Haplotype-Based Genome-Wide Prediction Models Exploit Local Epistatic Interactions Among Markers.
Genome-wide prediction approaches represent versatile tools for the analysis and prediction of complex traits. Mostly they rely on marker-based information, but scenarios have been reported in which models capitalizing on closely-linked markers that were combined into haplotypes outperformed marker-based models. Detailed comparisons were undertaken to reveal under which circumstances haplotype-based genome-wide prediction models are superior to marker-based models. Specifically, it was of interest to analyze whether and how haplotype-based models may take local epistatic effects between markers into account. Assuming that populations consisted of fully homozygous individuals, a marker-based model in which local epistatic effects inside haplotype blocks were exploited (LEGBLUP) was linearly transformable into a haplotype-based model (HGBLUP). This theoretical derivation formally revealed that haplotype-based genome-wide prediction models capitalize on local epistatic effects among markers. Simulation studies corroborated this finding. Due to its computational efficiency the HGBLUP model promises to be an interesting tool for studies in which ultra-high-density SNP data sets are studied. Applying the HGBLUP model to empirical data sets revealed higher prediction accuracies than for marker-based models for both traits studied using a mouse panel. In contrast, only a small subset of the traits analyzed in crop populations showed such a benefit. Cases in which higher prediction accuracies are observed for HGBLUP than for marker-based models are expected to be of immediate relevance for breeders, due to the tight linkage a beneficial haplotype will be preserved for many generations. In this respect the inheritance of local epistatic effects very much resembles the one of additive effects.


E1 of α-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress.
Enzymes of central carbon metabolism (CCM) in Mycobacterium tuberculosis (Mtb) make an important contribution to the pathogen's virulence. Evidence is emerging that some of these enzymes are not simply playing the metabolic roles for which they are annotated, but can protect the pathogen via additional functions. Here, we found that deficiency of 2-hydroxy-3-oxoadipate synthase (HOAS), the E1 component of the α-ketoglutarate (α-KG) dehydrogenase complex (KDHC), did not lead to general metabolic perturbation or growth impairment of Mtb, but only to the specific inability to cope with glutamate anaplerosis and nitroxidative stress. In the former role, HOAS acts to prevent accumulation of aldehydes, including growth-inhibitory succinate semialdehyde (SSA). In the latter role, HOAS can participate in an alternative four-component peroxidase system, HOAS/dihydrolipoyl acetyl transferase (DlaT)/alkylhydroperoxide reductase colorless subunit gene (ahpC)-neighboring subunit (AhpD)/AhpC, using α-KG as a previously undescribed source of electrons for reductase action. Thus, instead of a canonical role in CCM, the E1 component of Mtb's KDHC serves key roles in situational defense that contribute to its requirement for virulence in the host. We also show that pyruvate decarboxylase (AceE), the E1 component of pyruvate dehydrogenase (PDHC), can participate in AceE/DlaT/AhpD/AhpC, using pyruvate as a source of electrons for reductase action. Identification of these systems leads us to suggest that Mtb can recruit components of its CCM for reactive nitrogen defense using central carbon metabolites.


Characterization of the multiple forms of duck lens delta-crystallin with endogenous argininosuccinate lyase activity.
Duck lens delta-crystallins were the translational products of two tandem arranged genes, delta 1 and delta 2. Two fractions of the delta-crystallin (delta a and delta b) were resolved when the duck eye ball lens extract was passed through a Pharmacia-LKB Q-Sepharose column. These fractions were further separated by chromatofocusing into multiple forms with pI value ranging from 5.05 to 5.45. The charge heterogeneity of delta-crystallins was also demonstrated on the polyacrylamide gel when electrophoresis was performed under nonreducing conditions. All of those multiple forms possessed endogenous argininosuccinate lyase activity with activation energy approximately 12.5 +/- 1.6 kcal/mol. delta b-Crystallins showed higher enzyme activity than delta a-crystallins. Slightly different kinetic parameters were observed for the multiple forms of delta b-crystallins. On the other hand, delta a-crystallins could be further divided into two subgroups according to their kinetic parameters. There is 12-fold difference in kcat value between these two subgroups. delta a-Crystallins also have lower Km values than the delta b-crystallins. When examined by polyacrylamide gel electrophoresis under reducing conditions in the presence of sodium dodecyl sulfate, the multiple forms were shown to be composed of subunits with similar M(r) of 55,000. All of these forms showed same antigenicity toward the rabbit anti-duck delta-crystallin antiserum; however, different carbonyl contents were observed for these forms, indicating that the origin of these multiple forms was due to post-translational oxidative modification of the protein molecules. Two delta-crystallin forms were demonstrated to be the N-truncated delta 2-crystallin, lacking the first eight amino acid residues from N-terminus. Modification and/or truncation of the proteins resulted in changing of the intrinsic tryptophan and tyrosine fluorescence. Those forms with higher pI values were shown to be much more thermostable than those with lower pI values. Our system may represent the first in vivo information that oxidation does not always lead to inactivation of an enzyme.


p63: a crucial player in epithelial stemness regulation.
Epithelial tissue homeostasis is closely associated with the self-renewal and differentiation behaviors of epithelial stem cells (ESCs). p63, a well-known marker of ESCs, is an indispensable factor for their biological activities during epithelial development. The diversity of p63 isoforms expressed in distinct tissues allows this transcription factor to have a wide array of effects. p63 coordinates the transcription of genes involved in cell survival, stem cell self-renewal, migration, differentiation, and epithelial-to-mesenchymal transition. Through the regulation of these biological processes, p63 contributes to, not only normal epithelial development, but also epithelium-derived cancer pathogenesis. In this review, we provide an overview of the role of p63 in epithelial stemness regulation, including self-renewal, differentiation, proliferation, and senescence. We describe the differential expression of TAp63 and ΔNp63 isoforms and their distinct functional activities in normal epithelial tissues and in epithelium-derived tumors. Furthermore, we summarize the signaling cascades modulating the TAp63 and ΔNp63 isoforms as well as their downstream pathways in stemness regulation.


Recurrent Invasive Aspergillosis in Immunocompetent Patient.
Invasive cardiac aspergillosis is a rare form of disseminated Aspergillus infection which carries a very high mortality rate even with aggressive treatment. Importantly, patients with pre-existing cardiac lesions, prosthetic valves, stents, coronary bypass grafts, and implanted devices are at greater risk. A case of fatal, recurrent, disseminated Aspergillus infection in an immunocompetent patient with invasion of a structurally normal heart in the context of multiorgan involvement is presented. Supplemental material is available for this article. Keywords: CT, Echocardiography, Infection © RSNA, 2021.


N1-Substituted benzimidazole scaffold for farnesoid X receptor (FXR) agonists accompanying prominent selectivity against vitamin D receptor (VDR).
As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. With respect to the bone metabolism, FXR positively regulates bone metabolism through both bone formation and resorption of the bone remodeling pathways. Some of FXR agonists possessing isoxazole moiety are undergoing clinical trials for the treatment of non-alcoholic steatohepatitis. To date, therefore, the activation of FXR leads to considerable interest in FXR as potential therapeutic targets. We have identified a series of nonsteroidal FXR agonists bearing N1-methyl benzimidazole and isoxazole moieties that are bridged with aromatic derivatives. They showed affinity to FXR, but also weak affinity toward the vitamin D receptor (VDR) that involves regulation of calcium and phosphate homeostasis and is activated by bile acids. The deployment of FXR agonists without activity against VDR as off-target is therefore crucial in the development of FXR ligands. Our efforts focusing on increasing the agonist properties towards FXR led to the discovery of 19, which activates FXR at and below nanomolar levels (EC50 = 26.5 ± 10.5 nM TR-FRET and 0.8 ± 0.2 nM luciferase, respectively) and functions as a FXR agonist: the affinity toward FXR over eight nuclear receptors, including VDR [IC50 (VDR) / EC50 (FXR) > 5000] and TGR5, effects FXR target genes, and activates bone morphogenetic protein-2-induced differentiation of mouse bone marrow-derived mesenchymal stem cell-like ST2 cells into osteoblast.


Natural Enfumafungin Analogues from Hormonema carpetanum and Their Antifungal Activities.
Ibrexafungerp, an inhibitor of fungal β-(1,3)-d-glucan synthase, represents the first new class of antifungals to be approved in the last 20 years. Ibrexafungerp is a semisynthetic derivative of the naturally occurring triterpene glycoside enfumafungin. In order to search for new analogues of enfumafungin and to probe its biosynthesis, we undertook a reinvestigation of Hormonema carpetanum, which led to the isolation of two new analogues, enfumafungins B and C, together with enfumafungin. Due to the presence of a hemiacetal moiety in the structure, the enfumafungins appear as a mixture of two interconverting epimers during both the purification process and NMR data acquisition. The structure elucidation, including the differentiation of 25S* and 25R* epimers, was completed by combined analyses of NMR and MS spectroscopic data. The discovery of enfumafungins B and C may have implications for enfumafungin biosynthesis. The antifungal activity of enfumafungins B and C was significantly lower than that of enfumafungin, suggesting that the C-2 substituents and the C-19 carboxy acid are important for activity. Molecular docking simulations revealed significant hydrogen bond interactions between enfumafungins and β-(1,3)-d-glucan synthase, which may be useful for developing new antifungal agents.


Immunocompetent, Immunized Male With Mumps, Complicated by Orchitis and Meningitis.
Mumps is a rare pathology often not encountered in the emergency department setting. It is an especially unusual finding in a fully immunized individual. We present a case of a 26-year-old Army active duty male who was evaluated in the emergency department for mumps over the course of two visits. The military population is presumed fully immunized and immunocompetent, travels widely and often lives in close quarters. This case highlights the importance for providers to consider such a disease that carries a risk of significant morbidity, and rarely, mortality. A literature review was performed evaluating mumps in the vaccinated population.


Lipid peroxidation and antioxidant status in head and neck squamous cell carcinoma patients.
Oxidative stress, a consequence of an imbalance between the formation and inactivation of reactive oxygen species, may be involved in the pathogenesis of many diseases including cancer. To evaluate the magnitude of oxidative stress, a study on the plasma levels of superoxide dismutase, total thiols, ascorbic acid and malondialdehyde (MDA) has been done in head and neck squamous cell carcinoma patients before the start of any oncological treatment and compared with healthy controls. The specific activity of superoxide dismutase in cancer patients is decreased significantly when compared to the control (p < 0.05). The total thiol and ascorbic acid levels are significantly reduced (p < 0.005) whereas MDA levels are significantly increased in the patients (p < 0.00005). Our findings show that the oxidative stress is elevated in cancer patients as evidenced by elevated levels of lipid peroxidation products and depletion of enzymatic and non-enzymatic antioxidants.


Experimental infrared point-source detection using an iterative generalized likelihood ratio test algorithm.
This work documents the performance of a recently proposed generalized likelihood ratio test (GLRT) algorithm in detecting thermal point-source targets against a sky background. A calibrated source is placed above the horizon at various ranges and then imaged using a mid-wave infrared camera. The proposed algorithm combines a so-called "shrinkage" estimator of the background covariance matrix and an iterative maximum likelihood estimator of the point-source parameters to produce the GLRT statistic. It is clearly shown that the proposed approach results in better detection performance than either standard energy detection or previous implementations of the GLRT detector.


Nonsteroidal anti-inflammatory drugs and the risk of nonmelanoma skin cancer.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been assigned a promising role in the chemoprevention of various malignancies. However, epidemiological data on the association between NSAID use and nonmelanoma skin cancer (NMSC) are limited. To explore whether patients regularly exposed to systemic NSAIDs are at a reduced risk of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), we conducted a population-based case-control analysis using the Clinical Practice Research Datalink, a United Kingdom primary care database. We identified 65,398 patients with incident BCC and 7,864 patients with incident SCC diagnosed between 1995 and 2013 and matched 1 and 4 NMSC-free controls to each BCC and SCC case, respectively, on age, sex, general practice, calendar time and years of history in the database. We compared prior NSAID exposure between cases and controls using multivariate conditional logistic regression analyses controlling for several potential confounders. Overall, we found no association between NSAID use and BCC, but when looking exclusively at users of single NSAID substances there was a suggestion of a reduced BCC risk in regular users of aspirin and ibuprofen (adjusted odds ratio [adj. OR]: 0.92, 95% confidence interval [CI]: 0.85-0.99 and adj. OR: 0.61, 95% CI: 0.48-0.78, respectively). The risk of SCC was slightly decreased in regular users of any NSAIDs (adj. OR: 0.89, 95% CI: 0.82-0.97), with the strongest risk reduction observed in current users of coxibs (adj. OR: 0.77, 95% CI: 0.62-0.95). These findings provide evidence that patients predisposed to NMSC might benefit from chemoprevention with NSAIDs.


Increasing Treatment Rates for Hepatitis C in Primary Care.
Despite antiviral agents that can cure the disease, many individuals with Hepatitis C Virus (HCV) remain untreated. Primary care clinicians can play an important role in HCV treatment but often feel they do not have the requisite skills. We implemented a population-based improvement intervention over 10 months to support treatment of HCV in a primary care setting. The intervention included a decision-support tool, education for clinicians, enhanced interprofessional team supports, mentorship, and proactive patient outreach. We used process and outcome measures to understand the impact on the proportion of patients who initiated treatment and achieved Sustained Virologic Response (SVR). We used physician focus groups and pharmacist interviews to understand the context and mechanisms influencing the impact of the intervention. Between December 2018 and June 2020, the percentage of HCV RNA positive patients who started treatment rose from 66.0% (354/536) to 75.5% (401/531) with 92.5% (371/401) of those starting treatment achieving SVR. Qualitative findings highlighted that the intervention helped raise awareness and confidence among physicians for treating HCV in primary care. A collaborative team environment, education, mentorship, and a decision-support tool integrated into the electronic record were all enablers of success although patient psychosocial complexity remained a barrier to engagement in treatment. A multifaceted primary care improvement initiative increased clinician confidence and was associated with an increase in the proportion of HCV RNA positive patients who initiated curative treatment.


Rigid and flexible endoscopic rendezvous in spatium peritonealis may be an effective tactic for laparoscopic megasplenectomy: significant implications for pure natural orifice translumenal endoscopic surgery.
We recently experienced 10 patients with cirrhosis who underwent laparoscopic splenectomy. A portion of these patients underwent dissection with a flexible endoscope in the peritoneal cavity. This pilot study mainly focused on the technical aspects and immediate results. From November 2009 to September 2010, 10 patients with cirrhosis and hypersplenism were entered into this pilot study. They were indicated to undergo laparoscopic splenectomy to treat portal hypertension and to facilitate initiation and completion of either interferon therapy for liver cirrhosis or anticancer therapy for hepatocellular carcinoma. To dissect the upper end of the gastrosplenic ligament and the marginal region between the left diaphragm and upper pole of the spleen, a flexible single-channel endoscope was introduced into the peritoneal cavity simultaneously with the use of a rigid laparoscope. Dissection with the flexible endoscope in the peritoneal cavity was performed using an insulation-tipped electrosurgical knife through the channel of the flexible endoscope. The flexible endoscope offered a magnified operative view, a water-jet lens cleaner, and a powerful lavage and suction capability. The upper end of the gastrosplenic ligament and the marginal region between the left diaphragm and upper pole of the spleen were easily seen, and dissection of these critical regions was smoothly conducted with articulation of the tip of the flexible endoscope, even in patients with splenomegaly. No patient experienced major intraoperative complications or required conversion to open surgery. Dissection with a flexible endoscope in the peritoneal cavity may be an effective tactic for laparoscopic megasplenectomy, and significant implications for pure natural orifice translumenal endoscopic surgery have been raised. Although future randomized controlled prospective studies are needed to confirm these findings, surgeons might find this to be a typical example of an appropriate strategy for high-risk patients.


MIDDAS-M: motif-independent de novo detection of secondary metabolite gene clusters through the integration of genome sequencing and transcriptome data.
Many bioactive natural products are produced as "secondary metabolites" by plants, bacteria, and fungi. During the middle of the 20th century, several secondary metabolites from fungi revolutionized the pharmaceutical industry, for example, penicillin, lovastatin, and cyclosporine. They are generally biosynthesized by enzymes encoded by clusters of coordinately regulated genes, and several motif-based methods have been developed to detect secondary metabolite biosynthetic (SMB) gene clusters using the sequence information of typical SMB core genes such as polyketide synthases (PKS) and non-ribosomal peptide synthetases (NRPS). However, no detection method exists for SMB gene clusters that are functional and do not include core SMB genes at present. To advance the exploration of SMB gene clusters, especially those without known core genes, we developed MIDDAS-M, a motif-independent de novodetection algorithm for SMB gene clusters. We integrated virtual gene cluster generation in an annotated genome sequence with highly sensitive scoring of the cooperative transcriptional regulation of cluster member genes. MIDDAS-M accurately predicted 38 SMB gene clusters that have been experimentally confirmed and/or predicted by other motif-based methods in 3 fungal strains. MIDDAS-M further identified a new SMB gene cluster for ustiloxin B, which was experimentally validated. Sequence analysis of the cluster genes indicated a novel mechanism for peptide biosynthesis independent of NRPS. Because it is fully computational and independent of empirical knowledge about SMB core genes, MIDDAS-M allows a large-scale, comprehensive analysis of SMB gene clusters, including those with novel biosynthetic mechanisms that do not contain any functionally characterized genes.


Towards intelligent complex networks: the space and prediction of information walks.
In this paper we study the problem of walk-specific information spread in directed complex social networks. Classical models usually analyze the "explosive" spread of information on social networks (e.g., Twitter) - a broadcast or epidemiological model focusing on the dynamics of a given source node "infecting" multiple targets. Less studied, but of equal importance is the case of single-track information flow, wherein the focus is on the node-by-node (and not necessarily a newly visited node) trajectory of information transfer. An important and motivating example is the sequence of physicians visited by a given patient over a presumed course of treatment or health event. This is the so-called a referral sequence which manifests as a path in a network of physicians. In this case the patient (and her health record) is a source of "information" from one physician to the next. With this motivation in mind we build a Bayesian Personalized Ranking (BPR) model to predict the next node on a walk of a given network navigator using network science features. The problem is related to but different from the well-investigated link prediction problem. We present experiments on a dataset of several million nodes derived from several years of U.S. patient referral records, showing that the application of network science measures in the BPR framework boosts hit-rate and mean percentile rank for the task of next-node prediction. We then move beyond the simple information walk to consider the derived network space of all information walks within a period, in which a node represents an information walk and two information walks are connected if have nodes in common from the original (social) network. To evaluate the utility of such a network of information walks, we simulate outliers of information walks and distinguish them with the other normal information walks, using five distance metrics for the derived feature vectors between two information walks. The experimental results of such a proof-of-concept application shows the utility of the derived information walk network for the outlier monitoring of information flow on an intelligent network.


Quantitative Analysis of Drug Supersaturation Region by Temperature-Variable Nuclear Magnetic Resonance Measurements, Part 2: Effects of Solubilizer.
This study utilized temperature-variable nuclear magnetic resonance (NMR) spectroscopy to investigate the effects of a solubilizing agent on the ketoprofen (KTP) supersaturation region. Quantitative NMR analysis showed that the solubilizing agent cetyltrimethylammonium bromide (CTAB) increased both the crystalline and amorphous solubilities of KTP, shifting the KTP supersaturation region to a higher KTP concentration range. The amorphous solubility of KTP was found to be independent of the enantiomeric composition of KTP, even in the presence of CTAB. However, the supersaturation region of the S-enantiomer of KTP (s-KTP) in CTAB solutions was smaller than that of the racemic form of KTP (rac-KTP), likely because of the higher crystalline solubility of s-KTP. When KTP formed a KTP-rich phase via liquid-liquid phase separation from KTP-supersaturated solutions, CTAB was observed to be distributed into the KTP-rich phase, decreasing the chemical potential of KTP and the maximum thermodynamic activity of KTP in the aqueous phase. Additionally, the incorporation of CTAB into the KTP-rich phase diminished the solubilization effect of CTAB micelles in the aqueous phase, narrowing the KTP supersaturation region to a greater extent at higher KTP dose concentrations. Furthermore, the upper-temperature limit of the supersaturated dissolvable region of KTP was lowered in the presence of CTAB, which was rationalized by the melting point depression of the KTP crystal upon mixing with CTAB. The findings of this study highlight the importance of considering the molecular-level impact of solubilizing agents on the drug supersaturation region to fully exploit the potential benefits of supersaturated formulations.


Linear and curvilinear effects of inbreeding on production traits for walloon Holstein cows.
The nonlinear effects of inbreeding were studied by comparing linear and curvilinear regression models of phenotypic performances on inbreeding coefficients for production traits (milk, fat, and protein yields) of Holstein cows in their first lactation. Three different regression models (linear, quadratic, and cubic) were introduced separately into a single-trait, single-lactation, random regression test-day model. The significance of the different regression coefficients was studied based on a t-test after estimation of error variances and covariances associated with the different regression coefficients. All of the tested regression coefficients were significantly different from 0. The traditional regression coefficients of milk, fat, and protein yields on inbreeding were, respectively, -22.10, -1.10, and -0.72 kg for Holstein cows in their first lactation. However, the estimates of 305-d production losses for various classes of animals based on inbreeding coefficients showed that the effect of inbreeding was not a linear function of the percentage of inbreeding. The 305-d milk yield loss profiles attributable to inbreeding, obtained by the various regression models, were different. However, for inbreeding coefficients between 0 and 10%, these differences were small.


Serum proteins in hepatic amoebiasis.
Serum proteins were estimated in two patient groups, namely (i) 20 cases with proven ameobic liver abscess and (ii) 12 cases with hepatic amoebiasis without demonstrable pus, commonly referred to by the misnomer 'ameobic hepatitis'. In amoebic liver abscess a fall in albumin and an increase in alpha 2 and gamma globulin results in a serum protein pattern somewhat different from that in hepatic amoebiasis without demonstrable pus, where an elevation in gamma globulin was infrequent. Post-therapy serum protein estimations revealed that, irrespective of the presence or absence of pus, a rising gamma globulin level in hepatic amoebiasis may be of prognostic significance and post-treatment surveillance would be necessary in patients showing this type of response.


The effect of apatinib in the treatment of metastatic renal cell carcinoma: a case report and review of the literature.
The aim of this study was to explore the effect of apatinib in the treatment of metastatic renal cell carcinoma (mRCC) and related adverse events. A case of mRCC was reported which recurred after surgery and roferon treatment. The patient was treated with apatinib at a dose of 500 mg orally, twice daily, 28 days/cycle. The metastatic lesions improved based on computed tomography after apatinib administration in the fourth and eighth month. The progression-free survival of the patient had increased almost to 8 months. The patient showed a good tolerance with only an adverse effect of mild-to-moderate hand-foot syndrome which was managed well. Apatinib is an option for mRCC after previous treatment. However, more and larger trials are still needed.


Serum immunoreactive anodal trypsinogen and urinary amylase as biochemical markers for rejection of clinical whole-organ pancreas allografts having exocrine drainage into the urinary bladder.
Rejection of pancreas allografts is best measured today by co-monitoring the creatinine of a simultaneously transplanted kidney allograft from the same donor. This methodology discourages pancreas transplantation for patients who have previously received a kidney allograft and preuremic patients. Thus, an early, graft-specific marker of rejection is desirable. In this study we compared 2 putative biochemical markers for rejection of pancreas allografts, serum immunoreactive anodal trypsinogen and urinary amylase, with serum creatinine in 15 simultaneously transplanted type I diabetics. Serial values during hospitalizations were determined. Follow-up ranged from 18 to 134 postoperative days. Rejection was diagnosed clinically and considered real if the patient received a course of anti-rejection medication. Ten of these 15 patients experienced a total of 21 rejection episodes. For all episodes of rejection, serum trypsinogen rose from a baseline of 398.1 +/- 25 ng/ml to 1686.2 +/- 317.9 ng/ml (P less than 0.001) on the day of rejection. Urinary amylase fell from 88,310 +/- 7877 U/24 hr to 37,508 +/- 7142 U/24 hr (P less than 0.001). For 10 patients in whom rejection was diagnosed on the initial hospitalization so that serial prediagnosis sera and urines were available, anodal trypsinogen rose from a baseline of 756 +/- 263 ng/ml to 1936 +/- 582 ng/ml (P less than 0.001). Urinary amylase values for these same 10 patients did not change significantly (baseline = 55,788 +/- 18,404 U/24 hr, rejection = 47,133 +/- 14,737 U/24 hr, (P = 0.7). We conclude that serum anodal trypsinogen behaves as a graft-specific biochemical marker for rejection of vascularized pancreas allografts.


Formyl peptide receptors at the interface of inflammation, angiogenesis and tumor growth.
N-formyl peptide receptors (FPRs) belong to the family of pattern recognition receptors (PRRs) that regulate innate immune responses. Three FPRs have been identified in humans: FPR1-FPR3. FPR expression was initially described in immune cells and subsequently in non-hematopoietic cells and certain tissues. Besides their involvement in inflammatory disorders, FPRs have been implicated in the regulation of tissue repair and angiogenesis. Angiogenesis is not only a key component of pathogen defence during acute infection and of chronic inflammatory disorders, but also plays a critical role in wound healing and tissue regeneration. Moreover, pathologic uncontrolled angiogenesis is central for tumour growth, progression, and the formation of metastases. In this review, we summarise the evidence for a central role of FPRs at the intersection between inflammation, physiologic angiogenesis and pathologic neovascularisation linked to cancer. These findings provide insights into the potential clinical relevance of new treatment regimens involving FPR modulation.


Circulating D-dimer level correlates with disease characteristics in hepatoblastoma patients.
Hepatoblastoma (HB) is the most common pediatric liver malignancy, typically affecting children within the first 4 years of life. However, only a few validated blood biomarkers are used in clinical evaluation. The current study explored the clinical application and significance of D-dimer levels in patients with HB. Forty-four patients with HB were included in this retrospective study. D-dimer and plasma fibrinogen levels were examined, and their correlation with other clinical features was analyzed. D-dimer and plasma fibrinogen levels were examined between HB and other benign hepatic tumors. D-dimer levels were significantly associated with high-risk HB features, such as advanced stage and high α-fetoprotein (AFP) levels. Higher D-dimer levels were observed in stage 4 patients compared with stage 1/2/3 patients (P = .028). Higher D-dimer levels were also observed in patients with higher AFP levels before chemotherapy compared with patients with lower AFP levels after chemotherapy (P< 0.001). In addition, higher D-dimer levels were observed in HB compared with other benign hepatic tumors such as hepatic hemangioma and hepatocellular adenoma (P = .012). No significant difference in D-dimer levels was found between sex (P = .503) and age (≥12 vs <12 months, P = .424). There was no significant difference in plasma fibrinogen levels between sex or age and high-risk HB features, such as advanced stage and high AFP levels. Elevated D-dimer levels could be a useful determinant biomarker for high-risk features in patients with HB. This finding also supports the clinical application of D-dimer in HB.


Characterization of ciliated bronchial epithelium 1, a ciliated cell-associated gene induced during mucociliary differentiation.
Lung epithelial structure is altered in asthma; however, the precise mechanisms underlying epithelial repair, including differentiation from basal to columnar epithelial cells, are not well defined. In the course of random sequencing of a cDNA library from human lung biopsies, we have identified a novel gene, ciliated bronchial epithelium 1 (CBE1). Expression of CBE1 was induced during in vitro differentiation of bronchial epithelial cells. Synchronous expression with tektin and hepatocyte nuclear factor 3/forkhead homologue 4, down-regulation by interleukin-13, and its tissue distribution strongly suggested that CBE1 is associated with ciliated cells. Two isoforms of the 0.7-kb full-length cDNA were identified, resulting in open reading frames with different carboxyl termini, with no homology to known proteins. Expression of CBE1 in ciliated epithelial cells was confirmed by immunohistochemistry. Quantitative reverse transcription-polymerase chain reaction analysis using bronchial biopsies showed no difference of expression of CBE1 between normal subjects and subjects with asthma. Expression studies showed that CBE1 is nuclear- or perinuclear-localized, depending on cell type. Regulated expression during differentiation and the subcellular localization of CBE1 suggest that it may play an important role in the differentiation and/or function of ciliated cells in human airways.


Flexible thermoresponsive nanomembranes at the aqueous-air interface.
A synthetic pathway is described to construct thermoresponsive freestanding nanomembranes at the aqueous-air interface of a pendant drop. Dynamic control of the reaction kinetics allows formation of viscoelastic interfaces supporting anisotropic stresses and mechanical stability, which can be tuned by external stimuli.


Impaired hepatitis C virus-specific T cell responses and recurrent hepatitis C virus in HIV coinfection.
Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection. We measured T cell responsiveness by lymphoproliferation and interferon-gamma ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r(2) = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8(+) T cell interferon-gamma response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = -0.94, p = 0.017). These results indicate that HIV infection impairs the immune response to HCV-including in persons who have cleared HCV infection-and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.


Informed consent and patient's rights documents: a right, a rite, or a rewrite?
Both research participants and patients are presumably offered protection from harm through the processes of informed consent and patient's rights. However, both documents are often written at unacceptably high "college" reading levels, making them incomprehensible to the "average" reader who may be reading at a junior-high reading level. Readability researchers are often unfamiliar with important details of readability software, leading to consistent underestimates of document readability. Most informed consent and patient's rights documents are writtin in a one-size-fits-all style and fail to take into account important differences based on cognitive development. Several strategies are described to improve the quality and effectiveness of these materials.


Frequency, epidemiology, risk factors, clinical and bacteriological features of enterococcal disease in patients with HIV infection in a decade survey.
In order to assess the frequency and clinical significance of Enterococcus spp. infection during HIV disease, the epidemiological features, risk factors, microbiological issues, and therapeutic perspectives of all the 148 consecutive episodes observed in the past decade were analyzed. The overall frequency of these complications (which involved the genito-urinary tract in over 75% of cases) regarded 5.3% of all admission for HIV disease, with a clear prevalence of Enterococcus faecalis as the causative agent (86.5% of episodes), and a proportionally elevated frequency of polymicrobial infection (45.9% of cases). Among the 148 cultured bacterial strains, a complete susceptibility to glycopeptide antibiotics was documented, together with favorable sensitivity levels against semisynthetic penicillins, followed by chloramphenicol, macrolides, and clindamycin. An advanced underlying HIV disease characterized by a concurrent, severe immunodeficiency, concomitant, prolonged neurological complications, hospitalization itself (with prevalence of nosocomial infection), recourse to invasive diagnostic and/or therapeutic procedures, and prior administration of broad spectrum antimicrobial agents, all seem to support HIV-associated enterococcal disease (mostly involving the genito-urinary tract). The adjunct of neutropenia, a very low CD4+ lymphocyte count, and severe AIDS-defining illnesses represented significant risk factors for hematogenous dissemination of this bacterial infection with potentially life-threatening consequences (16.1% of lethal cases among our septic patients).


Surgical re-utilization of a pulmonary valve graft after failed percutaneous treatment.
The case is reported of a 22-year-old woman with severe right ventricular outflow tract (RVOT) homograft regurgitation and stenosis, after the repair of tetralogy of Fallot and complete atrioventricular canal, who was scheduled for percutaneous pulmonary valve implantation. In the catheterization laboratory, immediately after implantation, the stented pulmonary valve became dislodged back into the right ventricle. The patient required an emergency re-sternotomy in the operating room. When the RVOT had been incised the stented valve was rescued and successfully repositioned under direct surgical vision. The patient had an uneventful clinical outcome and was discharged home in good clinical condition, with a new, well-functioning pulmonary valve.


Identifying issue frames in text.
Framing, the effect of context on cognitive processes, is a prominent topic of research in psychology and public opinion research. Research on framing has traditionally relied on controlled experiments and manually annotated document collections. In this paper we present a method that allows for quantifying the relative strengths of competing linguistic frames based on corpus analysis. This method requires little human intervention and can therefore be efficiently applied to large bodies of text. We demonstrate its effectiveness by tracking changes in the framing of terror over time and comparing the framing of abortion by Democrats and Republicans in the U.S.


[A case of spontaneous perforation of a tension ulceration of the posterior vaginal vault in procidentia with subsequent small bowel prolapse (author's transl)].
A case of spontaneous perforation of a tension ulceration in procidentia in an 82 year old woman is reported. A similar case has not been reported in the literature. The extra-ordinary rarity of this observation justifies the publication of this case. The main etiologic factor is considered to be a local perfusion problem of the tissue due to arterial sclerosis of the terminal vessels of the area. The small bowel was replaced. The uterus was replaced. A vaginal packing with clauden and later local treatment of the vaginal ulcers resulted in spontaneous closure of the fistula, histology of the margin of the fistula showed inflammation only and no malignant change. Treatment was completed by a subtotal vaginal colpocleisis according to Labhardt.


Development of neuropsychological evaluation screening tool: An education-free cognitive screening instrument.
Due to the paucity of quick, cognitive screening tools available in India that are independent of cultural and educational influences, a 6-item paper and pencil test, covering areas of memory, executive functioning, attention, and visuospatial ability domains - the Neuropsychological Evaluation Screening Tool (NEST) was developed. NEST was administered to 84 healthy controls to analyze, revise, and review items. In the second phase, 408 patients, above 16 years of age, with their educational level ranging from being illiterate to having greater than 25 years of education, with various neurological and psychiatric conditions were independently administered NEST, Hindi Mental State Examination (HMSE), and a detailed cognitive evaluation using PGI Memory Scale (PGIMS). Using receiver operating characteristics analysis for 341 patients, ≥3 was identified as the optimum cut-off for NEST. NEST could correctly classify 87.9% of the patients with an impaired vs. an intact cognition. The diagnostic characteristics of NEST with PGIMS were sensitivity (95% CI): 94.78% (91.1, 97.3); specificity (95% CI): 60.31% (51.3, 68.7); positive predictive value (95% CI): 80.74% (78.1, 93.0); and negative predictive value (95% CI): 86.81% (75.6, 85.3). NEST had an 82.5% agreement (95% CI: 78.1, 86.2) with PGIMS. On the other hand, the diagnostic characteristics of HMSE with PGIMS were sensitivity (95% CI): 73.79% (67.5, 79.3); specificity (95% CI): 82.44% (74.8, 88.5); positive predictive value (95% CI): 88.02% (82.5, 92.2); and negative predictive value (95% CI): 64.3% (56.5, 71.5). HMSE had a 76.95% (95% CI: 72.2, 81.1) agreement with PGIMS. NEST has better sensitivity compared to HMSE for detecting cognitive impairment when compared to a detailed evaluation at all educational levels.


Leptin and chronic kidney diseases.
Chronic kidney diseases (CKD), a common outcome of various kidney diseases, cause a series of refractory complications, which lead to great economic burdens on patients. The clinical outcomes of CKD depend on various factors, including metabolic disorders. Leptin, a peptide hormone, produced in adipose tissues, plays an important role in regulating food consumption and energy expenditure. Leptin also influences the immune system and hematopoiesis. Increased leptin status is observed in CKD, leptin deficiency attenuates the immune response in nephritis. Conversely, leptin inhibits the development of obesity, which is closely associated glomerular disorder. Now, the precise role of leptin in CKD remains elusive. This review will give an integrated understanding of the potential role of leptin and its interactions with other signal molecules in CKD.


Conformational changes in receptor tyrosine kinase signaling: an ErbB garden of delights.
The ErbB family of receptor tyrosine kinases plays important roles in cell proliferation, differentiation, and apoptosis. Recent structural studies of these receptors have demonstrated dramatic conformational effects that are critical to their ligand binding and activation, and have shown that these receptors provide levels of control beyond the classic dimerization/activation mechanism. These results indicate that this class of receptors has evolved subtle regulatory mechanisms via genetic and protein structural changes to influence their effects on cell behaviors.


Potential biomarkers for bipolar disorder: Where do we stand?
Bipolar disorder (BD) is a severe, recurrent mood disorder, associated with a significant morbidity and mortality, with high rates of suicides and medical comorbidities. There is a high risk of mood disorders among the first-degree relatives of patients with BD. In the current clinical practice, the diagnosis of BD is made by history taking, interview and behavioural observations, thereby lacking an objective, biological validation. This approach may result in underdiagnosis, misdiagnosis and eventually poorer outcomes. Due to the heterogeneity of BD, the possibility of developing a single, specific biomarker is still remote; however, there is a set of promising biomarkers which may serve as predictive, prognostic or treatment markers in the future. The review presents a critical appraisal and update on some of the most promising candidates for biomarkers, namely, neuroimaging markers, peripheral biomarkers and genetic markers, including a brief discussion on cognitive endophenotypes as indicative of genetic risk. The lessons learnt from other fields and specialties in medicine need to be applied to psychiatry to translate the knowledge from 'bench to bedside' by means of clinically useful biomarkers. Overall, the biomarkers may help in pushing the shift towards personalized medicine for psychiatric patients.


How information literacy influences creative skills among medical students? The mediating role of lifelong learning.
This research investigated the influence of information literacy on the creative skills of medical students through the mediation of lifelong learning. A cross-sectional survey was conducted for data collection among medical students, recruited through a stratified convenient sampling procedure, of Khyber Pakhtunkhwa, Pakistan. The questionnaire was personally administered by visiting each college with written permission. A total of 473 survey responses were collected and analysed using the partial least squares structural equation modelling. The results revealed that the information literacy of medical students had a direct and indirect but positive influence on their creative skills. Lifelong learning not had a direct but positive effect on creative skills but also mediated the relationship between information literacy and creative skills. The empirical evidence for how information literacy influences creative skills through the mediated role of lifelong learning may inform policy and practice for information literacy instructions. These results may help academicians and information specialists to initiate a credited or integrated course on information literacy in the curriculum of medical students not only in Pakistan but also in other developing countries. This research would be a worthwhile contribution to the existing research on information literacy as the mediated role of lifelong learning between information literacy and creative skills has never been examined so far.


Artificial intelligence in clinical pharmacology: A case study and scoping review of large language models and bioweapon potential.
This paper aims to explore the possibility of employing large language models (LLMs) - a type of artificial intelligence (AI) - in clinical pharmacology, with a focus on its possible misuse in bioweapon development. Additionally, ethical considerations, legislation and potential risk reduction measures are analysed. The existing literature is reviewed to investigate the potential misuse of AI and LLMs in bioweapon creation. The search includes articles from PubMed, Scopus and Web of Science Core Collection that were identified using a specific protocol. To explore the regulatory landscape, the OECD.ai platform was used. The review highlights the dual-use vulnerability of AI and LLMs, with a focus on bioweapon development. Subsequently, a case study is used to illustrate the potential of AI manipulation resulting in harmful substance synthesis. Existing regulations inadequately address the ethical concerns tied to AI and LLMs. Mitigation measures are proposed, including technical solutions (explainable AI), establishing ethical guidelines through collaborative efforts, and implementing policy changes to create a comprehensive regulatory framework. The integration of AI and LLMs into clinical pharmacology presents invaluable opportunities, while also introducing significant ethical and safety considerations. Addressing the dual-use nature of AI requires robust regulations, as well as adopting a strategic approach grounded in technical solutions and ethical values following the principles of transparency, accountability and safety. Additionally, AI's potential role in developing countermeasures against novel hazardous substances is underscored. By adopting a proactive approach, the potential benefits of AI and LLMs can be fully harnessed while minimizing the associated risks.


Anaesthesia for daycase gynaecological laparoscopy: a survey of clinical practice in the United Kingdom.
Gynaecological laparoscopy is a daycase procedure that can be associated with significant morbidity and patients may require admission to hospital for overnight stay. Following a decision to administer intraperitoneal bupivacaine routinely to such patients in our day surgery unit, we wished to establish whether this was routine practice elsewhere. We therefore carried out a postal survey of consultant anaesthetists in the UK who regularly anaesthetise patients undergoing daycase gynaecological laparoscopy, addressing a number of clinical issues. The results of the survey are presented, discussed and compared with published advice.


The prophylactic effect of dexamethasone on postoperative sore throat in prone position surgery.
Sore throat and hoarseness are common complications after general anesthesia with tracheal intubation. The position for patients can affect the incidence of postoperative sore throat (POST) by causing displacement of the endotracheal tube. This study investigated the prophylactic effect of dexamethasone in prone position surgeries. One hundred-fifty patients undergoing lumbar spine surgery (18-75 yr) were randomly allocated into the normal saline group (group P, n = 50), dexamethasone 0.1 mg/kg group (group D1, n = 50) or dexamethasone 0.2 mg/kg group (group D2, n = 50). The incidence and severity of POST, hoarseness, and cough were measured using direct interview at 1, 6, and 24 h after tracheal extubation. The severity of POST, hoarseness, and cough were graded using a 4-point scale. At 1, 6, and 24 h after extubation, the incidence of sore throat was significantly lower in group D1 (1 h; P = 0.015, 6 h; P < 0.001, 24 h; P = 0.038) and group D2 (1 h; P < 0.001, 6 h; P < 0.001, 24 h; P = 0.017) compared to group P. There were less number of patients in the groups D1 and D2 than group P suffering from moderate grade of POST at 1, 24 h after extubation. The incidence of hoarseness at 1, 6, and 24 h after extubation was significantly lower in groups D2 than group P (P < 0.001). There were no significant differences in the incidence of cough among the three groups. The prophylactic use of dexamethasone 0.1 mg/kg and 0.2 mg/kg in prone surgery reduces the incidence of postoperative sore throat and dexamethasone 0.2 mg/kg decreases the incidence of hoarseness.


Analysis of Renal and Cardiac Outcomes in Male Participants in the Fabry Outcome Survey Starting Agalsidase Alfa Enzyme Replacement Therapy Before and After 18 Years of Age.
To determine the impact of initiating enzyme replacement therapy (ERT) with agalsidase alfa early in the course of Fabry disease, we evaluated renal and cardiac outcomes for ≤10 years after ERT initiation in males from the Fabry Outcome Survey (FOS). Male patients from FOS were stratified into three cohorts by age at ERT initiation: ≤18 years (cohort 1), >18 and ≤30 years (cohort 2), and >30 years (cohort 3). Analysis included age at symptom onset, diagnosis, and ERT initiation; ERT duration; FOS-Mainz Severity Score Index (FOS-MSSI); estimated glomerular filtration rate (eGFR); proteinuria level; and left ventricular mass indexed to height (LVMI). Mixed-effect models estimated renal and cardiac outcomes during follow-up between and within cohorts. The analysis included 560 male patients: 151 (27.0%) in cohort 1, 155 (27.7%) in cohort 2, and 254 (45.4%) in cohort 3. Mean±SD duration of ERT for cohorts 1, 2, and 3 was 6.3±4.3, 8.6±4.9, and 7.9±4.9 years, respectively. Mean±SD baseline FOS-MSSI scores increased with age from 9.8±7.2 in cohort 1 to 24.7±11.4 in cohort 3. Cohort 3 showed the lowest baseline mean±SD value for eGFR (87.1±29.0 mL/min/1.73m2) and highest baseline mean±SD values for proteinuria (801.9±952.6 mg/day) and LVMI (56.7±16.0 g/m2.7) among the three cohorts. Evaluation of mean annual rates of change in eGFR, proteinuria, and LVMI revealed no significant differences in any parameter for cohort 1. For cohort 2, proteinuria and LVMI remained stable, whereas eGFR significantly deteriorated annually (-1.12 mL/min/1.73m2; P<0.001). Cohort 3 demonstrated significant annual deteriorations in eGFR (-2.60 mL/min/1.73m2; P<0.001), proteinuria (+34.10 mg/day; P<0.001), and LVMI (+0.59 g/m2.7; P=0.001). Renal and/or cardiac disease progression appears attenuated in patients starting ERT in childhood or early adulthood versus patients starting ERT in later adulthood. These findings support early ERT initiation in Fabry disease. ClinicalTrials.gov identifier: NCT03289065.


An appraisal of physico-chemical and microbiological characteristics of Nanmangalam Reserve Forest soil.
A detailed evaluation was performed on the soils of Nanmangalam Reserve Forest (NRF) in order to understand its physico-chemical, microbiological and enzymatic characteristics. The results of analysis showed that soil pH was directly proportional to the soil depth and the soil moisture content was irreversibly related to varying soil depth. Soil organic carbon was positively correlated with (p < 0.01) with total nitrogen, total bacterial count, cellulytic microbes, nitrogen-fixing bacteria, microbial biomass carbon, dehydrogenase activity and soil respiration. During summer, microbial population in the organic layer was more diverse than in the deepest layer. Analysis showed that NRF had low organic carbon content (less than 1%), microbial biomass, nutrient and functional microbes. The overall results of the analysis reinstate that Nanmangalam forest soil is undergoing degradation.


Effect of antibiotics and chemotherapeutics on the cytotoxic reaction between HL-A antigens and corresponding sera.
Effects of antibiotics and chemotherapeutics on the interaction between the HL-A antigens and the corresponding lymphocytotoxic sera vary from case to case. Streptomycin, oleandomycin, cephaloridine and kanamycin completely inhibit the cytotoxic reaction when added in the first or second stage of the test. Cytembena weakens the reaction while chlortetracyclin exhibits various effects. The rest of the drugs under investigation proved ineffective.


Agreement between heart failure patients and providers in assessing New York Heart Association functional class.
Uncertainty persists regarding whether patient assessment of New York Heart Association (NYHA) functional classification should be preferred over provider assessment among patients with heart failure (HF). To compare patient against provider NYHA assessments, and both to distance walked on a 6-minute walk test (6MWT) among patients with HF. In this prospective study, we enrolled 101 HF patients who self-assessed NYHA classification. Health care providers who were blinded to patient ratings of NYHA also rated NYHA. Patients completed a 6MWT according to a standardized protocol. We used Spearman coefficients (rs) to evaluate the correlations between variables. Patient- and provider-determined NYHA class were poorly correlated, but the relationship was statistically significant (rs = 0.40, p < 0.001). Patients consistently reported better NYHA class (class I: 72% vs 15%) than providers. Provider-determined NYHA had a stronger correlation with 6MWT distance (rs = -0.36, p < 0.001 vs. rs = -0.22, p = 0.03). Providers assigned a worse class to older patients who had comorbidity; patients with dyspnea and longer HF duration assigned themselves a worse class. Patients and providers exhibited poor agreement in NYHA assignment.


No association between DCP1 genotype and late-onset Alzheimer disease.
In a study of 261 patients with Alzheimer disease (AD) and 306 cognitively normal control subjects from Germany, Switzerland, and Italy, we found no association between genotype counts or allelic frequencies of DCP1, the gene encoding angiotensin-converting enzyme. In accordance with several other studies, our data could not confirm previous association findings. Critical review about all studies available on DCP1 genotyping and AD, age-associated cognitive decline, longevity, and other conditions revealed remarkable inconsistencies. Several studies showed significant deviations of genotype counts from Hardy Weinberg equilibrium (HWE). Deviations from HWE may limit the comparability of study results and require clarification before drawing conclusions with respect to disease risk, health conditions, or longevity in association with DCP1 genotype.


Delayed Appendectomy Is Safe in Patients With Acute Nonperforated Appendicitis.
The present study examined whether acute, nonperforated appendicitis is a surgical emergency requiring immediate intervention or a disease that can be treated with a semielective operation. Immediate appendectomy has been the gold standard in the treatment of acute appendicitis because of the risk of pathologic progression. However, this time-honored practice has been recently challenged by studies suggesting that appendectomies can be elective in some cases and still result in positive outcomes. This was a retrospective study using the charts of patients who underwent an appendectomy for acute, nonperforated appendicitis between January 2007 and February 2012. Patients were divided into 2 groups for comparison: an immediate group (those who were moved to an operating room within 12 hours after hospital arrival) and a delayed group (those within 12 to 24 hours after hospital arrival). The end points were conversion rate, operative time, perforation rate, complication rate, readmission rate, length of hospital stay, and medical costs. Of 1805 patients, 1342 (74.3%) underwent immediate operation within 12 hours after hospital arrival, whereas 463 (25.7%) underwent delayed operation within 12 to 24 hours. There were no significant differences in open conversion, operative time, perforation, postoperative complications, and readmission between the 2 groups. Length of hospital stay was significantly greater (3.7 ± 1.7 days) and medical costs were also greater [$2346.30 ± $735.30 (US dollars)] in the delayed group than in the immediate group [3.1 ± 1.9 days; P = 0.000 and $2257.80 ± $723.80 (US dollars); P = 0.026]. Delayed appendectomy is safe for patients with acute nonperforated appendicitis.


NF-kB-dependent activation of STAT3 by H. pylori is suppressed by TFF1.
H. pylori infection is the main risk factor for gastric cancer. In this study, we investigated H. pylori-mediated activation of STAT3 and NF-κB in gastric cancer, using in vitro and in vivo models. To investigate the activation of NF-κB and STAT3 by H. pylori strains we used in vitro and in vivo mouse models, western blots, immunofluorescence, ChIP Assay, luciferase and quantitative real-time PCR assays. Following infection with H. pylori in vitro, we found an earlier phosphorylation of NF-kB-p65 (S536), followed by STAT3 (Y705). Immunofluorescence, using in vitro and in vivo models, demonstrated nuclear localization of NF-kB and STAT3, following H. pylori infection. NF-kB and STAT3 luciferase reporter assays confirmed earlier activation of NF-kB followed by STAT3. In vitro and in vivo models demonstrated induction of mRNA expression of IL-6 (p < 0.001), VEGF-α (p < 0.05), IL-17 (p < 0.001), and IL-23 (p < 0.001). Using ChIP, we confirmed co-binding of both NF-kB-p65 and STAT3 on the IL6 promoter. The reconstitution of Trefoil Factor 1 (TFF1) suppressed activation of NF-kB with reduction in IL6 levels and STAT3 activity, in response to H. pylori infection. Using pharmacologic (BAY11-7082) and genetic (IκB super repressor (IκBSR)) inhibitors of NF-kB-p65, we confirmed the requirement of NF-kB-p65 for activation of STAT3, as measured by phosphorylation, transcription activity, and nuclear localization of STAT3 in in vitro and in vivo models. Our findings suggest the presence of an early autocrine NF-kB-dependent activation of STAT3 in response to H. pylori infection. TFF1 acts as an anti-inflammatory guard against H. pylori-mediated activation of pro-inflammatory networks.


Identification of the larvae of the Simulium damnosum complex from Nigeria by analysis of cuticular hydrocarbons.
The larvae of three sibling species of the Simulium damnosum complex were studied with a view to identification, using a Gas Liquid Chromatograph to analyze the hydrocarbons in the cuticular wax extracts. Multivariate statistics were applied to the chromatographic data to differentiate three sibling species: S. damnosum s.s., S. squamosum and S. yahense. Paired comparisons between the species gave greater than 96% correct classifications in all cases.


Quantum dot as a drug tracer in vivo.
Quantum dots (QDs) have been applied to a wide range of biological studies by taking advantage of their fluorescence properties. There is almost no method to trace small molecules including medicine. Here, we used QDs for fluorescent tracers for medicine and analyzed their kinetics and dynamics. We conjugated QDs with captopril, anti-hypertensive medicine, by an exchange reaction while retaining the medicinal properties. We investigated the medicinal effect of QD-conjugated captopril (QD-cap) in vitro and in vivo. We also evaluated the concentration and the distribution of the QD-cap in the blood and the organs with their fluorescence. We demonstrate that the QD-cap inhibits the activity of ACE in vitro. The QD-cap reduced the blood pressure of hypertensive model rats. The concentration of the QD-cap in the blood was measured by using the standard curve of the fluorescence intensity. The blood concentration of the QD-cap decrease exponentially and QD-cap has approximately the same half-life as that of captopril. In addition, the fluorescence of the QDs revealed that QD-cap accumulates in the liver, lungs, and spleen. We succeeded in analyzing the dynamics and kinetics of small molecules using fluorescence of QDs.


Effect of fluorotelomer alcohol chain length on aqueous solubility and sorption by soils.
Fluorotelomer alcohols (FTOHs) are a group of polyfluorinated alkyl chemicals that have been widely studied as precursorsto perfluorocarboxylates such as perfluorooctanoic acid and for which knowledge on their fate in soils is sparse. The solubility and sorption by soil of the homologous 4:2 to 10:2 FTOHs were measured in water or cosolvent/ water solutions. For the smaller 4:2 and 6:2 FTOHs, solubility and sorption could be measured adequately in aqueous systems although transformation was apparent even in gamma-irradiated and autoclaved systems. Sorption coefficients estimated by measuring both sorbed and solution-phase concentrations were not significantly affected by the biotransformation process. The use of cosolvents was employed for probing the behavior of the longer-chain FTOHs with limited aqueous solubility. A single log-linear correlation between aqueous solubility and modified McGowan molar volumes resulted for the n-alkanols and FTOHs. Soil organic carbon (OC) consistently appeared to be the key soil property influencing sorption of the FTOHs while the perfluorocarbon chain length was the dominant structural feature influencing solubility and sorption. Each CF2 moiety decreased the aqueous solubility by -0.78 log units (compared to 0.60 log units for each CH2 addition in hydrogenated primary alcohols), and increased OC-normalized sorption coefficients (Koc) by -0.87 log units. Good log-log linear correlations between Koc and both octanol-water partition coefficients and solubility were observed for the FTOHs.


Socioeconomic inequalities in caries experience, care level and dental attendance in primary school children in Belgium: a cross-sectional survey.
Oral health inequality in children is a widespread and well-documented problem in oral healthcare. However, objective and reliable methods to determine these inequalities in all oral health aspects, including both dental attendance and oral health, are rather scarce. To explore oral health inequalities and to assess the impact of socioeconomic factors on oral health, oral health behaviour and dental compliance of primary school children. Data collection was executed in 2014 within a sample of 2216 children in 105 primary schools in Flanders, by means of an oral examination and a validated questionnaire. Intermutual Agency database was consulted to objectively determine individuals' social state and frequency of utilisation of oral healthcare services. Underprivileged children were compared with more fortunate children for their mean DMFt, DMFs, plaque index, care index (C, restorative index (RI), treatment index (TI), knowledge and attitude. Differences in proportions for dichotomous variables (RI100%, TI100% and being a regular dental attender) were analysed. The present study was approved by the Ethics Committee of the University Hospital Ghent (2010/061). All parents signed an informed consent form prior to data collection. All schools received information about the study protocol and agreed to participate. Children requiring dental treatment or periodic recall were referred to the local dentist. Underprivileged children had higher D1MFT (95% CI 0.87 to 1.36), D3MT (95% CI 0.30 to 0.64), plaque scores (95% CI 0.12 to 0.23) and lower care level (p<0.02). In the low-income group, 78.4% was caries-free, compared with 88.4% for the other children. Half of the low-income children could be considered as regular dental attenders, while 12.6% did not have any dental visit during a 5-year period. Oral health, oral hygiene, oral healthcare level and dental attendance patterns are negatively affected by children's social class, leading to oral health inequalities in Belgian primary school children.


Production of recombinant human colony stimulating factors in yeast.
Efficient yeast expression and purification systems for production of recombinant human GM-CSF, IL-3 and G-CSF have been established. Though yeast-derived production of recombinant CSFs (through the use of secretion based system) allows for generation of native molecules which can then be readily separated from fermentation broth, in many instances, natural cDNAs have had to be altered to allow for efficient expression, as well as production of a less heterogeneous product. In the case of CSFs described herein, beneficial mutations (made through site-directed mutagenesis) have included elimination of potential N-linked glycosylation sites, removal of KexII protease recognition sites (notably alterations in dibasic sequences) and elimination of extraneous cysteine residues which might complicate isolation of a homogeneous product due to intermolecular disulfide bonding.


The characteristics of genistin-induced inhibitory effects on intestinal motility.
Genistin belongs to isoflavones. Based on the facts that genistin exerts inhibitory effects on the contractility of vascular smooth muscle,the present study was designed to characterize the effects of genistin on intestinal contractility and evaluate its potential clinical implication. Ex vivo [isolated jejunal segment (IJS) of rat], in vitro, and in vivo assays were used in the study. The results indicated that genistin (5-80 μmol/L) inhibited the contraction of IJS in a dose-dependent manner and inhibited the increased-contractility of IJS induced by acetylcholine (ACh), histamine, high Ca(2+), and erythromycin, respectively. The inhibitory effects of genistin were correlated with the stimulation of alpha adrenergic and beta adrenergic receptors since these inhibitory effects were significantly blocked in the presence of phentolamine and propranolol respectively. No further inhibitory effects of genistin were observed in the presence of verapamil or in Ca(2+)-free condition, indicating genistin-induced inhibitory effects are Ca(2+)-dependent. Genistin decreased myosin light chain kinase (MLCK) protein contents and MLCK mRNA expression in IJS, and inhibited both phosphorylation and Mg(2+)-ATPase activity of purified myosin, implicating that the decrease of MLCK contents and inhibition of MLCK activity are involved in the genistin-induced inhibitory effects. The study suggests the potential clinical implications of genistin in relieving intestinal hypercontractility.


Chemical synthesis and serology of disaccharides and trisaccharides of phenolic glycolipid antigens from the leprosy bacillus and preparation of a disaccharide protein conjugate for serodiagnosis of leprosy.
We examined the structural requirements within the species-specific 3,6-di-O-methyl-beta-D-glucopyranosyl-(1 leads to 4)-2,3-di-O-methyl- alpha-L-rhamnopyranosyl-(1 leads to 2)-3-O-methyl-alpha-L-rhamnopyranose unit of the phenolic glycolipid I antigen of Mycobacterium leprae for binding to anti-glycolipid immunoglobulin M from human leprosy sera. We used chemically defined, partially deglycosylated fragments of phenolic glycolipid I, two other minor M. leprae-specific phenolic glycolipids (those containing 6-O-methyl-beta-D-glucopyranosyl-(1 leads to 4)-2,3-di-O-methyl-alpha- L-rhamnopyranosyl-(1 leads to 2)-3-O-methyl-alpha-L-rhamnopyranose and 3,6-di-O-methyl-beta-D-glucopyranosyl-(1 leads to 4)-3-O-methyl-alpha- L-rhamnopyranosyl-(1 leads to 2)-3-O-methyl-alpha-rhamnopyranose units), and phenolic glycolipids from other mycobacteria. Additionally, the trisaccharide of phenolic glycolipid I, the 3,6-di-O-methyl-beta-D-glucopyranosyl-(1 leads to 4)-2, 3-di-O-methyl-alpha-L-rhamnopyranose, the 6-O-methyl-beta-D-glucopyranosyl-(1 leads to 4)-2,3-di-O-methyl-alpha- L-rhamnopyranose, and the beta-D-glucopyranosyl-(1 leads to 4)-2,3-di-O-methyl-alpha- L-rhamnopyranose disaccharides were synthesized and characterized, and their activities were examined. Only the phenolic glycolipids containing 3,6-di-O-methyl-beta-D-glucopyranosyl at the nonreducing terminus were efficient in binding the anti-glycolipid immunoglobulin M, and the 3,6-di-O-methyl-beta-D-glucopyranosyl-containing di- and trisaccharides were the most effective in inhibiting this binding. Thus, the 3,6-di-O-methyl-beta-D-glucopyranosyl substituent was recognized as the primary antigen determinant in phenolic glycolipid I. With this information, bovine serum albumin containing reductively aminated 3,6-di-O-methyl-beta-D-glucopyranosyl-(1 leads to 4)-2,3-di-O-methyl- L-rhamnose was prepared and shown to be highly active in the serodiagnosis of leprosy.


Subtle Ecological Gradient in the Tropics Triggers High Species-Turnover in a Local Geographical Scale.
Our perception of diversity, including both alpha- and beta-diversity components, depends on spatial scale. Studies of spatial variation of the latter are just starting, with a paucity of research on beta-diversity patterns at smaller scales. Understanding these patterns and the processes shaping the distribution of diversity is critical to describe this diversity, but it is paramount in conservation too. Here, we investigate the diversity and structure of a tropical community of herbivorous beetles at a reduced local scale of some 10 km2, evaluating the effect of a small, gradual ecological change on this structure. We sampled leaf beetles in the Núi Chúa National Park (S Vietnam), studying changes in alpha- and beta-diversity across an elevation gradient up to 500 m, encompassing the ecotone between critically endangered lowland dry deciduous forest and mixed evergreen forest at higher elevations. Leaf beetle diversity was assessed using several molecular tree-based species delimitation approaches (with mtDNA cox1 data), species richness using rarefaction and incidence-based diversity indexes, and beta-diversity was investigated decomposing the contribution of species turnover and nestedness. We documented 155 species in the area explored and species-richness estimates 1.5-2.0x higher. Species diversity was similar in both forest types and changes in alpha-diversity along the elevation gradient showed an expected local increase of diversity in the ecotone. Beta-diversity was high among forest paths (average Sørensen's dissimilarity = 0.694) and, tentatively fixing at 300 m the boundary between otherwise continuous biomes, demonstrated similarly high beta-diversity (Sørensen's dissimilarity = 0.581), with samples clustering according to biome/elevation. Highly relevant considering the local scale of the study, beta-diversity had a high contribution of species replacement among locales (54.8%) and between biomes (79.6%), suggesting environmental heterogeneity as the dominant force shaping diversity at such small scale, directly and indirectly on the plant communities. Protection actions in the Park, especially these addressed at the imperative conservation of dry forest, must ponder the small scale at which processes shape species diversity and community structure for inconspicuous, yet extraordinarily diverse organisms such as the leaf beetles.


The Pds1 anaphase inhibitor and Mec1 kinase define distinct checkpoints coupling S phase with mitosis in budding yeast.
In most eukaryotic cells, DNA replication is confined to S phase of the cell cycle [1]. During this interval, S-phase checkpoint controls restrain mitosis until replication is complete [2]. In budding yeast, the anaphase inhibitor Pds1p has been associated with the checkpoint arrest of mitosis when DNA is damaged or when mitotic spindles have formed aberrantly [3] [4], but not when DNA replication is blocked with hydroxyurea (HU). Previous studies have implicated the protein kinase Mec1p in S-phase checkpoint control [5]. Unlike mec1 mutants, pds1 mutants efficiently inhibit anaphase when replication is blocked. This does not, however, exclude an essential S-phase checkpoint function of Pds1 beyond the early S-phase arrest point of a HU block. Here, we show that Pds1p is an essential component of a previously unsuspected checkpoint control system that couples the completion of S phase with mitosis. Further, the S-phase checkpoint comprises at least two distinct pathways. A Mec1p-dependent pathway operates early in S phase, but a Pds1p-dependent pathway becomes essential part way through S phase.


Evaluation of functionality of type II toxin-antitoxin systems of Clostridioides difficile R20291.
Clostridioides difficile is a nosocomial, Gram-positive, strictly anaerobic, spore-forming pathogen capable of colonizing and proliferating in the human intestine. In bacteria, it has been shown that the Toxin-Antitoxin systems mediate the cellular response to external stress by initiating processes such as biofilm formation and programmed cell death. This work aims to evaluate the functionality of four type II TA modules of Clostridioides difficile R20291. We performed bioinformatic analysis to search for putative TA systems using the TADB platform. Then we performed a heterologous expression assay to evaluate the functionality of these systems. Our results showed that the MazEF and RelBE systems were functional, suggesting that their corresponding toxins possess an endoribonuclease activity. In conclusion, MazEF and RelBE systems of C. difficile R20291 are functional in a heterologous expression system.


Animal adaptations for tolerance and exploitation of poisonous sulfide.
Many aquatic animal species can survive sulfide exposure to some extent through oxidation of the sulfide, which results mainly in thiosulfate. In several species, sulfide oxidation is localized in the mitochondria and is accompanied by ATP synthesis. In addition, blood-based and intracellular compounds can augment sulfide oxidation. The formation of thiosulfate requires oxygen, which results in an increase in oxygen consumption of some species. If not all sulfide is detoxified, cytochrome C oxidase is inhibited. Under these conditions, a sulfide-dependent anaerobic energy metabolism commences.


[Robot-assisted laparoscopic total hysterectomy in a patient with giant uterine fibroids and complex pelvic adhesions: a case report].
We report a case of giant hysteromyoma and complex pelvic adhesion treated by robotic assisted laparoscopic total hysterectomy and bilateral salpingectomy. The patient was diagnosed with uterine fibroids after physical examination in 1998 but did not receive any treatment, and regular examinations reported progressive growth of the fibroids. Ultrasound suggested multiple uterine fibroids, and pelvic MRI indicated large uterine fibroids with bleeding. Robot-assisted laparoscopic total hysterectomy and bilateral salpingectomy were performed after relevant examinations, and the operation was completed smoothly. The patient was discharged 4 days after surgery with good appearance of the abdominal wall and good recovery during the follow-up. With its unique advantages, robot-assisted laparoscopy provides a minimally invasive surgical approach for giant hysterectomy with complex pelvic adhesions.


MK-801 and NBQX prevent electrically induced status epilepticus.
MUSCARINIC, NMDA and metabotropic glutamate receptor antagonists were tested for anticonvulsant effects in a continuous hippocampal stimulation model in rats in order to identify the receptors involved in the initiation of electrically induced status epilepticus (SE). Whereas the muscarinic receptor antagonists scopolamine and atropine and the metabotropic receptor antagonist L(+)-2-amino-3-phosphonopropionic acid (AP3) did not affect SE initiation, the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) (1 mg kg-1 i.p.) and the non-NMDA ionotropic receptor antagonist 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo(F)-quinoxaline (NBQX) (two doses of 50 micrograms i.c.v.) prevented the induction of SE. It has been shown in a previous study that non-NMDA ionotropic receptors are involved in SE maintenance and it is now suggested that activation of NMDA receptors may principally initiate electrically induced SE, although non-NMDA ionotropic receptors may also be involved.


Simultaneous seeding and infecting of shell vials for rapid detection of cytomegalovirus infection.
Fifty cytomegalovirus isolates were used to infect shell vials containing confluent MRC-5 cell monolayers and shell vials which were seeded with MRC-5 cells at the time of inoculation. All 50 of the isolates were detected by immunofluorescence in shell vials containing confluent monolayers, whereas 39 (78%) of the isolates were detected in shell vials that had been seeded and inoculated simultaneously (P less than 0.001). Preformed monolayers of cells in shell vials provide the most sensitive system for the detection of cytomegalovirus infection.


cis-regulatory sequences responsible for alternative splicing of the Drosophila dopa decarboxylase gene.
The Drosophila dopa decarboxylase gene, Ddc, is expressed in the hypoderm and in specific sets of cells in the central nervous system (CNS). The unique Ddc primary transcript is alternatively spliced in these two tissues. The Ddc CNS mRNA contains all four exons (A through D), whereas the hypodermal mRNA contains only three exons (A, C, and D). To localize cis-regulatory sequences responsible for Ddc alternative splicing, a Ddc minigene and several fusion genes containing various amounts of Ddc sequences fused to fushi tarazu (ftz) exon 1 were constructed and introduced into flies by P-element-mediated germ line transformation. We find that Ddc intron ab and exon B are sufficient to regulate Ddc alternative splicing, since transcripts of a minimal fusion gene containing most of Ddc intron ab and exon B are spliced to exon B in the CNS but not in the hypoderm. These results indicate that Ddc alternative splicing is regulated by either a negative mechanism preventing splicing to exon B in the hypoderm or a positive mechanism activating splicing to exon B in the CNS. Our previous data suggest that Ddc hypodermal splicing is the actively regulated splicing pathway (J. Shen, C. J. Beall, and J. Hirsh, Mol. Cell. Biol. 13:4549-4555, 1993). Here we show that deletion of Ddc intron ab sequences selectively disrupts hypodermal splicing specificity. These results support a model in which Ddc alternative splicing is negatively regulated by a blockage mechanism preventing splicing to exon B in the hypoderm.


An Experimental Evaluation of Adaptogenic Potential of Standardized Epipremnum Aureum Leaf Extract.
Stress is a normal part of everyday life but chronic stress can lead to a variety of stress-related illnesses including hypertension, anxiety, and depression. In the present investigation, standardized leaf extract of Epipremnumaureum was evaluated for its anti-stress potential. For the evaluation of anti-stress activity, groups of mice (n = 6) were subjected to forced swim stress and anoxic stress tolerance test in mice 1h after daily treatment of E.aureumextract. Diazepam (5 mg/kg) was taken as a reference standard. Urinary vanillylmandelic acid (VMA) and ascorbic acid were selected as noninvasive biomarkers to assess the anti-stress activity and plasma cortisol, blood ascorbic acid, and weight of adrenal were measured. The 24 h urinary excretion of VMA and ascorbic acid were determined by spectrophotometric methods in all groups under normal and stressed conditions. The hematological parameters (neutrophils, lymphocytes, and eosinophils) were also determined. Administration of E.aureumat doses of 400 and 600 mg/kg wasfound to be effective in inhibiting the stress induced urinary biochemical changes in a dose-dependent manner. Treatment with E. aureum extract prevents the rise in blood ascorbic acid and plasma cortisol. Moreover, the extract prevented the increase in weight of adrenal gland also significantly increased the anoxia stress tolerance time. Dose-dependent significant reduction in white blood cell count was observed in anoxic stress tolerance test as compared to stressed group. Hence, the present study provides scientific support for the positiveadaptogenic effect of E. aureum extract.


Bioimaging and Biosensing of Ferrous Ion in Neurons and HepG2 Cells upon Oxidative Stress.
Iron ions, as a main component of intracellular labile iron, not only play an important function in oxygen transport, enzymatic reactions, and electron transport but also are vitally important in oxidative stress. In this work, we developed a ratiometric fluorescent biosensor for ferrous ion (Fe2+), in which gold nanoclusters (AuNCs) were synthesized as a stable fluorescent probe and a ligand (FeL) was designed for specific recognition of Fe2+ and conjugated onto AuNCs (AuNC@FeL). Meanwhile, water-soluble sulfocyanine 7 N-hydroxysuccinimide ester (Cy7 NHS ester) was immobilized onto AuNC@FeL as a reference element. The developed ratiometric fluorescent nansosensor displayed good linearity with the concentration of Fe2+ in the range of 1-105 μM, and detection limit was achieved down to 210 nM. In addition, this nanosensor responded to Fe2+ in less than 1.23 s and showed high selectivity against other metal ions, amino acids, and reactive oxygen species. With the advantages of high selectivity and accuracy, as well as quick response and long-term stability, this organic-inorganic ratiometric fluorescent probe was successfully applied in real-time biosensing and bioimaging of Fe2+ in neurons and HepG2 cells. By use of this tool, it was found that the increasing concentration of Fe2+ in live cells was closely related to oxidative stress.


The ethics of coercion in mental healthcare: the role of structural racism.
In mental health ethics, it is generally assumed that coercive measures are sometimes justified when persons with mental illness endanger themselves or others. Coercive measures are regarded as ethically justified only when certain criteria are fulfilled: for example, the intervention must be proportional in relation to the potential harm. In this paper, we demonstrate shortcomings of this established ethical framework in cases where people with mental illness experience structural racism. By drawing on a case example from mental healthcare, we first demonstrate that biases in assessing whether the coercive intervention is proportional are likely, for example, due to an overestimation of dangerousness. We then show that even if proportionality is assessed correctly, and the specific coercive intervention would thus be regarded as ethically justified according to the standard framework, coercion may still be ethically problematic. This is because the standard framework does not consider how situations in which coercive measures are applied arise. If structural racism causally contributes to such situations, the use of coercion can compound the prior injustice of racist discrimination. We conclude that the ethical analysis of coercion in mental healthcare should consider the possibility of discriminatory biases and practices and systematically take the influence of structural discrimination into account.


Accuracy of Korean-Mini-Mental Status Examination Based on Seoul Neuro-Psychological Screening Battery II Results.
The Korean-Mini-Mental Status Examination (K-MMSE) is a dementia-screening test that can be easily applied in both community and clinical settings. However, in 20% to 30% of cases, the K-MMSE produces a false negative response. This suggests that it is necessary to evaluate the accuracy of K-MMSE as a screening test for dementia, which can be achieved through comparison of K-MMSE and Seoul Neuropsychological Screening Battery (SNSB)-II results. The study included 713 subjects (male 534, female 179; mean age, 69.3±6.9 years). All subjects were assessed using K-MMSE and SNSB-II tests, the results of which were divided into normal and abnormal in 15 percentile standards. The sensitivity of the K-MMSE was 48.7%, with a specificity of 89.9%. The incidence of false positive and negative results totaled 10.1% and 51.2%, respectively. In addition, the positive predictive value of the K-MMSE was 87.1%, while the negative predictive value was 55.6%. The false-negative group showed cognitive impairments in regions of memory and executive function. Subsequently, in the false-positive group, subjects demonstrated reduced performance in memory recall, time orientation, attention, and calculation of K-MMSE items. The results obtained in the study suggest that cognitive function might still be impaired even if an individual obtained a normal score on the K-MMSE. If the K-MMSE is combined with tests of memory or executive function, the accuracy of dementia diagnosis could be greatly improved.


Thyroid Cytopathology Cancer Diagnosis from Smartphone Images Using Machine Learning.
We examined the performance of deep learning models on the classification of thyroid fine-needle aspiration biopsies using microscope images captured in 2 ways: with a high-resolution scanner and with a mobile phone camera. Our training set consisted of images from 964 whole-slide images captured with a high-resolution scanner. Our test set consisted of 100 slides; 20 manually selected regions of interest (ROIs) from each slide were captured in 2 ways as mentioned above. Applying a baseline machine learning algorithm trained on scanner ROIs resulted in performance deterioration when applied to the smartphone ROIs (97.8% area under the receiver operating characteristic curve [AUC], CI = [95.4%, 100.0%] for scanner images vs 89.5% AUC, CI = [82.3%, 96.6%] for mobile images, P = .019). Preliminary analysis via histogram matching showed that the baseline model was overly sensitive to slight color variations in the images (specifically, to color differences between mobile and scanner images). Adding color augmentation during training reduces this sensitivity and narrows the performance gap between mobile and scanner images (97.6% AUC, CI = [95.0%, 100.0%] for scanner images vs 96.0% AUC, CI = [91.8%, 100.0%] for mobile images, P = .309), with both modalities on par with human pathologist performance (95.6% AUC, CI = [91.6%, 99.5%]) for malignancy prediction (P = .398 for pathologist vs scanner and P = .875 for pathologist vs mobile). For indeterminate cases (pathologist-assigned Bethesda category of 3, 4, or 5), color augmentations confer some improvement (88.3% AUC, CI = [73.7%, 100.0%] for the baseline model vs 96.2% AUC, CI = [90.9%, 100.0%] with color augmentations, P = .158). In addition, we found that our model's performance levels off after 15 ROIs, a promising indication that ROI data collection would not be time-consuming for our diagnostic system. Finally, we showed that the model has sensible Bethesda category (TBS) predictions (increasing risk malignancy rate with predicted TBS category, with 0% malignancy for predicted TBS 2 and 100% malignancy for TBS 6).


An Integrated Approach Exploring the Synergistic Mechanism of Herbal Pairs in a Botanical Dietary Supplement: A Case Study of a Liver Protection Health Food.
Herbal pairs are used as a bridge between single herb and polyherbal formulas in Traditional Chinese Medicine (TCM) to provide rationale for complicated TCM formulas. The effectiveness and rationality of TCM herbal pairs have been widely applied as a strategy for dietary supplements. However, due to the complexity of the phytochemistry of individual and combinations of herbal materials, it is difficult to reveal their effective and synergistic mechanisms from a molecular or systematic point of view. In order to address this question, UPLC-Q-TOF/MS analysis and System Pharmacology tools were applied to explore the mechanism of action, using a White Peony (Paeoniae Radix Alba) and Licorice (Glycyrrhizae Radix et Rhizoma)-based dietary supplement. A total of sixteen chemical constituents of White Peony and Licorice were isolated and identified, which interact with 73 liver protection-related targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed along with network analysis. Results showed that the synergistic mechanism of the White Peony and Licorice herbal pair was associated with their coregulation of bile secretion and ABC transporter pathways. In addition, Licorice exhibits a specific response to drug and xenobiotic metabolism pathways, whereas White Peony responds to Toll-like receptor signaling, C-type lectin receptor signaling, IL-17 signaling, and TNF signaling pathways, resulting in the prevention of hepatocyte apoptosis and the reduction of immune and inflammation-mediated liver damage. These findings suggest that a White Peony and Licorice herbal pair supplement would have a liver-protecting benefit through complimentary and synergistic mechanisms. This approach provides a new path to explore herbal compatibility in dietary supplements derived from TCM theory.


Sublethal effects of chlorpyrifos-methyl on reproduction in female German cockroaches (Dictyoptera: Blattellidae).
Longevity and lifetime fecundity were significantly reduced after topical application of LC10, LC20, and LC60's of chlorpyrifos-methyl to 2-d-old female German cockroaches, Blattella germanica (L.). Low concentrations (LC10 and LC20) often resulted in failure of the first ootheca to hatch. This effect is temporary, and greater than or equal to 90% of subsequent oothecae hatched normally. Application of an LC60 also resulted in a high percentage of abortions of first oothecae, but also caused greater than 15% inviability in subsequent oothecae.


Gastric bezoars: treatment and prevention.
Gastric bezoars may occur in the normal stomach as a result of ingestion of various objects which do not pass through the pylorus. Most gastric bezoars occur as a complication of previous gastric surgery in which there is a loss of normal pyloric function, hypoperistalsis, and low gastric acidity. They may also occur as a complication of cimetidine therapy. Symptoms include epigastric fullness, regurgitation, nausea and vomiting, and epigastric pain. A simple treatment utilizing an ordinary Teledyne Water Pik jet stream through a gastroscope is described to break up a large phytobezoar. This method is probably the treatment of choice and should be used more widely.


Status Quo Analysis of Physical Fitness Test Data Based on Health Monitoring.
One of the important symbols of a country's level of social progress and the continuous spread of civilization throughout the world includes the level of national physique and health. People's living standards have been significantly improved, and a moderately prosperous society has been preliminarily realized. The national physique should be improved, especially the teenagers who are in the rapid and golden period of physical and psychological development. But not everything develops according to wishes. For the past 20 years, the physical health of Chinese students has been in a downward trend. Therefore, it is urgent to analyze and study the data of adolescent health monitoring and physical fitness test. Through the analysis of D-S evidence theory composition rules, SVM network protocol, and other technologies, the accuracy of adolescent physique monitoring data has been improved by 38.4%, enhanced students' willingness to exercise, 65% of students have enhanced physical health awareness, and a network data platform has been established, which can clearly reflect the physical health of students and summarize all monitoring data information. Teenagers are the future builders and successors of the country, and they play a pivotal role in the entire country. The analysis of the status quo of adolescent physical fitness test data is related to the strength of the country, the rise and fall of the nation, the happiness of the family, and the future of the individual.


Effect of pemetrexed on brain metastases from nonsmall cell lung cancer with wild-type and unknown EGFR status.
We aimed to evaluate the effectiveness of pemetrexed-based chemotherapy in wild-type nonsmall-cell lung cancer (NSCLC) patients with brain metastases (BM). Brain metastases are a common cause of mortality in NSCLC patients. For epidermal growth factor receptor (EGFR) wild-type patients, therapeutic options for BM are even limited. Pemetrexed-based therapy is a standard care for patients with EGFR-negative, nonsquamous NSCLC. Besides local therapy, pemetrexed is the preferred chemotherapy for wild-type BM patients, but the efficacy is uncertain.We retrospectively studied 138 NSCLC patients with BM whose EGFR status were unknown or wild-type. All patients received first-line pemetrexed-based chemotherapy from 2010 to 2015. Forty-six of 89 patients with unknown EGFR status were treated with EGFR TKIs after progression.Among the 138 patients, 49 (35.5%) were EGFR wild-type and 89 (64.5%) were unknown EGFR status. The median overall survival (OS), and the median intracranial progression-free survival (iPFS) was 21.0 months, 9.5 months, respectively. Patients who received more than 4 cycles of chemotherapy had significantly longer OS than those who received 3 to 4 cycles (Mantel-Byar X-squared = 6.65, P = .001). In the EGFR wild-type group, the median OS, and the median iPFS was 17.7 months, 7.6 months, respectively. And patients treated with pemetrexed plus platinum tended to have a longer OS than those who were treated with pemetrexed alone (P = .078). In the subgroup with unknown EGFR status, we noted a statistically significant improvement in OS for the patients who received EGFR tyrosine kinase inhibitors (TKIs) after progression of 29 months compared to 20.3 months of the EGFR TKIs naïve arm (P = .027).Pemetrexed shows an ideal effectiveness in EGFR wild-type and unknown status NSCLC patients with BM, and has a favorable control on brain localizations. EGFR wild-type patients can significantly benefit from pemetrexed continuation maintenance.