Influence of blood pressure reduction on composite cardiovascular endpoints in clinical trials.
The use of a composite cardiovascular endpoint (CCEP) is frequent in clinical trials. However, the relation between the reduction in blood pressure (BP) and the risk of CCEP is poorly known. We conducted a meta-analysis of trials, which compared different BP-lowering agents with placebo or active treatments in patients with hypertension or composite features of high cardiovascular risk. The outcome measure was a triple (myocardial infarction, stroke and cardiovascular death) or quadruple (those mentioned above and congestive heart failure) CCEP. Thirty trials fulfilled the inclusion criteria, for a total of 221 024 patients. Experimental treatments reduced the risk of CCEP by 9% (P < 0.0001). In a multivariable meta-regression analysis, for each 5-mmHg reduction in SBP, there was a 13% less risk of CCEP (95% confidence interval 8-19, P = 0.001) and, for each 2-mmHg reduction in DBP, there was a 12% less risk of CCEP (95% confidence interval 7-16, P = 0.001). Use of triple or quadruple CCEP (P = 0.150), its definition as primary or nonprimary endpoint (P = 0.305) and use of placebo or active control as comparators (P = 0.552) did not influence the estimates. A different BP reduction of at least 4.6 mmHg in SBP or at least 2.2 mmHg in DBP was required to achieve a 95% prediction interval entirely lying below the unity. BP reduction is important to reduce the risk of CCEP in clinical trials. A significant difference between two treatment groups in the risk of CCEP may be anticipated for a SBP/DBP reduction differing by 4.6/2.2 mmHg or more.


Estimation of wrist angle from sonomyography using support vector machine and artificial neural network models.
Sonomyography (SMG) is the signal we previously termed to describe muscle contraction using real-time muscle thickness changes extracted from ultrasound images. In this paper, we used least squares support vector machine (LS-SVM) and artificial neural networks (ANN) to predict dynamic wrist angles from SMG signals. Synchronized wrist angle and SMG signals from the extensor carpi radialis muscles of five normal subjects were recorded during the process of wrist extension and flexion at rates of 15, 22.5, and 30cycles/min, respectively. An LS-SVM model together with back-propagation (BP) and radial basis function (RBF) ANN was developed and trained using the data sets collected at the rate of 22.5cycles/min for each subject. The established LS-SVM and ANN models were then used to predict the wrist angles for the remained data sets obtained at different extension rates. It was found that the wrist angle signals collected at different rates could be accurately predicted by all the three methods, based on the values of root mean square difference (RMSD<0.2) and the correlation coefficient (CC>0.98), with the performance of the LS-SVM model being significantly better (RMSD<0.15, CC>0.99) than those of its counterparts. The results also demonstrated that the models established for the rate of 22.5cycles/min could be used for the prediction from SMG data sets obtained under other extension rates. It was concluded that the wrist angle could be precisely estimated from the thickness changes of the extensor carpi radialis using LS-SVM or ANN models.


Management of a Fragmented Angiocatheter During Central Venous Cannulation: A Case Report and Important Lessons.
Complications during central venous catheter (CVC) insertion are infrequent with an incidence of 0.1%-1%. We experienced a rare CVC complication with fragmentation of the angiocatheter at its hub during central venous cannulation while utilizing the modified Seldinger technique (ie, wire through the catheter technique). Vascular surgery was emergently required to remove the catheter fragment from the neck. Clinicians must remain vigilant during all aspects of CVC insertion, including awareness of the potential for fragmentation of the angiocatheter during its removal over the in situ guidewire. Prompt recognition and appropriate management included leaving the guidewire in place (to stabilize the distal fragmented segment) and promptly consulting vascular surgery for removal before potential vascular embolization of the angiocatheter fragment. We further recommend that all components of the insertion kit be inspected before and after patient use.


The effect of strain and age on the mechanical properties of rat Achilles tendons.
Achilles tendon (AT) ruptures are common in the middle age population; however, the pathophysiology and influence of age on AT ruptures is not fully understood. This study evaluates the effect and interactions between, strain and age on the in vitro biomechanical properties of ATs. Bilateral ATs were harvested from 17 young (8 months) and 14 middle-aged (24 months) rats and underwent stress-relaxation using Fung's quasilinear viscoelastic (QLV) modeling and load-to-failure testing. The initial viscoelastic response (parameter B) in middle-age animals was dependent on the amount of strain applied to the tendon and was significantly increased in middle-aged animals at higher strain. Higher strain in older animals led to a prolonged relaxation time (parameter tau 2). There was a trend toward an increased magnitude of the relaxation response (parameter C) at higher strain in the middle-aged animals. Middle-aged animals had a significantly lower mean stress at ultimate failure (p=0.01), while Young's modulus was similar in both groups (p=0.46). The passive biomechanical properties of the rat AT change with age and the influence stress-relaxation response of the AT, thereby possibly predisposing the AT of older animals to fail at lower loads compared to younger animals. Not applicable, this is a basic science study.


Familial resemblance in trabecular and cortical volumetric bone mineral density and bone microarchitecture as measured by HRpQCT.
To estimate the heritability of bone geometry, volumetric bone mineral density (vBMD) and microarchitecture of trabecular (Tb) and cortical (Ct) bone measured by high resolution peripheral quantitative computerised tomography (HRpQCT) at the distal radius and tibia and to investigate the genetic correlations of these measures. Participants were 177 mother-offspring pairs from 162 families (mothers, mean age (SD) = 52.1 (4.7) years; offspring, 25.6 (0.73) years). Trabecular and cortical bone measures were obtained by HRpQCT. Multivariable linear regression was used to analyse the association of bone measures between mother and offspring. Sequential Oligogenic Linkage Analysis Routines (SOLAR) software was utilised to conduct quantitative genetic analyses. All maternal bone measures were independently associated with the corresponding bone measures in the offspring before and after adjustment for age, sex, weight and height. Heritability estimates ranged from 24% to 67% at the radius and from 42% to 74% at the tibia. The relationship for most bone geometry measures was significantly stronger in mother-son pairs (n = 107) compared with mother-daughter pairs (n = 70) (p < 0.05). In contrast, the heritability for most vBMD and microarchitecture measures were higher in mother-daughter pairs. Bivariate analyses found moderate to strong genetic correlations across all measures between radius and tibia (Rg = 0.49 to 0.93). Genetic factors have an important role in the development of bone geometry, vBMD and microarchitecture. These factors are strongly shared for the radius and tibia but vary by sex implying a role for imprinting.


MaABI5 and MaABF1 transcription factors regulate the expression of MaJOINTLESS during fruit abscission in mulberry (Morus alba L.).
Mulberry holds significant economic value. However, during the ripening stage of its fruit, the phenomenon of abscission, resulting in heavy fruit drop, can severely impact the yield. The formation of off-zone structures is a critical factor in the fruit abscission process, and this process is regulated by multiple transcription factors. One such key gene that plays a significant role in the development of the off-zone in the model plant tomato is JOINTLESS, which promotes the expression of abscission-related genes and regulates the differentiation of abscission zone tissue cells. However, there is a lack of information about fruit abscission mechanism in mulberry. Here, we analyzed the MaJOINTLESS promoter and identified the upstream regulators MaABF1 and MaABI5. These two regulators showed binding with MaJOINTLESS promoter MaABF1 (the ABA Binding Factor/ABA-Responsive Element Binding Proteins) activated the expression of MaJOINTLESS, while MaABI5 (ABSCISIC ACID-INSENSITIVE 5) inhibited the expression of MaJOINTLESS. Finally, the differentially expressed genes (DEGs) were analyzed by transcriptome sequencing to investigate the expression and synergistic relationship of endogenous genes in mulberry during abscission. GO classification and KEGG pathway enrichment analysis showed that most of the DEGs were concentrated in MAPK signaling pathway, flavonoid biosynthesis, citric acid cycle, phytohormone signaling, amino acid biosynthesis, and glycolysis. These results provide a theoretical basis for subsequent in-depth study of physiological fruit abscission in mulberry.


Validating Patient-Specific Finite Element Models of Direct Electrocortical Stimulation.
Direct electrocortical stimulation (DECS) with electrocorticography electrodes is an established therapy for epilepsy and an emerging application for stroke rehabilitation and brain-computer interfaces. However, the electrophysiological mechanisms that result in a therapeutic effect remain unclear. Patient-specific computational models are promising tools to predict the voltages in the brain and better understand the neural and clinical response to DECS, but the accuracy of such models has not been directly validated in humans. A key hurdle to modeling DECS is accurately locating the electrodes on the cortical surface due to brain shift after electrode implantation. Despite the inherent uncertainty introduced by brain shift, the effects of electrode localization parameters have not been investigated. The goal of this study was to validate patient-specific computational models of DECS against in vivo voltage recordings obtained during DECS and quantify the effects of electrode localization parameters on simulated voltages on the cortical surface. We measured intracranial voltages in six epilepsy patients during DECS and investigated the following electrode localization parameters: principal axis, Hermes, and Dykstra electrode projection methods combined with 0, 1, and 2 mm of cerebral spinal fluid (CSF) below the electrodes. Greater CSF depth between the electrode and cortical surface increased model errors and decreased predicted voltage accuracy. The electrode localization parameters that best estimated the recorded voltages across six patients with varying amounts of brain shift were the Hermes projection method and a CSF depth of 0 mm (r = 0.92 and linear regression slope = 1.21). These results are the first to quantify the effects of electrode localization parameters with in vivo intracranial recordings and may serve as the basis for future studies investigating the neuronal and clinical effects of DECS for epilepsy, stroke, and other emerging closed-loop applications.


Gigapixel surface imaging of radical prostatectomy specimens for comprehensive detection of cancer-positive surgical margins using structured illumination microscopy.
Achieving cancer-free surgical margins in oncologic surgery is critical to reduce the need for additional adjuvant treatments and minimize tumor recurrence; however, there is a delicate balance between completeness of tumor removal and preservation of adjacent tissues critical for normal post-operative function. We sought to establish the feasibility of video-rate structured illumination microscopy (VR-SIM) of the intact removed tumor surface as a practical and non-destructive alternative to intra-operative frozen section pathology, using prostate cancer as an initial target. We present the first images of the intact human prostate surface obtained with pathologically-relevant contrast and subcellular detail, obtained in 24 radical prostatectomy specimens immediately after excision. We demonstrate that it is feasible to routinely image the full prostate circumference, generating gigapixel panorama images of the surface that are readily interpreted by pathologists. VR-SIM confirmed detection of positive surgical margins in 3 out of 4 prostates with pathology-confirmed adenocarcinoma at the circumferential surgical margin, and furthermore detected extensive residual cancer at the circumferential margin in a case post-operatively classified by histopathology as having negative surgical margins. Our results suggest that the increased surface coverage of VR-SIM could also provide added value for detection and characterization of positive surgical margins over traditional histopathology.


Neofiscalin A and fiscalin C are potential novel indole alkaloid alternatives for the treatment of multidrug-resistant Gram-positive bacterial infections.
Ten indole alkaloids were obtained from the marine sponge-associated fungus Neosartorya siamensis KUFA 0017. We studied the antimicrobial properties of these and of three other compounds previously isolated from the soil fungus N. siamensis KUFC 6349. Only neofiscalin A showed antimicrobial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE); with a minimum inhibitory concentration (MIC) of 8 μg mL(-1) against both strains. Another compound, fiscalin C, presented synergistic activity against MRSA when combined with oxacillin, although alone showed no antibacterial effect. Moreover, neofiscalin A, when present at sub-MICs, hampered the ability of both MRSA and VRE strains to form a biofilm. Additionally, the biofilm inhibitory concentration values of neofiscalin A against the MRSA and VRE isolates were 96 and 80 μg mL(-1), respectively. At a concentration of 200 μg mL(-1), neofiscalin A was able to reduce the metabolic activity of the biofilms by ∼50%. One important fact is that our results also showed that neofiscalin A had no cytotoxicity against a human brain capillary endothelial cell line.


Dynamic phase transition in the kinetic spin-1 Blume-Capel model under a time-dependent oscillating external field.
We study within a mean-field approach the stationary states of the kinetic spin-1 Blume-Capel model in the presence of a time-dependent oscillating external magnetic field. We use the Galuber-type stochastic dynamics to describe the time evolution of the system. We have found that the behavior of the system strongly depends on the crystal field interaction D . We have obtained two types of solutions: a symmetric one, which corresponds paramagnetic phase where the magnetization (m) of the system oscillates in time around zero, and an antisymmetric one where m oscillates in time around a finite value different from zero. There are regions of the phase space where both solutions coexist. The dynamic phase transition from one regime to the other can be a first- or a second-order depending on the region in the phase diagram. Hence, the system exhibits one or more dynamic tricritical point, which depends on the values D . We also calculate the Liapunov exponent to verify the stability of the solutions and the dynamic phase transition points.


Percutaneous embolization of refractory biliocutaneous fistula following radiofrequency ablation: A case report.
This case report presents a 73-year-old male with recurrent hepatocellular carcinoma who underwent serial surgical and interventional locoregional treatments, which resulted in asymptomatic intrahepatic bile duct dilatation. To address a recurrent tumor close to the pre-existing dilated bile ducts, radiofrequency ablation was performed, leading to a biliocutaneous fistula along the electrode tract. Attempts to close the refractory fistula by percutaneous transhepatic cholangial diversion and balloon dilatation of the stenotic central bile duct were unsuccessful. Ultimately, the fistula was successfully sealed with aggressive management, combining balloon-assisted retrograde fistulography and antegrade fistula embolization. This report aims to raise awareness of complex biliary complications after radiofrequency ablation in patients with preexisting bile duct dilatation, and emphasize the importance of aggressive intervention in cases of refractory biliocutaneous fistula based on our experience.


Spinal Cord Stimulation for Spasticity: Historical Approaches, Current Status, and Future Directions.
Millions of people worldwide suffer with spasticity related to irreversible damage to the brain or spinal cord. Typical antecedent events include stroke, traumatic brain injury, and spinal cord injury, although insidious onset is also common. Regardless of the cause, the resulting spasticity leads to years of disability and reduced quality of life. Many treatments are available to manage spasticity; yet each is fraught with drawbacks including incomplete response, high cost, limited duration, dose-limiting side effects, and periodic maintenance. Spinal cord stimulation (SCS), a once promising therapy for spasticity, has largely been relegated to permanent experimental status. In this review, our goal is to document and critique the history and assess the development of SCS as a treatment of lower limb spasticity. By incorporating recent discoveries with the insights gained from the early pioneers in this field, we intend to lay the groundwork needed to propose testable hypotheses for future studies. SCS has been tested in over 25 different conditions since a potentially beneficial effect was first reported in 1973. However, the lack of a fully formed understanding of the pathophysiology of spasticity, archaic study methodology, and the early technological limitations of implantable hardware limit the validity of many studies. SCS offers a measure of control for spasticity that cannot be duplicated with other interventions. With improved energy-source miniaturization, tailored control algorithms, novel implant design, and a clearer picture of the pathophysiology of spasticity, we are poised to reintroduce and test SCS in this population.


Importance of Individual Ghost Cells in Fine-Needle Aspiration Cytology Diagnosis of Pilomatricoma.
Although histological diagnosis of pilomatricoma is not difficult because of its unique histological features, cytological diagnosis through fine-needle aspiration cytology (FNAC) is often problematic due to misdiagnoses as malignancy. We reviewed the cytological features of 14 cases of histologically-proven pilomatricoma from Korea Cancer Center Hospital, with a discussion on the diagnostic pitfalls of FNAC. Among 14 cases of pilomatricoma, 10 (71.4%) were correctly diagnosed through FNAC, and two (14.3%) were misdiagnosed as carcinoma. Cytologically, all cases had easily recognizable clusters of basaloid cells and foreign body-type multinucleated cells. Although ghost cells were also found in all cases, some were inconspicuous and hardly recognizable due to their small numbers. An accurate diagnosis of pilomatricoma in FNAC is feasible with consideration of clinical information and close examination of ghost cells.


Clinical outcomes and risk factors for graft failure after deep anterior lamellar keratoplasty and penetrating keratoplasty for macular corneal dystrophy.
The aim of this study was to compare visual acuity, clinical outcomes, complications, and risk factors for graft failure after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PK) for macular corneal dystrophy. Retrospective comparative case series. The PK group consisted of 109 eyes of 84 patients and the DALK group consisted of 21 eyes of 20 patients. The mean logarithm of the minimum angle of resolution best-corrected visual acuity at 3 and 12 months was 0.5 versus 0.5 (P = 0.285) and 0.4 versus 0.4 (P = 0.67) in the DALK and PK groups, respectively. There was no significant statistical difference in astigmatism and spherical equivalent between the 2 groups at 12 months. In the PK group, graft rejection that was the most common cause of graft failure was seen in 27 eyes (25%), of which 55% occurred within 1 year. In the DALK group, Descemet membrane microperforation occurred in 5 eyes (24%) intraoperatively, and early postoperative Descemet membrane detachment with double anterior chamber occurred in 9 eyes (43%). Kaplan-Meier estimate of graft survival in PK versus DALK groups were 93% versus 80% at 1 year and 78% versus 70% at 4 years, respectively. Visual and refractive outcomes are comparable between DALK and PK groups. DALK was superior to PK in its safety against postoperative complications such as endothelial rejection and secondary glaucoma. Graft failure in DALK was mostly associated with either intraoperative or early postoperative complications. DALK is a viable surgical option in cases with macular corneal dystrophy.


Induction of the pho regulon and polyphosphate synthesis against spermine stress in Pseudomonas aeruginosa.
Growth of Pseudomonas aeruginosa on spermine requires a functional γ-glutamylpolyamine synthetase PauA2. Not only subjected to growth inhibition by spermine, the pauA2 mutant became more sensitive to β-lactam antibiotics in human serum. To explore PauA2 as a potential target of drug development, suppressors of the pauA2 mutant, which alleviated toxicity, were isolated from selection plates containing spermine. These suppressors share common phenotypic changes including delayed growth rate, retarded swarming motility, and pyocyanin overproduction. Genome resequencing of a representative suppressor revealed a unique C599 T mutation at the phoU gene that results in Ser200 Leu substitution and a constitutive expression of the Pho regulon. Identical phenotypes were also observed in a ΔpauA2ΔphoU double knockout mutant and complemented by the wild-type phoU gene. Accumulation of polyphosphate granules and spermine resistance in the suppressor were reversed concomitantly when expressing exopolyphosphatase PPX from a recombinant plasmid, or by the introduction of deletion alleles in pstS pstC for phosphate uptake, phoB for Pho regulation, and ppk for polyphosphate synthesis. In conclusion, this study identifies polyphosphate accumulation due to an activated Pho regulon and phosphate uptake by the phoU mutation as a potential protection mechanism against spermine toxicity.


Re-randomization tests in clinical trials.
As randomization methods use more information in more complex ways to assign patients to treatments, analysis of the resulting data becomes challenging. The treatment assignment vector and outcome vector become correlated whenever randomization probabilities depend on data correlated with outcomes. One straightforward analysis method is a re-randomization test that fixes outcome data and creates a reference distribution for the test statistic by repeatedly re-randomizing according to the same randomization method used in the trial. This article reviews re-randomization tests, especially in nonstandard settings like covariate-adaptive and response-adaptive randomization. We show that re-randomization tests provide valid inference in a wide range of settings. Nonetheless, there are simple examples demonstrating limitations.


Observation of quadrature squeezing in a chi2 nonlinear waveguide using a temporally shaped local oscillator pulse.
We report on the generation of quadrature squeezed light at 1.535 microm via single-pass optical parametric amplification in a periodically poled MgO:LiNbO(3) waveguide, and detection with a temporally shaped local oscillator. Squeezing of -4.1 dB was directly measured using the shaped local oscillator. Classical parametric gain of the shaped pulse was also investigated; a deamplification gain of -12.1 dB was observed with the amplification gain of only +13.8 dB. We experimentally show that the use of shaped pulse as local oscillator in homodyne detection allows us efficient squeezing detection with near-unit mode-matching efficiency.


Comparison of Adult Mosquito Abundance From Biogents-2 Sentinel and Biogents Gravid Aedes Traps In Northeastern Florida.
We compared the efficacy of the Biogents Gravid Aedes Trap (BG-GAT) and Biogents-2 Sentinel (BG2S) trap to assess differences in adult mosquito collection rates between these 2 mosquito surveillance methods in northeastern Florida. Species diversity of trap collections was significantly greater for BG2S than for BG-GAT, with 14 mosquito species collected from the former trap and 4 species from the latter. Aedes aegypti and Culex quinquefasciatus were the 2 predominant species collected in both traps. Overall, BG2S traps collected significantly more mosquitoes (in some instances nearly 5 times) than the BG-GAT, regardless of species. There was no significant difference between the 2 traps with respect to gravid status when total species and number of mosquitoes collected were compared. However, at the species level, 8% of Ae. aegypti were gravid from the BG-GAT collections compared with 1% from the BG2S. The number of gravid Cx. quinquefasciatus was also considerably greater (59%) for the BG-GATs than for BG2S traps (2%), but these relationships were not statistically significant due to high variability in collections between traps.


[Measurement of penile length in children and its significance].
Nowadays, more and more parents are paying increasing attention to the penile length of their children. At present, the methods of measuring penile length mainly include manual measurement and ultrasonography. The former can be used to measure the flaccid, stretched and erected penile lengths, and its use for measuring the stretched penile length has been internationally accepted for its precise definition, unified description, and high repeatability. The latter, as a new method, is being gradually accepted for its imaging visualization and measurement accuracy. This article reviews different measurements of penile length in the mainstream literature of recent years, with an analysis of their advantages and disadvantages.


Medical Student Attitudes Toward Communication Skills Training and Knowledge of Appropriate Provider-Patient Communication: A Comparison of First-Year and Fourth-Year Medical Students.
Drawing upon Bloom's taxonomy of educational objectives as a theoretical framework, this study examines attitudes toward communication skills training, knowledge of appropriate provider-patient communication, and confidence communicating with patients between first-year and fourth-year medical students at a large medical school in the southern United States. The study findings indicate that fourth-year medical students do not differ from first-year medical students in terms of attitudes towards communication skills training or knowledge of appropriate provider-patient communication, but they have significantly higher confidence scores about communicating with patients. In addition, positive attitudes towards communication skills training are significantly related to perceived importance of communication skills and confidence when communicating with patients. Finally, female medical students have more positive attitudes towards communication skills training than male medical students. The implications of the study findings and directions for future research are also discussed.


Recent advances in genetics of chorea.
Chorea presenting in childhood and adulthood encompasses several neurological disorders, both degenerative and nonprogressive, often with a genetic basis. In this review, we discuss how modern genomic technologies are expanding our knowledge of monogenic choreic syndromes and advancing our insight into the molecular mechanisms responsible for chorea. A genome-wide association study in Huntington's disease identified genetic disease modifiers involved in controlling DNA repair mechanisms and stability of the HTT trinucleotide repeat expansion. Chorea is the cardinal feature of newly recognized genetic entities, ADCY5 and PDE10A-related choreas, with onset in infancy and childhood. A phenotypic overlap between chorea, ataxia, epilepsy, and neurodevelopmental disorders is becoming increasingly evident. The differential diagnosis of genetic conditions presenting with chorea has considerably widened, permitting a molecular diagnosis and an improved prognostic definition in an expanding number of cases. The identification of Huntington's disease genetic modifiers and new chorea-causing gene mutations has allowed the initial recognition of converging molecular pathways underlying medium spiny neurons degeneration and dysregulation of normal development and activity of basal ganglia circuits. Signalling downstream of dopamine receptors and control of cAMP levels represent a very promising target for the development of new aetiology-based treatments for chorea and other hyperkinetic disorders.


Differential effects on effort discounting induced by inactivations of the nucleus accumbens core or shell.
The authors investigated the contribution of the nucleus accumbens (NAc) core and shell to effort-based decision making using a discounting procedure. Selection of 1 lever delivered a smaller, 2-pellet reward immediately, whereas the other lever delivered a 4-pellet reward after a fixed ratio of presses (2, 5, 10, or 20) that increased over 4 blocks of 10 discrete choice trials. Subsequent testing employed an equivalent delays procedure, whereby the relative delay to reward delivery after selection of either option was equalized. In well-trained rats, inactivation of the core, but not the shell, via infusion of GABA A/B agonists muscimol/baclofen reduced preference for the high-effort option under standard conditions and also when rats were tested using an equivalent delays procedure. However, inactivation of the core did not alter preference for 4-pellet versus 2-pellet rewards when the relative costs of each option were the same (1 press). Thus, the NAc core, but not the shell, appears to be part of a neural circuit that biases choice toward larger rewards associated with a greater effort cost. Furthermore, the contributions by the NAc core to this form of decision making can be dissociated from its role in delay discounting.


Real patient involvement in role development: evaluating patient focused resources for clinical procedural skills.
Simulated patients (SPs) are widely used in medical education. The literature offers little evidence for scenario or SP role development. Published materials describe guidelines for structuring roles but there is little information on process. Anecdotal evidence suggests that SP roles are usually created by health care professionals and teachers. Although this approach has advantages it places the role at risk of omitting or misrepresenting real patients' experiences. We wanted to explore a systematic approach to role development that was based on individual patient's experiences. Real patients were interviewed about their experiences of procedures they had undergone. This information formed the basis of our procedural skills SP roles. Eight new roles were created. Evaluation by SPs (n = 22) showed more positive comments about realism on roles based on real patients' experiences compared with those crafted by our multidisciplinary team although there were no statistically significant differences in numerical ratings. The approach to writing roles described here is not suited to all simulations. However, it offers guidance to those involved in writing scenarios and has led us to critically reflect on the ways in which we provide educational materials that are patient focused.


Colonoscopy polyp detection and classification: Dataset creation and comparative evaluations.
Colorectal cancer (CRC) is one of the most common types of cancer with a high mortality rate. Colonoscopy is the preferred procedure for CRC screening and has proven to be effective in reducing CRC mortality. Thus, a reliable computer-aided polyp detection and classification system can significantly increase the effectiveness of colonoscopy. In this paper, we create an endoscopic dataset collected from various sources and annotate the ground truth of polyp location and classification results with the help of experienced gastroenterologists. The dataset can serve as a benchmark platform to train and evaluate the machine learning models for polyp classification. We have also compared the performance of eight state-of-the-art deep learning-based object detection models. The results demonstrate that deep CNN models are promising in CRC screening. This work can serve as a baseline for future research in polyp detection and classification.


Canalith repositioning procedure for relief of post-stapedectomy benign paroxysmal positional vertigo.
A 41-year-old woman underwent a successful stapedectomy for relief of conductive hearing loss due to otosclerosis. Post-operatively, she developed persistent symptoms of benign paroxysmal positional vertigo (BPPV). Eight weeks later, a canalith repositioning procedure was performed in the office, with immediate complete resolution of her vertigo. Anatomic and pathophysiologic implications of these observations will be discussed.


Behcet's Disease with Intracardiac Thrombus Presenting with Fever of Unknown Etiology.
A young male was referred to us for evaluation of fever of unknown origin (FUO). He had history of recurrent painful oral ulcers for one year and moderate to high grade fever, pustulopapular rash, and recurrent genital ulcers for 6 months and hemoptysis for 3 days. He was detected to have intracardiac thrombi and pulmonary arterial thrombosis along with underlying Behcet's disease (BD). Patient responded to high dose prednisolone (1 mg/Kg/day) along with monthly parenteral cyclophosphamide therapy. This case highlights the fact that BD is an important cause for pulmonary artery vasculitis with intracardiac thrombus formation, and such patients can present with FUO.


On the intrinsic regulation of neuropeptide Y release in the mammalian suprachiasmatic nucleus circadian clock.
Timing of the circadian clock of the suprachiasmatic nucleus (SCN) is regulated by photic and non-photic inputs. Of these, neuropeptide Y (NPY) signaling from the intergeniculate leaflet (IGL) to the SCN plays a prominent role. Although NPY is critical to clock regulation, neither the mechanisms modulating IGL NPY neuronal activity nor the nature of regulatory NPY signaling in the SCN clock are understood, as NPY release in the SCN has never been measured. Here, microdialysis procedures for in vivo measurement of NPY were used in complementary experiments to address these questions. First, neuronal release of NPY in the hamster SCN was rhythmic under a 14L : 10D photocycle, with the acrophase soon after lights-on and the nadir at midday. No rhythmic fluctuation in NPY occurred under constant darkness. Second, a behavioral phase-resetting stimulus (wheel-running at midday that induces IGL serotonin release) acutely stimulated SCN NPY release. Third, bilateral IGL microinjection of the serotonin agonist, (+/-)-2-dipropyl-amino-8-hydroxyl-1,2,3,4-tetrahydronapthalene (8-OH-DPAT) (another non-photic phase-resetting stimulant), at midday enhanced SCN NPY release. Conversely, similar application of the serotonin antagonist, metergoline, abolished wheel-running-induced SCN NPY release. IGL microinjection of the GABA agonist, muscimol, suppressed SCN NPY release. These results support an intra-IGL mechanism whereby behavior-induced serotonergic activity suppresses inhibitory GABAergic transmission, promoting NPY activity and subsequent phase resetting. Collectively, these results confirm IGL-mediated NPY release in the SCN and verify that its daily rhythm of release is dependent upon the 14L : 10D photocycle, and that it is modulated by appropriately-timed phase-resetting behavior, probably mediated by serotonergic activation of NPY units in the IGL.


Effect of History and Context on Forensic Pathologist Interpretation of Photographs of Patterned Injury of the Skin.
In a previous study, a survey-based analysis of pathologist diagnoses of patterned injury was performed. Subjects were provided with photographs of "classic" injuries and asked to diagnose the lesion in the absence of history or context. There was a relatively low diagnostic consensus among respondents. A second survey suggested that the disparate answers were not due to a strong belief in different diagnoses, but instead reflected how the respondents dealt with ambiguity. A third survey was created that asked participants to evaluate patterned injuries of the skin, but provided history and contextual information. The addition of history and contextual information increased consensus from a median of 80% to 98% on a per-question basis. Confidence increased from a median of 56%-92%. These results demonstrate the importance of history and context in medical diagnosis of patterned injuries of the skin.


Synthesis of substituted [1]benzothieno[2,3-b]pyrazines and their ability to antagonize KCl induced contractions.
A series of substituted [1]benzothieno [2,3-b]pyrazines, structurally related to caroverine, was synthesized. Some of these compounds showed an appreciable inhibition towards KCl induced contractions on isolated rat aortic rings, and a lower potency towards negative inotropic activity tested on isolated guinea pig atrium.


Cytochemical studies on the prostate glands of the trematodes, Paramphistomum epiclitum and Paradistomoides orientalis.
Pear-shaped prostatic gland cells which surround the ejaculatory duct of Paramphistomum and Paradistomoides, secrete two types of products: (i) granules which are cytochemically complex containing lipids, proteins and polysaccharides (1:2, glycol groups) and (ii) globules which contain phospholipids only. The cytoplasm of these cells, in addition to high acid phosphatase activity, also contains RNA, proteins and polysaccharides.


Epidermal keratinocytes - genes and their regulation.
In recent years, the human epidermal keratinocyte has been extensively studied. These studies have shown that epidermal growth factor (EGF), transforming growth factor-beta (TGFbeta), retinoids, phorbol ester, vitamin D and other agents regulate keratinocyte proliferation, differentiation, apoptosis and gene expression. We review progress in understanding the mechanisms that regulate keratinocyte structural gene expression. In most cases little is known regarding the factors that regulate gene expression in response to a physiological agent. However, the available results suggest a role for a variety of transcription factors, including STAT factors, NFkappaB, octamer site (OCT) binding proteins and activator protein 1 (AP1) factors in regulating expression of these genes. Among these transcriptional regulators, AP1 appears to play a central role. We review the current literature regarding the regulation of involucrin, loricin, transglutaminase type 1 and cytokeratin gene expression. This survey indicates that the AP1 family of transcriptional regulators is implicated in the regulation of nearly all of these genes. We also discuss recent studies which describe the distribution of the AP1 factors, c-jun, junB, junD, Fra-1,Fra-2, c-fos and fosB, in epidermis.


SILAC-based quantification of changes in protein tyrosine phosphorylation induced by Interleukin-2 (IL-2) and IL-15 in T-lymphocytes.
This data article presents the first large-scale quantitative phosphoproteomics dataset generated to decipher the signaling networks initiated by IL-2 and IL-15 in T-lymphocytes. Data was collected by combining immunoprecipitation of tyrosine phosphorylated proteins and TiO2-based phosphopeptide enrichment with SILAC-based quantitative mass spectrometry. We report all the proteins and phosphotyrosine-containing peptides identified and quantified in IL-2- and IL-15-stimulated T-lymphocytes. The gene ontology analysis of IL-2 and IL-15 effector proteins detected in the present work is also included. The data supplied in this article is related to the research work entitled "Simultaneous dissection and comparison of IL-2 and IL-15 signaling pathways by global quantitative phosphoproteomics" [1]. All mass spectrometry data have been deposited in the ProteomeXchange with the identifier PXD001129.


The role of pre-expanded free flaps in revision of burn scarring.
The authors present two patients affected by scars resulting from burning of over 60 per cent of the total body area, in which the pre-expansion of a free flap has been used to increase the tissue surface useful for transfer from the only area of residual healthy skin (left forearm, left parascapular region). In both cases it was possible to transfer abundant healthy tissue into the desired areas, obtaining a rapid release of the region, which made possible an early physical rehabilitation of the patient starting after the second postoperative week. One of the main problems encountered, when facing surgical rehabilitation for the seriously burned patient, is the poor availability of skin donor areas suitable for reconstructive flaps. The pre-expansion of free flaps provides an advantage in that it allows the few integral residual areas to be used, improving vascularization and therefore increasing the available surface. Furthermore, as pre-expansion reduces tension on the margins, it allows for the easier closing of the donor area, with a minor risk of complications and a better scar outcome.


Intraoperative patient warming using radiant warming or forced-air warming during long operations.
Forced-air warming is the most commonly used and effective method of active warming. A new radiant warming device (Suntouch, Fisher and Paykel) may provide an alternative when the skin surface available for warming is limited. We conducted a randomized controlled trial to compare the efficacy of the Suntouch radiant warmer and forced-air warming. With ethics committee approval 60 surgical patients having procedures anticipated to be more than two hours in duration were recruited. Patients were randomized to either radiant warming or forced-air warming. All intravenous fluids were warmed but prewarming was not used. The final intraoperative core temperatures (degrees C) for the radiant warming and forced-air warming groups were 36.0 +/- 0.5 and 36.4 +/- 0.6 (P=0.002) respectively. No other patient variables were significantly different. The Suntouch is not as effective as the forced air warming for intraoperative warming during long surgical procedures. The device may be useful when forced-air warming is not possible.


Ischemic heart disease showing unusual angiographic findings.
Atherosclerotic lesions usually occur in the proximal and middle portion of the coronary arteries. Multiple obstructive lesions appearing only in the peripheral branches without lesions in the proximal or distal portion have not been reported. We encountered a patient with ischemic heart disease showing multiple obstruction in the peripheral branches of the right and left coronary arteries without significant stenotic lesions in the proximal or middle portion. This 49-year-old male was admitted to Yamada Red Cross Hospital due to angina pectoris. Coronary risk factors for him included hypertension, abnormal glucose tolerance, smoking habit, and obesity. Laboratory studies showed a complete blood count and normal blood chemistries, as well as thromboplastin and prothrombin times. Coronary angiography showed multiple obstruction or marked stenosis in the distal portion and peripheral branches; there was no stenosis in the proximal and middle portions. Left ventriculography showed severe hypokinesis in the diaphragmatic segment. Biopsy of the left ventricular endocardium showed interstitial fibrosis but showed no abnormalities in the myocardial fibers or cell infiltration to perivascular areas and vascular walls. Coronary angiography after two months showed multiple lesions, as previously observed. Although ischemic heart disease is caused by various types of vasculitis, embolism, coronary spasm, and fibromuscular dysplasia, in this patient, there were no findings suggestive of causes other than atherosclerosis. This case is interesting in terms of rare angiographic findings and its cause.


Recyclable magnetic nanocluster crosslinked with poly(ethylene oxide)-block-poly(2-vinyl-4,4-dimethylazlactone) copolymer for adsorption with antibody.
Surface modification of magnetic nanoparticle (MNP) with poly(ethylene oxide)-block-poly(2-vinyl-4,4-dimethylazlactone) (PEO-b-PVDM) diblock copolymers and its application as recyclable magnetic nano-support for adsorption with antibody were reported herein. PEO-b-PVDM copolymers were first synthesized via a reversible addition-fragmentation chain-transfer (RAFT) polymerization using poly(ethylene oxide) chain-transfer agent as a macromolecular chain transfer agent to mediate the RAFT polymerization of VDM. They were then grafted on amino-functionalized MNP by coupling with some azlactone rings of the PVDM block to form magnetic nanoclusters with tunable cluster size. The nanocluster size could be tuned by adjusting the chain length of the PVDM block. The nanoclusters were successfully used as efficient and recyclable nano-supports for adsorption with anti-rabbit IgG antibody. They retained higher than 95% adsorption of the antibody during eight adsorption-separation-desorption cycles, indicating the potential feasibility in using this novel hybrid nanocluster as recyclable support in cell separation applications.


[The distribution of amlodipine in the organism of the warm-blooded animals].
The objective of the present study was to elucidate the specific features of amlodipine distribution in the organism of the warm-blooded animals (rats) following a single intragastric administration of the poisonous substance at a dose of 686 mg/kg b/w/ (LD50). Amlodipine was isolated from the blood and various organs of the animals by means of acetone extraction and purified on the silica gel column (100/160 mcm) with the elution by an ethanol-hexane (7:3) mixture. The identification and the quantitative measurement of amlodipine were performed with the use of the TLC, GC-M, and UV-spectrophotometry. The study has shown that unmetabolized amlodipine was present in large amounts in the internal organs and blood of the poisoned animals. The principal organs of its accumulation were the stomach, kidneys, and blood.


Automatic detection of tooth cracks in optical coherence tomography images.
The aims of the present study were to compare the image quality and visibility of tooth cracks between conventional methods and swept-source optical coherence tomography (SS-OCT) and to develop an automatic detection technique for tooth cracks by SS-OCT imaging. We evaluated SS-OCT with a near-infrared wavelength centered at 1,310 nm over a spectral bandwidth of 100 nm at a rate of 50 kHz as a new diagnostic tool for the detection of tooth cracks. The reliability of the SS-OCT images was verified by comparing the crack lines with those detected using conventional methods. After performing preprocessing of the obtained SS-OCT images to emphasize cracks, an algorithm was developed and verified to detect tooth cracks automatically. The detection capability of SS-OCT was superior or comparable to that of trans-illumination, which did not discriminate among the cracks according to depth. Other conventional methods for the detection of tooth cracks did not sense initial cracks with a width of less than 100 μm. However, SS-OCT detected cracks of all sizes, ranging from craze lines to split teeth, and the crack lines were automatically detected in images using the Hough transform. We were able to distinguish structural cracks, craze lines, and split lines in tooth cracks using SS-OCT images, and to automatically detect the position of various cracks in the OCT images. Therefore, the detection capability of SS-OCT images provides a useful diagnostic tool for cracked tooth syndrome.


Framing tropical disease in London: Patrick Manson, Filaria perstans, and the Uganda sleeping sickness epidemic, 1891-1902.
Much of the historical literature on tropical medicine represents the periphery as the chief site for the production of western knowledge about disease in the British empire. This study on the Filaria perstans-sleeping sickness hypothesis revises this perspective by showing how the imperial metropole functioned as a culture space for the construction of knowledge about the empire. Beginning in 1891, Patrick Manson used the publicity resources of London to generate a rhetorical imperative for the confirmation of his hypothesis without ever leaving Britain. Later, while he was medical adviser to the imperial state, the 1900 sleeping sickness epidemic in Uganda presented Manson with a unique opportunity to determine the validity of his hypothesis. By exaggerating the possible spread of the epidemic privately among Foreign Office personnel and publicly in the medical press, he succeeded in mobilizing the first Royal Society sleeping sickness research expedition to Africa in 1902. While this expedition ultimately disproved Manson's hypothesis, this outcome ironically created the very conditions for the identification of the actual causal agent (Trypanosoma gambiense) and its vector (tsetse fly) by Aldo Castellani and David Bruce respectively.


Comet Bennett 1970 II.
The model for dust comets, formulated by Finson and Probstein, which had previously been tested only on Comet Arend-Roland 1957 III, has been successfully applied to three calibrated photographic plates of Comet Bennett. The size distribution, emission rate, and initial velocities of dust particles emitted from the comet's nucleus are given.


Histopathologic spectrum of benign proliferative and intraepithelial neoplastic reactions of the uterine cervix.
A working model for the histogenesis of carcinoma of the uterine cervix is summarized in Table I. The inclusion of squamous metaplasia in this chart does not imply that this reaction falls into the spectrum of cervical neoplasia or is necessarily an antecedent to neoplasia. It does simply imply that the carcinogenic event or events apparently occur in or involve an epithelium that is indistinguishable from squamous metaplasia. The chart intentionally implies that the lesions mentioned are not separate diseases but arbitrary points in the spectrum of cervical neoplasia. It must be emphasized that one stage does not necessarily progress to the next and that at any stage up to indisputable cancer the changes may regress, persist or progress. The careful evaluation of histologic material from the uterine cervix will permit the pathologist to exclude those epithelial abnormalities which are not a part of the spectrum of cervical neoplasia and allow him or her to place the patient with cervical neoplasia at the proper stage in the development of the process. With this information the clinician can then intelligently plan appropriate therapy.


Modified transjugular approach for percutaneous atrial septal defect closure.
Femoral venous route is routinely used for percutaneous closure of atrial septal defects (ASDs). However, a situation may arise where transfemoral approach is not feasible. We describe a successful transjugular closure of a moderate-sized ASD in a 49-year-old symptomatic man with interrupted inferior vena cava, using a novel deployment technique, which helped in overcoming difficulties such as maintaining stable sheath position and minimizing risk of air embolism.


Overexpression of FOXM1 as a target for malignant progression of esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) is one of the most common types of malignancies globally. Forkhead box M1 (FOXM1) has important functions in cancer progression. However, the function of FOXM1 signaling in ESCC remains unknown. The aim of the present study was to evaluate the expression level and function of FOXM1 in human ESCC. The present study first detected the FOXM1 expression level in 78 cases of primary ESCC tissues and matched normal tissue samples by immunohistochemistry, western blot analysis and reverse transcription-quantitative polymerase chain reaction. Subsequently, the present study investigated the impact of FOXM1 knockdown on the ability of cell proliferation and migration of ESCC cells by MTT, clonogenic and Transwell assays. The results revealed that the mRNA and protein expression levels of FOXM1 were upregulated in a series of ESCC tissue samples. Silencing of FOXM1 inhibited the proliferation and migration of ESCC cells. In conclusion, FOXM1 was significantly increased in cancerous tissue samples of patients with ESCC. It may serve as a selective target for the treatment of ESCC.


Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature.
Juvenile rheumatoid arthritis (JRA) is the most common systemic cause of pediatric uveitis in Europe and North America. Uveitis is commonly perceived as a frequent sequela of JRA and JRA-associated uveitis is commonly considered to have a complicated course with frequent adverse visual outcomes. We performed a systematic literature search for series of consecutive patients with JRA (as defined by the American College of Rheumatology criteria) reporting on the frequency of uveitis and/or complications of uveitis, published between January 1980 and December 2004. The main outcome measures were: the cumulative incidence of uveitis in JRA, the cumulative incidence of adverse visual outcome and that of complications in JRA-associated uveitis. Additionally, the influence of gender, presence of antinuclear antibody (ANA) and disease onset subtype to the likelihood of developing uveitis were examined. Analysis of pooled data from the 26 eligible series suggested a cumulative incidence of uveitis in JRA of 8.3% [95% confidence intervals (CI), 7.5-9.1%]. The cumulative incidence of uveitis varied according to geographic location, being highest in Scandinavia, then the US, then Asia and lowest in India. JRA-associated uveitis was more common in pauciarticular than polyarticular onset patients [odds ratio (OR) = 3.2, 95% CI, 2.33-4.36] and in ANA-positive than ANA-negative patients (OR = 3.18, 95% CI, 2.22-4.54). Female gender was only a weak risk factor for the development of uveitis in JRA patients (OR = 1.69, 95% CI 1.09-2.62) and was not statistically significant after considering disease onset subtypes. In JRA-associated uveitis the cumulative incidence of cumulative incidence of adverse outcome (visual acuity < 20/40 OU) was 9.2% (95% CI: 4.7-15.8) of cataracts 20.5% (95% CI: 15.5-26.3), of glaucoma 18.9% (95% CI: 14.4-24.2) and of band keratopathy 15.7% (95% CI: 10.9-21.7). The cumulative incidence of uveitis in JRA varies according to geographic location, presence of ANA, type of JRA onset and gender. Uveitis, adverse visual outcome, and complications in JRA are less frequent than commonly accepted.


A Review of Food Contaminants and Their Pathways Within Food Processing Facilities Using Open Food Processing Equipment.
This study focuses on the chemical, physical, and biological hazards that pose food contamination risks during the processing of food in facilities using open food processing equipment through a review of published literature from 2015 to 2023. Ten main pathways for food contamination were developed and a list of chemical, physical, and biological food hazards, along with descriptions of process parameters and inputs that can contribute to food contamination, and prevention strategies associated with each pathway were compiled. The paper briefly discusses the relation between food contamination and the sustainable development goals (SDGs). The presented overview of contamination pathways and their associated food hazards can provide insights for food safety management plans, food processing equipment design, food processing facility layout, HACCP programs, and further studies on hygienic monitoring methods.


Use of an autologous reaction in vitro to assess contributions of T and B lymphocytes to immune hyperreactivity of atopics.
The in-vitro proliferation reaction of peripheral blood lymphocytes (measured by [3H]thymidine incorporation) to autologous pokeweed mitogen (PWM)-induced lymphoblasts (PWM-lymphoblast-stimulated autologous mixed leucocyte reaction, PWM.AMLR) was used as a measure of immune hyperreactivity for comparison of atopic with non-atopic individuals. Accordingly, 10/24 non-atopics responded in the PWM.AMLR, and 19/19 atopics reacting to inhaled allergens responded. Autologous stimulation was associated with release of mitogenic factors from the PWM-activated stimulating cells (2/15 non-atopics, 9/15 atopics). For non-atopics, stimulation delivered by staphylococcus A (SAC)-activated cells was similar to that delivered by PWM-induced cells, while in atopics, the SAC.AMLR was never more than 50% of the PWM.AMLR, indicating a possible T cell component. Separation by panning of the stimulation cells into lymphocyte subsets supported the notion that stimulation involved a cooperation between B and T4+ T cells. It is proposed that a positive PWM.AMLR is dependent upon an initial B cell activation followed by the PWM stimulus dependent upon a previous T cell activation, where atopics have more lymphocytes in an activated state than healthy non-atopics. Such a baseline priming may contribute to an innate sensitivity of atopics to environmental allergens.


Comparative characterisation of recombinant invertebrate and vertebrate peptide O-Xylosyltransferases.
Chondroitin and heparan sulphates have key functions in animal development and their synthesis is initiated by the action of UDP-alpha-D-xylose:proteoglycan core protein beta-D-xylosyltransferase (EC 22.214.171.124). cDNAs encoding this enzyme have been previously cloned from mammalian species; this in turn facilitated identification of corresponding Caenorhabditis elegans (sqv-6) and Drosophila melanogaster (oxt) genes. In the present study, we report the expression in Pichia pastoris and subsequent assay using either MALDI-TOF MS or RP-HPLC of recombinant forms of the Caenorhabditis xylosyltransferase SQV-6 and the human xylosyltransferase I, in addition to extending our previous studies on the xylosyltransferase from Drosophila. The enzyme activities were tested with a number of peptide substrates based on portions of the human bikunin, human perlecan and Drosophila syndecan core peptides. Whereas a variant of the latter, containing two Ser-Gly motifs was only modified on one of these motifs, the perlecan peptide with three Ser-Gly motifs could be multiply modified in vitro. Using this substrate, we could for the first time follow, by mass spectrometry, the xylosylation of a peptide with multiple xylosyltransferase acceptor motifs.


Mitochondria Biogenesis and Bioenergetics Gene Profiles in Isogenic Prostate Cells with Different Malignant Phenotypes.
Background. The most significant hallmarks of cancer are directly or indirectly linked to deregulated mitochondria. In this study, we sought to profile mitochondria associated genes in isogenic prostate cell lines with different tumorigenic phenotypes from the same patient. Results. Two isogenic human prostate cell lines RC77N/E (nonmalignant cells) and RC77T/E (malignant cells) were profiled for expression of mitochondrial biogenesis and energy metabolism genes by qRT-PCR using the Human Mitochondria and the Mitochondrial Energy Metabolism RT(2) PCR arrays. Forty-seven genes were differentially regulated between the two cell lines. The interaction and regulatory networks of these genes were generated by Ingenuity Pathway Analysis. UCP2 was the most significantly upregulated gene in primary adenocarcinoma cells in the current study. The overexpression of UCP2 upon malignant transformation was further validated using human prostatectomy clinical specimens. Conclusions. This study demonstrates the overexpression of multiple genes that are involved in mitochondria biogenesis, bioenergetics, and modulation of apoptosis. These genes may play a role in malignant transformation and disease progression. The upregulation of some of these genes in clinical samples indicates that some of the differentially transcribed genes could be the potential targets for therapeutic interventions.


Protocol for a feasibility randomised controlled trial of targeted oxygen therapy in mechanically ventilated critically ill patients.
Oxygen is the most commonly administered drug to mechanically ventilated critically ill adults, yet little is known about the optimum oxygen saturation (SpO2) target for these patients; the current standard of care is an SpO2 of 96% or above. Small pilot studies have demonstrated that permissive hypoxaemia (aiming for a lower SpO2 than normal by using a lower fractional inspired oxygen concentration (FIO2)) can be achieved in the critically ill and appears to be safe. This approach has not been evaluated in a National Health Service setting. It is possible that permissive hypoxaemia may be beneficial to critically ill patients thus it requires robust evaluation. Targeted OXygen therapY in Critical illness (TOXYC) is a feasibility randomised controlled trial (RCT) to evaluate whether recruiting patients to a study of permissive hypoxaemia is possible in the UK. It will also investigate biological mechanisms that may underlie the links between oxygenation and patient outcomes. Mechanically ventilated patients with respiratory failure will be recruited from critical care units at two sites and randomised (1:1 ratio) to an SpO2 target of either 88%-92% or ≥96% while intubated with an endotracheal tube. Clinical teams can adjust FIO2 and ventilator settings as they wish to achieve these targets. Clinical information will be collected before, during and after the intervention and blood samples taken to measure markers of systemic oxidative stress. The primary outcome of this study is feasibility, which will be assessed by recruitment rate, protocol adherence and withdrawal rates. Secondary outcomes will include a comparison of standard critical care outcome measures between the two intervention groups, and the measurement of biomarkers of systemic oxidative stress. The results will be used to calculate a sample size, likely number of sites and overall length of time required for a subsequent large multicentre RCT. This study was approved by the London - Harrow Research Ethics Committee on 2 November 2017 (REC Reference 17/LO/1334) and received HRA approval on 13 November 2017. Results from this study will be disseminated in peer-reviewed journals, at medical and scientific meetings, in the NIHR Journals Library and patient information websites. NCT03287466; Pre-results.


The use of single-wavelength anomalous scattering to solve the crystal structure of a gramicidin A/caesium chloride complex.
Single-wavelength Cu K alpha anomalous scattering has been used to determine the structure of a crystalline complex of gramicidin A and caesium chloride. The asymmetric unit in these crystals, with space group P2(1)2(1)2(1) and a = 32.118 (6), b = 52.103 (12), c = 31.174 (7) A, contains four independent monomers (two dimers) of the pentadecapeptide. This structure falls in an intermediate size range for which direct methods and multiple isomorphous replacement are generally not successful for obtaining phase information. However, using the Bijvoet differences and the partial structure of the caesium atoms which have been incorporated in the crystals, it has been possible to obtain information on this crystal form. Because the caesium atoms dominate the scattering of these crystals, inclusion of the Friedel mate information in the restrained least-squares refinement has been essential. These studies extend the utility of single-wavelength anomalous-scattering phase determination to a macromolecular structure in which the partial structure of the anomalous scatterer is large.


Relationship between the brain natriuretic peptide (BNP) level and remission of diabetic nephropathy with microalbuminuria: a 3-year follow-up study.
The aim of the study was to examine the relationship between the brain natriuretic peptide (BNP) level and progression or remission of diabetic nephropathy with microalbuminuria for 3 years. The subjects were 100 Japanese type 2 diabetes mellitus outpatients with microalbuminuria. Associations between metabolic parameters at baseline [HbA1c, systolic blood pressure (SBP), urine albumin-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and BNP] and the progression or remission of diabetic nephropathy were examined for 3 years. A total of 83 patients were examined at the end of the 3-year period, including 17 with remission to normoalbuminuria, 47 with continuing microalbuminuria, and 19 with progression to macroalbuminuria. HbA1c, ACR, and BNP differed significantly among the 3 groups (p=0.024, p<0.001, p=0.002, respectively). Among baseline factors, HbA1c and BNP were significant predictors of the percentage increase in ACR for 3 years in multiple linear regression analysis (β=0.259, p=0.02; β=0.299, p=0.007, respectively). In multivariate logistic regression analysis, HbA1c and ACR were independently associated with progression of diabetic nephropathy (p=0.008, p=0.023, respectively), and ACR and BNP were independently associated with remission of diabetic nephropathy (p=0.029, p=0.012, respectively). ROC curve analysis gave a cutoff value for BNP of 14.9 pg/ml for prediction of remission of diabetic nephropathy (p=0.016). The BNP level has a relationship with diabetic nephropathy and a low BNP level predicts remission of diabetic nephropathy. Therefore, monitoring of BNP can play an important role in management of diabetic nephropathy.


Langerhans' cell histiocytosis after living donor liver transplantation: report of a case.
We report a case of Langerhans' cell histiocytosis (LCH) occurring after a living donor liver transplantation (LDLT) for fulminant hepatitis. A 9-month-old girl underwent an LDLT for fulminant hepatitis of an unknown cause. The histology of the native liver did not show any findings of LCH. On postoperative day 42, her Epstein-Barr virus (EBV)-DNA and cytomegalovirus antigenemia were both found to be positive. As a result, she was treated with antiviral agents and a reduction of the immunosuppression dosage. On postoperative day 98, acute rejection occurred, and she was treated with FK506, methylprednisolone, and finally, anti-CD3 murine monoclonal antibody was added. Subsequently, the EBV was re-activated. Thereafter, skin eruptions, swelling of the systemic lymph nodes, and pancytopenia appeared on postoperative day 127. LCH was diagnosed based on the typical histological findings as LCH, CD1a, and S-100-positive cells in her skin and a lymph nodes biopsy. She was treated by chemotherapy. The symptoms disappeared a few weeks after the start of the chemotherapy, and a clinical remission of LCH was obtained. We could not detect any evidence of EBV infection in the tumor cells. In spite of the fact that her LCH lesions thereafter remained in remission, she died of hepatic failure at 22 months after undergoing the liver transplantation. In conclusion, we discuss the factors influencing the occurrence of LCH in our patient after LDLT, while also evaluating the relationship between LCH and the immunosuppressive therapy administered to this patient.


On the advantages and disadvantages of virtual continuing medical education: a scoping review.
With the COVID-19 pandemic, most continuing medical education activities became virtual (VCME). The authors conducted a scoping review to synthesize the advantages and disadvantages of VCME to establish the impact of this approach on inequities that physicians face along the intersections of gender, race, and location of practice. Guided by the methodological framework of Arksey and O'Malley, the search included six databases and was limited to studies published between January 1991 to April 2021. Eligible studies included those related to accredited/non-accredited post-certification medical education, conferences, or meetings in a virtual setting focused on physicians. Numeric and inductive thematic analyses were performed. 282 studies were included in the review. Salient advantages identified were convenience, favourable learning formats, collaboration opportunities, effectiveness at improving knowledge and clinical practices, and cost-effectiveness. Prominent disadvantages included technological barriers, poor design, cost, lack of sufficient technological skill, and time. Analysis of the studies showed that VCME was most common in the general/family practice specialty, in suburban settings, and held by countries in the Global North. A minority of studies reported on gender (35%) and race (4%). Most studies report advantages of VCME, but disadvantages and barriers exist that are contextual to the location of practice and medical subspecialty. VCME events are largely organized by Global North countries with suboptimized accessibility for Global South attendees. A lack of reported data on gender and race reveals a limited understanding of how VCME affects vulnerable populations, prompting potential future considerations as it evolves.


Expression of MTA1 in nasopharyngeal carcinoma and its correlation with prognosis.
Metastasis-associated protein 1 (MTA1) is related to tumour metastasis and poor prognosis in various human cancers. The aim of this study was to investigate the expression of MTA1 in nasopharyngeal carcinoma (NPC) and explore the prognostic value of MTA1 in NPC patients. The expression of MTA1 in 136 human NPC tissues and 20 normal nasopharyngeal tissues was detected using immunohistochemistry, quantified and classified into low or high expression using a 50% cut-off level. The relationships of MTA1 expression with the clinical characteristics and survival of patients were analysed. MTA1-positive staining was observed in the nuclei of NPC cells, and MTA1 expression was significantly correlated with T stage (P = 0.006), clinical stage (P = 0.001) and distant metastasis (P < 0.001). Patients with high MTA1 expression exhibited significantly worse distant metastasis-free survival (DMFS) than those with low MTA1 expression (90.75% vs. 70.81%, P = 0.017). Multivariate survival analysis revealed that MTA1 expression was an independent prognostic factor for DMFS (P = 0.038). In this study, high MTA1 expression was significantly associated with poor DMFS in NPC, indicating that MTA1 could serve as a novel biomarker for assessing the metastatic potential of NPC and could act as a possible therapeutic target for the treatment of metastatic nasopharyngeal carcinoma.


Continuum of readiness for collaboration, ICWA compliance, and reducing disproportionality.
From 2008-2010, a California Breakthrough Series Collaborative (BSC) addressed the disproportionality of African American and American Indian/Alaska Native (AI/AN) children in public child welfare services in partnership with the Annie E. Casey Foundation, Casey Family Program, the Child and Family Policy Institute of California, and the California Department of Social Services. The result was the development of the Continuum of Readiness, to be utilized by California counties to make strategic decisions to achieve Indian Child Welfare Act (ICWA) compliance and address AI/AN dis-proportionality through collaboration with tribes and urban Indian communities.


Pleasure, risk perception and consent among group sex party attendees in a small Canadian Urban Centre.
From a health perspective, group sex parties represent risk environments, as multiple sexual partners and polysubstance use associated with these parties may present risk practices for sexually transmitted infection (STI) transmission. At the same time, group sex parties exemplify sex as recreation, expressed in contemporary sociological theory as sex as leisure or play. In this paper, we report on the findings of an exploratory qualitative study conducted with group sex party attendees and hosts/organisers in a mid-sized Canadian city. Thematic analysis of semi-structured interviews with thirteen individuals identified several sexual communities based on gender composition, sexual orientation, and sexual practice, with variation among and within groups in terms of sexual consent and STI disclosure. All the interviewees discussed at length issues of harm reduction and consent, suggesting that these factors contribute to participants' group sex party experiences regardless of their sexual community. These insights highlight the potential use of group sex parties as avenues to understanding the integration of harm reduction practices with the pursuit of sexual pleasure, information applicable in the context of a wide range of sexuality education programmes.


Biochemical and immunohistochemical characterization of prolactin binding in rat ventral, lateral, and dorsal prostate lobes.
A radioligand assay and the soluble peroxidase-antiperoxidase (PAP) technique were used to compare ovine and rat prolactin as ligands for the demonstration of prolactin binding sites in rat ventral, lateral, and dorsal prostate lobes. Biochemical techniques were effective in demonstrating prolactin binding sites in ventral prostate with both ovine and rat prolactin; however, binding sites could not be characterized in lateral or dorsal lobes with either ligand. Using the PAP technique, rat prolactin consistently produced a discrete, dense reaction product over binding sites in the Golgi zone of the ventral prostate; ovine prolactin produced a more dispersed pattern of staining throughout the entire supranuclear region of the cells. In ventral prostate, most epithelial cells were immunoreactive when either ligand was used. However, lateral prostate contained fewer densely immunoreactive cells than did ventral prostate, and rat prolactin was more effective in demonstrating these binding sites than was ovine prolactin. Dorsal prostate epithelium was highly immunoreactive for binding of both ligands; however, there was considerably more staining in this lobe that remained after absorption of the antibody with prolactin. These data suggest that the inability to demonstrate prolactin binding sites in the lateral lobe using radioligand assay may have been due to the fewer numbers of binding sites that were diluted below the sensitivity of the assay when a tissue homogenate preparation was used. Noncompetitive binding in the dorsal lobe, as seen in the radioligand assay, coincided with immunocytochemical findings of relatively high nonabsorbable background staining.


Programming Effects of Prenatal Stress on Neurodevelopment-The Pitfall of Introducing a Self-Fulfilling Prophecy.
There is increasing interest for the potential harmful effects of prenatal stress on the developing fetal brain, both in scientific literature and in public press. Results from animal studies suggest that gestational stress leads to an altered offspring neurodevelopment with adverse behavioral and cognitive consequences. Furthermore, there are indications in human studies that severe prenatal stress has negative consequences for the child's neurodevelopment. However, stress is an umbrella term and studies of maternal stress have focused on a wide range of stress inducing situations, ranging from daily hassles to traumatic stress after bereavement or a natural disaster. Mild to moderate stress, experienced by many women during their pregnancy, has not consistently been shown to exert substantial negative effects on the child's neurodevelopment. Additionally, the vast majority of human studies are observational cohort studies that are hampered by their fundamental inability to show a causal relationship. Furthermore, our limited knowledge on the possible underlying mechanisms and the effects of interventions for prenatal stress on child neurodevelopmental outcomes emphasize our incomplete understanding of the actual effects of prenatal stress on child neurodevelopment. Until we have a better understanding, it seems counterproductive to alarm all pregnant women for possible harmful effects of all sorts of prenatal stress, if only to avoid the induction of stress itself.


Dictyostelium RacH regulates endocytic vesicular trafficking and is required for localization of vacuolin.
Dictyostelium RacH localizes predominantly to membranes of the nuclear envelope, endoplasmic reticulum and Golgi apparatus. To investigate the role of this protein, we generated knockout and overexpressor strains. RacH-deficient cells displayed 50% reduced fluid-phase uptake and a moderate exocytosis defect, but phagocytosis was unaffected. Detailed examination of the endocytic pathway revealed defective acidification of early endosomes and reduced secretion of acid phosphatase in the presence of sucrose. The distribution of the post-lysosomal marker vacuolin was altered, with a high proportion of cells showing a diffuse vesicular pattern in contrast to the wild-type strain, where few intensely stained vacuoles predominate. Cytokinesis, cell motility, chemotaxis and development appeared largely unaffected. In a cell-free system, RacH stimulates actin polymerization, suggesting that this protein is involved in actin-based trafficking of vesicular compartments. We also investigated the determinants of subcellular localization of RacH by expression of green-fluorescent-protein-tagged chimeras in which the C-terminus of RacH and the plasma-membrane-targeted RacG were exchanged, the insert region was deleted or the net positive charge of the hypervariable region was increased. We show that several regions of the molecule, not only the hypervariable region, determine targeting of RacH. Overexpression of mistargeted RacH mutants did not recapitulate the phenotypes of a strain overexpressing nonmutated RacH, indicating that the function of this protein is in great part related to its subcellular localization.


Poor replication of candidate genes for major depressive disorder using genome-wide association data.
Data from the Genetic Association Information Network (GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P=0.038; odds ratio (OR) AT=1.10, 95% CI 0.95-1.29; OR TT=1.21, 95% confidence interval (CI) 1.01-1.47) and NPY (rs16139; P=0.034; OR C allele=0.73, 95% CI 0.55-0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T=1.35, 95% CI 1.13-1.63; P=0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P=0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.


ISOZYME VARIABILITY IN TRYPANOSOMA CRUZI, THE AGENT OF CHAGAS' DISEASE: GENETICAL, TAXONOMICAL, AND EPIDEMIOLOGICAL SIGNIFICANCE.
A genetic interpretation of the zymograms of 524 Trypanosoma cruzi stocks from various hosts and representing a broad geographical range (United States to Southern Brazil) reveals high genetic variability (only one monomorphic locus out of 15) and suggests that this parasite has a diploid structure. The data do not give any indication of Mendelian sexuality, although many opportunities are present for genetic exchange between extremely different genotypes. The population structure of T. cruzi appears to be multiclonal and complex. The natural clones evidenced by isozyme analysis are numerous (43 different ones are recorded among 121 stocks assayed at 15 gene loci) and exhibit a large range of genotypes, in a nonhierarchical structure; it is not possible to cluster them into a few strictly delimited groups which could represent natural taxa. The available data suggest that the genetic variability of T. cruzi reflects the long separate evolution of multiple clones. It is suggested that long clonal evolution may explain the present biological and medical variability of the causative agent of Chagas' disease.


Experimental Models for Aging and their Potential for Novel Drug Discovery.
An interesting area of scientific research is the development of potential antiaging drugs. In order to pursue this goal, it is necessary to gather the specific knowledge about the adequate preclinical models that are available to evaluate the beneficial effects of new potential drugs. This review is focused on invertebrate and vertebrate preclinical models used to evaluate the efficacy of antiaging compounds, with the objective to extend life span and health span. Research and online content related to aging, antiaging drugs, experimental aging models is reviewed. Moreover, in this review, the main experimental preclinical models of organisms that have contributed to the research in the pharmacology of lifespan extension and the understanding of the aging process are discussed. Dietary restriction (DR) constitutes a common experimental process to extend life span in all organisms. Besides, classical antiaging drugs such as resveratrol, rapamycin and metformin denominated as DR mimetics are also discussed. Likewise, the main therapeutic targets of these drugs include sirtuins, IGF-1, and mTOR, all of them being modulated by DR. Advances in molecular biology have uncovered the potential molecular pathways involved in the aging process. Due to their characteristics, invertebrate models are mainly used for drug screening. The National Institute on Aging (NIA) developed the Interventions Testing Program (ITP). At the preclinical level, the ITP uses Heterogeneous mouse model (HET) which is probably the most suitable rodent model to study potential drugs against aging prevention. The accelerated-senescence mouse P8 is also a mammalian rodent model for aging research. However, when evaluating the effect of drugs on a preclinical level, the evaluation must be done in non-human primates since it is the mammalian specie closest to humans. Research is needed to investigate the impact of new potential drugs for the increase of human quality of life.


Characterization of rapid extraction protocols for high-throughput metabolomics.
In the last five years, high-throughput metabolomics has significantly advanced scientific research and holds the potential to promote strides in the fields of clinical metabolomics and personalized medicine. While innovations in the field of flow-injection mass spectrometry and three-minute metabolomics methods now allow investigators to process hundreds to thousands of samples per day, time-sensitive clinical applications, particularly in the emergency department, are limited by a lack of rapid extraction methods. Here we characterized the efficacy of fast liquid-liquid extractions for characterization of hydrophilic compounds through ultra-high-pressure liquid chromatography/mass spectrometry. Internal stable-isotope-labeled standards were used to quantitatively characterize markers of energy and oxidative metabolism in human whole blood, plasma and red blood cells - three common matrices of clinical relevance. For all the tested matrices, vortexing time (4-60 min) did not significantly affect extraction yields for the tested hydrophilic metabolites. Coefficients of variations <<20% for all tested compounds, except for the redox-sensitive metabolite cystine (accumulating over time). Internal standards and second extractions confirmed recoveries >80% for all tested metabolites, except for basic amino acids and polyamines, which showed reproducible yields ranging from 50 to 75%. Global profiling and absolute quantitation of 24 metabolites revealed similarities between the plasma and red blood cell metabolomes. Rapid extraction (~4 min) of hydrophilic compounds is a viable and potentially automatable strategy to perform quantitative analysis of whole blood, plasma and red blood cells for research or clinical applications.


Imipramine in the treatment of social phobia.
We report the results of an 8-week open trial of imipramine in 15 patients with social phobia. Nine patients completed the trial; six dropped out early because of adverse effects. The mean reduction in the Liebowitz Social Anxiety Scale was 15% and 18% for the intent-to-treat and completer groups, respectively; the overall response rate (based on the Clinical Global Impression Scale of 1 or 2, very much or much improved) was 20% (3/15) and 22% (2/9), respectively. The results from this open trial do not support the efficacy of imipramine as a treatment for social phobia.


Dihydrocapsaicin (DHC) enhances the hypothermia-induced neuroprotection following ischemic stroke via PI3K/Akt regulation in rat.
Hypothermia has demonstrated neuroprotection following ischemia in preclinical studies while its clinical application is still very limited. The aim of this study was to explore whether combining local hypothermia in ischemic territory achieved by intra-arterial cold infusions (IACIs) with pharmacologically induced hypothermia enhances therapeutic outcomes, as well as the underlying mechanism. Sprague-Dawley rats were subjected to right middle cerebral artery occlusion (MCAO) for 2h using intraluminal hollow filament. The ischemic rats were randomized to receive: 1) pharmacological hypothermia by intraperitoneal (i.p.) injection of dihydrocapsaicin (DHC); 2) physical hypothermia by IACIs for 10min; or 3) the combined treatments. Extent of brain injury was determined by neurological deficit, infarct volume, and apoptotic cell death at 24h and/or 7d following reperfusion. ATP and ROS levels were measured. Expression of p-Akt, cleaved Caspase-3, pro-apoptotic (AIF, Bax) and anti-apoptotic proteins (Bcl-2, Bcl-xL) was evaluated at 24h. Finally, PI3K inhibitor was used to determine the effect of p-Akt. DHC or IACIs each exhibited hypothermic effect and neuroprotection in rat MCAO models. The combination of pharmacological and physical approaches led to a faster and sustained reduction in brain temperatures and improved ischemia-induced injury than either alone (P<0.01). Furthermore, the combination treatment favorably increased the expression of anti-apoptotic proteins and decreased pro-apoptotic protein levels (P<0.01 or 0.05). This neuroprotective effect was largely blocked by p-Akt inhibition, indicating a potential role of Akt pathway in this mechanism (P<0.01 or 0.05). The combination approach is able to enhance the efficiency of hypothermia and efficacy of hypothermia-induced neuroprotection following ischemic stroke. The findings here move us a step closer towards translating this long recognized TH from bench to bedside.


Synergy between adjacent zinc fingers in sequence-specific DNA recognition.
Zif268-like zinc fingers are generally regarded as independent DNA-binding modules that each specify three base pairs in adjacent, but discrete, subsites. However, crystallographic evidence suggests that a contact also can occur from the second helical position of one finger to the subsite of the preceding finger. Here we show for the three-finger DNA-binding domain of the protein Zif268, and a panel of variants, that deleting the putative contact from finger 3 can affect the binding specificity for the 5' base in the adjoining triplet, which forms part of the binding site of finger 2. This finding demonstrates that Zif268-like zinc fingers can specify overlapping 4-bp subsites, and that sequence specificity at the boundary between subsites arises from synergy between adjacent fingers. This has important implications for the design and selection of zinc fingers with novel DNA binding specificities.


Primary Ewing sarcoma/peripheral primitive neuroectodermal tumor of the vulva.
We report a case of Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) arising in the vulva in a 17-year-old adolescent girl. Primary extraskeletal ES/pPNET is uncommon and only rarely affects the female genital tract. Characteristic histologic features of ES/pPNET were present in this case including a monomorphic population of small round blue cells with cytoplasmic glycogen confirmed by periodic acid-Schiff and were immunohistochemically positive for CD99 in a membranous and Fli-1 in a nuclear pattern. The presence of an EWS/Fli-1 fusion transcript was demonstrated by reverse transcription polymerase chain reaction and confirmed by direct sequencing. This report described another very rare case of ES/pPNET arising in the vulva and confirmed by molecular analysis.


An audit of radiotherapy patient doses measured with in vivo semiconductor detectors.
Uncertainties exist both in the basic data from which a radiotherapy plan is produced and in the process whereby such a plan is translated into the patient set-up during treatment. Individual parts of the radiotherapy process are subject to checks, but the overall accuracy of treatment delivery is not routinely evaluated. In vivo dosimetry by means of a semiconductor detector system can be used to measure the cumulative error in the radiotherapy treatment dose delivered. A direct patient dosimetry system was commissioned and introduced in January 1993 for the routine evaluation of the doses patients receive. Since its introduction a total of 1000 patients have been monitored for a range of radiotherapy applications, comprising 300 breast treatments (6 MV X-rays), 150 head and neck treatments (6 MV X-rays) and 550 pelvis. abdomen and thorax treatments (10 MV X-rays). The results of this audit show that less than 5% of all patients monitored gave a systematic error more than +/- 5% for a single field, or more than +/- 2.5% for the "estimated overall error" in the isocentre dose. The causes of these errors were identified and appropriate action taken where necessary. It is suggested that this method could be used routinely in radiotherapy treatment to assess the overall performance of the treatment process.


Effect of delivery route on pulmonary response to oncostatin M.
The effect of delivery route on lung tissue response to oncostatin M (OM) was evaluated in isolated perfused rat lung (IPRL) and normal human bronchial epithelial cell line BEAS-2B in vitro models. In this study, the extent of induction of the cytokine IL-6 by OM was examined as evidence for local pharmacological activity in response to OM in lung tissue. OM stimulated dose-dependent release of IL-6 in both BEAS-2B cells and IPRL after exposure of either the apical (AP) or basolateral (BL) side of the epithelium. The increase in IL-6 was rapid, beginning 2 h after dosing, and sustained over 48 h. Similar amounts of IL-6 were released to both AP and BL sides of BEAS-2B cells, regardless of the side of OM dosing. However, in IPRL the extent of response of IL-6 induction to OM was always higher at the dosing side. In addition, airway dosing of OM resulted in an overall lower IL-6 response than perfusate dosing, which may result from the low rate of OM transport (<1%/h) across pulmonary epithelium. We conclude that the route of delivery significantly affects the overall extent of the pharmacological response to OM, with a lesser and more localized response after airway delivery to the lung.


Spinal cord or nerve root compression in patients with malignant disease: CT evaluation.
Fifty patients with malignant disease were seen on an emergency basis because they showed clinical signs of spinal cord or nerve root compression. All were studied with high resolution computed tomography (CT) of the spine; in addition, myelography was performed on 10 of the patients. We found that 48 cases (96%) could be accurately diagnosed by CT alone. In two cases (4%) CT was inconclusive, but myelography was diagnostic; one proved to be cerebrospinal fluid seeding with nerve root involvement, and the other showed conus medullaris involvement. In the remaining eight cases studied by both techniques, correlation between CT and myelography was very good.


A max-margin model for efficient simultaneous alignment and folding of RNA sequences.
The need for accurate and efficient tools for computational RNA structure analysis has become increasingly apparent over the last several years: RNA folding algorithms underlie numerous applications in bioinformatics, ranging from microarray probe selection to de novo non-coding RNA gene prediction. In this work, we present RAF (RNA Alignment and Folding), an efficient algorithm for simultaneous alignment and consensus folding of unaligned RNA sequences. Algorithmically, RAF exploits sparsity in the set of likely pairing and alignment candidates for each nucleotide (as identified by the CONTRAfold or CONTRAlign programs) to achieve an effectively quadratic running time for simultaneous pairwise alignment and folding. RAF's fast sparse dynamic programming, in turn, serves as the inference engine within a discriminative machine learning algorithm for parameter estimation. In cross-validated benchmark tests, RAF achieves accuracies equaling or surpassing the current best approaches for RNA multiple sequence secondary structure prediction. However, RAF requires nearly an order of magnitude less time than other simultaneous folding and alignment methods, thus making it especially appropriate for high-throughput studies. Source code for RAF is available at:http://contra.stanford.edu/contrafold/.


Re-expression of CA1 and entorhinal activity patterns preserves temporal context memory at long timescales.
Converging, cross-species evidence indicates that memory for time is supported by hippocampal area CA1 and entorhinal cortex. However, limited evidence characterizes how these regions preserve temporal memories over long timescales (e.g., months). At long timescales, memoranda may be encountered in multiple temporal contexts, potentially creating interference. Here, using 7T fMRI, we measured CA1 and entorhinal activity patterns as human participants viewed thousands of natural scene images distributed, and repeated, across many months. We show that memory for an image's original temporal context was predicted by the degree to which CA1/entorhinal activity patterns from the first encounter with an image were re-expressed during re-encounters occurring minutes to months later. Critically, temporal memory signals were dissociable from predictors of recognition confidence, which were carried by distinct medial temporal lobe expressions. These findings suggest that CA1 and entorhinal cortex preserve temporal memories across long timescales by coding for and reinstating temporal context information.


Animal Visitation to Wild Pig ( Sus scrofa) Wallows and Implications for Disease Transmission.
Knowledge of animal visitation to locations where species aggregate is valuable for evaluating potential pathways of inter- and intraspecific transmission of infectious diseases. There is no research evaluating the potential of wallows created by invasive wild pigs ( Sus scrofa) as locations of transmission of infectious diseases. We monitored wild pig wallows by using trail cameras to determine the frequency with which wild pigs and native vertebrate species visited wallows and to characterize these interactions for their potential for disease transmission. We placed cameras from 20 June 2016 to 21 September 2016 at 16 individual wallows within 10 wallowing sites. Wild pigs of both sexes visited wallows frequently (115 total visits) for varying durations and exhibited wallowing and drinking behavior. We also observed 12 native mammalian and avian wildlife species using wallows at various frequencies (165 total visits). Of particular interest, nine of these species were observed drinking from wallows. Given the high frequency of wild pig visits to wallows and the drinking behavior they and native wildlife species exhibited, these locations might have an important role in transmission of diseases.


Racially invariant stimuli may bias outcomes in assessment of emotion processing.
Difficulties identifying emotional facial expressions are commonly observed in alcohol use disorder (AUD). Critically, this work utilizes single-race stimulus sets, although study samples are not similarly constrained. This is particularly concerning given evidence among community samples showing the impact of racial incongruity, giving rise to interpretative caveats. Community controls (n = 55, 12 Black) and individuals with AUD (n = 46, 9 Black) completed a two-choice emotion judgment task. A similar nonaffective sex judgment task was employed as a covariate. Repeated measures mixed-model analyses were conducted with race, AUD status (AUD vs. control), and their interaction as fixed effects. Accuracy and reaction time (RT) were primary dependent measures. A post hoc analysis was conducted on efficiency (accuracy/RT). In addition to lower accuracy by individuals with AUD (p = .02), Black participants were less accurate than White participants (p = .0001) overall. Significant interactions between race and AUD were also detected for accuracy (p = .002), RT (p = .05), and efficiency (p = .01), wherein Black participants with AUD identified emotional expressions most poorly. This latter finding suggests that AUD-associated differences may be biased under racial incongruity. Taken together, these preliminary findings do not reflect a deficit among Black respondents. Instead, our results reflect the need for greater attention to stimulus diversity and sensitivity to respondent demographics in emotion-processing examinations. Given the purported role of emotion processing in alcohol-related problems and the increase in racial minority representation in the U.S., elucidating these differences remains critical. (PsycInfo Database Record (c) 2022 APA, all rights reserved).