 0.27% with the number of operated struts rising from 2 to 6. Besides, the constructions with the same number of operated struts but with different strut codes such as constructions 3-5, had similar bone axial load-sharing ratios. In addition, the proposed dynamization method of the hexapod circular external fixator can gradually increase the bone axial load-sharing ratio from 90.73 ± 0.19% to 102.68 ± 0.27% and maintain the bone radial load-sharing ratio below 8%. The laboratory study verified the effects of the type of operations and the number of operated struts on the bone axial load-sharing ratio, as well as the slight influence of the choice of the strut code. Besides, a dynamization method of the hexapod circular external fixator was proposed to increase the bone axial load-sharing ratio gradually.


Phospholipid composition modulates the Na+-Ca2+ exchange activity of cardiac sarcolemma in reconstituted vesicles.
Na+-Ca2+ exchange activity in cardiac sarcolemmal vesicles is known to be sensitive to charged, membrane lipid components. To examine the interactions between membrane components and the exchanger in more detail, we have solubilized and reconstituted the Na+-Ca2+ exchanger into membranes of defined lipid composition. Our results indicate that optimal Na+-Ca2+ exchange activity requires the presence of certain anionic phospholipids. In particular, phosphatidylserine (PS), cardiolipin, or phosphatidic acid at 50% by weight results in high Na+-Ca2+ exchange activity, whereas phosphatidylinositol and phosphatidylglycerol provide a poor environment for exchange. In addition, incorporation of cholesterol at 20% by weight greatly facilitates Na+-Ca2+ exchange activity. Thus, for example, an optimal lipid environment for Na+-Ca2+ exchange is phosphatidylcholine (PC, 30%)/PS (50%)/cholesterol (20%). Na+-Ca2+ exchange activity is also high when cardiac sarcolemma is solubilized and then reconstituted into asolectin liposomes. We fractionated the lipids of asolectin into subclasses for further reconstitution studies. When sarcolemma is reconstituted into vesicles formed from the phospholipid component of asolectin, Na+-Ca2+ exchange activity is low. When the neutral lipid fraction of asolectin (including sterols) is also included in the reconstitution medium, Na+-Ca2+ exchange activity is greatly stimulated. This result is consistent with the requirement for cholesterol described above. Proteinase treatment, high pH, intravesicular Ca2+ and dodecyl sulfate all stimulate Na+-Ca2+ exchange in native sarcolemmal vesicles. We examined the effects of these interventions on exchange activity in reconstituted vesicles of varying lipid composition. In general, Na+-Ca2+ exchange could be stimulated only when reconstituted into vesicles of a suboptimal lipid composition. That is, when reconstituted into asolectin or PC/PS/cholesterol (30:50:20), the exchanger is already in an activated state and can no longer be stimulated. The one exception was that the Na+-Ca2+ exchanger responded to altered pH in an identical manner, independent of vesicle lipid composition. The mechanism of action of altered pH on the exchanger thus appears to be different from other interventions.


Dose-finding designs using a novel quasi-continuous endpoint for multiple toxicities.
The aim of a phase I oncology trial is to identify a dose with an acceptable safety profile. Most phase I designs use the dose-limiting toxicity, a binary endpoint, to assess the unacceptable level of toxicity. The dose-limiting toxicity might be incomplete for investigating molecularly targeted therapies as much useful toxicity information is discarded. In this work, we propose a quasi-continuous toxicity score, the total toxicity profile (TTP), to measure quantitatively and comprehensively the overall severity of multiple toxicities. We define the TTP as the Euclidean norm of the weights of toxicities experienced by a patient, where the weights reflect the relative clinical importance of each grade and toxicity type. We propose a dose-finding design, the quasi-likelihood continual reassessment method (CRM), incorporating the TTP score into the CRM, with a logistic model for the dose-toxicity relationship in a frequentist framework. Using simulations, we compared our design with three existing designs for quasi-continuous toxicity score (the Bayesian quasi-CRM with an empiric model and two nonparametric designs), all using the TTP score, under eight different scenarios. All designs using the TTP score to identify the recommended dose had good performance characteristics for most scenarios, with good overdosing control. For a sample size of 36, the percentage of correct selection for the quasi-likelihood CRM ranged from 80% to 90%, with similar results for the quasi-CRM design. These designs with TTP score present an appealing alternative to the conventional dose-finding designs, especially in the context of molecularly targeted agents.


Efalizumab: an overview.
Efalizumab (anti-CD11a), a targeted T cell modulator, is a humanized monoclonal antibody being studied for plaque psoriasis. Phase I and II studies demonstrated that efalizumab treatment results in histologic improvement and clinical benefit in patients with moderate to severe disease. Phase III clinical trials confirmed the clinical activity and safety of weekly efalizumab. Efalizumab is associated with a rapid onset of clinical benefit, with significant improvements observed as early as 4 weeks. Extending treatment from 12 to 24 weeks both maintains and improves the initial responses achieved at 12 weeks. Both 12 and 24 weeks of efalizumab therapy were generally well tolerated. Ongoing studies are being conducted to further define the optimal dosing and administration schedules for efalizumab in patients with moderate to severe plaque psoriasis.


A new insight into the promotional effect of nitrogen-doping in activated carbon for selective catalytic reduction of NOX with NH3.
A series of N-doped carbons were prepared to investigate the effect of different N-containing groups on selective catalytic reduction (SCR) of NOx with NH3. Combined the SCR activity with the results of porosity analysis and X-ray photoelectron spectroscopy, it's deduced that the pyridinic N (N-6) rather than the surface area or doped total N was mainly responsible for the promoted SCR activity. The electron paramagnetic resonance and O2-temperature programmed desorption (O2-TPD) experiments indicated that N-6 created numerous of oxygen vacancy. The NO+O2-TPD and transient response of NH3 further demonstrated that the increased oxygen vacancy enhanced the absorbability and reactivity of NOx, therefore the SCR reaction was elevated by accelerating the reaction in the Langmuir-Hinshelwood (L-H) mechanism. Furthermore, the NH3-TPD suggested that N-6 was conductive to the NH3 adsorption. In situ DRIFTs of NH3 adsorption and reaction illustrated that the increased NH3 mainly existed as NH2 species, which were quickly consumed by NO+O2, further elevated the reaction between gaseous NO and adsorbed NH3 in the Eley-Rideal (E-R) mechanism. The N-6 groups doped in the activated carbons facilitated the L-H and E-R reactions and thus promoted the SCR activity.


Eleven times recurrences of a parasagittal falxmeningioma. Case report.
Although meningiomas are of benign character and generally of encapsulated growth, recurrence is a known problem in treatment. The authors present the time course of a recurrent parasagittal meningioma of the falx, which recurred eleven times. Despite modern radiological diagnostic methods, which made early diagnosis of recurrent tumour possible, and the use of modern microsurgical techniques with radical tumour extirpation and followed by radiotherapy, the fatal course of benign tumour disease could not be stopped.


Current and Future Advances in the Detection and Surveillance of Biosecurity-Relevant Equine Bacterial Diseases Using Loop-Mediated Isothermal Amplification (LAMP).
Horses play an important role throughout the world, whether for work, culture, or leisure, providing an ever-growing significant contribution to the economy. The increase in importation and movement of horses, both nationally and internationally, has inevitably allowed for the global equine industry to grow. Subsequently, however, the potential for transmission of fatal equine bacterial diseases has also escalated, and devasting outbreaks continue to occur. To prevent such events, disease surveillance and diagnosis must be heightened throughout the industry. Current common, or "gold-standard" techniques, have shown to be inadequate at times, thus requiring newer technology to impede outbreaks. Loop-mediated isothermal amplification (LAMP) has proven to be a reliable, rapid, and accessible tool in both diagnostics and surveillance. This review will discuss equine bacterial diseases of biosecurity relevance and their current diagnostic approaches, as well as their respective LAMP assay developments. Additionally, we will provide insight regarding newer technology and advancements associated with this technique and their potential use for the outlined diseases.


Evaluating agreement between clinic- and patient-reported outcomes for weight and co-morbidities at 1 year after bariatric surgery.
Development of patient-reported outcomes (PROs) to include traditionally clinic-reported data has the potential to decrease the data-collection burden for patients and clinicians and increase follow-up rates. However, replacing clinic report by patient report requires that the data reasonably agree. To assess agreement between PROs and clinical registry data at 1 year after bariatric surgery. Not-for-profit organization, bariatric surgery data registry, PROs platform. Patient- and clinic-reported 1-year postoperative weight and co-morbidities were compared for matched PROs and registry records. The co-morbidities evaluated were diabetes, sleep apnea, hypertension, gastroesophageal reflux disease, and hyperlipidemia. Weight difference in pounds and nominal groupings (binary, 4-level) for co-morbidities were assessed for agreement between data sources using descriptive statistics, Bland-Altman plots, multiple regression, and kappa coefficients. Sensitivity analyses and follow-up by response method were examined. Among 1130 patients with both 1-year PROs and registry weights, 95% of patient-reported weights were within 13 lb of the registry-recorded weight, and patients underreported their weight by ∼2 lb, on average. Percent agreement and kappa coefficients were highest for diabetes (n = 999; binary: 94%, κ = .72; 4-level: 86%, κ = .71) and lowest for gastroesophageal reflux disease (n = 1032; binary: 75%, κ = .40; 4-level: 57%, κ = .35). Of patients eligible for both PROs and registry 1-year follow-up, 21% had PROs only. One-year patient- and clinic-reported weights and disease status for patients with diabetes and hypertension showed high agreement. The degree of bias from patient report was low. Patient report is a viable alternative to clinic report for certain objective measurements and may increase follow-up.


Effects of zotepine and olanzapine on noradrenaline transporter in cultured bovine adrenal medullary cells.
Previously, it was demonstrated that the inhibitory effects of atypical antipsychotic drugs such as clozapine and risperidone on noradrenaline transporter (NAT) might in part be associated with their clinical profile. The present study examined the effects of zotepine on NAT in the cells and compared them with those of olanzapine. Adrenal medullary cells were isolated by a method of collagenase digestion of slices of fresh bovine adrenal medulla and the cells were plated at a density of 4 x 10(6) cells. Cells were incubated with [3H]noradrenaline (NA) in the presence or absence of zotepine or olanzapine. The amount of radioactivity taken into the cells was counted by a liquid scintillation counter. Plasma membranes of bovine adrenal medulla were prepared, and the binding of [3H]desipramine (DMI) was determined by incubating the membrane suspension in binding buffer together with zotepine or olanzapine. Specific binding of [3H] DMI was defined as that binding which was inhibited by nisoxetine. Both zotepine (10-1000 ng/ml) and olanzapine (10-1000 ng/ml) decreased [3H]NA uptake in a concentration-dependent manner. The IC50 values of zotepine and olanzapine on [3H]NA uptake were 10 +/- 4 and 14 +/- 8 ng/ml, respectively. Eadie-Hofstee analysis of [3H]NA uptake showed that treatment with zotepine and olanzapine decreased the V(max) of uptake without changing the K(m). Both zotepine (10-1000 ng/ml) and olanzapine (30-1000 ng/ml) inhibited [3H]DMI binding in a concentration-dependent manner. The IC50 values of zotepine and olanzapine on [3H]DMI binding were 50 +/- 18, and 120 +/- 38 ng/ml, respectively. Scatchard plot analysis of [3H]DMI binding showed that zotepine and olanzapine decreased the B(max) of binding without altering the K(d). The inhibitory effects of zotepine and olanzapine might be responsible in part for their clinical profile.


Breaking a habit: a further role of the phonological loop in action control.
Recent research has suggested that keeping track of a task goal in rapid task switching may depend on the phonological loop component of working memory. In this study, we investigated whether the phonological loop plays a similar role when a single switch extending over several trials is required after many trials on which one has performed a competing task. Participants were shown pairs of digits varying in numerical and physical size, and they were required to decide which digit was numerically or physically larger. An experimental cycle consisted of four blocks of 24 trials. In Experiment 1, participants in the task change groups performed the numerical-size judgment task during the first three blocks, and then changed to the physical-size judgment task in the fourth. Participants in the continuation groups performed only the physical-size judgment task throughout all four blocks. We found negative effects of articulatory suppression on the fourth block, but only in the task change groups. Experiment 2 was a replication, with the modification that both groups received identical instructions and practice. Experiment 3 was a further replication using numerical-size judgment as the target task. The results showed a pattern similar to that from Experiment 1, with negative effects of articulatory suppression found only in the task change group. The congruity of numerical and physical size had a reliable effect on performance in all three experiments, but unlike the task change, it did not reliably interact with articulatory suppression. The results suggest that in addition to its well-established role in rapid task switching, the phonological loop also contributes to active goal maintenance in longer-term action control.


Myocarditis and Cardiac Complications Associated With COVID-19 and mRNA Vaccination: A Pragmatic Narrative Review to Guide Clinical Practice.
Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus is likely to remain endemic globally despite widespread vaccination. There is increasing concern for myocardial involvement and ensuing cardiac complications due to COVID-19, however, the available evidence suggests these risks are low. Pandemic publishing has resulted in rapid manuscript availability though pre-print servers. Subsequent article retractions, a lack of standardised definitions, over-reliance on isolated troponin elevation and the heterogeneity of studied patient groups (i.e. severe vs. symptomatic vs all infections) resulted in early concern for high rates of myocarditis in patients with and recovering from COVID-19. The estimated incidence of myocarditis in COVID-19 infection is 11 cases per 100,000 infections compared with an estimated 2.7 cases per 100,000 persons following mRNA vaccination. For substantiated cases, the clinical course of myocarditis related to COVID-19 or mRNA vaccination appears mild and self-limiting, with reports of severe/fulminant myocarditis being rare. There is limited data available on the management of myocarditis in these settings. Clinical guidance for appropriate use of cardiac investigations and monitoring in COVID-19 is needed for effective risk stratification and efficient use of cardiac resources in Australia. An amalgamation of national and international position statements and guidelines is helpful for guiding clinical practice. This paper reviews the current available evidence and guidelines and provides a summary of the risks and potential use of cardiac investigations and monitoring for patients with COVID-19.


Orbital rhabdomyosarcoma: case report with immunohistochemical detection of muscle cell type intermediate filament proteins.
A 4 1/2-year-old girl had a rapidly growing tumor in the orbit. An extirpated mass consisted of small round or spindle neoplastic cells containing hyperchromatic mitotic nuclei. The cytoplasm had many lipids and glycogens with few organelles. A light and electron microscopic examination revealed an exceptional tumor cell with distinct cross striations compatible with typical rhabdomyoblast; occasional cells exhibited a few bundles of thin filaments scattered in the cytoplasm. Immunohistochemical studies for muscle cell-related proteins by avidin-biotin-peroxidase complex methods revealed positive reactions of the tumor cells to the antiserum against myoglobin, myosin, desmin and vimentin, providing evidence for muscle cell derivation of the neoplastic cells.


Regulation of growth and differentiation in Dictyostelium.
In general, growth and differentiation are mutually exclusive, but they are cooperatively regulated during the course of development. Thus, the process of a cell's transition from growth to differentiation is of general importance not only for the development of organisms but also for the initiation of malignant transformation, in which this process is reversed. The cellular slime mold Dictyostelium, a wonderful model organism, grows and multiplies as long as nutrients are supplied, and its differentiation is triggered by starvation. A strict checkpoint (growth/differentiation transition or GDT point), from which cells start differentiating in response to starvation, has been specified in the cell cycle of D. discoideum Ax-2 cells. Accordingly, integration of GDT point-specific events with starvation-induced events is needed to understand the mechanism regulating GDTs. A variety of intercellular and intracellular signals are involved positively or negatively in the initiation of differentiation, making a series of cross-talks. As was expected from the presence of GDT points, the cell's positioning in cell masses and subsequent cell-type choices occur depending on the cell's phase in the cell cycle at the onset of starvation. Since novel and somewhat unexpected multiple functions of mitochondria in cell movement, differentiation, and pattern formation have been well realized in Dictyostelium cells, they are reviewed in this article.


[The ligaments and menisci of the femorotibial joint of the wolf (Canis lupus L., 1758)--anatomic and functional analysis in comparison with the domestic dog (Canis lupus f. familiaris)].
Based on dissection of 11 (4 m and 7f) adult wolves (Canis lupus L., 1758) kept in captivity, the morphology and mechanics of the ligaments and menisci of the femorotibial joint are described. Compared with the anatomical data of the dog (Canis lupus f. familiaris), the differences are discussed with respect to their importance for functional considerations.


Clostridium Difficile-Associated Infection in Trauma Patients: Development of the Clostridium Difficile Influencing Factors (CDIF) Score.
Clostridium difficile-associated infection (CDAI) can result in longer hospitalization, increased morbidity, and higher mortality rates for surgical patients. The impact on trauma patients is unknown, however. To assess the effect of CDAI on trauma patients and develop a scoring system to predict CDAI in that population. Records of all trauma patients admitted to a Level I Trauma Center from 2001 to 2014 were retrospectively reviewed. Presence of CDAI was defined as evidence of positive toxin or polymerase chain reaction. Patients with CDAI were matched to patients without CDAI using propensity score matching on a ratio of 1:3. Primary outcome was inhospital mortality. Secondary outcomes included length of stay and need for mechanical ventilation. A decision-tree analysis was performed to develop a predicting model for CDAI in the study population. During the study period, 11,016 patients were identified. Of these, 50 patients with CDAI were matched to 150 patients without CDAI. There were no differences in admission characteristics and demographics. Patients in whom CDAI developed had significantly higher mortality (12% vs 4%, p < 0.01), need for mechanical ventilation (57% vs 23%, p < 0.01), and mean hospital length of stay (15.3 [standard deviation 1.4]) days vs 2.1 [0.6] days, p < 0.0). In trauma patients, CDAI results in significant morbidity and mortality. The C difficile influencing factor score is a useful tool in identifying patients at increased risk of CDAI.


Whole-stream phosphorus cycling: testing methods to assess the effect of saturation of sorption capacity on nutrient uptake length measurements.
The cycling rate of nutrients such as phosphorus (P) is a fundamental parameter in stream ecology. In whole-stream ecosystem experiments, cycling rates are often assessed using continuous short-term nutrient addition studies. While several simplifying assumptions are generally recognised, these are rarely, if ever, fully tested under field conditions. One principal assumption is that uptake (sorption) processes do not become saturated during periods of nutrient addition, which is perhaps questionable from laboratory studies of soluble reactive phosphorus (SRP) sorption kinetics. Three approaches were developed and tested, which bridged the gap between laboratory-based net (sum of uptake and release) sorption kinetics and whole-stream assessments of P uptake. These were applied to a short-term (three times mean travel time of water in the studied reach) whole-stream multiple-rate P addition. The results were then tested independently with a whole-stream long-term (15 times mean travel time) SRP addition. The net sorption kinetics were not altered during the short-term addition with low SRP additions, 9-16 microg L(-1) (two to three times the ambient concentration). Although this may not be the case at higher added concentrations (as possibly hinted at five times the ambient concentration), the long-term addition showed no change in P uptake length with a P addition (39 microg L(-1)) 16 times higher than the ambient concentration.


Relationship Between Low-Density Lipoprotein Cholesterol, Free Proprotein Convertase Subtilisin/Kexin Type 9, and Alirocumab Levels After Different Lipid-Lowering Strategies.
Alirocumab undergoes target-mediated clearance via binding of proprotein convertase subtilisin/kexin type 9 (PCSK9). Statins increase PCSK9 levels; the effects of nonstatin lipid-lowering therapies are unclear. Every-4-weeks dosing of alirocumab may be appropriate for some patients in absence of background statin but is not yet approved. Low-density lipoprotein cholesterol (LDL-C), PCSK9, and alirocumab levels were assessed in subjects (LDL-C >130 mg/dL, n=24/group) after a 4-week run-in taking oral ezetimibe, fenofibrate, or ezetimibe placebo, when alirocumab 150 mg every 4 weeks (days 1, 29, and 57) was added. Maximal mean LDL-C reductions from day -1 baseline (prealirocumab) occurred on day 71 in all groups: alirocumab plus placebo, 47.4%; alirocumab plus ezetimibe, 56.6%; and alirocumab plus fenofibrate, 54.3%. LDL-C reductions were sustained through day 85 with alirocumab plus placebo (47.0%); the duration of effect was slightly diminished at day 85 versus day 71 with ezetimibe (49.6%) or fenofibrate combinations (43.2%). Free PCSK9 concentrations were lowest at day 71 in all groups, then increased over time; by day 85, free PCSK9 concentrations were higher, and alirocumab levels lower, with alirocumab plus fenofibrate, and to a lesser extent alirocumab plus ezetimibe, versus alirocumab plus placebo. Alirocumab 150 mg every 4 weeks produced maximal LDL-C reductions of 47% in combination with placebo and 54% to 57% in combination with ezetimibe or fenofibrate. The oral lipid-lowering therapies appear to increase PCSK9 levels, leading to increased alirocumab clearance. Although the duration of effect was modestly diminished with alirocumab plus ezetimibe/fenofibrate versus placebo, the effect was less than observed in trials with background statins, and it would not preclude the use of alirocumab every 4 weeks in patients taking these nonstatin lipid-lowering therapies concomitantly. URL: http://www.Clinicaltrials.gov. Unique identifier: NCT01723735.


State-dependent indirect pseudospectral method for nonlinear optimal control problems.
The state-dependent Riccati equation (SDRE) method is an efficient approach to solve nonlinear optimal control problems (OCPs), but nonlinear necessary conditions for the first-order optimality are seldom met in the SDRE approach. In this paper, a state-dependent indirect pseudospectral (SDIP) technique is developed to design nonlinear optimal controllers. To preserve the nonlinearity of the system and reduce the computational cost as well, the state-dependent coefficient (SDC) parameterization technique is employed. Then the optimality conditions are derived under input and state constraints, and spectral methods are used to discretize the optimality conditions into a series of mixed linear complementarity problems (MLCPs). The developed SDIP method is able to handle the finite and infinite-horizon nonlinear OCPs in a unified framework. Numerical comparisons also verify the performance of the developed SDIP method.


Susceptibility of the black-legged tick, Ixodes scapularis, to the Lyme disease spirochete, Borrelia burgdorferi.
Experiments to determine whether Ixodes scapularis can be infected with the Lyme disease agent, Borrelia burgdorferi, demonstrated that infection and transstadial transmission occurs in up to 73% of larval ticks that had fed on spirochetemic rabbits. In a limited number of nymphal ticks examined, the spirochetes were found only in the midgut. Feeding nymphal I. scapularis on a normal rabbit resulted in blood infection characterized by two distinct periods of spirochetemia, suggesting the occurrence of a relapse phenomenon similar to that in tick-borne relapsing fevers. This was also indicated by the percentage of infected ticks recovered daily during the experiment. Accordingly, ticks fed during low spirochetemias or negative blood phase, showed low infection rates or were not infected whereas those fed during peak spirochetemias had high infection rates. Of 11 adult I. scapularis examined to date, 6 were infected but the spirochetes were restricted to the midgut. These preliminary findings establish the susceptibility of I. scapularis to B. burgdorferi and the potential role of this tick as an efficient vector of the Lyme disease spirochete.


A report from a conference jointly organised by the European Academy of Cancer Sciences and the Pontifical Academy of Sciences, The Vatican, November 16-17, 2018.
Cancer is a massive challenge with a significant impact on society, healthcare systems, the economy and an increasing number of patients and their families. To help meet this societal challenge, the European Commission has recently proposed a mission-oriented approach to cancer in Horizon Europe, and about 60 participants met at the Vatican to discuss a mission-oriented approach to cancer in Europe, as documented in this report. Painting: Rowe, Ernest Arthur. Courtyard of the Casina Pio IV (ca. 1911-1913).


Identification, expression, and functional analysis of Hsf and Hsp20 gene families in Brachypodium distachyon under heat stress.
The heat shock factor (Hsf) and small heat shock protein (sHsp, also called Hsp20) complex has been identified as a primary component in the protection of plant cells from ubiquitous stresses, particularly heat stress. Our study aimed to characterize and analyze the Hsf and Hsp genes in Brachypodium distachyon, an annual temperate grass and model plant in cereal and grass studies. We identified 24 Hsf and 18 Hsp20 genes in B. distachyon and explored their evolution in gene organization, sequence features, chromosomal localization, and gene duplication. Our phylogenetic analysis showed that BdHsfs could be divided into three categories and BdHsp20s into ten subfamilies. Further analysis showed that the 3'UTR length of BdHsp20 genes had a negative relationship with their expression under heat stress. Expression analyses indicated that BdHsp20s and BdHsfs were strongly and rapidly induced by high-temperature treatment. Additionally, we constructed a complex regulatory network based on their expression patterns under heat stress. Morphological analysis suggested that the overexpression of five BdHsp20 genes enhanced the seed germination rate and decreased cell death under high temperatures. Ultimately, our study provided important evolutionary and functional characterizations for future research on the regulatory mechanisms of BdHsp20s and BdHsfs in herbaceous plants under environmental stress.


Efficacy of tranexamic acid (TXA) for post-tonsillectomy hemorrhage.
To determine if tranexamic acid (TXA) reduces the need for operative re-cauterization in the setting of a post-tonsillectomy hemorrhage (PTH). A retrospective chart review was performed on 1428 adult and pediatric patients who underwent tonsillectomy over a two-year period at a tertiary care hospital with continuous otolaryngologic coverage. Collected data of PTH patients included age, body mass index (BMI), American Society of Anesthesiologists (ASA) classification, length of stay (LOS), the requirement of a blood transfusion, day of PTH, TXA usage and route, complications from TXA administration, and TXA failure requiring operative intervention. The incidence of pediatric PTH during the study period was 5.7 %. Twenty-seven out of fifty-five PTH patients received topical, nebulized, or intravenous TXA. No adverse effects were noted with TXA administration. TXA usage provided resolution of the PTH in 77.8 % of patients. No significant differences were found in age, gender, BMI, LOS, ASA classification, rate of blood transfusion, or TXA treatment modality between the patients that received TXA and those that did not. Treatment of PTH with TXA appears to reduce the need for operative control of PTH. In the setting of reducing operative risk, improving health care utilization, or in a setting without immediate otolaryngologic provider coverage, the role of TXA is promising. Further larger clinical or multi-institution studies are needed to determine the efficacy of TXA, its route of administration, and its optimal dosage. Level 4, Retrospective cohort study.


Emergent Dynamics of Artificial Spin-Ice Lattice Based on an Ultrathin Ferromagnet.
We present high-frequency dynamics of magnetic nanostructure lattices, fabricated in the form of "artificial spin-ice", that possess magnetically frustrated states. Dynamics of such structures feature multiple resonance excitation that reveals rich and intriguing microwave characteristics, which are highly dependent on field-cycle history. Geometrical parameters such as dimensions and ferromagnetic layer thickness, which control the interplay of different demagnetizing factors, are found to play a pivotal role in governing the dynamics. Our findings are highlighted by the evolution of unique excitations pertaining to magnetic frustration, which are well supported by static magnetometry studies and micromagnetic simulations.


Screening assays for tyrosine kinase inhibitors: A review.
Tyrosine kinases have been intensively investigated as drug targets for several decades, since they regulate many cellular processes including cell growth, differentiation, and proliferation. Indeed, the deregulation of tyrosine kinases has been confirmed to play a vital role in the pathophysiology of many diseases. During the last few years, varieties of techniques have been developed to search for new tyrosine kinase inhibitors for cancer therapy, such as traditional filtration binding assay, scintillation proximity assay and some high-throughput screening methods. In this review, we describe the basic rules, merits and demerits, and application of a number of general and advanced technologies. The purpose of this review is to provide an insight into the numerous assays to achieve the exploration of new tyrosine kinase inhibitors.


Facial nerve neuroma in the geniculate ganglion extending into the internal auditory canal: A case report.
Facial nerve schwannoma is a very rare benign tumor representing less than 1% of intrapetrous lesions. Our patient is a forty-one year old female who has suffered from recurrent right facial palsy for the last six years. She was first misdiagnosed as having Bell's palsy and received corticosteroids which resulted in little improvement. She then had facial nerve decompression surgery which resulted in a partial improvement. Since then, she has suffered from recurrent attacks of facial palsy. Two years ago, she came to our hospital seeking further treatment options. The final diagnosis made by MRI was a possible facial nerve tumor. To obtain a better facial outcome, total tumor removal was performed through the middle cranial fossa approach along with facial-hypoglossal nerve end-to-side anastomosis through transmastoid approach. Her hearing was preserved, and she obtained a better facial outcome than that of her preoperative level. In conclusion, facial nerve schwannoma has the potential to be misdiagnosed as Bell's palsy which might lead to a delay in diagnosis, and end-to-side neurorrhaphy may be an effective alternative in a selected case.


Serum methylmalonic acid concentrations at breast cancer diagnosis significantly correlate with clinical frailty.
Methylmalonic acid (MMA), a by-product of propionate metabolism, is known to increase with age. This study investigates the potential of serum MMA concentrations as a biomarker for age-related clinical frailty in older patients with breast cancer. One hundred nineteen patients ≥ 70 years old with early-stage breast cancer were included (median age 76 years). G8 screening, full geriatric assessment, clinical parameters (i.e., estimated glomerular filtration rate (eGFR) and body mass index (BMI)), and serum sample collection were collected at breast cancer diagnosis before any therapy was administered. MMA concentrations were measured via liquid chromatography with tandem mass spectrometry. MMA concentrations significantly increased with age and eGFR (all P < 0.001) in this older population. The group with an abnormal G8 (≤ 14, 51% of patients) had significantly higher MMA levels than the group with normal G8 (> 14, 49%): 260 nmol/L vs. 188 nmol/L, respectively (P = 0.0004), even after correcting for age and eGFR (P = 0.001). Furthermore, in the detailed assessment, MMA concentrations correlated most with mobility (Eastern Cooperative Oncology Group (ECOG) Performance Status and Activities of Daily Living (ADL) tools, all P ≤ 0.02), comorbidity (Charlson Comorbidity Index (CCI) tool, P = 0.005), and polypharmacy (P < 0.001), whereas no significant associations were noted for instrumental ADL (IADL), Mini-Mental State Examination (MMSE), Geriatric Depression Scale-15 (GDS15), Mini Nutritional Assessment-Short Form (MNA-SF), and pain (all P > 0.1). In addition, our results showed that higher MMA levels correlate with poor overall survival in breast cancer patients (P = 0.003). Elevated serum MMA concentrations at initial diagnosis are significantly associated, not only with age but also independently with clinical frailty, suggesting a possible influence of MMA on clinical frailty in older patients with early-stage breast cancer.


Metabolite Signature and Differential Expression of Genes in Washington Navel Oranges (Citrus sinensis) Infected by Spiroplasma citri.
Spiroplasma citri is the pathogen that causes citrus stubborn disease (CSD). Infection of citrus with S. citri has been shown to cause leaf mottling, reduce fruit yield, and stunt tree growth. Fruit from trees exhibiting symptoms of CSD are misshapen and discolored. The symptoms of CSD are easily confused with nutrient deficiencies or symptoms of citrus greening disease. In this study, young Washington navel oranges (Citrus sinensis) were graft-inoculated with budwood originating from trees confirmed to be infected with S. citri. Leaf samples were collected monthly for 10 months for metabolomics and differential gene expression analyses. Significant differences in the concentration of metabolites and expressed genes were observed between control and S. citri-infected trees throughout the experiment. Metabolites and genes associated with important defense and stress pathways, including jasmonic acid signaling, cell wall modification, amino acid biosynthesis, and the production of antioxidant and antimicrobial secondary metabolites, were impacted by S. citri throughout the study, and even prior to symptom development. This work fills a current gap in knowledge surrounding the pathogenicity of S. citri and provides an updated mechanistic explanation for the development of CSD symptoms in S. citri-infected plants.


eHealth 2015 Special Issue: Impact of Electronic Health Records on the Completeness of Clinical Documentation Generated during Diabetic Retinopathy Consultations.
Two years ago, the Diabetic Retinopathy (DRP) and Traumatology clinic of the Department of Ophthalmology and Optometrics at the Medical University of Vienna, Austria switched from paper-based to electronic health records. A customized electronic health record system (EHR-S) was implemented. To assess the completeness of information documented electronically compared with manually during patient visits. The Preferred Practice Pattern for Diabetic Retinopathy published by the American Academy of Ophthalmology was distilled into a list of medical features grouped into categories to be assessed and documented during the management of patients with DRP. The last seventy paper-based records and all electronic records generated since the switch were analyzed and graded for the presence of features on the list and the resulting scores compared. In all categories, clinical documentation was more complete in the EHR group. In our setting, the implementation of an EHR-S showed a statistically significant positive impact on documentation completeness.


Obese mice incur greater myofiber membrane disruption in response to mechanical load compared with lean mice.
Obesity is associated with modified transmembrane signaling events in skeletal muscle, such as insulin signaling and glucose transport. The underlying cause of these obesity-related effects on transmembrane signaling is still unknown. In general, the function of membrane proteins responsible for transmembrane signaling is modulated by the biochemical makeup of the membrane, such as lipid composition, in which they are embedded. Any obesity-related alterations in membrane composition would also be predicted to modify membrane biomechanical properties and membrane susceptibility to mechanical load-induced damage. The primary objective of this study was to investigate whether obesity influences myofiber membrane susceptibility to mechanical damage in skeletal muscle. Myofiber membrane damage was compared between 12-week-old obese, hypercholesterolemic (B6.V Lep(ob) /J) and isogenic, normocholesterolemic control (C57BL6/J) male mice following either normal cage activity or strenuous eccentric exercise (downhill running). Myofiber membrane damage was quantified in perfusion-fixed frozen sections of the gastrocnemius muscle via sarcoplasmic concentration of either albumin (cage activity experiment) or a fluorescent marker that had been injected immediately before activity (eccentric exercise experiment). Obese mice exhibited evidence of increased myofiber membrane damage compared with lean mice after both normal cage activity and eccentric exercise indicating that myofiber membranes of obese mice are more susceptible to mechanical damage in general and that eccentric exercise exacerbates this effect. These observations are consistent with the notion that obesity influences the biochemical and biomechanical properties of myofiber membranes.


Enthalpy-Entropy Compensation in the Binding of Modulators at Ionotropic Glutamate Receptor GluA2.
The 1,2,4-benzothiadiazine 1,1-dioxide type of positive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) are promising lead compounds for the treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind in a cleft formed by the interface of two neighboring ligand binding domains and act by stabilizing the agonist-bound open-channel conformation. The driving forces behind the binding of these modulators can be significantly altered with only minor substitutions to the parent molecules. In this study, we show that changing the 7-fluorine substituent of modulators BPAM97 (2) and BPAM344 (3) into a hydroxyl group (BPAM557 (4) and BPAM521 (5), respectively), leads to a more favorable binding enthalpy (ΔH, kcal/mol) from -4.9 (2) and -7.5 (3) to -6.2 (4) and -14.5 (5), but also a less favorable binding entropy (-TΔS, kcal/mol) from -2.3 (2) and -1.3 (3) to -0.5 (4) and 4.8 (5). Thus, the dissociation constants (Kd, μM) of 4 (11.2) and 5 (0.16) are similar to those of 2 (5.6) and 3 (0.35). Functionally, 4 and 5 potentiated responses of 10 μM L-glutamate at homomeric rat GluA2(Q)i receptors with EC50 values of 67.3 and 2.45 μM, respectively. The binding mode of 5 was examined with x-ray crystallography, showing that the only change compared to that of earlier compounds was the orientation of Ser-497 pointing toward the hydroxyl group of 5. The favorable enthalpy can be explained by the formation of a hydrogen bond from the side-chain hydroxyl group of Ser-497 to the hydroxyl group of 5, whereas the unfavorable entropy might be due to desolvation effects combined with a conformational restriction of Ser-497 and 5. In summary, this study shows a remarkable example of enthalpy-entropy compensation in drug development accompanied with a likely explanation of the underlying structural mechanism.


Floating novel object recognition in adult zebrafish: a pilot study.
The novel object recognition (NOR) tasks can be used to quantify memory function in zebrafish similarly to rodents. The development of zebrafish learning and memory tests provides a means for testing the effects of pharmacological manipulations of memory. Several authors reported on the successful application of different objects in NOR tests placed either at the bottom of test tanks or submerged into the tank water of zebrafish. This pilot study was designed to test the suitability of floating objects in NOR tests using adult zebrafish. Floating objects such as crumpled aluminum balls and pink plastic hollow pearls were found to be suitable for NOR tests when small groups of zebrafish are used as experimental animals. Adult zebrafish of both sexes were capable of distinguishing between the different colors and surface consistencies of certain floating objects. A significantly higher number of mouth-object contacts were recorded when either floating aluminum balls or floating plastic pearls were used as novel object during NOR tests.


Current status of lipid management in acute coronary syndrome.
The development of coronary revascularization has dramatically improved early cardiovascular outcomes in patients with acute coronary syndrome (ACS). However, patients who have experienced myocardial infarction (MI) are at high risk of recurrence of cardiovascular events compared with those who are healthy or have stable coronary artery disease. Acute coronary events induce further inflammatory responses and plaque vulnerability in either a coronary culprit or whole vessels. The majority of data have supported the importance of coronary risk management to prevent secondary events. Dyslipidemia is common and one of the therapeutic targets in patients with ACS. Statins can reduce coronary plaque burden and lower the risk of cardiovascular death, recurrent MI, stroke, and coronary revascularization in patients with ACS. Growing evidence from clinical trials and meta-analyses supports early, intensive, and continuous therapy with statins in patients with ACS. Statins are accepted worldwide as the first-line lipid-lowering therapy as guidelines recommend. However, some patients do not reach the target level of low-density lipoprotein cholesterol by statins alone or are contra-indicated for statins. Recently, several clinical trials showed the further benefit of ezetimibe combined with statins on cardiovascular outcomes and coronary plaque regression in patients with ACS. In addition, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, novel and powerful lipid-lowering agents, have been developed and used in clinical settings. In this review, we summarize the present statin therapy, and refer to ezetimibe and PCSK9 as novel or additional non-statin strategies in the management of ACS.


Influence of phenolic compounds on color formation at different stages of the VHP sugar manufacturing process.
Phenolic compounds are natural dyes contained in sugarcane juice and represent an important parameter in industrial processing, as they significantly affect the color formation of raw sugar. This study investigated the relationship between color formation and phenolic compounds during a Very High Polarization (VHP) sugar manufacturing process, in which the RB92579 genotype represents about 50% of the processed sugarcane. The products evaluated during the industrial processing of sugarcane were: raw juice, mixed juice, lime-treated juice, clarified juice, syrup, massecuite, and VHP sugar. The polyphenols catechin (CAT), chlorogenic acid (CGA), caffeic acid (CAF), vanillin (VAN), syringaldehyde (SYR), p-coumaric acid (p-COU), coumarin (CUM), and rutin (RUT) were quantified by high-performance liquid chromatography (HPLC). The highest concentrations of CGA and SYR were obtained from the sucrose crystallization product (massecuite), similarly to the parameters of color, total phenols and the total polyphenol content. CGA was the predominant polyphenol in the samples of clarified juice, syrup, massecuite and VHP sugar, with the latter presenting concentrations above 50%. The presence of phenolic compounds provided different indices of color during the production process. In this context, chlorogenic acid (CGA) was the compound that presented the most expressive results, contributing significantly to the formation of color in sugarcane processing products, which is a fact that has not yet been reported in the literature. The color of the VHP sugar crystals also had a positive relationship with the concentration of phenolics, with greater evidence for CGA.


Changes of resistance parameters of femoral bone in adult female rats after application of zoladex and vincristin.
The study consisted in testing the influence of vincristin and zoladex on mechanical resistance of the femur bone in adult female rats. Vincristin was administered intraperitoneally and zoladex--subcutaneously. The experiments imply that in the group of animals receiving vincristin the bone resistance decreased by 6.4% as compared to the control group, and in the group of animals receiving zoladex--by 14.3%.


Structure, staffing, and factors affecting infection control nurses: Hospital based exploratory survey- A study protocol.
The overall aim of the study is to develop a module for the structure, staffing, job responsibilities, training and workflow for the hospital Infection Control Department. An exploratory research design in two phases. Phase 1: Hospital based exploratory survey design. Phase 2: Delphi technique with Focus Group Discussion. Data will be collected through interviewing Infection Control Nurses (ICNs) or infection control in-charge using Infection Prevention and Control Assessment Framework (IPCAF) released by World Health Organization (WHO) in the first phase and Delphi technique in the second phase to determine the problems and solutions for the concerns pertaining to the ICNs. The study is funded by Indian Council of Medical Research from 15 October 2019 for 3 years duration. Healthcare Associated Infection (HAI) affects the care quality of millions of people around the globe. Many researchers have explored the evidence for causes and measures to contain infection. However, there are hardly few researches from the perspective to structure, staffing pattern and factors affecting ICNs. As staffing is considered as a vital component in infection prevention, there is a necessity for optimization to reduce the global burden related to HAI. This protocol on Structure, staffing, and factors affecting ICN will provide insight into developing strategy, policy or educational module for the ICNs across the country. The trial is registered with Central Trial Registry of India (CTRI) with reference ID: CTRI/2020/07/026286.


Increasingly Ruth: toward understanding sex reassignment.
Both the clinician and the patient present accounts of a 44-year-old male's search for a comfortable gender identity. The juxtaposition of these two perspectives illustrates many of the dilemmas inherent in the therapy of gender dysphoria. Ruth underwent sex reassignment surgery in 1976--one year after the assumption of a full-time female gender role. Six months after surgery, she made a serious suicide attempt. At age 50, she has now consolidated her feminine gender identity and has become a thoughtful, unusually honest, articulate person. The physician's "objective" and the patient's retrospective perspectives provide evidence of the psychodynamic nature of transsexualism and the limitations of evaluation criteria for sex reassignment surgery.


Combined effect of daily physical activity and social relationships on sleep disorder among older adults: cross-sectional and longitudinal study based on data from the Kasama study.
This study investigated whether daily physical activity of older adults, combined with social relationships, is associated with the risk of sleep disorder. Further, it determined whether a high level of one variable with a low level of the other, leads to a significantly lower risk of sleep disorder than low levels of both. The sample comprised 1339 community-dwelling older Japanese adults: 988 in Study 1 and 351 in Study 2. The level of daily physical activity and range of social relationships were assessed using the Physical Activity Scale for the Elderly and the Lubben Social Network Scale, respectively. The Pittsburgh Sleep Quality Index was used to assess sleep disorder. To test the combined relationships and effects in Studies 1 and 2, the medians for the respective scores of each of the following four groups that the participants were categorized into, were calculated: (1) low activity group with low social relationships, (2) low activity group with high social relationships, (3) high activity group with low social relationships, and (4) high activity group with high social relationships. After adjusting for potential confounders, a logistic regression analysis was conducted in Study 1. After adjusting for potential confounders, a Cox proportional hazards regression analysis was conducted in Study 2. Study 1 revealed that the high activity group with high social relationships showed a significantly lower risk of sleep disorder (ORs: 0.585, 95% CI: 0.404-0.847) than the low activity group with low social relationships. Study 2 also revealed that the high activity group with high social relationships showed a significantly lower prevalence of sleep disorder (HRs: 0.564, 95% CI: 0.327-0.974) than the low activity group with low social relationships. Our findings suggest that for older adults with high social relationships, being physically active is favorably associated with sleep quality. However, a high level of one variable with a low level of the other has not been confirmed in improving sleep quality among older adults.


Damage to apparel layers and underlying tissue due to hand-gun bullets.
Ballistic damage to the clothing of victims of gunshot wounds to the chest can provide useful forensic evidence. Anyone shot in the torso will usually be wearing clothing which will be damaged by the penetrating impact event and can reportedly be the source of some of the debris in the wound. Minimal research has previously been reported regarding the effect of bullets on apparel fabrics and underlying tissue. This paper examines the effect of ammunition (9 mm full metal jacket [FMJ] DM11 A1B2, 8.0 g; and soft point flat nose Remington R357M3, 10.2 g) on clothing layers that cover the torso (T-shirt, T-shirt plus hoodie, T-shirt plus denim jacket) and underlying structures represented by porcine thoracic wall (skin, underlying tissue, ribs). Impacts were recorded using a Phantom V12 high speed camera. Ejected bone debris was collected before wound tracts were dissected and measured; any debris found was recovered for further analysis. Size and mass of bony debris was recorded; fibre debris recovered from the wound and impact damage to fabrics were imaged using scanning electron microscopy (SEM). Remington R357M3 ammunition was characteristically associated with stellate fabric damage; individual fibres were less likely to show mushrooming. In contrast, 9 mm FMJ ammunition resulted in punch-out damage to fabric layers, with mushrooming of individual fibres being more common. Entry wound sizes were similar for both types of ammunition and smaller than the diameter of the bullet that caused them. In this work, the Remington R357M3 ammunition resulted in larger exit wounds due to the bullet construction which mushroomed. That fabric coverings did not affect the amount of bony debris produced is interesting, particularly given there was some evidence that apparel layers affected the size of the wound. Recent work has suggested that denim (representative of jeans) can exacerbate wounding caused by high-velocity bullet impacts to the thigh when the bullet does not impact the femur. That more bony debris was caused by Remington R357M3 rather than 9 mm FMJ ammunition was not surprising given the relative constructions of these two bullets, and is of interest to medical practitioners.


Induced cell toxicity originates dendritic cell death following magnetic hyperthermia treatment.
Magnetic hyperthermia (MH) is based on the use of magnetic nanoparticles (MNPs) to selectively increase the temperature of MNP-loaded target tissues when applying an alternating magnetic field (AMF) in the range of radiofrequency. To date, all MH research has focused on heat generation in an attempt to elucidate the mechanisms for the death of MNP-loaded cells submitted to AMF. However, recent in vitro studies have demonstrated the feasibility of inducing dramatic cell death without increasing the macroscopic temperature during AMF exposure. Here, we show that the cell death observed following AMF exposure, specifically that of MNP-loaded dendritic cells (DCs) in culture, was caused by the release of toxic agents into the cell culture supernatants and not due to a macroscopic temperature increase. We performed MH in vitro experiments to demonstrate that the supernatant of the cell culture following AMF exposure was highly toxic when added to control unloaded DCs, as this treatment led to nearly 100% cell death. Therefore, our results demonstrate that heat is not the only agent responsible for triggering cell death following MH treatment. This finding offers new perspectives for the use of DCs as the proverbial Trojan horse to vectorise MNPs to the target tumour area and these results further support the use of DCs as therapeutic agents against cancer when submitted to AMF. Furthermore, this discovery may help in understanding the mechanism of cell death mediated by exposure to AMF.


A straight choice: avoiding septal re-deviation using titanium plates. A 16 year retrospective patient follow-up evaluation.
To propose a new surgical technique for fixing the nasal septum to the midline, for long term prevention of nasal obstruction, in secondary and select cases of primary septoplasty. Retrospective study, within hospital medical center. Two hundred and twenty two patients who underwent septoplasty. Data collection occurred consecutively between March 1st of 2000 and May 1st 2016. Twenty six percent females and seventy four percent males. Patterns of septal deformity, materials used for titanium plates, surgical results, symptom improvement, and surgical complications were investigated. A total of 222 patients were included in this study. 163 patients (73%) had no previous nasal surgery. Fifty nine patients (27%) presented with a previous nasal surgery. Sixteen year follow up included more than 90% of patients and resulted in an overall 2.7% revision rate. The use of titanium plate for septoplasty has shown to be simple, safe, and easy to learn technique in both secondary and select cases of primary septoplasty. Most importantly the results indicate a long term prevention of the.


Neurological Complications of Cardiac Tumors.
This article reviews recent literature regarding the neurological manifestations of cardiac tumors, including diagnosis, pathophysiology, and treatment. Clinical cases of patients with acute ischemic stroke due to cardiac tumors who were treated with intravenous alteplase show a favorable safety profile. Mechanical thrombectomy seems to be a reasonable treatment alternative for these patients, when there is a large vessel occlusion. Histopathology analysis of mechanical thrombectomy specimens may allow the diagnosis of a cardiac tumor. Prolonged time interval between stroke and tumor excision surgery is significantly associated with stroke recurrence. Myxomatous aneurysms are a late complication of cardiac myxomas, which commonly demand imaging follow-up after excision of the primary tumor. Aneurysms are more frequent in patients who present with other embolic complications. Conservative treatment of myxomatous aneurysms is a reasonable strategy, as the majority of aneurysms remain stable over many years. Spontaneous regression of these formations has been documented after excision of the primary tumor. Other complications recently described include acute psychosis and mononeuropathy multiplex. Cardiac tumors are rare. There are mainly case reports and retrospective case series describing the neurological manifestations of cardiac tumors. Hyperacute stroke treatment seems to be safe, and mechanical thrombectomy is a reasonable treatment. A conservative approach towards myxomatous aneurysms should be considered.


Estimation of prevalence and incidence based on occurrence of health-related events.
A new method for estimating incidence and prevalence is developed, which only requires observation of occurrence of health-related events within a given time window. Occurrence data are often easy to collect but estimating incidence and prevalence of a disease from such data is non-trivial, since the true disease status is not directly observed for all at the beginning of the study period. Our method for overcoming this problem is based on an idea first presented in 'The waiting time distribution as a graphical approach to epidemiologic measures of drug utilization' (Epidemiology 1997; 8:666-670). Their fundamental idea is to analyse the waiting time from start of the window to the first event of each individual, and we formalize this by establishing a parametric likelihood which allows ordinary maximum likelihood analysis and explicit modelling of censoring. The developed method is used to analyse incidence and prevalence of hypertension in a Danish cohort of 70+-year-olds. A simulation study on the finite sample properties of the method is reported, which indicates that the method gives a quite robust and cost-effective alternative to ordinary surveys and follow-up studies for estimating incidence and prevalence.


Potency matters: Impacts of embryonic exposure to nAChR agonists thiamethoxam and nicotine on hatching success, growth, and neurobehavior in larval zebrafish.
Thiamethoxam (TM) is a neonicotinoid insecticide that acts as a nicotinic acetylcholine receptor (nAChR) agonist. While designed to specifically target invertebrate nAChRs, recent studies have reported adverse effects of neonicotinoid exposure in early life-stage fish. This study examined the health and neurobehavioral impacts of chronic exposure to various concentrations of TM or nicotine (NIC) in early life zebrafish (Danio rerio) in conjunction with in-silico molecular docking to compare their ligand-receptor interactions with vertebrate nAChR. Chronic exposure to both reduced survival by approximately 20% (163 µg TM/l) and 25-100% (≥0.49 µg NIC/l). Hatching and growth were impaired following exposure to ≥0.21 µg TM/l or 4.9 µg NIC/l. Both TM and NIC produced morphological and behavioral indicators of neurotoxicity, with more potent effects following NIC exposure. NIC impaired embryonic motor activity by 40% (49 µg NIC/l), while both TM and NIC significantly altered predator escape response in larvae, specifically the latency and the initial burst movement of the response were impacted. Molecular docking predicted variations in the type and strength of interactions that occur between NIC or TM and vertebrate nAChR. These findings demonstrate that chronic exposure to TM might impact general health and neurobehavior of early-stage zebrafish. Our data support hypotheses that TM presents low affinity for vertebrate nAChR but may still pose an adverse risk to larval fish growth and neurobehavior.


Detection of skin thickness and density in healthy Chinese people by using high-frequency ultrasound.
Due to a recent development of high-frequency ultrasound (HFUS) systems, it is easier to realize high-resolution in vivo imaging of the biological tissues. The object of this study was to map the thickness and echo density of skin layers in healthy Chinese people and assess the influence of gender, age, and region on it. A total of 189 volunteers (85 male, 104 female) with age range of 22-75-year old (mean age of 41.2-year old) were enrolled. The thickness and density of the epidermis and dermis layer were detected by high-frequency (22 or 75 MHz) ultrasonography at 13 different anatomical sites, including the forehead, cheeks, flexor and extensor forearms, flexor and extensor upper arms, inner and outer legs, inner and outer thighs, back, and abdomen. The thickness and density of epidermis/dermis between different anatomical sites were statistically significant (p < 0.05). The epidermis thickness of the face and trunk were less than that of the limbs, whereas the thicknesses of the dermis were on the contrary. The density of the epidermis/dermis of the face and trunk were less than that of the limbs. The thickness of dermis in most of the sites were higher in male than in female, and the density of epidermis and dermis in most of the sites were less in men than in women. The thicknesses/densities of dermis were lower in older age group in almost all sites, whereas only several sites reached statistical. The difference between the north and south regions showed the environment also influenced the thickness and density of the skin. HFUS provides a simple noninvasive method for evaluating the skin thickness and echo-density, which, reflecting intradermal structure, exhibit systematic regional variation. With the establishment of Chinese phenotypic database of skin thickness and density, it will be helpful for the skin disease assessment, skin surgery, and cosmetology technology.


The impact of pharmacist-led medication reconciliation and interprofessional ward rounds on drug-related problems at hospital discharge.
During transitions of care, including hospital discharge, patients are at risk of drug-related problems (DRPs). To investigate the impact of pharmacist-led services, specifically medication reconciliation at admission and/or interprofessional ward rounds on the number of DRPs at discharge. In this retrospective, single-center cohort study, we analyzed routinely collected data of patients discharged from internal medicine wards of a regional Swiss hospital that filled their discharge prescriptions in the hospital's community pharmacy between June 2016 and May 2019. Patients receiving one of the two or both pharmacist-led services (Study groups: Best Care = both services; MedRec = medication reconciliation at admission; Ward Round = interprofessional ward round), were compared to patients receiving standard care (Standard Care group). Standard care included medication history taken by a physician and regular ward rounds (physicians and nurses). At discharge, pharmacists reviewed discharge prescriptions filled at the hospital's community pharmacy and documented all DRPs. Multivariable Poisson regression analyzed the independent effects of medication reconciliation and interprofessional ward rounds as single or combined service on the frequency of DRPs. Overall, 4545 patients with 6072 hospital stays were included in the analysis (Best Care n = 72 hospital stays, MedRec n = 232, Ward Round n = 1262, and Standard Care n = 4506). In 1352 stays (22.3%) one or more DRPs were detected at hospital discharge. The combination of the two pharmacist-led services was associated with statistically significantly less DRPs compared to standard care (relative risk: 0.33; 95% confidence interval: 0.16, 0.65). Pharmacist-led medication reconciliation alone showed a trend towards fewer DRPs (relative risk: 0.75; 95% confidence interval: 0.54, 1.03). Our results support the implementation of pharmacist-led medication reconciliation at admission in combination with interprofessional ward rounds to reduce the number of DRPs at hospital discharge.


Oxidative stress indicators and trace element concentrations in tissues of mako shark (Isurus oxyrinchus).
Liver, kidney and muscle from juvenile mako sharks (Isurus oxyrinchus) were collected in Baja California Sur. Lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As) concentrations were determined by atomic absorption spectrophotometry. The production of superoxide radical (O2(•-)) was measured as an indicator of reactive oxygen species production; lipid peroxidation (TBARS) and protein carbonyl levels were quantified as indicators of oxidative damage, and the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) was assessed as indicator of antioxidant defenses. Two discriminant functions separated muscle from liver and kidney samples. Cd concentration was lower in muscle than in kidney (p<0.05) and Hg concentration was higher in muscle than in liver and kidney (p<0.05). Although GR and SOD activities were higher, oxidative damage (TBARS and carbonyl protein levels) was also higher in kidney (p<0.05). SOD activity, TBARS levels, and Cd and Hg concentration were the set of predictors with significant relevance during tissue discrimination. Tissue metabolism, physiology of the organisms and environmental factors may be related to the differences in trace elements and oxidative stress indicators found in muscle, liver and kidney of the mako shark.


Photoreactivation of UV damage in Escherichia coli uvrA6: lethality is more effectively reversed than either premutagenic lesions or SOS induction.
The effect of cyclobutyl pyrimidine dimers on cytotoxicity, induction of synthesis of the RecA and UmuC proteins, and mutagenesis was studied in Escherichia coli uvrA6 cells possessing excess amounts of photoreactivating enzyme. Exposure of 254 nm ultraviolet-irradiated (10 J/m2) cells to radiation from daylight fluorescent lamps reduced the amounts of thymine-containing dimers in a photoreactivating fluence-dependent manner, up to about 90% reduction at 5 min exposure. Of the lethal ultraviolet damage, 85% was photoreactivable (i.e. cyclobutyl pyrimidine dimers) and 15% was non-photoreactivable. An incident fluence of 1 J/m2 resulted in approximately a 5-fold increase in the synthesis of the RecA and UmuC proteins, as compared to the spontaneous level. If the UV-irradiated cell suspensions were illuminated with a fluorescent lamp at a dose which resulted in the full photoreactivation of viability, the yields of both proteins were reduced to 60% of the non-photoreactivated control cells. Furthermore, photoreactivation was shown to be more effective in the repair of lethal damage than in the repair of premutational damage. These experiments suggest that, among lethal damages, non-photoreactivable damage plays a more important role in both induction of the SOS functions and mutagenesis in uvrA6 cells than do cyclobutyl pyrimidine dimers.


Implementing guided ICBT for chronic pain and fatigue: A qualitative evaluation among therapists and managers.
Internet-based cognitive behavioural therapy (ICBT) for chronic pain and chronic fatigue syndrome (CFS) has a high potential to increase the number of patients who can receive an evidence based treatment aimed to reduce symptoms and/or disability and to lower burden on (mental) health care. However, implementing a new behaviour-change intervention, and especially an online intervention, has shown to be a challenge. This study aimed to identify factors influencing the implementation process of ICBT for chronic pain and CFS in mental health care. A qualitative study using semi-structured interviews with therapists and managers from twelve mental health care clinics was conducted. Questions and analysis were guided by the Consolidated Framework for Implementation Research (CFIR), covering five domains: (1) the implemented intervention, (2) individual characteristics of the users, (3) the inner setting of implementation, (4) the outer setting, and (5) the implementation process. In all five domains important facilitators and barriers were found. Key themes were: (1) the quality of the content, its perceived effectiveness and usability, (2) the attitude, self-efficacy and ability to learn new skills among therapists, and motivation to start online treatment among patients, (3) internal communication within a team, existing workload, and top-down support from the management, (4) availability of reimbursement options and marketing strategies, and (5) involvement of all key stakeholders, steering towards independence of the implementation sites during the process and adequate training of therapists. This study provides insight in the challenge of implementing ICBT for chronic pain and CFS in daily clinical practice. Several lessons can be learned from the interviews with therapists and managers which can also be more broadly applied to (ICBT) implementation projects in general. Development of practical tools to support the implementation process would be a valuable next step to overcome certain challenges at forehand and to properly prepare for those expected to come along.


Functional nucleic acid engineered double-barreled nanopores for measuring sodium to potassium ratio at single-cell level.
The use of double-barreled nanopipette (θ-nanopipette) to electrically sample, manipulate, or detect biomaterials has recently seen strong growth in single-cell studies, driven by the potential of the nanodevices and applications that they may enable. Considering the pivotal roles of Na/K ratio (RNa/K) at cellular level, herein we describe an engineered θ-nanopipette for measuring single-cell RNa/K. The two independently addressable nanopores, located within one nanotip, allow respective customization of functional nucleic acids but simultaneous deciphering of Na and K levels inside a single cell of a non-Faradic manner. Two ionic current rectification signals, corresponding to the Na- and K-specific smart DNA responses, could be easily used to derive the RNa/K. The applicability of this nanotool is validated by practical probing intracellular RNa/K during the drug-induced primary stage of apoptotic volume decrease. Especially, the RNa/K has been shown by our nanotool to be different in cell lines with different metastatic potential. This work is expected to contribute to futuristic study of single-cell RNa/K in various physiological and pathological processes.