Cognition in patients with post-bariatric hypoglycemia.
Bariatric surgery, a highly effective treatment for obesity and associated comorbidities, may improve cognition and brain volume in parallel with cardiometabolic function. However, some post-bariatric individuals develop post-bariatric hypoglycemia (PBH), which can be frequent and severe. The impact of recurrent hypoglycemia on cognition in PBH is unknown. The objective of this study was to determine whether individuals with PBH display reduced cognitive function compared with postsurgical counterparts without hypoglycemia. Fourteen adults with a history of Roux-en-Y gastric bypass with hypoglycemia (PBH+, n = 7) or without PBH (PBH-, n = 7) completed assessments of memory, executive function, attention, and psychomotor speed. PBH+ individuals displayed significantly decreased performance in category fluency (p < 0.01), category switching (p < 0.01), and category switching accuracy (p < 0.01), compared with PBH- individuals. Performance in the first (p = 0.03) and third intervals (p = 0.045) of verbal fluency was significantly lower in PBH+ individuals versus PBH- individuals. All other assessments did not differ. PBH+ individuals may be at greater risk for cognitive impairment compared with PBH- individuals, as suggested by impaired semantic processing and cognitive flexibility, as well as greater difficulty initiating and sustaining word retrieval.


Motor Recovery of the Affected Hand in Subacute Stroke Correlates with Changes of Contralesional Cortical Hand Motor Representation.
Objective. To investigate the relationship between changes of cortical hand motor representation and motor recovery of the affected hand in subacute stroke. Methods. 17 patients with motor impairment of the affected hand were enrolled in an in-patient neurological rehabilitation program. Hand motor function tests (Wolf Motor Function Test, Action Research Arm Test) and neurophysiological evaluations (resting motor threshold, motor evoked potentials, motor map area size, motor map area volume, and motor map area location) were obtained from both hands and hemispheres at baseline and two, four, and six weeks of in-patient rehabilitation. Results. There was a wide spectrum of hand motor impairment at baseline and hand motor recovery over time. Hand motor function and recovery correlated significantly with (i) reduction of cortical excitability, (ii) reduction in size and volume of cortical hand motor representation, and (iii) a medial and anterior shift of the center of gravity of cortical hand motor representation within the contralesional hemisphere. Conclusion. Recovery of motor function of the affected hand after stroke is accompanied by definite changes in excitability, size, volume, and location of hand motor representation over the contralesional primary motor cortex. These measures may serve as surrogate markers for the outcome of hand motor rehabilitation after stroke.


Incidence, associated factors and clinical impact of severe infections in a large, multicentric cohort of patients with systemic lupus erythematosus.
To estimate the incidence of severe infection and investigate the associated factors and clinical impact in a large systemic lupus erythematosus (SLE) retrospective cohort. All patients in the Spanish Rheumatology Society Lupus Registry (RELESSER) who meet ≥4 ACR-97 SLE criteria were retrospectively investigated for severe infections. Patients with and without infections were compared in terms of SLE severity, damage, comorbidities, and demographic characteristics. A multivariable Cox regression model was built to calculate hazard ratios (HRs) for the first infection. A total of 3658 SLE patients were included: 90% female, median age 32.9 years (DQ 9.7), and mean follow-up (months) 120.2 (±87.6). A total of 705 (19.3%) patients suffered ≥1 severe infection. Total severe infections recorded in these patients numbered 1227. The incidence rate was 29.2 (95% CI: 27.6-30.9) infections per 1000 patient years. Time from first infection to second infection was significantly shorter than time from diagnosis to first infection (p < 0.000). Although respiratory infections were the most common (35.5%), bloodstream infections were the most frequent cause of mortality by infection (42.0%). In the Cox regression analysis, the following were all associated with infection: age at diagnosis (HR = 1.016, 95% CI: 1.009-1.023), Latin-American (Amerindian-Mestizo) ethnicity (HR = 2.151, 95% CI: 1.539-3.005), corticosteroids (≥10mg/day) (HR = 1.271, 95% CI: 1.034-1.561), immunosuppressors (HR = 1.348, 95% CI: 1.079-1.684), hospitalization by SLE (HR = 2.567, 95% CI: 1.905-3.459), Katz severity index (HR = 1.160, 95% CI: 1.105-1.217), SLICC/ACR damage index (HR = 1.069, 95% CI: 1.031-1.108), and smoking (HR = 1.332, 95% CI: 1.121-1.583). Duration of antimalarial use (months) proved protective (HR = 0.998, 95% CI: 0.997-0.999). Severe infection constitutes a predictor of poor prognosis in SLE patients, is more common in Latin-Americans and is associated with age, previous infection, and smoking. Antimalarials exerted a protective effect.


[Repairing widespread traumatic soft tissue defects in lower limb with free latissimus dorsi muscle-skin flaps].
To explore the results of repairing widespread traumatic soft tissue defects in the heels and adjacent regions with free latissimus dorsi muscle-skin flaps. From March 1998 to May 2005, 10 cases of widespread traumatic soft tissue defects in the heels and adjacent regions were repaired with free latissimus dorsi muscle-skin flaps; Of the 10 patients, 9 were male and 1 was female, whose ages ranged from 32 to 60 years, and the disease course was 2 hours to 2 months. The defect was by plough-machine injury in 5 cases, by crush injury in 2 cases, by snake injury in 2 cases, and electricity injury in 1 case. Eight cases of defects involved in the posterior of heel and leg, the defect area ranged from 21 cm x 12 cm to 35 cm x 15 cm; 2 cases had widespread soft tissue defects on heel, ankle, sole and dorsal foot, and the defect area was 27 cmX 14 cm and 30 cm x 21 cm respectively. All cases were accompanied by the exposure of bone; 6 cases by fracture; 4 cases by open infection of ankle joint; and 2 cases by injuries of the posterior tibial vessel and the tibial nerve. The sizes of the dissected flap ranged from 25 cm x 14 cm to 33 cm x 24 cm. The donor sites were covered by large mid-thickness flap. There were no postoperative complication of vascular crisis and infection. Ten flaps survived completely and the wounds healed by first intention. After a follow-up of 3 to 24 months, five cases received two-stage plastic operation because bulky flaps bring some trouble in wearing shoes. In 5 cases of reconstructed sensation, two cases recovered pain and temperature sensation. All cases recovered the abilities to stand and walk without ulcer complication. The free latissimus dorsi muscle-skin flap is an ideal flap for repairing widespread traumatic soft tissue defects and infectious wounds with muscle defects and bone exposure in the heel and adjacent regions, because it has such advantages as adequate blood supply, big dermatomic area, and excellent ability to resist infection.


Alkylation of Sulfonamides with Trichloroacetimidates under Thermal Conditions.
An intermolecular alkylation of sulfonamides with trichloroacetimidates is reported. This transformation does not require an exogenous acid, base, or transition metal catalyst; instead the addition occurs in refluxing toluene without additives. The sulfonamide alkylation partner appears to be only limited by sterics, with unsubstituted sulfonamides providing better yields than more encumbered N-alkyl sulfonamides. The trichloroacetimidate alkylating agent must be a stable cation precursor for the substitution reaction to proceed under these conditions.


PLAC1-specific TCR-engineered T cells mediate antigen-specific antitumor effects in breast cancer.
Placenta-specific 1 (PLAC1), a novel cancer-testis antigen (CTA), is expressed in a number of different human malignancies. It is frequently produced in breast cancer, serving a function in tumorigenesis. Adoptive immunotherapy using T cell receptor (TCR)-engineered T cells against CTA mediates objective tumor regression; however, to the best of our knowledge, targeting PLAC1 using engineered T cells has not yet been attempted. In the present study, the cDNAs encoding TCRα- and β-chains specific for human leukocyte antigen (HLA)-A*0201-restricted PLAC1 were cloned from a cytotoxic T-lymphocyte, generated by in vitro by the stimulation of CD8+ T cells using autologous HLA-A2+ dendritic cells loaded with a PLAC1-specific peptide (p28-36, VLCSIDWFM). The TCRα/β-chains were linked by a 2A peptide linker (TCRα-Thosea asigna virus-TCRβ), and the constructs were cloned into the lentiviral vector, followed by transduction into human cytotoxic (CD8+) T cells. The efficiency of transduction was up to 25.16%, as detected by PLAC1 multimers. TCR-transduced CD8+ T cells, co-cultured with human non-metastatic breast cancer MCF-7 cells (PLAC1+, HLA-A2+) and triple-negative breast cancer MDAMB-231 cells (PLAC1+, HLA-A2+), produced interferon γ and tumor necrosis factor α, suggesting TCR activation. Furthermore, the PLAC1 TCR-transduced CD8+ T cells efficiently and specifically identified and annihilated the HLA-A2+/PLAC1+ breast cancer cell lines in a lactate dehydrogenase activity assay. Western blot analysis demonstrated that TCR transduction stimulated the production of mitogen-activated protein kinase signaling molecules, extracellular signal-regulated kinases 1/2 and nuclear factor-κB, through phosphoinositide 3-kinase γ-mediated phosphorylation of protein kinase B in CD8+ T cells. Xenograft mouse assays revealed that PLAC1 TCR-transduced CD8+T cells significantly delayed the tumor progression in mice-bearing breast cancer compared with normal saline or negative control-transduced groups. In conclusion, a novel HLA-A2-restricted and PLAC1-specific TCR was identified. The present study demonstrated PLAC1 to be a potential target for breast cancer treatment; and the usage of PLAC1-specific TCR-engineered T cells may be a novel strategy for PLAC1-positive breast cancer treatment.


Insecticide resistance mechanisms in the green peach aphid Myzus persicae (Hemiptera: Aphididae) I: A transcriptomic survey.
Insecticide resistance is one of the best examples of rapid micro-evolution found in nature. Since the development of the first synthetic insecticide in 1939, humans have invested considerable effort to stay ahead of resistance phenotypes that repeatedly develop in insects. Aphids are a group of insects that have become global pests in agriculture and frequently exhibit insecticide resistance. The green peach aphid, Myzus persicae, has developed resistance to at least seventy different synthetic compounds, and different insecticide resistance mechanisms have been reported worldwide. To further characterize this resistance, we analyzed genome-wide transcriptional responses in three genotypes of M. persicae, each exhibiting different resistance mechanisms, in response to an anti-cholinesterase insecticide. The sensitive genotype (exhibiting no resistance mechanism) responded to the insecticide by up-regulating 183 genes primarily ones related to energy metabolism, detoxifying enzymes, proteins of extracellular transport, peptidases and cuticular proteins. The second genotype (resistant through a kdr sodium channel mutation), up-regulated 17 genes coding for detoxifying enzymes, peptidase and cuticular proteins. Finally, a multiply resistant genotype (carrying kdr and a modified acetylcholinesterase), up-regulated only 7 genes, appears not to require induced insecticide detoxification, and instead down-regulated many genes. This study suggests strongly that insecticide resistance in M. persicae is more complex that has been described, with the participation of a broad array of resistance mechanisms. The sensitive genotype exhibited the highest transcriptional plasticity, accounting for the wide range of potential adaptations to insecticides that this species can evolve. In contrast, the multiply resistant genotype exhibited a low transcriptional plasticity, even for the expression of genes encoding enzymes involved in insecticide detoxification. Our results emphasize the value of microarray studies to search for regulated genes in insects, but also highlights the many ways those different genotypes can assemble resistant phenotypes depending on the environmental pressure.


Resistive index and peak systolic velocity for congenital talipes equinovarus: A color Doppler ultrasonography study.
This study aims to investigate whether resistive index (RI) and peak systolic velocity (PSV) are suitable parameters to determine if a clubfoot differs from feet of the normal population. Fifty-four feet of 27 clubfoot patients (22 males, 5 females; mean age 30.4±16.3 months; range, 5 to 72 months) were included in this retrospective study conducted between December 2017 and January 2019. Twenty-seven feet were conservatively treated, 19 had surgical treatment, and eight feet were healthy in patients with unilateral clubfoot. In addition, 22 feet of 11 normal controls (6 males, 5 females; mean age 33.4±15.3 months; range, 15 to 60 months) were studied. Color Doppler ultrasonography examinations were performed to evaluate the three major arteries of the leg and foot: dorsalis pedis (dp), tibialis posterior (tp), and popliteal (pop). Color filling, flow direction, spectral analysis, velocity, and RI were examined. With the exception of the dp artery RI, the PSV and RI values for all arteries differed significantly from those of the control group. There were no significant differences among the conservative, surgical, and healthy groups, while there were significant differences between each of the treated groups and the control group. Tibialis posterior artery PSV and pop artery RI were the best parameters to identify clubfoot and the cut-off points were 54 cm/second and 0.77, respectively. Peak systolic velocity and RI may be accepted as important parameters for identification of clubfoot deformity. Tibialis posteriorartery PSV and pop artery RI are the best- detailed parameters for this examination.


Nonparametric Calibration of Item-by-Attribute Matrix in Cognitive Diagnosis.
A nonparametric technique based on the Hamming distance is proposed in this research by recognizing that once the attribute vector is known, or correctly estimated with high probability, one can determine the item-by-attribute vectors for new items undergoing calibration. We consider the setting where Q is known for a large item bank, and the q-vectors of additional items are estimated. The method is studied in simulation under a wide variety of conditions, and is illustrated with the Tatsuoka fraction subtraction data. A consistency theorem is developed giving conditions under which nonparametric Q calibration can be expected to work.


Differentiating spontaneous echo contrast, sludge, and thrombus in the left atrial appendage: Can ultrasound enhancing agents help?
The accurate identification of thrombus in the left atrial appendage with transesophageal echocardiogram (TEE) in patients with atrial fibrillation (AF) before cardioversion is essential. Most of these patients have some grade of spontaneous echo contrast (SEC). Severe SEC is often called "sludge," and its prognosis and treatment are still controversial. Current guidelines suggest the use of ultrasound enhancing agents (UEAs) when significant SEC is present. However, little is known about the utility of the UEAs in the differentiation between sludge and less severe SEC.


High titers of hemagglutination inhibition antibodies against 2009 H1N1 influenza virus in Southern Iran.
Pandemic flu had at least two waves in Iran. Knowing how many of the general population were already exposed to this infection has a major impact on national preventive measures. As of December 30, 2009, a total of 3672 confirmed cases of human infection with a novel Influenza A (2009 H1N1) virus had been reported in Iran with 140 deaths. In this study we aim to measure, as a pilot study, the seroprevalence of positive antibody titer (humoral immunity) against 2009 H1N1 virus in Iranian population in Shiraz, Southern Iran. Through cluster random sampling of families residing in Shiraz, 2553 subjects were selected and after a medical interview blood samples were taken and checked for polyclonal antibody against 2009 H1N1 antigen using hemagglutination inhibition assay. An antibody titer of more than 1:40 dilution was considered positive. Data were analyzed considering the demographic characteristics of the population and were compared among different age groups. 1504 (58.91%) samples were tested positive for the presence of polyclonal antibody against 2009 H1N1 virus. The prevalence of positive titers were significantly higher in 60 to 64 years old group and significantly lower in 20 to 24 years old group (p<0.05). Data did not differ based on other demographic characteristics or the history of flu like illnesses in the past 6 months. High seroprevalence of antibody against 2009 H1N1 in the sera of our subjects describes either a high level of pre-existing immunity against H1N1 in Iranian population or a high rate of asymptomatic infection in our area compared to other countries.


Oestrogen-induced activation of preoptic kisspeptin neurones may be involved in the luteinising hormone surge in male and female Japanese monkeys.
The oestrogen-induced luteinising hormone (LH) surge is evident in male primates, including humans, whereas male rodents never show the LH surge, even when treated with a preovulatory level of oestrogen. This suggests that the central mechanism governing reproductive hormones in primates is different from that in rodents. The present study aimed to investigate whether male Japanese monkeys conserve a brain mechanism mediating the oestrogen-induced LH surge via activation of kisspeptin neurones. Adult male and female Japanese monkeys were gonadectomised and then were treated with oestradiol-17β for 2 weeks followed by a bolus injection of oestradiol benzoate. Both male and female monkeys showed an oestrogen-induced LH surge. In gonadectomised monkeys sacrificed just before the anticipated time of the LH surge, oestrogen treatment significantly increased the number of KISS1-expressing cells in the preoptic area (POA) and enhanced the expression of c-fos in POA KISS1-positive cells of males and females. The oestrogen treatment failed to induce c-fos expression in the arcuate nucleus (ARC) kisspeptin neurones in both sexes just prior to LH surge onset. Thus, kisspeptin neurones in the POA but not in the ARC might be involved in the positive-feedback action of oestrogen that induces LH surge in male Japanese monkeys, as well as female monkeys. The present results indicate that oestrogen-induced activation of POA kisspeptin neurones may contribute to the LH surge generation in both sexes. The conservation of the LH surge generating system found in adult male primates, unlike rodents, could be a result of the capability of oestrogen to induce POA kisspeptin expression and activation.


Apical defect - the essence of cystocele pathogenesis?
Lack of standardization causes misunderstandings in planning of cystocele treatment and the evaluation of surgical method effectiveness. The POP-Q System and DeLancey's three levels of pelvic support do not account for the phenomenon of cystocele caused by an apical defect. We aimed to evaluate the impact of level I defect on the formation of cystocele. Women reporting complaints related to bladder prolapse (cystocele) were subjected to a urogynecological examination. For this purpose, a simple and standardized method was used, based on the POP-Q System and DeLancey's three levels of pelvic support. Furthermore, it was expanded by evaluating the impact of level I defect (apical defect) on prolapse at level II of the anterior compartment. In total, contribution of an apical defect to the pathogenesis of cystocele was founded in 72.2% of 302 female patients included in this study. In 30.8% the cystocele was caused exclusively by an apical defect. In turn, in 41.4% of patients, it resulted from concomitant apical and level II defect of the anterior compartment (lateral or central). The results of this study indicate that an apical defect may play a significant role in the development of a cystocele. Hence, it could be essential to take the influence of an apical defect on level II in anterior compartment into account when planning a surgical procedure. The authors suggest that lack of such procedures potentially exposes some cystocele patients to ineffective treatment.


Can Location of Stiffness Measurement Impact Spleen 2-Dimensional Shear Wave Elastography Measurement?
Ultrasound-based spleen elastography is a promising surrogate to predict portal hypertension noninvasively. In contrast to defined standards for liver stiffness measurement, the standardized examination procedures for 2-dimensional (2D) shear wave elastography spleen elastography have not been established yet. The aim was to investigate the impact of location of stiffness measurement on 2D shear wave elastography spleen stiffness measurement (SSM). Patients with splenomegaly were enrolled. Both B-mode ultrasound and elastography of spleen were performed. For SSM, 3 regions were chosen for spleen measurement: lower pole region, central region, and the region between lower pole and center. Mean SSM value, success rate, and reliability predicators (standard deviation, standard deviation/mean, size of region of interest) were assessed. A total of 124 patients were included. For mean SSM value, there were no significant differences among 3 regions. Spleen stiffness measurement success rate in lower pole region, central region, and the region between them was 63.7% (79), 91.1% (113), and 78.2% (97), respectively. The success rate in the central region was significantly higher than that in the other 2 regions (P < 0.05). Reliability in the central region was also highest among the 3 regions. Location of stiffness measurement has a limited effect on SSM. Changing location of measurement will not influence mean stiffness value in spleen.


Interstitial lung diseases in Saudi Arabia: A single-center study.
There are relatively few epidemiological studies on interstitial lung disease (ILD) worldwide. To report the incident cases of ILD and compare our data with reports from other populations. Newly diagnosed ILDs were prospectively collected at a single tertiary care hospital from January 2008 to December 2011. Detailed demographic and clinical data were collected at the time of diagnosis, along with the results from diagnostic procedures, including high-resolution computed tomography (HRCT), serological tests, bronchoalveolar lavage (BAL), transbronchial lung biopsy, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and surgical lung biopsy. A total of 330 cases were included. The mean age was 55.4 ± 14.9 years. There was a slight predominance of females (202; 61.2%), and the male-to-female ratio was 1:1.37. The most frequent disease was connective tissue disease (CTD)-associated ILD (34.8%), followed by idiopathic pulmonary fibrosis (IPF) (23.3%), sarcoidosis (20%), and hypersensitivity pneumonitis (6.3%). Non-classifiable ILD was present in 1.8% of the total ILD cases. HRCT was performed in 97.3% of the cases, BAL in 17.5%, transbronchial lung biopsy in 21.8%, EBUS-TBNA in 4.5%, and surgical lung biopsy in 22.7% (38.6% of which were performed among the idiopathic interstitial pneumonia cases). CTD-ILD and IPF were the most frequently observed ILDs in this Saudi Arabian population. Similarities and differences were found with respect to the previous reports from other countries.


Nuclear survivin expression as a potentially useful tool for the diagnosis of canine cutaneous sebaceous lesions.
Sebaceous glands are specialized cutaneous adnexal glands, which work under constant hormonal control to produce sebum. They can give rise to several proliferative lesions, such as hamartoma, hyperplasia and neoplasms (adenoma, epithelioma and carcinoma). Their nomenclature is currently confusing, both in veterinary and in human medicine, owing to the difficulty of differentiating between some of these lesions. The present study used immunohistochemistry to determine the expression levels and patterns of survivin and Ki67 in five samples of normal canine skin and 44 cases of canine cutaneous lesions with sebaceous differentiation (10 hamartomas, nine hyperplasia, eight adenomas, eight epitheliomas and nine carcinomas). In normal glands, survivin, as well as Ki67, was expressed in scattered reserve cells. In hamartomas, survivin was more highly expressed than in normal skin, indicating a possible role of this molecule in the pathogenesis of these congenital lesions. In tumours, a moderate or high level of survivin and Ki67 expression (more than two and four and more than two positive cells, respectively) were significantly correlated with a malignant histotype, infiltrative growth and a moderate or high number of mitoses (more than two). The level of survivin expression increased with increasing malignancy, designating survivin as a new diagnostic marker in the assessment of malignancy of sebaceous tumours.


Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT.
The treatment of paroxysmal nocturnal hemoglobinuria has been revolutionized by the introduction of the anti-C5 agent eculizumab; however, eculizumab is not the cure for Paroxysmal nocturnal hemoglobinuria (PNH), and room for improvement remains. Indeed, the hematological benefit during eculizumab treatment for PNH is very heterogeneous among patients, and different response categories can be identified. Complete normalization of hemoglobin (complete and major hematological response), is seen in no more than one third of patients, while the remaining continue to experience some degree of anemia (good and partial hematological responses), in some cases requiring regular red blood cell transfusions (minor hematological response). Different factors contribute to residual anemia during eculizumab treatment: underlying bone marrow dysfunction, residual intravascular hemolysis and the emergence of C3-mediated extravascular hemolysis. These two latter pathogenic mechanisms are the target of novel strategies of anti-complement treatments, which can be split into terminal and proximal complement inhibitors. Many novel terminal complement inhibitors are now in clinical development: they all target C5 (as eculizumab), potentially paralleling the efficacy and safety profile of eculizumab. Possible advantages over eculizumab are long-lasting activity and subcutaneous self-administration. However, novel anti-C5 agents do not improve hematological response to eculizumab, even if some seem associated with a lower risk of breakthrough hemolysis caused by pharmacokinetic reasons (it remains unclear whether more effective inhibition of C5 is possible and clinically beneficial). Indeed, proximal inhibitors are designed to interfere with early phases of complement activation, eventually preventing C3-mediated extravascular hemolysis in addition to intravascular hemolysis. At the moment there are three strategies of proximal complement inhibition: anti-C3 agents, anti-factor D agents and anti-factor B agents. These agents are available either subcutaneously or orally, and have been investigated in monotherapy or in association with eculizumab in PNH patients. Preliminary data clearly demonstrate that proximal complement inhibition is pharmacologically feasible and apparently safe, and may drastically improve the hematological response to complement inhibition in PNH. Indeed, we envision a new scenario of therapeutic complement inhibition, where proximal inhibitors (either anti-C3, anti-FD or anti-FB) may prove effective for the treatment of PNH, either in monotherapy or in combination with anti-C5 agents, eventually leading to drastic improvement of hematological response.


Radiofrequency ablation of bundle branch reentrant tachycardia in a patient with atrial septal defect.
A 22-year-old woman with an atrial septal defect surgically corrected during childhood presented with a wide QRS complex tachycardia with left bundle branch block morphology. Electrophysiological study was performed and bundle branch reentrant tachycardia was induced with morphology identical to clinical tachycardia. Radiofrequency catheter ablation of the right bundle branch was successful, resulting in complete right bundle branch block and cure of her ventricular arrhythmia.


Cost-effectiveness and budget impact of pembrolizumab+axitinib versus sunitinib in patients with advanced clear-cell renal cell carcinoma in the Netherlands.
The phase 3 clinical trial KEYNOTE-426 suggested a higher efficacy regarding overall survival (OS) and progression-free survival (PFS) of pembrolizumab+axitinib compared to sunitinib as a first-line treatment for patients with advanced renal cell carcinoma. In this analysis, the potential cost-effectiveness of this combination treatment versus sunitinib for patients with advanced clear-cell renal cell carcinoma (accRCC) was examined from the societal perspective in the Netherlands. For this analysis, a partitioned survival model was constructed. Clinical data were obtained from the published KEYNOTE-426 trial reports; data on costs and (dis-)utilities were derived from published literature. Costs outside of the healthcare sector included treatment-related travel, informal care and productivity loss. Next to a probabilistic scenario analysis, various scenario analyses were performed that aimed at survival extrapolation, different utility values, treatment duration and drug pricing, as well as restricting the cohort to patients with an intermediate or poor prognosis. Further, a budget impact analysis over three years was conducted, in which a sensitivity analysis concerning ranges in costs and the number of patients was applied. Moreover, a scenario concerning increasing market penetration of pembrolizumab+axitinib up to a market share of 80% in the third year was analyzed. The incremental cost-effectiveness ratio (ICER) of pembrolizumab+axitinib was estimated at €368,396/quality-adjusted life year (QALY) gained, with an incremental QALY gain of 0.55 over sunitinib. The probability of cost-effectiveness at a willingness-to-pay threshold of €80,000/QALY was estimated at 0%, a 50% probability was estimated at €340,000/QALY. Cost-effectiveness was not achieved in any of the applied scenarios. The budget impact over three years amounted to €417.3 million upon instantaneous and full replacement of sunitinib, and to €214.9 million with increasing market penetration. Pembrolizumab+axitinib was not estimated to be cost-effective compared to sunitinib as a first-line treatment for patients with accRCC in the Netherlands from a societal perspective. In none of the analyzed scenarios, cost-effectiveness was achieved. However, price reductions and shorter treatment durations might lead to a more favorable ICER.


Synthesis of meta-arylphenol derivatives via acid-promoted rearrangement of cyclohexadienones.
A highly effective strategy for the synthesis of meta-arylphenol derivatives through the selective rearrangement of 4-alkyl-4-aryl-2,5-cyclohexadienones under metal-free conditions was developed, in which acid-promoted [1,2]-migration of the aryl group at C-4 occurred exclusively when the alkyl group at C-4 was a methyl group. Treatment of 4-methyl-4-aryl-2,5-cyclohexadienones with 37% HCl in Ac2O at room temperature provided polysubstituted meta-arylphenyl acetates in 75-94% yields. The application of this protocol in the synthesis of polycyclic aromatic compounds was also described.


Discovery of significant rules for classifying cancer diagnosis data.
We introduce a new method to discover many diversified and significant rules from high dimensional profiling data. We also propose to aggregate the discriminating power of these rules for reliable predictions. The discovered rules are found to contain low-ranked features; these features are found to be sometimes necessary for classifiers to achieve perfect accuracy. The use of low-ranked but essential features in our method is in contrast to the prevailing use of an ad-hoc number of only top-ranked features. On a wide range of data sets, our method displayed highly competitive accuracy compared to the best performance of other kinds of classification models. In addition to accuracy, our method also provides comprehensible rules to help elucidate the translation between raw data and useful knowledge.


Factors associated with surgical management in an underinsured, safety net population.
Few studies include significant numbers of racial and ethnic minority patients. The current study was performed to examine factors that affect breast cancer operations in an underinsured population. We performed a retrospective review of all breast cancer patients from January 2010 to May 2012. Patients with American Joint Committee on Cancer clinical stage 0-IIIA breast cancer underwent evaluation for type of operation: breast conservation, mastectomy alone, and reconstruction after mastectomy. The population included 403 patients with mean age 53 years. Twelve of the 50 patients (24%) diagnosed at stage IIIB presented with synchronous metastatic disease. Of the remaining patients, only 2 presented with metastatic disease (0.6%). The initial operation was 65% breast conservation, 26% mastectomy alone, and 10% reconstruction after mastectomy. Multivariate analysis revealed that Hispanic ethnicity (odds ratio [OR], 0.38; 95% CI, 0.19-0.73; P = .004), presentation with palpable mass (OR, 0.34; 95% CI, 0.13-0.90; P = .03), preoperative chemotherapy (OR, 0.25; 95% CI, 0.10-0.62; P = .003) were associated with a lesser likelihood of mastectomy. Multivariate analysis of factors associated with reconstruction after mastectomy showed that operation with Breast surgical oncologist (OR, 18.4; 95% CI, 2.18-155.14; P < .001) and adequate health literacy (OR, 3.13; 95% CI, 0.95-10.30; P = .06) were associated with reconstruction. The majority of safety net patients can undergo breast conservation despite delayed presentation and poor use of screening mammography. Preoperative chemotherapy increased the likelihood of breast conservation. Routine systemic workup in patients with operable breast cancer is not indicated.


SLAMF6/Ly108 promotes the development of hepatocellular carcinoma via facilitating macrophage M2 polarization.
Tumor-associated macrophages (TAMs) are capable of worsening hepatocellular carcinoma (HCC) prognosis by accelerating tumor growth and progression. Signaling lymphocyte activation molecule family member 6 (SLAMF6; Ly108 in mice) is an immune regulator that is involved in numerous diseases. However, whether SLAMF6 might affect macrophage function in HCC has not yet been reported. Therefore, the present study aimed to determine the relationship between SLAMF6 expression on macrophages and HCC progression. In the present study, the expression of SLAMF6 in human blood samples and mice was analyzed by flow cytometry. Furthermore, macrophage-related polarization markers were detected via reverse transcription quantitative PCR. Clonogenic formation and Transwell assay were performed to determine the proliferation, migration and invasion of HCC cells. In addition, a murine HCC model was established to detect the function of SLAMF6 in vivo. The results demonstrated that SLAMF6 expression was increased in CD14+ cells obtained from patients with HCC. It was also determined that this increase was associated with a positive hepatitis B virus DNA status and high levels of α-fetoprotein. Polarized TAMs from THP-1 cells, murine peritoneal macrophages and murine bone marrow-derived macrophages all exhibited higher levels of SLAMF6 compared with M1 cells. Furthermore, an increased expression of Ly108 was detected in macrophages obtained from mice tumor tissues, indicating that the tumor microenvironment may promote Ly108 expression and macrophage M2 polarization. Ly108 small interfering RNA was applied to macrophages, which resulted in the suppression of M2 polarization. Ly108-silenced macrophages attenuated HCC cell migration and invasion and prevented tumor growth by inhibiting the nuclear factor-κB pathway. Altogether, the results from the present study suggested that SLAMF6/Ly108 was upregulated in TAMs, which may in turn accelerate the development of HCC.


Mesonephric remnants involving renal pelvis and prostatic urethra: a diagnostic problem towards adenocarcinoma.
We report two cases of mesonephric remnants involving the renal pelvis and prostatic urethra, respectively. The morphological and immunohistochemical characteristics of the lesions with special emphasis on the differentiation towards adenocarcinoma are described.


Pathogenesis of emerging severe fever with thrombocytopenia syndrome virus in C57/BL6 mouse model.
The discovery of an emerging viral disease, severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), has prompted the need to understand pathogenesis of SFTSV. We are unique in establishing an infectious model of SFTS in C57/BL6 mice, resulting in hallmark symptoms of thrombocytopenia and leukocytopenia. Viral RNA and histopathological changes were identified in the spleen, liver, and kidney. However, viral replication was only found in the spleen, which suggested the spleen to be the principle target organ of SFTSV. Moreover, the number of macrophages and platelets were largely increased in the spleen, and SFTSV colocalized with platelets in cytoplasm of macrophages in the red pulp of the spleen. In vitro cellular assays further revealed that SFTSV adhered to mouse platelets and facilitated the phagocytosis of platelets by mouse primary macrophages, which in combination with in vivo findings, suggests that SFTSV-induced thrombocytopenia is caused by clearance of circulating virus-bound platelets by splenic macrophages. Thus, this study has elucidated the pathogenic mechanisms of thrombocytopenia in a mouse model resembling human SFTS disease.


Coronary artery disease screening in patients with diabetes.
Coronary artery disease (CAD) is the most common cause of death in patients with diabetes. Many diabetics have asymptomatic CAD, and may benefit from early diagnosis. We review the recent literature to evaluate whether the current evidence supports screening for CAD in asymptomatic diabetics. Currently, no single screening modality has shown sufficient accuracy to determine which patients will have significant CAD. The combination of imaging modalities may show promise in improving the accuracy of screening, and limited data suggest that screening in this population may be associated with improved outcomes. However, based on the current evidence we presently do not recommend screening for CAD in this population.


In situ Co-Delivery of Doxorubicin and Cisplatin by Injectable Thermosensitive Hydrogels for Enhanced Osteosarcoma Treatment.
Osteosarcoma is considered as the most common primary malignant bone tumor in children and adolescents, and the treatments including chemotherapy and surgery were far from satisfactory. Localized tumor treatments by hydrogels incorporating combined chemotherapeutic drugs have recently emerged as superior approaches for enhanced anti-tumor effects and reduced systemic toxicity. A novel injectable thermosensitive poly (lactide-co- glycolide)-poly (ethylene glycol)-poly(lactide-co-glycolide) triblock copolymer hydrogel containing doxorubicin and cisplatin for the localized chemotherapy of osteosarcoma were synthesized and characterized. The in vitro drug release properties of the drugs-loaded hydrogels were investigated. To study the anti-tumor efficacy of hydrogels depots in vitro, the cytotoxicity and apoptosis rate against Saos-2 and MG-63 cells were evaluated by MTT, Annexin V and PCR methods. The in vivo synergistic anti-tumor efficacy of the multi-drugs co-loaded hydrogels was investigated by human osteosarcoma xenografts. Additionally, the systemic toxic side effects were evaluated by ex vivo histological analysis of the major organs of the mice. The PLGA-PEG-PLGA copolymer solution underwent a sol-gel transition at appropriate temperature and degraded in the PBS, presenting a friendly biocompatibility in vitro. The in vitro cell viability tests demonstrated that DOX and CDDP co-loaded hydrogels exhibited synergistic anti-proliferation effect, due to the sustained release of drugs from the drugs-loaded hydrogel. The treatment with DOX and CDDP co-loaded hydrogel led to the highest efficiency in inhibiting the tumor growth, enhanced tumor necrosis rate and increased regulation of the apoptosis-related gene expressions, indicating a synergistic anti-tumor efficacy in vivo. Additionally, ex vivo histological analysis of the nude mice exhibited low systemic toxicity. The combination treatment of osteosarcoma by localized, sustained co-delivery of DOX and CDDP by PLGA-PEG-PLGA hydrogel may serve as a promising strategy for efficient clinical treatment of osteosarcoma.


Redox properties of CeO2 at low temperature: the direct synthesis of imines from alcohol and amine.
We disclosed the redox properties of CeO2 in organic reactions at low temperature of 303 K. CeO2 works as the most effective heterogeneous catalyst for imine formation from benzyl alcohol and aniline at 303 K among various metal oxides and showed more than 38-fold higher activity than other simple metal oxides. CeO2 is applicable to the reaction of various alcohols and amines and gives high yields (80-98%) and high selectivities (89->99%). Kinetic measurements, MS, and FTIR analyses demonstrated that the high activity of CeO2 is a result of reactive oxygen species at the redox sites on CeO2. This discovery can help to create a new field in metal oxide catalysis.


[Massive pulmonary thromboembolism found at autopsy in a patient with a 14-year history of polymyositis-associated nonspecific interstitial pneumonia].
A 64-year-old woman with a 14-year history of refractory nonspecific interstitial pneumonia (NSIP) associated with polymyositis was admitted urgently to our hospital due to acute exacerbation of dyspnea. The first episode of dyspnea had occurred 14 years earlier and the diagnosis of cellular and fibrotic NSIP had been made by radiographic examinations and open lung biopsy. Her NSIP initially responded well to high-dose prednisolone therapy (40mg/day), but flared when the dose of prednisolone was tapered. Three years after the diagnosis of NSIP, a diagnosis of polymyositis was made based on her elevated serum level of creatinine phosphokinase and muscle biopsy findings. Her polymyositis was controlled well by prednisolone therapy, but her NSIP gradually worsened, despite treatment with several courses of methylprednisolone pulse therapy and immunosuppressive agents. She was brought to our hospital by ambulance due to acute progression of dyspnea and was admitted. Chest X-ray film revealed diffuse interstitial shadows and marked enlargement of the right atrium and bilateral pulmonary arteries. Transthoracic echocardiogram revealed severe dilatation of the right atrium and right ventricle with an estimated pulmonary artery systolic pressure of 84mmHg. She died of progressive respiratory failure on day 4 of hospitalization. Autopsy revealed massive thrombi that completely obstructed the bilateral pulmonary trunks. Histological examination revealed that these thrombi were organized, and her interstitial lung disease (ILD) was specified as fibrotic NSIP with microscopic honeycomb. Massive pulmonary thromboembolism is extremely rare in patients with polymyositis-associated NSIP, but it should be considered as a possible cause of acute exacerbation of respiratory failure. This case provides valuable information on the clinical and pathological course of polymyositis-associated NSIP.


Palladium-catalyzed cross-coupling reaction of azides with isocyanides.
An efficient palladium-catalyzed cross-coupling reaction of azides with isocyanides is developed, providing a general synthetic route to unsymmetric carbodiimides with excellent yields. This method shows a broad substrate scope, including not only aryl azides, but also unactivated benzyl and alkyl azides. Furthermore, from readily available substrates, Pd-catalyzed coupling with a tandem amine insertion cascade to obtain unsymmetric trisubstituted guanidines has been achieved in a one-pot fashion.


Impaired in vivo tumor growth of human pancreatic carcinoma cells retrovirally transduced with GM-CSF gene.
We have examined the antitumor effect of human pancreatic carcinoma cells (AsPC-1) retrovirally transduced with mouse granulocyte macrophage-colony stimulating factor (GM-CSF) gene in nude mice. Growth retardation of the subcutaneous tumors of GM-CSF-producing AsPC-1 cells was observed, although their in vitro proliferation was not different from that of wild-type cells. Histological examination revealed infiltration of monocytic cells into the tumor of GM-CSF-producing cells, and they were shown to be mainly CD11b positive cells by immunohistochemical staining. The survival of the mice inoculated intraperitoneally with GM-CSF- producing AsPC-1 cells was significantly prolonged compared with that of the mice inoculated with wild-type AsPC-1 cells. Thus, the expression of GM-CSF gene in human pancreatic cells induced an antitumor effect in vivo even in the mature T cell-deficient condition.


Acute leukemia following cyclophosphamide therapy for Sjögren's syndrome.
A fatal myeloproliferative syndrome diagnosed as subacute myelomonocytic leukemia developed in a patient with Sjögren's syndrome following treatment with cyclophosphamide. Although patients with Sjögren's syndrome have a recognized increased risk of developing lymphoproliferative disorders, particularly reticulum cell sarcoma, there is no evidence to support a similar predisposition to leukemia. As immunosuppressive therapy is becoming more common in the treatment of patients with rheumatoid arthritis, there have been recent reports of patients developing fatal myeloproliferative disorders after receiving immunosuppressive therapy. Review of these cases shows similar duration of therapy, and cyclophosphamide, among others, has been implicated as the leukemogenic agent in other patients. We feel that great caution should be exercised in the use of immunosuppressive drugs in patients with chronic, nonfatal disorders sich as rheumatoid arthritis and Sjögren's syndrome.


Contributions of 5-HT neurons to respiratory control: neuromodulatory and trophic effects.
Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter produced by a small number of neurons in the midbrain, pons and medulla. These neurons project widely throughout the neuraxis, where they release 5-HT and co-localized neuropeptides such as substance P (SP) and thyrotropin-releasing hormone (TRH). Each of these chemicals produce effects largely through G protein-coupled receptors, second messenger systems and subsequent neuromodulatory effects on target neurons. Emerging evidence suggests that 5-HT has additional modes of action during development and in adult mammals, including trophic effects (neurogenesis, cell differentiation, proliferation, migration and maturation) and influences on synaptic plasticity. Here, we discuss some of the neuromodulatory and trophic roles of 5-HT in general and in the context of respiratory control, as well as the regulation of release of modulatory neurotransmitters from 5-HT neurons. Future directions of study are also discussed.


Cancer screening: Between appropriateness and effectiveness.
Two similar words, effectiveness and efficacy, have comparable insight and nearly describe analogous meaning for a screening test, yet clear understanding and perception of their diverse meanings will help clarify the basis of the differing conclusions about whether screening tests for different cancers reduce morbidity and mortality. Screening test may not be effective even when it sounds to be efficacious, on the other hand it should be efficacious when the test is effective.


A hybrid clustering and classification approach for predicting crash injury severity on rural roads.
As a threat for transportation system, traffic crashes have a wide range of social consequences for governments. Traffic crashes are increasing in developing countries and Iran as a developing country is not immune from this risk. There are several researches in the literature to predict traffic crash severity based on artificial neural networks (ANNs), support vector machines and decision trees. This paper attempts to investigate the crash injury severity of rural roads by using a hybrid clustering and classification approach to compare the performance of classification algorithms before and after applying the clustering. In this paper, a novel rule-based genetic algorithm (GA) is proposed to predict crash injury severity, which is evaluated by performance criteria in comparison with classification algorithms like ANN. The results obtained from analysis of 13,673 crashes (5600 property damage, 778 fatal crashes, 4690 slight injuries and 2605 severe injuries) on rural roads in Tehran Province of Iran during 2011-2013 revealed that the proposed GA method outperforms other classification algorithms based on classification metrics like precision (86%), recall (88%) and accuracy (87%). Moreover, the proposed GA method has the highest level of interpretation, is easy to understand and provides feedback to analysts.


Scale Effect of Land Cover Classification from Multi-Resolution Satellite Remote Sensing Data.
Land cover data are important basic data for earth system science and other fields. Multi-source remote sensing images have become the main data source for land cover classification. There are still many uncertainties in the scale effect of image spatial resolution on land cover classification. Since it is difficult to obtain multiple spatial resolution remote sensing images of the same area at the same time, the main current method to study the scale effect of land cover classification is to use the same image resampled to different resolutions, however errors in the resampling process lead to uncertainty in the accuracy of land cover classification. To study the land cover classification scale effect of different spatial resolutions of multi-source remote sensing data, we selected 1 m and 4 m of GF-2, 6 m of SPOT-6, 10 m of Sentinel-2, and 30 m of Landsat-8 multi-sensor data, and explored the scale effect of image spatial resolution on land cover classification from two aspects of mixed image element decomposition and spatial heterogeneity. For the study area, we compared the classification obtained from GF-2, SPOT-6, Sentinel-2, and Landsat-8 images at different spatial resolutions based on GBDT and RF. The results show that (1) GF-2 and SPOT-6 had the best classification results, and the optimal scale based on this classification accuracy was 4-6 m; (2) the optimal scale based on linear decomposition depended on the study area; (3) the optimal scale of land cover was related to spatial heterogeneity, i.e., the more fragmented and complex was the space, the smaller the scale needed; and (4) the resampled images were not sensitive to scale and increased the uncertainty of the classification. These findings have implications for land cover classification and optimal scale selection, scale effects, and landscape ecology uncertainty studies.


Using technology to support clinical care and research in rheumatoid arthritis.
As digital technology becomes more ubiquitous, understanding the current state-of-the-art in digital information use for clinical care and research for patients with rheumatoid arthritis (RA) is timely and relevant. The opportunities for recording and utilizing high-quality data from rheumatologists are reviewed, as well as opportunities from collecting, integrating and analysing patient-generated data to deliver a step-change in the support and management of RA. Once greater adoption, standardization and implementation of relevant RA measures are in place within electronic health records (EHRs), patient care will improve and the ability to learn from aggregate experiences increases dramatically. Incorporating passive and patient-reported outcomes into self-management apps and integrating such data into the patient's health record will provide more responsive and better treatment results.


Friend spleen focus-forming virus transforms rodent fibroblasts in cooperation with a short form of the receptor tyrosine kinase Stk.
Friend spleen focus-forming virus (SFFV) causes rapid erythroleukemia in mice due to expression of its unique envelope glycoprotein, gp55. Erythroid cells expressing SFFV gp55 proliferate in the absence of their normal regulator erythropoietin (Epo) because of constitutive activation of Epo signal transduction pathways. Although SFFV infects many cell types, deregulation of cell growth occurs only when SFFV infects erythroid cells, suggesting that these cells express unique proteins that the virus requires to mediate its biological effects. Not only do erythroid cells express the Epo receptor (EpoR), but those from mice susceptible to SFFV-induced erythroleukemia also express a short form of the receptor tyrosine kinase Stk (sf-Stk). In erythroid cells, SFFV gp55 interacts with the EpoR complex and sf-Stk, leading to activation of the kinase and constitutive activation of signal transducing molecules. In this study, we demonstrate that SFFV gp55 can also deregulate the growth of nonerythroid cells when it is coexpressed with sf-Stk. Expression of SFFV gp55 in rodent fibroblasts engineered to express sf-Stk induced their transformation, as demonstrated by focus formation and anchorage-independent growth in vitro. This transformation by SFFV gp55 requires the kinase activity of sf-Stk and the presence of its extracellular domain but not expression of the EpoR or the tyrosine kinase Jak2, which is required for activation of signal transduction pathways through the EpoR. Thus, expression of SFFV gp55 in nonerythroid cells coexpressing sf-Stk results in their uncontrolled growth, demonstrating a previously unrecognized mechanism for retrovirus transformation of rodent fibroblasts and providing insight into SFFV-induced disease.


Farnesoid X receptor in chronic liver diseases: an immunohistochemical study.
Chronic hepatitis C virus (HCV) related liver diseases are still an ongoing cause of hepatic failure despite the effective role of direct-acting anti-viral agents. Farnesoid X receptor (FXR) agonists have a potential therapeutic effect on the management of chronic liver diseases (CLD). However, data regarding FXR protein expression in human CLDs are limited and conflicting. We aimed to assess the immunohistochemical expression of FXR in HCV-related chronic hepatitis and cirrhosis in comparison with metabolic-associated fatty liver disease (MAFLD) and normal liver tissue. The expression of FXR was low both in hepatocytes and bile ducts of HCV-related chronic hepatitis and cirrhosis (p = .001, respectively). In addition, a significantly low expression of FXR was observed in HCV-related hepatitis and cirrhosis groups compared to MAFLD in hepatocytes (p < .001, for both) and bile ducts (p = .004 and p = .018). FXR expression in HCV-related cirrhosis was significantly associated with compensated liver function (p = .032) and low inflammatory activity (p = .022). FXR expression decreases in HCV-related CLDs. There was some evidence that FXR expression could protect against post-hepatitis cirrhosis.


Anaesthesia for robot-assisted anatomic prostatectomy. Experience at a single institution.
Robot-assisted anatomic prostatectomy is an emerging technique for management of prostate cancer It requires a coordinated approach by anaesthetist and surgeon as the surgery is performed using a modified laparoscopic technique and is potentially of long duration in a Trendelenberg position. We describe some aspects of the surgical technique and our anaesthetic approach with the first 40 cases at our institution. The mean hospital stay was 4.2 days and none of the patients required blood transfusion. A retrospective audit indicated that the use of epidural analgesia in the early postoperative period reduced opioid analgesic requirements.


Severe laryngeal injuries masked by fractured mandible.
A 17-year-old male was referred to the maxillofacial department regarding a fractured mandible. Airway compromise was suspected as a result of neck swelling, stridor, haemoptysis and surgical emphysema. Severe laryngeal injuries were diagnosed, including a fractured hyoid. His treatment and outcomes are summarized, with discussion of aetiology, symptoms, diagnosis and treatment of laryngeal injuries, including urgent airway management, if necessary. The risks and complications of delayed diagnosis and treatment are discussed, particularly if symptoms are delayed or the injury is masked by facial fractures. A high index of suspicion and thorough examination are emphasized in all head and neck trauma patients. Any dental professional may be the first to see a trauma victim. It is important to be aware of the risk of life-threatening laryngeal injuries which may be delayed in diagnosis, owing to later development of symptoms and signs or to more obvious injuries.


[Mesenchymal tumor in a female chamois. A case report].
A free-living 15-year old female chamois was shot because of illness and emaciation. The examination of the internal organs revealed numerous firm whitish tumour nodules in liver,spleen, mesenterium and peritoneum. Histologically the nature of tumour cells was identified as a metastasizing malignoma of mesenchymal origin. In addition to the blastoma, the parasite burden of the gastrointestinal tract and lungs did very likely contribute to the bad bodily condition of the chamois.


Objective standard setting (or truth in advertising).
Over the past 40 years criterion referencing has become the major method for setting passing standards on most high-stakes examinations. This paper serves three purposes. First it reveals the limitations and methodological weaknesses of most popular standard setting models, supported by a large volume of prior investigation. Second, it presents a radically different approach to the question of setting standards. The new model called Objective Standard Setting was developed in the early 1990s and has been successfully practiced in a variety of settings since that time. While presented in educational forums for many years, this paper represents the first published account of its methods. Thirdly,suggestions for new considerations of validity in standard setting are addressed. There port concludes with the suggestion that however well-intentioned popular standard setting efforts may be, psychometric experts must more carefully and fully understand the models behind their practices and the validity, meaning and implications of their thought processes.


Self-assembling cyclic peptides: molecular dynamics studies of dimers in polar and nonpolar solvents.
The self-assembly of cyclic D,L-alpha-peptides into hollow nanotubes is a crucial mechanistic step in their application as antibacterial and drug-delivery agents. To understand this process, molecular dynamics (MD) simulations were performed on dimers of cyclic peptides formed from cyclo [(-L-Trp-D-N-MeLeu-)4-]2 and cyclo [(-L-Trp-D-Leu-)4-]2 subunits in nonpolar (nonane) and polar (water) solvent. The dimers were observed to be stable only in nonpolar solvent over the full 10 ns length of the MD trajectory. The behavior of the dimers in different solvents is rationalized in terms of the intersubunit hydrogen bonding, hydrogen bonding with the solvent, and planarity of the rings. It is shown that the phi and psi dihedral angles of a single uncapped ring in nonane lie in the beta-sheet region of the Ramachandran plot, and the ring stays in a flat conformation. Steered MD (SMD) simulations based on Jarzynski's equality were performed to obtain the potential of mean force as a function of the distance between the two rings of the capped dimer in nonane. It is also shown that a single peptide subunit prefers to reside close to the nonane/water interface rather than in bulk solvent because of the amphiphilic character of the peptide ring. The present MD results build the foundation for using MD simulations to study the mechanism of the formation of cyclic peptide nanotubes in lipid bilayers.


Inflammation: a trigger for acute coronary syndrome.
Atherosclerosis is a chronic inflammatory disease of the vessel wall and a major cause of death worldwide. One of atherosclerosis' most dreadful complications are acute coronary syndromes that comprise ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, and unstable angina. We now understand that inflammation substantially contributes to the initiation, progression, and destabilization of atherosclerosis. In this review, we will focus on the role of inflammatory leukocytes, which are the cellular protagonists of vascular inflammation, in triggering disease progression and, ultimately, the destabilization that causes acute coronary syndromes.


Antibacterial activities of aminoglycoside antibiotics-derived cationic amphiphiles. Polyol-modified neomycin B-, kanamycin A-, amikacin-, and neamine-based amphiphiles with potent broad spectrum antibacterial activity.
Cationic amphiphiles containing multiple positively charged amino functions define a structurally diverse class of antibacterials with broad-spectrum activity and different modes of action. Oligocationic amphiphiles have been used as antibiotics to treat infections and as antiseptics and disinfectants for decades with little or no occurrence of resistance. We have prepared a novel class of cationic amphiphiles termed aminoglycoside antibiotics-derived amphiphiles in which the polyol scaffold of the aminoglycosides neomycin B, kanamycin A, amikacin, and neamine has been uniformly decorated with hydrophobic residues in the form of polycarbamates and polyethers. Our results show that the nature of the polyol modification as well as the nature of the aminoglycoside antibiotics has a strong effect on the antibacterial potency. The most potent antibacterials are polyol-modified neomycin B-based amphiphiles containing unsubstituted aromatic rings. These analogues exhibit up to 256-fold enhanced antibacterial activity against resistant strains when compared to neomycin B while retaining most of their activity against neomycin B-susceptible strains.


Museum specimens reveal loss of pollen host plants as key factor driving wild bee decline in The Netherlands.
Evidence for declining populations of both wild and managed bees has raised concern about a potential global pollination crisis. Strategies to mitigate bee loss generally aim to enhance floral resources. However, we do not really know whether loss of preferred floral resources is the key driver of bee decline because accurate assessment of host plant preferences is difficult, particularly for species that have become rare. Here we examine whether population trends of wild bees in The Netherlands can be explained by trends in host plants, and how this relates to other factors such as climate change. We determined host plant preference of bee species using pollen loads on specimens in entomological collections that were collected before the onset of their decline, and used atlas data to quantify population trends of bee species and their host plants. We show that decline of preferred host plant species was one of two main factors associated with bee decline. Bee body size, the other main factor, was negatively related to population trend, which, because larger bee species have larger pollen requirements than smaller species, may also point toward food limitation as a key factor driving wild bee loss. Diet breadth and other potential factors such as length of flight period or climate change sensitivity were not important in explaining twentieth century bee population trends. These results highlight the species-specific nature of wild bee decline and indicate that mitigation strategies will only be effective if they target the specific host plants of declining species.


Therapeutic monitoring of adalimumab at non-trough levels in patients with inflammatory bowel disease.
Adalimumab (ADA) trough level and anti-ADA antibody (AAA) positivity influence mucosal healing and loss of response in patients with inflammatory bowel disease (IBD). In this study, we clarified the correlation between ADA monitoring, including non-trough level, and real-world IBD clinical outcomes. This retrospective, observational, single-center study involved patients with ulcerative colitis (19) and Crohn's disease (33) treated with ADA from January 2007 to August 2018. Serum ADA and AAA levels were measured 4‒14 days after ADA administration. The AAA positivity rate was 23.1% (12/52). ADA continuity was higher in AAA-negative patients than in AAA-positive patients (P = 0.223). Receiver operating characteristic (ROC) analysis revealed that a serum AAA cut-off of 9.2 μg/mL was associated with ADA continuity. The ADA level was significantly higher in the endoscopic remission group than in the non-remission group (P = 0.02). Based on the ROC curve analysis results of serum ADA level and endoscopic remission, the cut-off value of the serum ADA level was set to 11.1 μg/mL. Under the combined use of ADA with immunomodulators and AAA positivity, ADA continuity was significantly higher when the serum AAA level at 4-14 days after ADA administration was ≥9.2 μg/mL. Furthermore, endoscopic remission can be expected with a serum ADA level of ≥11.1 μg/mL. Overall, to predict clinical outcomes, it would be useful to measure the blood level of ADA regardless of the timing of the trough.


The influence of exercise on ulcer healing in patients with chronic venous insufficiency.
Venous leg ulcer (VLU) affects millions of people, and yet there have been no major advances in its treatment for many decades. Is it the time to change our approach, and try a multidisciplinary one that could bring about a change? The aim of this study is to evaluate whether a regular, home-based exercise could be influential in healing the VLU. Eighty subjects (mean age: 65.13 years) were recruited for 12 weeks. The participants were randomized into a control group (N.=20), a compression therapy group (N.=20), an exercise group (N.=20) and a compression and exercise group (N.=20). The exercise comprised of 10 dorsiflexions each hour while the patient was awake. The first 2 groups did not perform any exercise while the other two did. Baseline and 3-month measurements were performed. These measurements include skin perfusion assessment and ulcer size. All patients showed low tcPO2 in the beginning of the study. At the point of 3 months of exercise, Laser Doppler flowmetry and ulcer size measurements showed significant decrease, P<0.001 in exercise groups, however, no real change was demonstrated in the non-exercise groups. Subjects who were performing exercise showed significant increase in tcPO2 readings after 3 months (P<0.001), whereas the tcPO2 readings remained the same in the non-exercise groups. We concluded that exercise had a significant effect on the VLU healing and this effect may be enhanced further with the help of the compression therapy. The tcPO2 and RF measurements may be seen as useful tools in evaluating the microvascular changes, and monitoring healing and follow up of the venous leg ulcer.


Molecular recognition of an ADP-ribosylating Clostridium botulinum C3 exoenzyme by RalA GTPase.
C3 exoenzymes (members of the ADP-ribosyltranferase family) are produced by Clostridium botulinum (C3bot1 and -2), Clostridium limosum (C3lim), Bacillus cereus (C3cer), and Staphylococcus aureus (C3stau1-3). These exoenzymes lack a translocation domain but are known to specifically inactivate Rho GTPases in host target cells. Here, we report the crystal structure of C3bot1 in complex with RalA (a GTPase of the Ras subfamily) and GDP at a resolution of 2.66 A. RalA is not ADP-ribosylated by C3 exoenzymes but inhibits ADP-ribosylation of RhoA by C3bot1, C3lim, and C3cer to different extents. The structure provides an insight into the molecular interactions between C3bot1 and RalA involving the catalytic ADP-ribosylating turn-turn (ARTT) loop from C3bot1 and helix alpha4 and strand beta6 (which are not part of the GDP-binding pocket) from RalA. The structure also suggests a molecular explanation for the different levels of C3-exoenzyme inhibition by RalA and why RhoA does not bind C3bot1 in this manner.


Screening of current post-traumatic stress disorder in patients with substance use disorder using the Depression, Anxiety and Stress Scale (DASS-21): a reliable and convenient measure.
Several instruments have been developed and validated as screens for post-traumatic stress disorder (PTSD) in substance use disorder (SUD) patients. Unfortunately, many of these instruments have one or several disadvantages (e.g. low specificity, low sensitivity or high costs). No research has been conducted on instruments that screen simultaneously for other psychiatric disorders, which would be a potentially time-saving and cost-effective approach. In the current study we tested the psychometric properties of the Depression, Anxiety and Stress Scale (DASS) as a screen for PTSD. The DASS was assessed in an inpatient facility during intake with 58 patients and again 4 weeks after admission. Another 138 patients were assessed 4 weeks after admission only. The results were compared to the Clinician-Administered PTSD Scale (CAPS) that was also administered after 4 weeks of abstinence. ROC curve analyses showed an area under the curve of 0.84 for the DASS at intake and 0.78 for the DASS after 4 weeks' abstinence. The DASS is therefore a reliable and convenient measure to use as a screen for PTSD in SUD patients.


Characterization of fusarium keratitis outbreak isolates: contribution of biofilms to antimicrobial resistance and pathogenesis.
Fusarium is a major cause of microbial keratitis, and its ability to form biofilms was suggested as a contributing factor in recent outbreaks. We investigated the ability of outbreak Fusarium isolates (F. solani species complex [FSSC] and F. oxysporum species complex [FOSC]) to form biofilms in vitro and in vivo, and evaluated their antifungal susceptibilities. Biofilm formation was assessed using our in vitro contact lens model and in vivo murine model. Biofilm architecture was assessed using confocal laser scanning microscopy (CLSM). Susceptibility against amphotericin B (AmB), voriconazole (VCZ), and natamycin (NAT) was determined using the CLSI-M38-A2 method and XTT metabolic assay. FSSC strains formed more biofilms than FOSC, in a strain- and clade-dependent manner. CLSM analyses revealed that "high biofilm forming" (HBF) strains had denser and thicker biofilms than "low biofilm forming" (LBF) strains of both species (thickness 51 vs. 41 μm for FSSC and 61 vs. 45 μm for FOSC strains, P < 0.05 for both comparisons). Fusarium biofilms exhibited species-dependent antifungal susceptibilities (e.g., FSSC biofilms AmB minimal inhibitory concentrations [MIC] ≥16 μg/mL, while NAT or VCZ MICs were 2-8 μg/mL). FSSC-infected mice had severe corneal opacification independent of biofilm thickness, while FOSC infection resulted in moderate corneal opacification. Corneal fungal burden of mice infected with HBF strains was higher than those of the LBF strains. In contrast, the reference ATCC isolate was unable to cause infection. The ability to form biofilms is a key pathogenicity determinant of Fusarium, irrespective of the thickness of these biofilms. Further studies are warranted to explore this association in greater detail.


Commentary on Cherpitel et al. (2015): Improving global estimates of alcohol-attributable injury.
The analyses by Cherpitel and colleagues on alcohol-injury risk relations will help to improve global estimates of the alcohol-attributable injury burden by supplying more specific and empirically based risk relations. However, several issues still need to be addressed: generalizability, heterogeneity of drinkers, mortality outcomes and the quantification of causal impact.


Proliferative versus hypertrophic growth in tissue subcompartments of human placental villi during gestation.
A cross-sectional sample of human placentae was collected at 12-41 wk, and growth mechanisms within villous subcompartments (trophoblast epithelium, stroma and fetal capillary endothelium) were assessed using state-of-the-art design-based stereological methods. Physical disectors (adjacent pairs of sections) were used to count nuclei in syncytiotrophoblast and in cells of the cytotrophoblast, stroma and endothelium. The volumes of trophoblast and stroma and the surface areas and lengths of capillaries were employed to assess the overall growth of each compartment. Growth within compartments was monitored as total number of nuclei (a measure of nuclear proliferation) and compartment size per nucleus (a measure of hypertrophy). During gestation, all compartments grew dramatically. Numbers of nuclei increased exponentially and followed an uninhibited growth model. Volumetric growth of the placenta did not keep pace with the increase in total nuclear number (all types). Growth of trophoblast was exclusively hyperplastic and proceeded at an average net recruitment rate of 15 million nuclei per hour with a numerical predominance of syncytiotrophoblast nuclei of 9:1. There was no evidence of hypertrophy: trophoblast volume per nucleus averaged 1080 microns 3. Growth within stroma involved cell proliferation (17 million nuclei per hour) and the volume of stroma per nucleus declined at a rate of about 24 microns 3 per week. Capillary growth was hyperplastic (5 million endothelial squames per hour) and, possibly, hypertrophic (the mean area of a squame increased by about 18 microns 2 per week). Linear growth of vessels exceeded cellular recruitment and the density of squames along the capillaries decreased each week by about 5 per mm.(ABSTRACT TRUNCATED AT 250 WORDS)


Morphological basis for a tonotopic design of an insect ear.
The tonotopically organized hearing organs of bushcrickets provide the opportunity for a detailed correlation of morphological and structural properties within hearing organs that are needed to establish tonotopic gradients. In the present study of a tonotopic insect hearing organ, we combine mechanical measurements of sound-induced hearing organ motion and detailed anatomical investigations to explore the anatomical basis of tonotopy. We compare mechanical data of frequency responses along the auditory organ to several anatomical parameters. Low frequency responses are related to larger organ and cap cell size in the proximal part of the hearing organ while in the distal part of the organ, small organ and cap cell size is related to high-frequency representation. However, the correlation between organ and cap cell size with continuous frequency representation along the organ is not very tight. Instead, the height of the organ and the corresponding length of the sensory dendrites are best correlated to tonotopic frequency representation. The sensory dendrite contains a ciliary root with a pronounced cross-banding of electron-dense material that should be important for the stiffness of the dendrite. The geometry of surrounding structures like the hemolymph channel and the acoustic trachea as well as the extension of the tectorial membrane are not correlated to the tonotopy. We provide evidence that tonotopy in the bushcricket hearing organ may depend on the size of ciliary structures. In particular, the ciliary root of the sensory cells is a likely cellular basis of tonotopy.


Prevalence and course of posttraumatic stress disorder in Dutch veterans of the civilian resistance during World War II: an overview.
This study concerns the prevalence of current and lifetime Posttraumatic Stress Disorder (PTSD) in various groups of officially recognized Veterans of the Dutch civilian Resistance against the Nazi occupation during World War II. In total, 1046 Resistance veterans living in The Netherlands and 52 who immigrated to the United States after the war were examined. Between four and five decades after the end of WW II, between 25 and 50% were suffering from current PTSD. The life-time prevalence is estimated to be substantially higher. The course of PTSD proved highly variable. There had often been a delay of several decades between the end of the war and reoccurrence or first onset of posttraumatic symptoms. The prevalence of PTSD in Resistance veterans who emigrated to the United States was hardly different from that of the veterans still living in The Netherlands.


Phenotypic and functional characterization of committed and primitive myeloid and lymphoid hematopoietic precursors in human fetal liver.
We studied the phenotypic and functional properties of colony-forming cells (CFCs), primitive long-term culture initiating cells (LTC-ICs) and lymphoid precursors present in human fetal liver (FL) and compared these with their adult bone marrow (BM) counterparts. FL (7-14-week) cells were selected by fluorescence-activated cell sorting based on increasing CD34 antigen expression (34+, 34++, or 34 ), CD38 antigen expression (CD34++/ CD38+, or CD38-), and HLA-DR antigen expression (CD34++/ HLA-DR+ or HLA-DR-). 13 +/- 0.6% of FL CD34-positive cells were 34 . Significantly more FL CD34++/ cells were CD38- (49 +/- 2.4%) and HLA-DR-(72 +/- 6.7%) than BM CD34++ cells (6.8 +/- 0.7% CD38- and 13.3 +/- 3.2% HLA-DR-). FL and BM CFCs were CD34+/++, CD38+, and HLA-DR+. However, significantly more FL CFCs were erythroid (40%) than adult BM CFCs (15%), and FL colonies were larger (8111 +/- 738 cells/CFC) than BM colonies (3466 +/- 272 cells/CFC, p < 0.001). As is seen in adult BM, FL LTC-ICs were CD34++/ CD38-. In contrast to BM LTC-ICs, FL LTC-ICs were almost exclusively CD34++/ HLA-DR+. In addition, a single FL LTC-IC gave rise to >30 CFCs at 5 weeks compared with only 5 +/- 0.9 CFCs per LTC-IC from BM. Finally, we demonstrate that the FL CD34++/ /CD38-/HLA-DR+ population, which contains 3.7% LTC-ICs, also contains primitive lymphoid progenitors capable of differentiating into natural killer (NK) cells. In conclusion, the phenotype of primitive human FL progenitors such as LTC-IC and primitive NK progenitors is CD34++/ /CD38-/HLA-DR+, suggesting that this population may contain FL hematopoietic stem cells. The phenotypic characterization of FL primitive LTC-ICs and NK progenitors will facilitate further studies of the functional properties of these progenitors.


[Medical school admission test at the University of Goettingen - which applicants will benefit?].
Medical schools in Germany may select 60% of the student applicants through their own admission tests. The influence of the school-leaving examination grades (EGs) in each of the procedural steps is controversial. At Goettingen Medical School, we combine a structured interview and a communicative skills assessment. We analysed how many applicants succeeded in our admission test, compared to a model which only takes EGs into account. Admission scores were transferred into SPSS-21. Sociodemographic data were submitted by the Stiftung Hochschulstart. Besides descriptive statistics, we used Pearson-correlation and means comparisons (t-test, analysis of variance). 221 applicants (EGs 1.0-1.9) were invited in the winter semester 2013/14 and 222 applicants (EGs 1.1-1.8) in the summer semester 2014. The proportion of women was 68% (winter) and 74% (summer). Sixteen and 37 applicants had a medical vocational training and performed slightly better. The analysis showed that our test was gender neutral. EGs did not correlate with interviews or skills assessment. Despite a two-fold impact of EGs, 26 (winter) and 44 (summer) of the overall 181 applicants had EGs of 1.4 -1.9, which would have been too low for admission otherwise. If EGs were only considered once, 40 (winter) and 59 (summer) applicants would have succeeded.


Hernia recurrence after laparotomy: how to close an incised light-weight mesh?
A rising number of patients require relaparotomy after implantation of mesh materials for incisional hernia (IH) repair. No published recommendation concerning how to close the incision in a surgical mesh exists. We describe a central IH recurrence through a partly absorbable mesh positioned in the retromuscular plane 16 months after laparotomy due to a small bowel ileus. This recurrence was repaired using a heavy-weight, monofilament polypropylene mesh, again in the retromuscular position. Reducing the amount of nonabsorbable material in large pore hernia meshes leads to markedly reduced scar formation rather than the formation of a thick scar plate. Once cut and resutured, this scar may be too weak to withstand the mechanical strain, giving rise to a 'blow-out' IH recurrence, as demonstrated in our case. In these cases, re-enforcement with a nonabsorbable, small, porous polypropylene mesh in the retromuscular space is feasible and leads to the development of a mechanically stable scar.


Perimortem Demonstration and Treatment of Recipient-to-Donor Transfusion in Monochorionic-Diamniotic Twin Gestation.
Twin-twin transfusion syndrome is a complication of monochorionic-diamniotic placentation. Should one twin die, ≈30% of co-twins will also die, and if they survive, ≈30% experience severe morbidity rates, each believed secondary to hemorrhage of the co-twin into the deceased twin. We report apparently the first ultrasound-documented case of perimortem hemorrhage in twin-twin transfusion syndrome and its treatment by emergent ultrasound-guided percutaneous cord occlusion followed by percutaneous fetal intravascular transfusion. The case illustrates three important pathophysiologic events. First, it confirms acute twin-to-twin hemorrhage occurs and reveals it can begin before the first twin dies. Thus, delivery of the survivor after its dead co-twin is discovered is unlikely to protect the survivor. Second, the elevated fetal middle cerebral artery peak systolic velocity due to acute anemia requires hours to develop. And thirdly, intracardiac epinephrine can correct the acute fetal bradycardia associated with hemorrhage that is presumably due to fetal hypotension.


[In vitro maturation of mammalian oocytes].
A review of authors' and published data on maturation of mammalian oocytes in vitro. The following problems are considered: conditions of in vitro oocyte maturation, morphological changes of oocytes during maturation, duration and synchrony of oocyte maturation, RNA and protein synthesis during oocyte maturation, fertilization of oocytes matured in vitro. The oocytes matured in vivo and vitro were shown not to differ morphologically but their ability of subsequent development differed even if meiosis proceeded in the normal way. Upon the resumption of meiosis after the effect of LH in vivo, there appear to occur some substantial changes in the oocytes which are absent during their in vitro maturation.


Disruption of CDK-resistant chromatin association by pRB causes DNA damage, mitotic errors, and reduces Condensin II recruitment.
Organization of chromatin structure is indispensible to the maintenance of genome integrity. The retinoblastoma tumor suppressor protein (pRB) mediates both transcriptional repression and chromatin organization, but the independent contributions of these functions have been difficult to study. Here, we utilize a synthetic Rb1 mutant allele (F832A) that maintains pRB association at cell cycle gene promoters, but disrupts a cyclin-dependent kinase (CDK)-resistant interaction with E2F1 to reduce occupancy of pRB on intergenic chromatin. Reduced pRB chromatin association increases spontaneous γH2AX deposition and aneuploidy. Our data indicates that the CDK-resistant pRB-E2F1 scaffold recruits Condensin II to major satellite repeats to stabilize chromatin structure in interphase and mitosis through mechanisms that are distinct from silencing of repetitive sequence expression.


The impact of lymph node number on survival in patients with lymph node-negative pancreatic cancer.
The role of lymph node (LN) dissection for pancreatic cancer remains uncertain, and guidelines for a minimum LN number have not been established. We hypothesized that LN number in node-negative (N0) pancreatic cancer influences survival. The Surveillance, Epidemiology, and End Results database was queried for patients undergoing resection for N0 pancreatic adenocarcinoma between 1988 and 2003. Lymph node number was categorized as 1-10, 11-20, and >20. In a cohort of 1915 patients, the median LN number was 7 (range 1-57); 1365 (71%) patients had <11 LN. Survival was significantly better in the 11 to 20 compared with the 1-10 group (median, 20 vs 15 months, respectively, P < 0.0001); no difference was observed between the 11-20 and >20 groups (median, 20 vs 23 months, respectively, P = 0.14). Multivariate analysis demonstrated the prognostic significance of LN number for determining overall survival (hazard ratio 0.98, 95% confidence interval: 0.97-0.99; P<0.0001). Pancreatic cancer lymphadenectomy with examination of >10 LN is associated with improved survival in N0 disease and should be considered a benchmark for adequacy of surgery and/or pathology. Currently, only a minority of patients are assessed by this measure. The variation in LN number may be indicative of diverse surgical technique and/or pathologic analysis and warrants further investigation.


Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers.
Markers are needed to facilitate early detection of pancreatic ductal adenocarcinoma (PDAC), which is often diagnosed too late for effective therapy. Starting with a PDAC cell reprogramming model that recapitulated the progression of human PDAC, we identified secreted proteins and tested a subset as potential markers of PDAC. We optimized an enzyme-linked immunosorbent assay (ELISA) using plasma samples from patients with various stages of PDAC, from individuals with benign pancreatic disease, and from healthy controls. A phase 1 discovery study (n = 20), a phase 2a validation study (n = 189), and a second phase 2b validation study (n = 537) revealed that concentrations of plasma thrombospondin-2 (THBS2) discriminated among all stages of PDAC consistently. The receiver operating characteristic (ROC) c-statistic was 0.76 in the phase 1 study, 0.84 in the phase 2a study, and 0.87 in the phase 2b study. The plasma concentration of THBS2 was able to discriminate resectable stage I cancer as readily as stage III/IV PDAC tumors. THBS2 plasma concentrations combined with those for CA19-9, a previously identified PDAC marker, yielded a c-statistic of 0.96 in the phase 2a study and 0.97 in the phase 2b study. THBS2 data improved the ability of CA19-9 to distinguish PDAC from pancreatitis. With a specificity of 98%, the combination of THBS2 and CA19-9 yielded a sensitivity of 87% for PDAC in the phase 2b study. A THBS2 and CA19-9 blood marker panel measured with a conventional ELISA may improve the detection of patients at high risk for PDAC.


PCNL in the management of lower pole caliceal calculi.
Several therapeutic methods are used in the management of lower pole caliceal calculi. This survey has been conducted to evaluate the safety and efficacy of percutaneous nephrolithotomy in the management of lower pole calculi. Fifty-five patients, 43 males and 12 females with a mean age of 41.5 (range 11 to 75) years, who had suffered from lower pole caliceal calculi and treated by standard percutaneous nephrolithotomy (PCNL) between 1997 and 2001, were enrolled in this study. The stones were classified as follows: small (less than 25 mm), intermediate (25 to 34 mm) and large (more than 35 mm). Mean follow-up was 6.2 months (range 2 weeks to 34 months). The stones were completely extracted by one session PCNL in 43 patients (79%). Repeat PCNL was needed in one patient and another method was used for stone extraction in another patient. Regarding the size of stone, 88%, 79%, and 74% of small, intermediate, and large stones were completely extracted, respectively. No major complication was noted. PCNL has high success rate in patients with stones larger than 2 cm and its morbidity would be low, provided that it is performed by skilled surgeons.


Pravastatin for Preventing and Treating Preeclampsia: A Systematic Review.
We have performed a systematic search to summarize the role of statins for preventing and treating severe preeclampsia. The aim of this study was to examine whether pravastatin is a useful and safe alternative for treating preeclampsia during pregnancy. A systematic MEDLINE (PubMed) search was performed (1979 to June 2017), which was restricted to articles published in English, using the relevant key words of "statins," "pregnancy," "preeclampsia," "obstetrical antiphospholipid syndrome," and "teratogenicity." The initial search provided 296 articles. Finally, 146 articles were related to the use of statins during pregnancy, regarding their effect on the fetus and the treatment of preeclampsia. Ten studies were related to in vitro studies, 25 in animals, and 24 in humans (13 case report series and 11 cohort studies). We found 84 studies on reviews of such guidelines on cardiovascular disease (35 studies), use of statins in the antiphospholipid syndrome (25 studies), statin's specific use during pregnancy (13 studies), or preeclampsia treatment (11 studies). Although the studies are of poor quality, the rate of major congenital abnormalities in the newborn exposed to statins during pregnancy is no higher than the expected when compared with overall risk population. The review shows a potential beneficial role of statins in preventing and treating severe preeclampsia that needs to be evaluated through well-designed clinical trials. This update could influence positively the clinical practice, giving an alternative therapy for clinicians who treat preeclampsia, particularly in severe cases.


A comparison of individual and group cognitive-behavioural treatment for female pathological gambling.
The current study aimed to determine the differential efficacy of a cognitive-behavioural treatment program for female pathological gamblers delivered in individual and group format. Fifty-six female pathological gamblers with electronic gaming machine gambling problems were randomly assigned to the control (waiting list) group or one of the treatment groups (individual or group treatment). Treatment comprised a 12-session program including financial limit setting, alternative activity planning, cognitive correction, problem solving, communication training, relapse prevention, and imaginal desensitisation. Treatment outcome was evaluated with conceptually related measures within the areas of gambling behaviour and psychological functioning. While individual and group treatment formats generally produced comparable outcomes in terms of gambling behaviour and psychological functioning, group treatment failed to produce superior outcomes to the control group in relation to several measures of psychological functioning. Moreover, by the completion of the six-month follow-up, 92% of the gamblers allocated to individual treatment compared with 60% allocated to group treatment no longer satisfied the diagnostic criteria for pathological gambling. These findings suggest that some caution should be employed when delivering cognitive-behavioural treatment in a group format until further research is conducted to establish its efficacy.


Quantification of heart fatty acid binding protein as a biomarker for drug-induced cardiac and musculoskeletal necroses.
Heart fatty acid binding protein (Fabp3) is a cytosolic protein expressed primarily in heart, and to a lesser extent in skeletal muscle, brain, and kidney. During myocardial injury, the Fabp3 level in serum is elevated rapidly, making it an ideal early marker for myocardial infarction. In this study, an MS-based selected reaction monitoring method (LC-SRM) was developed for quantifying Fabp3 in rat serum. Fabp3 was enriched first through an immobilized antibody, and the protein was digested on beads directly. A marker peptide of Fabp3 was quantified using LC-SRM with a stable isotope-labeled peptide standard. For six quality control samples with Fabp3 ranging from 0.256 to 25 ng, the average recovery following the procedure was about 73%, and the precision (%CV) between replicates was less than 7%. The Fabp3 concentrations in rat serum peaked 1 h after isoproterenol treatment, and returned to baseline levels 24 h after the dose. Elevated Fabp3 levels were also detected in rats administered with a PPAR α/δ agonist, which has shown to cause skeletal muscle necrosis. Fabp3 can be used as a biomarker for both cardiac and skeletal necroses. The cross-validation of the LC-SRM method with an existing ELISA method is described.


A novel ion-exchange carrier based upon liposome-encapsulated montmorillonite for ophthalmic delivery of betaxolol hydrochloride.
As a novel ion-exchange carrier with high surface area and excellent exchangeability, montmorillonite (Mt) was intercalated with betaxolol hydrochloride (BH) to form a nanocomposite and then encapsulated by liposomes (Mt-BH-LPs) for an ophthalmic drug-delivery system. The Mt-BH and Mt-BH-LPs were prepared by an acidification process and ethanol injection combined with ammonium sulfate gradient methods. The successful formation of Mt-BH and Mt-BH-LPs was verified by thermogravimetric analysis, X-ray diffraction, Fourier-transform infrared spectra, and transmission electron microscopy. Mt-BH-LPs possessed the favorable physical characteristics of encapsulation efficiency, drug loading, mean particle size, and ζ-potential. In vitro release studies indicated Mt-BH-LPs effectively maintained a relatively sustained slow release. Immortalized human corneal epithelial cell cytotoxicity, in vivo rabbit eye-irritation tests, and chorioallantoic membrane-trypan blue staining all revealed that Mt-BH-LPs had no obvious irritation on ocular tissues. A new in vitro tear-turnover model, including inserts containing human corneal epithelial cells, was designed to evaluate the precorneal retention time of Mt-BH-LPs. The results showed that Mt-BH-LPs maintained a certain BH concentration in tear fluid for a longer period than the BH solution. In vivo precorneal retention studies also indicated Mt-BH-LPs prolonged drug retention on the ocular surface more than the BH solution. Furthermore, pharmacodynamic studies showed that Mt-BH-LPs had a prolonged effect on decreasing intraocular optical pressure in rabbits. Our results demonstrated that Mt-BH-LPs have potential as an ophthalmic delivery system.


Machine Learning Developed a Programmed Cell Death Signature for Predicting Prognosis, Ecosystem, and Drug Sensitivity in Ovarian Cancer.
Ovarian cancer (OC) is the leading cause of gynecological cancer death and the fifth most common cause of cancer-related death in women in America. Programmed cell death played a vital role in tumor progression and immunotherapy response in cancer. The prognostic cell death signature (CDS) was constructed with an integrative machine learning procedure, including 10 methods, using TCGA, GSE14764, GSE26193, GSE26712, GSE63885, and GSE140082 datasets. Several methods and single-cell analysis were used to explore the correlation between CDS and the ecosystem and therapy response of OC patients. The prognostic CDS constructed by the combination of StepCox (n = both) + Enet (alpha = 0.2) acted as an independent risk factor for the overall survival (OS) of OC patients and showed stable and powerful performance in predicting the OS rate of OC patients. Compared with tumor grade, clinical stage, and many developed signatures, the CDS had a higher C-index. OC patients with low CDS score had a higher level of CD8+ cytotoxic T, B cell, and M1-like macrophage, representing a related immunoactivated ecosystem. A low CDS score indicated a higher PD1 and CTLA4 immunophenoscore, higher tumor mutation burden score, lower tumor immune dysfunction and exclusion score, and lower tumor escape score in OC, demonstrating a better immunotherapy response. OC patients with high CDS score had a higher gene set score of cancer-related hallmarks, including angiogenesis, epithelial-mesenchymal transition, hypoxia, glycolysis, and notch signaling. The current study constructed a novel CDS for OC, which could serve as an indicator for predicting the prognosis, ecosystem, and immunotherapy benefits of OC patients.


Head trauma by captive bolt gun.
An 80 year-old former cattle-breeder committed suicide with a captive bolt gun. He was transmitted unconscious to emergency department. He had a large penetrating wound in right temporal area. Lateral radiograph of skull revealed a large rounded bony defect. CT verified a large rounded entry site and bony defect at the right pterion. It disclosed a wide, zonal-like haemorrhagic wound canal bearing intraparenchymal bony fragments at its end with no associated metallic fragments. Subarachnoid haemorrhage with bilateral subepidural hematomas and significant brain oedema was demonstrated.


Cartilage destruction in experimentally induced osteoarthritis.
Section of the anterior cruciate ligament in the knee joint of mature dogs resulted in a progressive fibrillation of both tibial and femoral condylar cartilages. Reduced tissue microhardness and increased water content preceded fibrillation while fixed charge density remained unchanged. A different histological pattern of initial fibrillation was found, however, in femoral and tibial cartilages which exhibited tangential cleft and vertical splits, respectively. Tangential fibrillation alone was associated with necrosis of superficial cells. This suggests that the mechanism of early osteoarthritic cartilage destruction varies in different articular surfaces.