Thrombectomy Complications in Large Vessel Occlusions: Incidence, Predictors, and Clinical Impact in the ETIS Registry.
Procedural complications in thrombectomy for large vessel occlusions of the anterior circulation are not well described. We investigated the incidence, risk factors, and clinical implications of thrombectomy complications in daily clinical practice. We used data from the ongoing prospective multicenter observational Endovascular Treatment in Ischemic Stroke Registry in France. The present study is a retrospective analysis of 4029 stroke patients with anterior large vessel occlusions treated with thrombectomy between January 2015 and May 2020 in 18 centers. We systematically collected procedural data, incidence of embolic complications, perforations and dissections, clinical outcome at 90 days, and hemorrhagic complications. Procedural complications occurred in 7.99% (95% CI, 7.17%-8.87%), and embolus to a new territory (ENT) was the most frequent (5.2%). Predictors of ENTs were terminal carotid/tandem occlusion (odds ratio [OR], 5 [95% CI, 2.03-12.31]; P<0.001) and an increased total number of passes (OR, 1.22 [95% CI, 1.05-1.41]; P=0.006). ENTs were associated to worse clinical outcomes (90-day modified Rankin Scale score, 0-2; adjusted OR, 0.4 [95% CI, 0.25-0.63]; P<0.001), increased mortality (adjusted OR, 1.74 [95% CI, 1.2-2.53]; P<0.001), and symptomatic intracerebral hemorrhage (adjusted OR, 1.87 [95% CI, 1.15-3.03]; P=0.011). Perforations occurred in 1.69% (95% CI, 1.31%-2.13%). Predictors of perforations were terminal carotid/tandem occlusions (39.7% versus 27.6%; P=0.028). 40.7% of patients died at 90 days, and the overall rate of poor outcome was 74.6% in case of perforation. Dissections occurred in 1.46% (95% CI, 1.11%-1.88%) and were more common in younger patients (median age, 64.2 versus 70.2 years; P=0.002). Dissections did not affect the clinical outcome at 90 days. Besides dissection, complications were independent of the thrombectomy technique. Thrombectomy complication rate is not negligible, and ENTs were the most frequent. ENTs and perforations were associated with disability and mortality, and terminal carotid/tandem occlusions were a risk factor. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03776877.


Management of chronic dorsal root pain with epidural steroid.
Twenty-eight patients presenting with typical dorsal root pain of more than six months' duration were given a series of three epidural injections of methylprednisolone acetate. The patients were grouped according to known aetiologic factors. Improvement in symptoms was most marked in the post-herpetic group where 86% were free of pain after six months. In the post-trauma/surgical group, 50% of patients were free of pain after six months, while in the idiopathic group only minimal improvement occurred. The side-effects of steroid administration into the epidural space were in all cases minor.


The druggability of intracellular nucleotide-degrading enzymes.
Nucleotide metabolism is the target of a large number of anticancer drugs including antimetabolites and specific enzyme inhibitors. We review scientific findings that over the last 10-15 years have allowed the identification of several intracellular nucleotide-degrading enzymes as cancer drug targets, and discuss further potential therapeutic applications for Rcl, SAMHD1, MTH1 and cN-II. We believe that enzymes involved in nucleotide metabolism represent potent alternatives to conventional cancer chemotherapy targets.


Is there a Rosenberg school?
Since his first book The Cholera Years appeared in 1962, Charles Rosenberg has had an enormous influence on the history of medicine. Not the least of that influence has been exercised through his role as a graduate teacher, advisor, and mentor. This article compares Rosenberg's work with that of his students, to see if there is such a historiographic identity as the "Rosenberg School." The authors, two Rosenberg students from different generations, conclude that there is not such a school, at least in the classic sense of the term. Yet they argue that certain common assumptions, or "Rosenberg Rules," have been passed on from Rosenberg to the other scholars he has influenced. They also discuss the challenges they have encountered in applying Charles's conceptual framework, worked out primarily in pre-1920 terms, to the late twentieth-century history of American medicine.


Background parenchymal enhancement over exam time in patients with and without breast cancer.
To compare background parenchymal enhancement (BPE) over time in patients with and without breast cancer. This retrospective Institutional Review Board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant study included 116 women (25-84 years, mean 54 years) with breast cancer who underwent breast magnetic resonance imaging at 3T between 1/2/2009 and 12/29/2009 and 116 age and date-of-exam-matched women without breast cancer (23-84 years, mean 51 years). Two independent, blinded readers (R1, R2) recorded BPE (minimal, mild, moderate, marked) at three times (100, 210, and 320 seconds postcontrast). Subsequent cancers were diagnosed in 9/96 control patients with follow up (12.6-93.0 months, mean 63.6 months). Exact Mann-Whitney, Fisher's exact, and McNemar tests were performed. Mean BPE was not found to be different between patients with and without breast cancer at any time (P = 0.36-0.64). At time 2 as compared with time 1, there were significantly more patients, both with and without breast cancer, with BPE >minimal (R1: 90 vs. 41 [P < 0.001] and 81 vs. 36 [P < 0.001]; R2: 84 vs. 52 [P < 0.001] and 79 vs. 43 [P < 0.001]) and BPE >mild (R1: 59 vs. 10 [P < 0.001] and 47 vs. 13 [P < 0.001]; R2: 49 vs. 12 [P < 0.001] and 41 vs. 18 [P < 0.001]). BPE changes between times 2 and 3 were not significant (P = 0.083-1.0). Odds ratios for control patients developing breast cancer were significant only for R2 and ranged up to 7.67 (1.49, 39.5; P < 0.01) for BPE >mild at time 2. BPE changes between the first and second postcontrast scans and stabilizes thereafter in most patients. Further investigation into the most clinically relevant timepoint for BPE assessment is warranted. 3 J. Magn. Reson. Imaging 2017;45:74-83.


Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy: a randomized controlled trial.
To test the efficacy and safety of ursodeoxycholic acid (UDCA) in the treatment of patients with intrahepatic cholestasis of pregnancy (ICP). In the randomized (double-blind, placebo-controlled) study 20 pregnant women with ICP received (random allocation of) either 450 mg/day UDCA or placebo for 14 days during the third trimester of pregnancy. The severity of pruritus was registered and itching scores were assessed before the treatment and weekly thereafter. The effects of UDCA on liver function and fetoplacental hormone production were measured with covering laboratory testing: serum levels of alanine aminotransferase (ALAT), total bile acids (TBA), estradiol, progesterone, prolactin, cholesterol, HDL-cholesterol, triglycerides, activated partial thromboplastin time, fibrinogen D-dimers (FIDD) and platelet count were assessed before the treatment and weekly thereafter. Data on pregnancy and delivery outcome were recorded and analyzed. UDCA was well tolerated. A significant improvement in itching scores was detected in 2 weeks in the group receiving UDCA. Serum levels of ALAT and TBA fell after 2 weeks treatment. The other laboratory values were not modified by the treatment. UDCA improves maternal itching scores and liver function tests without interfering with the fetoplacental estrogen production in patients with ICP. UDCA is well tolerated by pregnant women. No fetal or neonatal side-effects could be detected.


Nuclear compartmentation of glycoprotein B of human cytomegalovirus.
Maturation of glycoprotein B (gB) of human cytomegalovirus (HCMV) includes a series of sequential glycosylation steps followed by proteolytic cleavage of the precursor protein. Inhibitors of glycosylation and glycoprotein processing, including tunicamycin, monensin, and bromoconduritol, were used to define further the processing pathway of HCMV gB. The results of these studies indicated that cotranslational glycosylation and intracellular transport are essential for subsequent cleavage of the precursor; early trimming in the endoplasmic reticulum is not a prerequisite but facilitates this processing event. Analysis of purified nuclei with gB-specific monoclonal antibody suggested that the mannose-rich gB-precursor intermediate(s) is (are) compartmentalized in the nuclear fraction. Immunoelectron microscopy revealed that HCMV gB was localized in the outer as well as in the inner nuclear membranes of HCMV-infected fibroblasts.


Progression of Menetrier's disease with postoperative gastrojejunal intussusception.
A unique case of Menetrier's disease of the stomach with long term follow-up is presented to document progression of extent of the disease radiologically and pathologically. This observation provides an insight into the natural history of the condition and suggests that local excision is not necessarily curative. In addition, this case demonstrates the complication of preoperative direct prolapse of involved gastric mucosa through the pylorus, and subsequent postoperative antegrade intussusception of the progressively involved gastric mucosa across a Billroth II gastrojejunostomy.


Expression of GABAergic system in pulmonary neuroendocrine cells and airway epithelial cells in GAD67-GFP knock-in mice.
Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain, is also located in many peripheral nonneuronal tissues. The glutamate decarboxylase 67-green fluorescent protein (GAD67-GFP) knock-in mouse is a useful model for studying the distribution of GABAergic cells in many tissues and organs. The lungs of these mice contain cells with an intense GFP signal exclusively in the airway epithelium. We aimed to characterize the GFP-positive cells and to clarify their relationship with the GABAergic system. We identified the GFP-positive cells as pulmonary neuroendocrine cells (PNECs) by immunohistochemistry for the protein gene product 9.5 and calcitonin gene-related peptide and by ultrastructural analysis. Immunohistochemistry for GADs and GABA revealed GAD65/67 and GABA in GFP-positive PNECs. Reverse transcription-polymerase chain reaction analyses revealed mRNAs encoding the GABA(B) receptor subunits necessary for the assembly of functional receptors, R1 and R2, in the lung. GABA(B) receptor subunit R1 and R2 proteins were expressed in many airway epithelial cells including alveolar epithelial cells other than GFP-positive PNECs. The present findings demonstrated that PNECs in the airway epithelium have a GABA production system and indicated that GABA plays functional roles in airway epithelial cells through GABA(B) receptors.


Hussein Suleiman Abusalih (1930-2021): First Neurosurgeon and Former Minister of Health of Sudan.
This historical account reviews the course and lasting impact of Dr. Hussein Suleiman Abusalih (October 5, 1930 to December 6, 2021) in neurosurgery. The conception of this project was sparked by the discovery of original scientific and bibliographical information about Dr. Abusalih, a prolific neurosurgeon and political figure in his home country of Sudan. This project aims to thoroughly describe the impact of Dr. Abusalih in his home country and in the field of neurosurgery. From humble beginnings, Dr. Abusalih traveled extensively to pursue his passions in education and medicine. He received his neurosurgical training with Dr. Ahmed El-Banhawi of Ain Shams University. Afterward, he returned to Sudan to become the nation's first neurosurgeon and formed the first neurosurgical department in the country in addition to being appointed as the Minister of Health of Sudan. Partnering with several neuroscientists and fellow physicians, Dr. Abusalih was one of the founders of the Pan African Association of Neurological Sciences and worked extensively for various indigenous populations. As a prolific researcher and educator, Dr. Abusalih authored many presentations, publications, and various books, such as "Inside the Ministry of Health" and "Neurosurgery in the Seventies." Dr. Abusalih was a prominent figure in both medical and political fields. Our article provides a look into the life and impact of Dr. Abusalih as a prominent political pioneer and the first neurosurgeon in Sudan.


Tissue factor deficiency increases alveolar hemorrhage and death in influenza A virus-infected mice.
Essentials H1N1 Influenza A virus (IAV) infection is a hemostatic challenge for the lung. Tissue factor (TF) on lung epithelial cells maintains lung hemostasis after IAV infection. Reduced TF-dependent activation of coagulation leads to alveolar hemorrhage. Anticoagulation might increase the risk for hemorrhages into the lung during severe IAV infection. Background Influenza A virus (IAV) infection is a common respiratory tract infection that causes considerable morbidity and mortality worldwide. Objective To investigate the effect of genetic deficiency of tissue factor (TF) in a mouse model of IAV infection. Methods Wild-type mice, low-TF (LTF) mice and mice with the TF gene deleted in different cell types were infected with a mouse-adapted A/Puerto Rico/8/34 H1N1 strain of IAV. TF expression was measured in the lungs, and bronchoalveolar lavage fluid (BALF) was collected to measure extracellular vesicle TF, activation of coagulation, alveolar hemorrhage, and inflammation. Results IAV infection of wild-type mice increased lung TF expression, activation of coagulation and inflammation in BALF, but also led to alveolar hemorrhage. LTF mice and mice with selective deficiency of TF in lung epithelial cells had low basal levels of TF and failed to increase TF expression after infection; these two strains of mice had more alveolar hemorrhage and death than controls. In contrast, deletion of TF in either myeloid cells or endothelial cells and hematopoietic cells did not increase alveolar hemorrhage or death after IAV infection. These results indicate that TF expression in the lung, particularly in epithelial cells, is required to maintain alveolar hemostasis after IAV infection. Conclusion Our study indicates that TF-dependent activation of coagulation is required to limit alveolar hemorrhage and death after IAV infection.


Molecular insights into the early stage of glomerular injury in IgA nephropathy using single-cell RNA sequencing.
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and defined by the presence of IgA-containing immune complexes in the mesangium that induce an inflammation leading to glomerulonephritis. Since we poorly understand early mechanisms of glomerular injury in IgAN we performed single-cell RNA sequencing (scRNA-seq) analysis of glomerulus-associated cells using SMARTseq2-technology at the early stage of IgAN in grouped ddY-mice. Cell-specific molecular signatures unraveled a key role of endothelial cells in the early pathogenesis of IgAN, especially in the recruitment and infiltration of immune cells. Mesangial and podocyte cells demonstrated less molecular changes. Several intra-glomerular paracrine pathways were detected, such as mesangial cell-derived Slit3 potentially activating Robo-receptors in podocyte/endothelial cells. Surprisingly, proximal tubular cells were strongly affected at the early stage and potential glomerulo-tubular cell-cell crosstalk pathways were identified. Importantly, many of the cellular transcriptomic signatures identified in this well-established mouse model were also detected in published bulk transcriptomic data in human IgAN. Moreover, we validated the functionality of key cell-cell crosstalk pathways using cell culture models, such as the effect of the Slit-Robo signalling axis. Thus, our study provides important novel molecular insights into the pathogenesis of early IgAN-associated glomerulopathy.


Human herpesvirus 6 glycoprotein M is essential for virus growth and requires glycoprotein N for its maturation.
Human herpesvirus 6 (HHV-6) is a T-lymphotropic virus belonging to the betaherpesvirus family. Several HHV-6-encoded glycoproteins are required for cell entry and virion maturation. Glycoprotein M (gM) is conserved among all herpesviruses, and therefore thought to have important functions; however, the HHV-6 g has not been characterized. Here, we examined the expression of HHV-6 g, and examined its function in viral replication, using a mutant and revertant gM. HHV-6 g was expressed on virions as a glycoprotein modified with complex N-linked oligosaccharides. As in other herpesviruses, HHV-6 g formed a complex with glycoprotein N (gN), and was transported from the endoplasmic reticulum to the trans-Golgi network only when part of this complex. Finally, a gM mutant virus in which the gM start codon was destroyed was not reconstituted, although its revertant was, indicating that HHV-6 g is essential for virus production, unlike the gM of alphaherpesviruses.


Preliminary evidence for reduced cortisol responsivity to psychological stress in women using oral contraceptive medication.
In two studies, saliva cortisol responses to the psychological stress of public speaking and mental arithmetic were investigated in women using oral contraceptives (OC; n = 28) and in control women (n = 29). While no significant differences in baseline levels were observed, altered adrenocortical responses were found in OC users. These women showed significantly attenuated cortisol responses to the experimental stressor in both studies, with peak cortisol levels only slightly elevated above baseline levels. These differences could not be attributed to affective responses as indicated in ratings on visual analogue scales assessing subjective stress responses (Study 2). A comparison between control women and men (n = 19) again revealed the previously reported result of larger cortisol responses to psychological stress in males. We conclude that the use of OC may interfere with the adrenocortical response to psychological stress and should therefore be viewed as an important intervening variable. While it appears that differences at a supra-adrenal site is responsible for the observed cortisol hyporesponsiveness in OC users, the physiological mechanisms remain to be elucidated.


Treatment of meniscus defects with reference to our operative method. Subtotal meniscectomy, resection of Hoffa's corpus adiposum, inner drainage.
Inspite of the advanced diagnostic possibilities in cases of meniscus injuries the time until the surgical treatment is still too long. In our patients the average period between the first discomfort until the operation came to 2 years. Satisfactory results in treating degenerating or traumatic meniscus injuries can only be achieved by early surgery. The various problems of diagnostic methods are discussed. Arthrography with double contrast is an excellent method to achieve 95% correct results. The reactive hypertrophy and inflammation of the Hoffa's fat pad in the course of the so called Hoffa's disease are explained. With 214 cases of subtotal meniscectomy we can demonstrate satisfactory functional results. They are attributed to the additional resection of the Hoffa's fat pad or likewise the partial synovectomy-combined with internal drainage. This operative method has been proven over the last 6 years in routine operation.


Primary Pulmonary Diffuse Large B Cell Non-Hodgkin's Lymphoma: A Case Report and Literature Review.
BACKGROUND Primary pulmonary diffuse large B cell lymphoma (DLBCL) is extremely rare neoplasm representing only 0.5-1% of primary pulmonary malignancies. These patients usually have non-specific clinical presentation and radiological findings. Therefore, it is important to increase awareness of this rare disease, as the correct characterization of the tumors will have therapeutic and prognostic implications. CASE REPORT We present the case of a middle-aged Hispanic woman with chronic cough and an abnormal chest X-ray revealing a lung mass, who was found to have primary pulmonary DLBCL. She underwent 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy and attained complete remission. CONCLUSIONS With its non-specific presentation, the diagnosis of primary pulmonary DLBCL is very challenging and often leads to misdiagnosis or delayed diagnosis. The pathogenesis of primary pulmonary DLBCL is still poorly understood. The choice of treatment approach should be based on the biological characteristic of the tumor, stage, and performance status.


Tracheal repair with fibrin glue.
This animal study evaluated Fibrin Sealant, a multicomponent biologic adhesive, in tracheal operations. We conclude that the use of Fibrin Sealant in tracheal reconstruction results in a stable, leakless trachea, has good systemic and local compatibility, promotes tracheal wound healing, and reduces significantly the number of sutures required for end-to-end anastomosis.


Norepinephrine depresses the capsaicin-evoked miniature excitatory postsynaptic currents in substantia gelatinosa of the rat spinal cord.
Capsaicin selectively excites nociceptive primary afferent fibers and increases the frequency of glutaminergic miniature excitatory postsynaptic currents (mEPSCs) in the substantia gelatinosa of the spinal dorsal horn. The whole-cell voltage-clamp recording technique was used to examine the effect of norepinephrine (NE) on the capsaicin-induced increase in the frequency of mEPSCs. In the presence of tetrodotoxin, bath application of capsaicin (1 microM) remarkably enhanced the frequency of mEPSCs (295+/-52% of control). Following pretreatment with NE (10 microM), the capsaicin-induced frequency facilitation of mEPSCs was significantly depressed to 151+/-17% of the control. NE-induced depression in capsaicin action was blocked by yohimbine, a selective alpha(2)-adrenergic receptor antagonist, indicating that NE exerts depression by activating the alpha(2)-adrenergic receptor. As the postsynaptic action of NE has been precluded in the present study, the results suggest that NE inhibits nociceptive input at a presynaptic site, the primary afferent terminal, during the nociceptive transmission in the spinal dorsal horn.


The microbial community, its biochemical potential, and the antimicrobial resistance of Enterococcus spp. in Arctic lakes under natural and anthropogenic impact (West Spitsbergen).
The sustainable management of small human communities in the Arctic is challenging. In this study, both a water supply system (Lake 1) under the natural impact of a bird-nesting area, and a wastewater receiver (Lake 2) were analysed in the vicinity of the Polish Polar Station on West Spitsbergen. Microbial community composition, abundance and activity were assessed in samples of the treated wastewater, lake water and sediments using next-generation sequencing and direct microscope counts. Special attention was given to the faecal indicator, Enterococcus spp., whose occurrence and antimicrobial resistance were tested in water and wastewater samples. The results indicate that Lake 1, at a tundra stream discharge (L-TS) and a water supply point (L-WS) were dominated by three phyla: Proteobacteria (57-58%) Bacteroidetes (27-29%) and Actinobacteria (9-10%), showing similar microbial composition up to the genus level. This suggests that nutrient-rich runoff from the bird colony was retained by surrounding tundra vegetation and reached Lake 1 at L-TS to a limited extent. Lake 2, being the wastewater recipient (WW-R), mirrors to some extent the core phyla of treated wastewater (WW-E), but in different shares. This suggests the possible washout of wastewater-related bacteria with activated sludge flocs, which was also supported by the microscopic observations. Compared to Lake 1, in WW-R an increase in all tested parameters was noted: total prokaryotic cell number, average cell volume, prokaryotic biomass and live cell percentage. The presence of Enterococcus spp. antibiotic resistance patterns highlight the importance of human associated microbiome and resistome dissemination via wastewater discharge. Moreover, it can be expected that temperature-related biochemical processes (e.g. nutrient cycling) may be accelerated by the ongoing climate change. Thus, proper wastewater treatment requires locally adapted solutions in increasingly visited and inhabited polar regions. Additionally, microbial community discharged to the environment with the treated wastewater, requires critical attention.


Host factors associated with Giardia duodenalis infection in dogs across multiple diagnostic tests.
The aim of this study was to assess potential associations between Giardia duodenalis infection in dogs, as determined by three diagnostic tests, and dog's group of origin, fecal consistency, age, sex, neuter status, and co-infections with other gastrointestinal parasites. Fecal samples from 1291 dogs from four groups (household, shelter, hunting and clinical dogs) were tested with qPCR, rapid enzyme immunochromatographic assay (IDEXX SNAP® Giardia), and direct immunofluorescence (DFA, Merifluor) for presence of G. duodenalis. Moreover, fecal samples were tested with centrifugation sedimentation flotation (CSF) coproscopical analysis for presence of gastrointestinal parasites. Associations were expressed as odds ratios (ORs). Several significant associations were found, of which a few were consistent for all three tests and Giardia positivity in general (positive with at least one of these tests). Dogs older than one year were significantly less likely to test positive for Giardia than younger dogs. Group-housed dogs, especially hunting dogs, were significantly more likely to test positive for Giardia compared to household and clinical dogs. A consistently significant association with Trichuris appeared to be driven by the high prevalence in hunting dogs. Although there was no significant association between loose stool and Giardia infection in the overall population, household dogs were significantly more likely to test Giardia-positive when having loose stool. Overall, Giardia-positive dogs with loose stool shed significantly more cysts, both determined semi-quantitatively with CSF and quantitatively by qPCR, than positive dogs with no loose stool. When other gastrointestinal parasites were present, significantly fewer cysts were detected with CSF, but this was not confirmed with qPCR. Giardia is the most common gastrointestinal parasite in Dutch dogs, except for hunting dogs, in which Trichuris and strongyle-type eggs (hookworms) prevailed. Giardia infection was not significantly associated with loose stool, except for household dogs. Young dogs and group-housed dogs were significantly more often Giardia-positive. These associations were consistent across diagnostic tests. Young dogs, clinical dogs and dogs with loose stool shed Giardia cysts in the highest numbers. If another gastrointestinal parasite was present lower numbers of cysts were observed by microscope (CSF), but not with a molecular method (qPCR).


Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson's disease.
Degeneration of dopaminergic neurones during Parkinson's disease is most extensive in the subpopulation of melanized-neurones located in the substantia nigra pars compacta. Neuromelanin is a dark pigment produced in the dopaminergic neurones of the human substantia nigra and has the ability to bind a variety of metal ions, especially iron. Post-mortem analyses of the human brain have established that oxidative stress and iron content are enhanced in association with neuronal death. As redox-active iron (free Fe2+ form) and other transition metals have the ability to generate highly reactive hydroxyl radicals by a catalytic process, we investigated the redox activity of neuromelanin (NM)-aggregates in a group of parkinsonian patients, who presented a statistically significant reduction (- 70%) in the number of melanized-neurones and an increased non-heme (Fe3+) iron content as compared with a group of matched-control subjects. The level of redox activity detected in neuromelanin-aggregates was significantly increased (+ 69%) in parkinsonian patients and was highest in patients with the most severe neuronal loss. This change was not observed in tissue in the immediate vicinity of melanized-neurones. A possible consequence of an overloading of neuromelanin with redox-active elements is an increased contribution to oxidative stress and intraneuronal damage in patients with Parkinson's disease.


Current status of the Scandiatransplant acceptable mismatch program.
This article describes the Scandiatransplant Acceptable Mismatch Program (STAMP), which was set into action in 2009. The aim of STAMP is to define human leukocyte antigens (HLA) toward which the potential kidney recipient has not developed antibodies, as "acceptable mismatches" in the Scandiatransplant database. In many cases this may improve the probability for a highly immunized recipient to receive a suitable kidney graft from a deceased donor. Using data extracted from the Scandiatransplant database on the outcomes of the program after the first 3 years, 31/115 recipients included in the program have undergone transplantation. From 2008 to 2011 the mean waiting time for highly immunized patients has decreased from 42 to 37 months. Continuous evaluation and follow-up of the program is essential to improve the procedures and outcomes. Calculation of transplantability based on a given set of acceptable mismatches was added to the program in 2011, based on the historical deceased donor pool providing the possibility of a specific patient to receive a kidney through STAMP. It is still a challenge for the tissue typing laboratories to determine which detected HLA antibodies are clinical relevant. We concluded that STAMP has had the intended effects, however adjustments and improvements is an ongoing process. As an improvment of the program HLA-C was added to the STAMP search algorithm in September 2012.


Enhancement of sludge dewaterability by repeated inoculation of acidified sludge: Extracellular polymeric substances molecular structure and microbial community succession.
Improving the dewatering performance of sewage sludge is of great scientific and engineering significance in the context of accelerated urbanization and increasingly strict environmental regulations. Acidified sludge (AS) can improve sludge dewatering performance, but the dewatering effect of repeated inoculation is unclear. The effects of long-term repeated inoculation of AS on the sludge dewaterability were investigated. The molecular structure and microbial community succession of extracellular polymeric substances (EPS) are emphasized. The results revealed that increasing the inoculation ratio of AS reduced the pH, absolute value of sludge zeta potential, and sludge particle size, and the decreasing trend was more evident with prolonging treatment time. Under the conditions of 30% and 50% AS inoculation, the dewatering performance of the sludge was significantly improved (p < 0.05). Compared with the raw sludge, the specific resistance of filtration (SRF) and capillary suction time of 30% inoculation were reduced by 64.3% and 50.1% after 30 cycles, respectively. Excluding loosely bound (LB)-EPS, soluble (S)-EPS and tightly bound (TB)-EPS exhibited a visible decrease, the protein in TB-EPS was significantly related to sludge dewaterability (p < 0.05). The fluorescent components of aromatic protein and fulvic acid-like substances in TB-EPS were significantly associated with SRF, with a correlation coefficient 0.99 (p < 0.05). Both the increase in the percentages of random coil and decrease in α-helix in TB-EPS contributed to improving dewaterability. Increasing Firmicutes and decreasing Chloroflexi levels improved the sludge dewatering capacity. Repeated inoculation did not disrupt the dewatering effect of AS rather increased the feasibility of the engineering application of AS. Considering the dewatering performance and cost synthetically, 30% AS inoculated ratio is feasible for practical applications.


Synthesis of novel sterically demanding carbo- and heterocyclic beta-ketoesters.
We present an easy method for the synthesis of beta-ketoesters starting from various carbocyclic and heterocyclic carboxylic acids and esters. The beta-ketoester side-chain was introduced by a sequence involving alpha-deprotonation and quenching with CO(2), conversion to the corresponding acid chloride and subsequent chain elongation using deprotonated ethyl acetate.


Efferent projections from the parabrachial nucleus demonstrated with the anterograde tracer Phaseolus vulgaris leucoagglutinin.
Efferent projections from the parabrachial complex (PBN) were studied in the rat using the anterograde tracer, Phaseolus vulgaris leucoagglutinin (PHA-L). Projections to the hypothalamus (ventromedial, dorsomedial, paraventricular, and supraoptic nuclei) originate primarily in the lateral PBN (1PBN). The amygdalar central nucleus (ACE) receives strong projections from all parts of the PBN although the external 1PBN projects primarily to the lateral ACE. Whereas the projections to the lateral bed nucleus of the stria terminalis, median preoptic nucleus, diagonal band of Broca, and lateral preoptic area originate primarily from the 1PBN, those to the insular cortex arise from the medial PBN (mPBN). The mPBN projects to the ventral posteromedial thalamus and the 1PBN and mPBN project to the zona incerta. Descending projections from the mPBN and Kölliker-Fuse area target the commissural nucleus tractus solitarius (NTS); the mPBN projects to the more rostral NTS. Similarly, the caudal parvicellular reticular formation (RF) receives projections from the mPBN and 1PBN, whereas input to the rostral RF arises from the former. All compartments of the PBN project to the ventrolateral medulla, although the projections arising from the 1PBN are densest. Finally, the raphe nuclei and periaqueductal gray receive some projections from most PBN divisions. These pathways provide a potential means whereby autonomic information can be relayed through the PBN to other structures important in regulating autonomic functions.


Th1/Th2 cytokine profile in childhood-onset systemic lupus erythematosus.
To determine the serum levels of Th1 (IL-12, IFN-γ,TNF-α) and Th2 (IL-5, IL-6 and IL-10) cytokines in childhood-onset SLE, first-degree relatives and healthy controls. To elucidate their association with disease activity, laboratory and treatment features. We included 60 consecutive childhood-onset SLE patients [median age 18 years (range 10-37)], 64 first-degree relatives [median 40 (range 28-52)] and 57 healthy [median age 19 years (range 6-30 years)] controls. Controls were age and sex-matched to SLE patients. SLE patients were assessed for clinical and laboratory SLE manifestations, disease activity (SLEDAI), damage (SDI) and current drug exposures. Mood and anxiety disorders were determined through Becks Depression (BDI) and Anxiety Inventory (BAI). Th1 (IL-12, IFN-γ,TNF-α) and Th2 (IL-5, IL-6 and IL-10) cytokines levels were measured by ELISA and compared by non-parametric tests. Serum TNF-α (p=0.004), IL-6 (p=0.007) and IL-10 (p=0.03) levels were increased in childhood-onset SLE patients when compared to first-degree relatives and healthy controls. TNF-α levels were significantly increased in patients with active disease (p=0.014) and correlated directly with SLEDAI scores (r=0.39; p=0.002). IL-12 (p=0.042) and TNF-α (p=0.009) levels were significantly increased in patients with nephritis and TNF-α in patients with depression (p=0.001). No association between cytokine levels and SDI scores or medication was observed. Th1 cytokines may play a role in the pathogenesis of neuropsychiatric and renal manifestations in childhood-onset SLE. The correlation with SLEDAI suggests that TNF-α may be a useful biomarker for disease activity in childhood-onset SLE, however longitudinal studies are necessary to determine if increase of this cytokine may predict flares in childhood-onset SLE.


Adenoid cystic carcinoma: significance of DNA ploidy.
DNA ploidy pattern is sometimes used as a prognostic factor. Heterogeneity of a tumor could, however, give false information when a single analysis is performed. Twenty-eight patients with adenoid cystic carcinomas were retrospectively studied with regard to clinico-histologic parameters, and in 24 of these the DNA pattern was assessed using flow cytometry, with multiple analysis from different tumor parts, to determine prognostic factors. Of the carcinomas, 33% (8/24) were DNA aneuploid, and 17% (4/24) of the tumors showed intratumoral heterogeneity of DNA content; two of them with mixture of diploid and aneuploid stemlines. The DNA aneuploid tumors were clinically more advanced and demonstrated a higher frequency of solid architecture than did diploid tumors (p < 0.05). The S-phase values were significantly higher in aneuploid samples than in diploid ones (p < 0.05). The recurrence rate was significantly higher in patients with aneuploid tumors (75%) than with diploid ones (19%) (p < 0.05). The cumulative survival was worse for patients with aneuploid tumors than for those with diploid ones (p < 0.05). Our findings suggest a potentially important role for flow cytometry in evaluation of adenoid cystic carcinoma. It is of interest to observe that in some tumors both diploid and aneuploid stemlines can co-exist. If one sample is analyzed and demonstrates diploid cells, there is a 3% chance that the tumor is also heterogeneous with aneuploid stemlines. If one sample demonstrates aneuploid cells, there is a 7% chance for heterogeneity with diploid cells, as well. Two samples from different tumor parts can be considered representative.


Atmospheric phthalate esters in a multi-function area of Hangzhou: Temporal variation, gas/particle phase distribution, and population exposure risk.
Phthalate esters (PAEs) are prevalent in both indoor and outdoor environments. However, there are relatively few studies on phthalate contamination in the air of multi-function areas. Experiments were conducted to analyze the concentrations of 14 distinct PAEs in outdoor air in the college town of Hangzhou throughout both the warm and cold seasons. Correlation and principal component analyses were performed to investigate the influence and source factors of PAEs. This study also focused on the relationship between the gas/particle partition coefficient Kp and temperature, as well as the application of the gas/particle partition model. The risk of exposure to PAEs via inhalation was predicted for four groups of the general population: toddlers, adolescents, adults, and older adults. The results indicated that the concentration levels of Σ14PAEs in outdoor air were 1573 ng/m3 in the gaseous phase and 126 ng/m3 in the particulate phase. Additionally, this study indicated three primary sources of PAEs: indoor diffuse sources, industrial emission sources, and building construction sources. The gas/particle partitioning of PAEs also revealed that low-molecular-weight PAEs are more prevalent in gas, whereas high-molecular-weight PAEs are more predominant in the particle phase. A health risk analysis revealed high estimations of daily intakes (EDI) for toddlers and adolescents and high lifetime average daily doses (LADD) for older adults. This study establishes a solid foundation for formulating scientific and effective air pollution control measures by analyzing the characteristics and assessing the health risks of PAEs.


RIP1 kinase activity promotes steatohepatitis through mediating cell death and inflammation in macrophages.
Hepatocyte cell death and liver inflammation have been well recognized as central characteristics of nonalcoholic steatohepatitis (NASH), however, the underlying molecular basis remains elusive. The kinase receptor-interacting protein 1 (RIP1) is a multitasking molecule with distinct functions in regulating apoptosis, necroptosis, and inflammation. Dissecting the role of RIP1 distinct functions in different pathophysiology has absorbed huge research enthusiasm. Wild-type and RIP1 kinase-dead (Rip1K45A/K45A) mice were fed with high-fat diet (HFD) to investigate the role of RIP1 kinase activity in the pathogenesis of NASH. Rip1K45A/K45A mice exhibited significantly alleviated NASH phenotype of hepatic steatosis, liver damage, fibrosis as well as reduced hepatic cell death and inflammation compared to WT mice. Our results also indicated that both in vivo lipotoxicity and in vitro saturated fatty acids (palmitic acid) treatment were able to induce the kinase activation of RIP1 in liver macrophages. RIP1 kinase was required for mediating inflammasome activation, apoptotic and necrotic cell death induced by palmitic acid in both bone marrow-derived macrophage and mouse primary Kupffer cells. Results from chimeric mice established through lethal irradiation and bone marrow transplantation further confirmed that the RIP1 kinase in hematopoietic-derived macrophages contributed mostly to the disease progression in NASH. Consistent with murine models, we also found that RIP1 kinase was markedly activated in human NASH, and the kinase activation mainly occurred in liver macrophages as indicated by immunofluorescence double staining. In summary, our study indicated that RIP1 kinase was phosphorylated and activated mainly in liver macrophages in both experimental and clinical NASH. We provided direct genetic evidence that the kinase activity of RIP1 especially in hematopoietic-derived macrophages contributes to the pathogenesis of NASH, through mediating inflammasome activation and cell death induction. Macrophage RIP1 kinase represents a specific and potential therapeutic target for NASH.


Contribution of HCAHPS Specific Care Experiences to Global Ratings Varies Across 7 Countries: What Can be Learned for Reporting These Global Ratings?
Given the increased international interest in improvement strategies for patient experiences with care, it is important to understand whether the same specific care experiences affect global ratings across countries. Moreover, reporting of these global ratings currently substantially varies in both research and public reporting. The objectives of this study were to examine the differential magnitude of associations between Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) specific care experiences and global ratings, and to explore implications for reporting these global ratings. HCAHPS data were collected from 11,289 patients across 7 European countries. We studied the association between 11 experience items and 2 global ratings (0-10 hospital rating, hospital recommendation) using multilevel ordered logistic regression analysis. Using interaction terms, we examined consistency of these associations across countries. Assuming homogeneous use and interpretations of response categories of these specific experiences across patients within and between countries, we investigated what the associations between specific experiences and global ratings imply for reporting global ratings across countries. All specific experiences were associated with both global ratings. "Being talked to about care after leaving the hospital" showed the strongest association. There were relatively little differential effects across countries. A reporting strategy with different cutpoints across countries might provide a more equitable comparison of global ratings. Our findings highlight a differential contribution of HCAHPS specific experiences to overall ratings across countries. Research and public reporting may consider examining in more detail within and across populations global rating cutpoints that represent the same true level of positive patient experiences.


Feature stability and setup minimization for EEG-EMG-enabled monitoring systems.
Delivering health care at home emerged as a key advancement to reduce healthcare costs and infection risks, as during the SARS-Cov2 pandemic. In particular, in motor training applications, wearable and portable devices can be employed for movement recognition and monitoring of the associated brain signals. This is one of the contexts where it is essential to minimize the monitoring setup and the amount of data to collect, process, and share. In this paper, we address this challenge for a monitoring system that includes high-dimensional EEG and EMG data for the classification of a specific type of hand movement. We fuse EEG and EMG into the magnitude squared coherence (MSC) signal, from which we extracted features using different algorithms (one from the authors) to solve binary classification problems. Finally, we propose a mapping-and-aggregation strategy to increase the interpretability of the machine learning results. The proposed approach provides very low mis-classification errors ( < 0.1 ), with very few and stable MSC features ( < 10 % of the initial set of available features). Furthermore, we identified a common pattern across algorithms and classification problems, i.e., the activation of the centro-parietal brain areas and arm's muscles in 8-80 Hz frequency band, in line with previous literature. Thus, this study represents a step forward to the minimization of a reliable EEG-EMG setup to enable gesture recognition.


Monoclonal antibodies specific for the IL-18 receptor.
Interleukin-18, a pleiotropic cytokine is a member of the IL-1 family and has multiple immunoregulatory functions. IL-18 action leads to IFNgamma production by NK or T cells, induces Th1 differentiation and suppresses IgE synthesis by B cells when acting on responding cells in association with IL-12. At present two subunits of the IL-18R have been characterized: IL-18 Ralpha and IL-18 Rbeta. Both receptors belong to the IL-1R family. IL-18 Ralpha has been described as the ligand-binding chain and IL-18 Rbeta as the signal-transduction chain. Three monoclonal antibodies (mAbs) submitted to the HLDA8 workshop, designated H44 (80438), B-B46 (80228), and B-E43 (80232) were evaluated. The mAb specificity was determined by ELISA using coated recombinant IL-18 Ralpha or IL-18 Rbeta. Cell staining was analyzed by flow cytometry. A positive staining with the mAb B-E43 or H44 demonstrated that IL-18 Ralpha is expressed on several myeloid cell lines. No positive cell staining was observed with the anti IL-18 Rbeta mAb B-B46. The mAb biological activity was studied using the cell line KG1. A downmodulation of IFNgamma production was observed with the mAbs B-B46 (80228) and B-E43 (80232).


Direct time-domain observation of attosecond final-state lifetimes in photoemission from solids.
Attosecond spectroscopic techniques have made it possible to measure differences in transport times for photoelectrons from localized core levels and delocalized valence bands in solids. We report the application of attosecond pulse trains to directly and unambiguously measure the difference in lifetimes between photoelectrons born into free electron-like states and those excited into unoccupied excited states in the band structure of nickel (111). An enormous increase in lifetime of 212 ± 30 attoseconds occurs when the final state coincides with a short-lived excited state. Moreover, a strong dependence of this lifetime on emission angle is directly related to the final-state band dispersion as a function of electron transverse momentum. This finding underscores the importance of the material band structure in determining photoelectron lifetimes and corresponding electron escape depths.


The amino acid sequence of fragment A, an enzymically active fragment of diphtheria toxin. III. The chymotryptic peptides, the peptides derived by cleavage at tryptophan residues, and the complete sequence of the protein.
Fragment A (21,145 daltons in its longest known form) may be derived from diphtheria toxin (60,000 daltons) by mild tryptic digestion and reduction. Purified Fragment A consists of a mixture of 3 molecules of 190, 192, and 193 residues; the first 190 residues are in common and correspond to the NH2-terminal region the toxin. All three species of Fragment A are active in catalyzing ADP ribosylation of elongation factor 2, an essential component of protein synthesis. This reaction inactivates the factor and is responsible for the toxin's action in inhibiting protein synthesis in animal cells. It is believed that Fragment A or similar enzymically active fragments released into the cytosol of toxin-treated cells mediate this inhibition. The complete amino acid sequence of Fragment A has been determined from 32 chymotryptic peptides, three peptides derived by chemical cleavage of Fragment A at its 2 tryptophan residues, five cyanogen bromide peptides, and six tryptic peptides from the maleylated protein.


Evidence for a coiled-coil structure in the spike proteins of coronaviruses.
The amino acid sequences of the spike proteins from three distantly related coronaviruses have been deduced from cDNA sequences. In the C-terminal half, an homology of about 30% was found, while there was no detectable sequence conservation in the N-terminal regions. Hydrophobic "heptad" repeat patterns indicated the presence of two alpha-helices with predicted lengths of 100 and 50 A, respectively. It is suggested that, in the spike oligomer, these alpha-helices form a complex coiled-coil, resembling the supersecondary structures in two other elongated membrane proteins, the haemagglutinin of influenza virus and the variable surface glycoprotein of trypanosomes.


Effect of a hyaluronic acid-based mesotherapeutic injectable on the gene expression of CLOCK and Klotho proteins, and environmentally induced oxidative stress in human skin cells.
Normal circadian rhythms are essential to the repair mechanisms of oxidative stress implicated in skin aging. Given reports that hyaluronic acid (HA) homeostasis exhibits a different profile in chronological skin aging, as compared to environmental or extrinsic aging, an improved understanding of the way HA interacts with its surroundings, and the impact of HA injectables in replacing lost HA and encouraging rejuvenation, is of key benefit to skin aging treatments. The objectives of these current studies were twofold. Firstly, to demonstrate the in vitro effects of two lightweight hyaluronic-based injectables on the expression of CLOCK protein in human skin fibroblasts, and their effects on Klotho protein expression as a marker for circadian rhythms in a combined human keratinocyte and Merkel cell model. Secondly, to ascertain whether these findings could be correlated with in vitro effects on various environmental oxidative stress aging markers (blue light, UVA/UVB, Urban Dust, and IR exposures). Oxidative stress studies were aimed to highlight possible protective effects through different challenge conditions in two models, ex vivo human skin explants and in vitro monolayer cultures of normal human dermal fibroblasts (NHDF). The protective effects of the test products were evaluated against an increase of cyclobutene pyrimidine dimers (CPDs) abundance within epidermal section of ex vivo skin explants after UVA/UVB radiation; effects of blue light on gene expression from NHDFs fibroblasts; effects of pollutants (Urban dust, UbD) on gene expression in NHDFs fibroblasts; and an increase of reactive oxygen species (ROS) production by NHDFs fibroblasts after infrared-A radiation. Gene expression was assayed and analyzed utilizing microfluidic TaqMan qPCR arrays. CLOCK expression was measured in young and senescing NHDFs by immunostaining, and Klotho and melatonin expression by immunostaining in Merkel cell-enriched normal adult human epidermal cell cultures. In an aging culture of mixed keratinocyte and Merkel skin cells, activation of Klotho expression was induced by the application of both HA test products. Moreover, the HA products increase Klotho protein expression in both Merkel cells and keratinocytes. The observed positive effect of the tested products on melatonin receptors 1A and 1B expression in aging Merkel cell culture and keratinocytes is also interesting. HA-Y (developed for patients 25+ years old) stimulated melatonin receptors type 1B expression in aging cell cultures more strongly than HA-S (developed for patients 35-65 years old). In age (stressed) cells, a lower expression of Klotho protein and melatonin receptors 1A and 1B is apparent. The addition of HA-Y and HA-S stimulates their expression thus providing a "protective" effect. The blue light irradiation at 40 J/cm2 performed in NHDF fibroblast cultures led to a modification of the expression of several genes, all involved in mechanisms known to be modulated in case of solar radiation stress. Although these are preliminary findings, they are the first we know of that demonstrate HA facial injectables having a benefit and possibilities beyond the "physical filling" of the skin. As regards the beneficial effects against blue light-induced oxidative stress, and a return to cellular homeostasis, there is a need to conduct further and more precise investigations into HA-S. Furthermore, the benefit of these HA injectables (Novacutan®) in the modulation of oxidative stressed circadian rhythms widens their potential benefit.


Extracellular protease activation of chemotherapeutics from hydrogel matrices: a new paradigm for local chemotherapy.
A novel paradigm for local cancer chemotherapy, based upon local activation of chemotherapeutic molecules by soluble proteases, is presented. In the presence of matrix metalloproteases, a family of cancer-associated proteases, cisplatin is released from a hydrogel matrix in an active form. In the absence of matrix metalloproteases, cisplatin is released at a much lower rate. The mesh size of the polymer controls metalloprotease-based cisplatin release from the hydrogel matrix with approximate doubling of cisplatin release in the presence of matrix metalloprotease. Overall, this novel paradigm shows much potential for local chemotherapy where local chemotherapeutic release is in response to the invasive properties of the tumor.


Causes of death in Prader-Willi syndrome: lessons from 11 years' experience of a national reference center.
In the last 20 years, substantial improvements have been made in the diagnosis, treatment and management of patients with Prader-Willi syndrome (PWS). Few data on causes of death are available since those improvements were made. Our study assessed the causes of death among French patients with PWS over the first 11 years of experience of the nationwide French Reference Center for PWS (FRC-PWS). Our study relied on two sources of mortality information at national level between 2004 and 2014: The French Epidemiological Centre for the Medical Causes of Death (CépiDc) Registry and the FRC-PWS database. Causes of death were classified into seven categories: respiratory, cardiovascular, gastrointestinal, severe infection, sudden death, other causes, and unknown. Descriptive statistics were calculated separately for children (< 18 years-old) and adults (≥18 years-old). One hundred and four deaths were identified in France from 2004 to 2014. The median age at death was 30 years, ranging from less than 1 month to 58 years. Seventeen deaths occurred in patients under 18 years, with 70% of them in children under 2 years. Respiratory causes accounted for more than 50% of the deaths in patients with PWS in both children and adults. Both cause and age of death did not significantly differ according to gender or genetic subtype. Patients with PWS die prematurely due to a respiratory cause in most cases at all ages. In those adult patients with data on obesity, 98% were reported to be obese.


[Behavior of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in relation to agonized suffering (I)].
The authors have studied the levels of 5-HT and 5-HIA,--in serum, CSP fluid and pericardial fluid of cadavers at the Forensic Anatomic Institute of Granada and its relations with the length of agonized suffering. The results showed us that the study of 5-HT and its main metabolite, the 5-HIAA, may be useful for the exact evaluation of agonized suffering, and the pericardial fluid is most suited for the analysis of 5-HT and 5-HIAA. We found that there was a significant correlation between the 5-HT and 5-HIAA and the agonized suffering. When the agonized sufferings of a moderate length (10 min-6h) were compared with the slow and long processes of death, the correlation was highly significant (P less than 0.001).


Addressing parental concerns about pain during childhood vaccination: is there enough time to include pain management in the ambulatory setting?
Pain from vaccine injections remains undertreated, despite the availability of numerous pain-relieving strategies. Healthcare providers report lack of time within current office workflows as a major barrier to routine pain management. The objective was to document the total time involved in outpatient vaccine appointments to test the hypothesis that offering pain-relieving strategies can be practically implemented when considering the element of time to vaccine injection. Prospective naturalistic study in 8 urban outpatient primary care clinics (4 pediatric and 4 family practice) in Toronto. For 48 to 59 consecutive childhood vaccination appointments at each site, child waiting time from clinic arrival until first vaccine injection was tracked. Altogether, 405 vaccine appointments were included. The median age of the child undergoing vaccination was 12 months. The mean (SD) time from clinic arrival until first vaccine injection was 41.6 minutes (20.9), with a range of 7 to 132 minutes. Linear regression identified a significant (P<0.05) difference according to clinic [ranging from 19.4 min (6.5) to 57.5 min (20.2)] and number of family members in the appointment [ranging from 40.6 min (21.0) for an appointment in the index child only to 50 min (14.3) for an appointment in the index child and 2 other family members]. Contrary to healthcare provider perceptions, the timing of outpatient childhood vaccine appointments allows for the inclusion of pain management interventions. Efforts should now focus on educating healthcare providers and parents about the value of pain management and how to implement evidence-based strategies.


The Hippo Signaling Core Components YAP and TAZ as New Prognostic Factors in Lung Cancer.
The Hippo pathway is an essential signaling cascade that regulates cell and organ growth. However, there is no consensus about (i) the expression levels of the Hippo signaling core components yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in lung cancer, especially in small cell lung cancer (SCLC), or (ii) their association with the prognosis of patients with SCLC. We screened relevant articles and identified eligible studies in the PubMed, EMBASE, COCHRANE, and WanFang databases. A combined analysis was performed to investigate (i) the expression levels of the major effectors, YAP and TAZ, in lung cancer and its subsets and (ii) their prognostic role in lung cancer, especially in SCLC. In total, 6 studies related to TAZ and 13 studies concerning YAP were enrolled in this meta-analysis. We found that high TAZ expression was significantly associated with poor overall survival (OS) of patients with non-small cell lung cancer (NSCLC) in the overall population [P h < 0.001, crude hazard ratio (HR) = 1.629, 95% CI = 1.199-2.214 for TAZ expression; P h = 0.029, adjusted HR = 2.127, 95% CI = 1.307-3.460 for TAZ], the Caucasian population (P h = 0.043, crude HR = 1.233, 95% CI = 1.030-1.477 for TAZ expression), and the Asian population (P h = 0.551, adjusted HR = 2.676, 95% CI = 1.798-3.982 for TAZ). Moreover, there was a significant negative association between YAP expression and an unsatisfactory survival of patients with lung cancer (P h = 0.327, crude HR = 1.652, 95% CI = 1.211-2.253 for YAP expression) and patients with NSCLC [disease-free survival (DFS): Ph = 0.693, crude HR = 2.562, 95% CI = 1.876-3.499 for YAP expression; Ph = 0.920, crude HR = 2.617, 95% CI = 1.690-4.052 for YAP-mRNA; OS: Ph = 0.878, crude HR = 1.777, 95% CI = 1.233-2.562 for YAP expression], especially in the Asian population (DFS: P h = 0.414, crude HR = 2.515, 95% CI = 1.755-3.063; OS: P h = 0.712, crude HR = 1.772, 95% CI = 1.214-2.587). However, no association was observed in the multivariate combined analysis. High YAP expression was significantly associated with short OS of patients with SCLC in our combined multivariate analysis in the Asian population (P h = 0.289, crude HR = 4.482, 95% CI = 2.182-9.209), but not with crude data (P h = 0.033, crude HR = 1.654, 95% CI = 0.434-6.300). The Hippo pathway is involved in carcinogenesis and progression of NSCLC and SCLC, and high expression levels of YAP and TAZ are independent and novel prognostic factors for lung cancer.


Empowering employees with chronic diseases: process evaluation of an intervention aimed at job retention.
Employees with a chronic disease may experience work-related problems that contribute to the risk of job loss. We developed a group-based intervention programme aimed at clarifying problems, making these a subject of discussion at work, and realizing solutions. This process evaluation investigates the intervention's feasibility and the satisfaction of 64 participants in eight groups. Data were collected through process evaluation forms and self-report questionnaires. The recruitment of participants was time-consuming. Highly educated women working in the service sector were overrepresented. The programme was administered as planned, although components were sometimes only discussed briefly, due to lack of time. Satisfaction with the overall programme among participants was high; it was perceived as effective and there were only three dropouts. In particular, the focus on feelings and thoughts about having a chronic disease was highly valued, as were the exchange of experiences and role-playing directed at more assertive communication. A vocational rehabilitation programme aimed at job retention is feasible and is perceived to be effective. Such a programme should address psychosocial aspects of working with a chronic disease beside practical problems. The recruitment of participants is time-consuming. Cooperation with outpatient clinics is necessary in order to reach all groups of employees with a chronic disease that might benefit from job retention programmes. ISRCTN77240155.


Modifying the ASPECT Survey to Support the Validity of Student Perception Data from Different Active Learning Environments.
Measuring students' perceptions of active learning activities may provide valuable insight into their engagement and subsequent performance outcomes. A recently published measure, the Assessing Student Engagement in Class Tool (ASPECT), was developed to assess student perceptions of various active learning environments. As such, we sought to use this measure in our courses to assess the students' perceptions of different active learning environments. Initial results analyzed with confirmatory factor analysis (CFA) indicated that the ASPECT did not function as expected in our active learning environments. Therefore, before administration within an introductory biology course that incorporated two types of active learning strategies, additional items were created and the wording of some original items were modified to better align with the structure of each strategy, thereby producing two modified ASPECT (mASPECT) versions. Evidence of response process validity of the data collected was analyzed using cognitive interviews with students, while internal structure validity evidence was assessed through exploratory factor analysis (EFA). When data were collected after a "deliberative democracy" (DD) activity, 17 items were found to contribute to 3 factors related to 'personal effort', 'value of the environment', and 'instructor contribution'. However, data collected after a "clicker" day resulted in 21 items that contributed to 4 factors, 3 of which were similar to the DD activity, and a fourth was related to 'social influence'. Overall, these results suggested that the same measure may not function identically when used within different types of active learning environments, even with the same population, and highlights the need to collect data validity evidence when adopting and/or adapting measures.


Impact of pH on efficacy of peroxy acetic acid against Salmonella, Campylobacter, and Escherichia coli on chicken wings.
Peroxy acetic acid (PAA) is widely used as an antimicrobial in poultry processing, specifically in the chiller. While the natural pH of PAA at the concentrations used is between 4.5 and 6.0, poultry processors adjust the pH to ≥8.0 to maintain product yield. The objective of this study was to evaluate 1) efficacy of PAA at different concentrations, pH, and contact times against Salmonella, Campylobacter, and Escherichia coli and 2) use of E. coli as a surrogate for Salmonella and Campylobacter to conduct validations studies for poultry processing. Fresh chicken wings (0.45 Kg) were inoculated with a cocktail of nalidixic acid-resistant Salmonella Typhimurium, rifampicin-resistant E. coli (5-strain cocktail), and gentamicin-resistant Campylobacter coli. Inoculated chicken wings were immersed in PAA solutions of 50, 250, and 500 ppm adjusted to pH 8.2 and 10.0 as well as nonadjusted PAA solutions for 10 s and 60 min. Treated chicken wings were rinsed in chilled buffered peptone water, serially diluted, and plated on Petrifilm APC for enumerating Salmonella and E. coli populations and spread plated on Campy Cefex Agar containing gentamicin (200 ppm) to enumerate Campylobacter. Immersion of chicken wings in 500 ppm of PAA (non-pH-adjusted) for 60 min resulted in greater microbial reductions (P ≤ 0.05) of Salmonella, Campylobacter, and E. coli populations of 2.56, 1.90, and 2.53 log CFU/mL, respectively. Higher concentrations and longer exposure times resulted in greater reductions (P ≤ 0.05) of Salmonella, E. coli, and Campylobacter populations, and increasing pH of PAA solution did not affect (P > 0.05) its efficacy. A high correlation (r = 0.93) was observed between E. coli (surrogate) and Salmonella populations suggesting that E. coli can be used as a surrogate for Salmonella for conducting validation studies for antimicrobial efficacy testing in poultry processing.


The Outcomes of Remote Administration of Combined Aphasia and Apraxia of Speech Treatment: A Single-Subject Experimental Design Study.
This study was designed to examine the outcomes of Combined Aphasia and Apraxia of Speech Treatment (CAAST) administered remotely in terms of acquisition and generalization effects and to compare these effects to previous in-person CAAST studies and Response Elaboration Training (RET)/Modified-Response Elaboration Training (M-RET) benchmarks. Multiple probe designs across participants and behaviors were employed with three speakers with chronic aphasia and apraxia of speech. Correct information units (CIUs) were the primary outcome measure to measure changes in language production. Percent consonants correct (PCC) was used as the secondary outcome measure to evaluate changes in speech sound accuracy. Production of CIUs was compared with existing benchmarks from Bunker et al.'s (2019) meta-analysis of previous RET/M-RET studies. In addition, both CIUs and PCC were compared with the most recent CAAST in-person studies. All participants demonstrated substantial increases in CIUs for treated and untreated picture sets, comparable to outcomes of in-person CAAST administration. These language changes were maintained at posttreatment intervals for all participants. PCC also improved for all participants, with gains in articulatory accuracy being maintained posttreatment. Improvements in CIU production and PCC for all three participants were in keeping with results from Wambaugh et al. (2017). These findings provide additional support for the efficacy of CAAST and indicate that remote administration may be a viable alternative to in-person application. https://doi.org/10.23641/asha.23418635.


Using computer algebra to determine rate constants in biochemistry.
In earlier work we have described how computer algebra may be used to derive composite rate laws for complete systems of equations, using the mathematical technique of Gröbner Bases (Bennett, Davenport and Sauro, 1988). Such composite rate laws may then be fitted to experimental data to yield estimates of kinetic parameters. Recently we have been investigating the practical application of this methodology to the estimation of kinetic parameters for the closed two enzyme system of aspartate aminotransferase (AAT) and malate dehydrogenase (MDH) (Fisher 1990a; Fisher 1990b; Bennett and Fisher, 1990): aspartate + alpha-ketoglutamate <--> glutamate + oxaloacetate; oxaloacetate + NADH <--> malate + NAD. In this paper we present a fuller (although not yet complete) analysis of the system. We show how symbolic estimates of the error behaviour of the parameters can be made, and used to identify those which are of kinetic significance. Finally we consider how metabolic control analysis can be applied directly to such a system.


Changes in haemostasis and thrombosis associated with thyroid disease: Presentation of 2 cases.
There is a relationship between thyroid diseases and primary and secondary changes in haemostasis. The most frequent association between them are hypocoagulability states with clinical hypothyroidism and vascular thrombophilia (hypercoagulability and/or hypofibrinolysis) with hyperparathyroidism. However, there are recent studies that have detected changes in haemostasis -primary and secondary- associated with thyroid diseases with normal hormone levels, suggesting other pathogenic mechanisms not yet known. The cases are presented of 2 patients with thyroid disease that required surgery: one multinodular goitre and one papillary carcinoma of the thyroid, both with normal hormone levels. They were shown to have haemostasis disorders during the preoperative work up. These showed a Factor VII deficiency and a Factor XI deficiency along with a thrombotic disease of unknown origin, respectively.


An analysis of the differences between early and late preeclampsia with severe hypertension.
Preeclampsia is clinically divided into early onset and late onset preeclampsia based on the gestational age at delivery. Although the diagnostic criteria are the same in each subgroup of preeclampsia, it has been suggested that the maternal and perinatal mortalities of early onset and late onset preeclampsia are different. However, studies that compare clinical parameters or laboratory biomarkers between early onset and late onset preeclampsia are limited. Data on 177 women with early or late preeclampsia with severe hypertension were collected from a University Teaching Hospital from January 2010 to January 2011 and analysed. Data included all the clinical parameters and laboratory biomarkers of liver and renal function. 63 women and 114 women were diagnosed with early and late preeclampsia with severe hypertension, respectively. There was no difference in the maternal age and the incidence of clinical symptoms including edema, vision disturbance, severe headache and stillbirth between two groups. There was a decrease in alkaline phosphatase levels in early preeclampsia with severe hypertension but other markers of liver function were not altered. However, renal function including blood urea nitrogen, creatinine and uric acid were significantly higher in early preeclampsia with severe hypertension. Umbilical artery systolic velocity/diastolic velocity ratio was significantly higher in early preeclampsia with severe hypertension. Our data demonstrates that the laboratory biomarkers of renal function differ between early and late preeclampsia with severe hypertension. The severity of renal dysfunction correlated with the time of delivery in preeclampsia with severe hypertension.


Bioinoculants as mitigators of multiple stresses: A ray of hope for agriculture in the darkness of climate change.
Plant encounters various biotic and abiotic stresses, that affect agricultural productivity and reduce farmer's income especially under changing global climate. These environmental stresses can advance plant senescence by inducing osmotic stress, nutrient stress, hormonal imbalance, production of oxygen radicals, and ion toxicity, etc. Additionally, these stresses are not limited to plant health but also deteriorate soil health by affecting the microbial diversity of soil. To tackle this global delinquent of agriculture, several methods are suggested to ameliorate the negative effect of different types of stresses, the application of beneficial microorganisms or bioinoculants is one of them. Beneficial microorganisms that are used as bioinoculants not only facilitate plant growth by fulfilling the nutrient requirements but also assist the plant to withstand these stresses. These microorganisms produce certain chemicals such as 1-aminocyclopropane-1-carboxylate (ACC) deaminase, phytohormones, antioxidants, extracellular polysaccharide (EPS), siderophores, antibiotics, and volatile organic compounds (VOCs), etc. which help the plants to mitigate various stresses. Besides, these microbes also activate plant defence responses. Thus, these bioinoculants can effectively replace chemical inputs to supplement nutrient requirements and mitigation of multiple stresses in plants.


Synthesis of chondroitin sulfate D and heparin proteoglycans in murine lymph node-derived mast cells. The dependence on fibroblasts.
Proteoglycans synthesized in cultured mast cells derived from horse serum-immunized lymph node cells were analyzed. Treatment of the 35S-proteoglycans extracted from these cells with either chondroitinase ABC or AC resulted in 95% +/- 7% and 84% +/- 7%, respectively (mean +/- S.E., n = 3), of the radioactivity associated with disaccharides eluting in the included volume of PD-10. The 35S-proteoglycans were not hydrolyzed by nitrous acid elimination treatment. The chondroitinase ABC-generated disaccharides were analyzed by aminocyano high performance liquid chromatography. 35S-Disaccharides eluted in a major peak at a retention time of 8.1 min, corresponding to the disaccharide of chondroitin 4-sulfate proteoglycan (delta Di-4S), and a second peak at 12 min, corresponding to the disaccharide of chondroitin sulfate D proteoglycan (delta Di-diSD). Further treatment with chondro-4-sulfatase did not affect the retention time of the disaccharide corresponding to delta Di-diSD whereas this peak disappeared after the digested proteoglycan was treated either by chondro-6-sulfatase or by both sulfatases. Therefore, this disaccharide was identified as chondroitin sulfate D. Quantification of the radiolabeled disaccharides showed that delta Di-diSD contributed 20% +/- 2% (n = 3) of the total sulfated disaccharides of the chondroitin sulfate of these cultured cells. The role of fibroblasts in inducing the shift of chondroitin sulfate D into heparin proteoglycan in these mast cells was also investigated by using three types of monolayers: mouse embryonic skin fibroblasts (MESF), rat embryonic skin fibroblasts (RESF), and 3T3 fibroblasts. 35S-Proteoglycans that were extracted from the lymph node-derived mast cells cultured for 30 days on MESF and on 3T3 fibroblast monolayers were 93% +/- 4% and 30% +/- 7% (n = 3) susceptible to nitrous acid elimination, respectively. No degradation by nitrous acid was observed in 35S-proteoglycans extracted from cells cultured on RESF monolayer. Since the MESF was found to be the most potent monolayer in the induction of heparin synthesis, the kinetics of changes in the synthesis of proteoglycan types were determined in lymph node-derived mast cells cultured on MESF for up to 30 days. It was found that the synthesis of chondroitin sulfate gradually declined whereas that of heparin starting between 4 and 7 days after plating gradually increased. From the 17th day on, only the synthesis of heparin was detected.


The International Consultation on Incontinence Questionnaires (ICIQ): An update on status and direction.
In its 22nd year, the International Consultation on Incontinence Questionnaire (ICIQ) project continues to promote its primary objective; the development and dissemination of patient completed questionnaires for the standardized, high-quality assessment of urinary, bowel, and vaginal symptoms. The paper gives an update on the ICIQ in the context of current scientific developments of PROM design and regulatory requirements, and plans are outlined for its future direction. An online library of all questionnaires, including over 300 translations has been launched to facilitate access through a semi-automated registration system. The ICIQ project continues to update its protocol to meet current scientific standards and incorporate methodological advances within PROM development. Nineteen psychometrically validated patient-reported outcome measures (PROMs) are published for use in clinical practice and research, including amongst others, a bladder diary, male and female lower urinary tract symptoms, long term catheter, pad use, and bowel symptom questionnaires. The original ICIQ-UI Short Form for the assessment of urinary incontinence continues to be the most internationally used questionnaire and has been translated into over 60 languages. New questionnaires which are under development include the ICIQ-Underactive Bladder and ICIQ-Satisfaction. We anticipate the new website and online library will further facilitate the ease of dissemination and availability of the questionnaires for clinical practice and research. The ICIQ continues to successfully achieve its primary objective. Going forward, a greater focus on promoting routine clinical use and the potential for electronic integration into databases and medical records is envisaged.


A combinatorial library of indinavir analogues and its in vitro and in vivo studies.
A combinatorial library of 300HIV protease inhibitors has been synthesized. The library was screened against recombinant wild-type and mutant HIV-1 protease enzymes. The pharmacokinetics of the library was evaluated by dosing in dogs. Compounds that are notably more potent than indinavir and have favorable pharmacokinetic properties were identified.


Cloning and characterization of two human Ro52-specific monoclonal autoantibodies directed towards a domain associated with congenital heart block.
Autoantibodies against amino acid 200-239 (p200) in the predicted leucine zipper region of the Ro52 protein are associated with congenital heart block, a potentially fatal condition that may affect fetuses of women with Ro52 autoantibodies. To allow detailed studies of the antibodies associated with congenital heart block, B-cell derived combinatorial antibody libraries from patients were screened for Ro52 and p200 specific antibody clones. Two human monoclonal anti-p200 antibody fragments, S3A8 and M4H1, were isolated and analysed with regard to VHand VL gene utilization, somatic mutations and binding properties. Both identified clones recognized recombinant and native intact Ro52, and reacted only with p200 in a set of related Ro52 peptides. The specificity and affinity was confirmed by biosensor measurements. Structural analysis of overlapping peptides revealed increased helicity in the p200 peptide compared to non-recognized peptides, indicating epitope conformation as essential for antibody binding. Both monoclonals produced punctate nuclear and diffuse cytoplasmic staining in human and mouse cell lines. The identified antibodies, which react specifically with the leucine zipper structure of Ro52, will be valuable in further exploration of the mechanisms operating during development of Ro52 antibody-associated congenital heart block.


Retrospective analysis of biological factors in a recurrent IV-S neuroblastoma with intermediate-grade malignancy.
A clinical stage of IV-S neuroblastoma is known to include heterogeneous tumors. The authors report a case of IV-S neuroblastoma that relapsed after regression 4 years and 10 months after diagnosis. Multiagent chemotherapy was necessary to control the disease, and the patient has been doing well with no evidence of disease for more than 5 years. Although Shimada's classification showed favorable characteristics, N-myc protein was positive and DNA ploidy was diploidy in the tumor at diagnosis. Discrepancy in DNA ploidy was observed and aneuploidy was shown in tumor specimens at recurrence. Experience in this case showed the following important clinical features: (1) IV-S neuroblastoma of intermediate-grade malignancy does exist, and patients with such a disease may be cured by aggressive treatment; (2) Identifying IV-S patients with an unfavorable clinical course is possible by examining biological prognostic factors.


The effect of chitosan on transcellular and paracellular mechanisms in the intestinal epithelial barrier.
Chitosan is employed as an absorption enhancer for drug delivery strategies. Aim of this study was to investigate the rapid effects on barrier properties of the intestinal epithelial cell model HT-29/B6. Chitosan (0.005%) induced a fast decrease in transepithelial resistance (R(t)) which was completely reversible after wash-out. Two-path impedance spectroscopy revealed that chitosan affects both, the paracellular (R(para)) and the transcellular (R(trans)) resistance. pH-dependence and inhibition of both effects by negatively charged heparin indicated a chitosan action only in the protonated form. The decrease in R(trans) was mediated by activation of a chloride-bicarbonate exchanger involved in intracellular pH regulation. This activation was coupled to the decrease in R(para) which was associated with an increase in ion permeability and permeability for paracellular flux markers up to 10 kDa. No effects on expression and subcellular distribution of tight junction (TJ) proteins or the actin cytoskeleton were observed. Accordingly, inhibition of actin-myosin interaction, Ca(2+)-dependent intracellular signaling, PKC, PI3K/Akt, MAP kinase p38, and endocytosis pathways did not impair the chitosan effect. These results suggest that the rapid and reversible absorption-enhancing chitosan effect is due to changes in intracellular pH caused by the activation of a chloride-bicarbonate exchanger resulting in the opening of the TJ.


Development and validation of a new scale to measure chronic suicidal ideation: The Chronic Suicidal Ideation Inventory-5 (CSI-5).
Little is known about characteristics that differentiate acute from chronic suicidal ideation. Studies have been hampered by the lack of a formal operational definition or measurement tool for chronic suicidal ideation (CSI). We sought to adapt a standardized measure of obsessive-compulsive thinking to rate chronic suicidal ideation in a mood disorder inpatient cohort. We devised a novel self-report instrument, based on constructs related to obsessive-compulsive thinking and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), as applied to preoccupations with suicidal thoughts and their persistence over 24 months in a previously described cohort of 97 inpatients with mood disorder. Exploratory factor analysis and principal components analysis were used to establish the factor structure of the instrument, and Cronbach's alpha and McDonald's omega were calculated to determine internal consistency of the scale. Significant Pearson correlations with individual scale items and total CSI-5 scores were evident in relation to the 2-, 6-, 12- and 24-month periods preceding the index hospitalization. A one-factor solution explained 75% of the variance in total CSI-5 scores. Cronbach's alpha was 0.914, and McDonalds's omega was 0.916. CSI-5 scores were not significantly associated with current depression severity scores or actual past suicide attempts. This 5-item adaptation of Y-BOCS-type questions provides an internally consistent and reliable assessment of chronic suicidal ideation in patients with mood disorder. The integrated assessment of time occupied by suicidal thoughts, activity interference, associated distress, efforts to resist suicidal thoughts, and degree of control over suicidal thinking provides a cohesive framework for understanding chronic suicidal ideation.


Naked-eye detection of amyloid aggregates using gold nanoparticles modified with amyloid beta antibody.
We developed a rapid method for estimating the amyloid beta (Aβ)-conformation state related with Alzheimer's disease. We prepared gold nanoparticle (AuNP)-Aβ antibody conjugates treated with bovine serum albumin to stabilize their dispersibility in a buffer. The prepared AuNPs were precipitated in the presence of Aβ aggregates, such as oligomers and fibrils. Aβ monomers did not precipitate AuNPs. The formation of AuNP precipitates by Aβ aggregates could be confirmed by the naked eye within 1 h.


Role of histamine in brain protection in surgical brain injury in mice.
Surgical resection of brain tissue is associated with tissue damage at the resection margin. Studies of ischemic brain injury in rodents have shown that administration of L-histidine and thioperamide reduces ischemic tissue loss, in part by inhibition of apoptotic cell death. In this study we tested administration of L-histidine and thioperamide in surgical brain injury in mice. Mice were randomized to one of three groups: Sham surgery (n=18), surgical brain injury without treatment (SBI) (n=33), and surgical brain injury with combined l-histidine and thioperamide treatment (SBI+H) (n=29). Surgical brain injury was induced via right frontal craniotomy with resection of the right frontal lobe. L-histidine (1000 mg/kg) and thioperamide (5 mg/kg) were administered to the SBI+H group immediately following surgical resection. Postoperative assessment included neurobehavioral scores, Evans blue measurement of blood-brain barrier breakdown, brain water content, Nissl histology, and immunohistochemistry for IgG and cleaved caspase 3. Postoperative findings included equivalent neurobehavioral outcomes at 24 and 72 h in the SBI and SBI+H groups, similar histological outcomes between SBI and SBI+H, and similar qualitative staining for cleaved caspase 3. SBI+H had increased BBB breakdown on Evans blue analysis and a trend towards increased brain edema which was significant at 72 h. We conclude that combined treatment with l-histidine and thioperamide leads to increased BBB breakdown and brain edema in surgical brain injury.


An assessment of the simulated performance of basic clinical procedures by junior doctors during the first year of clinical practice.
Upon entering the healthcare system, junior doctors may lack the skills required to care for patients, and feel unprepared for their role, with considerable variation in the level of proficiency in the performance of particular clinical procedures. To compare the performance and proficiency (self-report and observed) of the performance of nine basic clinical procedures. Seventeen interns were observed performing nine clinical procedures in a simulated setting in June 2021 (Assessment 1) and January 2022 (Assessment 2). The observers identified whether each step in the procedure was performed correctly, and provided an overall assessment of proficiency. The participants also rated their own level proficiency. At Assessment 1 the number of steps performed correctly ranged from a mean of 41.9-83.5%. At Assessment 2 the number of steps performed correctly ranged from a mean of 41.9-97.8%. The most common median proficiency rating for Assessment 1 was 'close supervision', and was 'indirect supervision' at Assessment 2. There was a significant and large effect size in the improvement in performance from Assessment 1 to Assessment 2. Low correlations were found between observer and self-reported proficiency in performance of the procedures. The large improvement in performance across the two assessments is encouraging. However, there is a need to address the variability in performance on graduation from medical school, and to ensure that any assessment of proficiency is not only reliant on self-report.


Neutropenia is an indicator of outcomes in metastatic colorectal cancer patients treated with FTD/TPI plus bevacizumab: a retrospective study.
Trifluridine/tipiracil (FTD/TPI) improves the overall survival (OS) of metastatic colorectal cancer (mCRC) patients. Additionally, FTD/TPI plus bevacizumab (BEV) has demonstrated promising efficacy for mCRC patients who are refractory to standard chemotherapy. Chemotherapy-induced neutropenia (CIN) has been reported to be an indicator of efficacy for FTD/TPI. This study investigated whether CIN was an indicator of efficacy for FTD/TPI plus BEV. We reviewed chemo-refractory mCRC patients who were treated with FTD/TPI alone (monotherapy) or FTD/TPI plus BEV (combination) at our institution and compared the safety and efficacy of the two. Progression-free survival (PFS) and OS were analyzed using Kaplan-Meier curves. We also investigated correlations between CIN and outcomes. In total, 56 patients received FTD/TPI, among whom 24 and 32 were treated with monotherapy and combination therapy, respectively. The median PFS was 1.8 and 4.7 months for the monotherapy and combination arms, respectively (hazard ratio [HR]: 0.28; 95% confidence interval [CI]: 0.15-0.51; P < 0.001). The median OS was 6.3 and 11.7 months for the monotherapy and combination arms, respectively (HR 0.25; 95% CI 0.13-0.48; P < 0.001). CIN (Grade 3 or worse) developed in five (20.8%) and 17 (53.1%) patients from the monotherapy and combination arms, respectively (P = 0.030). Patients with CIN in the combination arm had improved PFS and OS compared with non-CIN patients (P = 0.033 and P = 0.045, respectively). FTD/TPI plus BEV prolonged PFS and OS and had tolerable toxicity compared with FTD/TPI alone. CIN is an indicator of patients who will benefit from FTD/TPI plus BEV.


Preclinical Validation of the Located Hyperthermia Using Gold Macro-Rods and Ultrasound as an Effective Treatment for Solid Tumors.
Hyperthermia, the procedure of raising the temperature of a part of or the whole body above normal for a defined period of time, is applied alone or as an adjunctive with various established cancer treatment modalities such as radiotherapy and chemotherapy. In this study used a method for inducing hyperthermia in solid tumors with a combination of gold macro rod (GR) and ultrasound, the feasibility of this technique was described only with computational models and in vitro. The Ehrlich tumor, derived from a mouse adenocarcinoma, has been used to investigate the bio-heat transfer and the effect of gold rods irradiated with ultrasound. The in vivo measurements demonstrated that the technique inhibited more 80% of the tumor growth in both experimental models tested. These results not only confirm the bio heat transfer to tissue as predicted by analytical calculation and in vitro measurements, but are also proved to be a potential alternative to kill cancer cells.


A novel aromatic mutagen, 5-amino-6-hydroxy-8H-benzo[6,7]azepino[5,4,3-de]quinolin-7-one (ABAQ), induces colonic preneoplastic lesions in mice.
The benzoazepinoqunolinone derivative, 5-amino-6-hydroxy-8H-benzo[6,7]azepino[5,4,3-de]quinolin-7-one (ABAQ), which is produced in a mixture of glucose and tryptophan incubated at 37 °C under physiological conditions in the presence or absence of hydroxyl radicals caused by the Fenton reaction, is a novel aromatic mutagen. In the current study, we determined the tumor-initiating potency of ABAQ using an inflammation-relate, two-stage mouse colon carcinogenesis model. Male Crj: CD-1 (ICR) mice were treated with the single intragastric administration (100 or 200 mg/kg body weight) of ABAQ followed by subsequent 1-week oral exposure to 2% dextran sodium sulfate (DSS) in drinking water. The ABAQ treatment alone resulted in high-grade dysplasia, which is a precursor to colorectal cancer, in the colon. Following the administration of DSS after ABAQ treatment, the incidence and frequency of high-grade dysplastic lesions increased; the values were highest in the mice treated with 200 mg/kg body weight of ABAQ followed by DSS. The lesions expressing β-catenin in their nuclei and cytoplasm exhibited high proliferation activity without the expression of programmed cell death 4. These findings indicate that ABAQ has a tumor-initiating activity in the mouse colon, with or without inflammation, although the potential pro-inflammatory effect of high doses of ABAC should be investigated.


Characterization and application of a new ultraviolet derivatization reagent for amino acids analysis in capillary electrophoresis.
A new ultraviolet (UV) labeling reagent, p-acetamidobenzenesulfonyl fluoride (PAABS-F), was designed and synthesized to label and determine the amino acids by capillary electrophoresis (CE) with diode-array detector (DAD). PAABS-F is very stable and easy to synthesize. It reacted with primary or secondary amino acids very quickly under facile conditions to give corresponding derivatives in high yield with excellent sensitivity and stability. No by-products were observed in amino acid derivatives when stored at room temperature under natural daylight for at least 7 days. Both amino acids standard solution and real samples reacted with this new UV labeling reagent smoothly to form high UV-absorption derivatives. The labeled 20 standard amino acids were efficiently separated by CE and the mass detection limits (S/N=3) were ranged from 59.3 fmol for L-tryptophan to 1.70 pmol for L-histidine.


Oxidative pretreatment of lignocellulosic biomass for enzymatic hydrolysis: Progress and challenges.
Deconstruction of cell wall structure is important for biorefining of lignocellulose to produce various biofuels and chemicals. Oxidative delignification is an effective way to increase the enzymatic digestibility of cellulose. In this work, the current research progress on conventional oxidative pretreatment including wet oxidation, alkaline hydrogen peroxide, organic peracids, Fenton oxidation, and ozone oxidation were reviewed. Some recently developed novel technologies for coupling pretreatment and direct biomass-to-electricity conversion with recyclable oxidants were also introduced. The primary mechanism of oxidative pretreatment to enhance cellulose digestibility is delignification, especially in alkaline medium, thus eliminating the physical blocking and non-productive adsorption of enzymes by lignin. However, the cost of oxidative delignification as a pretreatment is still too expensive to be applied at large scale at present. Efforts should be made particularly to reduce the cost of oxidants, or explore valuable products to obtain more revenue.


Verification of criterion-related validity of the evaluation method of postural stability using the frame subtraction method.
It is important to quantify the postural stability. The frame subtraction method can calculate the motions of a subject, and might be easier to implement, with lower costs. However, validity of the evaluation of postural stability using this method have not been validated yet. Therefore, the purpose of this study was to verify criterion-related validity of the frame subtraction scores and the center of pressure (COP) parameters during maintenance of single leg standing. Twenty two healthy young subjects participated in this study. Motion tasks comprised right leg standing with eyes open and closed. The total length of COP displacements (LNG), Root mean square (RMS) area, anterior - posterior (AP) range, medial - lateral (ML) range were recorded using the force plate. Simultaneously, the motion images were acquired with digital video cameras from the front and right sides. After the motion images were analyzed using the frame subtraction method, the frame subtraction scores (maximum / sum of the frame subtraction score on each plane / the frontal and sagittal planes) were measured. To confirm the validity, Spearman's rank correlation coefficient between the frame subtraction scores and the COP parameters was calculated. The sum of the frame subtraction score on the frontal plane was significantly correlated with all COP displacements in the single leg standing. The result of this study indicated that the frame subtraction method could be applied to the evaluation of balance task with postural sway such as maintenance of single leg standing. The frame subtraction method is low cost and easy owing to its marker-less systems.


Silicone gel sheet tie-over for skin graft on the eyelid following release of scar contracture.
A simple tie-over dressing using a silicone gel sheet gives firm fixation and allows direct inspection of the underlying grafted skin. Moreover, if haematoma or any complication is recognised, the sheet can be easily removed and reapplied.


Bleomycin A5 suppresses Drp1‑mediated mitochondrial fission and induces apoptosis in human nasal polyp‑derived fibroblasts.
Intralesional injection of bleomycin‑A5 (BLE‑A5) is a novel treatment for nasal polyps. Our previous study clarified that BLE‑A5 could induce nasal polyp‑derived fibroblast (NPDF) apoptosis in nasal polyps. However, the detailed mechanisms are still unclear. The present study aimed to determine the effects of BLE‑A5 on NPDF mitochondrial dynamics and provide a theoretical basis for the local application of BLE‑A5 to treat nasal polyps. In the present study, an in vitro nasal polyp tissue culture model was used to define the BLE‑A5 target cell type in nasal polyps. NPDF primary cell culture was used to study the effects of BLE‑A5 on the mitochondrial dynamic‑related mechanism. The results showed that BLE‑A5 treatment of NPDFs caused mitochondrial‑mediated apoptosis. Dynamin‑related protein 1 (Drp1) was shown to be altered in BLE‑A5‑treated NPDFs. Drp1 knockdown increased the sensitivity of NPDFs to BLE‑A5 and exacerbated mitochondrial dysfunction. BLE‑A5 decreased cyclin B1‑CDK1 complex‑mediated phosphorylation of Drp1 and inhibited Drp1‑mediated mitophagy in NPDFs. Overall, the present study concluded that BLE‑A5 mainly induces NPDF apoptosis in nasal polyps. BLE‑A5 regulates the mitochondria by inhibiting Drp1 activation, resulting in NPDF mitochondrial dynamic disorder and apoptosis.