Private Video Consultation Services and the Future of Primary Care.
In many countries, private companies provide primary care services based predominantly on offering video consultations via smartphones. One example is Babylon GP at Hand (BGPaH), which offers video consultations to National Health Service patients, 24 hours a day, and has grown rapidly in London over the last 3 years. The development of this type of service has been controversial, particularly in the United Kingdom, but there has been little formal published evaluation of these services in any country. This paper outlines the main controversies about the use of privately provided video consultation services for primary care and shows how they are informed by the limited evaluations that have been conducted, particularly the evaluation of BGPaH. This paper describes the advantages of these services in terms of convenience, speed of access, the ability to consult without traveling or face-to-face patient-doctor contact, and the possibility of recruiting doctors who cannot work in conventional settings or do not live near the patients. It also highlights the concerns and uncertainties about quality and safety, demand, fragmentation of care, impact on other health services, efficiency, and equity. There are questions about whether private primary care services based on video consultations have a sustainable business model and whether they will undermine other health care providers. During the recent COVID-19 pandemic, the use of video consulting has become more widespread within conventional primary care services, and this is likely to have lasting consequences for the future delivery of primary care. It is important to understand the extent to which lessons from the evaluation of BGPaH and other private services based on a video-first model are relevant to the use of video consulting within conventional general practices, and to consider the advantages and disadvantages of these developments, before video consultation-based services in primary care become more widely established.


Isolation and characterization of mutants of human diploid fibroblasts resistant to diphtheria toxin.
Stable mutants highly resistant to the protein synthesis inhibitor diphtheria toxin (dipr) have been selected in human diploid fibroblast cells at a frequency of 1-8 X 10(-6). Treatment of cells with mutagens, (e.g., ethylmethanesulfonate, nitrosoguanidine, and ICR-170), increased the frequencies of dipr mutants by 50- to 500-fold in different experiments, and the optimal expression time for dipr mutation was about 5 days. All mutants examined thus far have bred true, and no effects of cell density or cross feeding have been observed on the selection. Fluctuation analysis showed that the dipr mutation occurs in these fibroblasts at the rate of 5-6 X 10(-7) mutations per cell per generation. Protein synthesis in mutant extracts was resistant to diphtheria toxin, indicating that the dipr lesion in such mutants lies in the protein synthesis machinery. The characteristics of the dipr marker should make this system particularly useful for studies of quantitative mutagenesis in human diploid cells.


Intracellular Dynamics and Fate of a Humanized Anti-Interleukin-6 Receptor Monoclonal Antibody, Tocilizumab.
Tocilizumab (TCZ), a humanized anti-interleukin-6 (IL-6) receptor (IL-6R) monoclonal antibody, abrogates signal transducer protein gp130-mediated IL-6 signaling by competitively inhibiting the binding of IL-6 to the receptor, and shows clinical efficacy in autoimmune and inflammatory diseases. Despite accumulating evidence for therapeutic efficacy, the behavior and fate of TCZ at the cellular level remain largely unknown. To address this, we evaluated the endocytosis and intracellular trafficking of IL-6R in HeLa cells. The results of our study provide evidence that IL-6R is constitutively internalized from the cell surface by ligand or TCZ binding and the expression of gp130 in an independent manner and is targeted via endosomes without being significantly directed to the recycling pathway to, and degraded in, lysosomes. Furthermore, the cytoplasmic tail of IL-6R is required for constitutive endocytosis of the receptor, which is mediated by the clathrin and AP-2 complex. We further demonstrate that FcRn, whose function is to regulate the serum persistence of IgG, is confined primarily to early/recycling endosomes and rapidly transits between these compartments and late endosomes/lysosomes without being degraded. Importantly, the expression of FcRn induces the segregation of TCZ from IL-6R, resulting in extensive colocalization of TCZ and FcRn in IL-6R-depleted endosomal compartments. Collectively, our results suggest that FcRn can accelerate the retrieval of the internalized TCZ, not only from endosomes but also from lysosomes. Our findings provide new insight into the mechanism by which the antibody internalized into cells is rescued from lysosomal degradation and into how its serum levels are maintained.


Fornix-based versus limbal-based conjunctival trabeculectomy flaps for glaucoma.
Glaucoma is one of the leading largely preventable causes of blindness in the world. It is usually addressed first medically with topical intraocular pressure-lowering drops or by laser trabeculoplasty. In cases where such treatment fails, glaucoma-filtering surgery such as trabeculectomy, is commonly considered. Surgeons can differ in their technique when performing trabeculectomy, for example, the choice of the type of the conjunctival flap (fornix- or limbal-based). In a fornix-based flap, the surgical wound is performed at the corneal limbus; while in a limbal-based flap, the incision is further away. Many studies in the literature compare fornix- and limbal-based trabeculectomy with respect to outcomes and complications. To assess the comparative effectiveness of fornix- versus limbal-based conjunctival flaps in trabeculectomy for adult glaucoma, with a specific focus on intraocular pressure (IOP) control and complication rates (adverse effects). We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2021, Issue 3); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 23 March 2021. There were no restrictions to language or year of publication. We included RCTs comparing the benefits and complications of fornix- versus limbal-based trabeculectomy for glaucoma, irrespective of glaucoma type, publication status, and language. We excluded studies on children less than 18 years of age, since wound healing is different in this age group and the rate of bleb scarring postoperatively is high. We used standard methodological procedures as per Cochrane criteria. MAIN RESULTS: We did not identify any new eligible studies for this review update. As presented in the original review, we included six trials with a total of 361 participants. Two studies were conducted in the USA and one each in Germany, Greece, India, and Saudi Arabia. The participants of four trials had open-angle glaucoma; one study included participants with primary open-angle or primary closed-angle glaucoma, and one study did not specify the type of glaucoma. Three studies used a combined procedure (phacotrabeculectomy). Trabeculectomy with mitomycin C (MMC) was performed in four studies, and trabeculectomy with 5-fluorouracil (5-FU) was performed in only one study. None of the included trials reported trabeculectomy failure at 24 months. Only one trial reported the failure rate of trabeculectomy as a late complication. Failure was higher among participants randomised to the limbal-based surgery: 1/50 eyes failed trabeculectomy in the fornix group compared with 3/50 in the limbal group (Peto odds ratio 0.36, 95% confidence interval (CI) 0.05 to 2.61)); therefore we are very uncertain as to the relative effect of the two procedures on failure rate. Four studies including 252 participants provided measures of mean IOP at 12 months. In the fornix-based surgeries, mean IOP ranged from 12.5 to 15.5 mmHg and similar results were noted in limbal-based surgeries with mean IOP ranging from 11.7 to 15.1 mmHg without significant difference. Mean difference was 0.44 mmHg (95% CI -0.45 to 1.33; 247 eyes) and 0.86 mmHg, (95% CI -0.52 to 2.24; 139 eyes) at 12 and 24 months of follow-up, respectively. Neither of these pooled analyses showed a statistically significant difference in IOP between groups (moderate certainty evidence). One trial reported number of anti-glaucoma medications at 24 months of follow-up with no difference noted between surgical groups. However, three trials reported the mean number of anti-glaucoma medications at 12 months of follow-up without significant difference in the mean number of postoperative IOP-lowering medications between the two surgical techniques. Mean difference was 0.02, (95% CI -0.15 to 0.19) at 12 months of follow-up (high certainty evidence). Because of the small numbers of events and total participants, the risk of many reported adverse events was uncertain and those that were found to be statistically significant may have been due to chance. For risk of bias assessment: although all six trials were randomised selection bias was mostly unclear, with unclear random sequence generation in four of the six studies and unclear allocation concealment in five of the six studies. Attrition bias was encountered in only one trial which also suffered from reporting bias. All other trials had an unclear risk of reporting bias as there was no access to study protocols. All included trials were judged to have high risk of detection bias due to lack of masking of the outcomes. Trabeculectomy is quite a standard procedure and unlikely to induce bias due to surgeon 'performance', hence performance bias was not evaluated. The main result of this review was that there was uncertainty as to the difference between fornix- and limbal-based trabeculectomy surgeries due to the small number of events and confidence intervals that cross the null. This also applied to postoperative complications, but without any impact on long-term failure rate between the two surgical techniques.


Rotator cuff tears in rheumatoid arthritis.
Rotator cuff tear secondary to chronic synovitis eroding the rotator cuff tendon is a complication of rheumatoid arthritis that has received little attention. Patients with such tears have a long history of active rheumatoid disease preceding the sudden onset of increased unilateral shoulder pain and immobility. The physician may interpret this change as indicating a joint infection or rheumatoid flare, and initiate a drastic change in the patient's therapy. Shoulder arthrography reveals the correct diagnosis. Appropriate treatment consists of heat, rest, range of motion exercises, and repeated intra-articular injection of steroids.


Aggregation of flexible polyelectrolytes: Phase diagram and dynamics.
Similarly charged polymers in solution, known as polyelectrolytes, are known to form aggregated structures in the presence of oppositely charged counterions. Understanding the dependence of the equilibrium phases and the dynamics of the process of aggregation on parameters such as backbone flexibility and charge density of such polymers is crucial for insights into various biological processes which involve biological polyelectrolytes such as protein, DNA, etc. Here, we use large-scale coarse-grained molecular dynamics simulations to obtain the phase diagram of the aggregated structures of flexible charged polymers and characterize the morphology of the aggregates as well as the aggregation dynamics, in the presence of trivalent counterions. Three different phases are observed depending on the charge density: no aggregation, a finite bundle phase where multiple small aggregates coexist with a large aggregate and a fully phase separated phase. We show that the flexibility of the polymer backbone causes strong entanglement between charged polymers leading to additional time scales in the aggregation process. Such slowing down of the aggregation dynamics results in the exponent, characterizing the power law decay of the number of aggregates with time, to be dependent on the charge density of the polymers. These results are contrary to those obtained for rigid polyelectrolytes, emphasizing the role of backbone flexibility.


Relationship between anxiety, depression, and health satisfaction among veterans with PTSD.
Depression and anxiety are associated with significantly increased healthcare costs that include costs of non-psychiatric medical care. PTSD has been found to be related to many negative health perceptions and outcomes (e.g., [Resnick, H.S., Acierno, R., Kilpatrick, D.G., 1997. Health impact of interpersonal violence: II. Medical and mental health outcomes. Behavioral Medicine 23, 65-78]). The presence of comorbid depression and anxiety disorders in patients with posttraumatic stress disorder (PTSD) is well documented. This study aims to examine the effects of depression and anxiety on health satisfaction in veterans with PTSD. The current study utilizes archival data from a clinical sample of combat veterans (N=249) with and without PTSD in order to examine the unique contributions of anxiety and depression to reported health satisfaction. After controlling for PTSD severity, combat exposure, and age, when both anxiety and depression are examined simultaneously in a regression to predict health satisfaction only depression significantly contributed and accounted for 10% of model variance. While both depression and anxiety are related to more negative reported health satisfaction among veterans in a PTSD clinic, depression appears to be a main contributor. Evaluation and treatment seeking veterans may differ from a full range of veterans with PTSD. Closer examination with measures of depression and anxiety that more precisely separate these constructs is warranted. Finally, it is not known whether reported health satisfaction is related to an objective difference in health status or is more indicative of subjective expression of distress.


Neuroimmune activation and increased brain aging in chronic pain patients after the COVID-19 pandemic onset.
The COVID-19 pandemic has exerted a global impact on both physical and mental health, and clinical populations have been disproportionally affected. To date, however, the mechanisms underlying the deleterious effects of the pandemic on pre-existing clinical conditions remain unclear. Here we investigated whether the onset of the pandemic was associated with an increase in brain/blood levels of inflammatory markers and MRI-estimated brain age in patients with chronic low back pain (cLBP), irrespective of their infection history. A retrospective cohort study was conducted on 56 adult participants with cLBP (28 'Pre-Pandemic', 28 'Pandemic') using integrated Positron Emission Tomography/ Magnetic Resonance Imaging (PET/MRI) and the radioligand [11C]PBR28, which binds to the neuroinflammatory marker 18 kDa Translocator Protein (TSPO). Image data were collected between November 2017 and January 2020 ('Pre-Pandemic' cLBP) or between August 2020 and May 2022 ('Pandemic' cLBP). Compared to the Pre-Pandemic group, the Pandemic patients demonstrated widespread and statistically significant elevations in brain TSPO levels (P =.05, cluster corrected). PET signal elevations in the Pandemic group were also observed when 1) excluding 3 Pandemic subjects with a known history of COVID infection, or 2) using secondary outcome measures (volume of distribution -VT- and VT ratio - DVR) in a smaller subset of participants. Pandemic subjects also exhibited elevated serum levels of inflammatory markers (IL-16; P <.05) and estimated BA (P <.0001), which were positively correlated with [11C]PBR28 SUVR (r's ≥ 0.35; P's < 0.05). The pain interference scores, which were elevated in the Pandemic group (P <.05), were negatively correlated with [11C]PBR28 SUVR in the amygdala (r = -0.46; P<.05). This work suggests that the pandemic outbreak may have been accompanied by neuroinflammation and increased brain age in cLBP patients, as measured by multimodal imaging and serum testing. This study underscores the broad impact of the pandemic on human health, which extends beyond the morbidity solely mediated by the virus itself.


Management of patients with patent foramen ovale and cryptogenic stroke: a collaborative, multidisciplinary, position paper: executive summary.
To organize a common approach on the management of patent foramen ovale (PFO) and cryptogenic stroke that may be shared by different specialists. The management of PFO related to cryptogenic stroke is controversial, despite an increase in interventional closure procedures. A consensus statement was developed by approaching Italian national cardiological, neurological, and hematological scientific societies. Task force members were identified by the president and/or the boards of each relevant scientific society or working group, as appropriate. Drafts were outlined by specific task force working groups. To obtain a widespread consensus, these drafts were merged and distributed to the scientific societies for local evaluation and revision by as many experts as possible. The ensuing final draft, merging all the revisions, was reviewed by the task force and finally approved by scientific societies. Definitions of transient ischemic attack and both symptomatic and asymptomatic cryptogenic strokes were specified. A diagnostic workout was identified for patients with candidate event(s) and patient foramen ovale to define the probable pathogenesis of clinical events and to describe individual PFO characteristics. Further recommendations were provided regarding medical and interventional therapy considering individual risk factors of recurrence. Finally, follow-up evaluation was appraised. Available data provided the basis for a shared approach to management of cryptogenic ischemic cerebral events and PFO among different Italian scientific societies. Wider international initiatives on the topic are awaited.


Evaluation of algebraic iterative image reconstruction methods for tetrahedron beam computed tomography systems.
Tetrahedron beam computed tomography (TBCT) performs volumetric imaging using a stack of fan beams generated by a multiple pixel X-ray source. While the TBCT system was designed to overcome the scatter and detector issues faced by cone beam computed tomography (CBCT), it still suffers the same large cone angle artifacts as CBCT due to the use of approximate reconstruction algorithms. It has been shown that iterative reconstruction algorithms are better able to model irregular system geometries and that algebraic iterative algorithms in particular have been able to reduce cone artifacts appearing at large cone angles. In this paper, the SART algorithm is modified for the use with the different TBCT geometries and is tested using both simulated projection data and data acquired using the TBCT benchtop system. The modified SART reconstruction algorithms were able to mitigate the effects of using data generated at large cone angles and were also able to reconstruct CT images without the introduction of artifacts due to either the longitudinal or transverse truncation in the data sets. Algebraic iterative reconstruction can be especially useful for dual-source dual-detector TBCT, wherein the cone angle is the largest in the center of the field of view.


On-chip dielectrophoretic coassembly of live cells and particles into responsive biomaterials.
We report how live cells and functionalized colloidal particles can be coassembled into a variety of freely suspended bioactive structures using dielectrophoresis on a chip. Alternating electric fields were applied to dilute suspensions of yeast (S. cerevisiae) and NIH/3T3 mouse fibroblast cells to yield 1D chains and 2D arrays. The effects of voltage, frequency, pH, electrolyte concentration, cell concentration, and particle size on the assembly process were investigated in detail. Numerical simulations of the field intensity and energy allow the capture of the dynamics of cell-cell and cell-particle assembly. The simulation results illustrate that the electric field draws the functionalized synthetic particles between the cells and enables the formation of permanent chains and monolayer membranes composed of alternating cells and particles. The cell structures were bound into permanent structures by different types of functionalized synthetic particles and ligands that attached to the cells through biospecific or electrostatic interactions. The technique allowed the fabrication of magnetically responsive biomaterials that could be manipulated and transported into and out of the microchambers where they were formed.


Toxoplasma gondii seroprevalence in reindeer (Rangifer tarandus tarandus L.) in northern Sweden: a cross-sectional study from 2014.
Toxoplasma gondii is a parasitic protozoan that can infect a wide range of warm-blooded animals, including humans. The infection with T. gondii, is of particular concern due to its potential impact on human and animal health. In Sweden, semi-domesticated reindeer (Rangifer tarandus tarandus L.) is an important species both economically and culturally, but susceptibility to Toxoplasma infection and seroprevalence in reindeer herds remain relatively understudied. A total of 528 reindeer, sampled at two slaughterhouses in Sweden in 2014, were investigated for antibodies to T. gondii. Specific antibodies to T. gondii were found in 5 of 209 (2.3%) tested adult reindeer and in 6 of 308 (1.9%) tested calves, giving an apparent total prevalence of 2.1% (95% confidence interval 1.1-3.8%). None of four putative risk factors studied (sex, age, type of grazing area, county) were statistically associated with T. gondii seroprevalence. Swedish semi-domesticated reindeer are exposed to T. gondii and may harbour infectious tissue cysts. To mitigate the risk of T. gondii infection in consumers, reindeer meat should be frozen or cooked thoroughly before consumption. The global climate change may influence the seroprevalence and possible associated risk factors for T. gondii in reindeer. To be able to manage the risk and get better advice to the consumers there is a need for further investigations covering the whole spectra of herding conditions for reindeer.


[Secondary posttraumatic correction of the face].
Any part of the face may present residual deviations in form and/or function after trauma, even if primary treatment has been executed optimally. Secondary corrections may be indicated as a consequence. The techniques are usually the same as for primary treatment. However since secondary corrections quite often are a consequence of complicated primary problems, it does not surprise, that frequently complex deformities present for secondary surgery. Depending on the nature of the lesion percentages of success between 60 and almost a 100% may be expected. This indicates that additional treatment after primary care may be a way out for quite a number of residual deformities.


ET-1 Lys198Asn and ET(A) receptor H323H polymorphisms in heart failure. A case-control study.
The endothelin (ET) system plays a central role in the control of myocardial function and its pathophysiology. The aim of the present study was to explore whether genetic variations of ET-1 (G/T substitution that predicts an Lys/Asn change at codon 198) and its receptor ET(A) (T/C in exon 6, H323H) could predispose carriers to heart failure (HF). Genotyping at these two loci was done in 122 patients with HF [echocardiographic left ventricular ejection fraction (LVEF) < or =40%] and 216 age-matched subjects without HF. Causes of HF included ischemic (n = 96) and idiopathic cardiomyopathies (n = 26). The ET-1 Lys198Asn was significantly associated with the occurrence of HF (p = 0.005). The risk of HF was independently increased among Asn/Asn in comparison to Lys carriers (OR = 3.2, p = 0.03). Moreover, homozygous carriers of both ET-1 and ET(A) variants showed a marked increase in the risk of HF (adjusted OR = 8.6, p = 0.005), displayed significantly lower LVEF (p = 0.002) and higher left ventricular end-diastolic (p = 0.03) and end-systolic diameters (p = 0.04; for Asn/Asn and TT vs. Lys and C carriers of the ET-1 and ET(A )polymorphisms, respectively). Furthermore, the extent of coronary artery disease (r = -0.62, p < 0.0001) and the Asn/Asn and TT double genotype (r = -0.30, p = 0.0001) were the only significant and independent predictors of LVEF by multivariate analysis. The ET-1 Lys198Asn and ET(A) receptor H323H polymorphisms seem to act synergistically to increase the risk of HF.


[Effect of proteinuria on tubulointerstitial damage].
Glomerular basal membrane represents a mechanical and electric barrier for plasma proteins. In physiological conditions only plasma proteins of low molecular weight are completely filtered through basal membrane. Due to damages of glomerular basal membrane there is an increase in filtration of plasma proteins of moderate and high molecular weight. In regard to its etiology proteinuria can be prerenal, renal and postrenal. By analyzing albumin, 1-microglobulin, immunoglobulin G and 2-macroglobulin, together with total protein in urine, it is possible to detect and differentiate causes of prerenal, glomerular, tubular and postrenal proteinuria. Abnormal glomerular permeability to macromolecules results in excessive protein delivery and reabsorption in proximal tubules. Excessive reabsorption in turn may cause congetion of intracellular endocytic and biosynthetic compartments leading to NFkB-dependent and -independent gene upregulation. Among those genes, monocyte chemoattractant protein-1 (MCP-1), cytokines, osteopontin and endothelin stimulate processes of interstitial inflammation and fibroblast proliferation and are ultimately responsible for enhanced extracellular matrix deposition and renal scarring. Human tubular cells exposed to albumin and HDL increase production of endothelin-1. Endothelin-1 affects microcirculation and fibroblasts and is a monocyte chemoattractant. Specific proteins that are cytotoxic are transferrin/iron, low-density lipoprotein, and complement components, all of which appear in urine in proteinuric states. Adequate and early diagnosis and differentiation of proteinuria are of immense therapeutic importance.


Acidic and hydrogen peroxide treatment of polyaluminum chloride (PACL) sludge from water treatment.
The water treatment sludge including coagulants cannot be easily removed by conventional dewatering methods. The possibility of hydrogen peroxide (H2O2) oxidation as a pretreatment to enhance the dewaterability of polyaluminum chloride (PACl) sludge from water works was investigated. H2O2 treatment alone was not effective but H2O2 treatment under acidic condition significantly reduced both the cake water content and specific resistance to filtration (SRF), indicating the enhancement of dewaterability and filterability. The filterability after acid/H2O2 treatment was comparable to polymer conditioning and even more dewatered cake than polymer conditioning was produced. By H202 combined with sulfuric acid (H2SO4), leached iron caused Fenton's reaction, which showed a potential to significantly reduce the amount of solids mass and to produce more compact cake with higher filterability.


Social cognitive predictors of first- and non-first-generation college students' academic and life satisfaction.
The present study tested Lent's (2004) social-cognitive model of normative well-being in a sample (N = 414) of first- and non-first-generation college students. A model depicting relationships between: positive affect, environmental supports, college self-efficacy, college outcome expectations, academic progress, academic satisfaction, and life satisfaction was examined using structural equation modeling. The moderating roles of perceived importance of attending college and intrinsic goal motivation were also explored. Results suggested the hypothesized model provided an adequate fit to the data while hypothesized relationships in the model were partially supported. Environmental supports predicted college self-efficacy, college outcome expectations, and academic satisfaction. Furthermore, college self-efficacy predicted academic progress while college outcome expectations predicted academic satisfaction. Academic satisfaction, but not academic progress predicted life satisfaction. The structural model explained 44% of the variance in academic progress, 56% of the variance in academic satisfaction, and 28% of the variance in life satisfaction. Mediation analyses indicated several significant indirect effects between variables in the model while moderation analyses revealed a 3-way interaction between academic satisfaction, intrinsic motivation for attending college, and first-generation college student status on life satisfaction. Results are discussed in terms of applying the normative model of well-being to promote first- and non-first-generation college students' academic and life satisfaction.


The spatial and single-cell analysis reveals remodeled immune microenvironment induced by synthetic oncolytic adenovirus treatment.
Oncolytic viruses are multifaceted tumor killers, which can function as tumor vaccines to boost systemic antitumor immunity. In previous study, we rationally designed a synthetic oncolytic adenovirus (SynOV) harboring a synthetic gene circuit, which can kill tumors in mouse hepatocellular carcinoma (HCC) models. In this study, we demonstrated that SynOV could sense the tumor biomarkers to lyse tumors in a dosage-dependent manner, and killed PD-L1 antibody resistant tumor cells in mouse model. Meanwhile, we observed SynOV could cure liver cancer and partially alleviate the liver cancer with distant metastasis by activating systemic antitumor immunity. To understand its high efficacy, it is essential to explore the cellular and molecular features of the remodeled tumor microenvironment (TME). By combining spatial transcriptome sequencing and single-cell RNA sequencing, we successfully depicted the remodeled TME at single cell resolution. The state transition of immune cells and stromal cells towards an antitumor and normalized status exemplified the overall cancer-suppressive TME after SynOV treatment. Specifically, SynOV treatment increased the proportion of CD8+ T cells, enhanced the cell-cell communication of Cxcl9-Cxcr3, and normalized the Kupffer cells and macrophages in the TME. Furthermore, we observed that SynOV could induce distant responses to reduce tumor burden in metastatic HCC patient in the Phase I clinical trial. In summary, our results suggest that SynOV can trigger systemic antitumor immunity to induce CD8+ T cells and normalize the abundance of immune cells to remodel the TME, which promises a powerful option to treat HCC in the future.


Evaluation and Management of Patch Test-Negative Patients With Generalized Dermatitis.
Patients with generalized dermatitis are common in dermatology practices. Allergic contact dermatitis is often suspected, and patients frequently undergo patch testing. When the patch testing result is negative, further evaluation and management of these patients are challenging. The purpose of this study was to survey members of the American Contact Dermatitis Society regarding the evaluation and management of patch test-negative patients with generalized dermatitis. Generalized dermatitis was the most common term identified for patch test-negative patients with diffuse dermatitis. After having negative expanded patch testing results, most physicians proceeded with additional testing including skin biopsy, complete blood cell count with differential, and liver and renal function tests. The most commonly used systemic treatment is prednisone, followed by methotrexate. Narrow-band ultraviolet B (UVB) is the most commonly used light source. Antihistamines are frequently prescribed. Food allergy is not felt to be causative. This cohort of patients experiences significant impairment in quality of life, stress on personal relationships, and time off work. The management of patch test-negative patients with generalized dermatitis is challenging. This study provides insight into management of these complex patients. It also demonstrates practice gaps in the management of these patients, indicating a need for further studies to direct the evaluation and management of this patient population.


Nucleus pulposus phenotypic markers to determine stem cell differentiation: fact or fiction?
Progress in mesenchymal stem cell (MSC) based therapies for nucleus pulposus (NP) regeneration are hampered by a lack of understanding and consensus of the normal NP cell phenotype. Despite the recent consensus paper on NP markers, there is still a need to further validate proposed markers. This study aimed to determine whether an NP phenotypic profile could be identified within a large population of mature NP samples.qRT-PCR was conducted to assess mRNA expression of 13 genes within human non-degenerate articular chondrocytes (AC) (n=10) and NP cells extracted from patients across a spectrum of histological degeneration grades (n=71). qRT-PCR results were used to select NP marker candidates for protein expression analysis.Differential expression at mRNA between AC and non-degenerate NP cells was only observed for Paired Box Protein 1 (PAX1) and Forkhead box F1 (FOXF1). In contrast no other previously suggested markers displayed differential expression between non-degenerate NP and AC at mRNA level. PAX1 and FOXF1 protein expression was significantly higher in the NP compared to annulus fibrosus (AF), cartilaginous endplate (CEP) and AC. In contrast Laminin-5 (LAM-332), Keratin-19 (KRT-19) and Hypoxia Inducible Factor 1 alpha (HIF1α) showed no differential expression in NP cells compared with AC cells.A marker which exclusively differentiates NP cells from AF and AC cells remains to be identified, raising the question: is the NP a heterogeneous population of cells? Or does the natural biological variation during IVD development, degeneration state and even the life cycle of cells make finding one definitive marker impossible?


Managing the opposite breast: contralateral symmetry procedures.
The importance of symmetry after unilateral breast reconstruction is becoming increasingly realized and important. As our reconstructive options have increased and our technical abilities have improved, the expectations of women with breast cancer have been enhanced by virtue of the fact that we are often able to reconstruct a breast with natural volume and contour. When embarking on a unilateral breast reconstruction, the plastic surgeon has several goals and one of which is to obtain breast symmetry. In many circumstances, breast symmetry is achieved without operating on the contralateral breast; however, in some cases, a contralateral operation will be necessary. This is usually based on the volume, contour, and position of the natural and reconstructed breast. Often, the need and/or desire for a contralateral procedure will be evident during the initial consultation. Otherwise, the need for a contralateral procedure will not be evident until after the primary reconstruction has been completed. In either case, it is important for plastic surgeons to be aware of the incidence of these procedures and the options available to them.


Infection by Wolbachia bacteria and its influence on the reproduction of the stored-product psocid, Liposcelis tricolor.
Wolbachia are maternally inherited intracellular bacteria that infect a wide range of arthropods and nematodes and are associated with various reproductive abnormalities in their hosts. The infection by Wolbachia of the psocid, Liposcelis tricolor (Psocoptera: Liposcelididae), was investigated using long PCR amplification of the wsp gene that codes for a Wolbachia surface protein. The results showed that L. tricolor was positive for Wolbachia . Phylogenetic analysis showed that the Wolbachia found in L. tricolor was related to the B-group. Wolbachia infection in L. tricolor could be removed through antibiotic treatment. The results of crosses including female(W+) x male(W+), female(W-) x male(W+), female(W+) x male(W-), and female(W-) x male(W-), suggested that the removal of Wolbachia resulted in lower egg production by L. tricolor . The mean embryonic mortality of offspring produced by L. tricolor without Wolbachia was significantly higher than that of control.


Efficacy of onabotulinumtoxinA in the treatment of unipolar major depression: Systematic review, meta-analysis and meta-regression analyses of double-blind randomised controlled trials.
OnabotulinumtoxinA is a novel therapeutic intervention whose mechanism of action is believed to modify the negative facial feedback, thus abating symptoms of depression. This putative new antidepressant agent offers minimal systemic side effects and negligible risk of pharmacological interactions. We set out to examine the evidence for the use of onabotulinumtoxinA in major depression. A systematic search of the literature identified double-blind randomised controlled trials (RCTs) investigating the use of onabotulinumtoxinA in the treatment of major depression versus placebo. Data, reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA), was combined in meta-analyses (PROSPERO registration ID: CRD42020183538). The search identified five RCTs (four double-blind) comparing onabotulinumtoxinA to placebo. OnabotulinumtoxinA was more effective than placebo when administered within the 20-40 IU dose range in double-blind RCTs. The analysis was free of publication bias and significantly heterogeneous. Meta-regression analyses indicated that onabotulinumtoxinA was more efficacious in women and in higher doses in female patients and less effective with polypharmacy, especially when an increasing number of antidepressants were prescribed. The effectiveness of onabotulinumtoxinA was higher in more recently published double-blind RCTs. The meta-analysis supports the efficacy of the intervention with the results being highly heterogeneous across studies. In view of the heterogeneity of the findings and the significant moderators of benefit (sex, year of study completion and the interaction between sex and dose), more research is required to better understand the role of onabotulinumtoxinA in the treatment of depression.


Impact of measurement of skeletal muscle mass on clinical outcomes in patients with esophageal cancer undergoing esophagectomy after neoadjuvant chemotherapy.
Some studies have reported that sarcopenia is linked to clinical outcomes in multiple types of malignancies, but this association has not been established in esophageal cancer. We assessed how sarcopenia affects clinical outcomes of multidisciplinary treatments for esophageal cancer. We included 165 esophageal cancer patients who had undergone neoadjuvant chemotherapy followed by esophagectomy. Computed tomography was used for cross-sectional measurement of the psoas muscle at the third lumbar vertebra; we then calculated the height-adjusted psoas muscle index. Pre- and postneoadjuvant chemotherapy psoas muscle indices were evaluated for associations with neoadjuvant chemotherapy response and neoadjuvant chemotherapy -related adverse events and postoperative complications, in addition to survival. Psoas muscle index cutoffs were 6.36 cm2/m2 for men and 3.92 cm2/m2 for women. Psoas muscle index decreased after neoadjuvant chemotherapy (from 7.17 to 6.96 cm2/m2; P = .0008), and specifically in men (from 7.45 to 7.23 cm2/m2; P = .0001) but not in women (from 5.21 to 5.17 cm2/m2; P = .810). Preneoadjuvant chemotherapy psoas muscle index (low versus high) was associated with neoadjuvant chemotherapy response (response rate: 65.1% vs 80.3%; P = .0494) and neoadjuvant chemotherapy-related adverse events (neutropenia: 93.0% vs 78.7%; P = .0337; febrile neutropenia: 53.5% vs 34.3%; P = .0278; hyponatremia: 51.2% vs 31.2%; P = .0190). Post-neoadjuvant chemotherapy psoas muscle index correlated with postoperative rate of complications (56.9% vs 33.3%; P = .0046), especially pneumonia (31.4% vs 9.7% P = .0008). Psoas muscle index was not associated with survival. Cross sectional measures of sarcopenia before and after neoadjuvant chemotherapy could predict tumor response, neoadjuvant chemotherapy -related adverse events, and postoperative complications in multidisciplinary treatments for esophageal cancer.


Influence of hemodialysis on gentamicin pharmacokinetics, removal during hemodialysis, and recommended dosing.
Aminoglycoside antibiotics are commonly used in chronic kidney disease stage 5 patients. The purpose of this study was to characterize gentamicin pharmacokinetics, dialytic clearance, and removal by hemodialysis and to develop appropriate dosing strategies. Design Setting, Participants, and Measurements: Eight subjects receiving chronic, thrice-weekly hemodialysis with no measurable residual renal function received gentamicin after a hemodialysis session. Blood samples were collected serially, and serum concentrations of gentamicin were determined. Median (range) systemic clearance, volume of distribution at steady state, and terminal elimination half-life were 3.89 ml/min (2.69-4.81 ml/min), 13.5 L (8.7-17.9 L), and 39.4 h (32.0-53.6 h), respectively. Median (range) dialytic clearance, estimated amount removed, and percent maximum rebound were 103.5 ml/min (87.2-132.7 ml/min), 39.6 mg (19.7-43.9 mg), and 38.7% (0%-71.8%), respectively. Gentamicin dialytic clearance was statistically significantly related to creatinine dialytic clearance (r(2) = 0.52, P = 0.04), although this relationship is not likely to be strong enough to serve as a surrogate for gentamicin monitoring. The pharmacokinetic model was used to simulate gentamicin serum concentrations over a one-wk period. In clinical situations where gentamicin is used as the primary therapy in a patient receiving hemodialysis with a CAHP hemodialyzer, conventional doses after each dialysis session are not as efficient at achieving treatment targets as predialysis dosing with larger doses.


Veterinary peer study groups as a method of continuous education-A new approach to identify and address factors associated with antimicrobial prescribing.
Within the dairy industry, most antimicrobials are used for dry-cow therapy or mastitis treatment. To reduce antimicrobial usage in dairy cows, increasing awareness and behaviour change is necessary. As veterinarians are known to be influenced by their peers, peer study groups as a continuous education might contribute to this. Therefore, the objective of this study was to analyse written records of veterinary peer study group meetings to identify factors associated with antimicrobial prescribing decisions, and to analyse veterinarians' attitude towards the benefits of this continuous education method. Twenty-three participating Swiss cattle practitioners were divided into three groups. Each group met every two to five months, together with a facilitator and an expert on the topic to be discussed. Written records from every meeting were taken and analysed qualitatively to identify factors influencing veterinarians' decisions on antimicrobial prescribing and mastitis therapy. In addition, focus group discussions were conducted after the last meeting, to assess the veterinarians' learning achievements gained during the peer study group meetings. Extrinsic factors such as external pressure, competition, farmer, individual animal, farm and diagnostics as well as intrinsic factors such as own experience/attitude, knowledge and change of mindset during career could be shown to influence veterinarians' decisions on antimicrobial prescribing. In the focus group discussions, the veterinarians stated that they gained new knowledge, received new stimuli, exchanged with their peers and felt supported in their relationship to their farmers. Since the identified factors are partly interrelated, it is not sufficient to change a single factor to achieve a change in the antimicrobial prescription behaviour of veterinarians. Veterinary peer study groups could contribute to the intention to change, because veterinarians experienced multiple benefits from this method of continuous education. In order to quantify this, the prescription data of the veterinarians are analysed in a next step.


Salvage of complicated open fractures by transfixation.
The use of a commercially available Reduction-Retention apparatus for transfixation of nine cases of open fractures with severe soft-tissue damage is reported. Seven patients are walking, two with drop foot braces. Two required amputations, one because of infection and the other because he had suffered severe vascular injury. These two are walking on protheses and are able to work. Of the other seven, five have returned to their previous occupations; one is receiving a disability pension and the other is awaiting further surgery. The problems and advantages of this method of treatment are discussed.


Capnocytophaga canimorsus: infection, septicaemia, recovery and reconstruction.
A case is presented of a life-threatening septicaemia and associated peripheral necrosing microembolic phenomenon, resulting from a dog lick to an insignificant burn wound. The isolated bacterium was Capnocytophaga canimorsus, a slow-growing Gram-negative bacillus commonly found in dog saliva. Any clinician seeing patients with a history of dog bite/saliva contact and progressive illness should consider this bacterium as a possible offender and take special care to elicit an accurate history, specifically including questions regarding animal contact.


Molecular cloning and expression of a new putative inositol 1,4,5-trisphosphate 3-kinase isoenzyme.
A human hippocampus cDNA library in lambda ZAP II was screened by hybridization with a rat brain inositol 1,4,5-trisphosphate (InsP3) 3-kinase cDNA. Two clones (hh6 and hh3) were isolated and sequenced. The insert of clone hh6 was shown to correspond to the 3' end of the coding sequence of 50,000-Mr InsP3 3-kinase (referred to as 3-kinase-A). Sequencing of the clone hh3 insert yielded an open reading frame encoding a 472-amino acid protein with a calculated Mr of 53,451 (referred to as 3-kinase-B). The C-terminal part of 3-kinase-B (residues 187-462) was 68% identical with 3-kinase-A in amino acid sequence. The cDNA of clone hh3 was rescued as a Bluescript plasmid and expressed in Escherichia coli as a beta-galactosidase fusion product. It showed InsP3 3-kinase activity that was stimulated in the presence of Ca2+/calmodulin (more than 7-fold in a crude bacterial lysate from expressed plasmid). Regeneration of InsP3 3-kinase activity after SDS/PAGE identified a major polypeptide (Mr 60,000-65,000). The Km for InsP3 of expressed 3-kinase-B was 1.6 microM. These data provide molecular evidence for the existence of InsP3 3-kinase isoenzymes.


Nanoleakage distribution at adhesive-dentin interfaces in 3D.
In spite of its role in the degradation of tooth-biomaterial interfaces, reports on nanoleakage are largely inconsistent. The aim of this work was to assess nanoleakage patterns qualitatively and quantitatively in 3D, to determine the influence of direction, position, and inclination of the field-of-view. Therefore, we applied a gold-standard 3-step etch-and-rinse adhesive to bur-cut dentin surfaces, after which interface samples were sectioned, infiltrated with an ammoniacal silver-nitrate solution, and embedded by common TEM procedures. High-resolution 3D models of interfaces were then generated by FIB and electron tomography, following strict conditions determined by Monte Carlo simulations. Inverted images in FIB tomography disclosed morphological characteristics analogous to those revealed by TEM. Quantitative analysis revealed large variations in silver-nitrate uptake between 2D image projections in different directions. Furthermore, silver-nitrate fractions in individual 2D image projections were seldom related to the total 3D volumetric fraction. Electron tomography showed that inclination also affected the morphology of silver-nitrate patterns. In conclusion, conventional nanoleakage evaluation is heavily influenced by direction, position, and inclination of the field-of-view, and thus may contain artifacts.


Influential factors in choosing adult/mental health nursing.
This paper describes a comparative survey to investigate the factors influencing twenty undergraduate nursing students on a 'Project 2000 style' course, in their choice of either the adult or mental health branch. The course was structured such that choice of branch was made at the end of the Common Foundation Programme, following experience of each type of nursing. Findings revealed that those choosing the mental health branch were more likely to have made their choice later in the course, and to have changed their mind. Students appeared to have been strongly influenced by positive experiences in mental health placements, both in relation to the work itself, and to the attitudes of ward staff and general atmosphere. These were compared favourably to their experiences in general wards. Reasons for choosing the adult branch included always having wanted to do general nursing and preferring a practically oriented career. Several students were influenced by future career plans for which an RGN qualification was necessary. Both groups had found decision making difficult, especially the mental health branch students who had changed their minds since they began the course. Many students felt that more information and experience, particularly in mental health nursing was needed in the Common Foundation Programme. Suggestions are made in relation to future recruitment to this and other mental health nursing courses.


Medulloblastoma stem cells: where development and cancer cross pathways.
Brain tumors are the leading cause of childhood cancer mortality, with medulloblastoma (MB) representing the most frequent malignant tumor. The recent molecular classification of MB has reconceptualized the heterogeneity that exists within pathological subtypes by giving context to the role of key developmental signaling pathways in MB pathogenesis. The identification of cancer stem cell (CSC) populations, termed brain tumor-initiating cells (BTICs), in MB has provided novel cellular targets for the study of these aberrantly activated signaling pathways, namely, Sonic hedgehog (Shh) and Wingless (Wnt), along with the identification of novel BTIC self-renewal pathways. In this review, we discuss recent evidence for the presence of a MB stem cell that drives tumorigenesis in this malignant childhood tumor. We focus on evidence from cerebellar development, the recent identification of BTICs, the presence of activated developmental signaling pathways in MB, the role of epigenetic stem cell regulatory mechanisms, and how these developmental and epigenetic pathways may be targeted for novel therapeutic options.


Epidermal inclusion cyst embedded in benign fibrous histiocytic lesion with prominent epithelioid morphology.
Benign fibrous histiocytoma also known as dermatofibroma is one of the common mesenchymal neoplasms. It commonly develops in young adult with female predominance and predilection for the extremities, particularly lower extremities. Implantation of epidermis in the dermis or subcutaneous tissues may lead to the formation of epidermal inclusion cyst, which is the most common type of epithelial cyst. Development of epidermal inclusion cyst within a benign fibrous histiocytoma is a rare occurrence. This is a unique case of two unrelated lesions.


Enhanced Activity of Exportin-1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain.
Brain aging is characterized by dysfunctional autophagy and cellular senescence, among other features. While autophagy can either promote or suppress cellular senescence in proliferating cells, in postmitotic cells, such as neurons, autophagy impairment promotes cellular senescence. CRM1 (exportin-1/XPO1) exports hundreds of nuclear proteins into the cytoplasm, including the transcription factors TFEB (the main inducer of autophagy and lysosomal biogenesis genes) and STAT3, another autophagy modulator. It appears that CRM1 is a modulator of aging-associated senescence and autophagy, because pharmacological inhibition of CRM1 improved autophagic degradation in flies, by increasing nuclear TFEB levels, and because enhanced CRM1 activity is mechanistically linked to senescence in fibroblasts from Hutchinson-Gilford progeria syndrome patients and old healthy individuals; furthermore, the exogenous overexpression of CRM1 induced senescence in normal fibroblasts. In this work, we tested the hypothesis that impaired autophagic flux during brain aging occurs due to CRM1 accumulation in the brain. We found that CRM1 levels and activity increased in the hippocampus and cortex during physiological aging, which resulted in a decrease of nuclear TFEB and STAT3. Consistent with an autophagic flux impairment, we observed accumulation of the autophagic receptor p62/SQSTM1 in neurons of old mice, which correlated with increased neuronal senescence. Using an in vitro model of neuronal senescence, we demonstrate that CRM1 inhibition improved autophagy flux and reduced SA-β-gal activity by restoring TFEB nuclear localization. Collectively, our data suggest that enhanced CRM1-mediated export of proteins during brain aging perturbs neuronal homeostasis, contributing to autophagy impairment, and neuronal senescence.


Sensory-based and higher-order operations contribute to abnormal emotional prosody processing in schizophrenia: an electrophysiological investigation.
Schizophrenia is characterized by deficits in emotional prosody (EP) perception. However, it is not clear which stages of processing prosody are abnormal and whether the presence of semantic content contributes to the abnormality. This study aimed to examine event-related potential (ERP) correlates of EP processing in 15 chronic schizophrenia individuals and 15 healthy controls. A total of 114 sentences with neutral semantic content [sentences with semantic content (SSC) condition] were generated by a female speaker (38 with happy, 38 with angry, and 38 with neutral intonation). The same sentences were synthesized and presented in the 'pure prosody' sentences (PPS) condition where semantic content was unintelligible. Group differences were observed for N100 and P200 amplitude: patients were characterized by more negative N100 for SSC, and more positive P200 for angry and happy SSC and happy PPS. Correlations were found between delusions and P200 amplitude for happy SSC and PPS. Higher error rates in the recognition of EP were also observed in schizophrenia: higher error rates in neutral SSC were associated with reduced N100, and higher error rates in angry SSC were associated with reduced P200. These results indicate that abnormalities in prosody processing occur at the three stages of EP processing, and are enhanced in SSC. Correlations between P200 amplitude for happy prosody and delusions suggest a role that abnormalities in the processing of emotionally salient acoustic cues may play in schizophrenia symptomatology. Correlations between ERP and behavioral data point to a relationship between early sensory abnormalities and prosody recognition in schizophrenia.


Core outcome domains for chronic pain clinical trials: IMMPACT recommendations.
To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of data, encourage more complete reporting of outcomes, simplify the preparation and review of research proposals and manuscripts, and allow clinicians to make informed decisions regarding the risks and benefits of treatment. Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 27 specialists from academia, governmental agencies, and the pharmaceutical industry participated in a consensus meeting and identified core outcome domains that should be considered in clinical trials of treatments for chronic pain. There was a consensus that chronic pain clinical trials should assess outcomes representing six core domains: (1) pain, (2) physical functioning, (3) emotional functioning, (4) participant ratings of improvement and satisfaction with treatment, (5) symptoms and adverse events, (6) participant disposition (e.g. adherence to the treatment regimen and reasons for premature withdrawal from the trial). Although consideration should be given to the assessment of each of these domains, there may be exceptions to the general recommendation to include all of these domains in chronic pain trials. When this occurs, the rationale for not including domains should be provided. It is not the intention of these recommendations that assessment of the core domains should be considered a requirement for approval of product applications by regulatory agencies or that a treatment must demonstrate statistically significant effects for all of the relevant core domains to establish evidence of its efficacy.


Policing native pleasures: a colonial history.
The moral modality of colonial power is still with us when it comes to the recreation of sexual norms of traditional or feudal society. We can examine the emergent properties of colonial knowledge anew by exploring how the colonial regime's strategic attention of regulating brothels in India differed from the analytic of power Foucault described for sexuality in European society. It turns out that amongst other things, public anxieties about the failure of adaptation by South Asians are incapable of leaving sexuality aside as a key interpretive device for their culture. The British preoccupation with reproducing the dynamics of the bourgeois matrimonial market on foreign soil in the mid-nineteenth century similarly necessitated a sociological pretext for racial purity. However, the kind of knowledge a typical traveller and employee of the East India Company brought to the Victorian public from his own researches in the brothels and streets of colonial India, which revealed how popular prostitution was as a vice amongst the officer class, was also more than a welcome imaginary relief from Christian morality; it was an alternative vision of modernity.


Inter and intra laboratory concordance of HLA antibody results obtained by single antigen bead based assay.
Single antigen bead based assays (SAB) to identify antibodies to HLA are marketed as a qualitative test, however often used as a quantitative test as the results provide mean fluorescence intensity (MFI) which is found to correlate with the strength/avidity of the antibody. We studied the between and within laboratory variability in performing the SAB from one manufacturer. Ten samples were tested at four laboratories according to the manufacturer's suggested protocol. Additionally same samples were tested on four consecutive days in one laboratory. All tests were performed using the same lot of beads and secondary antibody. Results were classified as positive at four different MFI cutoffs: 1000, 5000, 8000 and 10,000. MFI values across and within the laboratory were compared in a pair-wise fashion with Pearson's correlations. Overall concordance for Class-I was 97% between laboratories and 98% within laboratory at all cutoffs. Pair-wise Pearson correlation between laboratories was 0.989-0.99, while within laboratory it was 0.998-0.999. For Class-II, overall concordance between and within laboratory was 98%. Pair-wise Pearson correlation between laboratories was 0.991-0.997, while within laboratory it was 0.997-0.999. There is good correlation between laboratories and within laboratory using the same manufacturer, same lot and same protocol while performing SAB.


A conserved role for Snail as a potentiator of active transcription.
The transcription factors of the Snail family are key regulators of epithelial-mesenchymal transitions, cell morphogenesis, and tumor metastasis. Since its discovery in Drosophila ∼25 years ago, Snail has been extensively studied for its role as a transcriptional repressor. Here we demonstrate that Drosophila Snail can positively modulate transcriptional activation. By combining information on in vivo occupancy with expression profiling of hand-selected, staged snail mutant embryos, we identified 106 genes that are potentially directly regulated by Snail during mesoderm development. In addition to the expected Snail-repressed genes, almost 50% of Snail targets showed an unanticipated activation. The majority of "Snail-activated" genes have enhancer elements cobound by Twist and are expressed in the mesoderm at the stages of Snail occupancy. Snail can potentiate Twist-mediated enhancer activation in vitro and is essential for enhancer activity in vivo. Using a machine learning approach, we show that differentially enriched motifs are sufficient to predict Snail's regulatory response. In silico mutagenesis revealed a likely causative motif, which we demonstrate is essential for enhancer activation. Taken together, these data indicate that Snail can potentiate enhancer activation by collaborating with different activators, providing a new mechanism by which Snail regulates development.


Outpatient planning: still more art than science?
A general lack of comprehensive data on ambulatory care isn't preventing hospitals from engaging in high-quality planning in that area. "A good forecast" for future ambulatory care demand depends mainly on a "thoughtful determination of what needs to be forecasted and why," says Andrew McCulloch, chief operating officer at Harborview Medical Center, Seattle. The rapid pace of outpatient development has led some hospitals to invest a great deal of time and money to develop improved information systems. Those hospitals are heeding the statistical trends: Outpatient revenue grew far faster than inpatient did in 1990.


Cloning and sequence analysis of the DNA polymerase alpha gene of Leishmania donovani: comparison with the human homologue.
The gene encoding the DNA polymerase alpha catalytic subunit of the kinetoplastid parasite L. donovani has been isolated, sequenced and compared with other eukaryotic homologues. The coding region is 4020 bp in length and specifies an inferred protein sequence of 1339 amino acids (aa). There is a high level of variability between the human and L. donovani gene sequences, but functional substrate-binding residues identified in humans and yeast appear to also be conserved in this parasite. The discovery of a cysteine-rich region located in the midst of the active sites of the enzyme, which appears to be unique to the Kinetoplastids, and aa differences found between some of the conserved regions implicated in catalytic function, may aid in drug design. The putative DNA binding Zn finger at the C-terminus of the protein appears highly species specific and may have potential as a drug target for blocking enzyme catalysis in the parasite.


Relationship of subjective and objective sleep measures with physical performance in advanced-stage lung cancer patients.
Advanced lung cancer patients suffer from deteriorated physical function, which negatively impacts physical and psychological health. As little is known about sleep and physical function in this population, this study aimed to examine the association between subjective and objective sleep parameters and physical function among them. 164 advanced lung cancer patients were included. Objective sleep was measured by actigraphy (measured on non-dominant wrist for 72 h), and subjective sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Performance-based physical function was measured by Timed Up and Go Test (TUGT), 6-Minute Walk Test (6MWT), Sit-to-Stand Test, and One-leg Standing Test. Univariable and multivariable regression analyses were employed to examine the association between sleep and physical function. Total sleep time (TST) was significantly associated with the 6MWT (β = 0.259; 95% CI 0.120, 0.398; P < 0.001), TUGT (β = - 0.012; 95% CI = - 0.017, - 0.008; P < 0.001) and Sit-to-Stand Test (β = 0.027; 95% CI = 0.018, 0.035; P < 0.001) after adjustment for multiple covariates. PSQI global score was only significantly associated with TUGT (β = 0.140; 95% CI = 0.000, 0.280; P = 0.050) after adjustment for multiple covariates. Shorter sleep duration significantly predicted poorer physical performance in advanced lung cancer patients, and more attention is required for those with less than 4.3 h of sleep on average.Trial registration: ClinicalTrials.gov, NCT03482323. Registered 29 March 2018, https://clinicaltrials.gov/ct2/show/NCT03482323 ; ClinicalTrials.gov, NCT04119778. Registered 8 October 2019, https://clinicaltrials.gov/ct2/show/NCT04119778 .


Quantitative Proteomics of Cerebrospinal Fluid in Paediatric Pneumococcal Meningitis.
Streptococcus pneumoniae is responsible for diseases causing major global public health problems, including meningitis, pneumonia and septicaemia. Despite recent advances in antimicrobial therapy, pneumococcal meningitis remains a life-threatening disease. Furthermore, long-term sequelae are a major concern for survivors. Hence, a better understanding of the processes occurring in the central nervous system is crucial to the development of more effective management strategies. We used mass spectrometry based quantitative proteomics to identify protein changes in cerebrospinal fluid from children with Streptococcus pneumoniae infection, compared with children admitted to hospital with bacterial meningitis symptoms but negative diagnosis. Samples were analysed, by label free proteomics, in two independent cohorts (cohort 1: cases (n = 8) and hospital controls (n = 4); cohort 2: cases (n = 8), hospital controls (n = 8)). Over 200 human proteins were differentially expressed in each cohort, of which 65% were common to both. Proteins involved in the immune response and exosome signalling were significantly enriched in the infected samples. For a subset of proteins derived from the proteome analysis, we corroborated the proteomics data in a third cohort (hospital controls (n = 15), healthy controls (n = 5), cases (n = 20)) by automated quantitative western blotting, with excellent agreement with our proteomics findings. Proteomics data are available via ProteomeXchange with identifier PXD004219.


Hydrolysis of plant cuticle by plant pathogens. Purification, amino acid composition, and molecular weight of two isozymes of cutinase and a nonspecific esterase from Fusarium solani f. pisi.
The extracellular fluid of the plant pathogen, Fusarium solani f. pisi, grown on the plant cuticular polymer, cutin, was shown to contain cutinase and p-nitrophenyl palmitate hydrolase activities (R.E. Purdy and P.E. Kolattukudy (1973), Arch. Biochem. Biophys. 159, 61). From this extracellular fluid two isozymes of cutinase and a nonspecific esterase (p-nitrophenyl palmitate hydrolase) were isolated using Sephedex G-100 gel filtration, QAE-Sephadex chromatography, and SE-Sephedex chromatography. Phenolics contained in the extracellular fluid were found to be associated with the cutinase but not with the nonspecific esterase, and the phenolic materials were removed from cutinase at the QAE-Sephedex step. A 34-fold purification of the nonspecific esterase and a 6.5-fold purification of cutinase were achieved by the procedure described. The two isozymes of cutinase (I and II) and the nonspecific esterase were homogeneous as judged by polyacrylamide disc gel electrophoresis and sedimentation equilibrium centrifugation. Molecular weights of cutinase I, cutinase II, and the nonspecific esterase were determined by Sephedex G-100 gel filtration, sedimentation equilibrium centrifugation, amino acid composition, and sodium dodecyl sulfate polyacrylamide disc gel electrophoresis. The values obtained with these techniques agreed with each other and were about 22,000 for both cutinases and 52,000 for the nonspecific esterase. The dodecyl sulfate gel electrophoresis indicated that a small portion of cutinase II contained proteolylic clips, near the middle of the polypeptide chain, and that the nonspecific esterase might also have undergone some proteolylic modification. The amino acid composition of cutinase I was similar to that of cutinase II except for the presence of a larger number of tryptophan residues in the latter, while the amino acid composition of the nonspecific esterase showed more differences from that of either cutinase.


Advanced molecular imaging in large-vessel vasculitis: Adopting FDG-PET into a clinical workflow.
The use of fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging to detect vascular inflammation is increasingly common in the clinical management of patients with large-vessel vasculitis (LVV). In this review, the role of FDG-PET imaging to diagnose and monitor vascular disease activity will be detailed. Suggestions on incorporation of FDG-PET imaging into a clinical workflow will be provided with emphasis on patient preparation, image acquisition, and image interpretation. If FDG-PET imaging is obtained, multimodal imaging assessment, whereby FDG-PET imaging and non-invasive angiography are obtained concurrently, and correlation of imaging findings with clinical assessment is generally advisable. Considering the clinical scenario and treatment status of the patient is important when interpreting vascular FDG-PET image findings.


[Changes in the ultrastructure of inactive circular nucleoli from mature rat lymphocytes at early stages of blast transformation].
We studied the ultrastructure of lymphocyte nucleoli from rat peripheral blood within the first 6 hrs of their cultivation in the presence of phytohaemagglutinin (PHA). In the mixed population of intact lymphocytes there were observed several types of nucleoli, the localization and the ratio of individual nucleolar components being different. This seems to reflect functional peculiarities of these nucleoli. Some nucleoli are characteristic of the presence of several sites of intranucleolar condensed chromatin. However, all these nucleoli could be related to the so-called ring-shaped nucleoli with a fibrillar center surrounded by fibrillar and granular RNP-components, which points out to their low synthetic activity. The major changes in the nucleoli of stimulated lymphocytes were observed after the action of PHA within 1 hr. These changes were expressed in the elevation of electron density of the fibrillar centre and the loss by it of clear borders and correct shape, in the appearance of large zones of the dense fibrillar component with acquired an increased electron density, and also in the disappearance of condensed chromatin sites. By that time, there was revealed a peculiar shape of nucleoli with a "fragmented" fibrillar centre and the presence of vacuoles and strands consisting of fibrillar and granular RNP-components. The different types of changed nucleoli in the population of stimulated lymphocytes seem to be the consequence of a gradual transition of ring-shaped nucleoli to active nucleolonema-like ones. So, it is obvious that changes in the ultrastructure of nucleoli occur already by 1 hr after the PHA action. This points out to the intensification of pre-rRNA transcription that takes place by that time.


[Analysis of mortality rates among patients with pulmonary tuberculosis].
The outpatient medical cards and history cases of those who died, autopsy protocols of 428 dead patients with various forms of tuberculosis were analyzed. Of them, 86 patients had been followed up less than a year. The patients treated with antituberculous drugs died not only from a progressive specific process, but from nonspecific complications. The factors predisposing to death were late detection of tuberculosis and irregular treatment, alcohol and drug abuse.


Machine learning-based radiomic evaluation of treatment response prediction in glioblastoma.
To investigate machine learning based models combining clinical, radiomic, and molecular information to distinguish between early true progression (tPD) and pseudoprogression (psPD) in patients with glioblastoma. A retrospective analysis was undertaken of 76 patients (46 tPD, 30 psPD) with early enhancing disease following chemoradiotherapy for glioblastoma. Outcome was determined on follow-up until 6 months post-chemoradiotherapy. Models comprised clinical characteristics, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and 307 quantitative imaging features extracted from enhancing disease and perilesional oedema masks on early post-chemoradiotherapy contrast-enhanced T1-weighted imaging, T2-weighted imaging (T2WI), and apparent diffusion coefficient (ADC) maps. Feature selection was performed within bootstrapped cross-validated recursive feature elimination with a random forest algorithm. Naive Bayes five-fold cross-validation was used to validate the final model. Top selected features included age, MGMT promoter methylation status, two shape-based features from the enhancing disease mask, three radiomic features from the enhancing disease mask on ADC, and one radiomic feature from the perilesional oedema mask on T2WI. The final model had an area under the receiver operating characteristics curve (AUC) of 0.80, sensitivity 78.2%, specificity 66.7%, and accuracy of 73.7%. Incorporating a machine learning-based approach using quantitative radiomic features from standard-of-care magnetic resonance imaging (MRI), in combination with clinical characteristics and MGMT promoter methylation status has a complementary effect and improves model performance for early prediction of glioblastoma treatment response.


The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic.
Bailie et al. [In Vitro Cell Dev. Biol. (1992) 28A, 621-624] reported that primary cultures of rat hepatocytes possess low affinity binding sites for nerve growth factor (NGF). NGF treatment of primary cultures of rat hepatocytes with a maximally effective concentration of NGF (20 ng/ml, 0.8 nM) caused acute phasic activation of Raf-1 and p42(MAPkinase), and a smaller sustained activation of B-Raf. The transient increase in Raf-1 and p42(MAPkinase) activity returned to baseline within approximately 30 min. NGF treatment of hepatocytes did not induce expression of cyclin dependent kinase (cdk) inhibitor proteins, but instead stimulated cdk2 activity and increased [3H]thymidine incorporation into DNA. In contrast to hepatocytes, NGF treatment of PC12 pheochromocytoma cells caused large sustained activations of B-Raf and p42(MAPkinase), and a lower phasic activation of Raf-1. The sustained activations of B-Raf and p42(MAPkinase) were for more than 5 h. Treatment of PC12 cells with NGF increased p21(Cip1/WAF-1) expression, reduced cdk2 activity and inhibited DNA synthesis, the opposite to the effects of NGF treatment of hepatocytes. However when p42(MAPkinase) was chronically activated in hepatocytes, via infection with an inducible oestrogen receptor-Raf-1 fusion protein, expression of p21(Cip-1/WAF1) and p16(INK4a) cdk inhibitor proteins increased, cdk2 activity decreased, and DNA synthesis decreased. Equally, treatment of hepatocytes with 50 mM ethanol elevated the basal activity of p42(MAPkinase) and temporally extended the ability of NGF treatment to activate p42(MAPkinase). Ethanol and NGF co-treatment increased expression of p21(Cip-1/WAF1) and p16(INK4a) cdk inhibitor proteins and decreased hepatocyte DNA synthesis. These data demonstrate that NGF can cause either acute/phasic or sustained activation of the MAP kinase cascade in different cell types. Acute activation of the MAP kinase cascade correlated with increased DNA synthesis. In contrast, sustained activation of the MAP kinase cascade correlated with increased expression of cdk inhibitor proteins, a reduction in cdk activity, and an inhibition of DNA synthesis. These data suggest a general mechanism exists where acute activation of the MAP kinase cascade promotes G1 progression/S phase entry and that chronic activation of the MAP kinase cascade inhibits this process.


Vaccination approach to anti-angiogenic treatment of cancer.
Improvement of patient survival by anti-angiogenic therapy has proven limited. A vaccination approach inducing an immune response against the tumor vasculature combines the benefits of immunotherapy and anti-angiogenesis, and may overcome the limitations of current anti-angiogenic drugs. Strategies to use whole endothelial cell vaccines and DNA- or protein vaccines against key players in the VEGF signaling axis, as well as specific markers of tumor endothelial cells, have been tested in preclinical studies. Current clinical trials are now testing the promise of this specific anti-cancer vaccination approach. This review will highlight the state-of-the-art in this exciting field of cancer research.


Picrotoxin-mediated antagonism of alpha3beta4 and alpha7 acetylcholine receptors.
Picrotoxin (PTX) is a convulsant that antagonizes many inhibitory ligand-gated receptors. The mechanism of PTX block is believed to involve residues which line the pore in the second transmembrane domain (M2). The alpha(3)beta(4) and alpha(7) nicotinic acetylcholine receptors (nAChRs) have high homology to inhibitory LGICs in this M2 region and therefore could also be susceptible to block by PTX. Here, we report that PTX is an effective inhibitor at these nicotinic receptors (rat), with IC50 values of 96.1 +/- 5.5 and 194.9 +/- 19.2 microM for the alpha(3)beta(4) and alpha(7), respectively. These results provide insights into the structure-function relation of PTX-mediated antagonism in this family of ligand-activated receptors. Furthermore they should also be considered when employing PTX to selectively eliminate GABA- or glycine-mediated events.


Imaging covalent bond formation by H atom scattering from graphene.
Viewing the atomic-scale motion and energy dissipation pathways involved in forming a covalent bond is a longstanding challenge for chemistry. We performed scattering experiments of H atoms from graphene and observed a bimodal translational energy loss distribution. Using accurate first-principles dynamics simulations, we show that the quasi-elastic channel involves scattering through the physisorption well where collision sites are near the centers of the six-membered C-rings. The second channel results from transient C-H bond formation, where H atoms lose 1 to 2 electron volts of energy within a 10-femtosecond interaction time. This remarkably rapid form of intramolecular vibrational relaxation results from the C atom's rehybridization during bond formation and is responsible for an unexpectedly high sticking probability of H on graphene.


Value of Tracking Biopsy in Men Undergoing Active Surveillance of Prostate Cancer.
We compared the upgrading rate obtained by resampling precise spots of prostate cancer (tracking biopsy) vs conventional systematic resampling during followup of men on active surveillance. From 2009 to 2017 in 352 men prostate cancer was Gleason 3 + 3 in 268 and Gleason 3 + 4 in 84 at initial magnetic resonance imaging-ultrasound fusion biopsy. These men subsequently underwent a second fusion biopsy. At the first biopsy session all men underwent 12-core systematic biopsies and, when magnetic resonance imaging visible lesions were present, targeted biopsies. All cancerous sites were recorded electronically. During active surveillance at a second fusion biopsy session 6 to 18 months later tracking and systematic nontracking samples were obtained. The primary outcome measure was an increase in Gleason score (upgrading) at followup sampling, which was stratified by biopsy method. Overall 91 of the 352 men (25.9%) experienced upgrading at the second biopsy during a median 11-month interval. The upgrade rate in the Gleason 3 + 3 and 3 + 4 groups was 26.9% and 22.6%, respectively. The mean number of cores taken at second biopsy was 12.2 ± 3.3 in men with upgrading and 12.4 ± 4.1 in those who remained stable (p not significant). Men with grade 0 to 4 magnetic resonance imaging targets were all upgraded at approximately the same rate of 20% to 30% (p not significant). However, 58.8% of the men with grade 5 magnetic resonance imaging targets were upgraded. Of the 91 upgrades 48 (53%) were detected only by tracking. The tracking function of magnetic resonance imaging-ultrasound fusion biopsy warrants further study. When specific sites are resampled in men undergoing active surveillance of prostate cancer, upgrading is detected more often than by nontracking biopsy.


Genetic diversity of native bradyrhizobia isolated from soybeans (Glycine max L.) in different agricultural-ecological-climatic regions of India.
Fifty isolates from root nodules of soybean plants sampled in five agricultural-ecological-climatic regions of India were analyzed by PCR-restriction fragment length polymorphism analysis of the 16S rRNA gene, the intergenic spacer region between the 16S and 23S rRNA genes (IGS), and the nifH and nodC genes. Eight haplotypes assigned to the Bradyrhizobium genus were identified, and the genetic diversity was conserved across regions. Sequence analyses of the IGS and the dnaK, glnII, recA, and nifH genes revealed three groups. One of them (26% of isolates) was assigned to Bradyrhizobium liaoningense. A second group (36% of isolates) was identified as B. yuanmingense but likely forms a new biovar able to nodulate soybean plants. The third lineage (38% of isolates) was different from all described Bradyrhizobium species but showed the same symbiotic genotype as B. liaoningense and B. japonicum bv. glycinearum.


Functional Selectivity and Partial Efficacy at the Monoamine Transporters: A Unified Model of Allosteric Modulation and Amphetamine-Induced Substrate Release.
All clinically approved drugs targeting the plasmalemmal transporters for dopamine, norepinephrine, and serotonin act either as competitive uptake inhibitors or as amphetamine-like releasers. Monoamine transporter (MAT) ligands that allosterically affect MAT-mediated substrate uptake, release, or both were recently discovered. Their modes of action have not yet been explained in a unified framework. Here, we go beyond competitive inhibitors and classic amphetamines and introduce concepts for partial efficacy at and allosteric modulation of MATs. After we elaborate on a kinetic account for amphetamine action, we provide an explanation for partial release (i.e., the observation that some amphetamines are less efficacious than others in inducing monoamine efflux). We then elucidate mechanisms of allosteric inhibition and stimulation of MATs, which can be functionally selective for either substrate uptake or amphetamine-induced release. These concepts are integrated into a parsimonious kinetic framework, which relies exclusively on physiologic transport modes (without any deviation from an alternating access mechanism). The model posits cooperative substrate and Na+ binding and functional selectivity by conformational selection (i.e., preference of the allosteric modulators for the substrate-loaded or substrate-free states of the transporter). Thus, current knowledge about the kinetics of monoamine transport is sufficiently detailed to provide a quantitative description of the releasing action of amphetamines, of substrate uptake, and of selective modulation thereof by allosteric modulators.


Watson-Crick Base-Pairing Requirements for ssDNA Recognition and Processing in Replication-Initiating HUH Endonucleases.
Replication-initiating HUH endonucleases (Reps) are sequence-specific nucleases that cleave and rejoin single-stranded DNA (ssDNA) during rolling-circle replication. These functions are mediated by covalent linkage of the Rep to its substrate post cleavage. Here, we describe the structures of the endonuclease domain from the Muscovy duck circovirus Rep in complex with its cognate ssDNA 10-mer with and without manganese in the active site. Structural and functional analyses demonstrate that divalent cations play both catalytic and structural roles in Reps by polarizing and positioning their substrate. Further structural comparisons highlight the importance of an intramolecular substrate Watson-Crick (WC) base pairing between the -4 and +1 positions. Subsequent kinetic and functional analyses demonstrate a functional dependency on WC base pairing between these positions regardless of the pair's identity (i.e., A·T, T·A, G·C, or C·G), highlighting a structural specificity for substrate interaction. Finally, considering how well WC swaps were tolerated in vitro, we sought to determine to what extent the canonical -4T·+1A pairing is conserved in circular Rep-encoding single-stranded DNA viruses and found evidence of noncanonical pairings in a minority of these genomes. Altogether, our data suggest that substrate intramolecular WC base pairing is a universal requirement for separation and reunion of ssDNA in Reps. IMPORTANCE Circular Rep-encoding single-stranded DNA (CRESS-DNA) viruses are a ubiquitous group of viruses that infect organisms across all domains of life. These viruses negatively impact both agriculture and human health. All members of this viral family employ a multifunctional nuclease (Rep) to initiate replication. Reps are structurally similar throughout this family, making them targets of interest for viral inhibition strategies. Here, we investigate the functional dependencies of the Rep protein from Muscovy duck circovirus for ssDNA interaction. We demonstrate that this Rep requires an intramolecular Watson-Crick base pairing for origin of replication (Ori) recognition and interaction. We show that noncognate base pair swaps are well tolerated, highlighting a local structural specificity over sequence specificity. Bioinformatic analysis found that the vast majority of CRESS-DNA Oris form base pairs in conserved positions, suggesting this pairing is a universal requirement for replication initiation in the CRESS-DNA virus family.


Real-time intraoperative surgical guidance system in the da Vinci surgical robot based on transrectal ultrasound/photoacoustic imaging with photoacoustic markers: an ex vivo demonstration.
This paper introduces the first integrated real-time intraoperative surgical guidance system, in which an endoscope camera of da Vinci surgical robot and a transrectal ultrasound (TRUS) transducer are co-registered using photoacoustic markers that are detected in both fluorescence (FL) and photoacoustic (PA) imaging. The co-registered system enables the TRUS transducer to track the laser spot illuminated by a pulsed-laser-diode attached to the surgical instrument, providing both FL and PA images of the surgical region-of-interest (ROI). As a result, the generated photoacoustic marker is visualized and localized in the da Vinci endoscopic FL images, and the corresponding tracking can be conducted by rotating the TRUS transducer to display the PA image of the marker. A quantitative evaluation revealed that the average registration and tracking errors were 0.84 mm and 1.16°, respectively. This study shows that the co-registered photoacoustic marker tracking can be effectively deployed intraoperatively using TRUS+PA imaging providing functional guidance of the surgical ROI.


Basic characteristics of human lung mast cell desensitization.
Human lung parenchymal mast cells displayed both specific and nonspecific desensitization. The kinetics of both release and desensitization were approximately equal to 3 times faster than human basophils, but a similar relationship between release and desensitization suggests similar biochemistries in basophils and mast cells. Arachidonic acid metabolite (PGD2 and LTC4) release was slower to desensitize (t1/2 of 8 min) than histamine release (t1/2 of 3 min), the ratio of which is similar to the ratio observed in basophils. Ionophore A23187-induced release was unaffected by desensitization to anti-IgE antibody, and calcium-45 uptake was inhibited by desensitization, suggesting that desensitization inhibits the early post-cross-linking "influx" of calcium that is necessary for mediator release in mast cells. In contrast to the above similarities in basophil and mast cell desensitization, mast cell desensitization, unlike that of basophils was not inhibited by diisopropylfluorophosphate.


Red Light Irradiation In Vivo Upregulates DJ-1 in the Retinal Ganglion Cell Layer and Protects against Axotomy-Related Dendritic Pruning.
Retinal ganglion cells (RGCs) undergo dendritic pruning in a variety of neurodegenerative diseases, including glaucoma and autosomal dominant optic atrophy (ADOA). Axotomising RGCs by severing the optic nerve generates an acute model of RGC dendropathy, which can be utilized to assess the therapeutic potential of treatments for RGC degeneration. Photobiomodulation (PBM) with red light provided neuroprotection to RGCs when administered ex vivo to wild-type retinal explants. In the current study, we used aged (13-15-month-old) wild-type and heterozygous B6;C3-Opa1Q285STOP (Opa1+/-) mice, a model of ADOA exhibiting RGC dendropathy. These mice were pre-treated with 4 J/cm2 of 670 nm light for five consecutive days before the eyes were enucleated and the retinas flat-mounted into explant cultures for 0-, 8- or 16-h ex vivo. RGCs were imaged by confocal microscopy, and their dendritic architecture was quantified by Sholl analysis. In vivo 670 nm light pretreatment inhibited the RGC dendropathy observed in untreated wild-type retinas over 16 h ex vivo and inhibited dendropathy in ON-center RGCs in wild-type but not Opa1+/- retinas. Immunohistochemistry revealed that aged Opa1+/- RGCs exhibited increased nitrosative damage alongside significantly lower activation of NF-κB and upregulation of DJ-1. PBM restored NF-κB activation in Opa1+/- RGCs and enhanced DJ-1 expression in both genotypes, indicating a potential molecular mechanism priming the retina to resist future oxidative insult. These data support the potential of PBM as a treatment for diseases involving RGC degeneration.


Synthesis and magnetic properties of manganite multiple heterostructure nanoribbons.
The fabrication and applications of two-dimensional complex oxide heterostructures have gained great attention. However, the achievement of these materials in one-dimensional form with multiple interfaces is still elusive. Here, we report the growth of manganite CaMn(3)O(6)/CaMn(2)O(4) heterostructure nanoribbons via the use of CaMnO(3) powders as the precursor for the molten-salt process. In contrast with the antiferromagnetism in CaMn(3)O(6) and CaMn(2)O(4) in the bulk, magnetization measurements indicate the coexistence of a ferromagnetic phase with a spin-glass-like component in CaMn(3)O(6)/CaMn(2)O(4) heterostructure nanoribbons. An asymmetric magnetization hysteresis loop observed in the applied magnetic field H≤ 3 T is attributed to the coupling between the antiferromagnetic phase and the ferromagnetic or spin-glass-like phase in CaMn(3)O(6)/CaMn(2)O(4) heterostructure nanoribbons.


Cecum duplication in a 14-year-old female. Case report.
Duplications of the alimentary tract are a group of rare malformations occurring in about 1/5,000 live births. These may be either spherical or tubular and may communicate with the intestinal tract. Duplications of the cecum are very uncommon. A 14-year-old female was admitted to the emergency department with a 1-day history of abdominal pain, vomiting, constipation and abdominal distension. Abdominal examination revealed distension and tenderness around the umbilicus. Plain abdominal radiography showed dilated colon. The patient underwent surgical management with diagnosis of sigmoid volvulus. Laparotomy revealed spherical duplication from the cecum. Hemicolectomy was done and alimentary continuity was restored by end-to-end anastomosis. Pathological report was a spherical communicated duplication from the cecum (22 × 32 cm). Duplication of the cecum is extremely rare and is seen in 0.4% of duplications of the alimentary tract. The majority of cases (85%) are diagnosed before age 2 years. It is rare at 14 years of age. Diagnosis is difficult and volvulus, intussusception or appendicitis should be considered in the differential diagnosis. Ultrasonography and tomography are the imaging studies of choice. Plain abdominal x-ray is not specific. Resection of the duplication with restoration of alimentary continuity is the treatment of choice.


CXM: a new tool for mapping breast cancer risk in the tumor microenvironment.
The majority of causative variants in familial breast cancer remain unknown. Of the known risk variants, most are tumor cell autonomous, and little attention has been paid yet to germline variants that may affect the tumor microenvironment. In this study, we developed a system called the Consomic Xenograft Model (CXM) to map germline variants that affect only the tumor microenvironment. In CXM, human breast cancer cells are orthotopically implanted into immunodeficient consomic strains and tumor metrics are quantified (e.g., growth, vasculogenesis, and metastasis). Because the strain backgrounds vary, whereas the malignant tumor cells do not, any observed changes in tumor progression are due to genetic differences in the nonmalignant microenvironment. Using CXM, we defined genetic variants on rat chromosome 3 that reduced relative tumor growth and hematogenous metastasis in the SS.BN3(IL2Rγ) consomic model compared with the SS(IL2Rγ) parental strain. Paradoxically, these effects occurred despite an increase in the density of tumor-associated blood vessels. In contrast, lymphatic vasculature and lymphogenous metastasis were unaffected by the SS.BN3(IL2Rγ) background. Through comparative mapping and whole-genome sequence analysis, we narrowed candidate variants on rat chromosome 3 to six genes with a priority for future analysis. Collectively, our results establish the utility of CXM to localize genetic variants affecting the tumor microenvironment that underlie differences in breast cancer risk.


[Clinical practice guideline for the diagnosis and treatment of cardiorenal syndrome (2023 Edition)].
The guideline was co-authored by a working group composed of multidisciplinary experts in nephrology, cardiology, critical care medicine, and evidence-based medicine. It focused on eight clinical issues concerning prediction, diagnosis and assessment of cardiorenal syndrome, prevention, treatment of drugs and their selection, mechanical circulatory support and blood purification therapy, heart and/or kidney transplantation, treatment of major complications, multidisciplinary combination therapy, and special diagnosis and treatment in children and pregnant women, mainly based on evidence-based evidence of cardiorenal syndrome, heart failure and chronic kidney disease. Meanwhile, the domestic and foreign clinical guidelines in related fields were referenced to put forward recommendations. The present guideline aims to guide and standardize the clinical practice of diagnosis, prevention, treatment and management of cardiorenal syndrome, promote the development of clinical trials, and improve the level of prevention, treatment and scientific research.


A real-time approach of diagnosing rice leaf disease using deep learning-based faster R-CNN framework.
The rice leaves related diseases often pose threats to the sustainable production of rice affecting many farmers around the world. Early diagnosis and appropriate remedy of the rice leaf infection is crucial in facilitating healthy growth of the rice plants to ensure adequate supply and food security to the rapidly increasing population. Therefore, machine-driven disease diagnosis systems could mitigate the limitations of the conventional methods for leaf disease diagnosis techniques that is often time-consuming, inaccurate, and expensive. Nowadays, computer-assisted rice leaf disease diagnosis systems are becoming very popular. However, several limitations ranging from strong image backgrounds, vague symptoms' edge, dissimilarity in the image capturing weather, lack of real field rice leaf image data, variation in symptoms from the same infection, multiple infections producing similar symptoms, and lack of efficient real-time system mar the efficacy of the system and its usage. To mitigate the aforesaid problems, a faster region-based convolutional neural network (Faster R-CNN) was employed for the real-time detection of rice leaf diseases in the present research. The Faster R-CNN algorithm introduces advanced RPN architecture that addresses the object location very precisely to generate candidate regions. The robustness of the Faster R-CNN model is enhanced by training the model with publicly available online and own real-field rice leaf datasets. The proposed deep-learning-based approach was observed to be effective in the automatic diagnosis of three discriminative rice leaf diseases including rice blast, brown spot, and hispa with an accuracy of 98.09%, 98.85%, and 99.17% respectively. Moreover, the model was able to identify a healthy rice leaf with an accuracy of 99.25%. The results obtained herein demonstrated that the Faster R-CNN model offers a high-performing rice leaf infection identification system that could diagnose the most common rice diseases more precisely in real-time.