Genetics of Behçet's disease in Sardinia: two distinct extended HLA haplotypes harbour the B*51 allele in the normal population and in patients.
To define the contribution of HLA genes and extended HLA haplotypes to the susceptibility to Behçet's disease (BD) in Sardinia. Forty-five unrelated Sardinian patients with BD, diagnosed according to the ISG criteria, 45 HLA-B*51 positive and 185 unselected healthy controls were enrolled in the study. DNA samples were typed for HLA class I and class II alleles and genotyped for microsatellites (MICA-TM) and single-nucleotide polymorphisms (rs1264457 HLA-E; rs2281820 motilin; rs1799724 at -857, rs361525 at -238 TNF-alpha) spanning the HLA region. HLA-B*5101 was confirmed as conferring susceptibility to BD (pc=0.0042; OR=4.4; 95% CI=2.0 to 9.6). It is noteworthy that in Sardinia this allele was found more frequently within a haplotype (HLA-A2; -Cw2; -B*5101; -DRB1*11; -DQA1*05; - DQB1*03) that reached its highest frequency in patients with BD. Linkage disequilibrium analysis showed the existence of an additional B*51 haplotype (HLA-A2; -Cw2; -B*5101; -DRB1*04; -DQA1*03; -DQB1*03) not associated with susceptibility to the disease. In Sardinia, the BD-associated HLA-B*5101 allele is inherited as part of two distinctive haplotypes differently distributed in patients and controls. These findings can be interpreted as suggestive of the presence of additional genes within the MHC region conferring susceptibility to BD. The hypothesis that an environmental pressure could have contributed to the preservation of the BD-associated HLA haplotype in Sardinia is also discussed.


The nuclear entry of the aryl hydrocarbon receptor (AHR) relies on the first nuclear localization signal and can be negatively regulated through IMPα/β specific inhibitors.
The human aryl hydrocarbon receptor (AHR) undergoes continuous shuttling between nucleus and cytoplasm. Binding to exogenous or endogenous ligands promotes its rapid nuclear import. The proposed mechanism for the ligand-dependent import is based on exposing the bipartite nuclear localisation signal (NLS) to members of the importin (IMP) superfamily. Among this, the molecular interactions involved in the basal import still need to be clarified. Utilizing fluorescently fused AHR variants, we recapitulated and characterized AHR localization and nucleo-cytoplasmic shuttling in living cells. Analysis of AHR variants carrying NLS point mutations demonstrated a mandatory role of first (13RKRRK17) and second (37KR-R40) NLS segments on the basal import of AHR. Further experiments indicated that ligand-induced import is mainly regulated through the first NLS, while the second NLS is supportive but not essential. Additionally, applying IMPα/β specific inhibitors, ivermectin (IVM) and importazole (IPZ), slowed down the ligand-induced import and, correspondingly, decreased the basal nuclear accumulation of the receptor. In conclusion, our data show that ligand-induced and basal nuclear entry of AHR rely on the same mechanism but are controlled uniquely by the two NLS components.


Automated volumetric growth plate measurement using magnetic resonance imaging for monitoring skeletal toxicity in children treated on investigational drug trials.
Targeted anticancer agents have been reported to have side effects on the skeletal system such as thickening of the epiphyseal growth plate in preclinical models of juvenile, but not mature, animals. Careful evaluation of skeletal toxicity in the clinical development of targeted therapies for children is required. We validated a novel method to measure the growth plate volume using MRI. A semiautomated method of volumetric growth plate measurement was developed on the basis of the differences of pixel intensity of the growth plate from surrounding bone on T(1) sagittal MRI. Two observers measured the femoral growth plate volume and thickness on three different days using 20 pediatric knee MRIs obtained at the NIH. Five subjects had two knee MRIs obtained on the same day to evaluate intrasubject reproducibility. Volumetric analysis showed low intraobserver variability, with the coefficient of variation for the two observers ranging from 0.2% to 6.1%. Interobserver correlation was 0.99, and good concordance was shown with a mean volume difference of -1.8 mm(3). One-dimensional measurements had poorer intra and interobserver consistency. No statistically significant differences in volumetric measurements were observed between the two scans done on the same day in five subjects (P = 0.5). MRI volumetric growth plate measurement is a reproducible and sensitive method to evaluate meaningful growth plate volume changes over time. This tool, along with close monitoring of height and laboratory evaluations for bone metabolism, may be used to evaluate potential bone and growth toxicities of children enrolled in trials of investigational drugs.


Decreasing incidence of Staphylococcus aureus bacteremia over 9 years: greatest decline in community-associated methicillin-susceptible and hospital-acquired methicillin-resistant isolates.
The impact of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) emergence on the epidemiology of S aureus bacteremia (SAB) is not well documented. This was an observational study of adult (aged ≥18 years) inpatients with SAB in a single 808-bed teaching hospital during 2002-2003, 2005-2006, 2008-2009, and 2010 with period-stratified SAB rate, onset mode, patient characteristics, and outcome. We encountered a total of 1,098 cases over the entire study period. The rate decreased steadily over time (from 6.64/10(3) discharges in 2002-2003 to 6.49/10(3) in 2005-2006, 5.24/10(3) in 2008-2009, and 5.00/10(3) in 2010; P = .0001), with a greater decline in community-associated cases (0.99/10(3), 0.77/10(3), 0.58/10(3), and 0.40/10(3), respectively; P = .0005) compared with health care-associated cases (5.65/10(3), 5.72/10(3), 4.66/10(3), and 4.60/10(3), respectively; P = .005). The decline was principally in MSSA (3.11/10(3), 2.21/10(3), 2.24/10(3), and 1.75/10(3), respectively; P = .00006), including both community-associated (P = .0002) and health care-associated cases (P = .006). Although overall rate changes in MRSA were not significant (P = .09), hospital-onset MRSA decreased markedly (P < .00001), whereas CA-MRSA increased (P = .03). The all-cause 100-day mortality rate did not change significantly (25.6% for 2002-2003, 25.2% for 2005-2006, 28.1% for 2008-2009, and 32.2% for 2010; P = .10). Differences in MSSA/MRSA-associated mortality decreased (20.1% vs 30.6%, P = .03 for 2002-2003; 18.1% vs 28.9%, P = .05 for 2005-2006; 21.7% vs 32.9%, P = .05 for 2008-2009; and 29.3% vs 34.9, P = .5 for 2010). SAB incidence is decreasing, with the greatest decline in community-associated MSSA and hospital-onset MRSA cases. Most health care-associated cases currently are community-onset. MRSA/MSSA-related mortality is comparable. These changes are likely related to the emergence of CA-MRSA and the inpatient-to-outpatient shift in health care.


[About safety parameters for patient-controlled analgesia (PCA) devices].
During the course of preparation of an opioid prescription, the nurse in charge became aware that the patient-controlled analgesia (PCA) syringe driver did not permit programming for the delivery as required: a maximum bolus number (Bmax) was indicated but only a maximum cumulative dose (Dcmax) could be programmed. The prescription dose criteria were consistent with the guidelines of the French societies of palliative care, anesthesiology, and reanimation (Société française d'accompagnement et de soins palliatifs [Sfap] and Société française d'anesthésie réanimation [Sfar]). A Dcmax dose simulation was programmed and used in order to test this problem. This highlighted the following four defects: bolus delivery is not controlled, leading to potential overdose. When Dcmax is reached, the continuous flow stops, triggering an end dose failure and a new programming step is needed to restart infusion, increasing the risk of programming errors. Human intervention is required to stop the alarm, identify and solve the problem. Finally, Dcmax leads to random dose delivery in place of the predictability of dose delivery expected for opioid administration. On the other hand, Bmax is a limited dose, administered only as a bolus and regulated by the lockout interval. When the Bmax dose is reached, no alarm is triggered, the basal flow continues, but no additional doses can be delivered. Bmax and Dcmax systems are not interchangeable. No comparative study between Bmax and Dcmax could be found, and Sfap and Sfar guidelines are not precise and did not take into consideration the safety aspects of dose delivery however some facts tend to prefer that Bmax. Most of the syringe driver devices are configured for the Dcmax, but not all of them, and the physician is often forced to use the parameter of the available device restricting the choice between Bmax and Dcmax. This is not justified, whether by scientific evidence, industrial, manufacturing or commercial standards. It becomes only a technical option that does not promote standardization of dose delivery and compromises the main safety feature of PCA.


Studying implementation quality of a school-based prevention curriculum in frontier Alaska: application of video-recorded observations and expert panel judgment.
This study assesses the implementation quality of Think Smart, a school-based drug prevention curriculum that was designed to reduce use of harmful legal products (HLPs; e.g., inhalants and over-the-counter drugs), alcohol, tobacco, and other drugs among 5th- and 6th-grade students in frontier Alaska. Participating in the study were eight communities that took part in a larger randomized control trial to assess the short-term effects of the Think Smart curriculum. Video-recorded observations of the 12 core and 3 booster lessons were conducted in 20 classrooms. Ninety-five sessions were randomly selected from 228 usable videodiscs, and two pairs of researchers observed each video recording to code level of dosage, adherence to curriculum design, and teachers' delivery skills. Inter-rater reliability for all implementation quality measures was very high. An expert panel consisting of 16 scientists reviewed the results of the implementation study and concluded that the level of dosage and adherence to the curriculum design was at least as high as those yielded by similar studies. However, the panel assessed the delivery quality to be only marginal in comparison to results of other studies. The experts concluded that the implementation quality of the Think Smart curriculum was adequate even though the teachers' delivery skills were only marginal. A bootstrapping analysis, in which 1,000 samples were drawn for each implementation quality result, found the expert judgments to be reliable. The authors conclude that despite some limitations, video-recorded observations, as well as expert judgment, provide strong methodologies that should be considered for future implementation quality studies.


Determination of antioxidant capacity and flavonoid composition of onion (Allium cepa L.) landrace 'Krishnapuram' bulb using HPLC-ESI-ITMS.
This study reports for the first-time antioxidant activity and flavonoid composition of KP onion landrace which is useful for future breeding programs and to obtain geographical indication (GI) tag for the benefit of farmers. The present study was aimed to determine antioxidant capacity and flavonoid composition of bulbs of red onion (Allium cepa L.) landrace 'Krishnapuram' (KP) from India using high-performance liquid chromatography (HPLC)-Electrospray Ionization (ESI)-multistage Ion Trap Mass Spectrometry (ITMS). The antioxidant activity was assayed by Ferric Reducing Antioxidant Power (FRAP) and hypochlorous acid (HClO)-induced oxidative damage in human erythrocytes. The total phenolic (TPC) contents in KP onion bulb extract (with 80% methanol) found to be 1.10 ± 0.2 mg GAE/g FW and 38.88 ± 1.0 lM QE/g. The FRAP activity measured for the bulb extract was 13.20 ± 0.1 μM QE/g. KP onion bulb extracts protected red blood cells (RBC) effectively (23%) against the oxidative damage induced by HClO. HPLC-ESI-ITMS analysis showed the presence of eight flavonols and five anthocyanins. Quercetin 3,4' -O-diglucoside (384.71 ± 0.49 mg/kg FW) and cyanidin 3-(6″-malonylglucoside) (20.95 ± 0.60 mg/kg FW) were detected as major flavonol and anthocyanin, respectively. The study suggests that KP onion has a considerable antioxidant activity due to the presence of high TPC. Moreover, quercetin glucosides are found to be more abundant than quercetin. The differences in quercetin glycosides content among different red onions could be useful for breeding programmes in the future.


Study on drainage mode and anti-clogging performance of new waterproofing and drainage system in a tunnel.
With an increase in tunnel construction and retention, traditional waterproofing and drainage systems have been unable to meet the needs of tunnels in heavy rainfall areas, and disasters such as tunnel lining cracking, leakage, and even collapse, occur frequently. In order to ensure the safe operation and maintenance of tunnels, this paper analyses the characteristics of the traditional waterproofing and drainage system, and puts forward a new drainage structure through numerical simulation and indoor testing. This structure removes the circular drainage blind pipe and adds a convex shell drainage plate between the waterproof board and the secondary lining. The research shows that the new drainage system greatly decreases the water pressure in the easily blocked area of the drainage structure. With the special surface discharge model, the external water pressure of the lining far away from the blocked area can quickly fall back to the normal level. In addition, the drainage capacity of different waterproof and drainage boards is different. With an increase in support pressure, the drainage capacity decreases; the geotextile decreases the most, followed by the capillary drainage board and then the convex shell drainage board. At the same time, after the muddy water drainage test of the three materials, it is found that the convex shell type drainage plate has the best anti-sludge performance. The research in this paper provides a beneficial attempt for the design of waterproofing and drainage structure of a water-rich karst tunnel, and provides a guarantee for the safe operation and maintenance of the tunnel.


Symmetric drug-related intertriginous and flexural exanthema: Clinicopathologic study of 19 cases and review of literature.
Symmetric drug-related intertriginous and flexural exanthema (SDRIFE) is a cutaneous drug reaction characterized by gluteal/anogenital erythema and symmetric involvement of other intertriginous location(s) without systemic signs. Clinicopathologic characterization has been limited to case reports and small series. We describe 19 new cases and review the literature to better define the clinical and histopathologic spectrum of SDRIFE. Pathology archives were searched for "SDRIFE" and "baboon syndrome." Cases meeting clinical criteria were included. Clinical and histopathologic features were recorded. Previous reports of SDRIFE with histopathologic descriptions were reviewed. Nineteen new cases were included, over half triggered by antibiotics. Six new causative medications were identified. Median onset was 7 days. Typical lesions were erythematous plaques or papules with or without scale. The most common histopathologic finding was superficial perivascular lymphocytic infiltrate followed by dermal eosinophils, spongiosis, and orthokeratosis. Basal vacuolization and apoptotic keratinocytes were less common. Interstitial histiocytes were present in almost half of our cases. Other findings included atypical lymphocytes and "flame figure." Appreciation of the range of inciting medications and clinicopathologic features in SDRIFE will improve recognition of this condition. Although many histopathologic features overlap with other common dermatitides, biopsy may assist in excluding key clinical mimics.


The structure of the arginine repressor from Mycobacterium tuberculosis bound with its DNA operator and Co-repressor, L-arginine.
The biosynthesis of arginine is an essential function for the metabolism of Mycobacterium tuberculosis (Mtb) and for the metabolism of many other microorganisms. The arginine repressor (ArgR) proteins control the transcription of genes encoding the arginine biosynthetic enzymes; they belong to repressors having one of the most intricate oligomerization patterns. Here, we present the crystal structure of the MtbArgR hexamer bound to three copies of the 20 base-pair DNA operator and to the co-repressor, L-arginine, determined to 3.3 A resolution. This is the first ternary structure of an intact hexameric ArgR in complex with its DNA operator. The structure reported here is very different from the suggested models of the ternary ArgR-DNA complexes; it has revealed the sophisticated symmetry of the complex and the presence of two remarkably different protomer conformations, folded and extended. Both features provide flexibility to DNA binding and are important for understanding the detailed function of ArgRs. Two of the 20 base-pair DNA operators align in a unified double-helical structure, suggesting the possible presence of a double ARG box in the promoter region of the Mtb arginine operon. Two pairs of protomers bind to the unified double ARG box so that the two folded protomers bind to the central half-sites of the double ARG box, whereas the two extended protomers bind to the remote half-sites. The protomers of the third pair bound to the single DNA operator also have a folded and an extended conformation. A probable mechanism for arginine repression is suggested on the basis of this structure.


Toward a Cultural Evolutionary Psychology: Why the Evolutionary Approach does not Imply Reductionism or Determinism.
Does evolutionary psychology (EP) properly account for the sociocultural context? Does it underestimate both the developmental and the relational aspects of the human psyche? Is it instantiated in a mechanistic epistemology? Does it imply determinism or reductionism? The commentaries on our previous target article raised similar questions and we try to tackle them in the current response. Our "epistemological assessment" of Psychology and our consequent unification claim under the banner of the evolutionary approach (Zagaria et al., Integrative Psychological and Behavioral Science, 54(3), 521-562, 2020 ) was deeply examined and discussed. The objections to our target article can be grouped into four main categories. We sum them up and argue why: 1) the pre-paradigmatic status of psychology is a problem rather than a richness of perspectives; 2) EP's criticisms stem from common misconceptions-furthermore, developmental and relational aspects of human psyche might find their natural explanation in EP; 3) EP does not wipe out the emergence of the sociocultural context as something qualitatively different; 4) evolutionary meta-theory is not incompatible with subjectivity. Evolutionary psychology might be approached with caution and curiosity, rather than with prejudicial concepts. Incorporating some legitimate cultural criticisms, it may aspire to become a "cultural evolutionary psychology", hence an integrative psychological meta-theory that tries to connect the biological "plane of existence" (Henriques, Review of General Psychology, 7(2), 150-182, 2003) to the cultural "plane of existence". However, a basic philosophical concern has yet to be answered, i.e. what ultimately constitutes mind and thus the "psycho-logical" science. We argue that when trying to find the answer we know where to look at.


Results of radiation treatment of medulloblastoma in adults.
From 1961 to 1982, 20 adults (greater than 16 years of age) were treated with radiation therapy following surgery for medulloblastoma. All patients received neuro-axis irradiation. Five patients received adjuvant chemotherapy. A 5- and 10-year survival rate of 78 and 55%, respectively, were achieved. Treatment failures were mainly a result of local recurrences, but also of metastases. One patient died of acute myeloid leukemia. One patient developed paraplegia. The survival rate was better in males (2 deaths out of 14) than in females (5 deaths out of 6). All the survivors are free of deficit or sequelae, except the patient with paraplegia.


Review of analytical methods for identification and quantification of cannabis products.
About 100 recently published original papers, reviews, books and other communications concerning cannabis (hashish, marijuana) constituents have been reviewed with the aim of summarizing the status of analytical detection and quantitation. Detailed protocols of standard analytical methods are compared in order to recommend uniform methods for field and forensic samples and also to provide guidance to less experienced analysts in countries where cannabis sativa occurs (T. Maylon.In Big Deal: The Politics of the Illicit Drug Business, the Cannabis Commodity Market, pp. 63-107. Guernsey, London.). Because of its importance, there has been an increasing number of investigations of the chemical, botanical, pharmacological, clinical and sociological aspects of the marijuana (hashish) problem. Since analytical techniques have improved substantially during the last 10 years, many papers have been published containing a variety of methods for detection and quantification of cannabis constituents. Since the analytical situation is becoming increasingly confused and because many of the journals are unavailable in less developed countries, the aim of this paper is to give an overview of existing analytical techniques and to attempt to distinguish practical and effective methods from those which are complex or which provide questionable results.


Acoustic levitation and high-resolution synchrotron X-ray powder diffraction: A fast screening approach of niclosamide amorphous solid dispersions.
The levitation of samples in an acoustic field has been of interest in the preparation and study of amorphous solid dispersions (ASD). Here, niclosamide-polymer solutions were levitated in a multi-emitter single-axis acoustic levitator and analyzed for 10 min at a High-resolution synchrotron X-ray powder diffraction beamline. This assembly enabled high-quality and fast time-resolved measurements with microliter sample size and measurement of solvent evaporation and recrystallization of niclosamide (NCL). Polymers HPMCP-55S, HPMCP-50, HPMCP-55, Klucel®, and poloxamers were not able to form amorphous dispersions with NCL. Plasdone® and Soluplus® demonstrated excellent properties to form NCL amorphous dispersions, with the last showing superior solubility enhancement. Furthermore, this fast levitation polymer screening showed good agreement with results obtained by conventional solvent evaporation screening evaluated for five days in a stability study, carried out at 40 °C/75% RH. The study showed that acoustic levitation and high-resolution synchrotron combination opens up a new horizon with great potential for accelerating ASD formulation screening and analysis.


Assessing appropriate panel size and optimization of quality metrics for ambulatory care pharmacists in the primary care setting.
Chronic disease state management utilizing pharmacists improves quality metrics, allows providers to focus on acute issues, and decreases physician burnout risk. Minimal data exist on pharmacist panel size and its impact. This study aimed to determine appropriate pharmacist panel size based on workload, quality metrics, and patient access. This study was a retrospective, multiclinic cohort analysis of patients with diabetes managed by pharmacists at 7 outpatient clinics. The primary objective calculated panel size per full-time equivalent (FTE) utilizing the National Health Interview Survey. Secondary objectives calculated the ideal FTE based on provider to pharmacist ratio and determined the impact of pharmacist panel size on patient access and quality metrics. A total of 4,399 patients were analyzed from 2017 through 2019, with age (range, 57.4 to 62.6 years), sex (52.5% to 63.5% female), race (41.2% to 93.7% African American), insurance type (13.3% to 41% Medicaid), and mean number of medications (13.1 to 20.3) significantly different between sites. Primary outcome results showed that actual panel sizes were less than calculated. However, secondary outcomes indicated that each site was understaffed (actual 0.2 to 0.5 FTE vs calculated 2.52 to 7.34 FTEs) and overbooked (95% to 122% capacity, 17 to 54.2 days for time to third next available appointment). Patients met the composite quality metric 35.1% to 56.3% of the time across sites. This study supports the use of patient access data to determine appropriate pharmacist panel size. Utilizing provider panel size to pharmacist ratio and time to third next available appointment is preferable for determining appropriate pharmacist panel size. Further research is needed to evaluate return times to help determine an ideal pharmacist panel size.


The design, synthesis, and anti-inflammatory evaluation of a drug-like library based on the natural product valerenic acid.
The plant natural product, valerenic acid (1) was chosen as a desirable scaffold for the generation of a novel screening library due to its drug-like physicochemical parameters (such as LogP, hydrogen bond donor/acceptor counts, and molecular weight). An 11-membered amide library (2-12) was subsequently generated using parallel solution-phase synthesis and Ghosez's reagent. The chemical structures of all semi-synthetic analogues (2-12) were elucidated following analysis of the NMR, MS, UV and IR data. The structures of compounds 8 and 11 were also confirmed by X-ray crystallographic analysis. All library members were evaluated for their ability to inhibit the release of IL-8 and TNF-α. Six analogues showed moderate activity in the IL-8 assay with IC50 values of 2.8-8.3μM, while none of the tested compounds showed any significant effect on inhibiting TNF-α release.


BHA study in pigs.
Butylated hydroxyanisole (BHA) was given to pregnant SPF pigs (Danish Landrace) in doses of 0, 50, 200 and 400 mg/kg body weight/day from mating to day 110 of the gestation period. The BHA was mixed in the diet (pelleted). Caesarean section was performed on gestation day 110. BHA affected neither the reproduction data nor the incidence of defects in the foetuses. Significantly lower weight gain was observed in the group of dams on the highest dose. Absolute and relative organ weights for the liver and thyroid gland showed a dose-related increase. Proliferative and parakeratotic proliferative changes of the stratified epithelium of the stomach were found in both control and treated pigs. In addition, proliferative and parakeratotic changes of the oesophageal epithelium were observed in a few pigs in the two groups on the highest doses. Papillomas were not found, and no changes of the glandular part of the stomach were observed.


How are people with obesity managed in primary care? - results of a qualitative, exploratory study in Germany 2022.
Counselling and management of overweight and obesity are tasks for which general practitioners possess favourable qualifications. Based on a long-term doctor-patient relationship, GPs have various options for actions to deal with overweight problems. To date, however, there is only little evidence on the experiences which people with obesity have made with the primary physician model and the care needs and wishes they actually address to their GPs. This study investigated what experiences people with obesity have had with GP care and what care needs and wishes they communicated to their GPs. The results will be used to derive starting points for optimising the primary healthcare setting. A total of 32 individuals affected by obesity were recruited over 24 online health forums. With them, we conducted qualitative interviews in the time between April and October 2022. The respondents considered the primary care physician to be the central contact person when they sought advice and support with weight problems. The advice of the GP was associated with an increased willingness to deal with reducing one's own weight. Despite this positive perception, widespread drawbacks existed from the perspective of the respondents: (1) incidental or late discovery of obesity, (2) absence of continuous weight counselling, (3) no agreement on specific weight reduction goals, (4) no referrals to help and support services, (5) insensitive discussion. Only some of the respondents who have recently been able to reduce their weight sustainably attributed their success primarily to the support they received from their GP. GPs should be encouraged to address obesity consistently and promptly. In addition, concrete recommendations and realistic goals for weight loss should be formulated. Continuous and motivating discussions are crucial in this regard. A focus on nutrition and exercise counselling in the GP's office should also be encouraged. GPs should be strengthened in their role as mediators by integrating their patients into a network of further assistance as needed. The development of care structures for obesity management should be promoted.


mLoc-mRNA: predicting multiple sub-cellular localization of mRNAs using random forest algorithm coupled with feature selection via elastic net.
Localization of messenger RNAs (mRNAs) plays a crucial role in the growth and development of cells. Particularly, it plays a major role in regulating spatio-temporal gene expression. The in situ hybridization is a promising experimental technique used to determine the localization of mRNAs but it is costly and laborious. It is also a known fact that a single mRNA can be present in more than one location, whereas the existing computational tools are capable of predicting only a single location for such mRNAs. Thus, the development of high-end computational tool is required for reliable and timely prediction of multiple subcellular locations of mRNAs. Hence, we develop the present computational model to predict the multiple localizations of mRNAs. The mRNA sequences from 9 different localizations were considered. Each sequence was first transformed to a numeric feature vector of size 5460, based on the k-mer features of sizes 1-6. Out of 5460 k-mer features, 1812 important features were selected by the Elastic Net statistical model. The Random Forest supervised learning algorithm was then employed for predicting the localizations with the selected features. Five-fold cross-validation accuracies of 70.87, 68.32, 68.36, 68.79, 96.46, 73.44, 70.94, 97.42 and 71.77% were obtained for the cytoplasm, cytosol, endoplasmic reticulum, exosome, mitochondrion, nucleus, pseudopodium, posterior and ribosome respectively. With an independent test set, accuracies of 65.33, 73.37, 75.86, 72.99, 94.26, 70.91, 65.53, 93.60 and 73.45% were obtained for the respective localizations. The developed approach also achieved higher accuracies than the existing localization prediction tools. This study presents a novel computational tool for predicting the multiple localization of mRNAs. Based on the proposed approach, an online prediction server "mLoc-mRNA" is accessible at http://cabgrid.res.in:8080/mlocmrna/ . The developed approach is believed to supplement the existing tools and techniques for the localization prediction of mRNAs.


Beneath the cuff: Often overlooked and under-reported blood flow restriction device features and their potential impact on practice-A review of the current state of the research.
Training with blood flow restriction (BFR) has been shown to be a useful technique to improve muscle hypertrophy, muscle strength and a host of other physiological benefits in both healthy and clinical populations using low intensities [20%-30% 1-repetition maximum (1RM) or <50% maximum oxygen uptake (VO2max)]. However, as BFR training is gaining popularity in both practice and research, there is a lack of awareness for potentially important design characteristics and features associated with BFR cuff application that may impact the acute and longitudinal responses to training as well as the safety profile of BFR exercise. While cuff width and cuff material have been somewhat addressed in the literature, other cuff design and features have received less attention. This manuscript highlights additional cuff design and features and hypothesizes on their potential to impact the response and safety profile of BFR. Features including the presence of autoregulation during exercise, the type of bladder system used, the shape of the cuff, the set pressure versus the interface pressure, and the bladder length will be addressed as these variables have the potential to alter the responses to BFR training. As more devices enter the marketplace for consumer purchase, investigations specifically looking at their impact is warranted. We propose numerous avenues for future research to help shape the practice of BFR that may ultimately enhance efficacy and safety using a variety of BFR technologies.


Peripheral neuropathy as a component of the neuroleptic malignant syndrome.
The neuroleptic malignant syndrome, an idiosyncratic reaction to antipsychotic medication, is defined by the tetrad of autonomic dysfunction, rigidity, fever, and altered mental status. Two patients in whom this syndrome developed acquired severe peripheral neuropathies during the course of their illness. This demyelinative polyneuropathy has not been reported previously as occurring in the neuroleptic malignant syndrome.


Surgical Management of Early Esophageal Cancer.
Esophageal cancer is the eighth most common cancer worldwide, and its incidence has been increasing over the past several decades. Esophagectomy currently is the standard of care for more advanced early esophageal cancer and should be performed at centers of excellence with high volumes, appropriate supportive staff, and multidisciplinary expertise.


LC-MS-MS determination of ibuprofen, 2-hydroxyibuprofen enantiomers, and carboxyibuprofen stereoisomers for application in biotransformation studies employing endophytic fungi.
The purpose of this study was the development and validation of an LC-MS-MS method for simultaneous analysis of ibuprofen (IBP), 2-hydroxyibuprofen (2-OH-IBP) enantiomers, and carboxyibuprofen (COOH-IBP) stereoisomers in fungi culture medium, to investigate the ability of some endophytic fungi to biotransform the chiral drug IBP into its metabolites. Resolution of IBP and the stereoisomers of its main metabolites was achieved by use of a Chiralpak AS-H column (150 × 4.6 mm, 5 μm particle size), column temperature 8 °C, and the mobile phase hexane-isopropanol-trifluoroacetic acid (95: 5: 0.1, v/v) at a flow rate of 1.2 mL min(-1). Post-column infusion with 10 mmol L(-1) ammonium acetate in methanol at a flow rate of 0.3 mL min(-1) was performed to enhance MS detection (positive electrospray ionization). Liquid-liquid extraction was used for sample preparation with hexane-ethyl acetate (1:1, v/v) as extraction solvent. Linearity was obtained in the range 0.1-20 μg mL(-1) for IBP, 0.05-7.5 μg mL(-1) for each 2-OH-IBP enantiomer, and 0.025-5.0 μg mL(-1) for each COOH-IBP stereoisomer (r ≥ 0.99). The coefficients of variation and relative errors obtained in precision and accuracy studies (within-day and between-day) were below 15%. The stability studies showed that the samples were stable (p > 0.05) during freeze and thaw cycles, short-term exposure to room temperature, storage at -20 °C, and biotransformation conditions. Among the six fungi studied, only the strains Nigrospora sphaerica (SS67) and Chaetomium globosum (VR10) biotransformed IBP enantioselectively, with greater formation of the metabolite (+)-(S)-2-OH-IBP. Formation of the COOH-IBP stereoisomers, which involves hydroxylation at C3 and further oxidation to form the carboxyl group, was not observed.


Interfacial rheology of model water-air microgels laden interfaces: Effect of cross-linking.
The mechanical properties of model air/water interfaces covered by poly(N-isopropylacrylamide) microgels depend on the microgels deformability or in other words on the amount of cross-linker added during synthesis. The study is carried out by measuring the apparent dilational, the compression and the shear moduli using three complementary methods: (1) the pendant drop method with perturbative areas, (2) the Langmuir trough compression, and (3) shear rheology using a double wall ring cell mounted onto a Langmuir through. In the range of surface coverages studied, the interfaces exhibit a solid-like behavior and elasticity goes through a maximum as a function of the surface pressure. This is observable whatever the investigation method. This maximum elasticity depends on the microgel deformability: the softer the microgels the higher the value of the moduli. The mechanical behavior of model interfaces is discussed, taking into account the core-shell structure of the particles and their packing at the interface.


Treatment of peripheral tissue ischemia with topical nitroglycerin ointment in neonates.
Four neonates had resolution of peripheral tissue ischemia after the application of 2% nitroglycerin ointment. A dosage of 4 mm nitroglycerin ointment per kilogram of body weight was applied to two patients with ischemia caused by vasospasm from indwelling radial artery catheterization and to two patients with ischemia resulting from dopamine extravasation. No adverse effects were noted except mild episodes of decreased blood pressure in two of the patients.


Prior use of therapeutic anticoagulation does not protect against COVID-19 related clinical outcomes in hospitalized patients: A propensity score-matched cohort study.
The hypercoagulable state observed in COVID-19 could be responsible for morbidity and mortality. In this retrospective study we investigated whether therapeutic anticoagulation prior to infection has a beneficial effect in hospitalized COVID-19 patients. This study included 1154 COVID-19 patients admitted to 6 hospitals in the Netherlands between March and May 2020. We applied 1:3 propensity score matching to evaluate the association between prior therapeutic anticoagulation use and clinical outcome, with in hospital mortality as primary endpoint. In total, 190 (16%) patients used therapeutic anticoagulation prior to admission. In the propensity score matched analyses, we observed no associations between prior use of therapeutic anticoagulation and overall mortality (risk ratio 1.02 [95% confidence interval; 0.80-1.30]) or length of hospital stay (7.0 [4-12] vs. 7.0 [4-12] days, P = .69), although we observed a lower risk of pulmonary embolism (0.19 [0.05-0.80]). This study shows that prior use of therapeutic anticoagulation is not associated with improved clinical outcome in hospitalized COVID-19 patients.


Monoclonal antibodies against African swine fever viral antigens.
Monoclonal antibodies specific for African swine fever (ASF) viral proteins of 14, 32, 73, 174, and 240 kDa were produced and characterized. Immunoelectron microscopy detected the 73 kDa but not the 14-, 32-, or 240-kDa proteins at the surface of the virion. The 32-kDa protein was detected by radioimmunoassay 2 hr after infection of porcine monocytes and Vero cells, was detected in the seven widely divergent ASFV isolates tested, and stained brilliantly virus-infected cells in indirect immunofluorescence suggesting that monoclonal antibodies directed against this protein may be useful in ASFV diagnosis. Two monoclonal antibodies detected heterogeneity between ASF viruses.


Insights into the migration of the European Roller from ring recoveries.
Despite recent advances in avian tracking technology, archival devices still present several limitations. Traditional ring recoveries provide a complementary method for studying migratory movements, particularly for cohorts of birds with a low return rate to the breeding site. Here we provide the first international analysis of ring recovery data in the European Roller Coracias garrulus, a long-distance migrant of conservation concern. Our data comprise 58 records of Rollers ringed during the breeding season and recovered during the non-breeding season. Most records come from Eastern Europe, half are of juveniles and over three quarters are of dead birds. Thus, ring recoveries provide migration data for cohorts of Rollers-juveniles and unsuccessful migrants-for which no information currently exists, complementing recent tracking studies. Qualitatively, our results are consistent with direct tracking studies, illustrating a broad-front migration across the Mediterranean Basin in autumn and the use of the Arabian Peninsula by Rollers from eastern populations in spring. Autumn movements were, on average, in a more southerly direction for juveniles than adults, which were more easterly. Juvenile autumn recovery direction also appeared to be more variable than in adults, though this difference was not statistically significant. This is consistent with juveniles following a naïve vector-based orientation program, and perhaps explains the 'moderate' migratory connectivity previously described for the Roller. In the first (qualitative) analysis of Roller non-breeding season mortality, we highlight the high prevalence of shooting. The recovery age ratio was juvenile-biased in autumn but adult-biased in spring. Although not statistically significant, this difference points towards a higher non-breeding season mortality of juveniles than adults. Our study demonstrates the complementarity of ring recoveries to direct tracking, providing an insight into the migration of juvenile Rollers and non-breeding season mortality.


Effects of COVID-19 on the admissions of aneurysmal subarachnoid hemorrhage: the West Greece experience.
Acute subarachnoid hemorrhage (SAH) due to aneurysmal rupture is a devastating vascular disease accounting for 5% of strokes. COVID-19 pandemic resulted in a decrease in elective and emergency admissions in the majority of neurosurgical centers. The main hypothesis was that fear of COVID-19 may have prevented patients with critical medical or surgical emergencies from actively presenting in emergency departments and outpatient clinics. We conducted a single-center, retrospective, observational study searching our institutional data regarding the incidence of spontaneous subarachnoid hemorrhage (SAH) and compare the admissions in two different periods: the pre COVID-19 with the COVID-19 period. The study cohort was comprised of a total of 99 patients. The mean (SD) weekly case rate of patients with SAH was 1.1 (1.1) during the pre-COVID-19 period, compared to 1.7 (1.4) during the COVID-19 period. Analysis revealed that the volume of admitted patients with SAH was 1.5-fold higher during the COVID period compared to the pre-COVID period and this was statistically significant (ExpB = 1.5, CI 95% 1-2.3, p = 0.044). Difference in mortality did not reach any statistical significance between the two periods (p = 0.097), as well as patients' length of stay (p = 0.193). The presented data cover a more extended time period than so far published reports; it is reasonable that our recent experience may well be demonstrating a general realistic trend of overall increase in aneurysmal rupture rates during lockdown. Hospitalization of patients with SAH cannot afford any reductions in facilities, equipment, or personnel if optimum outcomes are desirable.


Discovery of natural product-like spirooxindole derivatives as highly potent and selective LSD1/KDM1A inhibitors for AML treatment.
Histone lysine specific demethylase 1 (LSD1) is a promising new therapeutic target for cancer therapy. Following the work on the discovery of natural LSD1 inhibitor higenamine, we herein performed further structure-based design, synthesis, and extensive structure-activity relationship (SAR) studies, affording structurally new spirooxindole derivatives. Particularly, FY-56 was identified to be a highly potent LSD1 inhibitor (IC50 = 42 nM) and showed high selectivity over monoamine oxidases (MAO-A/B). Mechanistic studies showed that FY-56 moderately inhibited the proliferation and clone formation of leukemia cells, induced H3K4me1/2 accumulation and p53 activation as well as reduced the mRNA levels of the transcription factors HOXA9 and MEIS1. Meanwhile, FY-56 induced differentiation of MOLM-13 and MV4-11 cells, accompanied by an enhanced percentage of markers characteristic to differentiated macrophages and monocytes. Further in vivo studies showed that FY-56 obviously reduced the proportion of CD45+/CD33+ leukocytes in peripheral blood and spleen, and significantly prolonged the survival rate of mice. Collectively, FY-56 represents a structurally novel, highly potent and selective LSD1 inhibitor and exhibits therapeutic promise for AML treatment. The spirooxindole scaffold derived from FY-56 could be used to design structurally new LSD1 inhibitors for treating human diseases.


Virulence structure and its genetic diversity analyses of Blumeria graminis f. sp. tritici isolates in China.
Blumeria graminis f. sp. tritici (Bgt), the causal agent of wheat powdery mildew severely affects yield security wheat production in China. Understanding the virulence structure and genetic variations of this pathogen is important for breeding wheat lines resistant to wheat powdery mildew. However, information related to genes controlling resistance remains elusive. This study analyzes the virulence structure and the genetic diversity of pathogenic Bgt populations isolated from northeastern (Liaoning, Heilongjiang) and northwestern (Gansu) China, two representative wheat producing areas, on 37 wheat cultivars each carrying a known powdery mildew resistance (Pm) gene. Bgt isolates from northeastern China show higher frequencies of virulence genes than populations from Gansu Province. Many of the known Pm genes failed to provide resistance in this study. However, Pm21 provided 100% resistance to all isolates from all three provinces, obtained during two consecutive years, while Pm13 provided 100% resistance in Gansu. Pm13, Pm16, Pm18, and Pm22 also showed partial resistance in northeastern China, while Pm16, Pm18, Pm22, Pm5 + 6 and Pm2 + 6 +? maintained some resistance in Gansu. Genetic diversity among populations in different regions was detected by cluster analyses using expressed sequence tag-simple sequence repeat (EST-SSR). When the genetic similarity coefficient is relatively high, populations from the same regional origin are mostly clustered into one group while populations from different regions exhibit large genetic differences. Pm21 remains the best choice for breeding programs to maintain resistance to Bgt. Only 58% of the isolates tested show a clear correlation between EST-SSR genetic polymorphisms and frequency of virulence gene data.


Mitochondrial Sirt3 contributes to the bone loss caused by aging or estrogen deficiency.
Altered mitochondria activity in osteoblasts and osteoclasts has been implicated in the loss of bone mass associated with aging and estrogen deficiency - the 2 most common causes of osteoporosis. However, the mechanisms that control mitochondrial metabolism in bone cells during health or disease remain unknown. The mitochondrial deacetylase sirtuin-3 (Sirt3) has been earlier implicated in age-related diseases. Here, we show that deletion of Sirt3 had no effect on the skeleton of young mice but attenuated the age-related loss of bone mass in both sexes. This effect was associated with impaired bone resorption. Osteoclast progenitors from aged Sirt3-null mice were able to differentiate into osteoclasts, though the differentiated cells exhibited impaired polykaryon formation and resorptive activity, as well as decreased oxidative phosphorylation and mitophagy. The Sirt3 inhibitor LC-0296 recapitulated the effects of Sirt3 deletion in osteoclast formation and mitochondrial function, and its administration to aging mice increased bone mass. Deletion of Sirt3 also attenuated the increase in bone resorption and loss of bone mass caused by estrogen deficiency. These findings suggest that Sirt3 inhibition and the resulting impairment of osteoclast mitochondrial function could be a novel therapeutic intervention for the 2 most important causes of osteoporosis.


Water-in-water Pickering emulsions stabilized by the starch nanocrystals with various surface modifications.
Using the platelet-like starch nanocrystals (SNCs) to stabilize emulsions is attractive because as-prepared emulsions have promising applications in cosmetics and food fields. Limited studies mainly focus on the oil-in-water system, and another important system, the water-in-water emulsions stabilized by SNCs, has not yet been unveiled. Two surface modification strategies, crosslinking and acetylation, were applied to tune surface property and aggregation of SNCs, and a common all-aqueous system (dextran/poly(ethylene glycol)) was used here as template. The viscoelasticity and morphology of emulsions were studied in terms of the SNC loadings and polymer ratios. Crosslinking results in aggregation of SNCs, and the particle size increases (from 110 nm to 370 nm) with increased levels of substitution. This favors improving emulsifying ability of particles. Acetylation decreases the particle size (∼90 nm) and weakens the affinity of SNCs to the two aqueous phases, improving the emulsifying efficiency of SNCs. More intriguingly, the two emulsion systems show different phase inversion behaviors. The depletion-stabilization mechanism for the cross-linked SNCs and the diffusion-controlled mechanism for the acetylated SNCs are proposed using the emulsion viscoelasticity as probe. This study makes a comprehensive insight into the regulation of water-in-water emulsion morphology and types with the platelet-like SNCs.


Scalable substrate development for aqueous sample preparation for atom probe tomography.
Reliable and consistent preparation of atom probe tomography (APT) specimens from aqueous and hydrated biological specimens remains a significant challenge. One particularly difficult process step is the use of a focused ion beam (FIB) instrument for preparing the required needle-shaped specimen, typically involving a "lift-out" procedure of a small sample of material. Here, two alternative substrate designs are introduced that enable using FIB only for sharpening, along with example APT datasets. The first design is a laser-cut FIB-style half-grid close to those used for transmission-electron microscopy, that can be used in a grid holder compatible with APT pucks. The second design is a larger, standalone self-supporting substrate called a "crown," with several specimen positions that self-aligns in APT pucks, prepared by electrical discharge machining (EDM). Both designs are made nanoporous, to provide strength to the liquid-substrate interface, using chemical and vacuum dealloying. We select alpha brass a simple, widely available, lower-cost alternative to previously proposed substrates. We present the resulting designs, APT data, and provide suggestions to help drive wider community adoption. Lay Description Atom probe tomography (APT) maps the composition of solid materials in three dimensions with sub-nanometre resolution. Preparation of specimens from aqueous specimens remains a significant challenge. To aid with preparation, we introduce here two substrate designs that can hold suitable volumes of liquid for freezing, prior to shaping the final specimen into a sharp needle for APT by using cryogenic focused ion beam milling. We also describe the complete setup that we designed for handling these substrates, including dedicated sample holders. Both substrates are made nanoporous, to provide strength to the liquid-substrate interface, using chemical and vacuum dealloying of alpha brass a simple, widely available, low-cost material. We finally showcase APT data and provide suggestions to help drive wider community adoption. This article is protected by copyright. All rights reserved.


Factors associated with knowledges and attitudes about measles and rubella immunization in a non-health care occupational setting in Japan.
Elimination of measles and rubella has been achieved in several countries and some regions. After verified measles elimination, some countries have reported outbreaks among adults in occupational settings such as health care institution and school setting. Studies have reported that knowledge and attitude for measles and/or rubella are significantly associated with immunization uptake in adults, but few studies have been conducted in settings other than health care facilities and schools. We conducted a cross-sectional study among 134 office employees during a routine health checkup in June 17-20, 2014, to examine the association between willingness to receive immunization and knowledge and attitudes. Approximately 75% had a protective level of antibody for measles (PA≥1:256) and rubella (HI ≥ 32 IU/mL). After adjustment for sex, age and immune status, the attitudes that immunization prevents measles (adjusted odds ratio [aOR] = 7.8, 95% confidence interval [95%CI]: 2.5-24.7) and prevents infection and transmission to others (aOR = 4.0, 95%CI: 1.4-11.4). Knowing that males are the vulnerable group for rubella infection (aOR = 5.8, 95%CI: 2.4-13.9), attitude that immunization prevents rubella infection (aOR = 7.9, 95%CI: 2.4-26.5), and prevents infection and transmit to others (aOR = 6.7, 95%CI: 2.2-20.1) were significantly associated with willingness to receive immunization after adjustment for sex, age, and immune status. Studies have shown that physicians and other health care workers are important source of information for promotion of immunization. Thus, we recommend that physicians educate and promote immunization for measles and/or rubella to adults working in offices during routine health checks.


Effects of concomitant pentazocine and tripelennamine on brain-stimulation reward.
Reinforcing thresholds for self-stimulation behavior to the medial forebrain bundle were determined in rats by means of a rate-free psychophysical method. The acute administration of either pentazocine or tripelennamine caused a small but significant lowering of the reward threshold. Combined administration of an ineffective dose of tripelennamine with various doses of pentazocine resulted in a potentiation of this lowering effect. These results suggest that the widespread abuse of the combination of pentazocine and tripelennamine may be due to a pharmacologic potentiation rather than just a summation of their two effects.


The effect of contrast media of low osmolality on the peripheral arterial blood flow in the dog.
The intravascular contrast media in current use are solutions of salts of tri-iodinated substituted benzoic acids. Haemodynamic changes following injection of these contrast media are due mainly to their high osmolar concentration which is five to eight times physiological levels. In this study we compare the effect in dogs on femoral arterial flow following femoral arterial injection of three new low osmolality contrast media (Amipaque, Iopamidol and Hexabrix) compared to conventional contrast media (Coronary 280). Conventional salts such as Conray 280 cause a marked vasodilatation and increase in femoral blood flow to about twice pre-injection levels. The three new low osmolality contrast media cause much less vasodilation and increase in femoral blood flow (+32%). There was no significant difference between the effects of any of the three new media. The experiment suggests that any of three new low osmolality contrast media should be suitable for femoral arteriography as they cause much less vasodilatation (and therefore discomfort) than conventional contrast media. Our results do not indicate a preference for any of the three new contrast agents.


Improved biotinylation of glucose-6-phosphate dehydrogenase using active-site-blocking agents.
Characteristics of the biotinylation of glucose-6-phosphate dehydrogenase are presented. The enzyme is inactivated in the presence of N-hydroxysuccinimido biotin but can be protected by an appropriate concentration of NADPH used as an active-site blocker. A Ki of 1.6 +/- 1.0 microM calculated for NADPH for this protection shows it to be an active-site phenomena. Enzyme inactivation is irreversible with consistent kinetic results requiring the presence of 10 mM EDTA. An improved methodology was developed for biotinylation allowing 100% protection of the enzyme with loading factors up to 30.8 mol of biotin per enzyme.


Direct posterior restorations: clinical results and new developments.
The longevity of dental restorations is dependent on many different factors, including those related to materials, the dentist, and the patient. The main reasons for restoration failure are secondary caries, fracture of the bulk of the restoration or of the tooth, and marginal deficiencies and wear. The importance of direct-placement, aesthetic, tooth-colored restorative materials is still increasing. Amalgam restorations are being replaced because of alleged adverse health effects and inferior aesthetic appearance. All alternative restorative materials and procedures, however, have certain limitations. Direct composite restorations require a time-consuming and more costly treatment procedure and are actually only indicated for patients with excellent oral hygiene. Glass ionomers can be considered only as long-term provisional restorations in stress-bearing posterior cavities. Future treatment regimens that are made possible by the development of sophisticated preparation techniques, improved dentin bonding agents, and resin-based restorative materials will result in the therapy of more small-sized lesions rather than large restorations. The importance of indirect inlay techniques will shift more and more toward the direct restoratives. As the cavities become smaller, it is to be expected that the use of improved direct restorative materials will provide excellent longevity even in stress-bearing situations.


Thrombolysis with recombinant human tissue-type plasminogen activator during instability in coronary artery disease: effect on myocardial ischemia and need for coronary revascularization. TRIC Study Group.
Two hundred five men, 40 to 70 years of age, admitted to the coronary care unit with unstable coronary artery disease (unstable angina or non-Q wave myocardial infarction), were randomized to double-blind placebo-controlled treatment with an intravenous infusion of recombinant tissue-type plasminogen activator (rTPA), 1 mg/kg body weight (maximum 100 mg) during 4 hours, in addition to aspirin, heparin, and beta-blockade. No severe complications occurred. Myocardial ischemia, defined as myocardial infarction, incapacitating angina despite medication, or signs of ischemia at the exercise test, was reduced by treatment with rTPA compared with placebo both at discharge, 53% compared with 70% (p = 0.02), and at 1 month, 61% compared with 80% (p = 0.005). Signs of myocardial ischemia during the exercise test were reduced at discharge 51.0% compared with 68% (p = 0.03) and at 1 month 48% compared with 62% (p = 0.09). Coronary angiography after 1 month showed no difference in major coronary lesions between the groups, nor was there any reduction in the number of performed coronary revascularization procedures. In conclusion, treatment with rTPA in unstable coronary artery disease in men reduced myocardial ischemia but did not significantly reduce the need for revascularization in long-term follow-up.


Evaluation of the Lubricating Effect of Hyaluronic Acid on Contact Lenses Using a Pendulum-Type Friction Tester Under Mimicking Physiological Conditions.
To evaluate the lubricating effect of hyaluronic acid (HA) on soft contact lenses (SCLs) measured using a pendulum-type friction tester. We measured the coefficient of friction (CoF) of narafilcon A, delefilcon A, and etafilcon A with polyvinylpyrrolidone (PVP), daily disposable SCL material, using a modified pendulum-type friction tester. Sample SCLs were set on an acrylic plastic half-ball and placed into the polyethylene terephthalate hemisphere cup filled with 0.4 mL of test lubricants that included saline and 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% (wt/vol) HA (molecular weight, 850 kDa). The viscosities of saline and HA were measured using an Ubbelohde viscometer. The CoF of the SCL under a low concentration (0.05%) of HA was the lowest and significantly lower than saline in narafilcon A and delefilcon A (P<0.05, Steel multiple comparison test). Under higher HA concentrations (0.3%, 0.4%, and 0.5%), the CoF was significantly higher than that of saline (P<0.01, Steel' multiple comparison test) in all three SCLs. There were no significant differences of CoF among three SCLs in saline and all concentrations of HA. The HA viscosities increased exponentially with the concentration (Y=1.2829e9.286X). The viscosity of a high concentration of HA may increase the friction of SCLs, which may have a deleterious effect on the ocular surface.


GaN surface acoustic wave filter with low insertion loss.
Surface acoustic wave (SAW) filter with a low insertion loss (IL) of 4.415 dB has been demonstrated on Carbon-doped semi-insulating c-plane bulk GaN without external lumped element matching. The center frequency, 3 dB bandwidth, out-of-band attenuation, return loss of the filter are 477.05 MHz, 0.308 MHz, 32.5 dB, and -9.72 dB, respectively. The electromechanical coupling coefficient (Kt2), and temperature coefficient of frequency (TCF) of the filter are 0.21 % and -26.0 ppm/°C, respectively. The impact of the number of interdigital transducers (NIDT) and acoustic propagation direction on filter performance has been studied. The IL of filters reduces from 16.07 dB to 4.415 dB with the increase of NIDT from 50 to 150 due to the enhanced acoustic superposition. The numerical distribution of elastic stiffness ([cij]), and piezoelectric constants ([eik]) of GaN has been calculated in Euler angle space, indicating that they are isotropic on c-plane. The small performance difference of filters along the m- and a-direction on c-plane bulk GaN can be attributed to the small offset angle of 0.5° of the bulk GaN wafer or IDT quality variation.


The Zoom Effect: A Google Trends Analysis.
Increased video-chatting, stimulated by the COVID-19 pandemic, has been correlated with increased appearance concerns. Initial lockdown restrictions correlated with a decrease in aesthetic/cosmetic plastic surgery case volumes. The authors aimed to delineate public interest in aesthetic procedures surrounding the COVID-19 pandemic via Google Trends. They hypothesized that because of the pandemic, public interest in plastic surgery procedures increased, especially localized above the shoulder. Trends in the United States for given search terms and volumes were gathered via Google Trends between January 2015 and March 2021. The search volumes were normalized, and a bivariate regression analysis of panel data was then applied to the aggregate trendlines to determine if a statistically significant change in search volume occurred following the stay-at-home orders. The following search terms had statistically significant (P < 0.000) increases in search volumes after February 2020: blepharoplasty, Botox, brachioplasty, breast implant removal, breast reduction, brow lift, buccal fat removal, hair transplantation, lip augmentation, mentoplasty, otoplasty, platysmaplasty, rhinoplasty, and thighplasty. Chi-squared analysis demonstrated a statistically significant association (chi-squared = 4.812, P = 0.028) between increases in search volume and above-the-shoulder procedures. Public interest in above-the-shoulder surgical procedures statistically significantly increased following February 2020 compared with below-the-shoulder procedures. Continued examination of specific procedure trends and determining correlations with more accurate procedural datasets will provide increased insight into consumers' mindsets and to what extent video conferencing plays a role in the public's interest in pursuing aesthetic surgery.


A multi-site service evaluation of the tinnitus care decision aid.
Shared decision-making is a principle of health care delivery across the world. The first international standard decision aid for tinnitus care was developed in 2018. This decision aid is in use across the UK. It is free to use and access from the British Tinnitus Association website. Our objective was to compare routine care with the care that also included the decision aid as part of care for their patients. A multi-site service evaluation included pre-post comparison of decisional conflict in sequential new patients seeking help with tinnitus. Informal interviews with staff and service managers explored how practical and feasible the decision aid was in routine practice. We present data from four contrasting clinical services, including services in England and Wales, acute and community services and those operated by Hearing Therapists and Audiologists. Across these contrasting services, the inclusion of the decision aid was associated with a reduction in decisional conflict in patients. The decision aid was feasible to administer, acceptable to patients and clinicians without creating a burden in appointments. These evaluations suggest that the decision aid is feasible to administer and reduces patient decisional conflict. It appears to benefit clinical services in practice.


Randomized trial using piperacillin versus ampicillin and amikacin for treatment of premature neonates with risk factors for sepsis.
Premature infants with risk factors for early onset sepsis who were less than seven days of age were blindly randomized to receive either piperacillin and placebo (200 infants) or ampicillin and amikacin (196 infants). One of 30 treated infants developed positive blood cultures. The overall mortality in the two groups was 8.5% for piperacillin/placebo and 13.8% for ampicillin/amikacin (p = 0.11). Serum creatinine elevation above 100 mumol/l (1.131 mg/dl) during treatment was similar in the two groups. The effectiveness of piperacillin/placebo is similar to that of ampicillin/amikacin for empiric treatment of premature newborns with risk factors for early onset sepsis.


Fibronectin in meningococcal sepsis. Correlation with antithrombin III and protein C.
Plasma fibronectin was measured with Laurell's immunoelectroassay in 44 patients with meningococcal sepsis. The average value (15.0 +/- 7.9 mg/dl) was lower than that in normal children (27.4 +/- 8.7 mg/dl) (p less than 0.001). Fibronectin in patients correlated positively with antithrombin III (AT-III) values (p less than 0.02), but not with protein C (0.05 less than p less than 0.1). The decrease of fibronectin had no prognostic value. The fibronectin levels were lower in patients with disseminated intravascular coagulation (DIC+), than in those without DIC (DIC-) (p less than 0.02), but were lower in both groups than in a normal control group. A negative correlation between fibronectin and protein C was only present in DIC- patients (r: -0.773 = p less than 0.01). Fibronectin varied independent of AT-III and protein C in DIC+ patients. The study was repeated in 11 patients 24 hours after admission when fibronectin had decreased in 7/11 cases (mean decrease: -2.7 +/- 8.7 mg/dl). This variation correlated in a negative way with AT-III (r: -0.659 = p less than 0.05). In meningococcal sepsis fibronectin decreases very early, even in DIC- patients and its relationship to AT-III and protein C is different, depending on the presence of DIC and on the stage of evolution of the disease.


Effective Radiotherapy in Tracheobronchial Adenoid Cystic Carcinoma With Positive Surgical Margin.
The study aimed to evaluate the role of postoperative radiotherapy (PORT) in the treatment of trachea and main bronchus adenoid cystic carcinoma (ACC) with a positive surgical margin. Patients with pathologically confirmed trachea or main bronchus ACC operated on at Shanghai Chest Hospital were enrolled. Survival, univariate, and multivariate analyses were performed. The χ2 test was applied to analyze the failure patterns among different groups (R0/0: negative margin resection without PORT; R1/0: positive margin resection without PORT; R1/1: positive margin resection with PORT). From January 2001 to December 2014, 77 patients were deemed eligible for the study. Pairwise comparisons showed that the overall survival rate of group R1/1 was comparable to that of group R0/0 (P = .438), and significantly longer than the rate of group R1/0 (P = .032). Additionally, the local disease-free survival rate of group R1/1 was much higher than that of group R0/0 (P = .023) and R1/0 (P = .001). Cox multivariate analysis identified the radiologic feature (P = .012) and PORT (P = .006) as significantly favorable prognostic factors for locoregional disease-free survival. By contrast, for overall survival, PORT (P = .032) was the only corresponding variable identified by univariate analysis. Furthermore, PORT significantly decreased the locoregional recurrence rate (P = .002) but not distant metastases (P > .999). PORT helped patients with tracheobronchial ACC and microscopic positive surgical margins to achieve a similar outcome as patients with complete resection. R0 resection may not be necessary for tracheobronchial ACC if it is difficult to be completely resected.


Minimizing abdominal incision for transverse uterine fundal incision by aspiration of amniotic fluid and reduction of uterine size.
Transverse uterine fundal incision (TUFI) was developed to avoid catastrophic hemorrhage associated with cesarean section of the placenta previa-accreta. Abdominal incisions extend as far as the upper abdomen in patients in the third trimester of pregnancy and require general anesthesia. Instead, we tried to aspirate amniotic fluid (AF) to reduce the uterine size. TUFI was performed in 19 of our patients in the third trimester in whom placenta previa accreta could not be ruled out between June 2012 and August 2016. After the lower abdominal vertical incision, we attempted to exteriorize the uterine fundus. If this was impossible, we inserted an 18-gauge spinal needle into the amniotic space. We aspirated AF until the uterine fundus could be exteriorized. We exteriorized the uterine fundus without extending the incision to the upper abdomen by aspirating 250-670 mL of AF in 12 patients who were between the 33rd and 37th week of pregnancy, and TUFI was performed under spinal anesthesia. AF aspiration was not required in four patients who were in the 30th or 31st week of pregnancy and in two patients with oligohydramnios in the 35th week of pregnancy. In one case, the trial was canceled due to hemorrhagic AF aspiration. No serious complications were observed in mothers or neonates. TUFI could be made by abdominal incision to the left of the umbilicus under spinal anesthesia without anesthesia by reducing the uterine size through AF aspiration, even for patients in the third trimester of pregnancy.


A mechanism for inhibiting the SUMO pathway.
The SUMO pathway parallels the classical ubiquitinylation pathway with three discrete steps: activation involving the enzyme E1, conjugation involving the E2 enzyme UBC9, and substrate modification through the cooperative association of UBC9 and E3 ligases. We report here that the adenoviral protein Gam1 inhibits the SUMO pathway by interfering with the activity of E1 (SAE1/SAE2). In vivo, Gam1 expression leads to SAE1/SAE2 inactivation, both SAE1/SAE2 and UBC9 disappearance, and overall inhibition of protein sumoylation. This results in transcriptional activation of some promoters and is directly linked to inhibition of sumoylation of the transcriptional activators involved. Our results identify a mechanism for interfering with the SUMO pathway and with transcription that could have an impact in the design of novel pharmaceutical agents. They also point out once again to the extraordinary ability of eukaryotic viruses to interfere with the biology of host cells by targeting fundamental biochemical processes.


Effects of landscape modification on coastal sediment nitrogen availability, microbial functional gene abundances and N2O production potential across the tropical-subtropical gradient.
Wetland sediment is an important nitrogen pool and a source of the greenhouse gas nitrous oxide (N2O). Modification of coastal wetland landscape due to plant invasion and aquaculture activities may drastically change this N pool and the related dynamics of N2O. This study measured the sediment properties, N2O production and relevant functional gene abundances in 21 coastal wetlands across five provinces along the tropical-subtropical gradient in China, which all had experienced the same sequence of habitat transformation from native mudflats (MFs) to invasive Spartina alterniflora marshes (SAs) and subsequently to aquaculture ponds (APs). Our results showed that change from MFs to SAs increased the availability of NH4+-N and NO3--N and the abundance of functional genes related to N2O production (amoA, nirK, nosZ Ⅰ, and nosZ Ⅱ), whereas conversion of SAs to APs resulted in the opposite changes. Invasion of MFs by S. alterniflora increased N2O production potential by 127.9%, whereas converting SAs to APs decreased it by 30.4%. Based on structural equation modelling, nitrogen substrate availability and abundance of ammonia oxidizers were the key factors driving the change in sediment N2O production potential in these wetlands. This study revealed the main effect patterns of habitat modification on sediment biogeochemistry and N2O production across a broad geographical and climate gradient. These findings will help large-scale mapping and assessing landscape change effects on sediment properties and greenhouse gas emissions along the coast.


Angiotensin II can trigger HSC-LX2 pyroptosis through both classical and non-classical pathways.
Current evidence suggests that liver fibrosis is reversible even at late stages. Pyroptosis is reportedly regulated by classical and non-classical pathways and is also involved in the activation of the human hepatic stellate cell line LX2. This study sought to identify regulatory pathways that pyroptosis of HSC during AngII-ROS-induced HSC activation and provides novel insights for anti-fibrosis therapy by targeting HSC. All experiments were conducted in HSC-LX2. The expressions of α-SMA, NLRP3, Caspases-1, -4, -5, ASC and GSDMD-N were detected in HSC-LX2 cells induced with AngII by Western blot and qRT-PCR. CCK8 was used to detect cell proliferation and activity. 2'-7'dichlorofluorescin diacetate (DCFH-DA) was used to measure ROS generation. An LDH assay kit was used to detect LDH released from damaged cells, and ELISA was used to quantify IL-18 and IL-1β levels. After AngII stimulation, HSC-LX2 cell viability, ROS, LDH, IL-18, and IL-1β were increased compared with Control group. At the same time, the protein and mRNA levels of α-SMA, NLRP3, Caspases-1, -4, -5, ASC and GSDMD-N were increased. In addition, after NAC and NSA treatment, LDH, IL-18 and IL-1β levels and the protein and mRNA expression of α-SMA, Caspases-4 and -5, and GSDMD-N were decreased. HSC-LX2 pyroptosis induced by AngII-ROS is mediated by the classical pathway involving NLRP3/Caspase-1 and the non-classical pathway involving Caspases-4 and -5. Our results provide compelling evidence that AngII could activate Caspases-4 and -5 by producing ROS.


Investigating the robustness of the AlignRT InBore™ co-calibration process and determining the overall tracking errors.
To determine the overall tracking errors inherent to the co-calibration procedure of AlignRT InBore™'s (Vision RT Ltd., London, UK) ceiling-mounted and ring-mounted cameras. Extrinsic calibration errors related to the mismatch between ceiling and InBore cameras' isocentres and treatment isocentre were determined using MV images and the SRS package and compared to traditional plate-based error. Next, using a realistic anthropomorphic female phantom, intrinsic calibration errors were determined while varying source-skin distance (80 to 100 cm), breast board inclination (0° to 12.5°), room lighting conditions (0 to 258 lx), skin colour (dark, white and natural skin colour), and pod occlusion. MV images of the cube proved plate-based calibration to suffer from large errors especially in the vertical direction (up to 2 mm). Intrinsic calibration errors were considerably lower. Indeed, RTD values of ceiling and InBore cameras showed little variability with isocentre depth (within 1.0 mm/0.4°), surface orientation and breast board inclination (within 0.7 mm/0.3°), changing lighting conditions (within 0.1 mm/0.2°), skin colour/tone (within 0.3 mm/0.3°) and camera pod occlusion (within 0.3 mm/0.2°). The use of MV-images proved critical to maintain co-calibrating errors of ceiling and InBore cameras to Halcyon's treatment isocentre below 1 mm.


Free arachidonic acid source for PGE2 and TXB2 production in guinea pig peritoneal macrophages exposed to insoluble glucan from Streptococcus mutans.
1. Macrophages are an important source of the lipid mediators arachidonic acid (AA) and its metabolites that are produced during inflammation. 2. Previously, we reported that insoluble glucans from Streptococcus mutans in dental plaque could induce macrophages to secrete PGE2 and TXB2. 3. Studies were undertaken to identify the phospholipid substrates that can serve as a source of AA in macrophages exposed to the insoluble glucan. 4. When macrophage cell prelabelled with [3H]AA, stimulation with insoluble glucan resulted in a loss of label mainly from phosphatidylcholine (PC) and phosphatidylinositol (PI). 5. In addition, the PC-, and PI-specific phospholipase A2-mediated mechanisms for AA release may be activated in guinea peritoneal macrophages exposed to the insoluble glucan from S. mutans.


A role for central nervous system PPAR-γ in the regulation of energy balance.
The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that is activated by lipids to induce the expression of genes involved in lipid and glucose metabolism, thereby converting nutritional signals into metabolic consequences. PPAR-γ is the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs, which have been widely prescribed to treat type 2 diabetes mellitus. A common side effect of treatment with TZDs is weight gain. Here we report a previously unknown role for central nervous system (CNS) PPAR-γ in the regulation of energy balance. We found that both acute and chronic activation of CNS PPAR-γ, by either TZDs or hypothalamic overexpression of a fusion protein consisting of PPAR-γ and the viral transcriptional activator VP16 (VP16-PPAR-γ), led to positive energy balance in rats. Blocking the endogenous activation of CNS PPAR-γ with pharmacological antagonists or reducing its expression with shRNA led to negative energy balance, restored leptin sensitivity in high-fat-diet (HFD)-fed rats and blocked the hyperphagic response to oral TZD treatment. These findings have implications for the widespread clinical use of TZD drugs and for understanding the etiology of diet-induced obesity.


Update on end-of-life care training during nephrology fellowship: a cross-sectional national survey of fellows.
Patients with end-stage renal disease have high mortality and symptom burden. Past studies demonstrated that nephrologists do not feel prepared to care for their patients at the end of life. We sought to characterize current palliative and end-of-life care education received during nephrology fellowship and compare this with data from 2003. Cross-sectional online survey of second-year nephrology trainees. Responses were compared to a similar survey in 2003. 104 US nephrology fellowship programs in 2013. Quality of training in and attitudes toward end-of-life care and knowledge and preparedness to provide nephrology-specific end-of-life care. Of 204 fellows included for analysis (response rate, 65%), significantly more thought it was moderately to very important to learn to provide care at end of life in 2013 compared to 2003 (95% vs 54%; P<0.001). Nearly all (99%) fellows in both surveys believed physicians have a responsibility to help patients at end of life. Ranking of teaching quality during fellowship in all areas (mean, 4.1±0.8 on a scale of 0-5 [0, poor; 5, excellent]) and specific to end-of-life care (mean, 2.4±1.1) was unchanged from 2003, but knowledge of the annual gross mortality rate for dialysis patients was nominally worse in 2013 because only 57% versus 67% in 2003 answered correctly (P=0.05). To an open-ended question asking what would most improve fellows' end-of-life care education, the most common response was a required palliative medicine rotation during fellowship. Assessments were based on fellows' subjective perceptions. Nephrology fellows increasingly believe they should learn to provide end-of-life care during fellowship. However, perceptions about the quality of this teaching have not improved during the past decade. Palliative care training should be integrated into nephrology fellowship curricula.


Utility of QuantiFERON®-TB Gold test in diagnosis and management of suspected tubercular uveitis in India.
The tuberculin skin test, used to detect latent systemic tuberculosis (TB), has its limitations. The utility of interferon-gamma assays, found useful in the diagnosis of latent TB, is still unestablished in tubercular uveitis. We present the results of QuantiFERON(®)-TB Gold (QFT-G) test and its relevance in the diagnosis and management of suspected tubercular uveitis in India. All suspected tubercular uveitis patients seen at our uveitis clinic between October 2006 and June 2008 who underwent relevant blood investigations, chest X-rays, Mantoux tests and QFT-G tests were included. Clinical profile, systemic correlation and outcome with treatment were analysed. Fifty suspected tubercular uveitis patients underwent QFT-G testing. The age range of the patients was 6-55 years (mean 32.66 years). Seven patients presented with active and three with a past history of systemic TB. The QFT-G test was positive in 29 patients. Radiological findings of TB were seen in four patients with a positive QFT-G and one patient with a negative QFT-G test. In 11 patients both QFT-G and Mantoux tests were positive. Eighteen Mantoux-negative patients were QFT-G-positive. Significantly, no patient with a positive Mantoux had a negative QFT-G test. Of the 32 patients with posterior uveitis, 17 patients had serpiginous choroiditis, four patients had a choroidal granuloma, six patients had multifocal choroiditis, four patients had retinal vasculitis, and one patient had a subretinal abscess. All QFT-G-positive patients were treated with anti-tuberculosis therapy as well as systemic steroids with a favorable clinical outcome. Our study shows that the QFT-G test is very useful in the diagnosis and management of suspected ocular TB. It was found to be very sensitive in identifying latent TB patients who, upon treatment, had a significantly reduced frequency of recurrences. It was more sensitive than the Mantoux test and is not significantly affected by previous treatment with systemic steroids or immunosuppressives. A negative QFT-G test can also be used as an adjunct before initiation of systemic steroids or immunosuppressives in uveitic patients particularly in an endemic setting like India.


Ophthalmic eponyms from the Mayo Clinic.
Numerous ophthalmic eponyms are associated with the Mayo Clinic. Some of the terms, such as "Hollenhorst plaque" and "Kearns-Sayre syndrome," are well known, whereas others are relatively obscure. Although eponyms have their detractors, the designations likely will appear in the medical lexicon for many more years.


Deep regional hyperthermia with preoperative radiochemotherapy in locally advanced rectal cancer, a prospective phase II trial.
The goal of the present study was to investigate the effect of deep regional hyperthermia on early and long-term oncological outcomes in the context of preoperative radiochemotherapy in rectal cancer. In this prospective phase II trial, patients with locally advanced rectal cancer were treated with 5-fluorouracil based preoperative radiochemotherapy with 50.4 Gy in 28 fractions. Deep regional hyperthermia was scheduled twice weekly. Pathological tumor regression was scored according to the Dworak regression system. The primary endpoint was pathological complete response (pCR). Further endpoints were local control (LC), distant control (DC), disease-free survival (DFS) and overall survival (OS). Hyperthermia was defined as feasible if 70% of patients received at least eight treatments. Quality of life was assessed at follow-up by the EORTC-QLQ-C30 and QLQ-CR29 questionnaires. Time to event data was analyzed according to Kaplan-Meier based on first-events. The study was registered on clinicaltrials.gov (NCT02353858). From 2012 until 2017, 78 patients were recruited. Median follow-up was 54 months. Based on magnetic resonance imaging, the mesorectal fascia was involved or threatened in 60% of the patients. Compliance with radiotherapy was 99%, 91% received both cycles of chemotherapy and 77% had eight or more hyperthermia treatments. Median time from the end of radiotherapy to surgery was 6.7 weeks. A pathological complete response was reported in 14% of the patients, 50% had either Dworak 4 (complete regression) or Dworak 3 regression (scattered tumor cells only). Three year estimates for OS, DFS, LC and DC were 94%, 81%, 96% and 87%. Patients with higher hyperthermia related cumulative temperatures showed stronger tumor regression. Global health status based on EORTC-QLQ-C30 was comparable with data from the general population. Deep regional hyperthermia was feasible, did not compromise standard treatments and resulted in promising long-term oncological outcomes and QoL.


A comparative in-vivo evaluation of the alignment efficiency of 5 ligation methods: A prospective randomized clinical trial.
To conduct a prospective randomized study comparing the efficiency of 5 different ligation systems (ELL; elastomeric ligature, SSL; stainless steel ligature, LL; leone slide ligature, PSL; passive self-ligation and ASL; active self-ligation) over the duration of mandibular crowding alleviation. Fifty consecutive patients (54.2% male, 45.8% female; mean age: 16.69 years) satisfying the inclusion criteria were randomly allocated to 5 ligation groups with an equal sample size of 10 per group. The 5 groups received treatment with 0.022-inch MBT pre-adjusted edge-wise technique (ELL: Gemini 3M Unitek, SSL: Gemini 3M Unitek, LL: Gemini 3M Unitek, PSL: SmartClip 3M Unitek and ASL: In-Ovation R Euro GAC International). The models and cephalograms were evaluated for anterior arch alignment, extraction space closure, and lower incisal inclinations at pre-treatment T1 and at the end of initial alignment T2. Analysis of variance (ANOVA) and Post-hoc tests were used for data analysis. Forty-eight participants completed the study, and SL systems showed a significant difference over CL groups in time to alignment, passive space closure, and incisal inclination. Multiple regression showed a reduction of 5.28 days in time to alignment by changing the ligation group in the order of ELL to ASL group and 1 mm increase in initial irregularity index increases time to alignment by 11.68 days. Self-ligation brackets were more efficient than conventional ligation brackets during initial leveling and alignment.


Efficient Treg depletion induces T-cell infiltration and rejection of large tumors.
There are a number of factors that hamper immunotherapy of cancer. For example, tumors exhibit an aberrant vasculature that appears to form a barrier against T-cell infiltration. Another major obstacle is created by Treg. So far, conventional depletion of Treg with anti-CD25 antibodies, which eliminate only 70% of Treg, has failed to significantly reduce the growth of established tumors. Using Foxp3.LuciDTR-4 mice, we show here that 90-95% Treg depletion resulted in complete regression of large established tumors, whereas 70% depletion was ineffective. The extensive Treg depletion induced a number of processes that are critical for tumor rejection, including activation of tumor-specific CD8(+) T cells and enhanced infiltration of these cells into the tumor. The precise mechanism of enhanced infiltration is not known, but normalization of the tumor vasculature is assumed to assist infiltration. Indeed, we observed that 90% Treg depletion caused normalization of the tumor vasculature as indicated by a reduction in leakiness and the number of dilated vessels. These results suggest that for clinical immunotherapy of cancer, it would be desirable to have reagents that allow high-level depletion of Treg, which, in conjunction with treatment modalities such as vaccination, may concomitantly increase T-cell activation and infiltration.


The number one myth of asset protection: why you can lose assets in a medical malpractice lawsuit.
The thinking of many physicians around the country, and unfortunately their advisers as well, is that there is little risk of a physician losing personal assets in a malpractice claim, especially with typical dollars 1-3 million malpractice insurance coverage. This article dispels that myth and shows that the benefit in engaging in asset protection planning far outweighs the cost.


Diagnosis of idiopathic intracranial hypertension: A proposal for evidence-based diagnostic criteria.
Based on expert opinion, abducens nerve palsy and a neuroimaging criterion (≥3 neuroimaging signs suggestive of elevated intracranial pressure) were added to the diagnostic criteria for idiopathic intracranial hypertension. Our objective was to validate this. This prospective study included patients with new-onset idiopathic intracranial hypertension for a standardized work-up: interview, neuro-ophthalmological exam, lumbar puncture, neuroimaging. Neuroimaging was evaluated by a blinded neuroradiologist. We included 157 patients classified as idiopathic intracranial hypertension (56.7%), probable idiopathic intracranial hypertension (1.9%), idiopathic intracranial hypertension without papilledema (idiopathic intracranial hypertension-without papill edema; 0%), suggested idiopathic intracranial hypertension-without papill edema (4.5%), or non-idiopathic intracranial hypertension (36.9%). Moderate suprasellar herniation was more common in idiopathic intracranial hypertension than non-idiopathic intracranial hypertension (71.4% versus 47.4%, p < 0.01), as was perioptic nerve sheath distension (69.8% versus 29.3%, p < 0.001), flattening of the globe (67.1% versus 11.1%, p < 0.001) and transverse sinus stenosis (60.2% versus 18.9%, p < 0.001). Abducens nerve palsy was of no diagnostic significance. Sensitivity of ≥3 neuroimaging signs was 59.5% and specificity was 93.5%. Moderate suprasellar herniation, distension of the perioptic nerve sheath, flattening of the globe and transverse sinus stenosis were associated with idiopathic intracranial hypertension. We propose that idiopathic intracranial hypertension can be defined by two out of three objective findings (papilledema, opening pressure ≥25 cm cerebrospinal fluid and ≥3 neuroimaging signs).


Pragmatic complexity in metaphor interpretation.
The main goal of verbal metaphor interpretation is traditionally believed to be the recovery of a context-sensitive metaphorical meaning. One focus of experimental studies is to assess when and how pragmatic information derived from context shapes the online processing of specific utterances as conveying metaphorical, but not literal, messages. My aim in this article is to raise several critical complications with these beliefs. People employ metaphorical language not just to convey metaphorical meanings, but to concretely achieve various social, pragmatic goals. I describe several pragmatic complexities in the ways verbal and non-verbal metaphors function in communication. These pragmatic complexities affect both the cognitive effort and effects which emerge from interpreting metaphors in discourse. This conclusion suggests the need for new experimental studies and for theories of metaphor to be more sensitive to the influence of complex pragmatic goals in online metaphor interpretation.


Correction to "Water-Soluble Blue Fluorescent Nonconjugated Polymer Dots from Hyaluronic Acid and Hydrophobic Amino Acids".
[This corrects the article DOI: 10.1021/acsomega.1c01343.].


A tailored e-learning gives long-term changes in determinants of GPs' benzodiazepines prescribing: a pretest-posttest study with self-report assessments.
Objective: Despite guidelines and campaigns, general practitioners (GPs) continue to overprescribe benzodiazepines (BZDs). New approaches to improve prescribing are needed. Using behavior change techniques and tailoring interventions to user characteristics are vital to promote behavior change. This study evaluated the impact of a tailored e-learning module on factors known to determine BZD prescribing within GPs.Design: A pretest-posttest study design with three self-report assessments concerning determinants of BZD prescribing: at baseline, immediately after the module (short term) and six months after completion (long term).Setting: Flanders (Belgium)Intervention: A tailored e-module that focuses on avoiding initial BZD prescriptions and using psychological interventions as an alternative.Subjects: 244 GPsMain outcome measures: Assessed determinants include GPs' attitudes concerning treatment options, perceptions of the patient and self-efficacy beliefs. Readiness to adhere to prescribing guidelines was evaluated through assessing motivation, self-efficacy and implementability of non-pharmacological interventions.Results: A significant and durable impact on determinants of BZD prescribing was observed. GPs underwent desirable changes in attitudes, perceptions and self-efficacy beliefs and these changes remained significant six months later.Conclusion: Tailoring an e-intervention to target group characteristics appears to be successful in promoting behavioral change in experienced GPs. Significant and lasting changes were observed in determinants of prescribing BZDs.Key PointsA tailored e-intervention resulted in significant and long term changes in previously identified determinants of prescribing BZDs. The e-module resulted in a positive impact on GPs' readiness to adhere to BZD prescribing guidance and the way they experience psychosocial consultations. Tailoring an e-intervention to target group characteristics appears to be successful in promoting behavioral change in experienced GPs.


Effects of intravenous cocaine on plasma cortisol and prolactin in human cocaine abusers.
The aim of the present work was to examine the cortisol and prolactin responses to acute cocaine administration in human cocaine users. Each subject served as his own control during intravenous saline placebo and cocaine (40 mg) infusion sessions. Cocaine significantly elevated plasma cortisol but did not affect prolactin. The rise in cortisol coincided with an increase in heart rate and blood pressure after cocaine. In agreement with studies in animals, our data suggest that cocaine activates the hypothalamic-pituitary-adrenal axis in humans. However, based on the well-known importance of dopamine as a prolactin-inhibiting factor, the failure of cocaine to suppress prolactin in the present study raises questions concerning the role of dopamine in the mechanism of acute cocaine action in humans.


Prevalence of nonalcoholic fatty liver disease and its association with age in patients with type 2 diabetes mellitus.
Type 2 diabetes mellitus (T2DM) is a risk factor for nonalcoholic fatty liver disease (NAFLD). To determine the prevalence and clinical correlates of NAFLD in a large cohort of patients with T2DM. Four hundred thirty-seven participants with T2DM who consulted at Meijo Hospital from April 2019 to September 2020 and underwent computed tomography (CT) were assessed. The mean age was 74 ± 13 years, and 269 were men. Hepatic attenuation minus splenic attenuation (CTL-S) less than 1 Hounsfield unit was considered fatty liver. NAFLD was defined as fatty liver in the absence of significant alcohol consumption and hepatitis virus infection. A multiple logistic regression was used to assess the independent factors associated with NAFLD. NAFLD was identified in 25.2% of the participants. Young age (odds ratio [OR] = -0.945; 95% confidence interval [CI]: 0.922-0.969), higher hemoglobin levels (OR = 1.501, 95%CI: 1.278-1.764), lower high-density lipoprotein (HDL) cholesterol levels (OR = 0.971, 95%CI: 0.953-0.989), and the absence of dialysis (OR = 0.109, 95%CI: 0.014-0.856) were independent predictors of NAFLD. NAFLD was detected with CT in 25.2% of the participants. NAFLD was associated with younger age, higher hemoglobin levels, lower HDL cholesterol levels, and an absence of dialysis.


[The back and neck in healthy young Norwegians. A radiologic examination of the spine of 232 applicants for air force pilot education].
Neck pain and neck injuries are common complaints among aviators flying modern fighter aircraft. For this reason all candidates for military flying training in the Air Force have to undergo a radiological examination of the spine as part of the selection procedure. Nine films are produced, with particular emphasis on cervical structures. Altogether 527 positive findings were made among 232 applicants, an average of 2.27 diagnoses per x-rayed spine. Since the candidates had been medically screened prior to the radiological examination, it is not unlikely that the results reported in this highly selected group represent minimum figures for young adult Norwegians.