A surface plasmon resonance biosensor assay for measurement of anti-GM(1) antibodies in neuropathy.
To develop a rapid assay for the detection and measurement of anti-GM(1) ganglioside antibodies in patients with neuropathy, using a surface plasmon resonance-based biosensor. Elevated levels of anti-GM(1) ganglioside antibodies are observed in patients with acute and chronic motor neuropathies. Assays for detecting anti-GM(1) antibodies in serum are increasingly being used to help the physician in the evaluation of these patients. Antigens were immobilized by adsorption of GM(1) (active) and GM(2) (control) gangliosides onto a dextran-based sensor chip which is in contact with a flow cell carrying the sample. Interaction of specific antibodies directed against GM(1) with the ganglioside-coated sensor chip caused a change in refractive index at the surface of the chip, which was detected by an optical sensor, using the phenomenon of surface plasmon resonance. Sera from patients and healthy individuals were analyzed by the new assay and results were compared with those from ELISA. Anti-GM(1) antibody isotype was identified by using a secondary antibody. The binding of anti-GM(1) antibodies to the immobilized GM(1) was observed in real time after reference subtraction of the response from GM(2) control. The response was proportional to antibody concentration. The assay exhibited high specificity for sera from patients with multifocal motor neuropathy and Guillain-Barré syndrome with antibodies against GM(1). The surface plasmon resonance biosensor assay offers a rapid system for directly measuring antibody levels in serum without the use of any labels, while comparing favorably with the ELISA system in sensitivity and specificity.


Baby and the brain: advances in child development.
As child morbidity and mortality declined during the twentieth century, a corresponding increase occurred in the relevance of child psychological well-being to public health. Evidence of this trend is the proliferation of programs intended to ameliorate conditions that place children in jeopardy of poor developmental outcome. Most recently, neurobiologic information on brain function and structure has been used to promote strategies for optimizing child development. This review will evaluate the current state of knowledge relating early child development to brain research and illustrate the potential misuse of this information. It will also suggest the following: (a) the extrapolation of neuroscience results to early academic and social enrichment programs obscures the magnitude of potential effects of these programs relative to the vast burden of risk imposed by poverty, and (b) an emphasis on intellectual functioning misses the most compelling evidence on the role of the early social environment in mediating establishment of neural networks that regulate a child's response to stress and capacity for self-control.


Lower respiratory capacity in extraocular muscle mitochondria: evidence for intrinsic differences in mitochondrial composition and function.
The constant activity of the extraocular muscles is supported by abundant mitochondria. These organelles may enhance energy production by increasing the content of respiratory complexes. The authors tested the hypothesis that extraocular muscle mitochondria respire faster than do mitochondria from limb muscles because of the higher content of respiratory complexes. Inner mitochondrial membrane density was determined by stereological analysis of triceps surae (a limb muscle) and extraocular muscles of adult male Sprague-Dawley rats. The authors measured respiration rates of isolated mitochondria using a Clark-type electrode. The activity of respiratory complexes I, II, and IV was determined by spectrophotometry. The content of respiratory complexes was estimated by Western blot. States 3, 4, and 5 respiration rates in extraocular muscle mitochondria were 40% to 60% lower than in limb muscle mitochondria. Extraocular muscle inner mitochondrial membrane density was similar to that of other skeletal muscles. Activity of complexes I and IV was lower in extraocular muscle mitochondria (approximately 50% the activity in triceps), but their content was approximately 15% to 30% higher. There was no difference in complex II content or activity or complex III content. Finally, complex V was less abundant in extraocular muscle mitochondria. The results demonstrate that extraocular muscle mitochondria respire at slower rates than mitochondria from limb muscles, despite similar mitochondrial ultrastructure. Instead, differences were found in the activity (I, IV) and content (I, IV, V) of electron transport chain complexes. The discrepancy between activity and content of some complexes is suggestive of alternative subunit isoform expression in the extraocular muscles compared with limb muscles.


The combination of vein grafting and two different types of corporeal plication in complex curvature due to Peyronie's disease.
This study aimed to investigate the surgical results of incision and vein grafting combined with two types of plication sutures, including Essed-Schroeder and longitudinal imbrication, to correct the cavernous sacculation in complex curvature resulting from Peyronie's disease. Between 2004 and 2008, 15 patients with complex curvature resulting from Peyronie's disease were surgically treated. Essed-Schroeder plication and venous grafting were performed in 10 patients. Five of the 15 patients had cavernous sacculation, which was defined as albugineal elongation, except for the normally morphological cavernosal structure, which caused some degree of penile torsion beside the angulation. Surgery was used to establish sufficient cosmetic results by performing longitudinal imbrication on the cavernous sacculation on the same side as that of the Essed-Schroeder plication combined with venous grafting in these five patients. Complete penile straightening was achieved in all the patients. Two patients (13.3%) reported penile shortening without showing dissatisfaction about it. One patient complained of anesthesia on part of the skin of the penile shaft. All the patients were satisfied with the final surgical results. A combination of the surgical methods might be necessary to correct the complex deformities due to Peyronie's disease. Further studies with larger patient populations are needed to standardize these procedures.


A multiplanar three dimensional echocardiographic study of mitral valvar annular function in children with normal and regurgitant valves.
The mitral valvar complex is difficult to visualise accurately in only two dimensions. Three-dimensional echocardiography gives new insight into the dynamic changes of intra-cardiac structures during the cardiac cycle. The aim of this study was to study the mitral annulus in systole and diastole in normal children using three-dimensional echocardiography, and to analyse the effect of regurgitation on annular function. Three-dimensional echocardiographic datasets, acquired in 11 consecutive subjects with mitral regurgitation, and 20 normal subjects, were analysed offline using simultaneous multiplanar review. The mitral valvar annular area decreased in diastole, and increased in systole, in both groups. The annulus in patients with mitral regurgitation is dilated compared to normal subjects, the systolic value for those with regurgitation having a mean of 6.79 plus or minus 2.55 centimetres2/metres2, and the diastolic value a mean of 5.01 plus or minus 1.78 centimetres2/metres2, as opposed to a systolic mean value of 5.28 centimetres2/metres2 plus or minus 1.68, p = 0.091, and diastolic mean value of 3.05 centimetres2/metres2 plus or minus 0.90, in normal subjects (p less than 0.0001). The proportional change in mitral valvar annular area from systole to diastole showed a trend towards being smaller in those with mitral regurgitation, although this did not reach significance (24.8% versus 41.13%, p equal to 0.249). Analysis of subgroups of patients with moderate or severe mitral regurgitation showed mitral excursion, expressed as percentage of left ventricular length, to be significantly less than in normal subjects, at 12.78 plus or minus 5.10% versus 15.84 plus or minus 4.23% (p equal to 0.012). Mitral valvar annular area in children decreases in diastole, and increases in systole. In those with mitral regurgitation, the annulus is dilated and the dynamic annular function is depressed.


Importance of Autoimmune Responses in Progression of Retinal Degeneration Initiated by Gene Mutations.
Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous rare disorders associated with retinal dysfunction and death of retinal photoreceptor cells, leading to blindness. Among the most frequent and severe forms of those retinopathies is retinitis pigmentosa (RP) that affects 1:4,000 individuals worldwide. The genes that have been implicated in RP are associated with the proteins present in photoreceptor cells or retinal pigment epithelium (RPE). Asymmetric presentation or sudden progression in retinal disease suggests that a gene mutation alone might not be responsible for retinal degeneration. Immune responses could directly target the retina or be site effect of immunity as a bystander deterioration. Autoantibodies against retinal autoantigens have been found in RP, which led to a hypothesis that autoimmunity could be responsible for the progression of photoreceptor cell death initiated by a genetic mutation. The other contributory factor to retinal degeneration is inflammation that activates the innate immune mechanisms, such as complement. If autoimmune responses contribute to the progression of retinopathy, this could have an implication on treatment, such as gene replacement therapy. In this review, we provide a perspective on the current role of autoimmunity/immunity in RP pathophysiology.


Development of one paediatric and one neonatal formulary list in hospital settings.
The aim of this study is to describe the stepwise process towards creating two formulary lists: one for paediatric and one for neonatal patients covering common diseases in hospital settings. This study presents the concept for developing a formulary list, namely how to: (1) organize the editorial board, (2) procure drug consumption data and database management, including information on labelling status, dosing options, excipients and problematic adverse events, current guidelines, evidence and price, (3) develop the first edition for the formulary list and formulary manual, and (4) to establish a paediatric sub-committee within the Regional Drug and Therapeutic Committee to maintain and continually develop the two formularies. The total number of drugs was 411 ATC level 5, which covers 1097 unique item numbers prior to the paediatric formulary list, of which 263 item numbers were included in the final list. In neonates, 201 drugs ATC level 5 were evaluated, covering 348 unique item numbers, of which 104 item numbers were included in the final neonatal formulary list. Eighty-eight percent of the included drugs in the paediatric formulary were licensed to children (not specified by age group), 2% were unlicensed in Denmark, and 7% were extemporaneous preparations. For neonates, the percentage was 48%, 4% and 16%, correspondingly. The process is time-consuming as studies are lacking and age-appropriate dosage forms and concentrations differ amongst countries. Nevertheless, the process should be somewhat similar between countries, albeit different drugs may be selected for the final formulary lists.


Clinical outcome of renin-angiotensin-aldosterone system blockers in treatment of hypertensive patients with COVID-19: a systematic review and meta-analysis.
Novel coronavirus disease 2019 has been stated as global disease pandemic due to its rapid spread worldwide. Up to 30% of coronavirus disease 2019 patients with hypertension are more susceptible to death. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been used as primary line of medication for hypertension; nonetheless, conflicting data arises as numerous studies showed contradictory results. Aiming to show clinical outcome of renin-angiotensin-aldosterone system blockers in hospital treatment of hypertensive patients with coronavirus disease 2019, systematically searched literatures through five databases were intensively appraised using The Grading of Recommendations Assessment, Development and Evaluation checklists for cohort studies. Based on the result evaluation from retrospective cohorts involving more than 15,000 patients across Asia and other regions of the world, ten encompassed studies divided into two subgroups in this meta-review showed that in-hospital hypertensive coronavirus disease 2019 patients receiving antihypertensive drugs were associated with overall risk reduction in subgroup 1 (hazard ratio, HR = 0.96, 95% CI = 0.82-1.12) to no outcome association of all-cause mortalities in subgroup 2 (HR = 0.26, 95% CI = 0.19-0.34). All appraised studies in synergism showed that mortality outcomes were not augmented with the employment of either ACE inhibitor or ARB in subjects. Therefore, the results support recommendation by the American Heart Association not to discontinue angiotensin-converting enzyme inhibitor or angiotensin receptor blocker regimens in coronavirus disease 2019 patients with hypertension.


Alfalfa (Medicago sativa L.) pho2 mutant plants hyperaccumulate phosphate.
In this article, we describe a set of novel alfalfa (Medicago sativa L.) plants that hyper-accumulate Phosphate ion (Pi) at levels 3- to 6-fold higher than wild-type. This alfalfa germplasm will have practical applications reclaiming Pi from contaminated or enriched soil or be used in conservation buffer strips to protect waterways from Pi run-off. Hyper-accumulating alfalfa plants were generated by targeted mutagenesis of PHOSPHATE2 (PHO2) using newly created CRISPR/Cas9 reagents and an improved mutant screening strategy. PHO2 encodes a ubiquitin conjugating E2 enzyme (UBC24) previously characterized in Arabidopsis thaliana, Medicago truncatula, and Oryza sativa. Mutations of PHO2 disrupt Pi homeostasis resulting in Pi hyper-accumulation. Successful CRISPR/Cas9 editing of PHO2 demonstrates that this is an efficient mutagenesis tool in alfalfa despite its complex autotetraploid genome structure. Arabidopsis and M. truncatula ortholog genes were used to identify PHO2 haplotypes in outcrossing tetraploid M. sativa with the aim of generating heritable mutations in both PHO2-like genes (PHO2-B and PHO2-C). After delivery of the reagent and regeneration from transformed leaf explants, plants with mutations in all haplotypes of PHO2-B and PHO2-C were identified. These plants were evaluated for morphology, Pi accumulation, heritable transmission of targeted mutations, segregation of mutant haplotypes and removal of T-DNA(s). The Agrobacterium-mediated transformation assay and gene editing reagents reported here were also evaluated for further optimization for future alfalfa functional genomic studies.


Lives in the balance: responsiveness of the corpus luteum to uterine and embryonic signals.
This review focuses on factors that may affect the sensitivity of the corpus luteum to uterine prostaglandin F2alpha (PGF2alpha) and embryonic signals. The heterogeneity of the types of cell that are present within the corpus luteum results in complex interactions that ensure complete luteal regression in response to PGF2alpha. There is not likely to be a single factor that determines responsiveness. The sensitivity of the corpus luteum depends on the proper balance of a variety of factors that are involved in mediating the effects of PGF2alpha. This balance is achieved as the early corpus luteum undergoes development, but may also be altered by embryonic factors to rescue the corpus luteum during early pregnancy.


Root cause analysis of delays to discharge for patients held for serial cardiac troponin levels.
Emergency department (ED) patients with symptoms of cardiac ischemia often require a second cardiac troponin (cTn) measurement to rule out non-ST elevation myocardial infarction. We measured the total turnaround time and the component event times following the ordering of the second cTn level to ED discharge to identify root causes of delays. We reviewed a random sample of ED discharges following a second normal cTn measurement and recorded associated event times. The central tendency of time intervals is reported as median and mean number of minutes with interquartile ranges (IQRs) and 95% confidence intervals, respectively. From 9,656 eligible cases, we randomly selected 226 for data collection. The median number of minutes for each event are as follows: from ordering the second cTn measurement to the time of ED discharge was 90 minutes (IQR 65-120); for blood collection from the time the collection was ordered for was 0 minutes (IQR -12-0); from blood collection to the time the blood was transported to the laboratory was 9 minutes (IQR 2-19); laboratory process duration was 44 minutes (IQR 39-52); from when the results were available to the time the patient was discharged was 30 minutes (IQR 15-52). For ED patients discharged following two normal cTn levels, the laboratory processing time and time from the result being available to the time of ED discharge represent the longest modifiable time periods to reduce ED length of stay.


The Role of Therapeutic Modalities in Surgical and Nonsurgical Management of Orthopaedic Injuries.
Rehabilitation professionals often use therapeutic modalities as a component of the surgical and nonsurgical management of orthopaedic injuries. Myriad therapeutic modalities, including cryotherapy, thermotherapy, ultrasonography, electrical stimulation, iontophoresis, and laser therapy, are available. Knowledge of the scientific basis of each modality and the principles of implementation for specific injuries enables musculoskeletal treatment providers to prescribe these modalities effectively. The selection of specific therapeutic modalities is based on their efficacy during a particular phase of rehabilitation. Therapeutic modalities are an adjunct to standard exercise and manual therapy techniques and should not be used in isolation.


Seat belt aorta: endovascular management with a stent-graft.
To report the endovascular treatment of a relatively uncommon type of deceleration injury to the abdominal aorta. A 21-year-old backseat passenger was wearing a single lap belt without shoulder harness when the car was involved in a collision. He sustained a transverse (Chance) fracture of the third lumbar vertebra and a circumferential dissection of the infrarenal abdominal aorta with pseudoaneurysm. As an interim measure while a stent-graft was obtained, a Wallstent was deployed to tack down the dissection and prevent distal embolization. Thirty-six hours later, an AneuRx endograft was successfully implanted inside the Wallstent to seal the pseudoaneurysm. The patient's recovery was uneventful, and the endograft remains secure and the pseudoaneurysm excluded at 10 months after the accident. Endovascular repair of "seat belt aorta" is a minimally invasive, straightforward method of management for this type of aortic injury. The potential for infection in a contaminated peritoneal cavity and the long-term outcome of this treatment have not been determined.


Anti-amyloid potential of some phytochemicals against Aβ-peptide and α-synuclein, tau, prion, and Huntington proteins.
Some molecules self-assemble to create complex structures through molecular self-assembly. Hydrogel preparation, tissue repair, and therapeutic drug delivery are a few applications of molecular self-assembly. However, the self-assembly of amino acids, peptides, and proteins forms amyloid fibrils, resulting in various disorders, most notably neurodegenerative ailments. Examples include the self-assembly of phenylalanine, which causes phenylketonuria; Aβ, which causes Alzheimer's disease; the tau protein, which causes both Alzheimer's and Parkinson's diseases; and α-synuclein, which causes Parkinson's illness. This review provides information related to phytochemicals of great significance that can prevent the formation of, or destabilize, amino acid, peptide, and protein self-assemblies.


Pcif1 modulates Pdx1 protein stability and pancreatic β cell function and survival in mice.
The homeodomain transcription factor pancreatic duodenal homeobox 1 (Pdx1) is a major mediator of insulin transcription and a key regulator of the β cell phenotype. Heterozygous mutations in PDX1 are associated with the development of diabetes in humans. Understanding how Pdx1 expression levels are controlled is therefore of intense interest in the study and treatment of diabetes. Pdx1 C terminus-interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation. Silencing of Pcif1 increased Pdx1 protein levels in cultured mouse β cells, and Pcif1 heterozygosity normalized Pdx1 protein levels in Pdx1(+/-) mouse islets, thereby increasing expression of key Pdx1 transcriptional targets. Remarkably, Pcif1 heterozygosity improved glucose homeostasis and β cell function and normalized β cell mass in Pdx1(+/-) mice by modulating β cell survival. These findings indicate that in adult mouse β cells, Pcif1 limits Pdx1 protein accumulation and thus the expression of insulin and other gene targets important in the maintenance of β cell mass and function. They also provide evidence that targeting the turnover of a pancreatic transcription factor in vivo can improve glucose homeostasis.


Evolution and maintenance of haploid-diploid life cycles in natural populations: The case of the marine brown alga Ectocarpus.
The evolutionary stability of haploid-diploid life cycles is still controversial. Mathematical models indicate that niche differences between ploidy phases may be a necessary condition for the evolution and maintenance of these life cycles. Nevertheless, experimental support for this prediction remains elusive. In the present work, we explored this hypothesis in natural populations of the brown alga Ectocarpus. Consistent with the life cycle described in culture, Ectocarpus crouaniorum in NW France and E. siliculosus in SW Italy exhibited an alternation between haploid gametophytes and diploid sporophytes. Our field data invalidated, however, the long-standing view of an isomorphic alternation of generations. Gametophytes and sporophytes displayed marked differences in size and, conforming to theoretical predictions, occupied different spatiotemporal niches. Gametophytes were found almost exclusively on the alga Scytosiphon lomentaria during spring whereas sporophytes were present year-round on abiotic substrata. Paradoxically, E. siliculosus in NW France exhibited similar habitat usage despite the absence of alternation of ploidy phases. Diploid sporophytes grew both epilithically and epiphytically, and this mainly asexual population gained the same ecological advantage postulated for haploid-diploid populations. Consequently, an ecological interpretation of the niche differences between haploid and diploid individuals does not seem to satisfactorily explain the evolution of the Ectocarpus life cycle.


Facing the Heat: Thermoregulation and Behaviour of Lowland Species of a Cold-Dwelling Butterfly Genus, Erebia.
Understanding the potential of animals to immediately respond to changing temperatures is imperative for predicting the effects of climate change on biodiversity. Ectothermic animals, such as insects, use behavioural thermoregulation to keep their body temperature within suitable limits. It may be particularly important at warm margins of species occurrence, where populations are sensitive to increasing air temperatures. In the field, we studied thermal requirements and behavioural thermoregulation in low-altitude populations of the Satyrinae butterflies Erebia aethiops, E. euryale and E. medusa. We compared the relationship of individual body temperature with air and microhabitat temperatures for the low-altitude Erebia species to our data on seven mountain species, including a high-altitude population of E. euryale, studied in the Alps. We found that the grassland butterfly E. medusa was well adapted to the warm lowland climate and it was active under the highest air temperatures and kept the highest body temperature of all species. Contrarily, the woodland species, E. aethiops and a low-altitude population of E. euryale, kept lower body temperatures and did not search for warm microclimates as much as other species. Furthermore, temperature-dependence of daily activities also differed between the three low-altitude and the mountain species. Lastly, the different responses to ambient temperature between the low- and high-altitude populations of E. euryale suggest possible local adaptations to different climates. We highlight the importance of habitat heterogeneity for long-term species survival, because it is expected to buffer climate change consequences by providing a variety of microclimates, which can be actively explored by adults. Alpine species can take advantage of warm microclimates, while low-altitude grassland species may retreat to colder microhabitats to escape heat, if needed. However, we conclude that lowland populations of woodland species may be more severely threatened by climate warming because of the unavailability of relatively colder microclimates.


Dry molten globule intermediates and the mechanism of protein unfolding.
New experimental results show that either gain or loss of close packing can be observed as a discrete step in protein folding or unfolding reactions. This finding poses a significant challenge to the conventional two-state model of protein folding. Results of interest involve dry molten globule (DMG) intermediates, an expanded form of the protein that lacks appreciable solvent. When an unfolding protein expands to the DMG state, side chains unlock and gain conformational entropy, while liquid-like van der Waals interactions persist. Four unrelated proteins are now known to form DMGs as the first step of unfolding, suggesting that such an intermediate may well be commonplace in both folding and unfolding. Data from the literature show that peptide amide protons are protected in the DMG, indicating that backbone structure is intact despite loss of side-chain close packing. Other complementary evidence shows that secondary structure formation provides a major source of compaction during folding. In our model, the major free-energy barrier separating unfolded from native states usually occurs during the transition between the unfolded state and the DMG. The absence of close packing at this barrier provides an explanation for why phi-values, derived from a Brønsted-Leffler plot, depend primarily on structure at the mutational site and not on specific side-chain interactions. The conventional two-state folding model breaks down when there are DMG intermediates, a realization that has major implications for future experimental work on the mechanism of protein folding.


A deconvolution approach for PET-based dose reconstruction in proton radiotherapy.
Positron emitters are activated by proton beams in proton radiotherapy, and positron emission tomography (PET) images can thus be used for dose verification. Since a PET image is not directly proportional to the delivered radiation dose distribution, predicted PET images are compared to measured PET images and an agreement of both indicates a successful irradiation. Such predictions are given on the basis of Monte Carlo calculations or a filtering approach which uses a convolution of the planned dose with specific filter functions to estimate the PET activity. In this paper, we describe and evaluate a dose reconstruction method based on PET images which reverses the just mentioned convolution approach using appropriate deconvolution methods. Deconvolution is an ill-posed inverse problem, and suitable regularization techniques are required in order to guarantee a stable solution. The basic convolution approach is developed for homogeneous media and additional procedures are necessary to generalize the PET estimation to inhomogeneous media. This generalization formalism is used in our dose deconvolution approach as well. Various simulations demonstrate that the dose reconstruction method is able to reverse the PET estimation method both in homogeneous and inhomogeneous media. Measured PET images are however degraded by noise and artifacts and the dose reconstructions become more difficult and the results suffer from artifacts as well. Recently used in-room PET scanners allow a decreased delay time between irradiation and imaging, and thus the influence of short-lived positron emitters on the PET images increases considerably. We extended our dose reconstruction method to process PET images which contain several positron emitters and simulated results are shown.


Pan Aurora Kinase Inhibitor: A Promising Targeted-Therapy in Dedifferentiated Liposarcomas With Differential Efficiency Depending on Sarcoma Molecular Profile.
Soft tissue sarcoma (STS) are rare and aggressive tumours. Their classification includes numerous histological subtypes of frequent poor prognosis. Liposarcomas (LPS) are the most frequent type among them, and the aggressiveness and deep localization of dedifferentiated LPS are linked to high levels of recurrence. Current treatments available today lead to five-year overall survival has remained stuck around 60%-70% for the past three decades. Here, we highlight a correlation between Aurora kinasa A (AURKA) and AURKB mRNA overexpression and a low metastasis - free survival. AURKA and AURKB expression analysis at genomic and protein level on a 9-STS cell lines panel highlighted STS heterogeneity, especially in LPS subtype. AURKA and AURKB inhibition by RNAi and drug targeting with AMG 900, a pan Aurora Kinase inhibitor, in four LPS cell lines reduces cell survival and clonogenic proliferation, inducing apoptosis and polyploidy. When combined with doxorubicin, the standard treatment in STS, aurora kinases inhibitor can be considered as an enhancer of standard treatment or as an independent drug. Kinome analysis suggested its effect was linked to the inhibition of the MAP-kinase pathway, with differential drug resistance profiles depending on molecular characteristics of the tumor. Aurora Kinase inhibition by AMG 900 could be a promising therapy in STS.


Jellyfish-Inspired Soft Robot Driven by Fluid Electrode Dielectric Organic Robotic Actuators.
Robots for underwater exploration are typically comprised of rigid materials and driven by propellers or jet thrusters, which consume a significant amount of power. Large power consumption necessitates a sizeable battery, which limits the ability to design a small robot. Propellers and jet thrusters generate considerable noise and vibration, which is counterproductive when studying acoustic signals or studying timid species. Bioinspired soft robots provide an approach for underwater exploration in which the robots are comprised of compliant materials that can better adapt to uncertain environments and take advantage of design elements that have been optimized in nature. In previous work, we demonstrated that frameless DEAs could use fluid electrodes to apply a voltage to the film and that effective locomotion in an eel-inspired robot could be achieved without the need for a rigid frame. However, the robot required an off-board power supply and a non-trivial control signal to achieve propulsion. To develop an untethered soft swimming robot powered by DEAs, we drew inspiration from the jellyfish and attached a ring of frameless DEAs to an inextensible layer to generate a unimorph structure that curves toward the passive side to generate power stroke, and efficiently recovers the original configuration as the robot coasts. This swimming strategy simplified the control system and allowed us to develop a soft robot capable of untethered swimming at an average speed of 3.2 mm/s and a cost of transport of 35. This work demonstrates the feasibility of using DEAs with fluid electrodes for low power, silent operation in underwater environments.


Obstetric cholestasis: current opinions and management.
Obstetric cholestasis (OC) is a pregnancy-specific liver condition that typically presents with generalised pruritus in the absence of a rash in the late second trimester or third trimester. It is more common in certain ethnic groups, particularly those from South Asian, South American, Nordic and Scandinavian regions, and has a familial and genetic basis. Recent research suggests that the pathophysiology may reside in mutations in genes that code for bile acid transporter proteins. Mutations involving the bile acid transporters may impair maternal excretion and influence transplacental passage of bile acids. It is hypothesised that the surge in pregnancy steroid hormones may result in genetically predisposed women developing cholestasis. The condition is also associated with increased perinatal morbidity and mortality, particularly from preterm labour, fetal distress and intrauterine deaths. Animal studies have shown that bile acids are cardiotoxic, which may help explain the condition's association with fetal distress and stillbirths. Accurate diagnosis relies on a high index of suspicion, and the findings of abnormal liver function tests and raised serum bile acid levels after the exclusion of other organic causes of liver disease. Ursodeoxycholic acid helps relieve symptoms, improve serum bile acid levels and possibly has a cardioprotective effect. Active management, in the form of close antepartum fetal monitoring and delivery before 37 weeks, helps to decrease the risk of intrauterine deaths, though possibly at the expense of increased obstetric intervention. Following delivery, there is usually a dramatic improvement of symptoms and resolution of the condition. Women should be counselled about the high recurrence risk of OC in subsequent pregnancies.


Small scientific journals from small countries: breaking from a vicious circle of inadequacy.
In this editorial we describe the confounding factors that contribute to the poor international recognition of small journals: author pool, review process, finances, language, and visibility. These factors originate from relative scientific inadequacy of the local environment and close a positive feedback loop (vicious circle) of journal inadequacy. We argue that small journals may provide important information and outline the ways in which they can be assisted.


Simultaneous rupture of two middle cerebral artery aneurysms presented with two aneurysm-associated intracerebral hemorrhages.
Simultaneous rupture of more than one intracranial aneurysm is a rare event and difficult to diagnose. In this case report, we present the case of a patient with a simultaneous rupture of two middle cerebral artery (MCA) aneurysms with two separately localized aneurysm-associated intracerebral hemorrhages (ICH). Initially, the patient presented with headache and neck stiffness as well as progressive decrease of consciousness. Computed tomography (CT) revealed a subarachnoid hemorrhage with a frontal and temporal space-occupying ICH. CT angiography demonstrated two MCA aneurysms located in adjacency to the ICHs, one located at the M1 segment and the other in the bifurcation of the left MCA. Rupture of both aneurysms was confirmed during surgery, and both aneurysms were clipped microsurgically without complications. Although rupture of one aneurysm in patients with multiple aneurysms is the most common event, this case indicates that simultaneous rupture should be kept in mind in patients with multiple aneurysms. In patients with multiple aneurysms, the identification of the ruptured aneurysm(s) is necessary to avoid leaving a ruptured aneurysm untreated.


Algal toxins in Alaskan seabirds: Evaluating the role of saxitoxin and domoic acid in a large-scale die-off of Common Murres.
Elevated seawater temperatures are linked to the development of harmful algal blooms (HABs), which pose a growing threat to marine birds and other wildlife. During late 2015 and early 2016, a massive die-off of Common Murres (Uria aalge; hereafter, murres) was observed in the Gulf of Alaska coincident with a strong marine heat wave. Previous studies have documented illness and death among seabirds resulting from exposure to the HAB neurotoxins saxitoxin (STX) and domoic acid (DA). Given the unusual mortality event, corresponding warm water anomalies, and recent detection of STX and DA throughout coastal Alaskan waters, HABs were identified as a possible factor of concern. To evaluate whether algal toxins may have contributed to murre deaths, we tested for STX and DA in a suite of tissues obtained from beach-cast murre carcasses associated with the die-off as well as from apparently healthy murres and Black-legged Kittiwakes (Rissa tridactyla; hereafter, kittiwakes) sampled in the preceding and following summers. We also tested forage fish and marine invertebrates collected in the Gulf of Alaska in 2015-2017 to evaluate potential sources of HAB toxin exposure for seabirds. Saxitoxin was present in multiple tissue types of both die-off (36.4 %) and healthy (41.7 %) murres and healthy kittiwakes (54.2 %). Among birds, we detected the highest concentrations of STX in liver tissues (range 1.4-10.8 μg 100 g-1) of die-off murres. Saxitoxin was relatively common in forage fish (20.3 %) and invertebrates (53.8 %). No established toxicity limits currently exist for seabirds, but concentrations of STX in birds and forage fish in our study were lower than values reported from most other bird die-offs in which STX intoxication was causally linked. We detected low concentrations of DA in a single bird sample and in 33.3 % of invertebrates and 4.0 % of forage fish samples. Although these results do not support the hypothesis that acute exposure to STX or DA was a primary factor in the 2015-2016 mortality event, additional information about the sensitivity of murres to these toxins is needed before we can discount their potential role in the die-off. The widespread occurrence of STX in seabirds, forage fish, and invertebrates in the Gulf of Alaska indicates that algal toxins should be considered in future assessments of seabird health, especially given the potential for greater occurrence of HABs in the future.


Measles virus antibody in cerebrospinal fluids from patients with multiple sclerosis.
A strong measles-specific gel precipitation reaction was found in the cerebrospinal fluid (C.S.F.) of two patients with multiple sclerosis (M.S.) (total of 15 tested). The serum and C.S.F. specimens from these two patients were tested for measles antibody by six assay methods. The results were compared with those obtained from serum and C.S.F. specimens of a patient with subacute sclerosing panencephalitis (S.S.P.E.). The gel precipitation line produced by the C.S.F. from the M.S. patients was identical with one of the three lines produced by the C.S.F. from the S.S.P.E. patient. The main antigenic component responsible for measles antibody appearing in the C.S.F. of the S.S.P.E. patient and the M.S. patients was also electrophoretically similar, and the corresponding antibody was associated with IgG. The serum/C.S.F. antibody titre ratios with the various assay methods used suggest that the C.S.F. antibodies are mainly to other than envelope components of measles virus. No complement-fixing antibody against 27 other viruses or Mycoplasma pneumoniae was found in the C.S.F. of the two M.S. patients.


Initial in vitro evaluation of DIAGNOdent for detecting secondary carious lesions associated with resin composite restorations.
To assess the potential of DIAGNOdent (DD) readings for detecting secondary enamel and dentin carious lesions associated with resin composite restorations in a set of preserved extracted adult teeth. Thirty test sites adjacent to resin composite restorations in 15 extracted teeth were evaluated visually and with DD readings for enamel and dentin caries. The results were compared to gold standard diagnosis determined by sectioning through each site and subsequent microscopic observation. Sensitivity, specificity, accuracy, and likelihood ratios at optimum threshold values for enamel and dentin caries were determined. Receiver operator characteristic (ROC) analysis was performed to compare visual and DD diagnostic methods. Histologic incidence of enamel caries was 20% and dentin caries was 36.67%. All composite restorations in the sample teeth fluoresced (range 5 to 22). For enamel caries detection with DD, the optimum threshold of > or = 26 produced a sensitivity of .67 and a specificity of .79. For dentin caries detection with DD, the optimum threshold of > or = 22 produced a sensitivity of .73 and a specificity of .84. ROC analysis showed that the DD readings do contain diagnostic information. DD readings for dentin caries diagnosis produced better diagnostic results compared to visual readings for the 30 test sites in the study, but these results were not significantly different. DIAGNOdent readings may have potential for resin composite secondary enamel and dentin carious lesion detection. DIAGNOdent instrument design factors and technique should be optimized to improve performance prior to clinical trial for this application.


FGWAS: Functional genome wide association analysis.
Functional phenotypes (e.g., subcortical surface representation), which commonly arise in imaging genetic studies, have been used to detect putative genes for complexly inherited neuropsychiatric and neurodegenerative disorders. However, existing statistical methods largely ignore the functional features (e.g., functional smoothness and correlation). The aim of this paper is to develop a functional genome-wide association analysis (FGWAS) framework to efficiently carry out whole-genome analyses of functional phenotypes. FGWAS consists of three components: a multivariate varying coefficient model, a global sure independence screening procedure, and a test procedure. Compared with the standard multivariate regression model, the multivariate varying coefficient model explicitly models the functional features of functional phenotypes through the integration of smooth coefficient functions and functional principal component analysis. Statistically, compared with existing methods for genome-wide association studies (GWAS), FGWAS can substantially boost the detection power for discovering important genetic variants influencing brain structure and function. Simulation studies show that FGWAS outperforms existing GWAS methods for searching sparse signals in an extremely large search space, while controlling for the family-wise error rate. We have successfully applied FGWAS to large-scale analysis of data from the Alzheimer's Disease Neuroimaging Initiative for 708 subjects, 30,000 vertices on the left and right hippocampal surfaces, and 501,584 SNPs.


Pharmacological Activity of Eriodictyol: The Major Natural Polyphenolic Flavanone.
Eriodictyol is a flavonoid that belongs to a subclass of flavanones and is widespread in citrus fruits, vegetables, and medicinally important plants. Eriodictyol has been anticipated to explain the method of its activity via multiple cellular signaling cascades. Eriodictyol is an effective natural drug source to maintain higher health standards due to its excellent therapeutic roles in neuroprotection, cardioprotective activity, hepatoprotective activity, antidiabetes and obesity, and skin protection and having highly analgesic, antioxidant, and anti-inflammatory effects, antipyretic and antinociceptive actions, antitumor activity, and much more. This review aims to highlight the modes of action of eriodictyol against various diseases via multiple cellular signaling pathways.


[The blood supply of galeotemporal flap: an anatomical and radiographic study].
Galea flap (GF) consists of two parts: Galea aponeurotica and superficial layer of temporal muscle. This flap is useful in plastic and reconstructive surgery of the defects of oral mucosa, lips, but also in reconstruction of orbital floor defects. Many authors have stressed that most of troubles in GF as reconstruction are caused by its neurosis due to its vascular net, i.e. one or several of important branches have been cut. Their experience have forced us, as GF is not the routine technique in our country, to provide an investigation using cadaveric material and arteriographies of the patients without pathological changes in GF area.


Influence of process parameters on tablet bed microenvironmental factors during pan coating.
Recent studies have shown the importance of monitoring microenvironmental conditions (temperature, relative humidity) experienced by the tablet bed during a pan coating process, thereby necessitating the need to understand how various process parameters influence these microenvironmental conditions. The process parameters studied in this work include exhaust air temperature, spray rate, inlet airflow rate, gun-to-bed distance, coating suspension percent solids, and atomization and pattern air pressure. Each of these process parameters was found to have an impact on the tablet bed relative humidity (RH), as measured using PyroButton data logging devices. A higher tablet bed RH was obtained with an increase in spray rate and atomization air pressure and with a decrease in exhaust air temperature, inlet airflow rate, gun-to-bed distance, suspension percent solids, and pattern air pressure. Based on this work, it can be concluded that the tablet bed thermodynamic conditions are a cumulative effect of the various process conditions. A strong correlation between the tablet bed RH and the frequency of tablet coating defect (logo bridging) was established, with increasing RH resulting in a higher percent of logo bridging events.


Artificial Intelligence in Endoscopic Ultrasound for Pancreatic Cancer: Where Are We Now and What Does the Future Entail?
Pancreatic cancer is a highly lethal disease associated with significant morbidity and mortality. In the United States (US), the overall 5-year relative survival rate for pancreatic cancer during the 2012-2018 period was 11.5%. However, the cancer stage at diagnosis strongly influences relative survival in these patients. Per the National Cancer Institute (NCI) statistics for 2012-2018, the 5-year relative survival rate for patients with localized disease was 43.9%, while it was 3.1% for patients with distant metastasis. The poor survival rates are primarily due to the late development of clinical signs and symptoms. Hence, early diagnosis is critical in improving treatment outcomes. In recent years, artificial intelligence (AI) has gained immense popularity in gastroenterology. AI-assisted endoscopic ultrasound (EUS) models have been touted as a breakthrough in the early detection of pancreatic cancer. These models may also accurately differentiate pancreatic cancer from chronic pancreatitis and autoimmune pancreatitis, which mimics pancreatic cancer on radiological imaging. In this review, we detail the application of AI-assisted EUS models for pancreatic cancer detection. We also highlight the utility of AI-assisted EUS models in differentiating pancreatic cancer from radiological mimickers. Furthermore, we discuss the current limitations and future applications of AI technology in EUS for pancreatic cancers.


A Review of Precision Oncology Knowledgebases for Determining the Clinical Actionability of Genetic Variants.
The increased availability of tumor genetic testing and targeted cancer therapies contributes to the advancement of precision medicine in the field of oncology. Precision oncology knowledgebases provide a way of organizing clinically relevant genetic information in a way that is easily accessible for both oncologists and patients, facilitating the genetic-based clinical decision making. Many organizations and companies have built precision oncology knowledgebases, intended for multiple users. In general, these knowledgebases offer information on cancer-related genetic variants as well as their associated diagnostic, prognostic, and therapeutic implications, but they often differ in their information curations, designs, and user experiences. It is advisable that oncologists use multiple knowledgebases during their practice to have them complement each other. In the future, convergence toward common standards and formats is needed to ensure that the comprehensive knowledge across all sources can be unified to bring the oncology community closer to the achievement of the goal of precision oncology.


[Right-sided colonic diverticular disease: quo vadis?].
Symptomatic diverticular disease of the right colon is a rare entity in our latitudes, where it represents only 1.5% of all diverticulitis. In contrary, this disease is endemic in Asian countries. Besides, it has several differences with its left counterpart. Indeed, a right-sided diverticular disease is more often symptomatic, while the risk of complicated episodes seems lower. Right-sided diverticular disease usually manifests as right iliac fossa pain or low gastrointestinal bleeding. First described on 1912, there are no clear guidelines. The approach is usually conservative in Asia; when surgery cannot be avoided, a limited resection is performed. In Western countries, a surgical approach is more often considered. We reviewed the current literature and propose a way to manage right diverticulitis.


[Medical support of the Navy ships during long-term sailing].
The article presents peculiarities of organization of medical equipment of ships on service. The main of them are: a big farness from the base, necessity of realizing a qualified medical aid on the board because of uncapability of evacuation the patients to medical treatment facility in time, unsteady sanitarian-epidemiological status in areas of floats and in places of put in, influence of negative factors of inhabitation of ships, which calls different changes in functional condition of staff. Medical security consists of 3 parts: avance-float period, float period and after-float period. Such periodicity allows dividing efforts of medical security more professionally. The authors presents data, based on the experience of medical securing of the ships of crash team, created in the Northern Navy during the period from 3.12.2007 to 3.02.2008, realized a float from the base to Mediterranean Sea and back. Total distance was 15 sea miles, total duration was 62 days.


Ulysses radio and plasma wave observations at high southern heliographic latitudes.
Ulysses spacecraft radio and plasma wave observations indicate that some variations in the intensity and occurrence rate of electric and magnetic wave events are functions of heliographic latitude, distance from the sun, and phase of the solar cycle. At high heliographic latitudes, solartype Ill radio emissions did not descend to the local plasma frequency, in contrast to the emission frequencies of some bursts observed in the ecliptic. Short-duration bursts of electrostatic and electromagnetic waves were often found in association with depressions in magnetic field amplitude, known as magnetic holes. Extensive wave activity observed in magnetic clouds may exist because of unusually large electron-ion temperature ratios. The lower number of intense in situ wave events at high latitudes was likely due to the decreased variability of the high- latitude solar wind.


[Selection of EBM resources on the internet].
To integrate Evidence-Based Medicine (EBM) into practice, the physician has access to a number of resources on the Internet. They belong to two distinct groups: tools intended for EBM learning and EBM syntheses prepared by different international organizations. The present article presents the main EBM resources on the network and comments on them. These information are also available on the URL site: http:www.ebm.lib.ulg.ac.be/prostate/link_ebm .htm.


MiR-30b Attenuates Neuropathic Pain by Regulating Voltage-Gated Sodium Channel Nav1.3 in Rats.
Nav1.3 is a tetrodotoxin-sensitive isoform among voltage-gated sodium channels that are closely associated with neuropathic pain. It can be up-regulated following nerve injury, but its biological function remains uncertain. MicroRNAs (miRNAs) are endogenous non-coding RNAs that can regulate post-transcriptional gene expression by binding with their target mRNAs. Using Target Scan software, we discovered that SCN3A is the major target of miR-30b, and we then determined whether miR-30b regulated the expression of Nav1.3 by transfecting miR-30b agomir through the stimulation of TNF-α or by transfecting miR-30b antagomir in primary dorsal root ganglion (DRG) neurons. The spinal nerve ligation (SNL) model was used to determine the contribution of miR-30b to neuropathic pain, to evaluate changes in Nav1.3 mRNA and protein expression, and to understand the sensitivity of rats to mechanical and thermal stimuli. Our results showed that miR-30b agomir transfection down-regulated Nav1.3 mRNA stimulated with TNF-α in primary DRG neurons. Moreover, miR-30b overexpression significantly attenuated neuropathic pain induced by SNL, with decreases in the expression of Nav1.3 mRNA and protein both in DRG neurons and spinal cord. Activation of Nav1.3 caused by miR-30b antagomir was identified. These data suggest that miR-30b is involved in the development of neuropathic pain, probably by regulating the expression of Nav1.3, and might be a novel therapeutic target for neuropathic pain. Perspective: This study is the first to explore the important role of miR-30b and Nav1.3 in spinal nerve ligation-induced neuropathic pain, and our evidence may provide new insight for improving therapeutic approaches to pain.


Protection of DNA against low-energy electrons by amino acids: a first-principles molecular dynamics study.
Using first-principles molecular dynamics simulations, we have investigated the notion that amino acids can play a protective role when DNA is exposed to excess electrons produced by ionizing radiation. In this study we focus on the interaction of glycine with the DNA nucleobase thymine. We studied thymine-glycine dimers and a condensed phase model consisting of one thymine molecule solvated in amorphous glycine. Our results show that the amino acid acts as a protective agent for the nucleobase in two ways. If the excess electron is initially captured by the thymine, then a proton is transferred in a barrier-less way from a neighboring hydrogen-bonded glycine. This stabilizes the excess electron by reducing the net partial charge on the thymine. In the second mechanism the excess electron is captured by a glycine, which acts as a electron scavenger that prevents electron localization in DNA. Both these mechanisms introduce obstacles to further reactions of the excess electron within a DNA strand, e.g. by raising the free energy barrier associated with strand breaks.


Responding to Parental Requests for Nondisclosure to Patients of Diagnostic and Prognostic Information in the Setting of Serious Disease.
Learning that one's child is seriously ill can be devastating, requiring families to decide when and how to share information about diagnosis and prognosis with their child. In most cases, this disclosure is made thoughtfully and collaboratively with the medical team. Some parents, however, may be concerned that disclosure will take away their child's hope, cause emotional pain, or exceed the child's capacity for understanding. Faced with competing obligations of truth-telling to their patient and respect for parental wishes, pediatricians may be unsure how to proceed. This clinical report examines ethical duties and legal considerations, providing practical and culturally sensitive case-based guidance for clinicians to approach parental requests for nondisclosure of diagnostic or prognostic information.


Outward currents of single hippocampal cells obtained from the adult guinea-pig.
1. Neurones were isolated from the hippocampus of adult guinea-pigs by enzymatic and mechanical treatment. The electrophysiological properties of these cells were examined immediately after dissociation by intracellular recordings using low-resistance electrodes (2-5 M omega). 2. Pyramidal-shaped cells were identified visually. Intracellular recordings showed that these cells have input resistances ranging from 200 to 1300 M omega. Passive voltage responses to hyperpolarizing current injection were fitted by single exponentials decaying with time constants ranging from 15 to 60 ms. This suggests that the electrotonic structure of these cells is compact such that injected current elicited isopotential intracellular responses. 3. Outward currents activated by depolarization were examined in these cells using voltage-clamp techniques. The amplitude and the time course of the outward currents were profoundly affected by the holding potential. For cells held at -50 mV or more positive, depolarizing steps produced a slowly rising outward current. At holding potentials negative to -55 mV depolarizing pulses produced an additional early transient outward current followed by a slowly rising component which decayed gradually during sustained depolarizations. 4. The outward currents were separated by their kinetic properties and their sensitivity to cobalt (Co2+), tetraethylammonium (TEA) and 4-aminopyridine (4-AP). 5. The transient current peaked within 6 ms of the onset of depolarizing pulses. It decayed exponentially with a time constant of 20-40 ms. The amplitude of the current activated by a fixed depolarization increased gradually as the duration or the amplitude of the hyperpolarizing pre-pulse increased. The current activated by a fixed depolarization reached its half-maximal level when the hyperpolarizing pre-pulse was at -83 mV. 6. 4-AP exerted two actions on the transient current. Firstly, the time constant of the falling phase decreased by about a factor of two. Secondly, the current was blocked in a time- and voltage-dependent manner: the block increased when the hyperpolarizing pre-pulse lengthened. TEA, up to 10 mM, did not affect the amplitude of the transient current. Co2+ suppressed this current. The effects of Co2+ consisted of a shift to the positive direction of the voltage dependence of the current. 7. The delayed currents can be divided into Ca2+-dependent and Ca2+-independent components. The component persistent in the Co2+ solution (K-current) decayed slowly with maintained depolarization (time constant greater than 3 s).(ABSTRACT TRUNCATED AT 400 WORDS)


Endothelial diaphragmed fenestrae: in vitro modulation by phorbol myristate acetate.
Cultured microvascular endothelial cells isolated from fenestrated capillaries have been shown to express many properties of their in vivo differentiated phenotype, yet they contain very few diaphragmed fenestrae. We show here that treatment of capillary endothelial cells with the tumor promoter, 4 beta-phorbol 12-myristate 13-acetate, induces more than a fivefold increase in the frequency of fenestrae per micron 2 of cell surface, as determined from a quantitative evaluation on freeze-fracture replicas. In quick-frozen, deep-etched preparations, the endothelial fenestrae appeared to be bridged by a diaphragm composed of radial fibers interweaving in a central mesh, as previously observed in vivo. These results indicate that diaphragmed fenestrae are inducible structures, and provide an opportunity to study them in vitro.


Investigation of a cluster of pituitary adenomas in workers in the aluminum industry.
Four cases of pituitary adenoma among employees at a primary aluminum production factory were identified over a five year period by a community physician. The objective of this investigation was to determine whether there has been a comparable high incidence in other aluminum factories, and if particular jobs, departments, or activities in the industry are associated with higher rates of the disease. Pituitary adenoma in employees at all United States factories of the company for the years 1989-94 was assessed by a search of a health data information bank and an insurance data base covering present and past employees of the corporation. The incidence in the aluminum workers was estimated and compared with the workers in the index plant. A nested case control study was conducted to compare employment histories of identified cases with those of age and sex matched controls selected from the health information data base. 25 cases, including the index cases, were identified which had been diagnosed during the period 1989-94. The resulting rate of 10.4/100,000 person-years was much lower than that at the index plant. Case-control analysis showed no coherent pattern of location, department, or job significantly associated with risk. In particular, jobs and departments associated with exposures common to aluminum smelting-such as coal tar pitch volatiles and fluorides-were shown to be uncommon among cases compared with age and sex matched controls. Overall, despite the unprecedented cluster at a single plant, no strong evidence was found that the rate of pituitary adenoma is increased in aluminum workers generally. We found no association with any work activity or location in the industry to suggest a work related or exposure related cause for the disease.


Advantages and limitations of particle-mediated transfection (gene gun) in cancer immuno-gene therapy using IL-10, IL-12 or B7-1 in murine tumor models.
Previous studies have shown that particle-mediated transfection (PMT; gene gun) is an efficient method of non-viral gene transfer. We have examined the advantages and limitations of PMT in cancer immuno-gene therapy using IL-10, IL-12 or B7-1, all of which have been shown to be effective in murine tumor models using retroviral vectors. Murine cell lines (MCA205, MCA207, NIH-3T3) were treated with in vitro PMT, liposome-mediated transfection (LMT) or retroviral transfection. In vivo PMT was also examined for in vivo experiments using C57BL/6. Transfection efficiency and cytokine expression of PMT were similar to those of LMT, another non-viral approach, in culture when murine adherent cells were used. Tumor establishment of MCA205 was suppressed when they were transfected with the mIL-12 and/or mB7-1 gene using PMT in vitro. In a treatment of established tumor, vaccination with tumor cells transfected with an IL-12 gene suppressed tumor growth, whereas a B7-1 gene was not effective. When an IL-10 gene was used to supply a high level of expression for antitumor effects, neither in vitro nor in vivo PMT could suppress even tumor establishment. These failures appear to be caused by the characteristics of PMT which allows high, but transient, expression of transfected genes. Particle-mediated transfection is a useful non-viral transfection method in a system which does not require high-level gene expression for a prolonged time of period.


Granulomatous Tumoral Melanosis Associated With Pembrolizumab Therapy: A Mimicker of Disease Progression in Metastatic Melanoma.
Immune checkpoint inhibitor therapy has revolutionized the treatment of advanced melanoma, with these agents significantly improving survival for patients with metastatic disease. With the increasing use of these agents, the number of adverse reactions secondary to their use has also increased. Sarcoidosis and sarcoid-like reactions are one such immune checkpoint inhibitor-related adverse event. We report a case of sarcoid-like granulomatous tumoral melanosis in a patient on the programmed cell death-1 (PD-1) receptor inhibitor pembrolizumab for metastatic melanoma. This is, to our knowledge, the first reported case of a sarcoidal form of tumoral melanosis in a patient on anti-PD-1 therapy. We postulate that this reflects tumor regression in response to pembrolizumab-induced immune activation, with concomitant therapy-triggered induction of a sarcoid-like reaction. These findings and the literature review presented herein should alert clinicians and pathologists to the possibility of regressed lesions with sarcoid-like features presenting as mimickers of disease progression in patients undergoing immunotherapy for advanced melanoma.


Increased poly(ADP-ribosyl)ation of nuclear proteins in Alzheimer's disease.
Experimental studies indicate that overactivation of the DNA repair protein poly(ADP-ribose) polymerase (PARP) in response to oxidative damage to DNA can cause cell death due to depletion of NAD+. Oxidative damage to DNA and other macromolecules has been reported to be increased in the brains of patients with Alzheimer's disease. In the present study we sought evidence of PARP activation in Alzheimer's disease by immunostaining sections of frontal and temporal lobe from autopsy material of 20 patients and 10 controls, both for PARP itself and for its end-product, poly(ADP-ribose). All of the brains had previously been subjected to detailed neuropathological examination to confirm the diagnosis of Alzheimer's disease or, in the controls, to exclude Alzheimer's disease-type pathology. Double immunolabelling for poly(ADP-ribose) and microtubule-associated protein 2 (MAP2), glial fibrillary-acidic protein (GFAP), CD68, A beta-protein or tau was used to assess the identity of the cells with poly(ADP-ribose) accumulation and their relationship to plaques and neurofibrillary tangles. Both PARP- and poly(ADP-ribose)-immunolabelled cells were detected in a much higher proportion of Alzheimer's disease (20 out of 20) brains than of control brains (5 out of 10) (P = 0.0018). Double-immunolabelling for poly(ADP-ribose) and markers of neuronal, astrocytic and microglial differentiation (MAP2, GFAP and CD68, respectively) showed many of the cells containing poly(ADP-ribose) to be neurons. Most of these were small pyramidal neurons in cortical laminae 3 and 5. A few of the cells containing poly(ADP-ribose) were astrocytes. No poly(ADP-ribose) accumulation was detected in microglia. Double-immunolabelling for poly(ADP-ribose) and tau or A beta-protein indicated that the cells with accumulation of poly(ADP-ribose) did not contain tangles and relatively few occurred within plaques. Our findings indicate that there is enhanced PARP activity in Alzheimer's disease and suggest that pharmacological interventions aimed at inhibiting PARP may have a role in slowing the progression of the disease.


Concerns of patients with systemic lupus erythematosus and adherence to therapy - a qualitative study.
The objectives of this study were 1) to identify the impact of systemic lupus erythematosus (SLE) on patients' lives and their reactions to this, as well as their main concerns and expectations regarding their disease and treatments; and 2) to assess the relationship between these concerns and the adherence to treatments, medical visits, and diagnostic tests. Qualitative study, using a convenient sample of SLE patients attending an outpatient rheumatology clinic. Semistructured interviews were conducted and audiotaped. The full transcripts were analyzed by two different coders using content analysis methodology. Fifteen participants were included. SLE had a major impact on these patients' lives. Their main concerns were fear of disease worsening and becoming dependent on other people, fear of not being able to take care of their children or provide for the family, and the possibility of transmitting SLE to their offspring. The main reasons for adherence to therapy were the wish to avoid manifestations of SLE and trust in the rheumatologist and routine. Nonadherence was more common in the beginning of the treatment because of the difficulty in accepting a chronic disease that requires lifelong therapy. Our data underlined the important interplay between adherence to medication and the possibility to gather accurate information and proper support during the treatment process. Good communication and efficient patient education strategies, focused on improving their knowledge about the disease and its treatments, may be important to improve adherence to therapy in SLE.


Molecular mapping across three populations reveals a QTL hotspot region on chromosome 3 for secondary traits associated with drought tolerance in tropical maize.
Identifying quantitative trait loci (QTL) of sizeable effects that are expressed in diverse genetic backgrounds across contrasting water regimes particularly for secondary traits can significantly complement the conventional drought tolerance breeding efforts. We evaluated three tropical maize biparental populations under water-stressed and well-watered regimes for drought-related morpho-physiological traits, such as anthesis-silking interval (ASI), ears per plant (EPP), stay-green (SG) and plant-to-ear height ratio (PEH). In general, drought stress reduced the genetic variance of grain yield (GY), while that of morpho-physiological traits remained stable or even increased under drought conditions. We detected consistent genomic regions across different genetic backgrounds that could be target regions for marker-assisted introgression for drought tolerance in maize. A total of 203 QTL for ASI, EPP, SG and PEH were identified under both the water regimes. Meta-QTL analysis across the three populations identified six constitutive genomic regions with a minimum of two overlapping traits. Clusters of QTL were observed on chromosomes 1.06, 3.06, 4.09, 5.05, 7.03 and 10.04/06. Interestingly, a ~8-Mb region delimited in 3.06 harboured QTL for most of the morpho-physiological traits considered in the current study. This region contained two important candidate genes viz., zmm16 (MADS-domain transcription factor) and psbs1 (photosystem II unit) that are responsible for reproductive organ development and photosynthate accumulation, respectively. The genomic regions identified in this study partially explained the association of secondary traits with GY. Flanking single nucleotide polymorphism markers reported herein may be useful in marker-assisted introgression of drought tolerance in tropical maize.


Is there diurnal variation in initial and delayed orthostatic hypotension during standing and head-up tilt?
Moving rapidly from a supine to a standing posture is a common daily activity, yet a significant physiological challenge. Syncope can result from the development of initial orthostatic hypotension (IOH) involving a transient fall in systolic/diastolic blood pressure (BP) of >40/20 mm Hg within the first 15 s, and/or a delayed orthostatic hypotension (DOH) involving a fall in systolic/diastolic BP of >20/10 mm Hg within 15 min of posture change. Although epidemiological data indicate a heightened syncope risk in the morning, little is known about the diurnal variation in the IOH and DOH mechanisms associated with postural change. The authors hypothesized that the onset of IOH and DOH occurs sooner, and the associated cardiorespiratory and cerebrovascular changes are more pronounced, in the early morning. At 06:00 and 16:00 h, 17 normotensive volunteers, aged 26 ± 1 yrs (mean ± SE), completed a protocol involving supine rest, an upright stand, and a 60° head-up tilt (HUT) during which continuous beat-to-beat measurements of middle cerebral artery velocity (MCAv), mean arterial BP (MAP), heart rate, and end-tidal Pco(2) (P(ET)co(2)) were obtained. Mean MCAv was ∼12% lower at baseline in the morning (p ≤ .01) and during the HUT (p < .01), despite a morning elevation in P(ET)co(2) by ∼2.2 mm Hg (p = .01). The decline in MAP during initial standing (morning vs. afternoon: 50% ± 4% vs. 49% ± 3%) and HUT (39% ± 3% vs. 38% ± 3%) did not vary with time-of-day (p > .30). In conclusion, although there is a marked reduction in MCAv in the morning, there is an absence of diurnal variation in the onset of and associated physiological responses associated with IOH and DOH. These responses, at least in this population, are unlikely contributors to the diurnal variation in orthostatic tolerance.


Volatility transmission between oil prices and banks' stock prices as a new source of instability: Lessons from the United States experience.
This paper examines whether American banks' exposure to the oil industry could lead to instability in both oil and financial markets. To address this issue, we investigate volatility spillovers between oil prices and the stock prices of the four major American banks involved in the oil industry by employing the vector autoregressive fractionally integrated moving average framework. We use high-frequency data from January 3, 2006, to June 30, 2016. Our results support the existence of such volatility spillovers, as evidenced by the significant volatility responses of oil price (banks' stock price) to a shock in banks' stock price (oil price). These responses, more pronounced following the banks' exposure to the shale industry, mainly reflect the financial fragility of shale companies and their high indebtedness levels. Thus, this paper emphasises how the shale oil industry could trigger turmoil in both oil and financial markets.


Study of morphology, chemical, and amino acid composition of red deer meat.
The aim of this study was to evaluate red deer (maral) meat quality based on chemical composition, pH, water-binding capacity (WBC), and amino acid content. Maral meat surface morphology measurements were obtained by scanning electron microscopy. Active acidity (pH) was determined by potentiometry. Samples were analyzed for WBC by exudation of moisture to a filter paper by the application of pressure. Chemical composition (moisture, protein, fat, and ash fractions) was obtained by drying at 150°C and by extraction, using ethylic ether, and ashing at 500-600°C. The amino acid composition was obtained by liquid chromatography. Maral meat, with a pH of 5.85 and an average moisture content of 76.82%, was found to be low in fat (2.26%). Its protein content was 18.71% while its ash content was 2.21%. The amino acid composition showed that lysine (9.85 g/100 g), threonine (5.38 g/100 g), and valine (5.84 g/100 g) predominated in maral meat, while phenylalanine (4.08 g/100 g), methionine (3.29 g/100 g), and tryptophan (0.94 g/100 g) were relatively low in maral meat compared to other meats. The average WBC was found to be 65.82% and WBC was found to inversely correlate with moisture content. Low-fat content, high mineral content, and balanced amino-acid composition qualify maral meat as a worthy dietary and functional food.


Comparative antimicrobial susceptibility of Listeria monocytogenes, L. innocua, and L. welshimeri.
The current study compared antimicrobial susceptibility of Listeria innocua, L. welshimeri, and L. monocytogenes isolated from various sources. Antimicrobial susceptibility testing was performed using a microbroth procedure with Sensititre minimum inhibitory concentration plates containing 18 antimicrobials. Resistant isolates were analyzed for the presence of antimicrobial resistance genes using PCR. The majority of L. monocytogenes isolates were resistant to oxacillin (99%, 89/90) and ceftriaxone (72%, 65/90), while few isolates were resistant to clindamycin (21%, 19/90) and ciprofloxacin (2%, 2/90). When selected sources of L. monocytogenes are compared, resistance to ceftriaxone, clindamycin, and oxacillin ranged from 27% to 86%, 7% to 43%, and 96% to 100%, respectively. Resistance to ciprofloxacin (6%, 2/34), quinupristin/dalfopristin (7%, 1/14), and tetracycline (7%, 1/15) was observed with L. monocytogenes isolated from food, animal, and environmental sources, respectively. All L. welshimeri isolates (6/6) were resistant to streptomycin, quinupristin/dalfopristin, ciprofloxacin, rifampin, oxacillin, penicillin, and clindamycin, while most isolates (67%, 4/6) were resistant to trimethoprim/sulfamethoxazole. All L. innocua isolates (4/4) were resistant to oxacillin and penicillin, whereas 75% (3/4) of isolates were resistant to tetracycline, ceftriaxone, and clindamycin. Resistant isolates were negative for aadA, strA-B, sul I-II, penA, vat(A-E), vga(A-B), and vgb(A-B). However, tetM was detected among tetracycline-resistant isolates. L. welshimeri was resistant to more of the tested antimicrobials than the other two Listeria species tested, but resistance was not attributed to selected resistance genes. These data demonstrate the variability in resistance among Listeria species. However, the human pathogen L. monocytogenes appears to be the least resistant among the tested species.


Effectiveness of structured patient-clinician communication with a solution focused approach (DIALOG+) in community treatment of patients with psychosis--a cluster randomised controlled trial.
Large numbers of patients with psychosis have regular meetings with key clinicians in the community. There is little evidence on how these meetings should be conducted to be therapeutically effective. DIALOG, a computer mediated procedure, was shown to improve outcomes in a European multi-centre trial. DIALOG structures the patient-clinician communication and makes it patient-centred, but does not guide clinicians as to how to respond to patients' concerns. DIALOG has been further developed into DIALOG+, which uses advanced software and, additionally, provides a four step approach--based on a solution focused model--for addressing patients' concerns. We designed a cluster randomised controlled trial to test the effectiveness of DIALOG+ in improving treatment outcomes of patients with psychosis in the community. Key workers are recruited from community mental health teams in East London and randomly allocated to either the intervention or control group. Out of their case loads, we identify patients with schizophrenia (F 20-29) and a moderate or lower level of subjective quality of life (MANSA score <5), who are treated according to the allocation of their key workers. Key workers in the intervention group are trained in using DIALOG+ and use it with each patient over a six-month period. Control patients rate their satisfaction with life and treatment on a tablet to control for the effect of regular ratings and the use of modern technology. We are recruiting up to 42 key workers to reach a total sample size of 180 patients. Clinical and social outcomes including costs are assessed after 3, 6 and 12 months. Primary outcome is subjective quality-of-life at 6 months. The trial aims to evaluate the effectiveness of a novel intervention (DIALOG+) which uses modern technology to support routine patient-clinician meetings in community care, makes the communication patient centred and guides patients and clinicians to address concerns. DIALOG+ is a generic and widely applicable intervention. If shown as effective, it can be used to improve outcomes of community care on a large scale, ensuring that routine encounters are therapeutically effective. DIALOG+ can also be implemented across services at relatively low additional costs. Current Controlled Trials ISRCTN34757603.


Defining the wheat gluten peptide fingerprint via a discovery and targeted proteomics approach.
Accurate, reliable and sensitive detection methods for gluten are required to support current EU regulations. The enforcement of legislative levels requires that measurement results are comparable over time and between methods. This is not a trivial task for gluten which comprises a large number of protein targets. This paper describes a strategy for defining a set of specific analytical targets for wheat gluten. A comprehensive proteomic approach was applied by fractionating wheat gluten using RP-HPLC (reversed phase high performance liquid chromatography) followed by a multi-enzymatic digestion (LysC, trypsin and chymotrypsin) with subsequent mass spectrometric analysis. This approach identified 434 peptide sequences from gluten. Peptides were grouped based on two criteria: unique to a single gluten protein sequence; contained known immunogenic and toxic sequences in the context of coeliac disease. An LC-MS/MS method based on selected reaction monitoring (SRM) was developed on a triple quadrupole mass spectrometer for the specific detection of the target peptides. The SRM based screening approach was applied to gluten containing cereals (wheat, rye, barley and oats) and non-gluten containing flours (corn, soy and rice). A unique set of wheat gluten marker peptides were identified and are proposed as wheat specific markers. The measurement of gluten in processed food products in support of regulatory limits is performed routinely. Mass spectrometry is emerging as a viable alternative to ELISA based methods. Here we outline a set of peptide markers that are representative of gluten and consider the end user's needs in protecting those with coeliac disease. The approach taken has been applied to wheat but can be easily extended to include other species potentially enabling the MS quantification of different gluten containing species from the identified markers.


A comparison of bayesian methods for haplotype reconstruction from population genotype data.
In this report, we compare and contrast three previously published Bayesian methods for inferring haplotypes from genotype data in a population sample. We review the methods, emphasizing the differences between them in terms of both the models ("priors") they use and the computational strategies they employ. We introduce a new algorithm that combines the modeling strategy of one method with the computational strategies of another. In comparisons using real and simulated data, this new algorithm outperforms all three existing methods. The new algorithm is included in the software package PHASE, version 2.0, available online (http://www.stat.washington.edu/stephens/software.html).


Why rectal douches may be acceptable rectal-microbicide delivery vehicles for men who have sex with men.
To explore age of onset of rectal douching among men who have sex with men (MSM) and reasons leading to and maintaining douching behavior; and to consider whether rectal douches containing microbicidal agents might be acceptable for men at HIV risk. In stage 1, we used qualitative methods to explore douching behavior in a sample of 20 MSM. Subsequently, we developed a structured questionnaire that was administered in stage 2 to 105 MSM. More than half of participants who completed stage 1 douched during the trial despite having been advised not to do so. Of the 105 human immunodeficiency virus uninfected participants in stage 2, 51% reported using rectal douches in the prior 6 months; 47% douched before and 25% after anal intercourse. Most participants reported douching frequently or always. On average, men reported douching about 2 hours before or 1 hour following intercourse. Average age of onset was late 20s. Most men who douched wanted to be clean or were encouraged to douche by their partners. Some men thought douching after sex could prevent sexually transmitted infections. Rectal douching appears to be a popular behavior among men who have receptive anal intercourse. It is necessary to identify harmless douches. If human immunodeficiency virus or sexually transmitted infections preventive douches can be developed, rectal douching before or following sexual intercourse could become an important additional prevention tool. To reshape an existing behavior to which some men strongly adhere, like douching, by suggesting use of 1 type of douche over another may be more successful than trying to convince MSM to engage in behaviors they never practiced before or those they resist (e.g., condom use).


NLRP3 Inflammasome Activation Contributes to Mechanical Stretch-Induced Endothelial-Mesenchymal Transition and Pulmonary Fibrosis.
Mechanical ventilation can induce lung fibrosis. This study aimed to investigate whether ventilator-induced lung fibrosis was associated with endothelial-mesenchymal transition and to uncover the underlying mechanisms. Randomized, controlled animal study and cell culture study. University research laboratory. Adult male Institute of Cancer Research, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) knockout and wild-type mice. Primary cultured mouse lung vascular endothelial cells. Institute of Cancer Research, NLRP3 knockout and wild-type mice were subjected to mechanical ventilation (20 mL/kg) for 2 hours. Mouse lung vascular endothelial cells were subjected to cyclic stretch for 24 hours. Mice subjected to mechanical ventilation exhibited increases in collagen deposition, hydroxyproline and type I collagen contents, and transforming growth factor-β1 in lung tissues. Ventilation-induced lung fibrosis was associated with increased expression of mesenchymal markers (α smooth muscle actin and vimentin), as well as decreased expression of endothelial markers (vascular endothelial-cadherin and CD31). Double immunofluorescence staining showed the colocalization of CD31/α smooth muscle actin, CD31/vimentin, and CD31/fibroblast-specific protein-1 in lung tissues, indicating endothelial-mesenchymal transition formation. Mechanical ventilation also induced NLRP3 inflammasome activation in lung tissues. In vitro direct mechanical stretch of primary mouse lung vascular endothelial cells resulted in similar NLRP3 activation and endothelial-mesenchymal transition formation, which were prevented by NLRP3 knockdown. Furthermore, mechanical stretch-induced endothelial-mesenchymal transition and pulmonary fibrosis were ameliorated in NLRP3-deficient mice as compared to wild-type littermates. Mechanical stretch may promote endothelial-mesenchymal transition and pulmonary fibrosis through a NLRP3-dependent pathway. The inhibition of endothelial-mesenchymal transition by NLRP3 inactivation may be a viable therapeutic strategy against pulmonary fibrosis associated with mechanical ventilation.


An Extra-Large-Pore Zeolite with 24×8×8-Ring Channels Using a Structure-Directing Agent Derived from Traditional Chinese Medicine.
Extra-large-pore zeolites have attracted much interest because of their important applications for processing larger molecules. Although great progress has been made in academic science and industry, it is challenging to synthesize these materials. A new extra-large-pore zeolite SYSU-3 (Sun Yat-sen University no. 3) has been synthesized by using a novel sophoridine derivative as an organic structure-directing agent (OSDA). The framework structure was solved and refined using continuous rotation electron diffraction (cRED) data from nanosized crystals. SYSU-3 exhibits a new zeolite framework topology, which has the first 24×8×8-ring extra-large-pore system and a framework density (FD) as low as 11.4 T/1000 Å3 . The unique skeleton of the OSDA plays an essential role in the formation of the distinctive zeolite structure. This work provides a new perspective for developing new zeolitic materials by using alkaloids as cost-effective OSDAs.


Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations.
Children with Down's syndrome (DS) have an increased risk of developing acute lymphoblastic leukemia (ALL) and have a low frequency of established genetic aberrations. We aimed to determine which genetic abnormalities are involved in DS ALL. We studied the frequency and prognostic value of deletions in B-cell development genes and aberrations of janus kinase 2 (JAK2) and cytokine receptor-like factor 2 (CRLF2) using array-comparative genomic hybridization, and multiplex ligation-dependent probe amplification in a population-based cohort of 34 Dutch Childhood Oncology Group DS ALL samples. A population-based cohort of 88 DS samples from the UK trials was used to validate survival estimates for IKZF1 and CRLF2 abnormalities. In total, 50% of DS ALL patients had ≥1 deletion in the B-cell development genes: PAX5 (12%), VPREB1 (18%) and IKZF1 (35%). JAK2 was mutated in 15% of patients, genomic CRLF2 rearrangements in 62%. Outcome was significantly worse in patients with IKZF1 deletions (6-year event-free survival (EFS) 45 ± 16% vs 95 ± 4%; P=0.002), which was confirmed in the validation cohort (6-year EFS 21 ± 12% vs 58 ± 11%; P=0.002). This IKZF1 deletion was a strong independent predictor for outcome (hazard ratio EFS 3.05; P=0.001). Neither CRLF2 nor JAK2 were predictors for worse prognosis. If confirmed in prospective series, IKZF1 deletions may be used for risk-group stratification in DS ALL.


Why do five-membered heterocyclic compounds sometimes not participate in polar Diels-Alder reactions?
The reactions of bicyclic enone (BCE, 1) with cyclopentadiene (Cp, 2) and the five-membered heterocyclic compounds (FHCs) furan 3 and N-methyl pyrrole 4 for the construction of polycyclic heterocyclic compounds have been studied at the B3LYP/6-31G* level. No reaction takes place in the absence of Lewis acid (LA) catalysts as a consequence of the high activation energy associated with these reactions. Electrophilic activation of BCE 1 by formation of a complex with the BF3 LA, 1-BF3, and solvent effects favor the reactions. However, a different reactivity is manifested by Cp 2 and FHCs 3 and 4. Thus, while the reaction of 1-BF3 with Cp 2 yields the expected exo [4 + 2] cycloadduct, the reactions of these FHCs yield Michael adducts. In any case, the reactions are characterized by the nucleophilic/electrophilic interaction between the most nucleophilic centers of these dienes and the most electrophilic center of complex 1-BF3. The greater ability of FHCs 3 and 4 to stabilize positive charges opposed to Cp 2 favors a stepwise mechanism with formation of a zwitterionic intermediate. Although in most stepwise Diels-Alder reactions, the subsequent ring closure has unappreciable barriers, in these FHCs the abstraction of a proton with regeneration of the aromatic ring becomes competitive. Thermodynamic calculations suggest that the exergonic character of the formation of the Michael adducts could be the driving force for the reactions involving FHCs.


CAM Based Fine-grained Spatial Feature Supervision On Surgical-PPE: A New Dataset For Surgical PPE Kit Presence Detection.
In the wake of Covid pandemic, usage of surgical PPE kit by surgeons has become essential. Since reliable localization of human joints is necessary for automated understanding of surgeons activity, the first step is surgical PPE kit detection. While there exist reported works on industrial PPE kit detection, task of surgical PPE kit detection has hardly been explored. To facilitate this, we construct "Surgical-PPE" dataset with 1150 Non-PPE instances and 2656 surgeon wearing PPE kit instances. In this work, we also propose a two-stage transfer learning based end-to-end training methodology. Novelty lies in (a) novel "Surgical-PPE" dataset to detect if surgeon is wearing PPE kit or not, (b) proposed supervised contrastive combined loss function for stage-1 training, (c) proposed spatial context aware combined loss function for stage-2 training. We qualitatively illustrate the improvement of HiResCAM and XGrad-CAM explanations for the proposed methodology. We also qualitatively illustrate that feature embeddings of same class are pulled closer together compared to feature embeddings of different classes on the proposed multi-stage training methodology, using T-SNE plots. We benchmark the performance of popular existing network architectures along with the proposed methodology on "Surgical-PPE" dataset. Using proposed methodology, we achieve peak accuracy of 97.63%, precision of 97.66%, recall of 97.63%, F1-score of 97.64%, JI of 95.41% and FPR of 2.5%. We report improvement by 1.7% in terms of FPR and 2% in terms of JI compared to second best performing model (ResNext50(CE)). Owing to the proposed training methodology, an improvement of 2.62% in terms of FPR and 5% in terms of JI was observed.Clinical relevance- To understand the OT activity of the surgeon in third-person perspective, it is important to determine whether or not, the surgeon is wearing PPE kit. Hence surgical PPE kit presence detection becomes the first step towards automated surgical video analysis.


Statistical grand rounds: design and analysis of studies with binary- event composite endpoints: guidelines for anesthesia research.
Composite endpoints consisting of several binary events, such as distinct perioperative complications, are frequently chosen as the primary outcome in anesthesia studies (and in many other clinical specialties) because (1) no single outcome fully characterizes the disease or outcome of interest, and/or (2) individual outcomes are rare and statistical power would be inadequate for any single one. Interpreting a composite endpoint is challenging because components rarely meet the ideal criteria of having comparable clinical importance, frequency, and treatment effects. We suggest guidelines for forming composite endpoints and show advantages of newer versus conventional statistical methods for analyzing them. Components should be a parsimonious set of outcomes, which when taken together, well represent the disease of interest and are very plausibly related to the intervention. Adding components that are too narrow, redundant, or minimally influenced by the study intervention compromises interpretation of results and reduces power. We show that multivariate (i.e., multiple outcomes per patient) methods of analyzing a binary-event composite provide distinct advantages over standard methods such as any-versus-none, count of events, or evaluation of individual events. Multivariate methods can incorporate clinical importance weights, compensate for events occurring at varying frequencies, assess treatment effect heterogeneity, and are often more powerful than alternative statistical approaches. Methods are illustrated with an American College of Surgeons National Surgical Quality Improvement Program registry study that evaluated the effects of smoking on major perioperative outcomes, and with a clinical trial comparing the effects of crystalloids and colloids on major complications. Sample data files and SAS code are included for convenience.


American Society for Enhanced Recovery (ASER) and Perioperative Quality Initiative (POQI) joint consensus statement on optimal analgesia within an enhanced recovery pathway for colorectal surgery: part 1-from the preoperative period to PACU.
Within an enhanced recovery pathway (ERP), the approach to treating pain should be multifaceted and the goal should be to deliver "optimal analgesia," which we define in this paper as a technique that optimizes patient comfort and facilitates functional recovery with the fewest medication side effects. With input from a multi-disciplinary, international group of clinicians, and through a structured review of the literature and use of a modified Delphi method, we achieved consensus surrounding the topic of optimal analgesia in the perioperative period for colorectal surgery patients. As a part of the first Perioperative Quality Improvement (POQI) workgroup meeting, we sought to develop a consensus document describing a comprehensive, yet rational and practical, approach for developing an evidence-based plan for achieving optimal analgesia, specifically for a colorectal surgery ERP. The goal was two-fold: (a) that application of this process would lead to improved patient outcomes and (b) that investigation of the questions raised would identify knowledge gaps to aid the direction for research into analgesia within ERPs in the years to come. This document details the evidence for a wide range of analgesic components, with particular focus from the preoperative period to the post-anesthesia care unit. The overall conclusion is that the combination of analgesic techniques employed in the perioperative period is not important as long as it is effective in delivering the goal of optimal analgesia as set forth in this document.


Tillage Management and Seasonal Effects on Denitrifier Community Abundance, Gene Expression and Structure over Winter.
Tillage effects on denitrifier communities and nitrous oxide (N2O) emissions were mainly studied during the growing season. There is limited information for the non-growing season, especially in northern countries where winter has prolonged periods with sub-zero temperatures. The abundance and structure of the denitrifier community, denitrification gene expression and N2O emissions in fields under long-term tillage regimes [no-tillage (NT) vs conventional tillage (CT)] were assessed during two consecutive winters. NT exerted a positive effect on nirK and nosZ denitrifier abundance in both winters compared to CT. Moreover, the two contrasting managements had an opposite influence on nirK and nirS RNA/DNA ratios. Tillage management resulted in different denitrifier community structures during both winters. Seasonal changes were observed in the abundance and the structure of denitrifiers. Interestingly, the RNA/DNA ratios were greater in the coldest months for nirK, nirS and nosZ. N2O emissions were not influenced by management but changed over time with two orders of magnitude increase in the coldest month of both winters. In winter of 2009-2010, emissions were mainly as N2O, whereas in 2010-2011, when soil temperatures were milder due to persistent snow cover, most emissions were as dinitrogen. Results indicated that tillage management during the growing season induced differences in denitrifier community structure that persisted during winter. However, management did not affect the active cold-adapted community structure.


[Fall risk in low-income elderly people in one urban area].
The purpose of this study was to investigate the factors that increase of the risk for falls in low-income elders in urban areas. The participants were elderly people registered in one of public health centers in one city. Data were collected by interviewing the elders, assessing their environmental risk factors, and surveying relevant secondary data from the public health center records. For data analysis, descriptive statistics and multiple logistic regression were performed using SPSS version 14. Stroke, diabetes, visual deficits, frequency of dizziness, use of assistive devices and moderate depression were statistically significant risk factors. The comorbidity of chronic diseases with other factors including depression, visual deficit, dizziness, and use of assistive devices significantly increased the risk of falls. From multiple logistic regression analysis, statistically significant predictors of falls were found to be stroke, total environmental risk scores, comorbidity of diabetes with visual deficits, and with depression. Fall prevention interventions should be multifactorial, especially for the elders with stroke or diabetes, who were identified in this study as the high risk group for falls. A fall risk assessment tool for low-income elders should include both the intrinsic factors like depression, dizziness, and use of assistive devices, and the extrinsic factors.